AKTOLUN - Nuclear Oncology

Nuclear
Oncology
Cumali Aktolun, MD, MSc

Visiting Professor
Department of Radiology
Molecular Imaging Program at Stanford, School of Medicine
Stanford University
Palo Alto, California
Stanley J. Goldsmith, MD
Professor
Department of Radiology and Medicine
Sanford and Joan Weill College of Medicine of Cornell University
Director-Emeritus
Division of Nuclear Medicine and Molecular Imaging
New York-Presbyterian Hospital / Weill Cornell Medical Center
New York, New York
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Library of Congress Cataloging-in-Publication Data
Nuclear oncology (Aktolun)

Nuclear oncology / [edited by] Cumali Aktolun, Stanley J. Goldsmith.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4511-8685-7 (alk. paper) – ISBN 1-4511-8685-1 (alk. paper)
I. Aktolun, C. (Cumali), 1961- editor. II. Goldsmith, Stanley J., editor. III. Title.
[DNLM: 1. Neoplasms–radionuclide imaging. 2. Neoplasms–radiotherapy. 3. Radionuclide
Imaging–methods. 4. Radiotherapy–methods. QZ 241]
RC270.3.R35
616.99′407575—dc23
2014009474
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To my wife, Miriam Goldsmith, who dedicated her life to
our family, to my professional goals, and to me. Her love
made possible the life that I have been fortunate enough
to have lived.
Stanley J. Goldsmith, MD
To Mustafa Kemal Ataturk, the founder of Republic of

Turkey, who established the foundations of modern
scientific education in my country.
Cumali Aktolun, MD, MSc

Con t r i b u t o r s
Gad Abikhzer, MDCM, NM Stefano Arcangeli, MD

Fellow Radiation Oncologist
Department of Nuclear Medicine Department of Radiotherapy and Radiosurgery
Rambam Health Care Campus Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Haifa, Israel Milan, Italy
Cumali Aktolun, MD, MSc Anna Maria Ascolese, MD
Visiting Professor Radiation Oncologist
Department of Radiology Department of Radiotherapy and Radiosurgery
Molecular Imaging Program at Stanford, School Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
of Medicine Milan, Italy
Stanford University
Palo Alto, California Antonija Balenovic, MD, PhD
Associate Consultant
Abass Alavi, MD, MD (Hon), PhD (Hon), DSc (Hon) Faculty of Medicine
Professor University of Rijeka
Department of Radiology Rijeka, Croatia
Associate Director Head
Center for the Study of Aging Department of Nuclear Medicine, PET/CT Center
University of Pennsylvania Medikol Outpatient Clinic
Faculty Zagreb, Croatia
Hospital of the University of Pennsylvania Aditya Bansal, PhD
Philadelphia, Pennsylvania Research Fellow
Alessandra Alessi, MD Mayo Clinic
Permanent Staff Rochester, Minnesota
Department of Nuclear Medicine
Fondazione IRCCS, Istituto Nazionale dei Tumori Jelle O. Barentsz, MD, PhD
Milan, Italy Professor
Filippo Alongi, MD Chairman
Senior Radiation Oncologist Prostate MR Center of Excellence
Department of Radiotherapy and Radiosurgery Radboud University Nijmegen Medical Centre
Istituto di Ricovero e Cura a Carattere Scientifico Nijmegen, The Netherlands
Humanitas
Milan, Italy Sandip Basu, MBBS (Hon), DRM, DNB, MNAMG
Nuclear Medicine Physician
Lujaien Al-Rubaiey Kadhim, MSc Head
Research Consultant Nuclear Medicine Academic Program
Tawam Molecular Imaging Centre Radiation Medicine Centre (Bhabha Atomic Research Centre)
Al Ain, United Arab Emirates Tata Memorial Centre
Mumbai, India
Valentina Ambrosini, MD, PhD
Assistant Professor Valentino Bettinardi, MSc
University of Bologna Associate Researcher
DIMES, Nuclear Medicine Department of Surgical Sciences
S.Orsola-Malpighi Hospital University of Milan–Bicocca
Bologna, Italy Medical Physicist
Nuclear Medicine Department
Lidija Antunovic, MD Ospedale San Raffaele
Nuclear Medicine Physician Milan, Italy
Istituto di Ricovero e Cura a Carattere Scientifico Sibaprasad Bhattacharyya, PhD
Humanitas Senior Scientist and Head
Milan, Italy Imaging Probe Development
Applied and Developmental Research Directorate, Science
Applications International Corporation (SAIC)–Frederick
Frederick National Laboratory for Cancer Research
Frederick, Maryland
vii

viii Contributors
Christina Blümel, MD Jean-Francois Chatal, MD, PhD

Resident Emeritus Professor
Department of Nuclear Medicine Department of Nuclear Medicine
University of Würzburg Groupement d’Intérêt Public Arronax
Würzburg, Germany Nantes, Saint-Herblain, France
Lisa Bodei, MD, PhD Muhammad Ali Chaudhry, MD
Deputy Director Clinical Assistant Professor
Division of Nuclear Medicine Radiology Division
European Institute of Oncology Johns Hopkins University School of Medicine
Milan, Italy Baltimore, Maryland
Medical Director
Carsten Bokemeyer, MD Tawam Molecular Imaging Centre
Professor Al Ain, United Arab Emirates
University Medical Center Hamburg-Eppendorf
Head Xiaoyuan Chen, PhD
Department of Oncology, Hematology and Bone Marrow Senior Investigator
Transplantation with the Section of Pneumology Laboratory of Molecular Imaging and Nanomedicine
Hamburg, Germany National Institute of Biomedical Imaging and Bioengineering,
National Institutes of Health
Emilio Bombardieri, MD Bethesda, Maryland
Physician
Department of Nuclear Medicine Gang Cheng, MD, PhD
Fondazione IRCCS, Istituto Nazionale dei Tumori Assistant Professor of Radiology
Milan, Italy Department of Radiology
Hospital of the University of Pennsylvania
Andreas K. Buck, MD Staff Radiologist
Professor and Chair Philadelphia Veterans Affairs Medical Center
Department of Nuclear Medicine Philadelphia, Pennsylvania
University of Würzburg
Würzburg, Germany Arturo Chiti, MD, FEBNM
Director
Maria Rita Castellani, MD Department of Nuclear Medicine
Permanent Staff Humanitas Research Hospital
Department of Nuclear Medicine Milan, Italy
Fondazione IRCCS, Istituto Nazionale dei Tumori
Milan, Italy Gary J.R. Cook, MBBS, MSc, MD, FRCP, FRCR
Professor
Paolo Castellucci, MD Clinical PET Imaging, Division of Imaging Sciences and
Consultant Biomedical Engineering
Department of Nuclear Medicine Kings College London
Azienda Ospedaliero-Universitaria di Bologna: Honorary Consultant
Policlinico S. Orsola-Malpighi Clinical PET Centre
Bologna, Italy Guy’s and St. Thomas’ NHS Foundation Trust
Zuzan Cayci, MD London, England, United Kingdom
Assistant Professor Flavio Crippa, MD
Attending Radiologist Permanent Staff, Department of Nuclear Medicine
Department of Radiology Fondazione IRCCS, Istituto Nazionale dei Tumori
University of Minnesota Milan, Italy
Minneapolis, Minnesota
Johannes Czernin, MD
Monica Celli, MD Professor
Fellow Department of Molecular and Medical Pharmacology
Department of Nuclear Medicine Chief, Ahmanson Translational Imaging Division
Azienda Ospedaliero Universitaria di Bologna: David Geffen School of Medicine at UCLA
Policlinico S. Orsola-Malpighi University of California Los Angeles, California
Bologna, Italy Los Angeles, California
Martin Charron, MD, FRCP(C) Maria Luisa De Rimini, MD
Professor Director of Nuclear Cardiology
Medical Imaging AORN–Ospedali dei Colli
University of Toronto Chief
Head Department of Diagnostic Imaging
Division of Nuclear Medicine Monaldi Hospital
Department of Diagnostic Imaging Naples, Italy
Hospital for Sick Children
Toronto, Ontario, Canada

Contributors ix
Timothy R. DeGrado, PhD Paola A. Erba, MD

Director Assistant Professor
Molecular Imaging Research Regional Center of Nuclear Medicine
Department of Radiology Department of Translational Research and Advanced
Mayo Clinic Technology in Medicine and surgery
Rochester, Minnesota University of Pisa
Staff Physician
Willem M. Deserno, MD, MSc, PhD Regional Center of Nuclear Medicine
Department of Radiology Department of Radiology, Interventional Radiology, and
Radboud University Nijmegen Medical Centre Nuclear Medicine
Nijmegen, The Netherlands University Hospital of Pisa
Radiologist Pisa, Italy
Laurentius Ziekenhuis Thomas Eugène, MD
Roermond, The Netherlands Physician
Linda de Wit–van der Veen, MSc, PhD Nantes University Hospital
Department of Nuclear Medicine Nantes, France
Antoni van Leeuwenhoek Hospital
The Netherlands Stefano Fanti, MD
Chief
Manish Dixit, PhD Department of Nuclear Medicine
Postdoctoral Fellow Azienda Ospedaliero Universitaria di Bologna:
Applied and Developmental Research Directorate, Science Policlinico S. Orsola-Malpighi
Applications International Corporation (SAIC)–Frederick Bologna, Italy
Frederick National Laboratory for Cancer Research
Frederick, Maryland Ansje S. Fortuin, MD
Radiologist
Sabina Dizdarevic, MD, MSc, FRCP Department of Radiology
Honorary Senior Clinical Lecturer Radboud University Nijmegen Medical Centre
Brighton and Sussex Medical School Nijmegen, The Netherlands
Lead Consultant Department of Radiology
Department of Imaging and Nuclear Medicine Deventer Ziekenhuis
Royal Sussex County Hospital Deventer, The Netherlands
Brighton, England, United Kingdom
Takako Furukawa, PhD
Mark Dunphy, DO Team Leader
Assistant Professor Diagnostic Imaging Program, Molecular Imaging
Department of Radiology Center
Weill Cornell Medical College National Institute of Radiological Sciences
Assistant Attending Physician Chiba, Japan
Molecular Imaging and Therapy Service
Memorial Hospital Stanley J. Goldsmith, MD
New York, New York Professor
Department of Radiology and Medicine
Matthias P.A. Ebert, MD Weill Medical College of Cornell University
Chairman and Head Director Emeritus
Department of Internal Medicine II Division of Nuclear Medicine and Molecular Imaging
University of Heidelberg New York-Presbyterian Hospital/Weill Cornell Medical
Heidelberg, Germany Center
Umut Elboga, MD New York, New York
Attending Physician Jun Hatazawa, MD, PhD
Department of Nuclear Medicine Professor
University of Gaziantep Department of Nuclear Medicine and Tracer
Gaziantep, Turkiye Kinetics
Ron Epelbaum, MD Osaka University Graduate School of Medicine
Chief
Clinical Assistant Professor Department of Nuclear Medicine and Tracer
Department of Oncology Kinetics
Technion–Israel Institute of Technology University of Osaka Hospital
Director Osaka, Japan
Ambulatory Care Unit, Department of Oncology
Rambam Health Care Campus Roland Haubner, PhD
Haifa, Israel Senior Scientist
Innsbruck Medical University
Innsbruck, Austria

x Contributors
Per Hellman, MD, PhD Kemal Metin Kir, MD

Professor Professor
Department of Surgical Sciences Department of Nuclear Medicine
Uppsala University Ankara University School of Medicine
Consultant Department of Nuclear Medicine
Department of Surgery Cebeci Research and Practice Hospital
Uppsala University Hospital Ankara, Turkey
Uppsala, Sweden
Francoise Kraeber-Bodéré, MD, PhD
Ken Herrmann, MD Professor
Visiting Assistant Professor Department of Nuclear Medicine
Department of Molecular and Medical Pharmacology, Nantes University Hospital
Ahmanson Translational Imaging Division Nantes, France
David Geffen School of Medicine Department of Nuclear Medicine
University of California Los Angeles ICO René Gauducheau Cancer Center
Los Angeles, California Saint-Herblain, France
Vice Chair
Department of Nuclear Medicine Thomas C. Kwee, MD, PhD
Universitätsklinikum Würzburg Resident
Würzburg, Germany Department of Radiology
University Medical Center Utrecht
Marina Hodolic̆, MD, PhD Utrecht, The Netherlands
Associate Professor
Nuclear Medicine Physician Marie Lacombe, MD
Department for Nuclear Medicine Nuclear Medicine Department, Integrated Center for Oncology
University Medical Centre ICO René Gauducheau Cancer Center
Ljubljana, Slovenia Saint-Herblain, France
Kayako Isohashi, MD, PhD Cinzia Landolfi, MD

Assistant Professor Fellow
Department of Nuclear Medicine and Tracer Department of Nuclear Medicine
Kinetics AORN - Ospedali dei Colli
Osaka University Graduate School of Medicine Department of Diagnostic Imaging
University of Osaka Hospital Monaldi Hospital
Osaka, Japan Naples, Italy
Revathy B. Iyer, MD William D. Leslie, MD, MSc, FRCPC

Professor Professor
Department of Diagnostic Radiology Department of Medicine and Radiology
The University of Texas MD Anderson Cancer University of Manitoba
Center Department of Internal Medicine
Houston, Texas St. Boniface General Hospital
Winnipeg, Manitoba, Canada
Zhao-Hui Jin, MD, PhD
Senior Researcher Scarlett Lewitschnig, Dr. Med. Univ., FRACP
Diagnostic Imaging Program, Molecular Imaging Department of Nuclear Medicine
Center St. Thomas’ Hospitals NHS Foundation Trust
National Institute of Radiological Sciences London, England, United Kingdom
Chiba, Japan Francesca Lobefalo, MSc
Zohar Keidar, MD, PhD Medical Physics
Clinical Assistant Professor University of Milan
Faculty of Medicine Medical Physicist
Technion–Israel Institute of Technology Department of Radiotherapy and Radiosurgery
Deputy Director Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Department of Nuclear Medicine Milan, Italy
Rambam Health Care Campus Egesta Lopci, MD
Haifa, Israel
Nuclear Medicine Physician
Mark Kidd, PhD Department of Nuclear Medicine
Assistant Professor Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Department of Surgery Milan, Italy
Yale School of Medicine Alice Lorenzoni, MD
Yale University
New Haven, Connecticut Physician
Fondazione IRCCS, Istituto Nazionale dei Tumori
Milan, Italy

Contributors xi
Roberto Luksch, MD Gang Niu, MD, MS

Permanent Staff Staff Scientist
Department of Pediatrics Laboratory of Molecular Imaging and Nanomedicine
Fondazione IRCCS, Istituto Nazionale dei Tumori National Institute of Biomedical Imaging and Bioengineering,
Milan, Italy National Institutes of Health
Bethesda, Maryland
Homer A. Macapinlac, MD
Distinguished Professor and Chair Abdul Jalil Nordin, MD
The University of Texas MD Anderson Cancer Department of Radiology
Center Director
Houston, Texas Centre for Diagnostic Nuclear Imaging
University Putra Malaysia
Chiara Manfredi, PhD Serdang, Malaysia
Fellow
Division of Nuclear Medicine Marco Maccauro, MD
Department of Translational Research and Advanced Permanent Staff
Technology in Medicine and Surgery Department of Nuclear Medicine
University of Pisa Fondazione IRCCS, Istituto Nazionale dei Tumori
Pisa, Italy Milan, Italy
Giuliano Mariani, MD Pietro Mancosu, MSc
Professor Medical Physicist
Department of Translational Research and Advanced Department of Radiotherapy and Radiosurgery
Technology in Medicine and surgery, Division of Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Nuclear Medicine Milan, Italy
University of Pisa
Chief Andrea Maurichi, MD
Department of Radiology, Interventional Radiology, and Department of Surgery
Nuclear Medicine Fondazione IRCCS, Istituto Nazionale dei Tumori
Regional Center of Nuclear Medicine Milan, Italy
University Hospital of Pisa Jasna Mihailovic, MD, PhD
Pisa, Italy
Associate Professor, Technical Faculty “Mihailo Pupin”
Irvin M. Modlin, MD, PhD, DSc, FRCS (Eng & Ed) University of Novi Sad
Professor Zrenjanin, Serbia
Department of Gastroenterological Surgery Chief
Yale University School of Medicine Department of Nuclear Medicine
New Haven, Connecticut Oncology Institute of Vojvodina
Sremska Kamenica, Serbia
Pietro Muto, MD
Director Cristina Nanni, MD
Department of Nuclear Medicine Consultant
AORN–Ospedali dei Colli Department of Nuclear Medicine
Chief Azienda Ospedaliero Universitaria di Bologna:
Department of Diagnostic Imaging Policlinico S. Orsola-Malpighi
Monaldi Hospital Bologna, Italy
Naples, Italy Karin Oechsle, MD
Kenneth J. Nichols, PhD Consultant
Professor Department of Oncology, Hematology and Bone Marrow
Department of Radiology Transplantation with the Section of Pneumology
Hofstra North Shore–LIJ School of Medicine University Medical Center Hamburg–Eppendorf
Hofstra University Hamburg, Germany
Hempstead, New York Christoph Oing, MD
Senior Medical Physicist
Nuclear Medicine and Molecular Imaging Resident
North Shore–LIJ Health System Department of Oncology, Hematology and Bone Marrow
New Hyde Park, New York Transplantation with the Section of Pneumology
University Medical Center Hamburg–Eppendorf
Sridhar Nimmagadda, PhD Hamburg, Germany
Assistant Professor Saabry Osmany, MBBS, FAMS, FACNM
Departments of Radiology, Oncology, and Medicine
Johns Hopkins University School of Medicine Consultant
Baltimore, Maryland Department of Nuclear Medicine
Radlink PET and Cardiac Imaging
Singapore

xii Contributors
Elgin Ozkan, MD Gregory C. Ravizzini, MD

Associate Professor Assistant Professor
Department of Nuclear Medicine Department of Nuclear Medicine
Ankara University Medical School The University of Texas MD Anderson Cancer Center
Department of Nuclear Medicine Houston, Texas
Cebeci Research and Practice Hospital
Ankara, Turkey Giacomo Reggiori, MSc
Department of Medical Physics
Giovanni Paganelli, MD University of Milan
Director Medical Physicist
Division of Nuclear Medicine Department of Radiotherapy and Radiosurgery
European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Milan, Italy Milan, Italy
Christopher J. Palestro, MD Marcello Rodari, MD
Professor Senior Nuclear Medicine Physician
Department of Nuclear Medicine and Radiology Department of Nuclear Medicine
Hofstra North Shore–LIJ School of Medicine Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Hofstra University Milan, Italy
Hempstead, New York
Chief Pietro Rossi, NMT
Division of Nuclear Medicine and Molecular Nuclear Medicine Technologist
Imaging Department of Nuclear Medicine
North Shore–LIJ Health System Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
New Hyde Park, New York Milan, Italy
Giovanna Pepe, MD Babak Saboury, MD, MPH

Nuclear Medicine Physician Scientific Director
Department of Nuclear Medicine Quantitative Medical Imaging Laboratory
Istituto di Ricovero e Cura a Carattere Scientifico Department of Radiology
Humanitas University of Pennsylvania
Milan, Italy Postdoctoral Clinical Research Fellow
Adrien Michael Peters, DSc, FMedSci Hospital of the University of Pennsylvania
Professor Philadelphia, Pennsylvania
Department of Applied Physiology
Brighton and Sussex Medical School Tsuneo Saga, MD, PhD
Honorary Consultant Director
Department of Nuclear Medicine Diagnostic Imaging Program, Molecular Imaging Center
Royal Sussex County Hospital National Institute of Radiological Sciences
Brighton, England, United Kingdom Chiba, Japan
Marc Peeters, MD, PhD Hideo Saji, PhD

Professor Professor
Department of Medical Oncology Department of Patho-Functional Bioanalysis
University of Antwerp Graduate School of Pharmaceutical Sciences
Wilrijk, Belgium Kyoto University, Japan
Head Mink S. Schinkelshoek, BSc
Department of Oncology
Antwerp University Hospital Student
Edegem, Belgium Leiden University Medical Center
Leiden, The Netherlands
Berna Degirmenci Polack, MD, FEBNM
Heiko Schöder, MD
Professor
School of Medicine Department of Radiology
Dokuz Eylül University Weill Cornell Medical College
Izmir, Turkey Clinical Director
Molecular Imaging and Therapy Service
Olaf Prante, PhD Memorial Sloan Kettering Cancer Center
Professor of Molecular Imaging and New York, New York
Radiochemistry Marta Scorsetti, MD
Friedrich-Alexander University Director
Chief Radiopharmacist Department of Radiotherapy and Radiosurgery
Nuclear Medicine Clinic Istituto di Ricovero e Cura a Carattere Scientifico
University Hospital Erlangen Humanitas
Erlangen, Germany Milan, Italy

Contributors xiii
Ettore Seregni, MD Drew A. Torigian, MD, MA

Permanent Staff Associate Professor
Department of Nuclear Medicine Department of Radiology
Fondazione IRCCS, Istituto Nazionale dei Tumori Hospital of the University of Pennsylvania
Milan, Italy Philadelphia, Pennsylvania
Anthony Shields, MD, PhD Giovanni Tosi, MSc
Professor Medical Physicist
Department of Oncology Unit of Medical Physics
Wayne State University Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Associate Center Director Milan, Italy
Clinical Sciences
Barabara Ann Karmanos Cancer Institute Angelo Tozzi, MD
Detroit, Michigan Radiation Oncologist
Department of Radiotherapy and Radiosurgery
Steven Staelens, MSc, PhD Istituto di Ricovero e Cura a Carattere Scientifico Humanitas
Professor Milan, Italy
Department of Oncology
University of Antwerp Masashi Ueda, PhD
Wilrijk, Belgium Associate Professor
Department of Pharmaceutical Analytical Chemistry
Marcel P.M. Stokkel, MD, PhD Graduate School of Medicine, Dentistry, and Pharmaceutical
Head Sciences
Nuclear Medicine and Division of Diagnostic Oncology Okayama University
Department of Nuclear Medicine Okayama, Japan
Netherlands Cancer Institute
Amsterdam, The Netherlands Muammer Urhan, MD
Associate Professor
H. William Strauss, MD Service of Nuclear Medicine
Molecular Imaging and Therapy Service GATA Haydarpasa Hospital
Memorial Sloan Kettering Cancer Center Istanbul, Turkiye
New York, New York
Reza Vali, MD
Sigrid Stroobants, MD, PhD Nuclear medicine physician
Professor Department of Diagnostic Imaging
Oncology (Nuclear Medicine) University of Toronto
University of Antwerp Hospital for Sick Children
Wilrijk, Belgium Toronto, Ontario, Canada
Head
Department of Nuclear Medicine Christel Vangestel, MSc, PhD
Antwerp University Hospital Postdoctoral Researcher
Edegem, Belgium Department of Oncology
University of Antwerp
Anders Sundin, MD, PhD Wilrijk, Belgium
Professor Antwerp University Hospital
Department of Radiology Edegem, Belgium
Karolinska Institute
Consultant Richard L. Wahl, MD, FACR
Department of Radiology Professor of Radiology and Oncology
Karolinska University Hospital Henry N. Wagner, Jr., Professor of Nuclear Medicine
Stockholm, Sweden Director, Division of Nuclear Medicine and PET Center
Vice Chairman for Technology and New Business Development
Takashi Temma, PhD The Russell H. Morgan Department of Radiology and
Assistant Professor Radiological Science
Department of Patho-Functional Bioanalysis Johns Hopkins University School of Medicine
Graduate School of Pharmaceutical Sciences Baltimore, Maryland
Kyoto University
Kyoto, Japan Tadashi Watabe, MD
Attending Staff
Noriyuki Tomiyama, MD, PhD Department of Nuclear Medicine and Tracer Kinetics
Professor Osaka University Graduate School of Medicine
Department of Radiology University of Osaka Hospital
Osaka University Graduate School of Medicine Osaka, Japan
Chief
Department of Radiology Hinrich A. Wieder, MD
University of Osaka Hospital Partner
Osaka, Japan Department of Radiology and Nuclear Medicine
ZRN Grevenbroich
Grevenbroich, Germany

xiv Contributors
Leonie Wyffels, PharmD, PhD Lucia Zanoni, MD

Postdoctoral Fellow Fellow
Molecular Imaging Center Antwerp Department of Nuclear Medicine
University of Antwerp Azienda Ospedaliero Universitaria di Bologna:
Wilrijk, Belgium Policlinico S. Orsola-Malpighi
Radiopharmacist Bologna, Italy
Nuclear Medicine Department
Antwerp University Hospital Pat Zanzonico, PhD
Edegem, Belgium Department of Medical Physics and Radiology
Memorial Sloan Kettering Cancer Center
Shinji Yamamoto, MD, PhD New York, New York
Researcher, Department of Clinical Science, Intervention,
and Technology Imene Zerizer, MBBS
Karolinska Institute Consultant Radiologist and Nuclear Medicine Physician
Staff Surgeon Nuclear Medicine and PET/CT
Department of Surgery, Division of Transplantation Surgery Royal Marsden Hospital
Karolinska University Hospital London, England, United Kingdom
Stockholm, Sweden Katherine Zukotynski, MD
Masahiro Yanagawa, MD, PhD Staff Radiologist
Assistant Professor Sunnybrook Health Sciences Centre
Department of Radiology Assistant Professor
Osaka University Graduate School of Medicine Faculty of Medicine
University of Osaka Hospital University of Toronto
Osaka, Japan Toronto, Ontario, Canada
Visiting Assistant Professor
Harvard Medical School
Boston, Massachusetts

f o r e w o r d
Nuclear Medicine has grown at an astonishing pace. When I first With this book, Drs. Cumali Aktolun and Stanley J. Goldsmith,
became involved in Nuclear Medicine, imaging had just transi- well-known authorities in nuclear medicine, have enlisted many
tioned from rectilinear scanners to gamma cameras; planar imag- internationally known specialists to present, for the first time, a
ing of the brain, of perfusion and ventilation of the lung, of colloid much needed comprehensive account of today’s nuclear oncology.
uptake in the liver and spleen, of gall bladder function and renal This “inventory” of today’s nuclear oncology appropriately pro-
blood flow and function dominated the daily nuclear medicine ceeds with a series of reviews of organ-related malignancies and
fare. Imaging of the cardiovascular system was in its infancy and of system-wide cancers, to practical issues in cancer imaging and,
nuclear oncology consisted bone imaging and an occasional gal- finally, to image-based assays of cancer biology and radionuclide
lium uptake study. therapy. Each chapter on organ-related or system-wide tumors
The introduction of cross-sectional imaging with computed presents the current knowledge of molecular cancer pathogenesis
tomography (CT) and later with magnetic resonance imaging (MRI) and development, early tumor manifestations and tumor spread,
profoundly transformed the field of diagnostic imaging. In fact, the established and emerging therapeutic strategies and clinical out-
arrival of CT was feared to threaten the very existence of nuclear comes. Advantages and limitations of diagnostic approaches are
medicine; radionuclide procedures like the many brain scans soon critically assessed, including biomarkers and image-based tech-
began to disappear from the daily nuclear medicine schedule as CT nologies for cancer diagnosis and staging, for cancer recurrence
became clinically available. and therapy response. Nuclear medicine approaches like planar
Yet, nuclear medicine has proved itself to be astoundingly resil- and SPECT imaging are included but applications of modern
ient. With single photon emission tomography (SPECT) and positron PET/CT imaging are emphasized appropriately. Their utility is
emission tomography (PET), nuclear medicine joined cross-sectional fully integrated with that of more conventional imaging technolo-
imaging, yet in a unique and specific way by focusing on assays gies like ultrasound, CT, and MRI for optimizing the diagnostic
of tissue function and biology rather than on anatomy. Combined approach to cancer diagnosis and characterization. Importantly,
with anatomic imaging with PET/CT or PET/MRI today, molecular the “inventory of nuclear oncology” extends into more specific
and cellular events visualized on radionuclide images can now be topics like cancer in the pediatric population, image-based moni-
localized precisely. Even more importantly, as these images dis- toring of treatment responses but also of chemotherapy-related
play biologic properties of anatomic alterations, hybrid function/ adverse effects, to image-based target identification and targeted
structure imaging has gained growing clinical interest and impor- radionuclide therapeutic strategies (“theranostics”) and the role of
tance. Accordingly, nuclear medicine schedules have dramatically nuclear medicine in response-adapted treatment strategies. Each
changed. Today, they are dominated by qualitative and quantitative topic is abundantly illustrated with high quality mostly color ren-
image-based tissue assays with SPECT/CT and especially PET/CT for ditions of cancer-specific findings made with CT, MR, SPECT, and
cancer diagnosis and staging, prediction of clinical outcomes, and PET/CT. Beyond these diagnostic radionuclide approaches largely
monitoring therapy responses, for planning radiation therapy and implemented in today’s clinical practice, the “nuclear oncology
for identifying treatment targets. inventory” ventures into emerging approaches and thus offers a
Nuclear medicine owes much of this change to impressive view of what may lie ahead. This prospect of the future includes
advances in cancer research which have led to an improved and radionuclide technologies employed primarily in the research
more detailed understanding of cancer biology, including tumor environment but attests to future clinical possibilities for targeting
growth and angiogenesis, growth receptor function and intracellu- specific aspects of molecular cancer biology such as for example
lar signaling chains, and cancer survival strategies. They have also growth receptors, hypoxia, cell replication, angiogenesis, extracel-
defined key regulatory steps as potential treatment targets. These lular matrix formation, and apoptosis.
advances have driven the development of highly targeted imaging The text succeeds in merging basic and clinical sciences
probes for the noninvasive visualization of molecular and cellular in oncology with knowledge in nuclear imaging and therapy.
events ranging from substrate utilization to amino acid metabolism As such, it is of considerable interest to both, the clinician and
and cell growth, angiogenesis and perfusion as well as cell mem- the imager. Importantly, it is destined to intensify and broaden
brane receptors regulating cell growth and replication. Labeled interactions and collaborations between nuclear and clinical
with radionuclides, many of these targeted imaging probes, tested oncologists.
and validated in the research laboratory, are now entering the clin-
ical environment. They arm both, the nuclear medicine physician Heinrich R. Schelbert
and the oncologist with specific tools for the image-based detection George V. Taplin
of cancer, estimation of its severity and extent, prediction of tumor Professor
progression and outcome and, importantly, measurements of ther- David Geffen School of Medicine at UCLA
apy responses. With these tools, the nuclear medicine physician Immediate Past Editor-in-Chief
participated as “nuclear oncologist” in the care of cancer patients. The Journal of Nuclear Medicine
xv

P r e fa c e
This volume, Nuclear Oncology, is a compendium of the state of the ers and technology are also detailed in plain language, emphasiz-
art of Nuclear Medicine procedures relevant to the current prac- ing their clinical potential in future practice. Up-to-date clinical,
tice of Oncology, primarily diagnostic imaging and to some extent experimental, and technical data are presented by expert authors
to targeted radionuclide therapy when appropriate. practicing or researching in the subject they described in their
Over a decade ago, both of the editors of this volume had chapters. The volume is divided into 5 parts and 43 chapters.
previously individually coedited a volume on Nuclear Oncology. Nineteen chapters are devoted to malignancies involving specific
Since that time, a great deal of progress has occurred; SPECT has organs such as the Brain, Breast, Lungs, Prostate, etc. Five addi-
evolved from SPECT to SPECT/CT and PET to PET/CT; 18F-FDG tional chapters are devoted to malignancies that may be found
PET/CT has revolutionized the practice of oncology; PET/MR has virtually anywhere in the body, such as Lymphoma and Neuroen-
been emerging as a clinical technology; and the scope of molecular docrine Tumors. In addition, there are nine chapters on special
imaging has remarkably expanded to the point that many new topics, such as Pediatric Tumors and Cancer of Unknown Pri-
molecules have gained acceptance as an imaging or therapeutic maries. Eight chapters are devoted to investigational aspects of
tracer. Tumor Biology and Molecular Imaging, such as Imaging of Multi-
It would not be an overstatement to say that 18F-FDG PET/ drug Resistance, Annexin, Human Epidermal Receptors, Integrins
CT is essential for the current practice of oncology including the and Hypoxia, as well as two chapters on Technical Issues, Instru-
determination of the extent of disease, evaluation of treatment mentation, Radiochemistry, and Radiopharmaceuticals. Pediatric
response, surveillance following treatment, and on some occa- tumors, the role of bone mineral densitometry in oncology, senti-
sions, even contributing to the diagnosis by differentiating benign nel lymph node imaging, assessment of lymph node involvement,
from malignant lesions or at least characterizing the metabolic response to antineoplastic treatment, non-FDG PET/CT imaging,
activity. emerging role of PET/CT in radiotherapy planning, angiogenesis,
Currently, we are on the brink of introducing into clinical prac- tumor cell proliferation, and apoptosis are given special emphasis
tice other tracers such as 18F-fluorocholine, 18F-fluorothymidine, in separate chapters. All chapters are delightfully comprehensive.
and a host of 68Ga- or 89Zr-labeled molecules to recognize spe- The editors are grateful to our chapter authors for their expertise
cific tumor characteristics. SPECT/CT is increasingly being applied and conscientious effort to communicate these complex ideas so
to imaging single photon emission tracers, thus improving both thoroughly and clearly.
sensitivity and specificity. Instrumentation, too, is on the brink Although our past efforts were inclusive of physicians and sci-
of another giant step forward: The development and application entists from many nations, this volume is even more diverse in
of MRI/PET devices that will perform, in this case, simultaneous the sources of expertise drawn upon to provide readers with a
acquisition of MRI anatomic data and PET images of the underly- view of Nuclear Oncology as it is perceived on a worldwide canvas.
ing metabolic process being imaged depending upon the tracer. We are pleased also that we were able to include many younger
There is no doubt that image fusion increases overall accuracy; physician-scientists who are bringing new ideas and renewed
it also improves the ability to communicate findings to clinicians energy to research and practice of nuclear medicine in oncology.
who are not imaging specialists and to physicians in training. In editing the chapters as they were completed, we were pleased
There has also been considerable growth in the number of tar- with the knowledge and wisdom contained in the texts and touched
geted radionuclide therapy agents, but the data published in this by the conscientious efforts of so many individuals from all around
volume are limited since more detailed descriptions have recently the world to provide comprehensive and authoritative reviews of
been published. the history and current status of these diverse topics in Nuclear
The editors, taking into consideration the above advances in Oncology.
the field of Nuclear Oncology, have tasked our authors to prepare Truly, we are fortunate to have been able to assemble the con-
reviews of the current applications of the available tracers using tributors who have enabled us to bring this remarkable volume to
these techniques but also to include information on techniques in our readers: Nuclear medicine and oncology physicians, scientists,
development and, when possible, to suggest likely future develop- and trainees. We are hopeful that this volume will contribute to
ments or needs. further utilization of nuclear medicine diagnostic and therapeutic
All aspects of Nuclear Oncology including topics directly procedures and to improved management and clinical outcomes
related to the practice of Oncology such as diagnostic and thera- in the care of patients with malignant diseases.
peutic radionuclide techniques are compiled in a single volume,
but experimental molecular imaging techniques and newest trac- Stanley J. Goldsmith, MD, and Cumali Aktolun, MD, MSc
xvii

IANc TR
k no
O DUCTI
w l e dO
g N
m e n t
The editors jointly express appreciation to the chapter authors for their conscientious contributions.
Cumali Aktolun and Stanley J. Goldsmith
xix

Co n t e n t s
Contributors vii
Foreword xv Pa r t I I • M a l i g n a n c i e s
Preface xvii I n v o lv i n g t h e E n t i r e B ody
Acknowledgment xix
20 Neuroendocrine Tumors 265
Lisa Bodei, Mark Kidd, Irvin M. Modlin, and Giovanni Paganelli
Pa r t I • O r g a n M a l i g n a n c i e s 21 Lymphoma and Leukemia 293
Jasna Mihailovic and Stanley J. Goldsmith
1 Brain Tumors 1
Zuzan Cayci
22 Melanoma 313
Alice Lorenzoni, Ettore Seregni, Marco Maccauro, Andrea Maurichi,
2 Head and Neck Carcinomas 16
Alessandra Alessi, and Flavio Crippa
Muhammad Ali Chaudhry, Lujaien Al-Rubaiey Kadhim,
and Richard L. Wahl
23 Neuroblastoma 324
Ettore Seregni, Alice Lorenzoni, Roberto Luksch, Cristina Nanni,
3 Thyroid Carcinoma 35
Maria Rita Castellani, and Emilio Bombardieri
Cumali Aktolun, Umut Elboga, and Muammer Urhan
24 Bone Tumors 340
4 Parathyroid Tumors 52
Johannes Czernin and Ken Herrmann
Christopher J. Palestro and Kenneth J. Nichols
5 Esophageal Carcinoma 68
Mark Dunphy and Heiko Schöder P a r t I I I • Sp e c i a l Topi c s
6 Gastric Carcinoma-I 85 i n Nu c l e a r O n c o l o g y
Ken Herrmann, Hinrich A. Wieder, Matthias P.A. Ebert,
and Johannes Czernin 25 Pediatric Tumors 363
7 Gastric Carcinoma-II 92 Reza Vali and Martin Charron
Kemal Metin Kir and Elgin Ozkan 26 Cancer of Unknown Primary 389
8 Pancreatic Carcinoma 101 Zohar Keidar, Gad Abikhzer, and Ron Epelbaum
Christina Blümel and Andreas K. Buck 27 Assessment of Lymph Nodes in Oncology 399
9 Colorectal Carcinoma 108 Ansje S. Fortuin, Thomas C. Kwee, Sandip Basu, Drew A. Torigian,
Gregory C. Ravizzini, Revathy B. Iyer, and Homer A. Macapinlac Babak Saboury, Willem M. Deserno, Jelle O. Barentsz, and Abass Alavi
10 Liver Tumors 124 28 Sentinel Lymph Node Detection and Imaging in

Scarlett Lewitschnig, Saabry Osmany, Imene Zerizer, and Gary Cook Oncology 412
Gang Cheng, Drew A. Torigian, and Abass Alavi
11 Breast Carcinoma 132
Cumali Aktolun, Muammer Urhan, and Umut Elboga 29 PET/CT Hybrid Imaging in Radiotherapy Planning 432
Egesta Lopci, Mink S. Schinkelshoek, Filippo Alongi, Lidija Antunovic, Stefano
12 Pulmonary Carcinoma 153
Arcangeli, Anna Maria Ascolese, Valentino Bettinardi, Francesca Lobefalo,
Pietro Muto, Maria Luisa De Rimini, Cinzia Landolfi,
Pietro Mancosu, Giovanna Pepe, Giacomo Reggiori, Marcello Rodari, Pietro
and Abdul Jalil Nordin
Rossi, Giovanni Tosi, Angelo Tozzi, Marta Scorsetti, and Arturo Chiti
13 Renal Carcinoma 179
Antonija Balenovic, Jasna Mihailovic, and Katherine Zukotynski
30 Bone Mineral Densitometry in Oncology 457
William D. Leslie
14 Bladder Carcinoma 191
Antonija Balenovic, Jasna Mihailovic, and Katherine Zukotynski
31 Non-FDG PET/CT Imaging in Oncology 482
Cristina Nanni, Valentina Ambrosini, Lucia Zanoni, Monica Celli,
15 Prostate Carcinoma 200
Paolo Castellucci, and Stefano Fanti
Marina Hodolič and Stanley J. Goldsmith
32 Assessment of Response to Antitumor Treatment 498
16 Uterine and Cervical Carcinoma 219
Masahiro Yanagawa, Noriyuki Tomiyama, Tadashi Watabe, Kayako Isohashi,
Berna Degirmenci Polack
and Jun Hatazawa
17 Ovarian Carcinoma 234
33 Radionuclide Imaging for the Assessment of Toxicity
Marie Lacombe, Thomas Eugène, Jean-François Chatal,
due to Chemotherapy 514
and Françoise Kraeber-Bodéré
Marcel P.M. Stokkel and Linda de Wit–van der Veen
18 Testicular Germ Cell Tumors 241
Christoph Oing, Carsten Bokemeyer, and Karin Oechsle
19 Tumors of the Adrenal Glands 251
Shinji Yamamoto, Per Hellman, and Anders Sundin
xxi

xxii Contents
40 Radionuclide Imaging of Integrins 616

P a r t IV • Investigative Methods Masashi Ueda, Takashi Temma, and Hideo Saji
for Studying Tumor Biology 41 Radionuclide Imaging of Annexins 622
a n d M i c r o e n v i r on m e n t Christel Vangestel, Leonie Wyffels, Marc Peeters, Steven Staelens,
and Sigrid Stroobants
34 Radionuclide Imaging of Multidrug Resistance 530
Sabina Dizdarevic and A. Michael Peters
35 Radionuclide Imaging of Tumor Hypoxia and Its
P a r t V • T e c hn i c a l I s s u e s
Clinical Implications 537 42 Radiochemistry in Nuclear Oncology 639
Gang Niu and Xiaoyuan Chen Roland Haubner and Olaf Prante
36 Radionuclide Imaging of Tumor Cell Apoptosis 549 43 Advances in Nuclear and Optical Imaging of Tumors:
Paola A. Erba, Chiara Manfredi, H. William Strauss, and Giuliano Mariani Multi-Modality, Small-Animal, and Intraoperative
37 Radionuclide Imaging of Tumor Angiogenesis 567 Technologies 664
Zhao-Hui Jin, Takako Furukawa, and Tsuneo Saga Pat Zanzonico
38 Radionuclide Imaging of Tumor Cell Proliferation 585
Sridhar Nimmagadda and Anthony F. Shields
Index 699
39 Radionuclide Imaging of Human
Epidermal Receptors 598
Sibaprasad Bhattacharyya, Aditya Bansal, Manish Dixit, and
Timothy R. DeGrado

P a r t I
Organ Malignancies
Chapter 1
Brain Tumors
Zuzan Cayci
Gliomas are the most common primary malignant brain tumors. radiotherapy with concurrent and adjuvant temozolomide.1
According to the World Health Organization (WHO), they are classi- “Pseudoprogression” is a relatively new term for the glioma cases
fied as astrocytomas, oligodendrogliomas, and mixed oligoastrocy- that have been undergoing concurrent radiotherapy and temozolo-
tomas. In this classification, anaplastic astrocytomas and anaplastic mide treatment and that demonstrate progression-like MR findings
PART I • Organ Malignancies

oligodendrogliomas are considered grade III, and glioblastoma such as increased areas of enhancement with larger areas of edema.
multiforme (GBM), the most common of all gliomas, is considered These could be accompanied by progressive clinical signs and symp-
grade IV. GBM tumors comprise 45% to 50% of all gliomas and have toms in a fraction of cases. In pseudoprogression cases, these find-
a dismal prognosis. Despite new treatment strategies and advanced ings typically eventually subside without any change in therapy.2
imaging techniques, prognosis of gliomas has been poor with max- This scenario is seen following radiation treatment in 20% to 30%
imum survival rates of 12 to 14 months for GBM.1 Accurate grading of cases and its incidence has been reported to be higher in patients
and diagnosis are important for directing the therapeutic approach who receive temozolomide in addition to radiation therapy. These
and providing prognosis. findings are thought to result from transiently increased permeabil-
ity of the tumor vasculature from irradiation and/or temozolomide
effects. In cases that demonstrate these MRI findings, it is necessary
Neuroimaging to decide whether to continue the current medication versus ceasing
and choosing an alternative treatment. Antiangiogenic agent (anti-
Neuroimaging plays a significant role in the detection of brain vascular endothelial growth factor [VEGF] and anti-VEGF receptor)
tumors, prediction of the histologic grade of tumor, evaluation of the treatment for gliomas was approved by the Food and Drug Adminis-
response to treatment, differential diagnosis between the recurrent tration (FDA) in 2008. This new adjuvant treatment strategy results
tumor and treatment-related changes, and estimation of survival in marked decrease in contrast enhancement on MRI, as early as 1 to
prognosis. 2 days following initiation of treatment in 25% to 60% of cases. This
is thought to be partly a result of normalization of abnormally perme-
Magnetic Resonance Imaging able tumor vessels and is not necessarily indicative of a true anti-
glioma effect.3 Nevertheless, only modest survival benefits have
The most commonly used imaging modality is magnetic resonance been reported following antiangiogenic treatment despite high MRI
imaging (MRI), which has an irreplaceable role in brain tumor response rates. This entity has been termed “pseudoresponse.”
imaging. For evaluation of previously undiagnosed brain neoplasm, Molecular imaging is a promising modality to further evaluate these
MRI is excellent to determine the size and location of the tumor and puzzling MRI findings, which could represent “pseudoresponse” or
to demonstrate the secondary findings such as mass effect, edema, “pseudoprogression.” One of the other entities that complicate
hemorrhage, necrosis, and possible signs of increased intracranial image interpretation on MRI is corticosteroid use for symptom con-
pressure. trol in glioma patients. Corticosteroids are known to decrease T2 sig-
MRI has certain limitations, however, in brain tumor evaluation. nal abnormalities and extent of gadolinium enhancement unrelated
“Gadolinium enhancement,” which is a basic criterion in brain tumor to tumor shrinkage. Transient gadolinium enhancement can also be
diagnosis by MRI, is not specific for tumor. Gadolinium enhancement seen with postictal states and postsurgical states,4 and gadolinium
is a result of blood–brain disruption, which can be seen with brain enhancement is typically seen in subacute phase of postoperative
tumors as well as secondary to infectious and inflammatory etiolo- contusion areas.5
gies. It is challenging to distinguish neoplasm from vascular, inflam- In all the situations that could possibly be seen in glioma patients,
matory, or other processes from brain parenchymal tumors with MRI alone is not adequate to guide the management of brain tumor
minimal or no enhancement. In tumors with minimal or no enhance- patients. Complementary studies such as functional and molecular
ment, it is not possible to rate glial neoplasms as low grade versus imaging (i.e., MR spectroscopy, single-photon emission tomography
high grade. Interpretation of MRI gets even more complicated in pre- [SPECT], and positron emission tomography [PET]) have been stud-
viously treated brain neoplasms. In fact, differentiation of treatment- ied and implemented by many centers in the diagnosis of brain
related changes from recurrent high-grade enhancing tumor and tumors to enhance patient care.
low-grade nonenhancing infiltrative tumor is simply not possible
with basic MRI sequences. With the recent addition of new adjuvant
treatment options such as antiangiogenic factors and alkylating
Single-Photon Emission Tomography
agents, namely bevacizumab and temozolomide, false-negative and Thallium 201 [201Tl] has been used for tumor localization. The
false-positive MRI findings have been seen. Currently the standard mechanism of uptake is related to multiple factors, including
therapy for glioblastoma is maximal safe tumor resection followed by regional brain blood flow, blood–brain barrier [BBB] permeability,

2 Part I Organ Malignancies
and cellular uptake that may involve transmembrane transport into

viable tumor cells.6,7 201Tl, as the thallous ion, behaves physiologi-
cally like potassium, and is transported through the cell membrane
by the Na-K ATPase membrane pump.7 Its transport is related to
blood flow, which is linked to growth rate.8 201Tl uptake reflects viable
tumor and not simply BBB breakdown.6,7 Sun et al.9 demonstrated
on 201Tl SPECT that delayed imaging at 3 hours was superior to early
imaging at 10 minutes to differentiate higher-grade tumors because
there is continuous accumulation of the tracer in high-grade brain
tumors. A disadvantage of 201Tl SPECT imaging of brain tumors is
their lower resolution which limits evaluation of smaller tumors.
Single-Photon Emission Tomography/Computed

Tomography and Positron Emission
A B
Tomography/Computed Tomography
Figure 1.1. F-FDG PET of newly diagnosed tumors: Glioblastoma (A) and grade II oligoden-
18
The concept of integrated imaging with SPECT/computed tomogra- droglioma (B). (Reprinted by permission of SNMMI from Chen W. Clinical applications of PET in
phy (CT) evolved in the late 1980s10,11 and with PET/CT in 1998.12 brain tumors. J Nucl Med. 2007;48(9):1468–1481. Figure 1.)
In both cases, the more functional imaging methods of SPECT and
PET are combined with anatomical CT imaging information within
a single examination. With the advent of clinical PET/CT in early
2001, it was shown that integration of PET and CT into a single transporters, higher hexokinase levels, and low glucose 6 phos-
system is advantageous and synergistic as it provides anatomic phatase levels. Brain tumor imaging is based on the fact that
referencing and at the same time permits attenuation correction in malignant transformation of gliomas and higher grades of gliomas
a much shorter time,13,14 thus making PET/CT more accurate15 and are related to high 18F-FDG uptake.21 However, although generally
faster16 imaging modality than PET alone, CT alone, and even PET high-grade tumors demonstrate hypermetabolism and low-grade
and CT read side by side.17–19 In a PET/CT examination, PET and CT tumors demonstrate lower metabolism compared with contralat-
are performed in rapid sequence, and as the CT is very fast and eral gray matter in most cases, it is also known that there is a high
provides data for PET attenuation correction, a PET/CT examination variability of 18F-FDG uptake among the glial tumors of the
is typically 25% to 30% less time consuming than the acquisition of same grade (Fig. 1.1).22 The limitations of 18F-FDG PET in brain
an attenuation-corrected PET scan. Since its clinical introduction tumor imaging are because of high physiologic activity of the nor-
in early 2001, it is evident that imaging with PET/CT has an impact mal gray matter limiting the detectability of modest increases in
on therapeutic management in 20% to 50% of the examined oncol- glucose metabolism in low-grade tumors and the nonspecific nature
ogy cases.20 of the 18F-FDG uptake. Increased 18F-FDG uptake can be seen in
tumor, inflammation, and tissue healing. In differentiation of recur-
rent tumor from radiation necrosis (a common indication of 18F-
Positron Emission Tomography FDG PET imaging in many centers), PET/CT should be performed
at least 6 weeks after completion of radiation treatment because
Tracers within the first 6 weeks following treatment, radiation-related
inflammatory changes might result in increased 18F-FDG uptake
Several PET radiotracers have been studied for brain tumor imag-
regardless of tumor presence. This will affect the image interpreta-
ing. These can be classified into three main groups (Table 1.1):
tion. In cases of recurrent tumor evaluation following radiation
• Marker of glucose metabolism treatment, having MRI images on site and, if possible, reviewing
• Markers of cellular proliferation MRI–PET fusion images is critical for correct interpretation. 18F-
• Hypoxia imaging FDG uptake equal to or more than the background in an area of
MRI abnormality is suggestive of recurrent tumor (Fig. 1.2).
Marker of Glucose Metabolism To increase the performance of 18F-FDG PET interpretation,
delayed imaging, imaging 3 to 8 hours rather than 60 minutes fol-
18
F-fluorodeoxy glucose (18F-FDG) is a marker of glucose metabo- lowing 18F-FDG injection, was studied and shown to improve dis-
lism and is the only FDA-approved radiotracer used in tumor imag- tinction between the tumor and normal gray matter, and could help
ing in the United States at the present time. 18F-FDG PET is the first in distinguishing recurrent tumor from radiation necrosis. The
PET oncologic application. The pathophysiology of 18F-FDG PET is rationale for this is that glucose washout from normal brain tissue
based on the following: Cancer cells are known to have higher and necrotic tissue is greater than in tumor at delayed times.23
levels of metabolic activities because of higher levels of glucose Because of these described inborn limitations of 18F-FDG in brain
tumor imaging, other hallmarks of tumor have been widely studied.
Table 1.1
Markers of Cellular Proliferation
Pet Radiotracers
Uncontrolled cellular proliferation is a hallmark of tumor. Although
increased glucose uptake is nonspecific, rapid proliferation of
Marker of Glucose Markers of Cellular cells is specific for tumor. This property makes the radiotracers
Metabolism Proliferation Hypoxia Imaging used to demonstrate cellular proliferation very promising for
18 11 18
“tumor” diagnosis. In addition, they also have potential in the eval-
F-fluorodeoxyglucose C-methionine F-fluoromisonidazole uation of early treatment response because the earliest events in
18
— F-fluoroethyl-tyrosine — response to successful treatment of tumors are decreased in cel-
18
— F-fluoro-L-phenylalanine —
18 lular proliferation. The most commonly investigated radiotracers
— F-fluorothymidine —
11 to evaluate cellular proliferation are 11C-methionine (11C-Met), 18F-
— C-choline —
fluoroethyl tyrosine (18F-FET), 18F-fluoro L phenylalanine (18F-F DOPA),

Chapter 1 Brain Tumors 3
A B
Figure 1.2. A: Postgadolinium T1-weighted MR image shows nodular enhancement along the medial aspect of the surgical cavity in the right frontotemporal

region. B: FDG PET image shows photopenia in the areas of signal abnormalities seen on MR, compatible with postradiation and postsurgical changes. (Reprinted
by permission of SNMMI from Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation injury. J Nucl Med. 2000;41:447–452.)
18
F-fluorothymidine (18F-FLT), and 11C-choline (11C-Cho). Markers prognostic factor role of 11C-Met was investigated. It was found that
for proliferation in a cell can further be broken down to: there was significant correlation between 11C-Met uptake and Ki-67
proliferative index. 11C-Met uptake was also found to be an inde-
• Protein synthesis
pendent prognostic factor in this study, whereas no correlation was
• DNA synthesis
found between the 18F-FDG uptake and the Ki-67 proliferation
• Choline (lipid) synthesis for better understanding of the mecha-
index, and 18F-FDG uptake and survival. The main limitation of
nism of radiotracer uptake 11
C-Met in clinical use is that it has a short half-life (20 minutes). It
cannot be used at sites without a cyclotron onsite. Another limita-
Protein Synthesis tion of amino acid PET tracers in general is that increased amino
In 1998, it was shown in animal models that the mechanism acid uptake is an indirect measure of proliferation status and its
responsible for increased amino acid transport into tumor cells is intensity is not affected by the malignant nature of the tumor, which
the upregulation of the amino acid transporter in the vasculature makes them not useful to grade brain tumors. Of note, caution must
of tumor tissues.24 Increased amino acid transport occurs within be taken to evaluate tumors with oligodendrial components on
11
the tumor cell regardless of the phase of the cell cycle. Upregula- C-Met PET. In these tumors, high uptake of 11C-Met was found to
tion of amino acid transport does not depend on but is enhanced be because of high microvessel count and tumor blood volume, and
by the breakdown of the BBB. One of the advantages of the amino not the proliferative activity.
18
acid radiotracers over FDG is the lack of background brain corti- F-FET is another amino acid that can be labeled with 18F. It has
cal activity, which makes diagnosis of low-grade glioma more reli- been used as a brain tumor PET imaging agent. In a study by
able. Another advantage is their specificity for tumor, which makes Popperl et al.,27 42 out of 42 recurrent tumor sites were correctly
them potential tracers for primary diagnosis of tumor and in cases diagnosed when focally increased 18F-FET uptake was considered a
with previous treatment, a valuable tracer to detect recurrent positive result. This pattern of uptake is because of the upregulation
tumor. On the other hand, amino acid tracers are less desirable in of amino acid transport. On the other hand, in this study, patients
tumor grading because similar uptake will be seen in both low- with no recurrent tumor showed low homogeneous uptake (uptake
grade and high-grade tumors. secondary to BBB disruption caused by treatment). One limitation
The most commonly investigated amino acid PET tracer in brain with 18F-FET was that authors could not find significant difference
tumor imaging is 11C-Met. Methionine is a natural essential amino of tracer uptake level in grade II versus grade III and IV tumors.
18
acid. It enters the tumor cell via an amino acid transporter after F-FDOPA has been used for years to image striatal dopamine
activation of carrier-mediated transport at the BBB to meet demands pathway in movement disorders but has also been shown to be
of accelerated protein and RNA synthesis in malignant cells. Methi- taken up by amino acid transporters of the normal BBB. Chen
onine accumulation is highly correlated with microvessel density (a et al.28 compared 18F-FDOPA with 18F-FDG in newly diagnosed and
product of angiogenesis). Terakawa et al.25 investigated the diag- previously treated brain tumor patients. The sensitivity of tumor
nostic accuracy of 11C-Met PET to differentiate recurrent tumor detection was significantly higher with 18F-FDOPA compared to
18
from radiation necrosis, and concluded that by using a threshold of F-FDG given lack of background physiologic uptake on 18F-FDOPA
mean lesion/normal tissue ratio of 1.58, the diagnosis of tumor images (Figs. 1.3 and 1.4). A disadvantage of 18F-FDOPA is its lim-
could be made with 75% sensitivity and 75% specificity. The speci- ited differentiation of tumor grades.
ficity of 11C-Met in brain tumor imaging was also shown by Chung
et al.26 Their study demonstrated that all benign lesions had normal
or decreased tracer uptake, whereas 31 out of 35 brain tumors (of
DNA Synthesis
all types) had positive 11C-Met uptake, and 22 out of 24 gliomas had 18
F-FLT uptake reflects thymidine kinase 1 activity in the cell,
positive uptake on 11C-Met PET. These lesions were all iso- or which is proportional to proliferation activity. Thymidine is one of
hypometabolic on 18F-FDG PET imaging. In another study, the the four bases that are incorporated in deoxyribonucleic acid

Figure 1.3. Newly diagnosed tumors, show-

ing glioblastoma (A) and grade II oligodendro-
glioma (B): MRI (left), 18F-FDG PET (middle),
and 18F-FDOPA PET (right). (Reprinted by
permission of SNMMI from Chen W, Cloughesy
T, Kamdar N, et al. Imaging proliferation in brain
tumors with 18F-FLT PET: Comparison with
B 18F-FDG. J Nucl Med. 2005;46(6):945–952.
Figure 2.)
synthesis. The 18F-FLT activity in normal brain tissue is low because uptake from that pertaining to new DNA synthesis and cell prolif-
of low proliferative activity and because it does not cross intact eration. Chen et al.28 compared 18F-FLT and 18F-FDG in 25 patients
BBB. This makes the interpretation of the 18F-FLT PET brain with either newly diagnosed or previously treated gliomas. 18F-FLT
images easier. However, a downside of 18F-FLT is that it is only imaging can be performed within 35 minutes following injection
retained in brain tumors with BBB breakdown. Hence, evaluation and dynamic imaging can be acquired. Because the background
of lower-grade brain tumor with intact BBB is limited. In addition, activity of the brain is very low, the tumor to normal uptake ratio is
there may be nonspecific accumulation of 18F-FLT in areas of blood much higher than 18F-FDG PET imaging. This increases sensitivity
brain disruption not necessarily because of the presence of high- of recurrent tumor detection. Specificity of high-grade tumor detec-
grade tumor but because of other benign etiologies. This requires tion is very high with 18F-FLT imaging. According to Chen et al., the
utilization of kinetic modeling to distinguish nonspecific 18F-FLT recurrent tumor cases who had 18F-FLT uptake but no 18F-FDG
A B C
Figure 1.4. Newly diagnosed glioblastoma. MRI (A; contrast-enhanced T1-weighted image) shows large area of contrast enhancement in right frontal lobe. Both
18
F-FDG PET (B) and 18F-FLT PET (C) show increased uptake in the same area. (Reprinted by permission of SNMMI from Chen W, Silverman DH, Delaloye S, et al.
18
F-FDOPA PET imaging of brain tumors: comparison study with 18F-FDG PET and evaluation of diagnostic accuracy. J Nucl Med. 2006;47:904–911. Figure 2.)

uptake demonstrated progression within 1 to 3 months representing with 18F-FMISO detects regions of hypoxia independent of anatomy
better prognostic power of 18F-FLT. Hatakeyama et al.29 compared (i.e., blood brain disruption) and of perfusion. Bruehlmeier et al.37
11
C-Met and 18F-FLT in 41 newly diagnosed patients with glioma. correlated hypoxia and perfusion characteristics of different kinds of
They found that 11C-Met was slightly more sensitive in tumor brain tumors, including GBM, anaplastic astrocytoma, meningioma,
detection, 18F-FLT was less useful in nonenhancing tumors; both and hemangioblastoma, using 18F-FMISO and 15O-H2O respectively
tracers were 100% sensitive in malignant glioma and 18F-FLT was (Fig. 1.5). 18F-FMSIO kinetics were calculated using two- and three-
valuable for tumor grading. 18F-FLT was superior to assess the cel- compartment models and distribution volume measurements, and
lular proliferation activity. An important downside of 18F-FLT is tumor perfusion was calculated using 15O-H2O perfusion. The study
that any process that will damage the BBB such as radiotherapy results show that 18F-FMISO uptake within 0 to 5 minutes is
results in passive influx of 18F-FLT and will result in false-positive increased in tumors where there is BBB disruption (such as GBM)
18
F-FLT uptake. or there is lack of BBB (such as meningioma). There was a positive
correlation between 18F-MISO tumor uptake at 0 to 5 minutes and
perfusion of 15O-H2O. However, there was no difference in distribu-
Choline (Lipid) Synthesis tion volumes of 18F-FMISO in meningioma. This was because of con-
Malignant transformation of cells is associated with induction of tinuous accumulation of 18F-FMISO in cases of GBM. The results of
choline kinase activity, which results in increased levels of phos- the study show that hypoxia in GBM develops irrespective of the
phatidyl choline (“lecithin” in cell membrane). Choline labeled with magnitude of perfusion. 18F-FMISO uptake can be seen in both
different positron emitters has been studied in brain tumor imag- hypo- and hyperperfused areas. Increased 18F-FMISO uptake was
ing. Kato et al.30 compared the utility of 11C-Met, 11C-Cho, and 18F- seen only in the periphery of the GBM, where there is viable tumor
FDG in evaluation of gliomas. They studied 95 glioma cases, WHO that can accumulate FMISO and delivery to necrotic tissue is low.
grades II, III, and IV. 11C-Met tumor-to-normal ratio was signifi- Spence et al.38 correlated regional hypoxia in GBM with time to pro-
cantly higher in oligodendroglial tumors than in astrocytomas. 11C- gression and survival using 18F-FMISO imaging. Severity of hypoxic
Cho uptake in tumor versus normal cortex uptake was found to show burden on 18F-FMISO PET after initial surgery prior to radiotherapy

positive correlation with different grades of oligodendrogliomas. significantly impacted time to progression and overall survival
Hence, 11C-Cho is a potential useful tracer in grading the oligoden- according to the results. Hypoxia imaging could be integrated into
drogliomas. The background uptake of normal brain tissues is less new regional and/or systemic treatment strategies to target hypoxia
with 11C-Cho compared with 11C-Met, making interpretation of 11C- more aggressively in GBM. Surgical resections could target hypoxic
Cho images easier. One limitation is that physiologic uptake of 11C- regions using co-registered images of 18F-FMISO and MRI.
Cho by the choroid plexus, venous sinuses, and the pituitary gland
make evaluation of tumors near these sites challenging.
Positron Emission Tomography/
Hypoxia Imaging Magnetic Resonance Imaging
Hypoxia is defined as reduction in pO2 (decreased intracellular
The advantages of CT over MRI are CT’s speed, robustness, avail-
oxygen pressure). Normal tissue pO2 is greater than 40 mm Hg.
ability, and lower cost. In areas where MR excels clinically, such
Hypoxia is a common feature of GBM. In fact, tumor hypoxia leads
as neuro- and musculoskeletal applications as well as some focal
to necrosis, which is a mandatory criterion to establish the diagnosis
applications in the upper abdomen, pelvis, and head and neck,
of GBM. As tumor growth exceeds vascular development, and oxy-
both MR and PET/CT are frequently performed. Given the known
gen delivery is decreased, cells become hypoxic. Hypoxia-inducible
advantages of MRI over CT such as higher soft tissue resolution,
factor 1-α transcription factor, which is constantly produced and
lack of radiation, and functional imaging aspects such as MR
only survives in hypoxic cells, results in activation of transcription
spectroscopy and other functional imaging offered by MRI, PET/
of more than 100 genes that promote invasiveness, aggressiveness,
MRI could have advantages over PET/CT. Integration of PET and
and VEGF production.31 Tumor cells adapt to hypoxia by decreasing
MR data can be achieved by either software-based fusion or by
the proliferation rate, remaining longer in resting phase G0, thus
integration of the hardware of the two devices. The feasibility of
escaping the impact of therapies that target cells in S phase. Two
simultaneous PET/MR imaging of the human head has been dem-
to three times the radiation dose is required to kill hypoxic tissue rela-
onstrated with an avalanche photodiode-based PET detector
tive to normoxic tissue.32 This resistance to radiotherapy becomes
technology, which is insensitive to high magnetic fields.12 For
evident when the oxygen pressure decreases below 3 mm Hg.33
PET/MRI system, a detector ring was constructed and placed in a
By limiting the tumor response, hypoxia is an adverse prognostic
clinical 3-Tesla MRI scanner (TRIO, Siemens Medical Solutions)
factor and is an indicator of higher rates of recurrence and fatality.
with a standard bird cage transmit/receive head coil.39 All PET
The discovery in the mid-1980s that some radiosensitizing drugs
detector components were selected and sized to exhibit minimal
such as misonidazole are selectively bound to molecules in viable
interference with the magnetic fields of the MR system (Fig. 1.6).
hypoxic cells in vitro and in vivo attracted interest from radiation
There are three ways to technically integrate PET and MR
biologists and nuclear medicine specialists.34
systems.
Fluoromisonidazole (FMISO) was found to bind stably to hypoxic
viable cells as misonidazole. FMISO is a 2-nitroimidazole derivative 1. Separate imaging in devices placed far from each other. The
that undergoes intracellular reduction by nitroreductases in viable patient has to move from one to the other imaging system. This
cells generating a radical anion. Necrotic tissue lacks this enzyme. approach requires integration through software-based image
Oxygen in oxygenated cells acts as an electron acceptor for the fusion (Figs. 1.7 and 1.8). This results in some temporal gaps in
18
F-FMISO radical anion. In the absence of oxygen, 18F-FMISO is the examination sequence of the patient. Separate PET/CT and
further reduced and covalently bound to intracellular macromole- MR data could alternatively be compared using “mental” fusion
cules and does not exit hypoxic cells.35 FMISO tagged with a positron rather than software fusion because there are enough anatomic
emitter 18F was found to be a useful noninvasive hypoxia PET imag- landmarks on both examinations. However, in the latter case,
ing agent.36 18F-FMISO is lipophilic and diffuses through cell mem- because the imaging is performed with separate imaging
branes and shows passive distribution in normal tissue. 18F-FMISO devices, requiring patient repositioning, there is a greater risk
concentration in normal, nonhypoxic tissue is always lower than of voluntary and involuntary patient movements between pro-
plasma. Retention of 18F-FMISO is inversely proportional to oxygen cedures. This results in time-consuming side-by-side image
concentration. Significant retention occurs below 3 mm Hg.36 PET interpretation.40

A
B C
D E F
Figure 1.5. (A and B) Gadolinium contrast-enhanced T1- and T2-weighted MR images in a patient with glioblastoma multiforme in the left temporal lobe.
(C) Late PET images show 18F-FMISO tumor uptake 150–170 minutes after injection. (D) Gadolinium contrast-enhanced T1-weighted MR image of a patient with
meningioma in left temporal lobe. (E) 18F-FMISO uptake in meningioma is visible in early PET image 0 to 5 minutes after injection but not in late PET images 150
to 170 minutes after injection (F). (Reprinted by permission of SNMMI from Bruehlmeier M, Roelcke U, Schubiger PA, et al. Assessment of hypoxia and perfusion
in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O. J Nucl Med. 2004;45(11):1851–1891. Figure 1.)
A B C
Figure 1.6. Simultaneously acquired (A) MR, (B) PET, and (C) superimposed combined MR/PET images of 66-year-old man after intravenous injection of 370 MBq
of FDG. Tracer distribution was recorded for 20 minutes at steady state after 120 minutes. (Reproduced by permission of the Radiological Society of North America
(RSNA) from Schlemmer HP, Pichler BJ, Schmand M, et al. Simultaneous MR/PET imaging of the human brain: Feasibility study. Radiology. 2008;248(3):1028–1035.)


Figure 1.7. 18F-FDG PET, contrast-enhanced axial T1-weighted image, PET/MR fused image. Patient with a history of treated malignant lesion with surgery and
radiation therapy presents with an enhancing lesion on follow-up imaging. The enhancing lesion does not demonstrate FDG uptake on MRI, compatible with radia-
tion necrosis.
Figure 1.8. 18F-FDG PET, postgadolinium axial T1-weighted, and MR/PET-fused images. Increased FDG uptake along the periphery of a surgical cavity where
there is ill-defined enhancement on MR, compatible with recurrent tumor.

2. Sequential imaging by systems linked by a patient “shuttle.” ferent treatments and different prognosis. Radiation necrosis is a
Transfer of the patient is accomplished by the “shuttle.” These delayed focal structural lesion, at or close to the original tumor
devices provide a “hardware-fused” data. site, that usually occurs within a 6-month to 2-year period after
3. Fully integrated systems with technically simultaneous data radiotherapy or stereotactic radiosurgery. This early delayed radi-
acquisition, which eliminates patient motion or table motion ation effect has been described for radiation-related enhancing
between acquisitions. Currently available PET/CT and SPECT/ lesions and/or increased edema on MRI within several weeks to
CT systems are of the sequential imaging type. The currently up to 3 months following radiation treatment. It is reported to be
described head PET/MR systems are fully integrated systems. facilitated with concomitant chemotherapy. There are also reports
Another challenging technical issue in the development of PET/ of late onset radiation treatment effects (up to 20 years after treat-
MR system is the need for attenuation correction. This is not ment).44–47 Clinical presentation of radiation necrosis is nonspe-
as straightforward with PET/MR as with PET/CT. In PET/CT, cific and includes seizures, focal neurologic deficits, personality
whole-body CT scans are an integral part of the PET/CT exami- changes, memory loss, dementia, and/or recurrence of the initial
nation. CT scans can easily be incorporated into the PET recon- tumor symptoms. Differential diagnosis between recurrent glioma
struction algorithm, thus correcting for patient attenuation. and radiation necrosis on conventional imaging is challenging for
MRI, on the other hand, does not provide any information about CT and/or MR, because radiation necrosis usually presents as a
photon attenuation but gives information about tissue proton lesion with surrounding edema and nodular, linear, or curvilinear
densities and magnetic relaxation times. Attenuation correction enhancement because of the BBB breakdown, often resembling
of PET/MR must therefore be based on indirect voxel-by-voxel residual/recurrent tumor about resection cavity. Moreover, if a
assignment of MR signal intensities to empirical values of pho- radiation-induced lesion is detected at a distant site from the pri-
ton attenuation coefficients.41 Several approaches have been mary tumor site it may be misinterpreted as multifocal glioma.48
studied to resolve this problem. One approach uses image seg- Different MRI techniques have been reported as possible tools to
mentation,42 and another approach uses a combination of local overcome these difficulties, including perfusion MR, diffusion MR,
pattern recognition with atlas registration for additionally cap- and MR spectroscopy.
turing global variations of anatomy.43 The latter approach has Newer MRI techniques such as arterial spin-labeled, dynamic
been shown to be successful for brain MR/PET images because susceptibility, and contrast methods also show promise but require
the brain tissues are relatively homogeneous. In summary, PET/ further validation.49–51 Nuclear medicine techniques, particularly
MR is likely to be superior to PET/CT in brain imaging. As an PET, have been investigated. 18F-fluorodeoxyglucose (FDG) is the
increasing number of PET/CT and PET/MR scanners are most studied radiopharmaceutical. It has been used to differenti-
installed, there will be an increasing demand for imaging spe- ate recurrent tumor from radiation necrosis for almost 30 years.52
cialists with appropriate training in both radiology and nuclear Typical sensitivities are reported between 81% and 86%, although
medicine. some results are reported to be up to 100%.53–57 Sensitivity may be
complicated by high metabolic activity in adjacent cortex and par-
tial volume effects because of the small size of lesions. Estimates
Differentiation of Recurrent Tumor of specificity are lower, ranging from 22% to 92%. Specificity may
be compromised by metabolic activity in areas of posttreatment
from Radiation Necrosis inflammatory change. Recurrent tumor is typically identified by
visually appreciable increased metabolic activity in the lesion of
Development of a new enhancing lesion on a gadolinium-enhanced interest compared with normal white matter (Fig. 1.9).
MRI within the radiation field could indicate either recurrent Other than 18F-FDG, there are multiple reports of investigational
tumor or radiation necrosis. It is crucial to differentiate recurrent PET radiotracers distinguish radiation necrosis from recurrent
tumors from radiation necrosis because the two entities have dif- tumor. These include 18F-FLT, 11C-Met, and 13N-ammonia PET.58–62
A B
Figure 1.9. A: Postgadolinium T1-weighted MR image showing ring-enhancing lesion in the right caudate head and anterior limb of the right internal capsule.
B: FDG PET image shows hypermetabolic activity of the lesion in the right caudate head suggestive of recurrent tumor. (Reprinted by permission of SNMMI from
Langleben DD, Segall GM. PET in differentiation of recurrent brain tumor from radiation injury. J Nucl Med. 2000;41:447–452.)

18
F-FLT directly assesses tumor proliferation.25,63–66 It has been 1/7 patients with radiation necrosis showed 11C-Met uptake. In
shown to be a marker of tumor aggressiveness and overall thera- 2004, Tsuyuguchi et al.79 reported a series of 11 patients with
peutic response.64–67 18F-FLT does not localize to normal brain recurrent malignant glioma or radiation injury after stereotactic
because of low proliferative activity and because it does not cross radiosurgery; 11C-Met PET correctly identified 6/6 patients with
an intact BBB. Methods have been developed and validated to recurrent tumors and 3/5 cases of radiation necrosis. From this
model the kinetic features of 18F-FLT PET by tumors, and the neces- result, the 11C-Met PET sensitivity, specificity, and accuracy in
sity for the kinetic modeling is thought to be critical to distinguish detecting tumor recurrence were determined to be 100%, 60%,
in nonspecific uptake of 18F-FLT from new DNA synthesis and cell and 82% respectively. Van Laere et al. performed a comparison
proliferation.65,68–70 Dynamic kinetic modeling requires extended between 18FDG PET and 11C-Met PET in suspected recurrence of
dynamic imaging in a single bed position, limiting analysis to a gliomas. They found an abnormal 11C-Met uptake in 28/30 cases,
specific target field of view. It also requires drawing multiple blood whereas only 17/30 cases showed 18FDG uptake. The main limita-
samples, ideally arterial or arterialized venous alternatives, and to tion of this study is the empirical classification of patients in radio-
process these samples by column chromatography to apply a cor- necrosis and recurrence groups, because histologic evidence was
rection to the input function to account for contribution of authentic available in only three cases. In fact, all cases of death were con-
18
F-FLT versus labeled metabolites. Even if dynamic kinetic model- sidered recurrent tumor, and all cases of surviving patients at the
ing of 18F-FLT PET is proven to be of irrefutable value, these meth- end of follow-up period were considered as radiation necrosis.72
ods are unlikely to be broadly adapted in clinical practice because More recently, Terakawa et al. reported an interesting series of
of the complexity of the procedure. In a study on 15 glioma patients 26 glioma patients who underwent conventional radiotherapy.
with new enhancing lesions on MRI, 18F-FLT SUVmax was derived Overall, 32 11C-Met PET scans were performed at a mean interval
from data 60 to 70 minutes following injection and metabolite- of 36 months from irradiation. Recurrence was confirmed by
corrected Patlak Kimax derived from the plasma input function.71 tumor resection or biopsy, whereas radiation necrosis diagnosis
There was a significant difference between recurrent tumor and was based on pathologic examination or on clinical course. Mean
radiation necrosis for 18F-FLT Kimax but not for 18F-FLT SUVmax. These standardized uptake value (SUVmean) and maximum standardized

findings support numerous previous reports that dynamic kinetic uptake value (SUVmax) were generated over the region of interest
modeling of 18F-FLT PET is necessary to ensure optimal results.69–71 and the lesion-to-normal tissue (L/N) count ratios were generated
The overall ranking of the performance of all quantitative and semi- by dividing the SUVmean of the lesion and the SUVmean of the contra-
quantitative tests in distinguishing recurrent rumor from radiation lateral frontal lobe gray matter (L/Nmean) and by dividing the SUVmax
necrosis was found to be 18F-FDG SUVmax/18F-FDG SUVmean contra- of the lesion and the SUVmax of the contralateral frontal lobe gray
lateral white matter > 18F-FDG SUVmax > 18F-FLT Kimax > 18F-FLT matter (L/Nmax). The authors found a significant difference in all
SUVmax. Each of these parameters showed equal specificity (75%). of the indices except for the L/Nmax between tumor recurrence
An optimized cutoff lesion–contralateral white matter 18F-FDG ratio and radiation necrosis. Receiver-operating characteristic (ROC)
of 1.83 or higher for recurrent tumor resulted in the highest sensi- curve analysis of each index indicated that L/Nmean is the most
tivity (100%) in this series to distinguish recurrent glioma from informative index between tumor recurrence and radiation necro-
radiation necrosis. In this study, of all patients with radiation necrosis and an L/Nmean of 1.58 provided the best sensitivity and specific-
sis, 50% had mild 18F-FLT uptake by visual assessment, presumably ity to define gliomas, 75% and 75%, respectively (Fig. 1.10). In this
because of nonspecific leakage of 18F-FLT across a disrupted BBB. study, however, some necrotic tissue also had some high levels of
Enslow et al. concluded that 18F-FLT PET offered no advantage over 11
C-Met uptake, which can be a factor that reduces the specificity
18
F-FDG PET in distinction between recurrent tumor and radiation of Met PET. This is most likely because of the BBB disruption that
necrosis for moderate and high-grade gliomas. In this series, a ratio may occur in radiation-induced lesion.25 Therefore, some authors
of 1.83 or higher 18F-FDG SUVmax in the target lesion to 18F-FDG suggested repeating the 11C-Met PET scan after corticosteroid
SUVmean in the contralateral white matter was the best performing administration in cases with borderline 11C-Met uptake; the repeat
indicator of recurrent glioma (sensitivity, 100%; specificity, 75%). scans may distinguish between radiation necrosis and tumor
11
C-Met is the most commonly studied amino acid tracer in lesions by reducing the 11C-Met uptake because of the BBB break-
brain tumor imaging. Brain tumors overexpress a variety of amino down in radiation injury while leaving the 11C-Met uptake because
acid transporters and the amino acid uptake in normal brain is of intact active transport in gliomas.73
low.72 Methionine, a sulfur-containing essential amino acid, has Other hypotheses that could explain the uptake of 11C-Met in
two main metabolic functions73: Protein synthesis and conversion radiation necrosis can be increased methionine metabolism
to S-adenosylmethionine, which is required in multiple metabolic induced by reactive gliosis mediated by astrocytes and microglial
pathways for transmethylation reactions, polyamine synthesis, cells80 or methionine accumulation as a result of proliferative
transsulfuration pathway that leads to the synthesis of cysteine changes in glial cells in the area of radiation necrosis.79 On the
and other derivatives such as glutathione. In cancer cells, there is other hand, false-negative results with 11C-Met PET are possible,
an increase in protein synthesis, transmethylation, and transsul- mainly because of the inability to detect small lesions.
furation, leading to an increased uptake of methionine. In vitro Kim et al. compared perfusion MR, 18FDG PET, and 11C-Met PET
methionine dependence has been demonstrated in human glioma to distinguish between radiation necrosis and tumor recurrence in
cell lines.74,75 Moreover, it has been shown that in a human 10 patients with high-grade glioma who underwent surgical resec-
glioblastoma cell line, the uptake of radiolabeled methionine is tion followed by radiotherapy with or without chemotherapy and
higher in proliferating cells than in resting plateau-phase cells.76 showed newly enhanced lesions on follow-up conventional MRI.
The use of 11C-Met in brain tumor imaging is restricted to PET After co-registering the PET images with the MR, the maximum
centers with a cyclotron facility because of the short half-life of the uptake values of the lesion and of the contralateral cerebral white
radionuclide. matter as reference area were measured to calculate the lesion/
Several studies evaluated the role of 11C-Met PET to differenti- reference uptake ratio. There was no difference between radiation
ate radiation necrosis from recurrent tumor. An early study by necrosis and tumor recurrence groups in terms of lesion/reference
Ogawa et al.77 presented a series of 15 patients with suspected uptake ratio as derived from the 18FDG and 11C-Met PET. The
recurrent brain tumor after radiotherapy: 10/15 patients under- authors also stated that a perfusion MR might be superior to 18FDG
went a 11C-Met PET that matched with histopathologic results in and 11C-Met PET to distinguish a recurrence of high-grade glioma
100% of the cases (three radiation necrosis and 7seventumor from radiation necrosis.81 In 2009, Nakajima et al. evaluated the
recurrences). Sonoda et al.78 also reported that 5/5 patients with usefulness of 11C-Met PET in the differential diagnosis between radi-
recurrent tumor showed increased 11C-Met uptake, whereas only ation necrosis and tumor recurrence in 18 patients with glioma.

A B
Figure 1.10. 18F-FDG PET, postgadolinium axial T1-weighted, and MR/PET-fused images. Increased FDG uptake along the periphery of a surgical cavity where
there is ill defined. (Reprinted by permission of SNMMI from Terakawa Y, Tsuyuguchi N, Iwai Y, et al. Diagnostic accuracy of 11C-methionine PET for differentiation
of recurrent brain tumors from radiation necrosis after radiotherapy. J Nucl Med. 2008;49:694–699. Figure 1.)
The uptake of 11C-Met was determined as the ratio of the lesion to as PET imaging. Many PET tracers have been studied and show
the contralateral reference region (L/R). The final diagnoses were promise in diagnosis, grading, and differentiation of recurrence
determined by histologic examination and/or follow-up MR imag- from treatment-related changes. Besides 18F-FDG which is a marker
ing and clinical course. 11C-Met PET demonstrated significant dif- of glucose metabolism and is commonly used in many centers for
ference in the L/R ratio between patients with tumor recurrence brain tumor imaging, these other tracers include markers of
and radiation necrosis (2.18 versus 1.49, p < 0.01). According to a cellular proliferation such as 11C-Met, 18F-FDOPA, 18F-FET, 18F-FLT,
2 × 2 factorial table analysis, the borderline values of L/R to dif- 11
C-Cho, and 18F-FMISO (used for hypoxia imaging). These tracers
ferentiate recurrence from necrosis was 2.82 In their retrospective have advantages over 18FDG in brain tumor imaging as they have
study, Yamane et al. examined the clinical efficacy of 11C-Met PET no significant background normal gray matter activity. This makes
in patients with brain neoplasm, especially whether the 11C-Met visual interpretation easier and more reliable.
PET changed the clinical management. The authors demonstrated In addition to the development of these new novel tracers,
that 11C-Met PET was useful in differentiating tumor recurrence there has also been technical development such as the integration
from radiation necrosis, changing the clinical management in half of PET and MR in the same system. This is a difficult and high-cost
of the scans.83 Recently, Okamoto et al. evaluated 29 patients sus- process but has been shown to yield state-of-the-art images. Hav-
pected of recurrent brain tumors by MR after radiation therapy ing PET/MR-fused images makes image interpretation less time
with C11 MET PET. Semiquantitative analysis was performed consuming and more reliable. This clearly results in improvement
using SUVmax and L/N ratio. ROC analysis was also assessed con- in patient care. As an increasing number of PET/MR scanners are
cerning the diagnostic value of 11C-Met PET. Histologic analysis or installed, there will be an increasing demand for imaging special-
clinical follow-up confirmed the diagnosis of tumor recurrence in ists with training in both radiology and nuclear medicine.
22 lesions, and radiation necrosis in 11 lesions. L/N ratios of recur-
rence and necrosis for all lesions were 1.98 and 1.27, respectively
(p < 0.01). The areas under the ROC curve were 0.886 for L/N ratio Targeted Radiotherapy
and 0.738 for SUVmax. The authors concluded that semiquantita- (Radioimmunotherapy)
tive analysis of 11C-Met PET provided high diagnostic value,
enabling early diagnosis of brain tumor recurrence in the follow- An emerging therapeutic approach for high grade (WHO grades III
up after the radiation therapy.84 In summary, to differentiate gli- and IV) brain tumor treatment is targeted radiotherapy, a strategy
oma recurrence from radiation necrosis, 11C-Met PET appears to that utilizes a molecular vehicle to selectively deliver a radionu-
have a high sensitivity, specificity, and accuracy. clide to malignant cell populations. One property of gliomas that
make them suitable for targeted radionuclide therapy is that they
recur at or near the site of origin and are characterized by a frequent
Conclusions: Imaging and Treatment tendency to infiltrate adjacent brain tissue. They rarely metastasize
outside the central nervous system.85,86 In fact, 80% of GBMs recur
Gliomas are the most common primary brain neoplasms. GBM, within 2 cm of the primary site.87 Investigations in brain tumor
which is a grade IV glioma, is the most common of all and has a patients have frequently utilized monoclonal antibodies (MoAbs) as
dismal prognosis. Survival rate is approximately 12 to 14 months the targeting vehicle; this the term: radioimmunotherapy. MoAbs
despite addition of new treatment strategies. Neuroimaging plays a reactive with tumor-associated antigens to target radioactive
crucial role in management of brain tumor patients. MRI has a agents to tumor cells for therapeutic purpose has been extensively
major role in diagnosis and follow-up of brain tumors but it has studied.88–91 Brain tumor–associated molecular targets that have
certain limitations. The recent addition of temozolomide and/or been evaluated include the epidermal growth factor receptor92 and
bevacizumab to surgical treatment and radiotherapy results in MRI the human neural cell adhesion molecule (NCAM) which is present
findings that may not solely reflect tumor response or recurrence both on glioma and normal neural tissue.93 However, the vast major-
but treatment-related changes. This has made MR interpretation ity of radioimmunotherapy studies in brain tumor patients have
more challenging and created the need for molecular imaging such utilized radiolabeled MoAbs reactive with tenascin-C molecule.

Tenascin-C Molecule and Anti-Tenascin istration of the radiolabeled MoAbs via an indwelling catheter
Monoclonal Antibody placed in the surgical resection cavity instead of systemic/intrave-
nous administration.
Tenascin-C is a six-armed glycoprotein that is overexpressed in the
extracellular matrix of gliomas. The level of tenascin-C expression
increases with advancing tumor grade.94 More than 90% of GBM
Locoregional Radioimmunotherapy Versus
biopsies exhibit very high levels of tenascin-C expression.95 Tenascin- Other Locoregional Therapies
C expression occurs primarily around tumor-supplying blood ves- Locoregional therapies other than radiolabeled MoAb method
sels. Furthermore, in grade II and grade III gliomas, there appears include reoperation and various types of radiotherapy (convention-
to be a correlation between perivascular staining and earlier ally fractionated radiotherapy, hypofractionated stereotactic radio-
tumor recurrence.94 Several anti-tenascin MoAbs have been stud- therapy, interstitial brachytherapy, and radiosurgery). Reoperation
ied for radioimmunotherapy: may improve neurologic status and prolong survival in some cases;
• BC-2 and BC-4 anti-tenascin MoAbs. These bind to different however, radiation therapy can provide similar benefit in a less
epitopes on the tenascin molecule. invasive manner. Locoregional radioimmunotherapy (LR-RIT) using
• MoAb 81C6 is another anti-tenascin MoAb. It is a murine IgG2b monoclonal antibodies (MoAbs) labeled with high-energy β-emitting
that reacts with an epitope present the alternatively spliced radionuclides has several advantages over other types of locore-
fibronectin type 3 CD segment.95 The ability of murine 81C6 to gional therapies. The radioemission can kill antigen-negative tumor
selectively localize and treat human glioma xenografts was cells that have no specific radiolabeled antibody localized on their
investigated extensively in rodent models before the initiation of surface in addition to antigen-positive antibody bound cells. This phe-
clinical studies. nomenon is called “crossfire effect.” Recent studies of LR-RIT using
monoclonal antibodies labeled with 131I and 90Y have been encour-
Intravenous administration of therapeutic levels of radiola- aging from the point of view of safety profile, objective response,
beled MoAb to tumor was found to result in excessive doses to liver and overall survival. According to two phase I studies utilizing 131I

and spleen, normal organs that express tenascin.96 It has been 81C6 MoAb into the resection cavities of recurrent high-grade
reported that the relative reactivity with tumor compared with liver gliomas, studied by Bigner et al.104 and Cokgor et al.,105 the dose
and spleen could be enhanced by utilization of antibodies reactive limiting toxicity was neurologic. The maximum tolerated doses
with alternatively spliced regions of the tenascin molecule instead were 100 mCi (3,700 MBq) and 120 mCi (4,440 MBq) respectively.
of those present on all isoforms.95 Reversible hematologic toxicity was also described in a subgroup of
patients in the Cokgor study. Riva et al.106 evaluated the efficacy of
Radioisotopes Used in Labeling of the 131
I- and 90Y-labeled BC-2 and BC-4 MoAbs for the locoregional
Monoclonal Antibodies treatment of malignant gliomas. For the 131I-labeled BC-2 and BC-4
MoAb study by Riva et al., patients received multiple cycles of radio-
The antitumor effect of radioimmunotherapy is primarily because immunotherapy at intervals of either 1 or 3 months, with a cumula-
of the associated radioactivity of the radiolabeled antibody, which tive administered activity of up to 20.35 GBq (550 mCi). The median
emits continuous slowing-down low–dose-rate irradiation.97,98 The survival was 46 months in anaplastic astrocytoma and 19 months
number of radionuclides available for the production of radiola- in glioblastoma according to the study results. The response rate in
beled compounds has increased. Suitable radionuclides with decay glioblastoma patients was better in those with small volume (56.7%)
properties matching the brain tumor characteristics include iodine compared with patients with larger tumors (17.8%). A subsequent
131 (131I), yttrium 90 (90Y), and lutetium 177 (177Lu). The two most study by the same group using this time 90Y-labeled MoAb therapy
commonly studied radionuclides in radioimmunotherapy of brain for recurrent GBMs has been conducted.106 Patients received
tumors are 131I and 90Y. 131I can directly be conjugated to antibodies. between three and five cycles of 90Y-labeled MoAbs with a cumula-
The use of radiometals like 90Y and 177Lu requires first conjugation tive activity up to 3.145 GBq (85 mCi). The median survival for
of a chelator with the antibody and subsequently labeling with the patients with anaplastic astrocytoma and glioblastoma was 90 months
radioisotope.99,100 The chelating agent frequently used for 90Y and and 20 months, respectively. The response rate in glioblastoma
177
Lu labeling is a macrocyclic chelating agent 1,4,7,10-tetraazacy- patients was 26.3% in those with bulky disease compared with
clododecane-N, N9, N0, N-tetraacetic acid, known as DOTA. 131I and 56.3% for those with smaller lesions. In another study by Goetz
90
Y are β-emitters and deposit 95% of their energy within 0.992 and et al.,107 131I- and 90Y-labeled BC-4 MoAb were evaluated in patients
5.94 mm, respectively.101 with grade III and IV gliomas. Multiple cycles of labeled MoAbs were
administered (mean, three per patient) at various activity levels. The
Systemic Versus Locoregional Administration median survival for glioblastoma patients was 17 months.
of the Radiolabeled Monoclonal Antibody These clinical studies confirm the potential of locoregionally
administered radiolabeled MoAbs as a means to improve the sur-
One limitation of systemic (intravenous) administration of radiola- vival of patients with malignant brain tumors. The low incidence of
beled MoAbs is that the amount of immunoglobulin localized side effects, even after multiple cycles, also is encouraging. However,
within neoplastic glial tissue has been measured to be less than it remains to be determined whether the use of multiple cycles of
0.001% of intravenously administered MoAbs per gram of tumor labeled MoAb results in a significant improvement in therapeutic
tissue whereas the remainder stays in the circulation bound to the efficacy compared to single-dose protocols.
radionuclide with toxic effects on other tissues, especially bone
marrow.102 Many factors contribute to this limitation of the sys-
temic treatment. These include large size of the MoAb macromol-
Tumor Pretargeting
ecule, high interstitial pressure inside the neoplastic tissue, limited Significant radiolysis occurs during the interval between radiola-
blood supply to the tumor, inhomogeneous and inconstant antigen beling and injection, with consequent decrease in immunoreactiv-
expression, possible presence of physiologic barriers (necrosis ity when the MoAb is directly labeled with a high-energy isotope.
and/or fibrosis), formation of immunocomplexes, and catabolism Pretargeting has been studied to overcome this radiolysis and poor
of immunoglobulins.103 Although often impaired in tumor, the BBB localization of radiolabeled MoAbs in the neoplastic tissues. In this
further hampers the accumulation of antibodies in the malignant method, first, modified MoAb is administered and allowed to dis-
tissue. Among strategies proposed to overcome these drawbacks tribute throughout the body, to bind to the cells expressing antigen
and to improve the tumor/nontumor uptake is locoregional admin- and clear substantially from other tissues.108 This is followed by the

radiolabeled second component that ideally localizes at sites where Addition of Temozolomide, an Alkylating
the modified MoAb has accumulated. If the second component has Agent to Radioimmunotherapy
higher permeability, clearance and diffusion rates than those of MoAb,
more rapid radionuclide localization to the tumor and higher tumor Recently, temozolomide, a novel alkylating agent with excellent
selectivity are achieved in the higher tumor-to-nontumor ratio.109 properties of penetration into brain, was introduced as standard
treatment for recurrent high-grade gliomas.115 Paganelli’s group
added temozolomide to their LR-RIT protocol for recurrent high-
The Avidin–Biotin Model grade glioma treatment.116 They studied the response rate, overall
survival, and progression-free survival. Although in a major clinical
One of the most clinically useful pretargeting techniques is the avidin–
study by Walker et al.,116 the median survival in GBM patients
biotin system. This three-step pretargeting approach takes advan-
treated with surgery, with or without EBRT was reported to be 35
tage of the extremely high affinity between avidin and biotin. Avidin
and 14 weeks respectively, in Paganelli’s study, within the subgroup
is a small oligomeric protein made up of four identical subunits,
of combined LR-RIT plus temozolomide, the overall survival was
each bearing a single binding site for biotin (vitamin H). The mol-
25 months and progression-free survival was 10 months, within
ecule can therefore bind up to 4 moles of biotin per mole of protein.
the subgroup of patients who underwent only LR-RIT, the overall
The affinity of avidin for biotin is extremely high.110 For practical
survival was 17.5 and progression-free survival was 5 months.115
purposes, their binding can be regarded as irreversible.111 Pretar-
The rationale for combining LR-RIT and temozolomide is that
geted antibody-guided radioimmunotherapy using avidin–biotin
temozolomide would kill microscopic disease outside the LR-RIT
technique is based on intravenous or locoregional sequential
radiation field; the two treatments have different toxicity profiles
administration of a biotinylated BC-4 MoAb, followed 24 hours later
and improved permeability of temozolomide into the resection cav-
by avidin, and finally, after an additional 18 hours, a 90Y-labeled
ity secondary to destructive effect of radiation on BBB.117 Regarding
biotin conjugate.110 Paganelli’s group has studied and applied this
safety, remarkably, only a low incidence of early and late neurotox-
method, both as systemic or LR-RIT in glioblastoma patients.
icity have been reported both with LR-RIT alone or combined with
Paganelli et al.112 performed the first trial with this pretargeting
temozolomide by Paganelli’s group. Reversible grade II and III lym-
approach in patients with recurrent glioma. The three reagents
phocytopenia and/or thrombocytopenia were observed in 62% of
were administered via a catheter placed into the surgical resection
patients treated with LR-RIT and temozolomide. This is comparable
cavity in the sequence that was described. WHO grade III and IV
to studies applying temozolomide and external radiotherapy.118
glial tumors were included in the study and two cycles of therapy
Neurotoxicity and skin infection caused by indwelling catheter are
administered 8 to 10 weeks apart. The maximum tolerated dose
the other possible complications of the locoregional treatment.
was 1.11 GBq (30 mCi) of 90Y-labeled DOTA. The dose-limiting fac-
Compared with EBRT where brain is the critical organ, during
tor was neurologic toxicity secondary to biotin. After the second
locoregional RIT, the normal brain receives negligible doses. The
operation, median survival was 19 and 11.5 months in patients
mean absorbed doses in normal brain were 0.16 ± 0.08 mGy/MBq
with grades III and IV, respectively. In another study by Grana
and 0.015 ± 0.005 mGy/MBq in the systemic and locoregional treat-
et al.,113 the efficacy of pretargeting radioimmunotherapy protocol
ments, respectively.119 With local administration, systemic toxicity is
was evaluated in an adjuvant setting. Newly diagnosed patients
reduced as well. The red marrow adsorbed dose was 0.22 mGy/
with grade III and IV gliomas were included in this study. Following
MBq in the systemic treatment compared to 0.03 mGy/MBq in the
surgery and external beam radiation, a subgroup of patients
locoregional treatment. The normal organs mainly involved in the
received the three reagents in the described sequence with the
90 biodistribution of the 90Y-biotin were liver (0.4 ± 0.3 mGy/MBq) and
Y-labeled biotin being given at a dose of 2.2 GBq/m2. A subgroup
kidneys (0.7 ± 0.4 mGy/MBq); 65 ± 28% of the injected activity was
of GBM patients undergoing surgery and external beam radiother-
eliminated via the kidneys in the first 24 hours after the treatment.
apy (EBRT) was used as a control group. The median survival esti-
Scintigraphic images acquired up to 48 hours after the LR-RIT with
mated for the grade IV glioma patients was 8 months in the control 90
Y-biotin showed the radiolabeled compound to be well localized
group (n = 12) and 33.5 months in the treated group (n = 8). The
within the injection site and minimal activity in the remainder of
results obtained with this pretargeting protocol are highly encour-
the body.118 Low 90Y activities were found in the bloodstream. Activ-
aging, particularly in light of the fact that survival prolongation
ity in other normal organs was negligible in most cases.
could be obtained even when then labeled compound was admin-
istered intravenously.
Radiolabeled Peptides for Targeted

Astatine-211–Labeled Chimeric 81C6 Radiotherapy of Distant Tumor Cells
Clinical Trial One of the limitations of MoAbs is that because they are large mol-
Another radioactive material that could potentially be used for ecules, their diffusion through tissues is slow. Peptides have been
radioimmunotherapy of brain tumors is astatine-211, or 211At. A studied as carrier molecules for targeted radiation therapy of dis-
phase I trial conducted by Zalutsky et al. using astatine-211–labeled tant tumor cells because they have molecular weight two orders of
chimeric 81C6 for therapy of recurrent GBM had promising results. magnitude less than intact MoAbs. Hofer et al.119 has utilized this
211
At is an α-emitter radio halogen with 7.2-hour half-life. It has strategy in patients with low-grade gliomas, many of which over-
high linear energy transfer radiation with higher cytotoxicity than express somatostatin type 2 receptors. In this study, five patients
β-emitters. Cell culture experiments have demonstrated that human with progressive gliomas (two WHO grade II, three WHO grade III)
tumor cell lines could be killed with only a few α-particle traversals and five patients with surgically debulked WHO grade II gliomas
per cell.114 Furthermore, the cytotoxicity of α-particles is nearly were treated with the labeled somatostatin analog [90Y]-DOTA0-D-
independent of dose rate, oxygen concentration, and cell cycle Phe1-Tyr3-octreotide. Patients received between one and five cycles
stage. Less than 0.2% of the injected dose was found in the blood of the labeled peptide at a cumulative activity of 555 to 7,030 MBq
pool and more than 95% of the 211At decays occurred within the (15 to 190 mCi). Responses of 13- to 45-month duration were
tumor resection cavity. Cavity interface radiation doses were in the observed in the progressive patients. Disease stabilization was
range of 150 to 35,000 Gy (2,986 Gy average dose) compared with observed in the five newly diagnosed low-grade glioma patients
0.01 Gy for normal organs including tenascin-expressing spleen who received radiolabeled peptide therapy following resection.
and liver. Encouraging responses have been obtained with a median Side effects included increased seizure frequency but this was
survival of 60 weeks observed in all patients according to this study. transient.

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1725–1731.

Chapter 2
Head and Neck Carcinomas

Muhammad Ali Chaudhry • Lujaien Al-Rubaiey Kadhim • Richard L. Wahl
Introduction Treatment Modalities

A total of 40,250 new cases of head and neck cancers (HNCs) will Appropriate surgical procedures, radiation targets, and indications
be diagnosed in 2013, with a mortality rate of approximately for chemotherapy are guided by the specific site of the disease,
7,850 in the United States.1 Incidence rates are twice as high in stage, and pathologic findings.12 Approximately 30% to 40% of
men than they are in women, with the incidence in women declin- patients who present with stage I or stage II disease will most likely
ing 1% from 2004 to 2008.1 HNCs are categorized according to the receive single-modality treatment with surgery or radiotherapy,
area in which they begin—the oral cavity, pharyngeal, laryngeal, whereas combined-modality therapy is generally recommended for
paranasal sinuses and nasal cavity, and salivary glands. It is a the remaining 60% of patients with locally or regionally advanced
heterogeneous type of cancer with each site having its own set of disease.12
symptoms and risk factors.2 A detailed description of staging of
the different types of HNCs is available in the AJCC Cancer Staging
Manual.3
Surgery
Unresectable tumors are defined as tumors that cannot be removed
or locally controlled after surgery, as well as tumors that cannot be
Risk Factors removed without causing unacceptable morbidity, and primary
tumors of patients with distant metastasis.12 Typically, these tumors
involve the cervical vertebrae, brachial plexus, deep muscles of
Several risk factors contribute to the development of HNC, with
the neck, or carotid artery.12 Conversely, patients with resectable
tobacco and alcohol use implicated in 75% of cases2; the risk is
tumors may or may not undergo surgery. Definitive treatment with
5- to 25-fold greater in smokers than in nonsmokers.4 Although
radiotherapy, with or without chemotherapy, may pose as a better
the risk of developing HNC substantially decreases with smoking
option than surgery in some patients.10,12,13
cessation, second-hand smoke has also been shown to be associ-
Typically, a comprehensive or selective cervical nodal dissection
ated with HNC—particularly pharyngeal and laryngeal cancers.4
will be performed along with primary tumor resection. Comprehen-
Alcohol, on the other hand, is related to a greater degree with
sive neck dissection removes all lymph node groups and is often
cancers of the oropharynx, hypopharynx, and larynx.4
recommended for N3 disease.12 Selective neck dissection takes into
Infectious agents also play a role in HNC. Epstein–Barr virus
account the fact that there is a common pathway for the spread
(EBV) and Human papillomavirus (HPV) are the only two viruses
of HNC to regional nodes and is often recommended even for N0
that can reliably be implicated as risk factors for HNC.5 EBV seems
disease.12 Lesions of the oropharynx, hypopharynx, nasopharynx,
to be associated with nasopharyngeal carcinomas whereas HPV
and larynx are usually managed by neoadjuvant therapy first in
accounts for approximately 50% of oropharyngeal carcinomas.5
order to control the tumor and preserve organs.14 Salvage surgery
Interestingly, the number of cases of HNC caused by HPV is on the
and neck dissection may then be indicated as a second line of treat-
rise in the United States, whereas the development of the disease
ment for patients who did not have a complete clinical response to
caused by other causes is decreasing.2 Other possible risk factors for
neoadjuvant therapy.10,12,13 Adding surgical resection of the residual
HNC include gastroesophageal reflux, ionizing radiation exposure,5
mass following induction chemotherapy to the treatment plan has
unhealthy diet, and low body mass index.6 In addition to the envi-
been reported to improve overall survival in patients with advanced
ronmental risk factors described above, genetic predisposition might
stage disease who achieve less than 90% partial response to the
also affect the incidence of HNC. Although a history of alcohol and
neoadjuvant chemotherapy.15
tobacco exposure are the dominant risk factors for HNC, genetic
susceptibility may be equally important. Family studies have
reported a three- to eight-fold increased risk of HNC in first-degree Radiotherapy
relatives of patients with HNC.7 In addition to familial predisposi-
Over the years, radiotherapy has become an increasingly impor-
tion, several genetic polymorphisms involved in carcinogen metab-
tant modality in the treatment of head and neck malignancies.
olism, alcohol cell cycle control, and alcohol metabolism have been
Intensity-modulated radiation therapy (IMRT) has revolutionized
identified and associated with an increased risk for HNC, namely
the treatment of a variety of malignancies including HNCs. It has
GSTM1-null genotype, GSTT1, EPHX1 genes and ALDH2*1/*2,
led to minimizing damage to adjacent normal/nondiseased organs.
p53 codon 72 Pro/Pro and EPHX1 codon 113 Tyr/His, and His/His
Natural history, anatomy, and clinical findings continue to guide
genotypes.8,9
radiotherapy planning. The selection of radiation dose depends on
the primary tumor and measurements of gross adenopathy.12
18
F-fluorodeoxyglucose positron emission tomography (18F-FDG
Symptoms PET) and positron emission tomography/computed tomography
(PET/CT) helps to delineate primary tumor volume (gross tumor
Early symptoms may be nonspecific, such as a lump or sore throat volume [GTV]). This was traditionally based on anatomical imaging
that does not heal, difficulty in swallowing, and a voice change or (e.g., CT, magnetic resonance imaging [MRI]); however, more and
hoarseness.10 Diagnosis, however, is often made at a late stage of more centers are using PET/CT to determine GTV (Fig. 2.1). A
the disease when patients clinically present with a neck mass, pain, reduction in the size of the GTV has been demonstrated in a land-
dysphagia, odynophagia, partial airway obstruction, foreign body mark study by Daisne et al.16 comparing the role of co-registered
sensation, cranial neuropathies, or trismus.11 As is the case in signs CT, MRI, and 18F-FDG PET in GTV delineation of laryngeal cancer
and symptoms, treatment options are variable and depend on in patients scheduled for laryngectomy. 18F-FDG PET was closest to
the site of cancer, making HNC one of the more complex cancers depict the true tumor volume compared to the reference surgical
to treat. specimen. All modalities overestimated the extension of the tumor,
16

Chapter 2 Head and Neck Carcinomas 17

B
Figure 2.1. Planning CT (A), corresponding 18F-FDG

PET scan (B), and fusion image (c) from a 46-year-old
patient with locally advanced nasopharyngeal carcinoma.
Notice differences in target volume delineation whereby CT
gross tumor volume (GTV) delineation (red ) overestimates C
the PET-GTV (yellow ).
with an average of 29%, 65%, and 89% for 18F-FDG PET, CT, and Chemotherapy
MRI, respectively. However, all three imaging modalities, including
18
F-FDG PET, failed to identify a small fraction of the macroscopic Chemotherapy alone is rarely used to treat patients with HNC;
tumor (approximately 10%), mainly superficial mucosal extensions.17 still, it may be used in combination with radiation therapy to
Postoperative irradiation, on the other hand, is determined by enhance its therapeutic effects.10,19 Some of the most commonly
stage, histology, and pathologic findings and is generally recom- used chemotherapy agents include cisplatinum, carboplatinum,
mended for patients with advanced disease, multiple positive and taxane. Studies have shown that concomitant chemoradiation
nodes, and perineural/lymphatic/vascular invasion.10,12,18 (e.g., cetuximab) increases survival time and reduces the risk of

recurrence.10,19 This advantage, however, does not come without possibility of achieving good functional results following ablation
costs, as chemoradiation causes severe adverse effects, and as of large posterior oral cavity tumors.28 Large primary lesions,
such, is not recommended for patients who are less fit or with regional lymph nodes, and bulky nodal metastasis are managed
metastatic disease.10,19 by external beam radiotherapy, with or without interstitial implan-
tation.28 For early stage cancers, the type of treatment is deter-
mined by the predicted functional or cosmetic results, typically
Biologic Therapy consisting of surgery or radiotherapy with high cure rates.28 Con-
Progress in molecular biology and immunology has led to a bio- sideration of the impact of therapy on the quality of life must also
logic approach to the treatment of HNC. In this setting, molecules be evaluated and prosthodontics and rehabilitation are equally as
that play a role in the development and maintenance of cancerous important as treatment in patients with lip and oral cavity cancer.
cells are targeted for treatment directed at growth factors, recep-
tors, inducing apoptosis, or regulating the antitumor immune
response.20 For example, the antitumor immune response may
Oropharyngeal Carcinoma
be enhanced by harvesting and activating patients’ lymphocytes Unlike other sites of HNC, the literature on the treatment of oro-
(specifically, T-cells) in vitro, then introducing them back into the pharyngeal cancer lacks comparisons between the different treat-
patients as a vaccination.21 Alternatively, dendritic cell vaccines ment options and, as a result, there is no single treatment that can
may also be used, as dendrites have the ability to initiate a primary reliably be identified as superior to other therapeutic regimens.2
immune response.21 Epidermal growth factor receptors (EGFR) are The choice of treatment thus is determined by stage and the phys-
overexpressed in many patients with HNC, leading to cellular resis- ical and emotional condition of the patient.2
tance to radiotherapy and poor prognosis.22 Thus, EGFR inhibitors
have been used in combination with chemoradiotherapy for the
treatment of HNC.22 Currently, the most commonly used antibody
Carcinoma of Salivary Gland
targeting EGFR is cetuximab which is FDA approved for patients Superficial parotidectomy is performed for low-grade malignancies
with recurrent or metastatic HNC; other agents under study include of the superficial portion of the parotid gland whereas total paroti-
hR3, matuzumab, panitumumab, gefitinib, and erlotinib.23 How- dectomy is indicated for all other types of lesions.25 Accumulating
ever, HNC is a highly heterogeneous disease with each subtype evidence suggests that surgical resection can be enhanced by post-
responding differently to treatment, including biologic therapy. In operative radiotherapy for high-grade tumors when margins are
addition, the complexity of HNC renders it difficult to achieve dis- involved, for large tumors, and for cases of lymph node metastasis.25
ease control by targeting only one molecular pathway; as such, it
may be worthwhile to use these biologic agents with conventional
therapy in combinations tailored to the patient depending on the
Hypopharyngeal Carcinoma
location and staging of HNC. With the exception of early stage disease, treatment primarily
involves surgery followed by postoperative radiation therapy. Some
early stage disease can be successfully treated with radiotherapy
Treatment alone whereas combined-modality treatment is considered for
patients who present with stage III or stage IV disease.29 Some
Carcinomas of Paranasal Sinus and studies report that combined radiotherapy and chemotherapy offer
better tumor control with tissue preservation than does radiother-
Nasal Cavity apy alone.30 Furthermore, patients with resectable advanced-stage
The standard mode of treatment for paranasal sinus and nasal disease should undergo neoadjuvant therapy while preserving the
cavity cancers is a combination of radiotherapy and surgery. Sur- larynx.31
gery usually consists of fenestration with removal of the tumor
bulk, resection of the floor of the anterior cranial fossa in selected
Laryngeal Carcinoma
patients, and removal of the eye if the orbit is extensively invaded
by cancer.24 High-dose radiation (up to 74 Gy) is typically indicated Radiation therapy may be preferred for superficial cancers without
when there are sufficient grounds to expect permanent control, laryngeal fixation or lymph node involvement in order to preserve
with treatment volume encompassing the maxillary antrum and the voice; surgery is typically preserved for salvaging failures.32
involved hemiparanasal sinus and contiguous areas.25 Some curative surgical procedures, however, are also capable of
maintaining vocal function.32 The selection of appropriate surgery
must take into account the anatomic problem and performance
Nasopharyngeal Carcinoma status. As is the case with hypopharyngeal cancer, advanced-stage
The principal treatment of nasopharyngeal carcinoma for the pri- laryngeal cancer is often treated with combined radiotherapy and
mary lesion site and the neck is high-dose radiotherapy with che- surgery.25 However, the cure rate for advanced tumors is low and
motherapy.26 The location and size of the primary tumor and lymph as such, it is recommended that the patient be placed into clinical
nodes dictate the dose and field margins of radiotherapy; usually trials of chemotherapy, hyperfractionated radiotherapy, radiation
consisting exclusively of external beam radiotherapy.26 Surgery in sensitizers, or particle beam radiotherapy.25
patients with nasopharyngeal cancer is reserved for nodes that fail
to regress after radiotherapy or for nodal recurrence after complete
clinical response.26 It is important to note that approximately 30%
to 40% of patients receiving external beam radiotherapy to the
Imaging in Head and Neck Carcinomas
entire thyroid gland or the pituitary gland develop hypothyroidism,
making it essential to incorporate thyroid-function testing in the
PET/CT Imaging in Head and Neck Cancer
pre- and posttherapeutic evaluation of these patients.27 Clearly, the choice of treatment for HNC requires careful evaluation
in order to select the optimal treatment for each individual patient.
It is thus essential to utilize the tools available through advances
Carcinomas of Lips and Oral Cavity in technology. Contrast-enhanced Computed Tomography (CE-CT)
Cervical node dissection in patients with lip and oral cavity carci- is, to date, the initial study in the assessment of HNC.33 CT scan-
noma is usually performed if regional nodes are positive with the ning is generally preferred over MRI to assess lymphadenopathy

because of higher accuracy at lesser cost and shorter study time.33 concluded that PET/CT may thus be recommended in the initial
MRI, on the other hand, is used to evaluate tumor spread to areas work up of CUP.40 Two recent studies corroborated the usefulness
closer to the skull base.33 These methodologies, however, have of PET/CT to detect unknown primaries in HNC. In a study by Roh
some limitations. For example, CT images have poor soft tissue et al.,43 patients with cervical metastasis of CUP were evaluated
contrast and MRI is susceptible to artifacts. In addition, the utility with head and neck CT and whole-body 18FDG PET/CT. PET/CT
of both anatomic modalities for nodal staging in HNC is debatable was significantly more sensitive to detect occult primary tumors in
and anatomic restaging becomes increasingly difficult following comparison to CT with a reported sensitivity of 87.5% versus
postoperative and postchemoradiotherapy changes to normal ana- 43.7%, respectively. The second study also evaluated patients with
tomic structures. As a result, fused imaging using PET/CT has CUP and reported the sensitivity, specificity, positive predictive
become increasingly popular.34 value (PPV), and negative predictive value (NPV) of 18FDG PET to
PET/CT combines anatomical and functional data into a single be 87%, 68%, 61%, and 90%, respectively, with only three false
image, allowing for accurate localization of metabolic abnormal- negatives and 13 false positives.38 Furthermore, PET scans resulted
ities by way of an IV-injected radiotracer.34 The most commonly in a therapeutic change in 25% of patients due its ability to localize
used radiotracer is a glucose analog, 18F-fluorodeoxyglucose the primary tumor.38 Therefore, combined PET/CT is a useful pri-
(18F-FDG)34 – PET/CT in this review refers to the use of 18F-FDG mary screening method to detect occult primary tumors presenting
unless otherwise specified. Quantification of tumor glucose uptake with metastatic neck lesions and should be considered in routine
is typically measured as a standard uptake value (SUV) with tumors clinical practice (Fig. 2.2).
exhibiting significantly greater SUV than normal tissue.34 PET/CT
scanning offers the advantage of a whole-body scan in one session.
In addition to planning treatment, it may be used in various stages
Staging
for the management of HNCs. Treatment selection for a given patient depends on the TNM stag-
ing, and as such, precise staging is a crucial aspect of therapy
planning in HNC. Conventional staging typically involves physical
Detection of Unknown Primaries

examination, endoscopy, and contrast-enhanced CT scan of the
In approximately 10% to 15% of patients with head and neck squa- head, neck, and chest. MRI is reserved for the assessment of oral
mous cell carcinoma, the source of the disease may remain obscure cavity and paranasal sinus cancers. These conventional tech-
despite clinical, radiographic, and endoscopic evaluation.35 PET/ niques rely solely on abnormal morphologic features of the tumor
CT may guide surgeons to the potential source of the primary that may be missed because of the presence of microscopic tumors
tumor and thus reduce morbidity associated with radiation of the in a structurally normal organ.39 Alternatively, PET/CT assesses
entire pharyngeal mucosa, larynx, and bilateral neck should the the physiologic properties of the tumor in addition to its structural
primary site remain unknown.35 In general oncology, only 20% to properties and can reliably provide information regarding the pri-
27% of metastatic cancer of unknown primary (CUP) origin is mary tumor, nodal metastasis, distant metastasis, and potential
detected by conventional radiologic methods (e.g., ultrasonogra- second primary tumors.
phy, CT, MRI, and PET alone).36 Typically in HNC, patients will pres-
ent with a pathologically confirmed enlarged cervical lymph node
in which conventional imaging has failed to localize the primary
Primary Tumor
tumor site.37 In a study by Nanni et al.,36 18F-FDG PET/CT scans Several studies have demonstrated that 18F-FDG PET is at least as
were obtained for patients with proven metastatic disease and sensitive as MRI for the detection of primary tumors, whereas the
negative conventional diagnostic procedures; PET/CT detected combination of PET/CT can provide more useful information with
occult primary tumors in 57% of cases, while failing to identify the higher sensitivity.40 Dammann et al.41 evaluated the efficacy of
18
primary malignancy in 39% of cases. Although it seems like a low FDG PET, CT, and MRI for preoperative evaluation of HNC.
value, the sensitivity of 57% for PET/CT is better than the sensitiv- Patients with histologically proven squamous cell carcinoma of the
ity of 24% to 40% described in literature for conventional imaging oral cavity and oropharynx were recruited for the study.41 18FDG
in the detection of unknown primaries (Table 2.1).36 PET correctly detected 86% of tumors; 75% of the tumors missed
A meta-analysis of studies published between 2000 and 2009 were less than 10 mm in diameter.41 MRI performed slightly better
evaluated the utility of PET/CT specifically to detect unknown pri- overall in comparison to CT and PET, with a reported sensitivity,
mary tumors in patients with cervical lymph node metastasis and specificity, and accuracy of 92%, 63%, and 88%, respectively, in
negative standard work up.40 PET/CT detected the primary tumor comparison to 61%, 100%, and 66%, respectively, for CT and
in 28% of patients, with 30/180 false-positive lesions.40 The authors 87%, 63%, and 84%, respectively, for PET.41 The low specificity of
PET may reflect its disadvantages compared to structural imag-
ing, which can be overcome by combined PET/CT scanning
(Fig. 2.3A,B). In another prospective study, patients with suspected
Table 2. 1
primary HNC cancer underwent diagnostic and imaging proce-
dures including panendoscopy, biopsy, PET, CT, and color-coded
Studies Evaluating the Performance of Pet/Ct
duplex sonography (CCDS).42 PET had the highest overall sensi-
for the Detection of Unknown Primaries in Hnc
tivity and specificity for primary tumor detection, 95% and 92%,
Following Negative Conventional Work Up
respectively.42 However, false-negative PET results were found in
cases of small metastatic lymph nodes located close to the primary
Number of Percent Detected by tumor. Despite these false negatives, the usefulness of PET for pri-
Author and Year Patients PET/CT (%) mary tumor evaluation was found to be similar to the “gold stan-
dard” panendoscopy whose sensitivity and specificity were 100%
Johansen et al., 200938 13 54
and 85%, respectively; although the authors concluded that panen-
Mak et al., 200739 38 68
doscopy is still the first-choice procedure to detect primary tumors
Al-Ibraheem et al., 200940 16 88
Dammann et al., 200941 21 19 because of its ability to assess the upper aerodigestive tract whereas
Di Martino et al., 200242 37 43 PET is better at detecting recurrence.42 CT and CCDS performed
Roh et al., 200743 60 50 poorly in comparison to PET, with a reported sensitivity of 68%
and 74%, respectively, whereas specificity was 69% and 75%,
PPV, positive predictive value. respectively.42

A B
Figure 2.2. A 45-year-old male with newly found cervical lymphadenopathy and subsequent biopsy showing squamous cell carcinoma with an unknown primary.
PET/CT required for diagnosis of primary site and staging. Coronal CT image (A), corresponding coronal PET/CT (B). The FDG PET/CT scan demonstrates intense
focal FDG uptake within the right fossa of Rosenmuller (SUVmax, 13.6); the underlying soft tissue mass, approximately measuring 1.4 × 1.9 cm, is the site of primary
malignancy (white arrow ).
More recent studies compared hybrid PET/CT to conventional Schwartz et al.47 evaluated patients with squamous cell carci-
imaging methods for primary tumor staging. Deantonio et al. stud- noma of oral cavity, oropharynx, larynx, and hypopharynx; all
ied patients with proven HNC, all of whom underwent PET/CT patients underwent preoperative FDG PET with contrast-enhanced
scanning and routine CT simulation. Typically, simulation CT uses CT scans. Histologic findings served as a tool to evaluate the effec-
low current/voltage parameters with much reduced diagnostic tiveness of PET/CT and CT alone for nodal staging. PET/CT was
capabilities. Clinical staging was analyzed by comparing findings found to be superior to CT with reported sensitivity and specificity
of PET/CT with CT alone.44 PET/CT correctly identified all primary of 96% and 98.5% for PET/CT and 78% and 98% for CT, respec-
tumors and resulted in a change in clinical stage in 22% of patients tively.47 Furthermore, PET/CT was able to detect nodal disease
in comparison to CT alone.44 These results, however, were based thought to be negative on CT scans alone and agreement between
on a very small sample size. Roh et al.45 tested PET/CT in a much scan results and pathologic findings were stronger for PET/CT
larger population of patients with untreated HNC. All patients than for CT.47 These findings are in line with those of Murakami
were evaluated by CT, MRI, PET, and/or PET/CT.45 PET and PET/ et al.48 who also compared PET/CT and CT alone for detection of
CT correctly identified the primary tumor in 97% of patients, with nodal involvement in various types of HNC and reported a sensi-
equal sensitivities reported for both modalities, 98% versus 97%, tivity, specificity, and accuracy of 84% versus 68%, 99% versus
respectively, and only four false negatives.45 In contrast, the pooled 94%, and 96% versus 89%, respectively.
accuracy for detecting primary tumors using CT and MRI was How to proceed when a PET/CT reveals a negative scan for nodal
87%, with 20 unidentifiable tumors, 16 of which were successfully disease is still a matter of debate. PET/CT is generally viewed as the
detected by PET/CT.45 The authors concluded, contrary to most method of choice to stage HNC cancer, with the exception of staging
literature, that PET/CT scanning does not offer significant advan- patients with N0 neck; that is, no identifiable metastatic disease on
tage over PET alone for the staging of primary tumors in HNC. physical examination or other diagnostic procedures.49 PET/CT may
Another study, however, compared fused PET/CT to PET alone for reveal false-positive or false-negative results when metastatic dis-
primary tumor detection in patients with nasopharyngeal carci- ease is not suspected or identified by physical examination or other
noma.46 PET/CT was found to be superior to CT alone and PET diagnostic procedures.49 Several studies evaluated the role of PET/
alone, with a reported sensitivity and accuracy of 90% each for CT in patients with oral cancer staged N0 by clinical examination.
PET/CT, 75% each for PET alone, and 75% each for CT alone One such study reported 53/72 false negatives and 11/72 false pos-
(Table 2.2).46 itives, resulting in a sensitivity and specificity of 26% and 99%,
respectively, for PET/CT identification of nodal disease.50 Because of
the high rate of false negatives from PET/CT evaluation, it is not
Nodal Metastasis recommended that treatment decisions be based on a negative PET/
At initial presentation, approximately 45% of patients with HNC CT scan. Conversely, a positive PET/CT test can reliably diagnose
have regional nodal metastasis (Fig. 2.3C–D).37 Cervical lymph metastatic disease with a high PPV (Table 2.3).
node metastasis (LNM) is an important prognostic indicator in
patients with HNC and is typically evaluated using radiologic imag-
ing. The detection values of cervical LNM are similar with CT and
Distant Metastases
MRI (1.5T scanner), with reported sensitivities ranging between The incidence of metastases in HNC is relatively low, approxi-
14% to 80% for CT and 29% to 85% for MRI.37 Several studies mately 2% to 18% of cases, with rates tending to increase as the
evaluated PET/CT in light of nodal involvement detection in HNC. disease advances, especially in patients with primary malignancy

A B

C D
Figure 2.3. A 41-year-old male with newly diagnosed laryngeal carcinoma. PET/CT was indicated for staging purposes after suspicion of nodal metastases on
CT. Axial PET (A) and fused PET/CT (B) demonstrate intensely FDG-avid laryngeal mass (SUVmax, 19.5), consistent with the patient’s primary malignancy (black
and white arrows). Intensely avid right cervical lymphadenopathy is also noted involving level II and level III on axial PET (C) and fused coronal PET/CT (D) (black
and white arrows ).
of the hypopharynx and nasopharynx.39 Screening for metastasis ability to detect metastases in patients diagnosed with nasopha-
is, therefore, reserved for patients with locally advanced disease. ryngeal carcinoma. PET/CT was found to be superior to the other
Conventional work up for M staging includes chest radiography, three modalities, especially in comparison to conventional meth-
abdominal ultrasonography, and skeletal scintigraphy.51 The com- ods; the sensitivity, specificity, and accuracy are summarized
bined sensitivity of these conventional techniques in detecting in Table 2.4.53 These findings are supported by several other
metastasis is reported to be 32.8% only.51 In a recent meta-analysis, studies,52,54–56 all reporting a significant discrepancy between the
PET/CT was compared to PET alone and CT alone.51 As expected, sensitivity of PET/CT and conventional techniques in M staging.
PET/CT was found to be superior to either modality alone (CT
or PET). Of additional interest is the finding that 3.0T whole-body
MRI and PET/CT had comparable sensitivities and specificities;
Second Primaries
indicating that 3.0T MRI might aid staging of M disease in the In addition to detecting distant metastasis, PET/CT is also recom-
future.51,52 mended for the detection of second primary tumors that, unlike
18
FDG PET has been shown to be useful in defining perineural metastasis, are typically present in patients with early stage dis-
spread as well as osseous extension of the primary tumor.35 Per- ease.37 Patients with HNC are at an increased risk to develop sec-
haps the role of 18F-FDG PET/CT is strongest when evaluating its ond synchronous tumors in the upper aerodigestive tract because
potential to detect metastatic disease (Fig. 2.4A–F). Chua et al.53 a large majority of patients consume alcohol and nicotine heavily.57
compared conventional work up, CT, PET, and PET/CT in their Evaluating additional foci of FDG uptake with PET/CT allows early

22
Tab le 2 .2
Studies Evaluating the Performance of Fdg Pet/Ct in Comparison to Conventional Methods for T Staging of Primary Tumors in Hnc
PET/CT CT PET MRI

Author Sensitivity Specificity Accuracy Sensitivity Specificity Accuracy Sensitivity Specificity Accuracy Sensitivity Specificity Accuracy
and Year Number (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
Mak 79 — — — 61 100 66 87 63 84 93 63 88
et al., 200439
Dammann 50 — — — 68 69 68 95 92 94 — — —
et al., 200041
Deantonio et al., 167 98 96 97 87 91 86 96 96 98 87 91 88
200744
Roh et al., 70 90 — — 75 — 75 75 — 75 — — —
200645
PET, positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging.
Tab le 2 .3
Studies Evaluating the Performance of Fdg Pet/Ct in Comparison to Conventional Methods for N Staging in Hnc
PET/CT CT PET MRI

and Year Number (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)

Chen 63 96 98.5 — 78 98.5 — — — — — — —
et al.,
200446
Schwartz 23 84 99 96 68 94 89 — — — — — —
et al.,
200747
Nahimas et al., 38 — — — 79 84 73 71 82 73 — — —
200750
Xu et al., 15 100 97 98 57 97 84 — — — — — —
200951
Ng et al., 33 92 90 91 92 15 60 92 65 80 92 — 60
200752
PET, positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging.
A B

C D
E F
Figure 2.4. Axial CT (A) and axial-fused PET/CT (B) of a 56-year-old female with a history of T4 squamous cell carcinoma of the floor of the mouth. FDG PET/
CT was obtained for the purposes of staging. Scan demonstrates intensely FDG avid mass in the anterior floor of the mouth (white arrow ). Intensely FDG-avid
centrally necrotic bilateral cervical lymphadenopathy also noted involving levels I–IV (red arrows). Coronal PET (C) and axial-fused PET/CT (D) show moderate to
intensely FDG-avid omental thickening with scattered foci noted in the lower abdomen and pelvis (black and white arrows). Axial PET (E) and axial-fused PET/CT
scan (F) also demonstrate intensely FDG-avid left common iliac lymph node along with the left para-aortic lymph node (black and white arrows).

24
Tab l e 2.4
Studies Evaluating the Performance of Fdg Pet/Ct in Comparison to Conventional Methods for Initial M Staging in Hnc
PET/CT CT PET CWU

and Year Number (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
Ng et al., 78 83 97 96 66 91 89 83 94 93 33 90 85
200952
Xu et al., 111 81 96 94 — — — — — — 25 98 88
200951
Chua et al., 145 63 95 84 37 95 75 53 93 80 — — —
200853
Senft et al., 149 — — — 55 63 — 85 93 — 20 92 —
200954
Krabbe et al., — — — — — — — 82 97 94 32 96 83
200755

PET, positron emission tomography; CT, computed tomography; CWU, conventional work up (x-ray, skeletal scintigraphy, ultrasound).
Table 2.5 plement the CT/MRI-based delineation; namely, by using 18F-FDG

PET.62 Research regarding the use of PET in radiotherapy planning
Studies Evaluating 18f-Fdg Pet/Ct for the Detection for HNC is still in its early stages, however, there is already evidence
of Secondary Primary Tumors in Hnc that radiation portals and planning target volumes (PTV) may be
more accurately delineated with fusion PET/CT, with PET report-
Author Sensitivity Specificity PPV NPV edly altering decision in approximately one-third of cases.35 Because
and Year Number (%) (%) (%) (%) PET has the capability of distinguishing metabolically active disease
from surrounding tissue, it also has the potential to reduce interob-
Strobel et al., 311 100 96 59 100 server variability in GTV delineation and localize tumors or dis-
201057 eased lymph nodes missed by anatomical imaging.62
Haerle et al., 349 98 93 63 100 IMRT allows for precise targeting and delivery of high-radiation
200758 doses to the primary tumor while minimizing radiation-induced
Harari, 103 83 95 79 96 damage to neighboring tissue.61,63 The introduction of this high-
201159 precision technology created the need for more-precise GTV
PPV, positive predictive value; NPV, negative predictive value. delineation; and there have been several studies in literature that
addressed this need specifically for cancer of the head and neck,
and as such, HNC was one of the first applications of IMRT.61
An important study by Daisne et al.16 examined the differences
detection of second primaries and, consequently, affects the thera- between GTV delineation using PET, CT, and MRI and validated
peutic plan.35 Furthermore, PET/CT offers a whole-body scan, their accuracies by comparing the results of the three imaging
making it an attractive choice to evaluate patients with suspected modalities to surgical specimens. The study recruited 29 patients
metastasis and/or second primary tumors. To date, standard meth- with stage II–IV squamous cell carcinoma of the oropharynx, hypo-
ods to stage second primary tumors of HNC include panendoscopy pharynx, or larynx.16 There were no significant differences between

and radiologic imaging, namely contrast-enhanced CT.58 A large CT-based GTV and MRI-based GTV delineation, whereas GTVs
study of 589 consecutive patients assessed the ability of PET/CT to delineated with 18FDG PET were smaller in average compared to
detect synchronous primaries in the initial work up of patients the other two modalities.16 Interestingly, even though PET-GTVs
with proven head and neck squamous cell carcinoma.57 PET/CT were smaller, they did not completely encompass the areas delin-
detected 84% of the second tumors confirmed pathologically; eated by CT and MRI.16 With respect to surgical specimen, the GTV
which led to a change in therapy in 80% of patients.57 There was a was even smaller than all three modalities, GTV at 18FDG PET
small number of tumors not detected by PET/CT, however, PET/CT being 16.3 cm in comparison to 12.6 cm of the surgical GTV.16 Of
will not replace endoscopy to evaluate small and superficially interest as well, CT, MRI, and PET all overestimated tumor exten-
growing tumors in the aerodigestive tract; the majority of tumors sion and all three modalities failed to detect macroscopic tumor
can be detected by PET/CT to a greater degree than conventional extensions.16 It is important to note, however, that GTV-PET was
imaging.57 the closest imaging-derived GTV to the reference volume assessed
In a similar comparison between PET/CT and panendoscopy, it from the surgical specimen; highlighting PET’s potential role in
was reported that PET/CT had a slightly higher sensitivity to detect radiotherapy planning of HNC.16 Limited spatial resolution of PET,
second primaries; with a sensitivity of 100% and specificity of 93.8%, however, might lead to reduced sensitivity in targeting small
for PET/CT versus 74% and 99.7%, respectively, for panendoscopy.58 lesions not identified by PET. This limitation is overcome by acquir-
The higher specificity of PET/CT was partly because of detecting ing a combined CT and PET imaging (PET/CT).
lesions outside the area of coverage of panendoscopy (Table 2.5). Deantonio et al.44 contoured GTVs on CT, PET, and PET/CT for 22
Early detection of these second primary tumors, as well as accurate HNC patients who were candidates for radiotherapy; the resulting
staging of HNC is paramount for the selection of appropriate treat- volumes were analyzed and compared.44 In concordance with Daisne
ment. Examinations by PET/CT should thus be evaluated with care et al., PET-delineated GTVs were smaller than their CT counterparts,
as their interpretation will dictate patient management. however, PET/CT-GTV were significantly greater than CT-GTV.44
Scarfone et al.64 also reported greater PET/CT-GTVs in comparison
to CT-GTV, presumably because of the PET inclusion of 18FDG active
Radiotherapy Planning regions missed by anatomical CT scanning. As was the case in Daisne
External beam radiation therapy is the most widely used conven- et al., PET-derived volumes and CT-derived volumes did not com-
tional treatment in HNC.59 However, because of the proximity of ana- pletely overlap; 82% of the primary tumor volume defined by PET
tomical structures in the head and neck, conventional radiotherapy was entirely contained in the CT-GTV, whereas only 76% of PET-
targets both malignant and normal tissue, leading to a high proba- derived nodal volume was entirely contained in the nodal CT-GTV.64
bility of healthy tissue loss.59 Nonimage-guided radiation therapy Literature, however, is inconclusive with several other studies report-
further exposes normal tissue to radiation beams as the location of ing smaller PET/CT GTVs compared to CT-GTVs47 and others report-
tumors and landmarks are inferred.60 Image-guided radiotherapy ing larger PET/CT GTVs in comparison to CT-GTVs.65
(IGRT), on the other hand, reduces the size and frequency of geomet- It is important to interpret the above results with caution, how-
ric uncertainty (Fig. 2.1).60 Technical precision, however, is still an ever, since false positives with PET/CT can still pose as a problem
issue and as such, IMRT, which minimizes radiation to healthy tissue, due to 18FDG being a nontumor-specific tracer. Also, the reported
was introduced for the treatment of HNC.59 smaller GTVs might lead to a failure to target macroscopic tumor
Traditionally, clinical target volume selection (CTV) was almost extensions. Conversely, larger GTVs based on PET/CT reported in
exclusively based on anatomic imaging and physical examination of some studies might reduce the possibility of geographic misses,
the primary tumor and affected nodes. Although standard anatomic thereby reducing tumor size more effectively and decreasing the
radiotherapy planning still consists of the use of CT and MRI, it does probability of local recurrence.
have several shortcomings. Interobserver variability in GTV delin-
eation is a source of major concern, possibly caused by the diffi-
Observer Variability
culty in determining the exact boundary of a tumor by using CT.61
This problem with CT scans results in images that poorly differenti- A major source of imprecision in GTV delineation is interobserver
ate between soft tissue structures and tumor extensions. There has variability.66 Riegel et al. assessed interobserver and intermodality
been a growing interest in obtaining biologic information to com- variation analysis in 16 HNC patients. Four physicians contoured

volumes for CT and PET/CT each. As was the case of mixed results level-set technique, and FCM-SW underestimated it.70 Despite
in the studies described above, two physicians delineated PET/CT underestimation, the FCM-SW method was reportedly the most
GTVs greater than CT-GTVs, whereas the other two physicians had accurate technique in delineating the tumor as determined by
fusion volumes smaller than CT volumes.66 Of great importance to comparison to the surgical specimen standard.70
the results of this study is the finding that all four physicians used New tools are continuously being developed because GTV
their own methodology in delineating GTVs, with some physicians delineation will ultimately affect the outcome of radiation therapy.
using contradictory methodology in comparison to the others.66 It Although the results of the above studies have shed some light on
is possible that some physicians do not know how to proceed when the methodologies for PET-based delineation, experience with
CT delineation is significantly different from delineation derived implementing these tools in the research field is necessary before
from PET; there is no consensus as to which modality should be definitive conclusions can be made.
given more weight.66 These findings highlight the importance of
developing standard methodology to reduce observer variability. In
a follow-up study, the four physicians were given a tutorial of PET/
Positioning
CT coregistered imaging and were asked to re-contour the images PET/CT radiotherapy planning images must first be co-registered
of the same 16 patients recruited for the previous study.67 Interob- with the treatment-planning CT. In order to reliably register the
server variability was significantly reduced, albeit not eliminated; PET/CT to the CT image, it is preferable to perform the PET/CT
nonetheless, marked improvement between the four observers scan in the treatment position; however, doing so is problematic
was reported.67 A similar study examined interobserver variability and might cause a financial burden on the patient if they have to
between eight physicians across the same three modalities—PET, acquire another PET/CT for diagnostic/staging purposes as well.
CT, and fused PET/CT.68 The authors reported a large range of Ireland et al.73 recruited five patients with HNC, all patients under-
volume as well as substantial variation between observers on all went PET/CT in addition to conventional x-ray CT for radiother-
three modalities.68 Furthermore, mean CT volumes were larger apy treatment planning. The authors reported that nonrigid
than PET/CT volumes68; once again demonstrating the inconsisten- registration in the diagnostic position PET/CT resulted in a more
cies in the literature. Interestingly, the lowest interobserver reli- accurate match to the planning CT, compared to rigid registration
ability was found with contouring using PET/CT; contrary to the in the treatment position PET/CT.73 Furthermore, the nonrigid
perception that tumor delineation with PET/CT would be more algorithm reduced the registration error significantly compared to
accurate and more consistent across physicians.68 This finding rigid registration PET/CT of the treatment position.73 Despite the
might be because of the lack of familiarity of the physicians with relatively small sample size, the study demonstrates quantitative
PET/CT delineation, due to the relatively recent introduction of evidence that nonrigid, diagnostic-position PET/CT registration is
fused PET/CT in oncology.68 Evidently, it is of utmost importance to more accurate than a rigid transformation for radiotherapy plan-
develop standardized methods in PET/CT delineation in order to ning. It is thus possible for some patients to undergo a single PET/
obtain the maximum potential of PET/CT. CT session for both staging and radiotherapy planning purposes.73
A similar study evaluated the accuracy of both diagnostic-
position PET/CT and stand-alone PET for radiotherapy treatment
Segmentation planning.74 The study included image data for 12 patients with HNC
Another reason for the varied PET-derived GTVs is segmentation. treated with external beam radiotherapy who underwent both
Due to PET’s low spatial resolution, identifying tumor borders using diagnostic PET/CT scans and treatment CT scans.74 Registration
PET in many cases creates an indistinct visual of the tumor.69 As accuracy was reported to be better for PET/CT than PET alone;
such, various methods have been developed for PET-GTV delinea- with manual registration yielding better results than rigid registra-
tion; the most common being visual interpretation.69 The study tion.74 However, registration errors with PET/CT can be greater
compared five segmentation tools for 18FDG PET-GTV relative to than 5 mm, going up to 17 mm, when acquiring the scan in the
CT-based GTV delineation.69 77 patients with stage II–IV HNC were nontreatment position, a finding which renders the utility of PET/
recruited for the study, all of whom underwent scans in both modal- CT GTV delineation questionable in the head and neck region.74
ities.69 The five PET segmentation tools were visual interpretation, Because of the changes in patient placement from diagnostic to
40% and 50% of the maximum tumor signal intensity, fixed SUV of treatment position affecting the accuracy of registration, the authors
2.5, and the signal-to-background ratio method).69 Three key find- concluded that PET/CT acquired in the treatment-planning position
ings were highlighted by the authors. First, GTV-SUV of 2.5 failed is the optimal method to minimize registration errors.74
to provide successful delineation in 35/77 patients.69 This finding
might have partly been due to the substantial amount of back-
ground activity in the head and neck, resulting in poor differentia-
Adaptive Radiotherapy Planning
tion of the boundaries between tumor FDG uptake and muscle Metabolic activity might be indicative of tumor cell density; there-
metabolic uptake.69 Second, each segmentation tool resulted in fore, monitoring changes in 18FDG uptake during treatment might
marked differences on the PET-GTV.69 Third, greater than 20% of aid in decision making, namely in escalating treatment dose if
the PET-GTV were outside the CT-GTV domain in the majority of required. Only two studies to date addressed the possibility of
cases, regardless of the segmentation tool utilized.69 adapting treatment dose as per changes in PET/CT results taken at
A more recent study assessed the performance of nine baseline and again during therapy.75 Ten patients with pharyngo-
PET image-segmentation techniques in patients with pharyngolaryngeal cancer treated with chemoradiation underwent CT,
laryngeal squamous cell carcinoma; these included five thresh- T2-MRI, and 18FDG PET scans.75 As expected, the mean primary
olding methods, level-set technique (active contour), stochastic tumor GTVs decreased significantly during the course of treat-
expectation-maximization approach, fuzzy clustering-based segment, with reductions ranging from 54% to 74% compared to pre-
mentation (FCM), and spatial wavelet-based algorithm (FCM-SW).70 treatment GTVs.75 Furthermore, PET-based adaptive planning
The discussion of the technical aspects of these PET delineation reduced the irradiated volumes by 15% to 40% compared to pre-
tools is beyond the scope of this chapter, however, for recent treatment planning CT.75 These results were not replicated by a
reviews, see Zaidi and El Naqa71 and Thorwarth et al.72 The seg- second study which reported an increase in median values of GTV-
mentation results were compared to the 3D biologic tumor volume PET over the course of treatment (Table 2.6).76 More research is
defined by histology.70 Four of the thresholding methods and warranted to replicate these results and subsequent studies should
the expectation-maximization overestimated the average tumor evaluate the efficacy of adaptive radiotherapy on several end
volume whereas the contrast-oriented thresholding method, the points such as overall survival and progression-free survival. Some

Ta b l e 2 . 6
Results Summary of Two Studies Utilizing Serial 18f-Fdg Pet/Ct for Adaptive
Radiotherapy Planning
Average PET-GTV
Author and Year Number Baseline First/Second Wk Third/Fourth Wk Fifth/Sixth Wk Seventh Wk
Hwang et al., 200774 8 25.4 ± 5.4 18.7 ± 5.4 14.9 ± 5.5 12.9 ± 4.5 11.8 ± 3.8
Geets et al., 200975 27 9.3 12.4 14 17.9 —
PET, positron emission tomography; GTV, gross tumor volume.
studies have reported that maximum SUV of the primary tumor activity masking the metabolic activity of a residual mass; there-
was not predictive of risk of disease recurrence and as such, meta- fore, it is recommended to wait at least 8 to 12 weeks before
bolically active areas on 18FDG PET might not provide just cause obtaining a posttreatment PET/CT scan (Fig. 2.5A,B).
for escalating or reducing radiation dose during therapy.77,78
Adjusting radiation dose and GTV delineation through repetitive 18
PET/CT imaging is a promising approach that would ultimately
FDG PET/CT Postsurgery
result in less damage to normal tissue and possibly improved prog- Postoperative tissue changes cause difficulties in interpreting clin-
nosis. It is important to note, however, that 18FDG might not be the ical and anatomic test results; consequently, malignant activity in
most suitable tracer for adaptive radiotherapy as it is not tumor HNC patients treated with surgical resection must be evaluated on

specific. This is especially an issue, during and after radiotherapy, a metabolic basis. Shintani et al.82 evaluated the utility of 18FDG
where inflammatory processes might hinder accurate differentia- PET/CT in HNC patients early after surgery and before beginning
tion between normal and malignant tissue 18FDG uptake. Future adjuvant radiotherapy; PET/CT results were compared to biopsy
studies should thus also focus on evaluating the efficacy of tumor- findings. Only 45.8% of biopsies positive for cancer were correctly
specific tracers. identified by PET/CT; with PET/CT changing postoperative adju-
vant treatment plan in 15.4% of patients.82 Despite this low PPV,
Assessment of Treatment Response PET/CT scans have the potential of changing patient management
Evaluating the head and neck that has been exposed to chemora- and sparing them overly aggressive treatment as well as reducing
diation is challenging becasue of the loss of normal fat planes and toxicity; as such, the value of PET/CT for adjuvant treatment plan-
distortion of normal structures.35 This problem renders anatomic ning needs to be studied further.
imaging difficult to interpret and as such, 18FDG PET has been
18
proposed as a solution for imaging the posttherapy neck. FDG PET/CT During Treatment
18 Brun and colleagues examined whether the metabolic rate (MR –
FDG PET/CT Postneoadjuvant Therapy calculated from multiplying blood glucose with tissue concentration
Martin et al.79 evaluated the accuracy of PET in assessing 78 HNC of 18FDG in a region at the time, and dividing the product over the
patients treated with primary chemoradiotherapy. Each patient lumped constant set to 1 and assumed constant over time and
underwent a pretreatment scan, a posttreatment scan after 12 weeks plasma 18FDG concentration as a function of time and the 18FDG
of completing treatment, and was followed up for a minimum of six SUV could predict therapy outcome after only one cycle of chemo-
months.79 In comparison to clinical examination and CT scans, PET therapy.83 Low MR values of the primary tumor were found to be
demonstrated higher accuracy in predicting complete response significantly correlated with complete remission, locoregional con-
(92%), with a reported NPV of 95%.79 There were only three false trol, and survival; with estimated overall survival measuring at 72%
positives from PET, two of which were caused by inflammatory pro- for low MR and 35% for high MR of the primary tumor.83 Analysis
cesses.79 However, PET’s inability to distinguish between inflamma- of MR of the primary tumor accurately predicted complete remis-
tion and residual tumor led to a relatively low PPV of 82%.79 sion in 23/24 patients, whereas only 13 of 21 patients with a high
Similar results were reported by Moeller et al.80 Patients with MR achieved complete remission.83 Interestingly, SUV reportedly
locally advanced cancer of the oropharynx, larynx, or hypopharynx had a poorer association with survival, indicating that, contrary to
underwent PET/CT and contrast-enhanced CT imaging 6 to 8 weeks popular belief, MR might be of greater prognostic value than SUV.83
after completion of neoadjuvant treatment; imaging responses were The scientific community is still unclear about the optimal tim-
correlated with clinical and pathologic response. Baseline SUV mea- ing to perform an interim PET/CT scan; and despite these promis-
sures did not reveal any significant differences between responders ing findings, the results must be interpreted with caution because
and nonresponders; however, postradiation SUV values were higher of the small sample size.83 However, there is a general consensus
in nonresponders compared to responders for both primary tumor that predicting response to treatment as early as possible is more
and nodes.80 As in Martin et al., the PPV of PET/CT was relatively beneficial than waiting to obtain a scan after completion of therapy
low, whereas the NPV was very high. Although PET/CT did outper- as the ultimate goal of therapy monitoring is modification of inef-
form contrast-enhanced CT, the differences were not significant.80 fective treatments. Much more data is needed before conclusions
The findings from this and other similar studies are summarized in can be made regarding the utility of interim PET/CT in HNC.
Tables 2.7 and 2.8.
Timing of the PET/CT might also play a role in the effectiveness
of 18FDG uptake to predict treatment response. Obtaining a PET/
Restaging, Recurrence, and Surveillance
CT scan soon after completion of therapy (i.e., 4 to 8 weeks) Despite aggressive therapy with curative intent, recurrence rate
results in higher false-positive rates compared to obtaining the remains relatively high in HNC, especially within the first 2 years
scan at 8 weeks post chemoradiotherapy.81 Increase in 18FDG after treatment (Fig. 2.6A,B).84 Second tumors are highly prevalent
uptake from inflammatory processes following treatment might in HNC and improved lesion localization can be achieved
also result in false negatives because of the elevated background by the combination of PET and CT.35 Detecting residual disease

Table 2.7
Diagnostic Accuracy of Fdg Pet/Ct for Detecting Primary Residual Tumor in Hnc After Definitive Crt
PET/CT CT
Sensitivity Specificity Accuracy Sensitivity Specificity Accuracy
Author and Year Number (%) (%) (%) PPV (%) NPV (%) (%) (%) (%) PPV (%) NPV (%)
Martin et al., 98 70 93 — 58 96 80 89 — 50 97
200979
Moeller et al., 31 83 54 — 31 92 — — — — —
200980
Andrade et al., 200981 80 88 88 — 44 98 — — — — —
Shintani et al., 28 76 93 85 90 82 92 46 67 60 87
200682
Brun et al., 201183 39 91 65 79 — — 86 41 67 — —
Deantonio et al., 63 91 87 89 88 90 76 83 79 83 76
200744
PET/CT MRI
Sensitivity Specificity Accuracy PPV Sensitivity Specificity Accuracy
Author and Year Number (%) (%) (%) (%) NPV (%) (%) (%) (%) PPV (%) NPV (%)
Krabbe et al., 200884 63 82 89 86 85 86 96 89 92 87 97

Anzai et al., 200385 67 100 93 96 88 10% 62 44 49 33 71
Fakhry et al., 200686 34 96 83 91 91 91 96 75 88 88 90
Brun et al., 201183 39 91 65 79 — — 86 41 67 — —
PET, positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging; PPV, positive predictive value; NPV, negative predictive value.
and/or recurrence by conventional methods, however, is challeng- Anzai et al.85 18FDG PET yielded a sensitivity and specificity of 88%
ing because of the structural tissue distortion induced by therapy.35 and 100%, respectively in comparison to 25% and 75%, respec-
As is the case in monitoring treatment response, PET/CT has the tively, for MRI or CT.85 More recently, Krabbe et al.84 evaluated the
ability to distinguish between malignant tissue and postoperative role of 18FDG PET to detect recurrence in patients with advanced
tissue changes. One of the first prospective studies to evaluate squamous cell carcinoma of the oral cavity. Sensitivity and NPVs
the diagnostic accuracy of 18FDG PET in comparison to conventional were high; however, because of a substantial number of false pos-
imaging for the detection of recurrence in HNC was conducted by itives, specificity and PPV were found to be low (Table 2.9). When
Table 2.8
Diagnostic Accuracy of Fdg Pet for Detecting Lymph Node Metastasis in Hnc After Definitive Crt
PET/CT CT
Shinagl et al., 78 82 95 92 82 95 67 66 66 29 91
200878
Martin et al., 200979 98 75 76 — 27 96 87 65 — 23 97
Kao et al., 200887 65 71 89 88 38 97 — — — — —
Moeller et al., 31 75 94 — 75 94 — — — — —
200980
Andrade et al., 80 100 97 — 65 100 — — — — —
200981
Gandhi et al., 48 25 83 76 15 90 57 76 74 22 94
200788
Brun et al., 201183 39 89 95 91 — — 76 74 75 — —
PET/CT MRI
Krabbe et al., 63 95 98 97 95 98 91 91 91 83 95
200884
Yen et al., 200389 23 — 74 — — — — 85 — — —
Brun et al., 201183 39 89 95 91 — — 76 74 75 — —
PET, positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging; PPV, positive predictive value; NPV, negative predictive value.


Figure 2.5. A 45-year-old male with a his-
tory of nasopharyngeal carcinoma, now status
postchemoradiation therapy. FDG PET/CT scan
(A, top) demonstrates interval resolution of
intense FDG uptake noted within the right
fossa of Rosenmuller/nasopharyngeal area,
as noted previously in the staging PET/CT scan
(A, bottom). Staging PET/CT shows intensely
FDG-avid lymphadenopathy involving the left
retropharyngeal, left intraparotid, right level II
and III cervical regions (B, bottom, white
arrow ). Posttherapy scan demonstrates inter-
val resolution of FDG uptake noted within the
right level II/III cervical lymph node with resid-
ual non-FDG–avid lymph node within the right
level II (B, top). Overall, the pattern is consis-
tent with complete metabolic response to
A B
interval therapy.
A B
Figure 2.6. Axial CT (A) and axial-fused PET/CT (B) of an 89-year-old female with a history of squamous cell carcinoma involving the tongue. The patient com-
pleted chemoradiotherapy and the FDG PET/CT was obtained for the purpose of assessing clinical suspicion of recurrence. Scan demonstrates intense FDG uptake
within the base of the mouth (white arrow), highly suggestive of recurrence.

30
Tabl e 2.9
Studies Evaluating the Performance of Fdg Pet/Ct in Detecting Recurrence in Hnc
Primary Tumor Nodal Involvement Distant Metastasis

Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity
Author and Year Number Diagnosis (%) (%) PPV (%) NPV (%) (%) (%) PPV (%) NPV (%) (%) (%) PPV (%) NPV (%)
Brun et al., 200983 48 SCC of the 100 84 42 100 100 95% 50% 100 94 92 60 99
oral cavity or
oropharynx
Anzai et al., 200785 32 HNSCC 94 57 74 89 — — — — — — — —
Fakhry et al., 200186 36 Nasopharyngeal 100 96 — — — — — — — — — —
Yen et al., 200989 91 HNSCC 100 85 77 100 — — — — — — — —
Abgral et al., 200790 49 HNC 84 95 97 79 — — — — — — — —
Yao et al., 200991 64 HNSCC — — — — — — — — 86 84 60 95
Gandhi et al., 200388 67 Nasopharyngeal 100 93 87 100 — — — — — — — —
Murphy et al., 200592 47 HNC 95 60 90 — — — — — — — — —
Kao et al., 200587 29 HNC 100 58 77 100 — — — — — — — —

PPV, positive predictive value; NPV, negative predictive value.
comparing PET/CT to PET alone, fusion imaging was reported to to the other using the same bed.97 Although accurate positioning is
have higher specificity and positive and NPVs, with equivalent sen- possible, this system, however, utilizes sequential scanning and as
sitivity measures.86 Overall, PET/CT was more accurate than PET a result, is time consuming.97 This prototype being evaluated in
alone for the detection of recurrence and led to avoidance of Geneva and New York as of April 2010.97 Another prototype, avail-
unnecessary invasive procedures in 57% of patients in comparison able in Germany, obtains PET and MR images simultaneously by
to 35% for PET.86 18FDG PET was also found to be superior to CT using a removable brain PET-detector that can be placed in the MR
and technetium-99m tetrofosmin single photon emission com- gantry of a modified 3.0 T MRI scanner.98,99 Excellent image quality,
puted tomography (SPECT),87 CT/MRI,88 and MRI89 for the detec- detailed resolution, and image contrast were reported by the
tion of recurrent HNC. authors, with no artifacts or interference by either MR or PET.98,99
With respect to follow-up, the National Comprehensive Cancer However, the PET insert offers a very small field of view, limiting
Network has recommended that a posttreatment 18FDG PET/CT registration to brain structures and the nasopharynx while omit-
be performed a minimum of 12 weeks after completion of chemo- ting the possibility of imaging laryngeal, hypopharyngeal, and
radiation/radiation therapy. Follow-up PET/CT has also been oropharyngeal carcinomas.98,99 Whole-body imaging is still possi-
shown to be useful in detecting recurrence during posttreatment ble and the first simultaneous whole-body hybrid PET/MRI scan-
surveillance when clinical follow-up examinations are negative.90 ner was recently installed at the Technische Universitat Munchen
In fact, Abgral et al. reported that 33% of the recurrences identi- in Germany, allowing scientists to begin studying whether PET/
fied by PET/CT were missed on conventional follow-up.90 The MRI will indeed offer a clear advantage over PET/CT in oncology.97
prognostic value of posttreatment PET/CT has also been evalu- Because of the proximity of anatomic structures in the head
ated. Patients with a negative PET/CT scan have significantly bet- and neck region, hybrid PET/MRI might be favored over PET/CT
ter overall survival and disease-free survival in comparison to for T staging since the tumor border can be much more clearly
patients with positive scans; 57% versus 73% and 70% versus defined in MR images.100 PET/MRI for N staging, on the other
42%, respectively.91 It is important to note, however, that although hand, does not seem to offer a clear advantage over PET/CT, with
a negative posttreatment PET/CT scan is highly predictive of com- studies reporting similar accuracy in detecting lymph node

plete response, false-positive PET/CT findings are highly frequent involvement.100 Furthermore, as is the case with PET/CT, a large
and subsequently render the PPV of questionable worth. number of patients will be understaged with PET/MRI and as
The use of more quantitative parameters, namely, metabolic such, the new hybrid system will not likely replace staging by neck
tumor volume (MTV), has been shown to be a better predictor of dissection.100 There is not yet sufficient literature to quantify PET/
outcome compared to SUV measures. Murphy et al.92 found that MRI’s utility in M staging, however, PET/MRI will most likely be
response to treatment, as measured by posttreatment MTV, was preferred over PET/CT in areas of the body where MR offers supe-
more predictive of overall survival and disease-free survival than rior soft tissue contrast in comparison to CT.
initial tumor burden, as measured by pretreatment MTV. Similar A recent study reported that PET/MRI fusion might offer a lim-
results were reported in other studies and, interestingly, SUV ited advantage over PET/CT for staging new cases of HNC since
measures did not show any correlation with disease outcomes.93–95 abnormalities can easily be detected by anatomic imaging because
However, tumor burden measured as a metabolic index (combina- of the clear asymmetry of abnormal structures.101 The advan-
tion of SUV and MTV) was reported to be a better predictor of tages of PET/MRI, however, are apparent in posttreatment and/or
long-term survival than MTV and SUV alone.96 postoperative patients in whom normal anatomical structures lost
their symmetry caused by treatment.101 In such cases, asymmetry
alone is no longer indicative of malignancy. PET/MRI can clearly
delineate tumor borders and differentiate between residual mass
Future Direction and scar tissue.101 Manual registration, however, was used for this
study. Another group of scientists, on the other hand, successfully
PET/MRI established an MR protocol for the neck using a whole-body MR
Although PET/CT in clinical oncology is the most advanced and Dixon sequence, which can be used for attenuation correction on
well-established multimodality system available to date, there has the hybrid PET/MRI scanner.102
been increasing interest in developing PET/MRI scanners.97 MRI In summary, MR offers clear advantages over CT imaging such
offers superior soft tissue contrast in comparison to CT, especially as superior soft tissue contrast, tumor delineation, and reduced
in the head and neck area, and its combination with functional metallic artifacts. Studies of the technical feasibility of hybrid PET/
PET imaging might offer promising advances in the management MRI scanners are still ongoing, and the clinical application of these
of HNC. Generally speaking, there are currently two methods to systems has only been recently introduced in the field of oncology.
combine PET and MR images; sequential and simultaneous.97 Once technical limitations are overcome, research can begin to
Sequential image fusion consists of retrospectively combining PET focus on the different combinations of MRI parameters and PET
and MR images that were obtained from two different devices at radiotracers, with the possibility of creating specific parameter/
different times.97 Using a process termed “image registration”, radiotracer combinations relevant to each type of cancer.
certain software are capable of aligning the data sets from PET
and MR so that both images correspond to the same anatomic
location; this can either be done manually by visual assessment
Newer Non-18FDG Radiotracers
using landmarks or fully automatically.97 Retrospective image reg- As mentioned previously, 18F-FDG is not a tumor-specific tracer and
istration, however, is time-consuming and may lead to inaccurate it can accumulate in normal tissue because of other processes such
fusion caused by motion artifacts.97 The latter limitation might not as inflammation. Tumor cells, in addition to increased glucose
pose as big a problem in the head and neck region as the head can metabolism, display abnormal characteristics that may be quantified
be secured to prevent movement; as such, fused images can be by non-FDG PET tracers. New radiotracers are continuously being
aligned with greater accuracy than dual images obtained from synthesized and tested to target hypoxia and proliferation.
different sites of the body (e.g., gastrointestinal tract).97 1-11C acetate has been utilized to measure anabolic metabolism
Simultaneous image fusion involves the use of hardware-based of malignant tissue as hypoxia has been associated with a more
hybrid PET/MRI systems.97 This application is technically difficult aggressive cancer phenotype and its quantification may aid in
as MRI may interfere with the image quality of PET and vice versa. appropriate treatment selection.103 Sun et al.104 demonstrated,
Interference can be avoided by hybrid scanners that separate PET in vivo, the change from oxidative metabolism to aerobic glycolysis
and MRI in the same room and rotating the patient from one scanner in tumor cells during radiotherapy. This switch was much more

significantly pronounced in patients with partial response in com- equivocal conventional imaging as well as patients who demon-
parison to those with complete response; the former group also strate increased 18FDG uptake because of posttherapeutic inflam-
had reportedly poorer outcomes.104 The authors concluded that mation. GTV delineation by 11C-methionine (MET)-PET was shown
poor oxygenation leads to radioresistance and local failure, which to be similar to results obtained from CT, and different from the
may be reversed if detected early during the course of treatment.104 contours defined by 18FDG PET GTV delineation119; there is insuf-
In addition to measuring hypoxia, 11C-acetate may aid in the detec- ficient evidence, however, to determine whether 18FDG-defined
tion of well-differentiated tumors as well as delineation for radio- GTV results reliably in improved overall survival over MET-PET–
therapy planning. Few studies have examined this role of defined GTV.
11
C-acetate in HNC with one study reporting promising results. Ten It is clear that the PET tracers other than 18FDG have the
newly diagnosed patients with pathologically confirmed HNC were potential to overcome some of the limitations of 18FDG PET scan-
recruited for the study, with each subject receiving both 18FDG PET ning, with the most promised evidence in adaptive radiotherapy
and 11C-acetate PET (ACE-PET).105 ACE-PET detected 100% of pri- planning and dose painting. For additional discussion of non-
mary tumors, whereas 18FDG PET detected only 90%.105 Further- 18
FDG tracers, the reader is referred to Heuveling et al. (2011).120
more, 95% of LNF was detected by ACE-PET with only one false
negative, in comparison to 62% detection rate of 18FDG PET with
eight false negatives.105 Despite the small number of patients, the Conclusion
results imply that ACE-PET may be more sensitive than FDG PET
for the detection of primary tumors and LNF.105 These results, Because of the introduction of PET/CT in clinical oncology over
however, must be interpreted with caution as choline uptake may two decades ago, evidence has been accumulating regarding the
be altered by hypoxia. In addition to differences between ACE and advantages of PET/CT over conventional imaging in the head and
18
FDG in staging, GTV delineation by ACE-PET was 51% larger neck region. These benefits have been reported to a great degree
than the volumes delineated by 18FDG PET; however, it is not yet in the settings of radiation therapy planning and recurrence
clear whether the results indicate poor GTV delineation by 18FDG, detection, as well as in staging and treatment response evaluation.
and if the extra 51% delineated by ACE-PET should receive a dif- With ongoing research on multimodality imaging (such as PET/
ferent dose regimen.105 More studies are needed to evaluate the MRI) and non-18FDG tracers, the use of PET in HNC will likely gain
role of ACE-PET relative to 18FDG PET in HNC. more popularity as technical improvements are made which allow
Another more commonly used tracer to image hypoxia is for patient-tailored imaging and disease management.
18
F-fluoromisonidazole (FMISO). FMISO has been studied to a
greater extent than 11C-acetate and results also imply good poten-
tial for imaging in HNC. 18FMISO-PET was reported to be a stronger
predictor of survival in comparison to 18FDG PET; with possible
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93. La T, Filion EJ, Turnbull BB, et al. Metabolic tumor volume predicts for recur- ferential diagnosis of head and neck tumors: Comparison with 18F-FDG PET.
rence and death in head and neck cancer. Int J Radiat Oncol Biol Phys Physics. Ann Nucl Med 2004;18(5):409–417.
2009;74(5):1335–1341. 112. Ito K, Yokoyama J, Kubota K, et al. Comparison of 18F-FDG and 11C-choline
94. Chung MK, Jeong HS, Park SG, et al. Metabolic tumor volume of 18F-FDG PET/ PET/CT for detecting recurrences in patients with nonsquamous cell head and
CT predicts short-term outcome to radiotherapy with or without chemother- neck malignancies. Nucl Med Commun. 2010;31:931–937.
apy in pharyngeal cancer. Clin Cancer Res. 2009;15(18):5861–5868. 113. Ito K, Yokoyama J, Kubota K, et al. 18F-FDG versus 11C-choline PET/CT for
95. Kim G, Kim YS, Han EJ, et al. FDG PET/CT as a prognostic factor and surveil- the imaging of advanced head and neck cancer after combined intra-arterial
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96. Xie P, Yue JB, Zhao H, et al. Prognostic value of 18F-FDG PET/CT metabolic 1327.
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97. Loeffelbein DJ, Souvatzoglou M, Wankerl V, et al. PET-MRI fusion in head-and- FDG-PET in the evaluation of response to cetuximab and radiation therapy
neck oncology: Current status and implications for hybrid PET/MRI. J Oral in advanced head and neck malignancies. J Nucl Med Radiat Ther. 2012;
Maxillofac Surg. 2012;70:473–483. 3(1):1–6.
98. Boss A, Stegger L, Bisdas S, et al. Feasibility of simultaneous PET/MR imaging 115. Troost E, Bussink J, Hoffmann AL, et al. 18F-FLT PET/CT for early response
in the head and upper neck area. Eur Radiol. 2011;21:1439–1446. monitoring and dose escalation in oropharyngeal tumors. J Nucl Med. 2010;
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100. Buchbender C, Heusner TA, Lauenstein TC, et al. Oncologic PET/MRI, part 1: between reactive and metastatic lymph nodes in primary head and neck can-
Tumors of the brain, head and neck, chest, abdomen, and pelvis. J Nucl Med. cer patients. J Nucl Med. 2010;48:726–735.
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101. Nakamoto Y, Tamai K, Saga T, et al. Clinical value of image fusion from MR FDG PET and CT in patients with head and neck cancer. J Nucl Med. 2006;
and PET in patients with head and neck cancer. Mol Imaging Biol. 2009;11: 47:256–261.
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104. Sun A, Johansson S, Turesson I, et al. Imaging tumor perfusion and oxidative 120. Heuveling D, de Bree R, van Dongen GA. The potential role of non-FDG-PET in
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C h apt e r 3
Thyroid Carcinoma
Cumali Aktolun • Umut Elboga • Muammer Urhan
Introduction roduced in the follicular cells. Increasing serum Tg after thy-

p
roidectomy and radioactive iodine ablation in a patient with dif-
Thyroid cancer, the most common endocrine malignancy, accounts ferentiated thyroid cancer suggests the development of
for approximately 1% to 3% of all human malignancies, and its recurrence and/or metastasis. Hence, Tg is a valuable clinical
incidence has been increasing in the past three decades.1 Although tool as a tumor biomarker and it is commonly used in the follow-
differentiated thyroid cancers are generally slow growing tumors up and management of the patients with follicular and papillary
with a 10-year survival of 85%, metastatic spread, especially metas- thyroid cancers (PTC).
tasis to regional lymph nodes is seen in approximately 20% of The production and secretion of thyroid hormones is modu-
patients in the first 10 years following initial diagnosis. In approxi- lated by thyroid stimulating hormone (TSH), a two-polypeptide
mately 5% of patients, the tumor develops aggressive behavior and glycoprotein chain (α and β). It is secreted by the anterior pituitary
does not respond to radioiodine therapy; these patients die from and controlled positively by thyrotropin-releasing hormone (TRH)
this disease, accounting for 0.5% of all cancer deaths. which is produced in the hypothalamus and controlled negatively
In the fetal period, thyroid cells may fail to complete the emi- by thyroid hormones. The β-subunit confers the major biologic
gration process, and are trapped at various sites between the and immunologic function of TSH. The TSH receptor is located on
base of the tongue and the anterior mediastinum causing thyroid base of the follicular cells. The colloid lined with a single layer of
ectopia.2 These sites may also develop thyroid cancer. Therefore, thyrocytes containing thyroid hormones and Tg is taken back into

ectopic thyroid neoplasm may theoretically arise at any site in the follicular cells from the pool by endocytosis through the apical
mouth, neck, or mediastinum. margin of the follicular cells. Inside the cytoplasm, colloid droplets
The lymphatics of the thyroid usually follows the branches of fuse with intracellular lysosomes containing proteolytic and deio-
the superior and inferior thyroid arteries and drain into the deep dinase (dehalogenase) enzymes. T4 and T3 are subsequently
and superficial lymphatic chains of the neck. Cervical lymph nodes released into the circulation and then they are transported by the
located at levels IV, V, and VI are most likely invaded by thyroid serum proteins such as thyroxin-binding globulin (TBG), trans-
cancer, but lymph nodes located below or above these levels can thyretin, and pre-albumin. Serum T3 is 99.7% protein bound and
also be involved in metastatic spread. 0.3% is free whereas only 0.03% of T4 is free. T4 and T3 are metab-
olized (deiodination) with a specific enzyme “5’-deiodinase” which
is found in the liver, kidney, muscle, white blood cells, brain, and
Thyroid Physiology pituitary. The liver can be visualized on post-therapy scans in
patients with thyroid cancer because of metabolism of iodine
There are two groups of hormone-producing cells within the thy- incorporated in the thyroid hormone in the liver through conjuga-
roid gland; follicular cells called thyrocytes that secrete triiodothy- tion with glucuronide or sulfate, deamination, and decarboxyl-
ronine (T3) and thyroxine (T4); parafollicular cells called C cells ation of the amino terminal of the molecule.
that produce calcitonin. Although both groups of hormones are Calcitonin, a 32-amino acid peptide, is produced and secreted
secreted from the thyroid gland, traditionally, only the hormones by parafollicular C cells that are scattered among the thyroid fol-
(T3 and T4) produced by thyrocytes are called “thyroid hormones.” licular cells. Increased serum calcitonin after thyroidectomy in a
The principle units of thyroid gland secreting T3 and T4 are the patient with medullary thyroid cancer (MTC) suggests recurrence
follicles: small pools of colliod lined with a single layer of thyro- or metastasis. Thus calcitonin is a unique tumor biomarker in
cytes (follicular cells). these patients.
Iodine is an essential component of thyroid hormones. Iodide,
as iodide ion rapidly absorbed in the upper gastrointestinal tract
and enters the circulation. The main route of iodine excretion is Thyroid Cancer Pathology
the kidney; and only about one-fifth of the circulating iodine is
taken up by the thyroid gland. The first step of thyroid hormone Thyroid cancer is a group of tumors with different histologic and
production is the trapping of the iodine by follicular cells of the biologic features. The majority of thyroid cancers originate from
thyroid gland. Iodine is transported against an electrochemical follicular cells (papillary, follicular, Hürthle cell, and anaplastic car-
gradient by a protein transporter system called the sodium–iodide cinomas), parafollicular C cells (medullary carcinoma) and to a
symporter (NIS) located on the basolateral membrane of the fol- lesser extent, from the connective and lymphoid tissues of the thy-
licular cells. The NIS gene is encoded on chromosome IX and is roid (sarcoma, lymphoma, and germ cell tumor). Of these cancers,
also expressed in non-thyroidal organs including salivary glands, about 85% are differentiated thyroid cancers (DTC) (papillary and
stomach, kidney, placenta, and thymus accounting for the uptake follicular thyroid cancers), of which 90% is papillary. Based on
of radioactive iodine in extrathyroideal tissues. histo pathologic features of PTC, several variants and subtypes
When iodine is trapped by the follicular cells, it is enzymati- have been recognized including classic type, follicular variant,
cally linked to the amino acid tyrosine in the presence of thyroid mixed type, and tall cell, diffuse sclerosing, and columnar variants.
peroxidase (thyroperoxidase or TPO), hydrogen peroxide, and The last three variants (tall cell, diffuse sclerosing, and columnar
thyroglobulin (Tg). TPO catalyzes the iodination of tyrosine-pro- variants) require special clinical attention because they are associ-
ducing monoiodotyrosine (MIT) and diiodotyrosine (DIT) (the ated with lack of or diminished uptake of 131I or other radioiso-
process is also called organification of iodine). Two molecules of topes of iodine and tend to develop aggressive clinical behavior
DIT are coupled to produce T4; one molecule of DIT and MIT resulting in less favorable response to 131I therapy and also more
produce T3. Iodine as a component of the thyroid hormones as frequent local recurrence and metastasis. The simultaneous pres-
well as non-hormonal compounds (e.g., reverse T3, MIT, and DIT) ence of two tumors of different cellular origins such as papillary
is bound by Tg and stored within the colloid for about 100 days. carcinoma and medullary carcinoma in the thyroid gland in a sin-
Tg, one of the largest biologic molecules (660K daltons), is gle patient can be seen. This rare, interesting condition is called
35

“collision tumor” and requires treatment of both tumors with dif- cancers, radionuclide imaging, except for general use of thyroid
ferent modalities and protocols. scintigraphy, has limited role for the initial diagnosis of the primary
Genetic alterations in thyroid cancers, particularly the BRAF tumor in patients with thyroid cancer. Imaging techniques have
(V600E) mutation has recently attracted interest as a link between been refined to find the optimal protocols for therapy. Currently,
genetic mutations and the clinical and pathologic features of these almost all of radionuclide techniques used in thyroid cancer are
tumors has been discovered. Nevertheless, there have been no thus treatment-related procedures including detection of metasta-
studies that resulted in modification of current therapeutic protocol. ses before or after therapy, prognostication, ablation of residual
thyroid tissue, therapy of metastatic disease, and assessment of
response to therapy.
Clinicopathologic Features
PTC tends to metastasize to regional lymph nodes but axillary,
pulmonary, and disseminated distant metastases are also seen.3 Radiopharmaceuticals used for
In about 45% of PTC, the tumor is multifocal. Regional spread to
the cervical and mediastinal lymph nodes is a common feature
Thyroid Cancer Management
at initial diagnosis. Unlike papillary cancers, hematogenous The principal mechanism for radionuclide thyroid imaging is the
spread to the bone marrow, lungs, brain, liver, skin, and bladder “trapping” of the radionuclide in the thyroid follicular cells and the
are frequent in patients with follicular thyroid carcinoma (FTC) concentration inside the colloidal pool for a certain time sufficient
which has a less favorable prognosis than PTC, particularly if to be visualized by dedicated imaging systems. Although thyroid
distant metastasis occurs or capsular or vascular invasion is scintigraphy is a “functional picture” of the gland, the structural
present.4 information about the location, shape, and global size of the thy-
Hürthle cell carcinoma (HCC) contains oncocytic cells which roid lobes are clinically useful in selected patients. Although dimin-
are rich in mitochondria. This tumor is associated with an ished or absence of uptake in any nodule (hypoactive nodule) is
increased incidence of regional and distant metastasis compared associated with higher risk of malignancy, there is no definite scin-
to other differentiated thyroid cancers.5 Anaplastic thyroid carci- tigraphic pattern of thyroid cancer.
noma (ATC), the most aggressive subtype of thyroid cancer, is seen
most often in the elderly and in patients with long-standing nodu-
lar goiter. The 10-year survival rate is less than 20% in patients
with advanced disease. Patients usually present with distant Iodine-131 (131I)
metastasis most commonly in the lungs, bone marrow, brain, and The principal mechanism for radionuclide thyroid imaging is the
liver.6 Both HCC and ATC do not accumulate 131I excluding the pos- “trapping” of the radionuclide in the thyroid follicular cells and the
sibility of using 131I in diagnosis and therapy. concentration inside the colloidal pool for a time sufficient to be
Medullary thyroid carcinoma (MTC) originates from calcitonin- visualized by dedicated imaging systems. Although thyroid scintig-
secreting parafollicular C cells and accounts for about 20% of all raphy is a “functional picture” of the gland, the structural informa-
thyroid cancer deaths. MTC may be either sporadic or familial tion about the location, shape, and global size of the thyroid lobes
(associated with other neoplasms and exhibits distinctive biochem- are clinically useful in selected patients. Although diminished or
ical and genetic features). Most of the patients with MTC (80%) have absence of uptake in any nodule (hypoactive cold nodule) is asso-
a sporadic (non-familial) form of the disease. The remaining 20% ciated with higher risk of malignancy, there is no definite scinti-
inherit the autosomal dominant trait resulting in one of the multiple graphic pattern of thyroid cancer.
endocrine neoplasm syndromes (in MEN 2A and 2B). Familial MTC 131
I is an isotope of stable iodine with a physical half-life of 8.1
is accepted as a phenotypic variant of MEN 2A with decreased pen- days. It decays to 131Xe by emitting a negatively charged β-particle
etrance for pheochromocytoma and primary hyperparathyroidism of 0.610 MeV. After ingestion, iodine is absorbed from the gastro-
rather than a distinct pathologic and clinical entity. The disease may intestinal tract and approximately 90% of the radionuclide
spread to the neck musculature, local cervical lymph nodes, and to ingested reaches the thyroid follicular cells within a couple of
distant organs including the lungs, liver, bone marrow, and adrenal hours but images are taken after 24 to 72 hours post-ingestion to
glands. When metastasized, the overall prognosis is poor. In patients obtain better tissue–background contrast. Use of 131I requires
with good prognostic factors including early diagnosis, young age at high-energy collimators for its 364-keV γ-emission. Poor image
initial diagnosis, female gender, and absence of thyroid capsule quality and long physical half-life which result in high radiation
invasion, the survival rate might be as high as 80%.7 exposure to the thyroid by its β-particle emission are the main
Lymphoma is a rare malignancy of the thyroid gland and disadvantages of 131I as an imaging agent for diagnostic thyroid
accounts for only 2% of all extranodal lymphomas. Most lymphoscintigraphy. 131I is no longer used for routine thyroid scan except
mas involving the thyroid are non-Hodgkin lymphomas and fre- for the evaluation of retrosternal goiter. 131I is commonly used in
quently occur in the setting of Hashimoto thyroiditis.8 thyroid cancer management for the thyroid uptake test, whole
Risk stratification is important to choose the right therapeutic body scan (WBS), ablation and therapy of thyroid cancer.
tool, especially the optimal amount of 131I activity for thyroid can-
cer therapy. Examining the detailed histopathologic report of sur-
gically removed tissue is thus a prerequisite to determine the
correct dose of radiation to be delivered to the region. The pres-
Iodine-123 (123I)
123
ence of malignancy in the surgical border, metastatic involvement I is another isotope of iodine with a physical half-life of
of regional lymph nodes, multiple foci of tumor within the thyroid 13.3 hours. Physiologically, it is almost an ideal agent for thyroid
gland, extension of tumor tissue to surrounding structures, inva- scintigraphy in many respects: a single γ-ray of 159 keV ideal for
sion of lymphatic channels, veins, and tumor and thyroid cap- modern γ-cameras equipped with thin NaI crystal. The radiation
sules are associated with higher risk of recurrence and metastasis. exposure to the thyroid is substantially lower than 131I because of
The prognosis of thyroid malignancy is poorer in patients younger the shorter half-life, lack of particle radiation, and a relatively
than 20 or older than 60 years. Differentiated thyroid cancer lower γ-photon energy of 123I. Despite unique advantages offered
behaves more aggressively in men, but, more commonly affects by 123I,9–11 its use has been limited because of its high cost and the
women. necessity for an onsite or nearby cyclotron. In North America, 123I
Although for the past 60 years, nuclear medicine has been is frequently used for diagnostic thyroid scintigraphy and less fre-
at the heart of diagnosis and treatment of patients with thyroid quently for whole body imaging.

Chapter 3 Thyroid Carcinoma 37
Technetium 99m Pertechnetate (99mTcO4) by revealing the increased glucose metabolism in thyroid cancer
99m
cells, but, focal FDG accumulation can also be seen in benign
TcO4 is a non-iodine alternative tracer for thyroid scintigraphy. lesions including hyperplastic thyroid nodules. There is increasing
It is the most commonly used agent because of its availability in evidence of a high rate of malignancy in thyroid nodules showing
almost every nuclear medicine department as a generator- incidental 18F-FDG uptake (incidentaloma) in patients who were
produced radionuclide. 99mTcO4 is trapped by the NIS mechanism, imaged for other reasons.13 18F-FDG PET/CT imaging is currently
but it is not organified. The relatively short physical half-life used for the management of ATC, MTC, and persistent, recurrent,
(6 hours) and the (140-keV) γ-photon emitted is optimal for and metastatic differentiated thyroid cancer, especially in patients
γ-camera imaging. Except its use for postoperative scan to demon- with negative radioiodine whole body scan and elevated serum
strate remaining thyroid tissue (“remnant scan”), 99mTcO4 thyroid Tg.14 Although clinical experience in a large number of patients is
scintigraphy has no role in thyroid cancer management. not available yet, indications of 18F-FDG PET/CT imaging in thy-
roid cancer management will likely expand.14
Iodine-124 (124I)
124
I is a novel positron-emitting iodine isotope that provides useful
information in patients with differentiated thyroid cancer. It has a Treatment of Thyroid Cancer
physical half-life of 4.2 days and a decay scheme characterized by
22% of the disintegrations producing positrons of relatively high Standard treatment guidelines in DTCs include total thyroidec-
energies (1,532 and 2,135 keV). With dedicated positron emission tomy followed by radioactive iodine and TSH suppression. Thyroid
tomography (PET) systems, it provides three dimensional high- cancers with aggressive behavior and disseminated metastases as
resolution images of functioning thyroid tissue along with quantita- well as MTCs require a different therapeutic approach.
tive data. Initial studies confirmed the feasibility and precision of 124I
PET for tumor dosimetry in the 131I ablation and therapy of thyroid
Surgery

cancer. Although its diagnostic potential as an imaging agent has not
been fully exploited because of the cost and, in general, lack of avail- When the diagnosis of differentiated thyroid cancer is established
ability, 124I PET/CT is a valuable research tool (Fig. 3.1).12 with fine-needle cytology, the treatment of choice is the surgery.
Total thyroidectomy coupled with cervicocentral lymph node sam-
18 pling is the standard procedure, because of the necessity to remove
F-Fluorodeoxyglucose
all thyroid tissue before consequent 131I treatment.15,16 Even in the
18
F-fluorodeoxyglucose (18F-FDG) PET/CT provides information hands of experienced thyroid surgeons, it is quite common that
that differentiates between benign and malignant thyroid nodules some residual thyroid tissue will remain in the thyroid bed.
Remnant scan: Thyroid scan using 123I or 99mTcO4 can be used
in the presence of elevated TSH to determine the amount of
131I 124I residual thyroid tissue in the thyroid bed after thyroidectomy. If
a significant amount of residual thyroid tissue is detected on
remnant scan, reoperation and removal of the remaining thyroid
parenchyma is usually recommended and to minimize the
chance of complications during remnant ablation and to increase
the effectiveness of subsequent high dose 131I therapy on meta-
static foci.
Sentinel Lymph Node Detection,

Imaging, and Biopsy
Selective dissections of lymph nodes may lessen the possibility of
locoregional relapse and complications. Sentinel lymph node (SLN)
detection is well known to guide selective lymph node dissection in
breast carcinoma and melanoma. Initial reports describing its appli-
cation in thyroid cancers are encouraging.17–21 Following the injec-
tion of radiolabeled material into the nodule or thyroid tissue
surrounding the nodule with malignant tissue detected with fine-
needle aspiration biopsy, γ-probes can be used for intraoperative SLN
identification as an alternative to central or lateral neck dissection.
Mobile dedicated γ-cameras can also be used for lymph node imag-
ing either in the nuclear medicine department or in surgical theatre.
Identification of sentinal lymph nodes that lie outside the central
compartment is also possible with this technique. SLN imaging may
be further useful in malignant Hürthle cell tumors and well-differen-
tiated follicular carcinomas which are difficult to identify cytologically
on fine-needle aspiration; identifying SLNs with metastasis can guide
SLNBx in such cases establishing the diagnoses before surgery.18
A B Lymphoscintigraphy of the SLN: A practical technique has been
described that involves a lymphoscintigraphy performed prior to
Figure 3.1. A: Several foci of radioiodine uptake on anterior post-therapy 131I whole body surgery following a single intratumoral injection of 99mTc nanocol-
image suggesting disseminated functional metastases in a patient with differentiated thyroid loid. Immediately after peritumoral radiotracer injection, a sequen-
carcinoma. B: Many additional radioiodine avid foci were detected on 124I PET/CT maximum tial scintigraphic acquisition is performed using a low-energy,
intensity projection (MIP) image. (Reproduced with permission from the article by Van Nostrand
D, Moreau S, Bandaru VV, et al. (124I) positron emission tomography versus (131I) planar imaging high-resolution collimator. Multiple images are collected at 120 sec-
in the identification of residual thyroid tissue and/or metastasis in patients who have well- onds per frame in anterior and oblique positions, followed by mul-
differentiated thyroid cancer. Thyroid. 2010;20(8):879–883.) tiple static images until there is clear visualization of sentinel node(s).

The last image at 90 minutes after injection includes the neck and Tabl e 3 . 1
body. In this image, the activity in all nodes visualized is deter-
mined and background corrected. Addition of single photon emis- Commonly used FIXED Amounts of Activity
sion computed tomography and computed tomography (SPECT/ of 131I for Thyroid Cancer Management
CT) allows preoperative identification of lymph nodes, especially
in the lateral neck compartment. It may reduce surgical time and Condition Activity (mCi)
improves surgical planning.21
Gamma Probe Detection of SLN: Intraoperative SLN localiza- Uptake in thyroid bed (no lymph node metastasis) 100
tion can be performed using a handheld γ-probe. Before incision,
Uptake in the neck (with lymph node metastases) 150
the handheld γ-probe is placed in a sterile surgical wrap, and
slowly moved from the injection site to the cervical regions to Distant metastases 200
identify a focus with the highest count rate. Following thyroidec- Lung/bone metastases 250
tomy (removal of thyroid gland as the main source of radioactiv-
ity), the central compartment is also scanned. The node with the
most counts as well as nodes with count rates greater than 10%
of the hottest node are removed. On the basis of lymphoscinti-
131
graphic mapping prior to surgery by lymphoscintigraphy, the lat- I Activity for Therapy: The recurrent and the metastatic thy-
eral compartment of the neck can be scanned also with a γ-probe; roid cancer may be evident at the time of initial diagnosis and/or
nodes with a count rate at least 10% of the hottest node are surgery or may become evident any time during the follow-up
removed. Colloid labeled with 99mTcO4 yielded higher SLN detec- period. The overall risk of recurrence in patients with thyroid can-
tion rate compared with those using the blue dye technique for cer is related to the age at diagnosis, size of the primary tumor,
SLN detection.20 extent of the primary disease, and presence of metastasis at initial
diagnosis. 131I treatment of functioning recurrent or metastatic
thyroid cancer is similar to thyroid remnant ablation in many
Radioiodine Ablation and Therapy aspects, but the activity used is higher than the 131I activity used
Although differentiated thyroid carcinoma expresses NIS, the to ablate remnant thyroid tissue. High amount of 131I is usually
uptake of iodine and radioiodine is less vigorous than normal tis- recommended if there exists local persistent or distant metastatic
sue. Currently, 131I is the only radionuclide used to ablate residual disease or the tumor mass is large as the destructive effect of 131I
normal thyroid tissue after thyroidectomy and to treat recurrent inversely correlates with the tumor mass. Bony and pulmonary
and metastatic thyroid cancer. In ablation, the goal is to “ablate” metastases may require repeated high amounts of 131I to destroy
the remaining healthy thyroid tissue. Ablation of thyroid remnants functioning tumor cells (Table 3.1). An important feature of treat-
after surgery is usually recommended for almost all patients ing metastatic disease with high amount of 131I is to be observant
except for non-iodine avid thyroid cancers (e.g., medullary, onco- for complications because of toxicity (especially to bone marrow,
cytic, and ATCs). In “curative treatment,” the aim is to destroy liver, and kidneys) caused by high amount of radiation, swelling of
tumor cells in both residual, otherwise normal tissue as well as in metastatic focus, and also local and systemic comorbidities caused
the metastatic foci. by metastatic disease. Airway obstruction in metastatic involve-
ment of the neck and upper mediastinum may require emergency
interventions. Brain edema that may occur after high dose 131I
Determination of the Amount of Radioiodine treatment of intracranial metastases is a potentially fatal compli-
The term “dose” properly refers to the radiation absorbed by or cation.
delivered to the individual tissue whereas the term “activity” There are several approaches to selecting the amount of 131I for
refers to the amount of radioactive substance administered to the the treatment of residual or metastatic DTC. The most common
patient. Despite this clear distinction, it is not unusual for “dose” practice is to administer a fixed dose of 131I. Although this is an
to be used for both of these situations. There are two important “empirical” method, several variables are considered in this choice;
areas of debate in nuclear medicine and endocrinology experts: that is, risk stratification based on clinical findings and histopatho-
amount of activity to use (low versus high) and the method of logic features of the primary tumor. These include tumor size, sub-
selection of the activity (fixed activity versus dosimetric determi- type, features indicating the degree of de-differentiation, necrosis,
nation of the activity to be ingested). capsule invasion, genetic mutations, invasion of surrounding struc-
131
I Activity for Ablation: The appropriate radiation dose for thy- tures, and multicentricity. Additional features include the patient’s
roid remnant ablation is a source of continuing controversy in age, the number of local and distant metastases, and comorbidi-
cumulative literature. Although some clinical practitioners still pre- ties. Patients are classified as low, medium, or high risk based on
fer a fixed activity of 3.7 GBq (100 mCi) or higher amount of 131I for these pathologic and clinical features.
patients with non-metastatic, non-recurrent, low- to medium-risk Dosimetry provides, before the ingestion of therapeutic activity
thyroid cancer,22 other experts challenge this approach and propose of 131I, calculation of 131I radiation dose to be absorbed by the
a low dose ablation with activities as low as 1,110 GBq (30 mCi) of tumor, the whole body and some individual, critical organs and
131 23,24
I. Defenders of high dose ablation have reported higher abla- tissues including the salivary glands, liver, bone marrow, and the
tion rate with single ingestion and equally low complication rates. blood. Tumor dosimetry allows the treating physician to decide on
Those who prefer lower amounts of 131I in low-risk patients refer to the precise amount of 131I activity to deliver sufficient radiation
the reports of equally high ablation rate at a reduced radiation bur- dose to the tumor tissue whereas the whole body dosimetry pro-
den to the patient and family. There is no consensus on this issue, vide data about the radiation absorbed dose to the critical organs
but, reducing radiation dose in younger individuals with low-risk and tissues to predict the possible complications which actually
thyroid cancer during childbearing ages and who also have a long limit the amount of 131I to be ingested.
life expectancy during which potential tumorigenic effects may be In patients with disseminated disease, the physician cannot
seen sounds reasonable. Nevertheless, there is a need to validate the adjust the administered amount for each tumor site, and thus a
efficacy of lower amounts of 131I in terms of preventing recurrent high amount of activity is preferred after it is determined that it can
disease requiring additional treatment with more 131I activity or pos- be given “safely.” The first determinant of “safety” is the radiation
sibly even death caused by recurrent thyroid carcinoma due to absorbed dose to the bone marrow; the limit selected is 200 cGy
insufficient treatment. although the data shows that close to 300 cGy can often be tolerated

by the bone marrow but, there are often other confounding vari- Following near-total or total thyroidectomy, T4 replacement
ables including age, prior therapy, and comorbidities. is withheld for 4 to 6 weeks to increase endogenous secretion
Dose-Limiting Toxicity (DLT): Radiation injury to any critical of TSH to stimulate 131I uptake by functioning remnant tissue
organ or tissue will limit the amount of therapeutic 131I activity to and metastases. If the patient has been placed on thyroid hor-
be ingested. In many departments, dosimetric information about mone replacement after thyroid surgery to promote wound
the radiation absorbed dose to the bone marrow is taken as the healing and avoid post-surgical complications, thyroid hormone
most important dose-limiting criterion. An important consider- replacement is changed from T4 to triiodothyronine (25 μg) for
ation at doses >150 mCi and even below is the secondary organ 2 weeks after which all thyroid hormone replacement is stopped
toxicity, which frequently limits the amount of 131I activity when before radioiodine treatment. During the withdrawal period,
whole body dosimetry in terms of radiation dose absorbed by the the patient is asked to comply with low iodine diet and avoid
bone marrow would allow the use of higher amount of activity. food and beverages rich in iodine. Nevertheless, in a subset of
One of the most important secondary organ toxicities seen in patients, withdrawal of thyroid hormones may fail to elevate
patients who have ingested high amount of therapeutic 131I activ- serum TSH because of production of thyroid hormones by func-
ity is the radiation injury to salivary glands. tioning remnant tissue and metastatic foci. rhTSH administra-
123
I, 124I, and 131I have been used for dosimetric studies. There tion is therefore necessary to augment uptake. In addition,
are different methods of dosimetric calculations for thyroid cancer there may be clinical contraindications to withdrawal of thyroid
therapy with 131I.25 Although 131I is the most widely studied radio- hormone in patients with serious cardiopulmonary disease.
nuclide for dosimetric studies using γ-camera technology, recent Finally, patients who for one reason or another have non-func-
efforts with 124I and PET imaging have provided greater accuracy tioning pituitary glands will be unable to augment their TSH
based on improved quantitation using PET technology. level. This too provides justification for the use of rhTSH even
Most of the dosimetric data have been obtained from studies in locations where the expense of the material precludes the
which utilized the basic formula of the Medical Internal Dose routine use of rhTSH to prepare patients in this category for 131I
Committee (MIRD) of the Society of Nuclear Medicine. MIRD for- diagnostic procedures, remnant ablation or therapy of meta-

mula is based on the specific S values of radionuclides defined as static disease.
the “mean absorbed dose” to a target organ per radioactive decay. In many parts of the United States and in some locations in
It provides mean absorbed dose only to organs. No data is avail- Europe, rhTSH is available for routine use in the various situations
able for tumor dosimetry as the absorbed dose would vary with in which it is essential to assure 131I uptake of residual thyroid tis-
location and other variables. In addition, the data provided by sue or tumor. It has been demonstrated that follow-up imaging in
these determinations does not take into account the nonuniform patients receiving rhTSH after having undergone thyroidectomy is
source distribution within the target organ. Dosimetric calculation equivalent to thyroid hormone withdrawal. Although originally,
at the voxel level has been introduced to solve these problems in introduced only for diagnostic purposes, it was subsequently dem-
MIRD Pamphlet No.17.26 Voxel-based dosimetry with tomographic onstrated that ablation of remnant thyroid tissue can be achieved
slices using SPECT or PET provide three-dimensional data. Stud- with the same degree of success as thyroid hormone withdrawal.
ies with 124I PET dosimetry have been attempted to select a Finally, there is also cumulative experience substantiating the the
patient-specific 131I dose. use of rhTSH to prepare patients for 131I treatment of metastatic
Since the imaging data is attenuation corrected, 124I PET pro- disease.
vides high-resolution images with quantitative information,
which can be used to estimate the functional volume of thyroid
tissue. With this added advantage of 124I PET, more accurate
Low Iodine Diet
tumor dosimetry becomes available possibly leading to improving Prior to 131I ingestion for diagnostic whole body scanning, a low
management of the patient with thyroid cancer. 124I PET is also iodine diet for 2 to 3 weeks is recommended to increase the radio-
helpful in volume estimations with an imprecision of approxi- iodine uptake by functioning healthy thyrocytes and recurrent and
mately 20%. This is superior to information from 131I WBS in metastatic tumor cells. Iodine intake through foods and beverages
detecting recurrent or metastatic disease foci, and localizing and should be restricted to stimulate radioiodine uptake in healthy
differentiating between the thyroid remnant and cervical lymph thyrocytes and thyroid cancer cells before the ingestion of thera-
node metastases.27,28 peutic radioactive iodine. Each department has its own protocols
Voxel S values that are necessary for voxel-based dosimetry to diminish the daily iodine intake of the patients. The major
can be calculated for each radionuclide and voxel dimension source of iodine is the food containing iodinated salt and seafood.
through direct Monte Carlo transport simulation.29 Recent There is no consensus on the time interval for low iodine diet,
efforts to refine voxel-based dosimetry in nonuniform activity however many departments initiate iodine deficient diet at least
distributions provide a practical solution by avoiding the calcu- 2 weeks before radioiodine treatment. Iodinated contrast agents
lation of the S values at the voxel level.30 Simplified and highly commonly used in radiologic procedures and use of amiodarone,
refined three-dimensional methods are now available for an antiarrhythmic agent, also interfere with 131I uptake for about
absorbed dose calculations to both the tumor lesions and critical 1 year.
organs. The biggest problem with dosimetric calculations
reported in the literature is that none of these methods has been 131
validated in a clinical setting in a large number of patients and
Administration of I
multicenter trials. Nuclear medicine physician has the medicolegal responsibility to
take the record of the negative pregnancy test (preferably measur-
ing serum level of β-human chorionic gonadotropin, β-HCG)
Evaluation of Serum TSH within the last 24 hours before the ingestion of radioiodine in the
Ablative or therapeutic doses of 131I are usually administered 4 to reproductive age because radioiodine ingestion is contraindicated
6 weeks after thyroidectomy. If the patient has not been treated during pregnancy. In addition, the treating physician should
with replacement thyroid hormone, serum TSH at that time will inform the patient about the radiation protection instructions and
exceed 30 mU/L to stimulate 131I uptake by thyroid cancer cells.31 the presence of fecal and urinal incontinence should be addressed
There are two methods to elevate serum TSH prior to 131I diagnos- clearly.
tic procedures or treatment: withdrawal of thyroid hormone or Although it is not a common practice in the USA, many depart-
injection of recombinant human TSH (rhTSH). ments in other parts of the world require that the patient should

fast at least 6 hours to avoid interference with the gastrointestinal Hematologic abnormalities such as thrombo/leucopenia may
absorption of radioiodine. Many departments prefer a single oral occur in approximately 5% of the patients, and depending on the
capsule; however, others still use liquid form of 131I because of total administered activity of 131I, bone marrow aplasia and leuke-
lower cost. Liquid form is less expensive but it is associated with mia may develop in 0.2% to 2% of the patients.
potentially higher radiation exposure to the medical staff and sup- Pulmonary fibrosis, a severe side effect of 131I therapy in
posedly to the patient’s mouth and esophagus. The patients should patients with thyroid cancer may occur in patients with diffuse
be hydrated orally or intravenously if oral route is not available lung metastases.34 Nasolacrimal duct obstruction, dacryocystitis,
before 131I treatment to facilitate urinary excretion of the radioio- and epiphora are rare adverse effects that can be seen after 131I
dine to minimize the radiation exposure to blood and salivary therapy in patients with thyroid cancer.
gland.
Pretreatment administration of steroids is recommended if 131
metastatic involvement of any critical organ is detected before
Post-therapy Whole Body I Scan (PTS)
radioiodine therapy. Thus, some precautions can be taken to avoid Post-therapy whole body images obtained 7 to 10 days after dis-
serious side effects caused by inflammatory changes and edema charge is useful for the assessment of the distribution of 131I within
that may happen following administration of high amount of 131I patient’s body and its localization in the thyroid remnant tissue
in patients with brain metastasis. and functional metastatic foci. Small metastatic deposits, particu-
larly those in the lungs can been seen only on post-therapy images
(Fig. 3.2). Both American and European guidelines recommend
Salivary Stimulation routine use of post-therapy scan.35,36 The time for performing
In 24 hours following radioiodine administration, liberal oral post-therapy whole body scan after 131I therapy varies from 3 to
hydration and the use of lemon juice or sour candy or chewing 10 days,37 although the optimal time for performing the PTS still
gum increases salivary flow and reduces radiation exposure of the remains controversial. It is generally believed that the longer the
salivary glands. It is not evident whether lemon juice may be even time elapsed before imaging, the greater the target-to-background
more effective 24 hours after than immediately after radioiodine ratio, but, recent data surprisingly suggest that earlier imaging at
administration.32 Recently, it was also reported that salivary stim- 72 to 96 hours may be preferred for the detection of metastatic
ulation may result in higher radiation burden to salivary glands.33 disease.37 Because the therapeutic dose of 131I is much greater
than the low dose of 131I used for routine follow-up whole body
scan, the PTS can reveal additional unexpected sites of uptake,
Hospitalization Versus Outpatient Protocol such as pulmonary or skeletal lesions, which may alter staging,
The maximum activity allowed for outpatient use and the release follow-up strategy, and prognosis in some patients.16,38 As a
criteria after the ingestion of therapeutic activity differ greatly in result, the PTS can change patient management by leading to
many countries. The laws and regulations that control patient dis-
charge after ingestion of therapeutic dose of 131I are more strict in
Japan and Europe than North America. In many countries, inges-
tion of 131I activity greater than 30 mCi requires hospitalization in
a specially shielded room under strict isolation rules. In the USA
and Canada, the regulations have been amended to allow practi-
tioners to administer higher amounts of 131I provided that they
can demonstrate that no member of the public, including family,
will receive more than an allowable exposure. In some locations,
it has become permissible to treat patients with up to 250 mCi and
release the patient to a proper environment if the accommodation
otherwise fulfills the requirement. Despite these modifications, the
main criterion for discharge is the dose rate as determined by
official bodies in each country.
131
Side Effects of Therapeutic I
To reduce radiation-induced side effects and avoid unexpected
consequences, treating nuclear physician must be aware of the
potential side effects which can be seen immediately after radio-
iodine administration and during the period that follows. Early
side effects include nausea and vomiting in the first 5 to 7 days
following 131I ingestion. Swelling and pain in the thyroid remnant
is not rare and respond well to common analgesics such as
paracetamol and aspirin. If swelling gets severe, corticosteroids
are effective medications in most of the patients, but airway
obstruction caused by swelling of large amount of thyroid rem-
nant after high amount of 131I activity requires emergency inter-
vention for tracheostomy.
Damage to the salivary glands because of 131I therapy results in
sialadenitis and xerostomia (dryness of the mouth). Among all
salivary glands, parotid glands are more frequently affected. The
A B
risk of sialadenitis and xerostomia, seen in approximately 4% of
the patients, is dose dependent; the risk increases with higher
amount of 131I activity. Sialadenitis can be avoided by stimulation Figure 3.2. 131I post-therapy whole body scan in a patient with papillary thyroid cancer treated
with 200 mCi of radioiodine. Anterior (A) and posterior (B) images show high uptake in the
of salivary glands by lemon juice or chewing gums although other- functioning residual thyroid tissue (arrows) and diffuse uptake in the miliary metastases in both
wise is also reported about the benefits of salivary stimulation. lungs (arrowheads).

immediate additional imaging studies, prompting an earlier metastases. Post-therapy 131I SPECT/CT provided new information
follow-up time frame or altering plans for subsequent WBS and for nodal staging in 35% to 36.4% of patients and resulted in a
additional 131I therapy.39–41 new risk stratification in 6.4% to 25%.56–58
Compared with low dose 131I WBS routinely performed after 48 Menges et al.59 reported that incremental diagnostic value is
to 72 hours of ingestion of 131I activity, PTS which provides a higher with 131I SPECT/CT in lesions outside the neck than in those
greater target-to-background ratio can be more sensitive than the in the neck and absent in patients without iodine-positive foci on
131
WBS for detection of thyroid remnant and metastatic disease, I WBS imaging. Chen et al.60 conducted 37 SPECT/CT studies in
because, in addition to the high amount of 131I activity deposited 23 patients with inconclusive foci on WBS and reported a change
within the body after the ingestion of therapeutic activity, it is in management in 34.7%8,23 of the patients with the addition of
typically acquired several days after therapy allowing excretion of SPECT/CT. In follow-up studies comparing planar and tomographic
circulating activity reducing background uptake.40 techniques, 131I SPECT/CT images had greater diagnostic value in
57.7% to 73.9% of DTC patients based on precise localization and
characterization of foci accumulating 131I.59–60 SPECT/CT in long-
123
I Whole Body Scan term follow-up changes the management of patients contributes to
change in the management of patients with DTC, including surgical
Although 131I is a readily available in most departments, it has
management, 131I and external radiation therapy.
certain disadvantages as an imaging agent for use before ablation
or therapy. Moreover, the efficiency of the consequent 131I treat-
131
ment is claimed to decrease because of the stunning effect on I Whole Body Scan Versus Tg Measurement
functioning thyroid tumor tissue possibly caused by even small and Neck Ultrasonography
amount of β-particle radiation emitted by diagnostic dose of 131I.42–44
123
I may be an alternative radionuclide as it emits low-energy Tg is exclusively produced by functional thyroid tissue and follicu-
g-rays which are ideal for imaging with standard g-cameras and lar cell-derived differentiated thyroid cancer cells. Stimulated
serum Tg measurement provides a reliable method for detecting

has neither particle radiation nor stunning effect theoretically. It
was shown that 123I whole body was comparable to those of high the presence of recurrent disease and monitoring the response to
131
dose posttreatment 131I whole body images.45 The short half-life of I treatment. The sensitivity of serum Tg measurement is about
123
I and its high cost however limit the worldwide use of this agent 80% to 90% in the absence of anti-Tg antibodies after withdrawal
for imaging in the diagnostic workup of thyroid cancer. of thyroid hormone replacement. Some studies suggest that, espe-
cially for low-risk patients, radioiodine scanning is of low sensitiv-
ity, and thus can be replaced with neck ultrasound and stimulated
131 serum Tg determination as a false positive radioiodine scan
I SPECT/CT Imaging
because of physiologic radioiodine accumulation in some organs
SPECT/CT is feasible in both low dose 131I whole body scan and also (i.e., salivary glands, pharynx, stomach, colon, urinary bladder,
for high dose post-therapy 131I whole body imaging. Sensitivities etc.) and at areas of inflammation may lead to an unnecessary
ranging between 45% and 75% have been reported in the literature high dose 131I treatment.61
for diagnostic 131I planar whole body scan in detecting recurrences
or metastases from DTC.46–51 Lack of anatomical landmarks and the
nonspecific uptake of the tracer in other pathologic conditions or Thyroglobulin-Positive, Iodine-Negative
normal tissues somewhat complicate the interpretation of the 131I Patients (TENIS Syndrome)
planar whole body images. SPECT/CT provides valuable information Increasing number of papers report discrepancy between serum Tg
about precise location of increased uptake in the neck and other measurement and low dose 131I whole body imaging in some
areas of interest by coronal, sagittal, and transaxial slices. Several patients with DTC. In these patients, serum Tg is high while 131I
studies have demonstrated that SPECT/CT images are significantly WBS fails to localize any focus of increased iodine uptake (TENIS
more accurate for the diagnosis of recurrence and metastasis, stag- syndrome). Serum Tg provides no diagnostic information for local-
ing of thyroid cancer, and distinguishing between benign and malig- izing the site of recurrent or metastatic disease secreting Tg, there-
nant foci of radioiodine accumulation more efficiently than fore patients with a negative radioiodine scanning and elevated
conventional γ-camera imaging.52–53 Thus, 131I SPECT/CT is a useful serum Tg pose a diagnostic challenge. 18F-FDG PET/CT is able to
clinical tool for the evaluation of DTC patients with its superior tech- demonstrate tumor foci in a significant portion of these patients
nical ability of three-dimensional imaging. (Fig. 3.3). Thus, one of the indications of 18F-FDG PET/CT in thyroid
A recent retrospective analysis showed that SPECT/CT improved cancer is the demonstration of iodine-negative tumors secreting Tg
the performance of 131I imaging for the diagnosis, staging, and fol- because treatment with high amount of 131I activity (“blind treat-
low-up of patients with DTC.52 Wakabayashi et al.52 reported that ment”) seems to be the unique available radionuclide therapeutic
SPECT/CT improved image interpretation, showing higher confi- technique before proceeding to systemic chemotherapy with novel
dence levels of both benign and malignant lesions, and more pre- agents. In some patients with disseminated disease, some of the
cise localization of the true lesions as compared with 131I WBS metastatic lesions are iodine avid and thus can be demonstrated
image.50 In a study by Ciappuccini et al.,53 the sensitivity and spec- on 131I whole body scan whereas additional foci can be shown by
ificity of 131I SPECT/CT for postablation scintigraphy were 78% and 18
F-FDG PET/CT (Fig. 3.4). This advantage of 18F-FDG PET/CT may
100%, respectively. In another study, the sensitivity of 131I SPECT/ have some therapeutic implications in the management of thyroid
CT and planar imaging were both 62%, and the overall specificity cancer.
of imaging increased from 78% to 98% with the addition of 131I
SPECT/CT.51 Recent studies showed that SPECT/CT improved the
diagnosis in 47.6% to 88% of patients and modified therapeutic Stimulation with Recombinant Human TSH:
strategies in 23.5% to 25%.50,52,53 Its Implications on Serum Thyroglobulin
In low-risk and intermediate/high-risk subjects, the risk strati- Measurement, 131I Whole Body Scan,
fication can be further refined by ongoing assessment within the
first 2 years.51,54 Avram et al.55 concluded that risk stratification
and Ablation
and staging of patients should not be based solely on clinical and For patients who are at risk of serious health hazards because of
histopathologic criteria, but should include specific imaging, in severe hypothyroidism (elderly patients with cardiovascular insuf-
particular 131I SPECT/CT imaging, to identify regional and distant ficiency, poorly controlled hypertension, and renal insufficiency),

Figure 3.3. Invasion of the esophageal wall by papillary thy-

roid carcinoma in a patient with increasing serum thyroglobulin
(Tg: 39 ng/dL). The post-therapy scan obtained following
200-mCi 131I ingestion failed to demonstrate any focus of
increased uptake on anterior (A) and posterior (B) images.
18
F-FDG PET/CT images (C: MIP image, D: transaxial PET scan,
E: transaxial CT scan, F: transaxial PET/CT fusion scan) showed
an FDG-avid metastatic lesion in the esophageal wall (arrow).
A B C
D E F
exogenous stimulation by rhTSH injections can be used to obtain detection of residual or recurrent DTC, Eustatia-Rutten et al.70
prompt increase of serum TSH before follow-up WBS.62 performed a meta-analysis on more than 9,000 patients with DTC
With the use of rhTSH, the sensitivity of Tg measurement to and concluded that, with the use of appropriate thresholds,
detect recurrent disease during the follow-up of DTC patients is rhTSH-stimulated Tg has a sensitivity comparable to that under
enhanced. Indeed, many studies consistently have shown that hormone withdrawal, although specificity is lower.
rhTSH-stimulated Tg measurement has a good diagnostic accu- Although the clinical role of TSH stimulation by rhTSH injections
racy.63–65 Pacini et al.63 showed that 88% of patients with undetect- expands gradually to include Tg measurement and 131I thyroid abla-
able serum Tg under rhTSH-stimulation also had a negative Tg tion and therapy, thyroid hormone withdrawal is still the most widely
result under hypothyroidism. In the remaining 12% of patients used method for 131I whole body imaging performed for evaluation
with positive Tg only under hypothyroidism, diagnostic whole prior to 131I ablation, and low dose 131I whole body scanning coupled
body scan was either negative (83% of patients) or showed a faint with serum Tg/anti-Tg measurement to localize recurrent and meta-
uptake in the thyroid bed. Mazzaferri and Kloos64 reported that 11 static disease during follow-up.71 Because of the side effects of hor-
of 11 patients with locoregional or distant metastases had an mone withdrawal, 131I WBS during follow-up period has been
rhTSH-stimulated Tg >2 ng/mL. In another study, Kloos and Maz- progressively abandoned by many departments. More frequent use
zaferri65 confirmed the good sensitivity of rhTSH in predicting of TSH stimulation with rhTSH injections may potentially result in
persistent tumor, whereas a single rhTSH Tg <0.5 ng/mL had 98% reinventing the merits of routine follow-up 131I whole body scan. In
likelihood of identifying patients completely free of tumor. locales where rhTSH is available, it is being used simply to evaluate
However, the levels of serum Tg after rhTSH stimulation are if the Tg levels rise in response to the rhTSH to a level suggestive of
lower by a factor of two to four compared to the hypothyroid recurrence. A randomized international study, demonstrated compa-
state.66–68 Consequently, the American consensus on the manage- rable remnant ablation rates in patients prepared for 131I remnant
ment of DTC sets a threshold as low as 2 ng/mL, above which an ablation with 3,700 MBq by either administering rhTSH or thyroid
empiric trial of 131I therapy might be considered.69 To respond to hormone withdrawal.72 However, Pacini et al.73 suggests that an
the concerns that were raised as to whether rhTSH-stimulated Tg activity of 30 mCi does not provide a satisfactory thyroid ablation
measurement could be as accurate as Tg measurement in the rate when rhTSH is preferred for TSH stimulation. In Europe, and
hypothyroid state during thyroid hormone withdrawal in the more recently in the United States, the use of rhTSH for post-surgical


A B C D
Figure 3.4. Low dose (5 mCi) and post-therapy 131I whole body
scans compared with 18F-FDG PET/CT in a patient with papillary thy-
roid cancer and increased thyroglobulin level (209 ng/dL). Focal radio-
iodine accumulation is seen on low dose 131I scan in the upper part of
the right lung (arrowheads, A: anterior and B: posterior), and additional
lesions (arrowheads, lung lesions previously seen on low dose 131I
scan) were noted on post-therapy whole body scan following 200-mCi
131
I ingestion in the right lung (arrows, C: anterior and D: posterior),
and more lesions in the lungs not detected on 131I images were clearly
depicted on 18F-FDG PET/CT images (arrows, E: MIP image, F: trans- E G
axial CT scan, G: transaxial fusion PET/CT scan).

remnant ablation is approved for low-risk patients receiving an abla- Tabl e 3 . 2

tive 131I dose of 3,700 MBq (100 mCi). Pilli et al.74 reported that the
rate of successful ablation after rhTSH administration is high with Widely Accepted Clinical Indications for 18F-FDG
1,850 MBq (50 mCi) and that the procedure can be used even in PET/CT Imaging in Thyroid Cancer Management
patients with lymph node metastases. It should be noted that the
number of patients with nodal disease in this study is quite small and • Patients with high serum thyroglobulin and negative whole body iodine scan
the follow-up period is short. In fact, although rhTSH has proven to (TENIS syndrome)
be almost as good as withdrawal-induced endogenous stimulation for • Evaluation and management of Hürthle cell thyroid carcinoma
the ablation of normal thyroid tissue, long-term follow-up data is not • Evaluation of poorly differentiated thyroid carcinomas (PDTCs) and anaplastic
yet available compare the efficacy rates in terms of preventing recur- thyroid malignancies
rences. Although some reports suggest that high-risk patients should • Preoperative staging and postoperative follow-up in medullary thyroid carcinoma
undergo post-surgical initial 131I therapy with thyroid hormone with- with high serum calcitonin levels
drawal to maximize radioiodine uptake by residual cancer tissue and
to optimize the early detection of occult distant metastases,75 it is
widely accepted in the United States and some countries in Europe
that rhTSH is as effective as withdrawal in high-risk patients, too. glucose metabolism in thyroid cells.79–81 TSH stimulation can be
achieved by T4 withdrawal (endogenous TSH stimulation) or
exogenous administration of human recombinant TSH. Increased
rhTSH Stimulation Before 131I Therapy of in TSH levels therefore can improve the sensitivity of 18F-FDG PET/
Patients with Metastatic Differentiated CT to identify residual normal thyroid as well as malignant thy-
Thyroid Cancer roid tissue.131I FDG PET/CT imaging has become useful in thy-
roid cancer management (Table 3.2). Patients with larger
Functioning metastatic foci can secrete sufficient amount of thyroid volumes of 18F-FDG avid disease or higher SUVs are less likely to
hormone to suppress TSH. One of the most important applications respond to radioiodine therapy. They have a higher mortality
of rhTSH stimulation is its use prior to the treatment of residual or over a 3-year follow-up compared with patients whose tumors
metastatic cancer in patients in whom elevation of TSH after thy- do not demonstrate 18FDG uptake.82 Conversely, tumors that take
roid hormone withdrawal is difficult to achieve and/or contraindi- up 131I are less likely to yield positive 18F-FDG PET scans.83
cated. It is clinically well tolerated, even in elderly and frail patients
who could be negatively affected by hypothyroidism. The use of 18
rhTSH avoids long period of hypothyroidism necessary to achieve F-FDG PET/CT in TENIS Syndrome
high endogenous TSH serum levels. rhTSH enhances 131I uptake DTC cells expressing the NIS concentrate radioiodine and the
into metastatic lesions and prolongs the tumoral and thyroid tissue patient will also have elevated Tg, indicating the presence of
retention of the 131I, but the respective efficacy of rhTSH and hypo- persistent, recurrent, or metastatic disease. When the NIS pro-
thyroid stimulation in this group of patients have not been com- tein expression is low (dedifferentiation, more aggressive dis-
pared in randomized trials. From retrospective analysis of the ease), the thyroid tumor cells lose their iodine trapping capacity,
literature, complete remission in metastatic DTC is achieved in rendering the whole body iodine scan negative. 18F-FDG PET/
about 33% to 50% of patients treated in the hypothyroid state CT imaging has become an established imaging modality in
whereas this figure is about 2% in the case of rhTSH-aided treat- DTC patients with elevated Tg level but negative whole body
ment. It must be underlined that these populations are hardly com- iodine scans (TENIS syndrome) to identify nonfunctioning
parable, as rhTSH has often been used on a compassionate basis in metastases. False positive Tg (i.e., mild-to-moderately elevated
frail patients and in those with a more advanced disease. There are Tg) can be encountered in certain non-thyroidal malignancies
few case reports, however, when direct intrapatient comparison like histiocytic lymphoma, Hodgkin lymphoma, breast and alve-
was available, suggesting that rhTSH may be less effective than olar lung carcinoma, laryngeal malignancies, spindle cell, and
hormone withdrawal to treat metastatic lesions.76,77 Pötzi et al.78 Kaposi sarcomas.84
studied the time course of radioiodine specifically in metastatic tis- The prognosis of patients with 131I-negative DTC metastases, the
sue in four patients by comparing results in the hypothyroid state so-called nonfunctioning metastases, is significantly worse. In these
induced by thyroid hormone withdrawal with those after rhTSH patients, early diagnosis of nonfunctioning metastasis and their sur-
administration. All patients had lesser uptake of radioiodine under gical extirpation if possible is the optimal therapeutic approach. At
rhTSH stimulation than after hormone withdrawal (median uptake that stage there is an activation of cellular glucose metabolism, pro-
dose in percent in tumor tissue: 0.05 versus 0.08). The median half- moting 18F-FDG uptake in these dedifferentiated cells. The whole
life in tumor tissue was also shorter under rhTSH (21.9 hours ver- body iodine and the 18F-FDG PET/CT scans are therefore comple-
sus 39.8 hours). The authors concluded that when cancerous tissue mentary in this clinical scenario. Most often, a tumor lesion will take
is stimulated by rhTSH, higher radioiodine activities would be up either only radioiodine or 18F-FDG, but some patients can have
required to achieve the same therapeutic effect. However, the radi- both radioiodine and 18F-FDG avid lesions because of varying grades
ation absorbed dose to the tumor is also influenced by the biologic of differentiation among various lesions.83,85,86 Whole body 18F-FDG
half-life of the localized 131I. PET/CT is a dependable imaging tool in assessing patients with
It is thus expected that rhTSH may be used for the treatment TENIS syndrome with a reported sensitivity of 70% to 95%.85 The
of patients with metastatic DTC in whom hormone withdrawal is optimal goal here is to identify surgically resectable lesions to render
medically contraindicated or in whom adequate endogenous TSH a patient disease free. Shammas et al.87 found that, in patients with
levels cannot be obtained because of reduced pituitary reserve or negative 131I whole body scan, 18F-FDG PET/CT improved diagnostic
continued T4 production by metastatic tissue. accuracy and changed therapeutic management regardless of the Tg
level. They reported an overall sensitivity, specificity, and accuracy of
18
F-FDG PET/CT in localizing recurrent or metastatic disease to be
PET/CT Imaging in Thyroid Cancer 68.4%, 82.4%, and 73.8%, respectively.
Comparatively, the sensitivity of 18F-FDG PET/CT in clinical
Glucose transporters (GLUT 1 to 5), which are essential to trans- applications is typically limited to lymph nodes with a cross-
port glucose into cells, are expressed in aggressive thyroid carci- sectional diameter of 8 to 9 mm. Depending on the degree of
nomas. TSH stimulation increases GLUT 1 expression and hypermetabolism, smaller lesions are likely to be missed. It is

generally felt that the higher the Tg value, the greater the sensitiv- mortality in this study. The 5-year overall survival in patients with
ity of 18F-FDG PET studies. Clinically, it would be a good strategy SUVmax less than 10 was 92%, but declined to 64% in those with
to perform 18F-FDG PET/CT studies in TENIS patients with more SUVmax of more than 10.
than 10 ng/mL serum Tg levels especially if the neck ultrasonog-
raphy fails to identify any locoregional disease. 18
Pulmonary metastases are the most common distant metasta- F-FDG PET/CT in Poorly Differentiated
ses in DTC and can be responsible for many of DTCs presenting and Anaplastic Thyroid Carcinoma
as TENIS syndrome.88 18F-FDG PET/CT has a high detection rate Poorly differentiated thyroid carcinomas (PDTC) and ATC com-
in these cases. However, one must bear in mind that 18F-FDG PET prise of highly undifferentiated thyroid cells and do not accumu-
shows almost negligible or no uptake and thus has decreased sen- late radioiodine but overexpress GLUT 1 receptors making
sitivity to identify miliary pulmonary metastases as a stand-alone 18
F-FDG PET/CT the imaging method of choice. These lesions
18
F-FDG PET study.89 Thus, a high-resolution thorax CT is manda- show high 18F-FDG avidity, a sign of aggressive clinical behavior
tory when performing an 18F-FDG PET study. of tumors, and poor prognosis doubling its volume in 7 days.92
Beyond its diagnostic utility, 18F-FDG PET/CT also provides Poisson et al.93 evaluated 20 consecutive ATC patients with
prognostic information in TENIS syndrome. Wang et al.82 have 18
F-FDG PET/CT and contrast-enhanced total-body CT for initial
shown that in 125 patients with thyroid cancer (93 papillary, 18 staging, prognostic assessment, therapeutic monitoring, and fol-
follicular, 12 Hürthle cell, and 2 anaplastic carcinomas) with TENIS low-up. A total of 265 lesions in 63 organs were demonstrated in
syndrome using multivariate analysis, the volume of 18F-FDG 18 patients. Thirty-five percent of involved organs were visual-
avid disease was the single strongest predictor of survival. The ized only with 18F-FDG PET/CT and one with CT only. In three
3-year survival probability of patients with 18F-FDG avid tumor patients, 18F-FDG PET/CT also demonstrated unknown sites of
volumes of 125 mL or less was 0.96 (95% confidence interval metastases. Initial treatment modalities were modified by PET/
0.91, 1) compared with 0.18 (95% confidence interval 0.04, 0.85) CT findings in 25% of cases. The volume of 18F-FDG uptake
in patients with 18F-FDG volume greater than 125 mL. (≥300 mL) and the intensity of 18F-FDG uptake (SUVmax ≥18) were

More recently the same investigators showed strong inverse significant prognostic factors for survival. 18F-FDG PET/CT per-
correlation between the SUV in metastatic lesions and survival in mitted an earlier assessment of tumor response to treatment
thyroid cancer patients. Intensity of 18F-FDG uptake is correlated than CT in four of the eleven patients in whom both examina-
with progressive dedifferentiation. They quantified 18F-FDG uptake tions were performed. After chemoradiation, only two patients
by SUV and found that an intense 18F-FDG uptake with the con- with a negative PET/CT had complete remission at 14 and 38
comitant loss of 131I uptake indicates progression of disease. months; whereas eight patients who had persistent 18F-FDG avid
Patients with an initially high SUV had an unfavorable clinical lesions during treatment had a clinical recurrence and expired
course whereas decreasing 18F-FDG uptake together with persis- in 6 months. The authors concluded that 18F-FDG PET/CT
tent 131I uptake was associated with a good prognosis. Apart from appears to be the reference imaging modality for ATC at
age, the number of 18F-FDG avid lesions and higher SUV (espe- initial staging and seems promising in the early evaluation of
cially more than 13) has been found to have a negative impact in treatment response and follow-up.93
the prognosis of TENIS syndrome patients.82
Surgery is considered as the first-line therapy in 131I-negative
18
patients with gross nodal or recurrent neck disease whereas most F-FDG PET/CT in Preoperative Staging
patients with disseminated metastatic disease will need systemic and Postoperative Follow-Up of MTC
therapy. 18F-FDG avid, iodine-negative tumors are accepted as
good candidates for systemic treatment. Symptomatic patients MTCs do not accumulate radioiodine. Routine preoperative 18F-
with metastatic thyroid cancer or progressive disease who are FDG PET/CT imaging is not indicated in MTCs. 18F-FDG PET/CT
radioiodine nonresponsive can be considered for investigational imaging is a valuable clinical tool when conventional imaging
therapies with novel agents including angiogenesis inhibitors and techniques are either negative or inconclusive or if there is a per-
tyrosine–kinase inhibitors. sistent elevated serum calcitonin level (more than 150 pg/mL 3
months post-thyroidectomy) or carcinoembryonic antigen (CEA)
18 beyond 30 ng/mL.94 CEA levels greater than 30 ng/mL suggest
F-FDG PET/CT in the Evaluation central and lateral (ipsilateral) lymph node metastases, whereas
of Hürthle Cell Carcinoma CEA levels greater than 100 ng/mL signify lateral (contralateral)
Hürthle cell variant of DTC attract special attention because they, lymph node metastases and distant metastasis.95
as a group, have low radioiodine avidity and are more likely to be Considerable overlap exists with results of conventional imag-
falsely negative on a whole body iodine scan.90 Recurrence is a ing modalities (neck ultrasonography, chest CT, MRI abdomen) and
18
strong possibility in these patients with high Tg despite negative F-FDG PET/CT imaging in the detection of locoregional (neck)
whole body iodine scan. Thus, they need to be further worked out and distant metastases. In general, there is a correlation between
by imaging with 18F-FDG PET/CT. the calcitonin doubling time and 18F-FDG PET/CT positivity. It is
Normally patients with Hürthle cell thyroid carcinoma are usu- believed that the shorter the doubling time the higher the sensitiv-
ally monitored with sequential serum Tg measurements, because ity for 18F-FDG PET/CT which is especially recommended for
more than 80% of these patients have non-iodine avid tumor and patients with calcitonin higher than 150 to 500 pg/mL.36
the clinical utility of radioiodine imaging is limited in this popula- Other PET tracers that may be potentially useful in detecting
tion. This subset of thyroid malignancy also carries a worse prog- recurrence of metastatic disease in MTC patients include somatosta-
nosis and a greater risk of distant metastases. 18F-FDG PET/CT tin receptor analogs and dihydroxyphenylalanine (DOPA). The sen-
has thus a potential role to play in identifying locoregional disease sitivity of 18F-DOPA PET/CT was found to be 94% whereas the
and distant metastases.36,90 Pryma et al.91 showed that 18F-FDG corresponding value for 18F-FDG PET/CT was 62%.96,97
PET/CT is the imaging modality of choice with a high sensitivity
and specificity (95% each) for immediate thyroidectomy risk strat- Correlation of anti-Tg Antibody and
ification and also in Hürthle cell carcinoma patients with detect- 18
able Tg and negative conventional 131I imaging. SUVmax provided a
F-FDG PET/CT
dependable prognostication in high-risk patients. Each increase in Kingpetch et al.98 studied 22 consecutive DTC patients with elevated
intensity by one SUVmax unit was associated with a 6% increase in anti-Tg antibodies. 18F-FDG PET/CT findings were correlated with

histopathology, follow-up imaging, or clinical follow-up. Twelve uptake in thyroid gland, either focal or diffuse, is approximately
patients had positive findings on 18F-FDG PET/CT, six were true 2% to 3% and prevalence of focal versus diffuse 18F-FDG uptake is
positives, and six were false positives. 18F-FDG PET/CT results were found to be almost equal.13,101,102 The incidence of 18F-FDG uptake
true negative in 10 patients and the authors found no false negative in thyroid is yet much lower than the percentage of thyroid abnor-
patients. The overall sensitivity, specificity, and accuracy of 18F-FDG malities detected during a routine neck ultrasound but, the risk of
PET/CT were 100%, 62.5%, and 72.7%, respectively. They con- a malignant process in an 18F-FDG avid thyroid lesion is much
cluded that those patients with negative whole body iodine scan higher than ultrasound abnormality suggesting a higher clinical
and anti-TgAb levels equal to or higher than 414.6 IU/mL should significance of 18F-FDG-positive thyroid lesion (Fig. 3.5).102–104 It is
undergo 18F-FDG PET/CT scan. They demonstrated that 18F-FDG observed that 18F-FDG uptake in a completely normal thyroid
PET/CT results were highly positive if SUVmax value is equal or gland is rare, and either a focal or diffuse 18F-FDG uptake is viewed
greater than 4.5. with high suspicion of an occult thyroid disorder. Diffuse 18F-FDG
Another recent study by Ozkan et al.99 have retrospectively uptake is almost always benign and is usually caused by autoim-
investigated the clinical value of 18F-FDG PET/CT in detecting the mune (Hashimoto) thyroiditis. Another common cause for the dif-
recurrence of disease with negative 131I whole body scans, unde- fuse 18F-FDG uptake is Graves disease. Malignancy as a cause of
tectable Tg, and increased anti-Tg antibody levels taking the clin- diffuse uptake is very rare.
ical follow-up and histologic results as the reference standard in Focal uptake on the other hand significantly points to a nodule
27 women and 4 men, with average age of 50.2 years. Time from and possibly a thyroid malignancy. Estimated risk of malignancy
thyroidectomy to 18F-FDG PET/CT scan was 30 months on aver- in a focal 18F-FDG-positive thyroid lesion is as high as 30% to 50%
age. All patients had undetectable serum Tg and increased anti-Tg (versus 4% to 13% risk of malignancy in ultrasound detected nod-
antibody levels. The authors calculated the performance charac- ules).103,104 Most of these cases are primary thyroid malignancy,
teristics of 18F-FDG PET/CT for the detection of recurrent DTC and particularly papillary type. In patients with a mixed uptake pat-
found the sensitivity 75%, specificity 76%, negative predictive tern (focal and diffuse), the risk is estimated to be as equal to the
value 86%, positive predictive value 75%, and accuracy 80%. They focal 18F-FDG uptake.
concluded that 18F-FDG PET/CT can be useful in patients with Although diffuse 18F-FDG uptake points to a more precise
suspected DTC recurrence, whose Tg levels are undetectable benign etiology, a focus of 18F-FDG uptake in the thyroid may not
because of high anti-Tg antibodies. always be malignant. Value of SUVs in the differentiation of benign
from malignant lesion is controversial in thyroid incidentalomas.
18 Hürthle cell adenoma or autonomous adenomas, although benign,
F-FDG PET/CT for Prognostication have been found to have higher SUVs. Generally, it is found that
and Determination of Disease Extent hypothyroid status is associated with higher FDG uptake than
in High-Risk Group euthyroid status.
Although highly differentiated thyroid malignant lesions can
Although not a standard practice yet, several studies have shown have low or no FDG uptake, high FDG uptake in malignant thyroid
that 18F-FDG PET/CT correlates with overall survival.100 The SUV- lesions always point to a higher degree of malignancy, aggressive
max, the number of lesions, and the location are essential for an behavior, and poor prognosis. Tall cell variant, sclerosing papillary,
effective patient management to determine the need for addi- insular, and Hürthle variants of DTC are expected to have higher
tional systemic treatment or if the metastases are refractory/ 18
F-FDG uptake. Extrathyroidal extension at presentation has been
resistant to 131I or if they have achieved the maximum benefit especially observed in most of patients with tall cell variant if SUV
from the treatment. Robbins et al.101 hypothesized that the meta- is considerably high. Undifferentiated thyroid malignancies tend to
bolic activity of metastatic lesions, as defined by retention of FDG, show higher SUVs than the DTC varieties. Experience in patients
would correlate with prognosis. They studied the age, serum Tg, with thyroid incidentalomas on 18F-FDG PET/CT scan showed that
American Joint Committee on Cancer (AJCC) stage, histology, (a) there is higher chance of incidence of malignancy with focal
radioiodine avidity, 18F-FDG PET positivity, number of FDG avid 18
F-FDG uptake; (b) incidentally detected thyroid malignancies
lesions, the glycolytic rate of the most active lesion, and PET/CT with higher 18F-FDG uptake demonstrate a high rate of unfavor-
outcomes in all patients correlated with survival by univariate able prognosis, and may represent an aggressive variant of thyroid
analysis. However, only age and PET results continued to be the carcinoma; (c) there is less than 1% chance for a focal 18F-FDG
strong predictors of survival under multivariate analysis. The ini- uptake to be representing a secondary metastatic deposit in thy-
tial AJCC stage was not a significant predictor of survival by mul- roid gland.104
tivariate analysis. There were significant inverse relationships
between survival and both the glycolytic rate of the most active
lesion and the number of 18F-FDG avid lesions. Metastatic 18
thyroid deposits with negative iodine avidity are found to have
F-FDG PET/CT Indeterminate/Inconclusive
higher positive 18F-FDG rate and higher SUVmax than the lesions Thyroid Nodules on Fine-Needle Aspiration
with iodine avidity. Survival was reduced in patients having dis- Cytology
tant metastatic lesions with negative iodine, positive 18F-FDG Ten to fifteen percent of thyroid nodules are classified as “indeter-
scans, and high Tg level. Volume of metastatic disease identified minate” on fine-needle aspiration cytology (FNA) suggesting uncer-
by anatomical imaging had the strongest influence of any vari- tain cellular etiology and/or failure to differentiate between benign
able on survival. The study found that tumors that did not con- and malignant cells (i.e., follicular or Hürthle cell lesion). Based on
centrate 18F-FDG had a significantly better prognosis (after a their acquired capacity of cancerous cells to concentrate more glu-
median follow-up of about 8 years) than tumors that avidly con- cose, it may be feasible to use 18F-FDG PET/CT in the preoperative
centrated 18F-FDG. assessment of cytologically indeterminate thyroid lesions, thereby
avoiding unnecessary “diagnostic” thyroidectomies.105,106
107
Evaluation of Incidental 18F-FDG Uptake A recent study by Deandries et al. however demonstrated that
adding 18F-FDG PET/CT findings to neck ultrasound in patients
in Thyroid Gland: Thyroid Incidentalomas with indeterminate thyroid nodules provided no additional diag-
Focal or diffusely increased 18F-FDG uptake in the thyroid gland in nostic benefit. The sensitivity and specificity of 18F-FDG PET/CT in
a patient with no past medical history of thyroid disease is defined the presurgical evaluation of indeterminate thyroid nodules is too
as an incidental thyroid lesion. Prevalence of incidental 18F-FDG low to recommend its use routinely.


C
A D
Figure 3.5. Thyroid incidentaloma. A large thyroid nodule with a peripheral hypermetabolic rim and central hypometabolism (necrosis) was detected in the left
lower lobe of the thyroid gland on 18F-FDG PET/CT scan (arrows) in a 62-year-old man with laryngeal carcinoma who was being investigated for mediastinal lymph-
adenopathy detected on previous CT images of the chest (A: MIP image; B: transaxial FDG PET; C: transaxial CT; D: transaxial fusion PET/CT scan). The cytologic
findings obtained from the nodule through fine-needle aspiration biopsy were indeterminate for thyroid malignancy. The patient underwent thyroidectomy and poorly
differentiated thyroid cancer was histopathologically confirmed on surgical specimen.
Radionuclide Imaging in Medullary tion reported in the literature. Some of the agents used for radio-
nuclide imaging of MTC such as 201Tl chloride and 99mTc MIBI are
Thyroid Cancer nonspecific tumor-seeking radiopharmaceuticals but others such
as 123/131I metaiodobenzylguanidine (MIBG) and gallium-68 (68Ga)
MTC exhibits similar features of other neuroendocrine tumors DOTA complexes are are highly specific agents and thus can be
such as carcinoid and islet cell tumors. The surgical intervention used in the management of neuroendocrine tumors.
is the only option for a potential cure when distant organ metas- The sensitivity of radionuclide imaging with 99mTc MIBI and
201
tasis is excluded. Following surgery, differentiation between post- Tl chloride, somatostatin receptor compounds, 99mTc labeled
operative changes and recurrent tumor in the neck poses a pentavalent dimercaptosuccinic acid (99mTc-DMSA[V]), and MIBG
diagnostic challenge. Nuclear medicine modalities are less affected labeled with either 131I/123I ranges from 25% to 95%. Among them,
99m
by postoperative changes and permit whole body scanning for Tc MIBI and 201Tl chloride were sensitive in the diagnosis of
distant metastases. MTC, particularly in cases with basal calcitonin level greater than
There is no radiopharmaceutical yet that is universally accepted 1,000 pg/mL. 201Tl chloride has the same characteristics with iso-
and can be used in all patients with MTC whereas each agent nitriles; therefore it exhibits similar sensitivity as with 99mTc
described below shows reasonable success in the patient popula- MIBI.108,109 DMSA(V) labeled with 99mTc has a valance of (+5)

r esembling the phosphate ion. The mechanism of uptake still of detecting local persistent disease in the thyroid bed and neck,
remains unknown.99mTc DMSA(V) was found to be useful for local- and distant organ metastasis leading to a potential complete cure
izing the MTC lesions; however false negative results on 99mTc by cervical dissection.
DMSA(V) scan were frequent particularly in patients with mildly Despite the ability of 18F-FDG PET/CT to detect more malignant
elevated serum calcitonin levels, most probably because of low lesions than other nuclear medicine imaging tools, a more specific
tumor burden.109–111 agent is needed to work up neuroendocrine tumors including
The parafollicular C cells from which MTC originates are MTC. Somatostatin receptors are present on cell surface of MTC
derived from neuroectodermal tissues like adrenal medulla. MIBG cells. The persistent or metastatic tumor can be visualized with
is similar to the adrenergic neuron blocker guanethidine and the somatostatin receptor scintigraphy (SRS). Somatostatin receptor
neurotransmitter noradrenalin. MIBG labeled with either 131 or analogs are labeled with technetium compounds via hydrazino
123 is localized in neurosecreting granules of tumors including nicotinamide (HYNIC) to take advantage of using a readily avail-
pheochromocytoma of the adrenal medulla, neuroblastoma, carci- able agent and reduce the cost. The sensitivity, specificity, and the
noid tumors, nonsecreting paragangliomas, and MTC. Radioiodine accuracy of imaging with 99mTc EDDA/HYNIC-Tyr3-octreotide
labeled MIBG has been found to be less sensitive than sestamibi, (99mTc TOC), another somatostatin receptor analog labeled with
201 99m
Tl chloride, and DMSA(V) imaging, however it is highly specific Tc was reported to be 88.4%, 92.3%, and 89.3%, respectively.117
and thus can be used in conjunction with other localization SRS is less sensitive in detecting hepatic lesions because of the
modalities.112–114 presence of physiologic hepatic uptake. The contribution of the
It was reported that 18F-FDG-PET/CT could be useful for preop- novel agents such as radiolabeled anti-CEA antibodies and gastrin
erative staging and postoperative follow-up particularly in patients receptor scintigraphy was reported to be limited in the diagnostic
with elevated serum calcitonin levels. de Groot et al.115 reported work-up of patients with MTC118,119
that 18F-FDG PET detects more lesions than 99mTc DMSA(V) and Because of poor physical characteristics of 111In as an imaging
indium-111 (111In) labeled Octreotide, as well as bone scintigraphy agent, which has been widely used in the past to label somatostatin
combined with morphologic imaging such as ultrasonography, CT, receptor analog octreotide, recent studies have focused on soma-
or MRI. The performance of 18F-FDG-PET/CT has been superior to tostatin receptor analogs labeled with various positron emitters
the conventional nuclear medicine. The performance of 18F-FDG- such as 68Ga.120,121 Imaging is principally based on binding to the
PET/CT in identifying lymph node metastasis was also assessed somatostatin receptors which are found on many different malig-
and the reported results were comparable to those of anatomical nant cells including thyroid medullary cancer. 68Ga is a generator-
imaging modalities. Szakall et al.116 reported that 18F-FDG-PET/CT produced radionuclide that can be chelated with DOTA to form
detected more cervical, supraclavicular, and mediastinal lesions stable complexes including 68Ga DOTATOC, 68Ga DOTANOC, and
than structural imaging methods did. 18F-FDG-PET/CT failed to 68
Ga DOTATATE.120,121 Initial limited experience with PET/CT using
68
localize subcentimetric hepatic and pulmonary lesions which were Ga DOTA complexes are promising but clinical validation of these
detected by CT and MR imaging because of their superior spatial highly selective radiopharmaceuticals in the management of MTC
resolution. 18F-FDG-PET/CT whole body imaging has the advantage is required in large number of patients (Fig. 3.6). If initial results
Figure 3.6. 18F-FDG PET/CT and 68Ga-DOT-

ATATE PET/CT in medullary thyroid carcinoma. A
65-year-old man with surgically removed medul-
lary thyroid carcinoma underwent 18F-FDG PET/
CT for the investigation of elevated serum calcito-
nin (1967 pg/mL) and CEA (71.8 ng/mL) during
follow-up. 18FDG PET/CT MIP image (A) demon-
strates multiple foci of benign reactive uptake in
the spine (arrows) and a focal uptake in the right
shoulder joint (thick arrow), but no other focus of
pathologic uptake. In an ongoing trial, 68Ga-DOT-
ATATE PET/CT (B) was performed to assess the
eligibility of this patient for experimental peptide
receptor radionuclide therapy revealing focal
uptake in the left retropharyngeal, upper medias-
tinal, and paratracheal lymph nodes (arrows) sug-
gestive of metastases which showed high
177
Lutetium-DOTATATE uptake on post-therapy
scan (image not provided). The patient
responded to 177Lutetium-DOTATATE therapy
with dramatic decrease in both calcitonin and
CEA levels within 3 months. (Images courtesy of
Serkan Kuyumcu, MD, Department of Nuclear
A B Medicine, School of Medicine, University of
Istanbul).

are confirmed in multicenter trials, DOTA complexes labeled with

177
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Chapter 4
Parathyroid Tumors
Christopher J. Palestro • Kenneth J. Nichols
Introduction Hyperparathyroidism
Oversecretion of PTH results in hyperparathyroidism, which is
Parathyroid Glands classified as primary, secondary, or tertiary.
Anatomy and Embryology
Primary hyperparathyroidism
The parathyroid glands, typically four in number, are small ellipsoid-
shaped structures generally located immediately posterior to the The most common cause of hypercalcemia, primary hyperparathy-
thyroid gland. The normal gland measures approximately 5 to 7 mm roidism (PHP), is a generalized disorder of calcium, phosphate, and
in length and 3 to 4 mm in width and weighs approximately 40 to bone metabolism because of the excess PTH secretion. It is a result
60 mg. The parathyroid glands arise from the dorsal endoderm of of the loss of normal feedback control of PTH by extracellular cal-
the third and fourth pharyngeal pouches. They undergo differen- cium and usually leads to hypercalcemia with an elevated (or inap-
tiation in the fifth week of gestation and lose their pharyngeal propriately normal) PTH concentration and resultant hypercalciuria
connections by the seventh week of gestation.1 and hypophosphatemia. The estimated incidence of PHP in the
The superior glands, together with the upper pole of the thyroid United States is approximately 22 cases per 100,000 persons per
gland, descend from the base of the tongue and eventually come to year and peaks in the seventh decade. Most cases occur in women
lie midway along the posterior borders of the thyroid. In about 75% (74%), but the incidence is similar in men and women before 45
of the population, the superior parathyroid glands are located at the years of age. Head and neck irradiation in childhood and long-
junction of the upper and middle third of the thyroid gland, postero- term lithium therapy are associated with a greater prevalence of
lateral to the cricothyroid junction. In about 20% of the population, PHP. With increased detection caused by the routine calcium
they are immediately posterior to the upper poles of the thyroid screening, the clinical profile of PHP in Western countries has
gland. In up to 5% of the population, the glands are intrathyroidal, shifted from a symptomatic disease, characterized by hypercalce-
and in about 1%, they are retroesophageal in location.1 mic symptoms, nephrolithiasis, frank bone disease, and neuro-
The inferior parathyroid glands arise from the third pharyngeal muscular symptoms to a disease with few or no specific symptoms.3
pouch and migrate caudally along with the thymus. Their location Although PHP most commonly occurs as a sporadic disease, it
is more variable than that of the superior glands; they can be is also associated with various hereditary syndromes including
found anywhere from above the carotid bifurcation to the medias- familial isolated hyperparathyroidism, multiple endocrine neopla-
tinum. In about 40% of the population, they are near, or adjacent sia types 1 and 2A, hyperparathyroidism–jaw tumor syndrome,
to, the lower poles of the thyroid gland. In another 40% of the and neonatal severe PHP. Approximately 85% of all cases of PHP
population, they are near the thymic tongue. Occasionally they are are caused by parathyroid adenomas; 10% to 15% are caused by
found at the angle of the mandible, in the tracheoesophageal parathyroid hyperplasia; parathyroid carcinoma accounts for less
groove, the retroesophageal and pretracheal regions, and even in than 1% of the cases.3
the pericardium.1
Secondary hyperparathyroidism
Histology Secondary hyperparathyroidism (SHP) is the overproduction of
PTH secondary to a chronically low concentration of calcium.
The normal parathyroid gland is composed of equal amounts of
Most often it results from chronic renal failure; occasionally it is
parenchyma and stroma. The chief cells constitute the majority of
associated with intestinal malabsorption. Calcium reabsorption by
the parenchymal cells, and are responsible for most of the hor-
the small intestine is impaired; there is phosphate retention, and
monal secretion. Oxyphil cells usually do not appear before 5 to
because of a lack of 1,25-hydroxycholecalciferol, the normal effect
7 years of age and gradually increase in number after puberty.
of PTH on bone calcium release is lost. In an attempt to maintain
They contain abundant mitochondria, but do not possess a signifi-
calcium homeostasis, the serum PTH level rises, causing general-
cant secretory function. The stroma is made up of adipose tissue
ized parathyroid gland hyperplasia. Other causes of SHP include
with an abundant vascular supply and provides support for the
rickets, osteomalacia, pseudohyperparathyroidism, and high-dose
parenchyma.1
phosphate therapy in patients with x-linked hypophosphatemia.1,4
The vast majority of patients with SHP are on dialysis and
present with a very variable frequency and severity of symptoms.
Function
These individuals may develop osteitis fibrosa cystica or osteoma-
The parathyroid glands secrete parathyroid hormone (PTH) which, lacia which can lead to skeletal deformities and fractures. Bone
together with calcitonin and 1,25-hydroxycholecalciferol, acts to pain occurs primarily in the thoracolumbar spine and lower
maintain calcium homeostasis. PTH is a polypeptide that consists of extremities and is exacerbated by weight bearing and sudden
an 84-amino acid sequence with a molecular weight of 95,000 Da. movements. Soft tissue calcification affects about 25% of patients
The 34 amino acids at the amino terminal are the active part of the at the outset of dialysis and nearly 60% of those who have been
hormone. PTH acts at several sites in the body to increase serum on dialysis for more than 5 years. Pruritus, attributed to increased
calcium. In bone, in the presence of 1,25-hydroxycholecalciferol, calcium concentration in the skin, can be severe and disabling,
PTH stimulates both osteoclasts and osteoblasts, even though the but usually improves after parathyroidectomy. Calciphylaxis, a
net effect is osteolysis. In the kidneys, it acts on the renal tubules, rare condition associated with hemodialysis and renal transplan-
promoting calcium retention and increasing phosphate, sodium, tation, is characterized by high PTH concentration and increased
and potassium excretion. PTH also facilitates calcium absorption serum phosphate product. Patients develop extensive hard, tender
by the small bowel. The normal fasting serum level of PTH is less subcutaneous plaques that can progress to necrosis, nonhealing
than 100 pg/mL.2 ulcers, and gangrene that can be life-threatening.4
52

Chapter 4 Parathyroid Tumors 53
There are data that suggest that high PTH levels may be car-
diotoxic. In a study of 52 hemodialysis patients, one of the best
predictors of left ventricular hypertrophy was an elevated PTH
concentration. It was postulated that PTH acts directly on specific
PTH receptors in the cardiomyocytes.5
The diagnosis of SHP is confirmed by hyperphosphatemia and
normocalcemia or hypocalcemia, together with an elevated intact
PTH level. Medical management is directed at maintaining calcium
and phosphate levels close to normal levels and suppressing PTH
secretion and is successful in the majority of patients. Medical ther-
apy fails in up to 10% of patients and these individuals undergo
either subtotal parathyroidectomy or total parathyroidectomy plus
autotransplantation of one of the resected glands into the forearm.
Typically the gland selected for autotransplantation is small and
shows diffuse, rather than the more aggressive nodular, hyperplasia.4
Tertiary hyperparathyroidism
Tertiary hyperparathyroidism (THP) is a complication of SHP. In the
Figure 4.1. There is a 2.5- × 2- × 1-cm hypoechoic focus (arrows ) posterior to the lower
patient with long-standing SHP, the normal autoregulatory feed- pole of the right thyroid lobe (arrowheads ) on this transaxial ultrasound image. At surgery a
back mechanism governing PTH secretion is lost, resulting in 5,930-mg ectopic right superior parathyroid adenoma was resected.
uncontrolled hormone secretion. The sensitivity of the parathyroid
glands to PTH output decreases, and therefore the threshold for

inhibiting PTH output increases. The parathyroid glands exhibit ability to identify ectopic parathyroid glands in the retrotracheal
gross hyperplasia and focal adenomas may develop. THP can be and retroesophageal spaces as well as in the mediastinum. False-
very difficult to distinguish from PHP because both disorders are positive results are usually caused by thyroid nodules or lymph
characterized by inappropriately elevated PTH in the setting of nodes.1 Krusback et al.6 reviewed the results of ultrasound in 100
hypercalcemia. The diagnosis is made based on the patient history patients with PHP and found that the sensitivity and specificity of
and the context of disease. For all practical purposes, THP is almost neck ultrasound were 55% and 95%, respectively. For lesions
exclusively a disease of patients with long-standing, advanced renal located below the level of the thyroid gland, the sensitivity fell to
failure who have undergone successful renal transplant.1,5 44%. Clark et al.,7 in a study of 36 patients with recurrent or per-
sistent hyperparathyroidism, reported that the sensitivity of ultra-
sound was 50%. Eight of the patients in this series had parathyroid
Treatment lesions below the level of the sternal notch.
Although hyperparathyroidism can be managed conservatively if
the patient’s condition is stable, surgical removal of the offending Computed Tomography
gland(s) is the only definitive treatment. At one time, the surgical
approach to the patient with hyperparathyroidism consisted of CT occasionally is used to identify enlarged parathyroid glands
bilateral neck exploration, identification of all four glands, exci- (Fig. 4.2). In contrast to ultrasound, both the neck and mediastinum
sion of the grossly enlarged gland(s) and biopsy, with intraopera-
tive frozen section, of the remaining glands. The success rate of
this approach, for skilled surgeons, is in excess of 90%. Conse-
quently, preoperative parathyroid localization was reserved for
cases of recurrent disease or following failed parathyroidectomies.
However, especially in patients with PHP, because 80% to 85% are
caused by a solitary lesion, unilateral neck exploration or mini-
mally invasive surgery often is sufficient. The success of minimally
invasive parathyroidectomy depends on accurate preoperative
parathyroid lesion localization, and consequently, the impor-
tance of accurate preoperative localization even in surgically
naive patients, has increased dramatically in recent years.1
Parathyroid Gland Localization

Procedures
Morphologic Imaging
Ultrasonography
Diagnostic ultrasound of the neck is a useful procedure for local-
izing the parathyroid glands (Fig. 4.1). The resolution of this tech-
nique actually exceeds that of computed tomography (CT) and
magnetic resonance imaging (MRI) when a high-frequency probe
(10 MHz) is used. Structures can be visualized in a variety of pro-
Figure 4.2. There is a 10- × 6-mm ovoid-shaped soft tissue density (arrow ) anterior to the
jections, and ultrasound can be used as a guide to biopsy and fine ascending aorta. A 1,080-mg ectopic left inferior parathyroid adenoma was removed at surgery.
needle aspiration. Another advantage of ultrasound is that patients Reproduced with permission from Palestro CJ, Tomas MB, Tronco GG. Radionuclide imaging of
are not subjected to ionizing radiation. Ultrasound is limited in its the parathyroid glands. Sem Nucl Med. 2005;35:266–276.

can be examined with this technique. Nonopacifying vessels, Ta b l e 4 . 1

lymph nodes, and thyroid nodules all can cause false-positive
results, and intrathyroidal parathyroid glands can be overlooked. Agents used for Molecular Imaging of the
The overall sensitivity of CT in PHP is about 70%.1 Parathyroid Glands
Recently 4D-CT has been used for preoperative parathyroid lesion
localization. This technique involves acquisition of three CT scans: Agent Thyroid Subtraction Imaging Technique
Precontrast, postcontrast, and delayed imaging. 4D-CT uses CT
reconstruction of tissue volumes (3D) in conjunction with changes in 201
Tl Required (99mTcO4– used for Planar only
perfusion contrast over time (1D) to take advantage of the more rapid thyroid imaging)
99m
rate of uptake and washout in parathyroid adenomas compared to Tc-sestamibi Optional (123I or 99mTcO4– used Planar and tomographic
normal parathyroid glands and other tissues. In one investigation of for thyroid imaging)
99m
75 patients, sensitivity of 4D-CT for localizing parathyroid lesions to Tc-tetrofosmin Optional (123I or 99mTcO4– used Planar and tomographic
the surgically verified correct quadrant was significantly higher than for thyroid imaging)
18
that of double phase planar MIBI imaging with single photon emis- F-FDG No Tomographic only
11
C-methionine No Tomographic only
sion computed tomography (SPECT)/CT (88% versus 65%;
p < 0.001).8 A recent application of 4D-CT, augmented by ultrasound,
found sensitivity, for localizing parathyroid lesions to the surgically
verified correct quadrant, of 75% (N = 12) for lesion weights <150 mg, was introduced in the early 1980s (Table 4.1). 201Tl, developed
89% (N = 65) for 150 to 500 mg, and 94% (N = 62) for >500 mg as a myocardial perfusion imaging agent, is an inorganic cationic
lesions.9 analog of potassium. It is cyclotron-produced, has a half-life of 73
hours, emits a spectrum of 68 to 80 keV mercury x-rays, as well as
135 and 167 keV γ-rays, and with the aid of the sodium–potassium–
Magnetic Resonance Imaging ATP pump, is actively transported into the cell, where it is integrated
MRI can be used to examine both the neck and the mediastinum. rapidly into the intracellular potassium pool. Thallium accumulates
Images can be reconstructed in multiple planes. In general, parathy- not only in parathyroid tissue, but in thyroid tissue as well, and
roid adenomas have a longer relaxation time than thyroid tissue and consequently thyroid activity usually has to be removed in order to
exhibit higher signal intensity on T2-weighted images. The reported identify parathyroid activity. This is accomplished by administering
99m
sensitivity of this technique, using surface coils, is about 75%.1 Tc-pertechnetate, which accumulates in the thyroid gland but not
in the parathyroid glands. 201Tl and 99mTc-pertechnetate images are
obtained in a single session without moving the patient. The 99mTc-
Other Tests pertechnetate, or thyroid, image is digitally subtracted from the
201
With the development of accurate noninvasive localizing tests, the Tl, or parathyroid, image. Residual activity in the “subtraction”
role of more invasive procedures such as angiography and para- image represents activity in abnormal parathyroid tissue (Fig. 4.3).
thyroid venous sampling which are time consuming, costly, and There are several limitations to the test. The principal photon energy
highly dependent on operator skill, has diminished. These tests spectrum, 69 to 80 keV, of 201Tl is suboptimal for γ-camera imaging,
are reserved for those situations in which noninvasive modalities and the relatively high radiation-absorbed dose imparted by this
have failed to localize the offending gland(s), and even then they tracer limits the amount that can be administered. Consequently,
are rarely used.1 image quality is poor and SPECT is not performed. The sensitivity of
the test has varied from as low as 44% to as high as 95%.1
Basso et al.10 reported a sensitivity of 20% for adenomas less
Molecular Imaging than 300 mg in weight and 76% for adenomas weighing more
201 than 1,250 mg. Sandrock et al.,11 in contrast, found no correlation
Tl/99mTc-Pertechnetate Subtraction Technique
between lesion size and test sensitivity. Hauty et al.,12 in a retro-
The ability of the parathyroid glands to concentrate a variety of spective review of 49 thallium/technetium parathyroid scans,
chemical substances, including radiopharmaceuticals, has been reported a sensitivity of 78% and an overall accuracy of 73% com-
exploited for localization purposes. Although several radiopharma- pared to the 82% sensitivity and 78% accuracy in an extensive
ceuticals have been used to localize the parathyroid glands over the review of 14 previous series of a total of 317 scans. Regardless of
past 50 years, the first radionuclide technique for preoperative para- the variations in the overall sensitivity of the test, 201Tl/99mTc-
thyroid lesion localization to gain widespread acceptance was pertechnetate imaging consistently has been reported to be less
201
Tl/99mTcO4−, or thallium/pertechnetate, subtraction imaging, which sensitive for hyperplastic glands than for adenomas.
201TI 99mTcO – Subtraction

4
Figure 4.3. There is focally increased activity

(arrow ) just below the lower pole of the left thyroid
lobe on the thallium image, but not on the
pertechnetate thyroid image. This focus is obvious
on the subtraction image (arrow ). At surgery an
ectopic 50-mg left inferior parathyroid adenoma
in the thyrothymic tract was resected.

Early Late Early Late

Figure 4.4. There is focally increased MIBI activity (arrows ) at the lower pole of the left thyroid Figure 4.6. A 210-mg ectopic left inferior parathyroid adenoma (arrow ), in the thyrothymic
lobe on both early and late images. The thyroid gland, clearly seen on the early image, is barely tract, is seen only on the early MIBI image.
discernible on the late image. A 690-mg eutopic left inferior parathyroid adenoma was subse-
quently removed.
retained for a longer period of time, presumably because of the

99m presence of mitochondria-rich oxyphil cells in these lesions.16 The
Tc-Sestamibi (MIBI) single isotope double phase technique is simple and easily per-
Coakley et al.13 reported on MIBI parathyroid imaging more than formed, requiring only a single injection of MIBI followed by imag-

20 years ago, and several larger series soon followed. Because of ing approximately 15 minutes and 1.5 to 3 hours later. A persistent
superior image quality, more favorable dosimetry, and improved focus of activity on delayed images, relative to thyroid gland activ-
accuracy, MIBI rapidly replaced 201Tl as the radiopharmaceutical of ity, indicates a parathyroid lesion (Figs. 4.4 and 4.5). The reported
choice for parathyroid imaging. MIBI (hexakis 2-methoxyisobutyl sensitivity of the test has ranged from 43% to 91%. Taillefer et al.,17
isonitrile) is a lipophilic, monovalent, cationic isonitrile compound in a study of 23 patients, reported 90% sensitivity. Neumann
that diffuses passively across the cell membrane, sequestered pri- et al.,18 in an investigation of 15 patients, reported sensitivity, spec-
marily in the mitochondria, and trapped intracellularly.14,15 The ificity, and accuracy of 53%, 86%, and 76%, respectively. In what
primary route of excretion (33%) is hepatobiliary; approximately probably is the largest series reported to date, Nichols et al.,19 in
25% is excreted via the kidneys. The critical organ is the large an investigation of 462 patients (534 lesions) with PHP, reported
bowel, which receives approximately 0.048 mGy/MBq (5.4 rad/ sensitivity, specificity, and accuracy of 84%, 90%, and 87%, respec-
30 mCi). The total body dose is approximately 5 mGy (500 mrad). tively for the single isotope double phase technique. These investi-
Tracer retention in parathyroid lesions presumably is related to gators also reported that the test was significantly more sensitive
the presence of oxyphil cells, which are rich in mitochondria, in (90% versus 61%) in single gland disease (SGD) than in multi-
these lesions.16 gland disease (MGD).
Imaging Techniques Subtraction. Some parathyroid lesions do not retain MIBI, whereas
Single Isotope Double (Dual) Phase MIBI Imaging. Over the years, numer- some thyroid lesions do, resulting in both false-negative and
ous methods of performing MIBI parathyroid imaging have been false-positive double phase studies (Figs. 4.6 and 4.7). Subtrac-
suggested. Taillefer et al.17 introduced the concept of the “single tion imaging often is helpful in these situations, especially in
isotope, double phase technique,” which is based on the differential patients with concomitant thyroid disease (Fig. 4.8). In addition
washout rates of MIBI from the thyroid and parathyroid glands. to MIBI, the subtraction method requires administration of 123I or
99m
MIBI washes out more rapidly from both normal and abnormal Tc-pertechnetate to obtain a thyroid image. When using 123I, the
thyroid tissues than from abnormal parathyroid tissue, where it is thyroid image is usually acquired prior to MIBI injection. Wei et al.20
Early Late
Figure 4.5. There is focally increased MIBI activity (arrows ) just below the lower pole of the Early Late
right thyroid lobe on both early and late images. A second focus of increased activity, a thyroid
nodule (arrowhead ), at the level of the midpole of the right thyroid lobe, is seen only on the early Figure 4.7. There are two foci of increased MIBI uptake seen on both the early and late
images. Figure 4.4 and this figure illustrate the principle of the single isotope double phase MIBI images. One focus is at the level of the midpole of the right thyroid (arrows ) and the other is at
technique: MIBI washes out more rapidly from both normal and abnormal thyroid tissue than the lower pole of the left thyroid lobe (arrowheads ). Based on the single isotope double phase
from abnormal parathyroid tissue, where it is retained for a longer period of time. method both likely are parathyroid lesions.

Early Late Thyroid Subtraction

Figure 4.8. By adding thyroid subtraction (with pertechnetate thyroid imaging in this case) to the case illustrated in Figure 4.7, it is apparent that only the left-sided
focus (arrowheads ) is a parathyroid lesion; the focus on the right (arrows ) is a thyroid lesion. At surgery a 1,025-mg left inferior parathyroid adenoma was resected.
prospectively investigated MIBI/123I thyroid subtraction imaging in double phase (early plus late) 123I/MIBI imaging. The localization
20 patients, including 16 with PHP and 4 with SHP. Among the success rate of 66% for double phase MIBI was significantly less
patients with PHP all 11 solitary adenomas were successfully (p < 0.01) than the 94% success rate for the dual tracer single
localized. In four of five patients with diffuse hyperplasia, bilat- phase technique and the 90% success rate for dual tracer double
eral localization consistent with enlarged glands was seen. In one phase technique. There was no significant difference between the
patient who previously had undergone parathyroidectomy, recur- single and double phase dual tracer techniques. The degree of
rent disease was found. Among the four patients with SHP, three certainty of localization was significantly higher (p < 0.001) with
had bilateral localization consistent with enlarged glands. Recur- the dual tracer protocols than with MIBI imaging alone.
rent disease was identified in one patient who previously had Neumann et al.18 investigated the utility of 123I/MIBI SPECT sub-
undergone parathyroidectomy. Casas et al.,21 in an investigation of traction. They studied 15 patients with PHP who underwent preop-
22 patients with PHP, including 16 with single adenomas, 5 with erative double phase MIBI SPECT and simultaneous l23I/MIBI
diffuse hyperplasia, and 1 with a double adenoma compared subtraction SPECT. At surgery, 17 parathyroid adenomas were
MIBI/123I subtraction imaging to high-resolution ultrasound. found. The sensitivity, specificity, and accuracy were 88%, 97%, and
MIBI/123I subtraction imaging correctly localized all 18 adenomas. 94%, respectively, for simultaneous 123I/MIBI SPECT subtraction
All five patients with diffuse hyperplasia had images consistent versus 53%, 86%, and 76%, respectively, for double phase MIBI
with diffuse hyperplasia, although delineation of individual glands SPECT. The differences in sensitivity and accuracy were statistically
was not possible. High-resolution ultrasound, in contrast, identi- significant (p = 0.031 and p = 0.016, respectively).
fied only 11 of the 18 adenomas. Among the five patients with Although some investigators have used 123I for thyroid imag-
diffuse parathyroid hyperplasia, ultrasound was completely nega- ing, others have used pertechnetate for this purpose. Wei et al.26
tive in one case, identified a single enlarged gland in two cases, performed preoperative MIBI/pertechnetate subtraction imaging
and identified two enlarged glands in two cases. The authors con- on 30 patients with PHP, SHP, or THP. Patients underwent thyroid
cluded that MIBI/123I subtraction imaging is more sensitive than imaging 30 minutes after pertechnetate injection. Although still
high-resolution ultrasound for preoperative parathyroid lesion under the camera, they were injected with MIBI, after which they
localization. immediately underwent parathyroid imaging. The sensitivity of
Wakamatsu et al.22 in an investigation of 39 patients reported the test was 92% (12/13) for detecting parathyroid adenomas and
that MIBI/123I subtraction was more sensitive (56%) than double 79% (37/47) for other parathyroid lesions (46 hyperplasias and
phase MIBI (39%), MRI (43%), and ultrasound (51%). Chen et al.23 one carcinoma). These results were similar to the 123I/MIBI sub-
compared MIBI/123I subtraction to double phase MIBI imaging in traction technique results that these same investigators previously
25 patients with recurrent PHP. The sensitivity of MIBI/123I, 70% had reported.20 The authors felt that the MIBI/pertechnetate sub-
(19/27), was higher, but not significantly, than that of double traction technique was less cumbersome and faster than the 123I/
phase MIBI, 59% (16/27). MIBI technique.
Hindie et al.,24 in a study of 30 patients with PHP, performed Chen et al.27 compared double phase MIBI imaging with MIBI/
simultaneous dual isotope MIBI/123I acquisition. As with sequential pertechnetate and MIBI SPECT in 55 patients. In this investiga-
acquisition, these investigators found that the subtraction tech- tion, pertechnetate was injected first and thyroid imaging was
nique using simultaneous dual isotope acquisition was more sensi- performed followed by MIBI injection and early MIBI imaging.
tive than double phase MIBI imaging (94% versus 79%; p < 0.04). Two-and-one-half to four hours afterward, late MIBI imaging and
The false-positive rate for the subtraction technique was 3% ver- SPECT were performed. Using visual comparison the sensitivity of
sus 10% for the double phase technique. An advantage of the early MIBI/pertechnetate and late MIBI/pertechnetate were 72%
simultaneous dual isotope acquisition was the shortened study to 75% and 73% to 78%, respectively. The sensitivity of computer
time, which resulted in fewer motion artifacts associated with the subtraction of pertechnetate from early MIBI images was 71% to
prolonged immobilization required for sequential acquisition. 74%. The sensitivity of double phase MIBI and MIBI SPECT were
Caveny et al.25 also investigated simultaneous dual isotope 123I/ 62% to 65% and 79%, respectively. The authors concluded that
MIBI imaging in 37 patients with PHP. Patients were injected with visual comparison of pertechnetate thyroid imaging with early
MIBI 2 hours after 123I was given. Fifteen minutes and three hours MIBI imaging was sufficient for preoperative parathyroid lesion
after MIBI administration, simultaneous dual isotope acquisitions localization.
were performed. These investigators compared three different Leslie et al.28 compared MIBI/pertechnetate subtraction imaging
protocols: Early plus late MIBI images (conventional double phase alone to double phase MIBI and to double phase MIBI plus subtraction
MIBI imaging) with single phase (early) 123I/MIBI subtraction and imaging in 88 patients, including 68 with single adenomas. After


Figure 4.9. False-negative subtraction study following iodinated contrast. A 240-mg right inferior parathyroid adenoma is clearly seen on early and late MIBI
images. The pertechnetate thyroid image is virtually identical to the late MIBI image resulting in a false-negative subtraction image. This patient had undergone a
CT study with contrast approximately 1 week previously. The importance of obtaining a thorough pertinent history cannot be overemphasized.
pertechnetate injection patients underwent continuous dynamic images sensitivity and specificity both were 88%. For all three
imaging for 30 minutes. Midway through the acquisition, patients methods, sensitivity was significantly higher for SGD than for MGD.
were injected with MIBI. Delayed MIBI images were performed The subtraction technique, though useful, has limitations.
about 2 hours later. Subtraction images only, double phase MIBI Patient motion during data acquisition may lead to misregistration
images and subtraction images together with early and late MIBI of the MIBI and thyroid images, resulting in a false-positive study.

images were interpreted separately. Among the 68 patients with When 123I is used for thyroid imaging, this potential problem can be
single adenomas, double phase MIBI imaging correctly localized 49 reduced by simultaneous dual isotope acquisition. In our institution,
(72%) of the lesions significantly less than the 58 (85%) that were where pertechnetate is used for the thyroid image, we try to mini-
localized on subtraction images and the 61 (90%) that were localized mize patient motion by placing an intravenous line in the patient’s
with the double phase plus subtraction images. Reader confidence arm before beginning the test, which can be accessed for pertech-
was greater with the subtraction-only and combined images than netate injection without disturbing the patient or interrupting imag-
with the MIBI-only images. Results in the 20 patients with MGD ing. Instead of acquiring separate late MIBI and thyroid images, we
were much less satisfactory for all three methods, with no significant perform a dynamic acquisition consisting of 25 2-minute images;
differences among them. pertechnetate is injected at about the 11th frame. Frames with
Thyroid uptake of MIBI can be three to five times higher than excessive movement can be eliminated without discarding the
parathyroid uptake, which potentially could mask low MIBI uptake by entire data set after which, with computer manipulation, the para-
some parathyroid lesions. Rubello et al.29 reasoned that this problem thyroid and thyroid images are separated, group-added, pixel re-
could be minimized by administering potassium perchlorate (KClO4), registered, and normalized for proper digital subtraction.
which causes a rapid washout of pertechnetate from the thyroid Another important pitfall of the subtraction technique is
gland. In their investigation of MIBI/pertechnetate imaging, they decreased or absent thyroid uptake of pertechnetate or iodine,
administered KClO4 after completing thyroid imaging and before which may render the subtraction image invalid and result in a
injecting MIBI. All 18 adenomas were correctly localized with this false-negative study (Fig. 4.9). Obtaining a detailed history, includ-
method. ing recent iodinated contrast administration, and performing the
Nichols et al.,19 as part of a larger investigation, retrospectively thyroid image before MIBI injection can reduce the likelihood of
studied MIBI/pertechnetate subtraction imaging. In their study, this occurring. In our institution, because pertechnetate is admin-
pertechnetate was injected midway through the late MIBI acquisi- istered after MIBI, we review the dynamic imaging after pertech-
tion. Following image normalization and background subtraction, netate injection to confirm uptake by the thyroid gland.
the pertechnetate thyroid image was subtracted from the late MIBI Very intense MIBI uptake by a parathyroid lesion occasionally
image. Sensitivity and specificity of double phase MIBI imaging may “shine through” on the thyroid image and be interpreted erro-
were 84% and 90%. Sensitivity and specificity of the subtraction neously as a “thyroid nodule.” Sometimes a parathyroid lesion is
images read in isolation were 80% and 93%, respectively. When the situated immediately behind a thyroid lesion and is eliminated
subtraction images were read together with the early and late MIBI with the subtraction technique (Fig. 4.10). Occasionally thyroid

Figure 4.10. False-negative subtraction study in a patient with a multinodular goiter. The double phase study demonstrates a focus of increased MIBI activity at the
upper pole of the left thyroid lobe and another at the midpole of the right thyroid lobe. The pertechnetate thyroid and subtraction images suggest, incorrectly, that both
foci are thyroid lesions. At surgery, however, a 910-mg left superior parathyroid adenoma immediately posterior to a thyroid adenoma was removed.


Figure 4.11. A large MIBI-avid lesion at the lower pole of the left thyroid lobe is seen on both the early and late MIBI images. This lesion does not concentrate
pertechnetate resulting in a false-positive subtraction image. Note the small focus of activity along the lower pole of the right thyroid lobe (arrows ) seen only on the
late MIBI and subtraction images. At surgery a 670-mg hypercellular right inferior parathyroid gland was removed.
lesions concentrate MIBI, but not pertechnetate or iodine (Fig. 4.11).1 that SPECT may not be necessary for preoperative parathyroid
Subtraction images are most useful when reviewed together with lesion detection since it provides only marginally increased sensi-
early and late images, rather than in isolation.19 tivity compared with visual comparison of early MIBI images with
pertechnetate images.
Single Photon Emission Computed Tomography. Single photon emission Jorna et al.34 reported that late SPECT (90 minutes post injec-
computed tomography (SPECT) frequently is incorporated into tion) increased diagnostic confidence and changed surgical strat-
MIBI parathyroid imaging protocols. Tomography improves con- egy in 21% of the 64 patients studied. Civelek et al.35 prospectively
trast and provides a 3D visualization, increasing diagnostic con- studied 338 patients with PHP and reported a sensitivity of 87%,
fidence and assisting in more precise lesion localization, specificity of 94%, and positive predictive value of 86% for delayed
especially in the case of ectopic parathyroid lesions. This in turn (2.5 hours post injection) MIBI SPECT. These authors reported
can affect surgical planning. A variety of acquisition protocols that SPECT precisely localized 82% of the abnormal glands.
have been used; some incorporate SPECT and planar imaging Moka et al.36 found that in 92 patients with PHP and parathy-
whereas others use SPECT alone. In some protocols, early SPECT roid adenomas, the addition of delayed (2 hours post injection)
has been performed and in others late SPECT was used. Dual SPECT to planar MIBI/pertechnetate subtraction imaging increased
isotope SPECT and pinhole SPECT also have been investigated. the sensitivity of the test from 87% to 95%. In addition to providing
Billotey et al.30 compared early SPECT to planar imaging and more precise information about lesion location, SPECT was more
factor analysis of dynamic structures (FADS) in patients undergoing sensitive than planar imaging for detecting lesions weighing less
preoperative MIBI parathyroid imaging and reported slightly higher than 500 mg.
sensitivity for SPECT (90.5% versus 86%) than for planar imaging. Perez-Monte et al.37 compared early (15 to 30 minutes post
They also observed, not surprisingly, that SPECT provided superior injection) and delayed (2 to 4 hours post injection) MIBI SPECT in
localization of ectopic parathyroid glands. 37 patients with PHP. Thirty-four patients had parathyroid adeno-
Martínez-Rodríguez et al.31 compared early and late planar mas and three had hyperplasia. The sensitivity of early SPECT for
imaging, plus early SPECT, to early planar imaging plus early SPECT detection and localization was 91% (31/34), whereas the sensitiv-
and found that the sensitivity was identical: 93.4%. ity of delayed SPECT images was 74% (25/34) for detection and
Lorberboym et al.32 compared double phase MIBI, MIBI/ 32% (11/34) for localization. Early SPECT was significantly better
pertechnetate subtraction, and early SPECT in 52 patients with for localization ( p < 0.001) and detection ( p = 0.03).
PHP. SPECT had the highest sensitivity (96%), followed by subtrac- Thomas et al.38 investigated 36 patients with hyperparathyroid-
tion (79%) and double phase imaging (60%). In another investiga- ism. All patients underwent double phase MIBI planar and double
tion, Lorberboym et al.33 compared double phase MIBI and MIBI/ phase SPECT imaging. These investigators reported that double
pertechnetate subtraction to early SPECT in 41 patients with PHP phase SPECT was significantly more sensitive than double phase
and multinodular goiter. Sensitivities were: SPECT: 95%, subtrac- planar imaging for adenomas (79% versus 67%; p < 0.05). Neither
tion: 68%, double phase MIBI: 61%. planar nor SPECT imaging were sensitive (0% versus 25%; p = ns)
Nichols et al.19 performed early SPECT on 462 patients with for detecting hyperplastic glands.
534 parathyroid lesions. In their investigation, SPECT sensitivity Neumann et al.18 compared double phase MIBI SPECT and
(83%) was not significantly different than planar double phase simultaneous early 123I/MIBI subtraction SPECT in 15 patients
MIBI (84%) or MIBI/pertechnetate subtraction (88%) for all 534 with PHP. At surgery, 17 parathyroid adenomas were identified.
lesions. SPECT was significantly less sensitive ( p < 0.05) for MGD The sensitivity, specificity, and diagnostic accuracy were 88%,
lesions (59%) than for SGD lesions (90%). 97%, and 94%, respectively, for 123I/MIBI subtraction SPECT and
Chen et al.27 compared double phase MIBI, MIBI/pertechnetate 53%, 86%, and 76%, respectively, for double phase MIBI SPECT.
subtraction, and late SPECT imaging in 55 patients with hyper- The differences in sensitivity and diagnostic accuracy were statis-
parathyroidism. The sensitivity of visual comparison of early tically significant (p = 0.031 and p = 0.016, respectively).
images and pertechnetate was 72% to 75%; for late images and As should be evident from the preceding summary, there are
pertechnetate images it was 73% to 78%, and for double phase no well-established criteria regarding either the timing of SPECT
(early and late) MIBI images, sensitivity was 62% to 65%. Sensitiv- imaging in relation to the injection of MIBI, or the number of
ity of computer subtraction of pertechnetate from early images was SPECT acquisitions that should be performed. We perform a single,
71% to 74%; sensitivity of SPECT was 79%. The authors concluded early, SPECT acquisition approximately 30 to 45 minutes after

Figure 4.12. Selected coronal images from a

MIBI SPECT study (anterior to posterior, from
left to right, top to bottom.) There is focally
increased MIBI activity in the plane of the thy-

roid gland (arrow ), which is a thyroid nodule.
There is a second focus of increased MIBI activ-
ity posterior to the thyroid gland (arrowhead )
which is a parathyroid lesion. SPECT is useful
for differentiating thyroid from parathyroid
lesions. When located in the axial plane of the
thyroid gland, as in this case, the parathyroid
glands are almost always posterior to and only
rarely within the thyroid gland. They are never
anterior to the thyroid gland. (This is the same
case as illustrated in Fig. 4.10.)
tracer injection, just after completing early planar imaging. Our usually are located posterior to the thyroid gland, and occasionally
rationale is that some parathyroid lesions demonstrate rapid wash- a parathyroid lesion lies directly behind a thyroid lesion. It may
out and may go undetected if only late tomography is performed. In not be possible, on planar images, to differentiate between the
addition, when SPECT is performed shortly after MIBI injection two. By determining the precise location of the lesion SPECT can
there is sufficient activity remaining in surrounding structures, help differentiate a thyroid lesion from a parathyroid lesion, and
such as the thyroid gland, to generate the anatomic information can identify the parathyroid lesion located behind a thyroid lesion
necessary to localize the lesion. This of course is not an issue when (Fig. 4.12).
performing SPECT/CT. SPECT is also useful for detecting and localizing ectopic para-
Regardless of when or how many times it is performed, SPECT thyroid lesions. Although these lesions may be seen on planar
is a useful complement to planar imaging. Although it may provide imaging, tomographic images provide more detailed topographic
only marginal, if any, increase in sensitivity compared with planar information about the lesion and its relation to other structures
imaging, SPECT provides information, not readily available on (Fig. 4.13).1
planar imaging, about the location of a lesion. This information is
valuable for localizing a parathyroid lesion as well as for differen- SPECT/CT. Radiotracers primarily reflect function. Only gross
tiating a parathyroid from a thyroid lesion. The parathyroid glands anatomic detail can be inferred from the images and the precise
A Early Late Thyroid Subtraction B
Figure 4.13. A: There is a well-circumscribed MIBI-avid focus in the midline of the neck, between the two lobes of the thyroid gland. B: On the axial SPECT image
this focus (arrow ) lies well posterior to the left thyroid lobe (arrowhead ). At surgery a 2,100-mg retroesophageal left superior parathyroid adenoma was found. Note
the linear photopenic defect between the thyroid and parathyroid glands on this image. This finding is invariably present in the setting of a retroesophageal
parathyroid gland.

anatomic detail necessary to localize radiotracer accumulation both were 95%. The authors reported that SPECT/CT provided
often is lacking, even when SPECT is performed. Integrating superior topographic information, especially in patients with
radionuclide and anatomic images with SPECT/CT improves ectopic lesions, facilitating the surgical approach by providing
diagnostic confidence and accuracy. Patel et al.39 compared dou- preoperative anatomic mapping. The authors found that the
ble phase MIBI planar imaging plus late SPECT/CT to ultrasound increased sensitivity of SPECT and SPECT/CT compared with pla-
in 63 patients with PHP, including 59 with SGD and 4 with MGD. nar scintigraphy can be attributed to improved detection of small
MIBI sensitivity for SGD was 90% versus 64% for ultrasound. Sen- lesions related to superior contrast resolution, depth information,
sitivity of MIBI plus ultrasound was 95%. None of the MGD lesions and accurate 3D localization.
were detected with either method. There were several cases in Lavely et al.46 retrospectively studied 98 patients with SGD, all
which planar MIBI imaging was equivocal but SPECT/CT demon- of whom underwent early and late planar MIBI imaging and
strated a definite abnormality. SPECT/CT. Six image sets (early and delayed planar imaging,
Serra et al.40 studied MIBI double phase planar with SPECT SPECT, and SPECT/CT) and combinations of the two image sets
and SPECT/CT in 16 patients with hyperparathyroidism, including were reviewed for lesion localization at 13 possible sites by two
10 with PHP and 6 with SHP. The sensitivity of the double phase reviewers in two reviewer groups. Sensitivity, specificity, area
technique in PHP was 57% versus 100% for SPECT and SPECT/CT. under the curve, positive predictive and negative predictive values,
The sensitivity of the double phase technique in SHP was 43% as well as κ inter-rater agreement values, were determined for
versus 64% for SPECT and SPECT/CT. Although the sensitivity of each method. The highest values were for double phase studies
SPECT and SPECT/CT were the same, in 39% of the cases SPECT/ that included SPECT/CT (0.76 to 0.79). Double phase planar imag-
CT provided additional information concerning the precise loca- ing, SPECT, and SPECT/CT were statistically significantly better
tion of lesions, simplifying the surgical procedure. than single phase early or delayed imaging in sensitivity, area
Ciappuccini et al.41 evaluated double phase planar MIBI plus under the curve, and positive predictive value. Neither single phase
late MIBI SPECT/CT in 54 patients with PHP. The sensitivity of the nor double phase SPECT was statistically superior to double phase
test was 92%, the specificity was 83%. The authors concluded that planar imaging. Early phase SPECT/CT together with any delayed
double phase MIBI scintigraphy with SPECT/CT has a major imaging method was superior to double phase planar imaging or
impact on parathyroid surgery for patients having parathyroid SPECT in sensitivity, area under the curve, and positive predictive
tumors in expected as well as unexpected locations. value. Double phase acquisition was more accurate than single
Gayed et al.42 compared MIBI double phase planar plus early phase MIBI scintigraphy for planar imaging, SPECT, and SPECT/
SPECT to SPECT/CT in 32 patients with PHP. They reported that CT. The authors noted that a major advantage of SPECT/CT was its
the sensitivity of the test was 89% with and without SPECT/CT. ability to differentiate inferior glands from ectopic superior glands
SPECT/CT changed the diagnosis in only one patient and better in the tracheoesophageal groove.
located abnormal glands in only four patients. SPECT/CT was help- As with SPECT, it is not clear that SPECT/CT improves the sen-
ful in locating the two ectopic parathyroid adenomas in this inves- sitivity of MIBI parathyroid imaging. SPECT/CT does however facil-
tigation. They concluded that SPECT/CT has no significant clinical itate the differentiation of parathyroid from thyroid lesions and
value beyond that of SPECT except for localizing ectopic parathy- affords more precise lesion localization than does SPECT, especially
roid glands. in the case of ectopic lesions (Figs. 4.14 and 4.15). We have found
Pata et al.43 studied 33 patients with PHP and concomitant MIBI SPECT/CT particularly valuable for localizing mediastinal
nodular thyroid goiter, all of whom underwent double phase MIBI parathyroid lesions. In fact, the anatomic detail provided by this
planar imaging. Eighteen patients underwent delayed MIBI SPECT technique is sufficiently precise that, at our institution, diagnostic
and fifteen underwent delayed MIBI SPECT/CT. The authors com- CTs no longer are performed to localize scinitigraphically detected
pared the ability of the two techniques to correctly localize lesions mediastinal lesions (Fig. 4.16).
both to the right or left side of the neck as well to the four quad-
rants of the neck. Although there were no significant differences Limitations of MIBI Parathyroid Imaging
in sensitivity and specificity between SPECT and SPECT/CT for False-Positive Results. The most frequent cause of false-positive MIBI
lateralizing lesions to one side of the neck or the other, SPECT/CT parathyroid imaging results is the solid thyroid nodule, either soli-
was significantly more sensitive (87.5% versus 55.6%; p < 0.0001) tary or in a multinodular gland (Table 4.2). False-positive results
than SPECT for localizing lesions to the correct quadrant of the are associated with various benign and malignant tumors as well
neck. The mean operative time was shorter for patients who as with lymph node disease, both benign, such as inflammation and
underwent SPECT/CT than for those who underwent SPECT (38 sarcoidosis, and malignant including lymphoma, and metastatic
versus 56 minutes; p = 0.034). Though the results are not surpris- disease (Fig. 4.17). MIBI uptake in brown tumors of hyperparathy-
ing, it should be noted that two different populations were com- roidism has been reported.1
pared and that the role of planar imaging in study interpretation
was not provided.
Krausz et al.44 evaluated the contribution of early SPECT/CT in False-Negative Results. The failure of MIBI imaging to identify
36 patients with PHP who underwent double phase MIBI planar some parathyroid lesions is likely caused by several factors. Cer-
imaging, some of whom also underwent pertechnetate thyroid tainly, lesion size is important, as it relates to both the system
subtraction imaging. The overall sensitivity of MIBI imaging was
92% (33/36). Three patients, two with MGD and one with SGD,
were completely negative on MIBI imaging. Among the 33 patients
Ta b l e 4 . 2
with positive studies, 23 parathyroid lesions were in the neck and
10 were in the lower neck/mediastinum. SPECT/CT contributed to
Factors Adversely Affecting Specificity of MIBI
the localization of parathyroid lesions in patients with PHP and to
Parathyroid Imaging
planning the surgical exploration in 14 of 36 (39%) patients, pre-
dominantly those with ectopic lesions or who had distorted neck
anatomy. Solid thyroid nodule
Oksuz et al.45 evaluated MIBI imaging in 60 patients with PHP. Multinodular thyroid disease
Benign and malignant lymph node diseases
All 60 patients underwent planar imaging, including thyroid sub-
Benign and malignant tumors
traction; 35 also underwent SPECT/CT. The sensitivity of planar Brown tumor of hyperparathyroidism
imaging was 76%, whereas sensitivity of SPECT and SPECT/CT

A Early Late TcO4– Subtraction

B
Figure 4.14. A: The pinhole images demonstrate an MIBI-avid focus at the lower pole of the left thyroid lobe. B: On the SPECT/CT this focus is in the
retroesophageal space (arrows ). A 2,780-mg retroesophageal left superior parathyroid gland was found at surgery.
resolution and to the amount of tracer uptake by the parathy- the small structures in this region. Studies have shown that the
roid tissue. Nichols et al.19 found that, regardless of the imaging use of pinhole collimation significantly improves the sensitivity of
protocol used, MIBI was significantly more sensitive for heavier the test.47,48 Tomas et al.48 reported that planar imaging performed
(larger) than for lighter (smaller) lesions. Parathyroid lesions, even with a pinhole collimator is significantly ( p = 0.0003) more sensi-
when markedly enlarged, are relatively small structures, and may tive (89%; 48/54) than planar imaging performed with a parallel
go unrecognized. Using a pinhole collimator, rather than a parallel hole collimator (56%; 30/54) (Fig. 4.18). In their investigation, 18
hole collimator, can reduce false-negative planar MIBI imaging. lesions were detected only on pinhole images. All lesions detected
The pinhole collimator, which provides the highest resolution of on parallel hole collimator images were identified on pinhole col-
all the collimators used in nuclear medicine, magnifies the struc- limator images. There were no lesions seen only on parallel hole
tures being imaged. Its conical shape fits well in the neck, which collimator images. Furthermore, there was no significant differ-
is recessed in between the head and the chest when the patient is ence ( p = 0.29) in specificity between pinhole collimator (93%)
supine, making the pinhole collimator ideally suited for imaging and parallel hole collimator (96%) images.

A Early Late TcO4– Subtraction
Figure 4.15. A: 1,650-mg retropharyngeal right superior parathyroid adenoma. There is a MIBI-avid focus in the midline of the neck above the multinodular
thyroid gland (arrows ). More precise localization of this focus is not possible on these images. B: Although the SPECT images (top row) indicate that the focus is in the
same coronal plane as the thyroid gland (arrows ), the retropharyngeal location of the lesion (arrows ) is evident only on the fused SPECT/CT images (bottom row).
The sensitivity of MIBI parathyroid imaging also may be higher MIBI uptake correlated with the active growth phase of
affected because of the cellular function. There are data that the cells.
indicate that MIBI uptake is related to parathyroid cellular The presence of mitochondria-rich oxyphil cells presumably
function. Sun et al.49 reported that parathyroid tissue that accounts for MIBI uptake in parathyroid tissue, and glands with
expresses P-glycoprotein (PgP) does not accumulate MIBI. They
observed that normal parathyroid glands, as well as some Ta b l e 4 . 3
parathyroid adenomas, express PgP. They found that large
parathyroid adenomas that express either PgP or the multidrug
Factors Adversely Affecting Sensitivity of MIBI
resistance-related protein, MRP, did not accumulate MIBI whereas
Parathyroid Imaging
adenomas lacking both proteins accumulated the tracer
(Table 4.3).
MIBI is less sensitive for detecting hyperplastic parathyroid Decreasing lesion size (weight)
Presence of P-glycoprotein
glands than for detecting adenomatous ones and it has been sug-
Presence of multidrug resistance-related protein
gested that this is because hyperplastic glands usually are
Parathyroid gland hyperplasia
smaller than adenomatous ones. Recent investigations however Oxyphil poor parathyroid lesions
indicate that, at least in SHP, MIBI uptake is more closely related Multigland disease
to cell cycle than to gland size. Torregrosa et al.50 reported that


Figure 4.16. Mediastinal parathyroid lesion. Although SPECT localizes the ectopic parathyroid lesion to the anterior mediastinum, SPECT/CT localizes it precisely
to the thymus. At surgery a 1,700-mg hypercellular parathyroid gland, attached to the anterior surface of the thymus, was resected. If only SPECT had been per-
formed, the patient would have undergone a separate diagnostic CT scan.
fewer oxyphil cells, and hence fewer mitochondria, may explain for SGD. They also observed that the sensitivity of the test
both lower uptake and rapid washout of MIBI from some parathy- decreased as the number of lesions increased.
roid lesions.15,16,51 The explanation for the lower sensitivity in MGD is not clear.
Although most cases of PHP are caused by SGD, up to 20% are Lesion location is one possible explanation. The spatial distribution
caused by MGD, which is one of the more intriguing causes of of MGD lesions in the study of Nichols et al.55 was statistically simi-
false-negative results in patients with PHP.52 Milas et al.53 reported lar to that of SGD lesions and consequently lesion location does not
that MIBI imaging identified two sites of disease in only 5 of 84 explain the lower sensitivity. Several investigations have found that,
patients (6% sensitivity) with hyperparathyroidism and double in general, MIBI is less sensitive for lesions of lower weight and
adenomas. Chiu et al.54 reviewed the results of MIBI imaging in there are data indicating that MGD lesions are smaller than those
401 patients with PHP and reported that whereas the test was 76% of SGD.51,54–56 To test the theory that decreased sensitivity in MGD is
sensitive for detecting SGD lesions, among 38 patients with MGD, related to lesion weight, Nichols et al.55 analyzed data for 249 MGD
the test identified more than two lesions in 7 patients, one lesion lesions in 111 patients whose lesions were matched by weight,
in 13 patients, and no lesions in the remaining 18 patients. Nichols lesion by lesion, to 249 SGD lesions (median weight 260 mg [48 to
et al.19 in a retrospective investigation of 409 patients, including 53 13,800 mg] versus median weight 240 mg [48 to 12,600 mg]; Wil-
with MGD, found that MIBI imaging was significantly less sensitive coxon p = 0.68). Despite similar weights for paired SGD and MGD
for detecting MGD lesions than for SGD lesions. This was true lesions, sensitivity was consistently and significantly lower for MGD
regardless of how images were interpreted: Double phase MIBI lesions (65% versus 94%; p < 0.0001) independent of lesion weight.
alone, MIBI/pertechnetate subtraction alone, SPECT alone, and all Thus decreased MIBI sensitivity in MGD does not appear to be
images together. Even if all lesions in a patient with MGD are not related to lesion weight.
detected, it would be useful for surgical planning if patients with Another explanation offered for lower MIBI sensitivity in MGD
MGD could be identified preoperatively. In that same investigation, is related to histology. MGD is usually caused by hyperplasia
however, MIBI was no more sensitive for identifying patients with whereas SGD is usually caused by an adenoma, and MIBI imaging
MGD than for identifying the lesions themselves. is less sensitive for detecting hyperplastic than adenomatous
In a subsequent investigation, Nichols et al.55 studied 651 glands.57 Differentiating hyperplasia from adenoma is not always
patients with PHP (851 lesions), including 520 with SGD and 131 clear cut and depends on subtle, often ill-defined morphologic cri-
with MGD (331 lesions). They again found that MIBI was signifi- teria. It may be necessary to remove, or at least inspect, other
cantly less sensitive (61% versus 97%; p < 0.0001) for MGD than parathyroid glands at the time of surgery. When only one gland is

Figure 4.17. There is focally increased MIBI uptake at the level of the thymus in a patient undergoing preoperative parathyroid localization. Although this was
interpreted as a mediastinal parathyroid lesion, a benign thymoma was found at surgery. It is important to be cognizant of the fact that MIBI is not specific for
parathyroid glands and accumulates in a variety of benign and malignant conditions.
removed, and other glands are not even examined, an increas- ogy alone is no longer sufficient to perform this differentiation
ingly common situation in minimally invasive surgery, it may not with a high degree of confidence.58 Finally, it is important to note
be possible to differentiate between the two.58 The problem of that MIBI imaging, in addition to being less sensitive for detecting
establishing unambiguous histologic criteria to diagnose parathy- hyperplasic glands, is also significantly less sensitive for detecting
roid disease has resulted in wide variations in the incidence with double adenomas in MGD.53 This makes the argument that lower
which relative proportions have been reported of adenomas, sensitivity in MGD is caused by differences in histology even more
hyperplasias, and carcinomas among tissue samples.59–62 Histol- tenuous.
A Early Late B Early Late

Figure 4.18. A: Eutopic 210-mg right inferior parathyroid lesion. On the late pinhole image, there is a small MIBI-avid focus at the lower pole of the right thyroid
lobe (arrow ). B: The parallel hole images fail to demonstrate any abnormality.

The explanation for the decreased sensitivity of MIBI in MGD

remains elusive. It does not appear to be related to lesion location
or weight. Given the limitations inherent in histologic analysis,
further studies, at the molecular level, of factors affecting MIBI
sensitivity in MGD are warranted.
99m
Tc-Tetrofosmin
99m
Tc-tetrofosmin is a lipophilic cationic diphosphine, which like
MIBI, was developed for myocardial perfusion imaging. Unlike the
intracellular retention of MIBI, which depends primarily on the
mitochondrial membrane potential, the intracellular retention of
tetrofosmin is dependent on the cell membrane potential.63 Several
investigations suggest that tetrofosmin is useful for parathyroid
lesion localization.
Hiromatsu et al.64 studied 20 patients with PHP, using double
phase tetrofosmin imaging and reported that 19/20 lesions (95%
sensitivity) were correctly localized. Tetrofosmin was somewhat
more sensitive than ultrasound CT and MRI, all with 85% sensitivity,
in this investigation.
Wu et al.65 performed double phase tetrofosmin imaging in 40
patients with PHP, including 20 with lesions weighing more than
1.5 g and 20 with lesions weighing between 500 mg and 1,500 mg.

Sensitivities were similar: 85% (17/20) for the larger lesions and
80% (16/20) for smaller lesions. They correlated their findings Early Late
with PgP expression and found that all positive results were PgP
expression negative and all false-negative results were PgP expres- Figure 4.19. Early and late tetrofosmin (upper) and early and late MIBI image (lower) stud-
ies performed on a patient with a 500-mg parathyroid lesion at the lower pole of the left thyroid
sion positive. lobe. On the tetrofosmin study the lesion is seen only on the early image, whereas on the MIBI
Vallejos et al.66 studied 31 patients, 19 with PHP and 12 with study the lesion is seen on both the early and late images. Reproduced with permission from
SHP, with double phase tetrofosmin imaging. Some patients also Palestro CJ, Tomas MB, Tronco GG. Radionuclide imaging of the parathyroid glands. Sem Nucl
underwent pertechnetate thyroid imaging. The sensitivity of the Med. 2005;35:266–276.
test for SGD was 95% and the sensitivity for MGD was 58%. All
abnormal glands were identified on early images. Some lesions
were better seen on early images and the authors concluded that, in intensity from early to late images was considered positive. All 16
when using tetrofosmin, early imaging might be sufficient. lesions were correctly identified with both tracers, although image
Ishibashi et al.67 studied double phase tetrofosmin imaging in quality was judged to be slightly better with MIBI.
26 patients with hyperparathyroidism, including 7 with PHP and Wakamatsu et al.72 compared tetrofosmin/pertechnetate and
19 with SHP. Tetrofosmin correctly localized all 7 lesions (100% MIBI/pertechnetate subtraction imaging in 28 patients with PHP,
sensitivity) in patients with PHP and 27/37 lesions in patients with including 25 with SGD and 3 with MGD and found no significant
SHP (73%). differences in sensitivity between the two agents: 63.2% for tetro-
Gallowitsch et al.68 studied double phase tetrofosmin imaging fosmin versus 68.4% for MIBI. Both agents were less sensitive
plus SPECT in 48 patients, including 35 with PHP and 13 with SHP. (47.7% for both) for MGD than for SGD.
Among the patients with PHP double phase imaging detected 25 of Aigner et al.73 compared late tetrofosmin and MIBI imaging
36 (69.2% sensitivity) lesions, whereas SPECT detected 34 lesions in 10 patients with PHP, and reported that, although MIBI image
(94.4% sensitivity). The sensitivity of planar imaging in SHP was contrast was somewhat better, all 10 lesions were detected with
38% whereas the sensitivity of SPECT was 61.5%. both tracers. Tetrofosmin showed a slower elimination from the
The results of intraindividual comparisons of tetrofosmin and parathyroid adenomas than MIBI in 6 of the 10 cases.
MIBI imaging have been mixed. Froberg et al.69 compared tetro- Although it is easier to prepare, offers a somewhat lower radi-
fosmin and MIBI parathyroid imaging using a double phase tech- ation exposure to the patient, and probably has comparable sen-
nique. In their investigation, all nine lesions were correctly sitivity when performed and interpreted appropriately, tetrofosmin
identified with MIBI, whereas only two were detected with tetrofos- has never enjoyed the popularity of MIBI for parathyroid imaging.
min. There was a significant increase in lesion to thyroid ratio over
time with MIBI, but not with tetrofosmin, and the authors con-
cluded that tetrofosmin is not suitable for double phase parathyroid
PET Tracers
scintigraphy. A variety of positron-emitting tracers have been used to localize
Fjeld et al.70 compared double phase tetrofosmin and MIBI parathyroid lesions, including 18F-fluorodopa, 11C-methionine, and
18
imaging in 16 patients with PHP. Using focally increased activity F-fluorodeoxyglucose.
on early or delayed images as the criterion for a positive study, the
11
sensitivity of both tests was the same: 75%. The authors noted that C-Methionine (MET PET)
in six cases, lesion visualization on MIBI images improved on Beggs and Hain74 performed MET PET on 51 patients with hyper-
delayed imaging, whereas none of the lesions showed improved parathyroidism. Final diagnoses were based on surgery or clinical
visualization over time with tetrofosmin (Fig. 4.19). follow-up. Sensitivity of the test was 83% for adenomas. None of
Kibar et al.71 compared tetrofosmin with MIBI in 16 patients with the hyperplastic parathyroid glands were detected.
PHP. Only patients who had focal abnormalities on MIBI imaging Otto et al.75 compared MET PET and MIBI SPECT in 30 patients
underwent tetrofosmin imaging. The imaging protocol and interpre- with hyperparathyroidism. Sixteen patients had PHP, twelve
tation was identical for both tracers. Patients underwent double patients had SHP, and two patients had parathyroid carcinoma.
phase imaging at 15 to 20 minutes and again at 2 to 3 hours after Imaging was performed 10 and 40 minutes after injection. Sensi-
injection. A focal area of increased uptake that persisted or increased tivity of MET PET was 94% for SGD (17/18) and 69% (25/36) for

MGD. Sensitivity of MIBI was 50% (9/18) for SGD and 47% (17/36) 4. Mihai R, Farndon JR. Parathyroid disease and calcium metabolism. Br J Anaesth.
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Sundin et al.76 performed MET PET on 34 patients with 37 7. Clark OH, Okerlund MD, Moss AA. Localization studies in patients with persis-
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8. Rodgers SE, Hunter GJ, Hamberg LM, et al. Improved preoperative planning for
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18 18. Neumann DR, Esselstyn CB Jr, Go RT, et al. Comparison of double phase 99mTc-
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21. Casas AT, Burke GJ, Sathyanarayana, et al. Prospective comparison of techne-
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collimation, thyroid subtraction imaging, and SPECT or SPECT/CT 834–839.
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30. Billotey C, Sarfati E, Aurengo A, et al. Advantages of SPECT in technetium-99m
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Histopathology. 2010;56:835–851. 1809–1815.

Chapter 5
Esophageal Carcinoma
Mark Dunphy • Heiko Schöder
Introduction Multimodality radiologic imaging plays an essential role in the

initial staging of esophageal cancer, and in evaluating response to
therapy. It also offers prognostic information in the pre- and post-
Esophageal cancer includes cancers involving the esophagus,
treatment settings. Imaging procedures with accepted clinical
including the cervical and the thoracic esophagus, as well as can-
roles in esophageal cancer management include x-ray fluoroscopy
cers involving the gastroesophageal junction (GEJ). In the current
(barium swallowing study), endoscopic ultrasound (EUS), com-
(seventh edition) American Joint Committee on Cancer (AJCC)
puted tomography (CT), and 18FDG PET/CT; MRI has no standard
guidelines, cancers with an epicenter in the stomach that is less
role at the present time. Although a barium swallowing study may
than 5 cm from the GEJ with extension of this lesion to involve the
provide some useful information, upper gastrointestinal endos-
GEJ are considered esophageal carcinoma.1 If a tumor is located
copy with biopsy is the primary modality leading to cancer diag-
within 5 cm distal to the GEJ but does not extend into it, this is
nosis.13 Bone scintigraphy, previously used for the detection of
considered gastric cancer. Other guidelines, for instance those of
osseous metastases, has been effectively supplanted by 18FDG PET/
the National Comprehensive Cancer Network (NCCN), do not
CT in most major cancer centers.14 This chapter focuses on the role
include the proximal 5 cm of the stomach.2 Esophageal cancer
of 18FDG PET/CT.2
includes two major histologic subtypes: Adenocarcinoma (AC) and
squamous cell carcinoma (SCC), both arising from the inner lining
of the esophagus, the mucosa. Some tumors demonstrate a mixed
histopathologic type, containing AC and SCC; these are considered
Staging of Esophageal Cancer
essentially SCC because of their poorer prognosis. The Siewert
The seventh edition of the AJCC and the International Union
classification of AC of the GEJ (AEG) defines AEG as a tumor
Against Cancer (UICC) staging system classify the disease based
whose center is within 5 cm proximal of, or distal to, the ana-
on disease biology, prognosis, and therapeutic regimens. For
tomical gastric cardia, including tumors with a center within the
instance, this new classification recognizes that in the absence of
distal esophagus and margins that may infiltrate the GEJ (AEG
nodal metastases, prognosis depends only on T-stage, histology
type I); tumors arising at the GEJ and gastric cardiac epithelium
(SCC versus AC), tumor grade, and, for SCC, also on the location of
(AEG type II); and tumors centered in the stomach beyond the
the primary tumor within the esophagus.15 Some important
gastric cardia, infiltrating the GEJ and distal esophagus “from
changes compared to earlier classifications include the following.
below.”3
In 2013, in the United States, esophageal cancer claimed the • SCC and AC have separate staging schemes (Tables 5.1 and 5.2).
lives of about 15,000 people, and an estimated 17,000 people • Tumors arising in the GEJ and proximal 5 cm of stomach are
were newly diagnosed with this disease.4 Worldwide, SCC is the included (previously considered primary gastric cancer16).
most common form of esophageal cancer, particularly in eastern • Tumor grade is now a component of the stage groupings (previ-
countries. However, in western countries the incidence of esopha- ously TNM, now TNMG).
geal SCC has been declining over the past decades; AC is now the • Tumor location is a new component in patients with SCC.
most common form of esophageal cancer in the United States.4,5 • Tis has been redefined and T4 subclassified.
Overall, esophageal cancer incidence and mortality in the United
States have declined progressively since the late 1980s, with dif-
ferences among demographic groups.4,6 Risk factors for the devel- Ta b l e 5 . 1
opment of esophageal cancer include columnar metaplasia of the
distal esophagus (Barrett esophagus),7 obesity, cigarette smoking, Squamous Cell Carcinoma, American Joint Committee
and various autoimmune diseases such as celiac disease, reactive on Cancer (AJCC)/Union For International Cancer
arthritis, or systemic sclerosis; and polycyclic aromatic hydrocar- Control (UICC) Staging
bon exposure.7–9 Interestingly, use of aspirin and other NSAIDs
appears associated with a reduced incidence of esophageal AC.10
Worse clinical outcomes have been associated with a variety of Stage T N M Grade Tumor Location
clinical and biologic factors, including several inflammatory genes
0 Tis (HGD) N0 M0 1, X Any
and microRNA biomarkers. IA T1 N0 M0 1, X Any
Patient survival depends upon whether and how far the disease IB T1 N0 M0 2–3 Any
has spread. Analysis of the National Cancer Institute’s Surveillance, — T2–3 N0 M0 1, X Lower, X
Epidemiology, and End Results (SEER) database for patients diag- IIA T2–3 N0 M0 1, X Upper, middle
nosed with esophageal cancer—either SCC or AC—between 2001 — T2–3 N0 M0 2–3 Lower, X
and 2007, revealed 5-year survival rates of 37% for patients with IIB T2–3 N0 M0 2–3 Upper, middle
localized disease limited to the esophagus; 18% for patients with — T1–2 N1 M0 Any Any
regional spread to lymph nodes or adjacent tissues, and 3% for IIIA T1–2 N2 M0 Any Any
patients with distant spread.11 Despite some progress in earlier — T3 N1 M0 Any Any
detection, more than one-half of esophageal cancer patients pres- — T4a N0 M0 Any Any
ent with incurable locally advanced or metastatic disease. Detec- IIIB T3 N2 M0 Any Any
tion of early disease is rare because small primaries are usually IIIC T4a N1–2 M0 Any Any
— T4b Any M0 Any Any
asymptomatic and even small tumors have often already metasta-
— Any N3 M0 Any Any
sized. The prognosis of these patients remains poor overall, and IV Any Any M1 Any Any
the optimal treatment strategy remains the subject of debate and
research.12 Approximately 15% of patients can achieve complete HGD, high-grade dysplasia; X, cannot be assessed.
clinical remission after multimodality therapy. Source: AJCC. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
68

Chapter 5 Esophageal Carcinoma 69
Ta b l e 5 . 2
Adenocarcinoma, American Joint Committee

on Cancer (AJCC)/Union for International
Cancer Control (UICC) Staging
Stage T N M Grade
0 Tis (HGD) N0 M0 1, X
IA T1 N0 M0 1–2, X
IB T1 N0 M0 3
— T2 N0 M0 1–2, X
IIA T2 N0 M0 3
IIB T3 N0 M0 Any
— T1–2 N1 M0 Any
IIIA T1–2 N2 M0 Any
— T3 N1 M0 Any
— T4a N0 M0 Any
IIIB T3 N2 M0 Any
IIIC T4a N1–2 M0 Any
— T4b Any M0 Any
— Any N3 M0 Any
IV Any Any M1 Any

Source: AJCC. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
• N-stage is no longer simply divided into N0 (absence) or N1

(presence of metastasis), but as N0, N1, N2, or N3 according to
the number of regional lymph node metastases and the defini-
tion of “regional” lymph nodes is changed.
• M-stage has been simplified into M0 or M1 (previously, M1 was
subclassified).
Accurate staging is vital for appropriate therapeutic manage-
ment. If patients have potentially resectable disease, their median
survival strongly correlates with disease stage. For instance, resec-
tion alone is considered sufficient treatment for superficial cancers
without metastatic disease (T1N0M0) and may also be appropriate
for (true) T2N0M0 disease. Apart from gross extraesophageal infil-
Figure 5.1. A 68-year-old man with poorly differentiated adenocarcinoma of the distal esoph-
tration, the depth of primary tumor penetration within the layers of agus. Staging CT scan of the chest, including supraclavicular regions, showed no evidence of
the esophageal wall cannot be determined with CT or PET/CT, and metastatic disease. Staging FDG PET/CT revealed abnormal hypermetabolic activity in a sub-
small lymph nodes, especially when located near the primary, may centimeter left supraclavicular lymph node. The subcentimeter node was below CT-size criteria
not be recognized. Instead, EUS has a pre-eminent role in evaluat- for abnormality. Shown are corresponding companion CT (upper) and fusion PET-CT (lower)
transaxial images showing the small hypermetabolic lymph node (arrows ). Ultrasound-guided
ing the primary tumor (size and depth of invasion) and locoregional biopsy found the sonographic appearance of the lymph node abnormal; biopsy pathology con-
lymph nodes. It is superior to CT, MRI, or 18FDG PET/CT for this firmed metastatic adenocarcinoma. FDG PET/CT improved disease staging.
purpose.17–19 CT and 18FDG PET/CT are especially useful to detect
metastatic disease.2,20–22 This may spare patients the morbidity of
surgery and/or toxicity of other therapeutic regimens that only
benefit patients of lesser stage disease. It also appears to be cost-
effective.23,24 However, to avoid “overstaging,” suspicious findings
Characterization of the Primary
that could potentially alter the patient management should be con- Tumor: Tumor Location
firmed by biopsy. The addition of 18FDG PET/CT to other tests changes
the disease stage in about 40% of patients, leading to changes in Esophageal SCC is found in the midregion of the thoracic esopha-
patient management in 10% to 40% of patients.25–29 Changes in man- gus more often than elsewhere (Fig. 5.2). SCC primary tumors in
agement may involve a change in therapeutic intent (about one-half the GEJ are more favorable, associated with lower disease stage
of cases, usually will be reclassified from curative to palliative intent) (Table 5.1).
with changes in treatment modalities or methods of treatment The SCC staging classification categorizes primary esophageal
delivery. When 18FDG PET/CT detects heretofore unknown distant tumor location as upper, middle, or lower. “Upper” includes the upper
disease, it is usually found in supraclavicular or abdominal lymph thoracic esophagus, which is between thoracic inlet and the lower
nodes (Fig. 5.1), as well as liver and bone.28 In a recent study in 139 border of the arch of the azygos vein (i.e., its arch over the right
patients with esophageal cancer,26 PET/CT correctly changed the mainstem bronchus), and the cervical esophagus, which is between
stage group in 40% of patients (e.g., upstaged from group I-IIA to the thoracic inlet and the upper esophageal sphincter (UES). The
stage group IIB-III or stage group IV, reflecting differences in thera- UES can sometimes be visualized on CT as a small mass-like con-
peutic approach) and changed the management in 34% of patients traction of the esophagus musculature posteriorly to the cricoid car-
(26% high impact change, 8% medium impact change). tilage and on 18FDG PET as a site of focally prominent 18FDG uptake.
In patients with GEJ tumors, diagnostic laparoscopy may be The UES is an important landmark because it also defines resect-
pursued in search of intraperitoneal disease but this is not consid- ability: Cervical or “cervicothoracic” (thoracic esophagus but <5 cm
ered mandatory, particularly if no metastatic disease is evident from the UES) primary tumors are usually unresectable and, there-
elsewhere.2 fore, preferentially treated with definitive chemoradiotherapy.2

Incisors
UES 15 cm
Cervical esophagus
Sternal notch 20 cm
Upper thoracic
Azygos vein 25 cm
Middle thoracic
Inferior pulmonary vein 30 cm
Lower thoracic
GEJ 40 cm
Figure 5.2. Anatomy of esophageal cancer primary site, including typical

endoscopic measurements of each region measured from the incisors.
Exact measurements are dependent on body size and height. (Reprinted
with permission from Springer-Verlag New York Inc., Publisher of American
Joint Committee on Cancer (AJCC). AJCC Cancer Staging Manual. 7th ed.
New York, NY: Springer, 2010.) GEJ, gastroesophageal junction; UES, upper
esophageal sphincter.
“Middle” is defined as the region between the transaxial levels esophagus and esophagitis, caused by reflux disease or prior
of the azygos vein arch and the inferior pulmonary veins, and irradiation, can also be 18FDG avid35–37 and interfere with the
“lower” is defined as the region below the inferior pulmonary evaluation of the primary tumor.
veins, including the GEJ. The lower esophagus normally has an The esophageal wall includes three layers: Mucosa (Tis and
intra-abdominal portion, passing through the diaphragm before T1a), submucosa (T1b), and muscularis propria (T2). The mucosa
connecting to the stomach, but this can be absent because of hia-
tal hernia. Like the UES, the contracted lower esophageal sphinc- Ta b l e 5 . 3
ter (LES) can appear “mass-like” and intensely 18FDG avid on PET/
CT; in the presence of hiatal hernia, a contracted LES can mimic T-Stage Criteria, American Joint Committee on
an 18FDG-avid tumor of the lower thoracic esophagus. Cancer (AJCC)/Union for International Cancer Control
(UICC) Staging System for Esophageal Carcinoma
TX Primary tumor cannot be assessed

Staging and Grading T0 No evidence of primary tumor
Tis High-grade dysplasiaa
In contrast to many other malignancies, T-stage is not defined by T1 Tumor invades lamina propria, muscularis mucosae, or submucosa
size, but by depth of tumor penetration through the layers of the T1a Tumor invades lamina propria or muscularis mucosae
esophageal wall and involvement of extraesophageal tissues T1b Tumor invades submucosa
(Table 5.3 and Fig. 5.3). Nevertheless, T3 and T4 tumors are usu- T2 Tumor invades muscularis propria
ally larger than T1 and T2 tumors.30 On CT, a thoracic esopha- T3 Tumor invades adventitia
geal wall may be considered abnormally thick if it measures >5 T4 Tumor invades adjacent structures
mm when contracted or nondistended31–34 or >3 mm if ade- T4a Resectable tumor invading pleura, pericardium, or diaphragm
quately distended.31,34 The normal wall of the nondistended T4b Unresectable tumor invading other adjacent structures (e.g., aorta,
intra-abdominal portion of the esophagus may be up to 6 mm in vertebral body, trachea, etc.)
thickness. Noncancerous esophageal disease can cause wall a
Carcinoma in situ is no longer part of TNM nomenclature for esophageal cancer; instead, high-
thickening that may confuse CT-delineation of primary tumor grade dyplasia refers to noninvasive neoplastic epithelia.
extent—notably Barrett esophagus and esophagitis.33 Barrett Source: AJCC. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

T1a
HGD (intramucosal)
(high-grade
dysplasia)
T4b
T1b Epithelium
T3 T4a
(submucosal)
Basement membrane
T2
Lamina propria
Muscularis mucosae
Submucosa
Muscularis propria
Periesophageal tissue
N0
Aorta
N1=1–2

N2=3–6
N3=7 or more
M1
Pleura
Figure 5.3. T, N, and M classifications, American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. Primary tumor
(T) is classified by depth of tumor invasion. Regional lymph node classifications are determined by metastatic burden. Distant metastatic sites are designated M1.
(Reprinted with permission from Springer-Verlag New York Inc., Publisher of American Joint Committee on Cancer (AJCC). AJCC Cancer Staging Manual. 7th ed.
New York, NY: Springer, 2010).
is further divided into three sublayers: Epithelium (m1), lamina Although EUS is the primary modality for detailed evaluation
propria (m2), and muscularis mucosae (m3). Table 5.3 describes of the primary tumor, CT findings may suggest T4 disease or the
the depth of invasion into these layers and extraesophageal struc- absence of T4 disease. Invasion may be obvious, such as gross
tures that define each T-stage. The submucosa has no internal extension into adjacent organs, or more subtle, such as a loss of
anatomic separations, but pathologists often measure invasion of fat planes between primary and other mediastinal structures. For
the submucosa according to thirds of its depth: Inner third (sm1), aortic involvement (T4b), loss of fat planes is considered more
middle third (sm2), and outer third (sm3). These histologic layers specific for invasion if the tumor is inseparable from ≥90 degree
and sublayers are far below the spatial resolution of PET but are of the aortic circumference38 or if the small triangular region
often discussed in the PET literature when correlating imaging between the esophagus, aorta, and spine (normally occupied by
and histopathology findings. The muscularis propria has inner cir- fat) is occupied by tumor.39 Displacement of the tracheobronchial
cular and outer longitudinal muscle layers. Extraesophageal inva- airways or heart/pericardium by an abutting tumor, especially if
sion begins with the connective tissues enveloping the esophagus, associated with focal impingement/deformity, is suspicious for
the adventitia (T3). The esophagus has no serosa. T4b disease.38,40 Pericardial effusion, thickening, and loss of peri-
Higher T-stages are associated with higher risks of metastatic cardial fat are other suspicious signs.41 If distinct fat planes exist
disease and worse overall survival. T1 to T2 tumors may undergo between the esophageal tumor and other mediastinal structures,
primary surgical resection if no metastatic disease is evident. T3 an absence of T4 findings can be reported, and EUS can be used
or T4 tumors may receive neoadjuvant therapy, followed by resec- to distinguish among T1- to T3-stages.
tion, or definitive treatment by a nonsurgical approach with com- EUS is the imaging modality of choice for primary tumor delin-
bined modality (chemoradio-) therapy. Unresectable (T4b) tumors eation, because it can visualize the depth of tumor penetration
include those involving heart, great vessels, trachea, liver, pan- within the esophageal wall. The overall accuracy for T-stage is
creas, lung and/or spleen. Tumors involving pericardium, pleura, 70% to 90%, with lesser accuracies in tiny superficial lesions and
or diaphragm alone are usually resectable (T4a). tumors associated with esophageal stenosis.42,43 For histologic

grading (G), tumor differentiation is scored from G1, for well- of 18FDG PET (not PET/CT), reported a highly variable sensitivity
differentiated tumors, to G4, for undifferentiated tumors. for the detection of nodal involvement (22% to 93%).48,49,61,62 These
Of note, even small tumors with only mucosal or submucosal numbers are probably no longer applicable in the current era.
involvement (T1a-b) can present with extensive nodal or even Combined PET/CT provides better detection of nodal metastases
distant metastatic disease. Therefore, 18FDG PET/CT may be use- than PET alone (because of accurate localization of mediastinal
18
ful even for staging of very small primaries. FDG activity). Table 5.5 summarizes the sensitivity and specific-
ity of 18FDG PET for detection of lymph node metastases from
various published studies.19,29,48,61–69
Primary Tumor 18FDG Avidity and 18FDG The extensive lymphatic network of the esophagus facilitates
Pet Imaging of the Normal Esophagus the spread of metastatic disease even from primary tumors limited
to the mucosa of the esophageal wall.70 Lymphatic channels are
Both AC and SCC of the esophagus usually demonstrate intense found in highest concentration in the submucosa, frequently drain-
18
FDG uptake.25 18FDG PET/CT fusion imaging has markedly supe- ing directly into the thoracic duct, facilitating the spread of sys-
rior diagnostic accuracy compared to PET alone and also in com- temic metastatic disease. Lymphatic channels are also present, to
parison to the sum of information gained from interpretation of a lesser degree, in the lamina propria of the mucosa, allowing the
separately acquired PET and CT data.44–46 When the PET/CT is per- potential lymphatic spread of T1a tumors. Therefore, occasionally
18
formed with intravenous contrast, artifacts from high-concentration FDG PET/CT may detect nodal metastases even in patients with
contrast material in mediastinal vessels can rarely be seen and small T1 primaries. The submucosal lymphatics are oriented along
should not be confused with 18FDG uptake in metastatic lymph the same longitudinal axis as the overall esophagus, and lymph
nodes. This question is easily addressed by careful review of CT may flow from the region of the primary esophageal tumor to a
and PET data sets as well as review of nonattenuation corrected “local” lymph node that is not on an adjacent transaxial plane.
PET images. 18FDG avidity appears independent of the primary Hence, for esophageal cancer, “local” lymph node involvement is
location within the esophagus.47 Sometimes focal prominence of defined as metastatic lymphadenopathy found anywhere from the
18
FDG uptake can be seen in the retrocardiac (mid-) region of the cervical periesophageal region to the celiac nodal basin.70 If nodal
thoracic esophagus as a normal variant. Mild diffuse 18FDG uptake involvement is found outside these anatomic regions, it is consid-
along the course of the entire esophagus may be related to ered distant metastatic (M) disease. Although celiac adenopathy
increased peristalsis/spasm or esophagitis. Many T1 tumors are was previously considered distant metastatic disease, the seventh
not detectable on PET—probably because of their small volume edition of the AJJ staging criteria now considers this locoregional
and the partial volume effects on PET.48,49 disease and, hence, not necessarily an indication of unresectable
Some (but not all) studies have shown that the intensity of 18FDG disease. Nevertheless, the presence of celiac adenopathy is still
uptake correlates with dedifferentiation,47,50 presence of nodal considered an adverse prognostic factor71 and merits special men-
metastases,47,51 vascular invasion,47 as well as GLUT-1 and hexoki- tion in the 18FDG PET report. For GEJ tumors, the lymphatic drain-
nase II expression.47,52 Moreover, the SUV of the primary esopha- age pattern depends on the exact location: Tumor of the distal
geal tumor correlates weakly with T-stage.50 Higher primary tumor esophagus may drain into the mediastinum and along the celiac
SUV has been associated with advanced disease stage.50,51 axis, whereas tumors of the gastric cardia and below drain to
nodes in the celiac axis, splenic hilum, and para-aortic region.72
The main reason for a false-negative 18FDG PET/CT in nodal
Nodal Involvement (N-Stage) staging is probably the small size of metastatic deposits in some
The presence or absence of nodal (or other) metastatic disease is nodes; when PET/CT shows no evidence of nodal involvement,
the most important prognostic factor in esophageal cancer.11,53 up to half of such patients may actually harbor nodal metastases
N-stage is defined by the number of regional lymph nodes involved (pN+).69 In one series, 38% of PET-N0 patients harbored pN1
(Table 5.4), based upon data suggesting the prognostic importance disease and 8% harbored pN2 disease; pN3 disease was not
of the number of involved locoregional lymph nodes.54–59 The detec- observed.69 Yasuda et al.69 studied the PET detection rates of
tion of 18FDG-avid locoregional lymph nodes on PET/CT is associ- metastatic disease within a particular nodal station and showed
ated with worse survival in both AC (76) and SCC (77). Of note, even a sensitivity and specificity of 34.8% and 99.9%, respectively.
microscopic nodal metastatic disease, invisible to CT and often They measured the area (mm2) occupied by the “nest” of cancer
undetectable on FDG PET, is an adverse prognostic factor.60 cells within each node and the cancer cell density (cells/mm2).
EUS is the single most accurate imaging modality for detection Metastatic disease in lymph nodes with false-negative PET/CT
of nodal metastases, but it is imperfect. Hence, oncologists often contained smaller tumor cell nests than PET-positive nodes
rely upon the combined sensitivity of EUS, CT, and sometimes (median of <2 mm2 versus 85 mm2). The density of metastatic
18
FDG PET/CT to avoid understaging. Several small early studies cells was similar in both true-positive and false-negative PET
groups. In a small surgical series of 39 patients with AC,46 PET/
CT identified 70% (55 out of 79) of the nodal groups harboring
Ta b l e 5 . 4 metastatic disease. The 24 lymph node groups with false-nega-
tive PET/CT were randomly distributed and contained lymph
Nodal Staging, American Joint Committee on Cancer nodes with mean diameters of 4 to 5 mm. Despite these limita-
(AJCC)/ Union for International Cancer Control (UICC) tions, patients with PET-N0 disease have better relapse free sur-
Staging System, for Esophageal Carcinoma vival, better overall survival, and lower postoperative recurrence
rates than patents with PET-N+ disease; this probably reflects
the metastatic disease volume.69
N-Stage Extent of Regional Lymph Node Involvement There are many potential reasons for false-positive lymph
nodes on a staging 18FDG PET/CT scan. Therefore, suspicious
Nx Regional nodes cannot be assessed
N0 No regional node metastases
lymph nodes on 18FDG PET/CT are usually confirmed by tissue
N1 1–2 regional node metastases sampling. For instance, false-positive FDG uptake may occur
N2 3–6 regional node metastases because of nodal inflammation associated with reactive or granu-
N3 >6 regional node metastases lomatous adenopathy (e.g., sarcoidosis),46 in particular when
occurring symmetrically in the pulmonary hila where PET speci-
Source: AJCC. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. ficity is much lower (hilar specificity only 29% as compared to

Ta b l e 5 . 5
Clinical Studies Comparing the Accuracy of Positron Emission Tomography (PET) or Fusion PET-CT with Computed
Tomography (Without PET) and/or Endoultrasonography for the Detection of Lymph Node Metastases
References Histology Patients (n ) Imaging Sensitivity (%) Specificity (%) Prospective/Retrospective
Flamen et al.48 SCC/AC 33 PET 39 97 Prospective

CT 63 88
EUS 22 96
EUS/CT 54 90
Lerut et al.61 SCC/AC 42 PET 22 91 Prospective
CT + EUS 83 45
Yoon et al.63 SCC 81 PET 30 90 Prospective
CT 11 95
Sihvo et al.64 AC 55 PET 35 91 Prospective
CT 42 45
EUS 85 60
Lowe et al.19 SCC/AC 75 PET 82 60 Prospective
CT 84 67
EUS 86 67
Shimizu et al.65 SCC 20 PET-CT 11–50 85–100 Prospective

Thin slice CT 22–100 69–100
Kneist et al.62 SCC/AC 58 PET (only) Abdomen: 24 (8–47) Abdomen: 95 (77–100) Prospective
Thorax: 42 (23–63) Thorax: 94 (72–100)
CT Abdomen: 73 (50–87) Abdomen: 74 (50–89)
Thorax: 75 (55–89) Thorax: 71 (46–88)
Choi et al.66 SCC 48 PET alone 57 (per nodal group) 97 (per nodal group) Prospective
CT 18 (per nodal group) 99 (per nodal group)
Tanabe et al.67 SCC 102 PET 46 96 Prospective
CT 67 81
Choi et al.68 SCC/AC 109 EUS 42 91 Retrospective
CT 35 93
PET 49 87
Yasuda et al.69 SCC 121 PET-CT 35 100 Retrospective
29
Salahudeen et al. SCC/AC 15 PET-CT 47 100 Retrospective
CT-EUS 93 93
PET, positron emission tomography; CT, computed tomography; EUS, endoscopic ultrasound; SCC, squamous cell carcinoma; AC, adenocarcinoma.
93% in mediastinal nodes in one study).63 Of note, sarcoid adenop- this was not confirmed by biopsy; assuming up to 50% false posi-
athy classically demonstrates a fairly symmetrical pattern of tives, the true rate of unexpected PET-detected metastases may
mediastinal and particularly hilar/perihilar 18FDG-avid uptake thus have been 5% to 10%. Of note, these data from the PET-only
(“too symmetrical” for nodal metastatic disease). False-positive era may have limited applicability at the present time. In patients
18
FDG uptake can also be seen in brown adipose tissue in the with GEJ tumors staged M0, by imaging, diagnostic laparoscopy
neck, various areas of the mediastinum, and upper abdomen may be performed because CT and PET are poor at detecting
(perihepatic, perinephric). This can sometimes obscure true-positive small peritoneal metastases.77,78
18
FDG uptake in lymph nodes.
Prognostic Value of Pretreatment
Distant Metastases (M-Stage) FDG PET/CT
Current AJCC classification defines patients according to the
absence (M0) or presence (M1) of distant metastases. Common Primary esophageal tumor SUV has been variably reported as
sites of distant metastases in esophageal cancer patients are liver, prognostic for survival in SCC50 and AC.79 In studies that exclu-
lungs, bone, and adrenal glands.27,73 AC, especially of the GEJ, sively or predominantly enrolled SCC patients, SUV and other
more frequently metastasizes to intra-abdominal sites—notably parameters quantifying the 18FDG avidity of the primary tumor
liver and peritoneum. SCC metastases are usually intrathoracic. was often shown to be prognostic, with higher 18FDG avidity por-
Preoperative 18FDG PET changes clinical management in up to tending a worse outcome.50,51,80,81
20% of such esophageal cancer patients—usually by revealing In cancer studies that exclusively or predominantly enrolled
metastatic disease that aborts fruitless surgery and/or prompts AC patients, quantitative 18FDG-avidity parameters again have
induction therapy.18,24,73–76 In the prospective Z0060 trial by the frequently proven prognostic.79,82 However, other studies did not
American College of Surgeons Oncology Group, 18FDG PET-only confirm this.83–85 For instance, Rizk et al.79 studied AC patients
(not PET/CT) after standard clinical staging for esophageal carci- and found that baseline 18FDG SUV predicted outcome for
noma identified confirmed M1b disease in only 5% of patients.74 resectable early stage disease, independent of clinical and
In an additional 9% of patients, PET suggested distant disease, but pathologic stages; but it did not predict the survival of patients

with locally advanced disease receiving preoperative chemora- When pathologic response serves as the gold standard, the Man-
diotherapy.86 In fact, these authors found that tumors with dard tumor regression grading (TRG) system95 or similar systems
higher 18FDG avidity were more likely to demonstrate a patho- are commonly used. In essence, the pathologic response is scored
logic response to neoadjuvant therapy, which may have acted as by the percentage of tumor cells that remain viable under the
an equalizing factor among patient groups with otherwise dif- microscope: Nonresponders show >10% tumor cells viable; par-
ferent prognosis.86 Along the same lines, a small study in 31 tial responders 0% to 10%; and complete responders 0% viable
patients noted that the subgroup of patients with SCC and high tumor cells. A “major” pathologic response is often defined as
baseline SUV responded better to trimodality therapy than those ≤10% viable tumor cells, grouping together the pPR and pCR cat-
with lower SUV but this trend was not seen when considering egories.
all histologies.87 This may reflect the different tumor biology of Changes in tumor extent, measured by EUS and/or CT, have a
SCC versus AC and highlights the need to study AC and SCC poor accuracy for predicting pathologic complete response at the
histologies separately. time of subsequent surgery.96–99 A randomized study of 162 patients
In some studies, parameters of tumor 18FDG avidity, besides with locally advanced SCC compared overall survival in patients
SUV, were found to be prognostic even when SUV was not.80–82,88 receiving chemoradiotherapy with or without surgery. With a
More recently, the metabolic tumor volume (MTV) of the primary median follow-up of 6 years, the outcome of patients receiving
tumor was found to be a better predictor of overall survival than chemoradiotherapy alone was similar to that in patients who
was SUV.80 underwent subsequent surgical resection. Because pathologic
A proper assessment of data from studies regarding the prog- response data were not available in the nonsurgical cohort, clinical
nostic significance of FDG uptake in esophageal cancer is compli- tumor response was found to be the single independent prognostic
cated by several methodologic issues: For example, some studies factor for overall survival (hazard ratio, 0.30; 95% CI, 0.19 to
used a variety of PET scanners, and many combined all patients 0.47)—with clinical response defined as improved dysphagia, CT
regardless of histology and treatment modalities into one analysis.89 tumor shrinkage by >50%, and a 50% reduction in esophageal
Finally, most studies only examined 18FDG uptake in the primary lumen encroachment by barium swallow. However, in other trials
tumor as a prognostic biomarker, but disease response to neoad- of locally advanced SCC, CT could not predict pathologic or clinical
juvant therapy may vary between the primary tumor and lymph response to neoadjuvant therapy.100–102 For instance, in a study of
nodes. 51 patients with locally advanced disease, 18FDG PET response
using PET response criteria in solid tumors (PERCIST) crite-
ria102 predicted disease-free and overall survival, whereas CT
Evaluating Tumor Response to tumor response using conventional response evaluation criteria in
solid tumors (RECIST) criteria102 did not (CT often underestimated
Cancer Treatment tumor response, and the CT response could not be evaluated in
10% of patients). CT volume measurements and changes in tumor
The optimal therapeutic approach to advanced esophageal cancer volume over time have been proposed as better response param-
remains a subject of debate. Current NCCN guidelines discuss mul- eters than simple assessment of tumor length or diameter. How-
tiple therapeutic options for a particular esophageal cancer stage ever, in one small trial, CT volume changes after 2 weeks of
with no definitive recommendation regarding what constitutes the induction therapy did not predict histopathologic response to
optimal treatment.2 There is general agreement2 that surgery is chemoradiation.103
unsuitable for patients with a cervical esophageal cancer or “cer-
vicothoracic” primary (<5 cm from the UES). For tumors in other
18
locations, chemoradiotherapy without surgical resection is asso- FDG PET for Response Assessment
ciated with a high local failure rate. Trimodality therapy (i.e.,
chemotherapy + radiotherapy + surgical resection) offers some Data regarding the predictive value of 18FDG PET for response
survival benefit over chemoradiotherapy alone,90 even though assessment (Table 5.6) need to be interpreted considering sev-
postsurgical mortality may be as high as 13%.91 A recently pub- eral major variables, such as tumor histology (AC versus SCC),
lished multicenter trial indicates that preoperative chemotherapy disease stage, therapeutic regimen (chemotherapy with various
plus resection offers an improved survival for esophageal cancer drug combinations versus chemoradiotherapy), and the time of
patients (n = 366; predominantly AC histology) compared to sur- imaging (e.g., during or at the end of neoadjuvant ther-
gery alone.92 One rationale for neoadjuvant (or induction) therapy apy).27,87,101,104–121 Of note, the published studies on this subject
is to downsize the primary tumor in hope of making it more resect- have been rather heterogeneous; readers are encouraged to
able, because a complete primary resection (R0) is associated with review the methodology in each study carefully before accepting
more favorable clinical outcome than incomplete (R1, R2) resec- conclusions. This difficulty in interpreting PET-response studies
tions.93 Yet neoadjuvant chemotherapy benefits only a subgroup of in esophageal cancer was also highlighted in a recent meta-
patients, while potentially exposing nonresponders to significant analysis.89
toxicity.93,94 In general, a greater decline in 18FDG SUV during therapy cor-
There is a clear need to identify those patients who are not relates with better histopathologic response and better clinical out-
benefiting from induction chemotherapy as quickly as possible, come but this is not a linear relationship. Lack of residual FDG
both to avoid unnecessary delay in surgery that may be beneficial uptake after completion of treatment (or minimal residual uptake)
(possibly curative) or to switch those “metabolic nonresponders” conferred prognostic information in some but not all trials. Other
from the ineffective and potentially toxic neoadjuvant treatment parameters of tumor 18FDG metabolism have been reported predic-
to an alternative salvage drug regimen. For these purposes, tive of therapeutic response but these require further validation
researchers have tested the efficacy of imaging as a surrogate and are not clearly superior to standard SUV analysis.88,104 In most
biomarker of tumor response. Moreover, if resection is not per- clinical studies, investigators used changes in 18FDG tumor SUV
formed, and pathologic response therefore not quantifiable, mea- under therapy to segregate patients into two groups: Metabolic
surement of clinical tumor response by imaging becomes a crucial responders versus metabolic nonresponders. This was done by
response parameter. The ultimate “gold standard” of response is retrospective analysis, either dichotomizing the data set or using
improved patient survival, but tumor response on imaging stud- ROC analysis to find the percentage change in SUV that best sepa-
ies can also be correlated with other surrogate markers, such as rates metabolic responders from nonresponders, using histopathol-
time to disease progression or primary tumor pathologic response. ogy of the tumor specimen or clinical outcome as the gold standard.

Ta b l e 5 . 6
Selected Published Clinical Trial Data Regarding The Efficacy of FDG PET for Predicting the Histopathologic and/or Clinical Response of Esophageal
Cancer to Various Therapeutic Regimens
Adenocarcinoma
Histopathologic Response Clinical Response
Patients PET-Response
a
References (n) Therapy PET Timepoint(s) Criteria Sensitivity Specificity Sensitivity Specificity Notes
Kroep 11 ACs Neoadjuvant chemo After two cycles and SUV decrease ≥40% 100% (early); 100% 86% (early); Not assessed Not assessed —
et al.104 1 SCC (gemcitabine + cisplatin; after all six cycles after 2 cycles; (late) 100% (late)
1 large cell 3-wk schedule; 6 cycles). ≥60% decrease
Tumor resection in 9 of after all 6 cycles
12 only
Westerterp 20 ACs 5-wk course of preop CRT 2 wks into treatment SUV decrease ≥31% 75% 75% Not assessed Not assessed —
et al.105 6 SCCs and hyperthermia
van Heijl106 119 ACs 5-wk period of concurrent CRT 2 wks into treatment Any SUV decrease Sensitivity 91% 50% — — —
26 SCCs (paclitaxel + carboplatin (≥0%) R0 resection: 87% (13
once weekly; EBRT total of 15 patients; CI,
dose of 41.4 Gy in 23 frac- 60–98%) of PET
tions of 1.8 Gy, 5 fractions responders; 41% (9
a wk). 100 underwent of 22; CI, 21–64%)
resection of PET nonre-
sponders (p = 0.01)
Weber 37 ACs Neoadjuvant chemo (cisplatin, 2 wks into treatment SUV decrease ≥35% 89% (eight of nine 75% (21 of 28 95% (CI, 77–100%), 93% (CI, —
et al.107 leucovorin, fluorouracil, cis- responders; CI, nonre- 68–100%)
platin. AEG I tumors also 52–100%) sponders; CI,
received paclitaxel) 55–89%)
Two cycles, 36 d each.
Surgical resection 3–4 wk
postchemo
Lordick 119 ACs 2 wks of induction chemother- 2 wks into treatment SUV decrease ≥35% PPV: 58% of PET NPV: 100%. Zero Median OS: PET respond- Median event-free —
et al.108 apy (platinum + fluoroura- responders had percent of ers not yet reached survival: PET

MUNICON I cil-based chemo). PET pathologic response patients with after 2.3-y follow-up; responder 29.7
nonresponders underwent (<10% viable tumor an unfavorable PET nonresponders mos, PET non-
early tumor resection. PET tissue at resection) FDG PET 25.8 mos ( p = 0.015) responders
responders completed (up response had 14.1 mos
to 12 wks) of preop chemo a pathologic ( p = 0.002)
then resection response.
Swisher 90 ACs CRT + surgery 4–6 wks after Post-CRT SUV ≥4 Primary post-CRT SUV: — Post-CRT PET SUV — Post-CRT FDG PET
et al.109 13 SCCs completion of CRT SUV decrease (for responders = 3.1 ± predicted long-term cannot rule out
primary or meta- 1.7; nonresponders survival residual micro-
static tumor SUV) = 5.8 ± 6.8 ( p = scopic disease
on pre- versus 0.01) Primary SUV so that esopha-
post-CRT PET was decrease pre- versus gectomy should
not significant ( p = post-CRT PET: remain a thera-
0.12–0.29) responders = 58% ± peutic option
25.2; nonresponders
= 45% ± 37.1
( p = 0.12)
(continued )
75
Ta b l e 5 . 6
76
Cancer to Various Therapeutic Regimens (Continued )
Adenocarcinoma
Patients PET-Response Histopathologic Response Clinical Response
References (n ) Therapy PET Timepoint(s)a Criteria Sensitivity Specificity Sensitivity Specificity Notes
Monjazeb 122 ACs CRT no surgery n = 75 Mean 45 d after CRT SUV ≤ 3 allowing for Not assessed Not assessed Median OS: PET respond- — The trimodality
et al.110 41 SCCs end “mild hypermeta- ers = 38 mos; PET patients demon-
bolic activity which nonresponders = 11 strated a better
may represent mos (p < 0.01) clinical outcome
posttreatment 2-y survival: PET overall than the
esophagitis” responders = 71%; definitive CRT
PET nonresponders = (without surgery)
11% (p < 0.01) group overall. Yet
PET responders
within the defini-
tive CRT group
demonstrated
outcomes equally
favorable as the
trimodality group
— — CRT + surgery (trimodality) After CRT preop SUV ≤3 No significant correla- — No significant correlation — —
n = 88 tion ( p = 0.18) between PET response
between PET and clinical outcomes
response and patho-
logic response
zum Buschen- 56 ACC 2 wks of preop chemother- 2 wks into treatment SUV decrease ≥35% Major histologic remis- — 1-y progression-free rate — —
felde apy. PET nonresponders sions were observed was 74 ± 8% in PET
et al.111 switched to salvage CRT. in 12 metabolic responders and 57 ±
MUNICON II PET responders completed responders (36%; 10% in metabolic non-
(up to 3 mos) of preop 95% CI, 22–53%) responders (log rank
chemo. Surgery then in and 6 nonresponders test, p = 0.035). 1-y
54 of 56 (26%; 95% CI, overall survival was
13–46%). R0 resec- comparable between the
tion rate 82% (95% groups (∼80%), and 2-y

CI, 66–91%) in met- overall survival was esti-
abolic responders mated to be 71 ± 8% in
and 70% (95% CI, metabolic responders
49–84%) in meta- and 42 ± 11% in PET
bolic nonresponders nonresponders (hazard
( p = 0.51) ratio, 1.9; 95% CI,
0.87–4.24; p = 0.10)
Malik et al.112 37 ACs 6-wk regimen of presurgical 2 wks into treatment SUV decrease ≥26% 62% 71% No associated survival — —
CRT benefit (p = 0.68)
Klayton 49 ACs Induction CRT + surgery; 47 26 d into CRT (range: Focal hotspot at pri- Complete pathologic — Not assessed Not assessed —
et al.113 8 SCCs patients received cisplatin– 10–76) mary site on post- response (pCR):
5-FU, 6 received cisplatin– CRT PET Focal hotspot PPV: 86%
5-FU–paclitaxel (qualitative PET non-pCR (residual
visual analysis) disease); NPV (no
hotspot): 64% pCR
Change in SUV pre- ver-
sus post-CRT PET: No
pCR = 44% decrease
SUV; pCR = 47%
decrease SUV ( p = ns)
Squamous Cell
Patients PET-Response Histopathologic Response Clinical Response
References (n ) Therapy PET Timepoint(s)a Criteria Sensitivity Specificity Sensitivity Specificity Notes
Brücher 27 Preop CRT 5-FU 3-wk post-CRT 52% SUV decrease 100% sensitivity 55% Nonresponders to PET — —
et al.114 (preop) scanning had a signifi-
cantly worse survival
after resection than
responders
Wieder 38 Preop CRT 2 wks (n = 27 of 38) SUV decrease ≥30% 93% (95% CI, 88% (95% CI, PET responders had better — —
et al.115 and/or at 3–4 wks 68–100%) 47–100%), survival ( p = 0.011)
(n = 38 of 38)
Higuchi 50 Preop chemo (n = 35; 2-wk postchemo or Posttreatment SUV 86% 93% Cause-specific 5-y sur- —
et al.116 cisplatin + doxorubicin + FU) 4-wk post-CRT. <2.5 (primary site) vival: PET negative =
Preop CRT (n = 15; EBRT 2-wk preop Percent changes in 68%; PET positive =
4 wks, 5 d/wk, 40 Gy total; tumor SUV (30– 37% ( p = 0.0042)
plus 4 wks of cisplatin + FU, 80%) were not pre- Local recurrence: p = ns
5 d/wk) dictive of histologic Distant recurrence: PET
or clinical response positive = 48%; PET
negative = 24%
( p = 0.08)
Hematogenous recurrence:
PET negative = 5%;
PET positive = 37%,
(p = 0.0083)
Jingu et al.117 20 SCCs Concurrent CRT (EBRT 2 Gy/d, <7 d after CRT Post-CRT SUV(max) Not assessed — Cause-specific survival and — PET did not predict
Postop 5 d/wk, total dose of 60 Gy; ≤2.4 local control rates were RECIST response,
recur- chemo was platinum based; ≥69% decrease in significantly better for despite its prog-
rence usually with FU; SUVmax patients with post-CRT nostic value
usually two cycles) SUV(max) ≤2.4 ( p =
0.033 and 0.010, respec-
tively). Decreased SUVmax
pre- versus post-CRT was
significantly correlated with
local control rate ( p =
0.042) but not cause-spe-

cific survival ( p = 0.89)
Makino 100 SCCs 5-FU, adriamycin, and 2–3 after end of neo- SUVmax drop 70% Sensitivity/specificity — Multivariate analysis: 2-y — —
et al.101 cisplatin followed by adjuvant tx (preop) not reported PFS associated with
surgical resection Significant correlation number of cN before
between SUVmax NACT (HR = 2.537;
percentage reduction p = 0.0092), SUVmax
and tumor area reduction (HR = 3.202;
reduction were weakly p = 0.0072), and num-
correlated (R2 = ber of pN (HR = 2.226;
0.369; p < 0.0001) p = 0.0146)
Yang et al.118 61 SCCs CRT, no surgery. FU plus cispl- 4–6 wks into CRT SUV decrease ≥51% Not assessed — 5-y PFS: PET sensitivity of Clinical response —
atin and irradiation with a 76.9% and a specific- (WHO criteria):
total dose of 5,600–6,400 ity of 79.2% ( p <0.01). responders =
centigray (cGy) within 7 wks Median PFS and OS 49% SUV
were significantly longer decrease; nonre-
in PET responders sponders = 38%
(p < 0.01) decrease
( p < 0.01)
77
(continued )
Ta b l e 5 . 6
78
Cancer to Various Therapeutic Regimens (Continued )
Both
Patients
(n ) Histopathologic Response Clinical Response
SCC (n ) PET-response
a
References ACC (n ) Therapy PET Timepoint(s) Criteria Sensitivity Specificity Sensitivity Specificity Notes
Flamen 27 SCCs Concomitant CRT (EBRT 4 4–5 wks after end of No residual tumor PET sensitivity for pCR: — Improved survival for PET — —
et al.119 9 ACs wks, 5 d/wk, 40 Gy total; CRT uptake (visual, 4 of 6 (67%) responders: 16 mos
cisplatin and 5-FU) plus qualitative PET PET PPV for pCR: 4 of versus 6 mos
resection analysis) 8 (50%) (p = 0.01)
Thurau 42 SCCs 24 of the patients underwent 6 wks after induction Tumor SUV decrease SUV reduction ≥50% — SUV reduction ≥50% — —
et al.27 39 ACs primary esophagectomy, 9 of chemotherapy ≥50% correlated with major associated with a signif-
2 anaplas- had palliative treatment, histomorphologic icantly better survival
tic carci- and 50 neoadjuvant radio- response (tumor (33.1 ± 3.5 mos) than
nomas chemotherapy (cisplatin, regression grade 4, for nonresponders (21.7
5-FU; 50.4 Gy) <10% vital tumor ± 3.3 mos; p = 0.02)
cells) and histopatho- and than for patients
logic response (ypT0 having primary surgery
ypN0) (29 ± 3.2 mos; p =
0.05)
Vallböhmer 66 SCCs Neoadjuvant CRT (cisplatin, 2–3 wks after the Tumor SUV decrease Borderline association — No significant association — —
et al.120 53 ACs 5-FU, 36 Gy) plus surgery end of CRT (threshold not was seen between between PET parame-
specified) major responders ters and prognosis was
and SUV decrease found
(p = 0.056), but sig-
nificant association
between complete
pathologic response
and percentage SUV
decrease (p = 0.049)

Klaeser 20 SCCs Two cycles of induction che- 2 wks after induction Nonresponder = PET nonresponse pre- — Not assessed — Multiple centers,
et al.121 25 ACs motherapy followed by chemotherapy, SUVmax decrease dicted histopathologic different scan-
chemoradiotherapy (CRT) before CRT and ≤40% nonresponse after ners—no details
and surgery surgery completion of CRT,
with a sensitivity of
68% and a specificity
of 52% ( p = 0.021)
Schmidt 31 ACs CRT then resection 3–4 wks after the SUVmax drop ≥70% SUVmax drop >70% did — No significant association — —
et al.87 24 SCCs end of preop correlate with path between metabolic
therapy response in SCC imaging and prognosis
subgroup, but with was found
significant overlap
with nonresponders
Note that the citations are grouped according to whether the patient population studied consisted wholly or predominantly adenocarcinoma (AC) or squamous cell carcinoma (SCC) patients or was a mixture of both patient cancer types.
a
All studies included a pretreatment PET scan for baseline tumor assessment.
These studies show considerable overlap in the ranges of SUV metabolic responders (initially defined as any decline in 18FDG
changes between these two patient groups. The most stringent PET SUV > 0%), and this was correct in 58. Overall, the accuracy and in
criterion to diagnose a complete pathologic response (pCR) is the particular negative predictive value in this trial remained subopti-
complete lack of any residual abnormal 18FDG uptake at the previ- mal, even when other cutoffs for % decline in SUV were applied.
ously visualized tumor site. However, even using this stringent Interestingly, six of the 24 metabolic “nonresponders” actually
criterion, McLoughlin et al.122 reported poor negative predictive showed a clinically significant pathologic response, raising concern
value (35%) and poor specificity (44%) to exclude residual viable that potentially effective therapy might be abandoned mistakenly
tumor cells. In fact, this is not entirely surprising because small based on a false negative PET scan. Two other trials also reported
volume (microscopic) tumor deposits are not detectable by PET that pathologic nonresponders to CRT can demonstrate significant
imaging. Similarly, persistent increased activity at the tumor site decreases in SUV of up to 26% to 47% at the same time point.112,113
after treatment also has suboptimal specificity as a marker of resid- In one trial, the SUV decreases were in fact quite similar in patho-
ual disease (slightly better when residual activity is focal rather logic responders and nonresponders112; moreover, in both trials
than diffuse113) because inflammation can cause false-positive SUV decreases were not associated with prognosis.
18
FDG uptake. Other studies also investigated the utility of 18FDG PET early dur-
The potential clinical implications of PET-response studies vary ing combined CRT, but they included both SCC and AC patients in
with the time when imaging is performed. Studies performed dur- near-equal proportions. Because SCC and AC are different dis-
ing neoadjuvant therapy provide an insight into the kinetics of eases—different in radiosensitivity, natural history, and other impor-
tumor cell kill in response to therapy; early changes in 18FDG tant clinical–biologic features — this pooling of patients makes the
uptake during therapy are used as a predictor of ultimate response interpretation of study results difficult. Another group of investiga-
at the completion of such therapy. Patients identified as metabolic tors combined neoadjuvant chemoradiotherapy with hyperthermia
nonresponders at an early time point can possibly be switched to (believed to enhance tumor response105); again these data are diffi-
a different induction regimen (noncross resistant therapy or com- cult to compare to standard treatment regimens. Overall, published
bined chemoradiotherapy instead of chemotherapy alone), or pro- clinical trial data regarding the utility of “early” 18FDG PET for pre-

ceed straight to surgery. The latter approach avoids potential dicting esophageal AC response suggest: (1) An early (∼2 weeks)
toxicity and tumor progression during ineffective neoadjuvant favorable 18FDG PET response to induction chemotherapy (without
therapy. In contrast, studies obtained at the end of induction ther- radiation) indicates that the primary tumor will show a significant
apy serve two aims: Restaging of distant disease and prediction of pathologic response at resection (about 50-50 chance); and (2) a
pathologic response at the primary site. These end-of-treatment primary tumor failing to demonstrate an early PET response to
studies should be obtained at least 5 to 6 weeks after the last induction chemotherapy is very unlikely to exhibit a significant
therapy dose in order to avoid false-positive PET findings second- pathologic response. However, the same conclusions do not neces-
ary to treatment-induced inflammation.2,112 sarily apply to patients treated with induction chemoradiotherapy.
Based on the data mentioned above, two pertinent questions
needed to be addressed: (1) Would the overall survival of metabolic
PET Studies in Adenocarcinoma nonresponders who proceeded straight to early tumor resection
without continued ineffective chemotherapy be at least as good or
better than the overall survival of a historical control group of PET
Early Response Evaluation nonresponders who completed the standard 3 months of preop-
The role of 18FDG PET early during neoadjuvant chemotherapy erative chemotherapy123 and (2) could the outcome of metabolic
(without radiation) in locally-advanced AC of the esophagogastric nonresponders whose treatment regimen is escalated to combined
junction (AEG) has been addressed in a series of studies by inves- CRT be improved compared to the historical control group receiv-
tigators in Munich (Germany). In early studies, they performed ing continued chemotherapy alone. The second question was
18
FDG PET pretreatment and after 2 weeks into a 3-month preop- addressed in 56 patients in the MUNICON-II trial.111 Twenty-three
erative chemotherapy regimen. A favorable histopathologic and early nonresponders were switched to combined CRT. Their histo-
clinical response was best defined as an SUV decrease of ≥35%.107 pathologic tumor response rates were better than those of MUNI-
Poor response (defined as SUV decrease <35%) was associated CON-I nonresponders who had proceeded directly to surgery
with a lack of histopathologic response at the time of subsequent without further neoadjuvant treatment. However, the R0 resection
surgery, increased risk for tumor recurrence, and worse overall rate, median time to progression of disease, and overall survival
survival.107,111 These investigators subsequently tested the hypoth- did not improve in MUNICON-II versus MUNICON-I nonresponders.
esis that patients with AC who were metabolic nonresponders to A limitation in MUNICON-II was the lack of randomization, which
induction therapy at 2 weeks might benefit from a change in ther- would have required a much larger patient sample. Such prospec-
apeutic strategy. In this prospective, nonrandomized MUNICON-I tive, randomized trials are now ongoing. For instance, in the
trial,108 PET metabolic nonresponders underwent early tumor United States, the multicenter CALGB 80803 trial (NCT01333033)
resection, whereas PET responders received a full course (up to is enrolling patients with GEJ cancer who will be randomized to
12 weeks) of preoperative therapy. In the surgical specimen, 58% either FOLFOX or carboplatin/paclitaxel therapy. Early PET nonre-
of patients with favorable PET response also had a favorable sponders (SUV decrease <35% at 40 days) will be switched to the
pathologic response (<10% viable tumor tissue at resection), other drug regimen. Early PET responders continue to receive
whereas 0% of patients with an unfavorable 18FDG PET response their initial drug regimen for several more weeks. Radiotherapy
had a pathologic response. will be added to both arms after the early PET-response assess-
The use of “early” PET to predict AC tumor pathologic response ment. Patients will then undergo surgical resection. Study end-
to neoadjuvant combined chemotherapy plus radiation therapy points include the comparison of pathologic response rates,
(CRT) has been studied by van Heijl et al.106 at 2 weeks into treat- progression free and overall survival in both arms. In the ongoing
ment (same time point as in the Munich trials of neoadjuvant che- prospective HICON trial (Heidelberg Imaging program in Cancer of
motherapy alone). In this study, 100 patients underwent potentially the esophagogastric during Neoadjuvant treatment), patients with
curative esophagectomy and 2 PET scans. Among the 64 patho- AEG type I and II AC who are early PET nonresponders to neoad-
logic responders, the mean decline in 18FDG SUV was 30% (range juvant chemotherapy will undergo salvage CRT. This trial will test
-17% to -51%); among the 36 pathologic nonresponders, the mean whether sequential FDG PET studies can predict histopathologic
decline in SUV was 2% (range -36% to +17%). PET predicted response to salvage CRT.124 Although some of the initial data are
response better in AC than in SCC. 76 patients were classified as promising, we recommend that clinical management decisions not

Figure 5.4. A 68-year-old man with poorly

differentiated adenocarcinoma of the distal
esophagus. Shown are 3D maximum intensity
projection FDG PET images, spanning neck,
chest, and abdomen, from scans obtained
before (left) and 9 days after (right) five cycles
of chemotherapy (oxaliplatin, leucovorin, and
5-fluorouracil [5-FU]). Hypermetabolic activity
visualized by the pretreatment scan in the pri-
mary tumor (arrow ) and a biopsy-proven left
supraclavicular nodal metastasis (arrowhead )
completely resolved, on the posttreatment scan.
be based on percentage changes in FDG SUV outside of clinical patients who did not. However, this difference in clinical outcome
trials at this time. seemed limited to patients treated with CRT only (no additional
surgery), suggesting that the end of induction SUV lost its prognos-
tic value in patients who underwent subsequent esophagectomy
End-of-Treatment Evaluation because any residual disease was resected. However, this notion
The use of “late” 18FDG PET for evaluating AC tumor response that radical surgery can overcome the negative prognostic value of
after the completion of neoadjuvant therapy has been investigated residual abnormal 18FDG uptake after induction chemo- or chemo-
in patients treated with induction chemotherapy only (Fig. 5.4) radiotherapy remains controversial. Another concern is the poten-
and in patients who underwent combined CRT. In patients treated tially high rate of false-positive PET scans in this setting. In the
with neoadjuvant chemotherapy only, a 67% decrease in SUVmax Swisher trial, the rate of false-positive PET scans was estimated at
from baseline predicted complete or “subtotal” histopathologic 34%. This would undermine the justification for additional neoad-
response with 79% sensitivity and 75% specificity.125 In 55 patients juvant therapy in patients with positive end-of-treatment scan
treated with combined neoadjuvant CRT, Swisher et al.109 found (lack of benefit but additional toxicity). A high rate of false-positive
that the changes in tumor SUV (either in the primary or at any scans at the end of induction therapy could also explain the lack of
metastatic site) did not separate responders from nonresponders; prognostic value of PET in the surgical cohort (if the PET signal
however, an SUV of ≥4 after completion of CRT could be used to does not correlate with the presence and amount of residual dis-
identify patients lacking a major histopathologic response, with a ease, it could not possibly predict outcome after surgery).
sensitivity of 62% and a specificity of 84%. In multivariate analy-
sis, tumor SUV <4 was an independent predictor of survival. As
expected, a negative PET could not distinguish pathologic com- PET Studies in Squamous Cell
plete response from microscopic residual disease and could there-
fore not spare patients a potentially unnecessary esophagectomy.
Carcinoma
As stated before, absolute SUV numbers or thresholds proposed
in one trial must be validated prospectively and may not be appli-
Early Response Evaluation
cable in other institutions with different PET protocol and equip- In patients with esophageal SCC undergoing neoadjuvant combined
ment or in other patient groups with different clinical risk features CRT, an SUV decrease ≥30% at 2 weeks into treatment predicted
and histologic profile. For instance, Monjazeb et al.110 defined PET histopathologic response with a 93% sensitivity and an 88% speci-
complete response as residual SUV ≤3 rather than SUV <4 in the ficity.115 In a group of 61 patients, Yang et al.118 observed a more
Swisher study after neoadjuvant CRT. Thirty-one percent of 105 favorable 5-year progression-free survival in nonsurgical patients
evaluable patients in that retrospective study achieved such PET- who showed a ≥51% decline in 18FDG SUV at 4 to 5 weeks into
CR, and their clinical outcome was better than the outcome in definitive CRT.

End-of-Treatment Evaluation sensitivity typically reported as being ≥90% to 94%48,132,133; this is

clearly superior to CT alone. An exception is subcentimeter pul-
Studies in SCC are smaller and data more heterogeneous than in monary metastasis, which is better identified on dedicated CT.
AC. For instance, metabolic response has been defined variably as However, because patients with pulmonary metastases often also
lack of residual uptake after end of induction therapy, or a 50% to have concomitant recurrence in other organs, the overall PET sen-
70% decrease from baseline SUV. In a study that predominantly sitivity for disease recurrence on a per-patient basis remains
included patients with locally advanced SCCs (27 SCCs and 9 ACs)119 excellent.133 The specificity of 18FDG PET/CT for the detection of
the complete disappearance of tumor 18FDG uptake at the end of recurrent disease is not as high (typically ∼80% to 90%), but still
induction therapy had a poor sensitivity for a pathologic complete generally superior to other modalities. False-positive 18FDG uptake
response: Four out of six patients with pCR were correctly identified, occurs most commonly at the primary site48 where specificity can
the other two patients with pCR showed marked inflammation in the be as low as 50%. Potential reasons for false-positive and false-
specimen, explaining the false-positive 18FDG uptake. Nevertheless, negative 18FDG scans were already discussed above.
patients with a “major” PET response, defined as a disappearance
of metastatic nodes and disappearance or near disappearance of
primary tumor 18FDG uptake, had a better survival than PET non-
responders. Brücher et al.114 found that a 52% decrease in tumor Novel Imaging Agents
uptake after completion of CRT identified patients with major his-
topathologic response (<10% viable cells) with 100% sensitivity Several other radiotracers, beyond FDG, are under study in esoph-
and 55% specificity and predicted better survival. However, this ageal cancer. Of particular interest may be the proliferation marker
study included only 27 patients and the 52% threshold was based Fluorine-18 fluorothymidine (18FLT). 18FLT uptake is considered a
on retrospective ROC analysis. In contrast, in a study by Higuchi biomarker of thymidine kinase 1 activity (FLT is trapped intracel-
et al.116 percentage changes in tumor SUV did not predict histo- lularly after phosphorylation by TK1) and tumor cell proliferation.
18
logic or clinical response, but a lack of residual 18FDG uptake post- FLT is not a suitable agent for tumor detection or staging because

chemotherapy (defined as SUV <2.5) identified patients with major the intensity of uptake is generally lower than that of 18FDG.
histologic response and predicted better survival. This study Instead, the primary application for 18FLT may lie in response
included 35 patients undergoing chemotherapy and 15 patients assessment and possibly radiotherapy planning. For instance, Yue
undergoing CRT. et al.134 reported a pilot clinical trial describing PET/CT findings in
esophageal SCC patients undergoing both 18FDG PET/CT and 18FLT
PET/CT scans during radiotherapy. 18FLT uptake in the primary
Role of PET in Radiotherapy tumor steadily diminished with cumulative delivery of radiation
doses. In two patients, scans were obtained after 40 Gy to the tumor:
Planning 18
FLT uptake had completely disappeared, whereas 18FDG uptake
remained high. At histopathology, only soft tissue inflammation (no
Radiotherapy planning requires the precise delineation of the pri- tumor) was present. These anecdotal findings—supplemented by
mary tumor and all locoregional disease. Several studies have other 18FLT PET literature135—suggest that 18FLT may offer the
reported a favorable impact of 18FDG PET upon delineation of the specificity that 18FDG lacks, for early response assessment; how-
target volume in radiotherapy planning. Target volumes based ever, much more clinical validation is needed. Some ongoing stud-
upon CT alone appear to both over- and underestimate the extent ies are investigating the potential utility of 18FLT for radiotherapy
of disease in many patients compared to 18FDG PET,126–128 with a dose painting (whereby higher doses would be delivered to areas
predicted impact on normal tissue toxicity and antitumor efficacy.126 of higher tumor cell proliferation). Other investigators are compar-
This is related, in part, to the greater accuracy of 18FDG PET/CT in ing histopathologic tumor length to PET-based gross tumor vol-
identifying the presence and extent of locoregional disease. In addi- umes (with 18FDG and 18FLT) and associated radiation doses to
tion, in many settings 18FDG PET/CT provides more reproducible lungs and heart. One such study reported a potential dosimetric
measures of target volume compared to CT alone, and thus better advantage for 18FLT PET/CT-based treatment planning, leading to
inter- and/or intraobserver agreement.129 In a recent study, PET- lower radiation doses to lungs and heart as compared to 18FDG
based measurement of tumor length corresponded to the subse- PET/CT-based planning.136
quent pathologic tumor length measurement with a mean difference Another novel radiotracer with potential application in esopha-
of –0.05 cm (SD: 2.16 cm).130 Of note, tumor measurements may be geal cancer is radiolabeled trastuzumab, which may potentially
affected by respiratory motion. Differences in tumor positions serve as a noninvasive imaging biomarker of HER2-neu overex-
affected gross tumor volumes predominantly by associated changes pression. It is currently under investigation in early clinical trials.137
in the tumor SUVmax—including a >20% change in SUVmax in HER2-neu-targeted immunotherapy with trastuzumab is a poten-
17% of the esophageal cancer cases.131 There is still a lack of data tial treatment option in patients with HER2-positive metastatic
showing a potential benefit of 18FDG PET/CT-based radiotherapy disease.2,138
planning with regard to locoregional control and survival.129 Clini-
cal trials addressing this question are ongoing (e.g., NCT01156831).
Acknowledgment
Role of PET in Detecting The authors gratefully acknowledge the assistance of Franklin
Tumor Recurrence Torres in the editing of this text.
Recurrences after R0 resection are most common in the mediasti-

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Med. 2000;41(5):808–815. regression after preoperative chemoradiotherapy of esophageal carcinoma.
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the preoperative locoregional staging of resectable esophageal cancer. Surg mine suitability for esophagectomy after aggressive chemoradiotherapy for
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69. Yasuda T, Higuchi I, Yano M, et al. The impact of 18F-fluorodeoxyglucose posi- 98. Schneider PM, Metzger R, Schaefer H, et al. Response evaluation by endoscopy,
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70. Stephen BE, David RB, Carolyn CC, et al. (eds) AJCC Cancer Staging Handbook. 99. Griffin JM, Reed CE, Denlinger CE. Utility of restaging endoscopic ultrasound
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71. Boonstra JJ, Koppert LB, Wijnhoven BP, et al. Chemotherapy followed by sur- 1855–1859; discussion 60.
gery in patients with carcinoma of the distal esophagus and celiac lymph node 100. Yanagawa M, Tatsumi M, Miyata H, et al. Evaluation of response to neoadju-
involvement. J Surg Oncol. 2009;100(5):407–413. vant chemotherapy for esophageal cancer: PET response criteria in solid

72. Aikou T, Shimazu H. Difference in main lymphatic pathways from the lower tumors versus response evaluation criteria in solid tumors. J Nucl Med. 2012;
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73. Meltzer CC, Luketich JD, Friedman D, et al. Whole-body FDG positron emission 101. Makino T, Miyata H, Yamasaki M, et al. Utility of response evaluation to neo-
tomographic imaging for staging esophageal cancer comparison with com- adjuvant chemotherapy by (18)F-fluorodeoxyglucose-positron emission tomog-
puted tomography. Clin Nucl Med. 2000;25(11):882–887. raphy in locally advanced esophageal squamous cell carcinoma. Surgery.
74. Meyers BF, Downey RJ, Decker PA, et al. The utility of positron emission tomog- 2010;148(5):908–918.
raphy in staging of potentially operable carcinoma of the thoracic esophagus: 102. Wahl RL, Jacene H, Kasamon Y, et al. From RECIST to PERCIST: Evolving
Results of the American College of Surgeons Oncology Group Z0060 trial. Considerations for PET response criteria in solid tumors. J Nucl Med. 2009;
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75. Walker AJ, Spier BJ, Perlman SB, et al. Integrated PET/CT fusion imaging and 103. van Heijl M, Phoa SS, van Berge Henegouwen MI, et al. Accuracy and repro-
endoscopic ultrasound in the pre-operative staging and evaluation of esopha- ducibility of 3D-CT measurements for early response assessment of chemora-
geal cancer. Mol Imaging Biol. 2011;13(1):166–171. diotherapy in patients with oesophageal cancer. Eur J Surg Oncol. 2011;37(12):
76. Vyas S, Markar SR, Iordanidou L, et al. The role of integrated F-18-FDG-PET 1064–1071.
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77. van Vliet EP, Heijenbrok-Kal MH, Hunink MG, et al. Staging investigations for advanced gastroesophageal cancer; a comparison of different analytical meth-
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78. Romagnuolo J, Scott J, Hawes RH, et al. Helical CT versus EUS with fine needle 105. Westerterp M, Omloo JM, Sloof GW, et al. Monitoring of response to pre-oper-
aspiration for celiac nodal assessment in patients with esophageal cancer. ative chemoradiation in combination with hyperthermia in oesophageal can-
Gastrointest Endosc. 2002;55(6):648–654. cer by FDG-PET. Int J Hyperthermia. 2006;22(2):149–160.
79. Rizk N, Downey RJ, Akhurst T, et al. Preoperative 18[F]-fluorodeoxyglucose 106. van Heijl M, Omloo JM, van Berge Henegouwen MI, et al. Fluorodeoxyglucose
positron emission tomography standardized uptake values predict survival positron emission tomography for evaluating early response during neoadju-
after esophageal adenocarcinoma resection. Ann Thorac Surg. 2006;81(3): vant chemoradiotherapy in patients with potentially curable esophageal can-
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80. Hyun SH, Choi JY, Shim YM, et al. Prognostic value of metabolic tumor volume 107. Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative che-
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81. Hatt M, Visvikis D, Albarghach NM, et al. Prognostic value of 18F-FDG PET 108. Lordick F, Ott K, Krause BJ, et al. PET to assess early metabolic response and
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C h apt e r 6
Gastric Carcinoma-I
Ken Herrmann • Hinrich A. Wieder • Matthias P.A. Ebert • Johannes Czernin
Introduction including perioperative chemotherapy, radiotherapy, or chemora-

diotherapy in combination with surgical resection have been
widely evaluated. A recently published meta-analysis comprising
In 2011, an estimated number of 21,520 new cases of gastric can-
17 randomized controlled trials of adjuvant and neoadjuvant che-
cer and 10,340 gastric cancer related deaths were expected in the
motherapy in gastric cancer demonstrated a statistically signifi-
United States.1 Corresponding worldwide incidence rates were
cant overall (p < 0.001) and disease-free survival (p < 0.001)
approximately 989,000 new cases of gastric cancer in 2008 and
benefit for patients treated with fluorouracil-based adjuvant che-
around 738,000 gastric cancer related deaths during the same
motherapy versus surgery alone.23 A trial initiated by the Euro-
year.2 Incidence rates of gastric cancer are twice as high in males
pean Organisation for Research and Treatment of Cancer (EORTC)
as in females, and around 70% of new cases and deaths occur in
investigating the value of neoadjuvant treatments in gastric can-
developing countries with the highest rate in Eastern Asia.2 Long-
cer randomized patients with tumors in the proximal third of the
term survival of gastric cancer remains poor despite a significant
stomach to preoperative chemotherapy followed by surgery or to
increase over the past years (5 years relative survival rates: 1975–
surgery alone. A significantly increased R0 resection rate (macro-
1977: 16% and 1999–2006: 27%, respectively).1
and microscopically negative resection margins) was found for
In contrast to other malignancies, such as lung cancer and
patients with neoadjuvant chemotherapy prior to surgery but
prostate cancer, gastric cancer rates have decreased substantially
no survival benefit was shown.24 As a consequence of the incon-
in most parts of the world.1,2 This decrease is reported to be

clusive results for survival, the currently valid German S3 guide-
caused by factors related to the increased use and availability of
line “Diagnosis and Treatment of Esophagogastric Cancer” lacks a
refrigeration, reductions in chronic Helicobacter pylori infection
clear recommendation regarding the benefit of neoadjuvant
and smoking.3–5
treatment.25
Carcinogenesis of gastric cancer is a multistep process that
The aim of this chapter is to discuss the relevant clinically
involves many environmental and genetic factors. It was shown
approved and investigational applications of nuclear medicine
that H. pylori is implicated in more than 80% of gastric cancers.6
techniques for staging, restaging, treatment response monitoring,
In contrast, most of the approximately 1 billion people infected
and radio-guided sentinel lymph node surgery in gastric cancer.
worldwide do not develop gastric cancer demonstrating that
H. pylori infection alone is not sufficient to cause the disease.7 More-
over, a number of other causes comprising levels of the hormone
gastrin,8 genetic and dietary factors,9,10 and other chronic gastric Detection and Staging of
inflammation-causing factors11 contribute to the development of
gastric cancer. Altogether, gastric cancers are complex diseases
Gastric Carcinoma
and their etiology is not fully understood at this time.
As prognosis of gastric cancer remains poor, it is crucial to
State of the Art
identify pretherapeutic predictive marker for response and prog- Endoscopy has become the primary tool for detection of gastric
nosis. Tumor localization, Lauren classification, tumor differentia- cancer and is recommended as “good clinical practice” in numer-
tion, mucin production, and clinical stage have all been previously ous clinical guidelines.25,26 Endoscopic procedures allow the deter-
shown to be prognostic factors in patients who did not undergo mination of the presence and location of gastric cancer and the
preoperative chemotherapy.12–14 More recently, tumor localization, biopsy of suspicious lesions. Endoscopy is a safe procedure with
Lauren classification, and tumor differentiation were reported to low complication rates (1:1000). Therefore, endoscopy should be
be positive predictive factors even in patients undergoing neoad- considered the modality of choice for detection of gastric cancer.
juvant treatment.15 For staging of gastric cancer, endoscopic ultrasound (EUS) and
Correct clinical staging is crucial to stratify risk in patients and B-mode ultrasound have proven to be very accurate for T-staging
assign the optimal treatment. In 2010, the International Union and moderately accurate for N- and M-staging. These modalities
Against Cancer and the American Joint Committee on Cancer (AJCC) are, therefore, considered the primary imaging modalities for stag-
have revised the staging system and published the seventh edition ing. In a meta-analysis pooled sensitivities and specificities for
in 2010.16 For gastric cancer, the following changes were made.17 T-staging based on these modalities were: T1: 88% and 100%, T2:
82% and 96%, T3: 90% and 95%, and T4: 99% and 97%.27,28 The
• Gastroesophageal junction (GEJ) tumors are staged as esopha-
sensitivities and specificities for N-staging were 58% and 92% and
geal cancers, except tumors arising in the stomach >5 cm from
65% and 92% for N1 and N2, respectively.27 Whereas EUS has only
the GEJ.
a limited accuracy for M-staging, sensitivities of 77% and 81%
• T classification categories have been redefined, and the T clas-
for detection of liver metastases have been reported for B-mode
sification of stomach cancer and esophageal cancer have been
ultrasound.29,30
harmonized.
In addition to EUS and B-mode ultrasound, a diagnostic contrast-
• N categories have been modified to better represent the distri-
enhanced CT of thorax and abdomen is recommended. Overall accu-
bution of the number of positive lymph nodes.
racy of CT for T-staging is reported to be 43% to 82% according to
• M1 category has been amended to include positive peritoneal
the NCCN guidelines, whereas the German S3 guideline reports
cytology.
accuracies of 77% to 89%.31,32 Corresponding sensitivity and speci-
• Stage IV now includes only patients with M1 disease.
ficity for detection of local lymph node metastases are 78% and 62%,
• New stage groups have been added to the staging system (IIB
respectively.31,33 For contrast-enhanced CT, a sensitivity of 70% and
and IIIC).
a specificity of 72% for detection of distant metastases had been
In addition to staging, restaging and assessment of response to reported.32 CT revealed a high sensitivity but not specificity to detect
treatment are also important for the management of gastric cancer lung metastases. The use of MRI, however, is only recommended for
patients. To improve the outcome, combined modality treatments patients who cannot undergo EUS and/or CT.9,15
85

Figure 6.1. A 61-year-old female undergo-

ing 18F-FDG PET/CT for staging of an endo-
scopically detected gastric cancer. Coronal
(A), sagittal (B), and transaxial (C) images
display an increased 18F-FDG uptake in projec-
tion of the known primary cancer (single
arrows). Moreover, 18F-FDG PET/CT also depicts
A B D increased glucose metabolism in the bone mar-
row and in the mesentery (double arrows, D).
Role of Nuclear Medicine cancers of the intestinal type.25,32 The routine use of 18F-FDG PET/
CT, however, is not recommended. Both NCCN and the German S3
According to the most recent NCCN and German guidelines, there guideline list the low tracer accumulation in diffuse and mucinous
is no clear recommendation for the routine use of 18F-FDG PET/CT tumor types (Fig. 6.2) as a major limitation contributing to the infe-
and/or bone scintigraphy in the staging of gastric cancer rior detection rate compared to diagnostic CT and EUS.25,31,34 The
patients.25,31 The German S3 guideline proposes that PET/CT might NCCN guideline reports a lower sensitivity (56% versus 78%) but a
provide useful additional information, especially regarding the higher specificity (92% versus 62%) for 18F-FDG PET/CT compared
detection of distant metastases (Fig. 6.1), in locally advanced gastric with contrast-enhanced CT in detection of local lymph node
A C
Figure 6.2. A 62-year-old male with biopsy proven gastric signet ring cell tumor undergoing 18F-FDG PET/CT for staging (A: coronal view, B and C: transaxial
views of CT, PET, and fused PET/CT of mediastinum and upper abdomen). 18F-FDG PET/CT does not show increased uptake in the primary tumor (single arrows) or
in the lung lesion (histopathologically proven lung metastasis).

Chapter 6 Gastric Carcinoma-I 87
involvement.31,33 However, the NCCN guideline also mentions that tumors (67% and 43%). Interestingly, 18F-FDG PET/CT had, in the
combined 18F-FDG PET/CT has a number of potential advantages larger study population of 45 patients, only a sensitivity of 69%,39
over 18F-FDG PET alone.31 18F-FDG PET/CT was reported to be whereas the study with 21 patients reported a sensitivity of 95%.40
more accurate for staging (68%) than PET (47%) or CT (53%) alone. This might reflect selection bias; that is, the percent of various
Bone scintigraphy, as part of the routine staging of gastric cancer gastric carcinoma subtypes in the group studied.
patients, is not recommended in the absence of specific symptoms.32 These investigational approaches are currently not part of the
clinical routine yet. Randomized multicenter trials are necessary
to study the impact of the new imaging approaches on patient
Investigational Approaches management and outcome with special regard to potential reim-
A recently published prospective single center trial investigated bursement and/or legal approval.
the value of 18F-FDG PET/CT for adding relevant information to
routine CT, EUS, and laparoscopic staging in 113 patients with Summary
locally advanced gastric cancer.35 In 31 patients, occult metastatic Nuclear medicine techniques currently play no significant role in
disease was discovered by either laparoscopy (n = 21) and/or the clinical routine of staging gastric cancer. 18F-FDG PET/CT
18
F-FDG PET/CT (n = 11) with overlap in only one patient. 18F-FDG might provide important additional information for staging espe-
PET/CT provided crucial additional information in approximately cially regarding the detection of distant metastases. To date, how-
10% of the patients by describing occult metastatic lesions pro- ever, insufficient data are available to determine whether the
tecting the patients from increased morbidity by futile surgeries inclusion of 18F-FDG PET/CT has a meaningful impact on the ini-
(Fig. 6.3). A cost-analysis reported an estimated cost saving of tial staging of patients with gastric cancer.
$13,000 per patient.35
The recent introduction of combined MR PET whole-body scan-
ners raises the potential of a new dimension in whole-body oncology
imaging.36 First results show that integrated whole-body PET/MR Diagnosis of Recurrence

is feasible in a clinical setting with high quality imaging in a short
examination time.37 Staging of gastric cancer might be an interest-
and Restaging
ing application for MR PET but no clinical data is available.
As previously mentioned, 18F-FDG PET/CT has a limited sensi-
State of the Art
tivity for the detection of diffuse and mucinous gastric tumors.25,31,34 The available guidelines only address restaging after neoadjuvant
This observation was recently confirmed when detection rates of treatment.25,26,31 According to the German S3 guideline, the accu-
97% for pure intestinal subtype tumors but only 44% for diffuse racy of EUS and CT regarding the staging of the primary tumors is
tumors, respectively, were reported.35 As increased proliferative low.25,41,42 Downstaging of T and N category by EUS42 or reduction
activity has been shown to be potentially more specific for malig- of tumor thickness of more than 50% by EUS, however, were cor-
nant tumors than are alterations of glucose metabolism,38 a num- related with better survival.41 Moreover, if clinical symptoms indi-
ber of groups have investigated the in vivo proliferation tracer cate tumor progression during chemotherapy, a symptom-oriented
3′-deoxy-3′-18F-fluorothymidine (18F-FLT) for detection of gastric restaging is recommended to consider immediate surgery.43 Inter-
cancer and compared it to 18F-FDG PET/CT.39,40 Reported sensi- estingly, the prognostic relevance of achieving histopathologic
tivities for 18F-FLT PET were 100% and 95%, respectively with response after neoadjuvant chemotherapy is not established as
both studies comprising a significant percentage of nonintestinal only two studies that included 36 and 30 patients have addressed
Figure 6.3. A patient with 18

F-FDG-avid
gastric cancer undergoing 18F-FDG PET/CT
scan for staging. Coronal (A), transaxial (B and
C), and sagittal (D) views display the increased
18
F-FDG uptake in the primary tumor (single
arrow). Moreover, 18F-FDG PET/CT depicted
lymph node involvement and a liver metasta- A C D
sis (double arrows).

this issue.44,45 In only one of these two studies was a correlation and accuracy of 18F-FDG PET/CT for diagnosing true recurrence on
between tumor regression grade and survival reported.44 a per patient basis were 75%, 77%, 89%, 55%, and 75%, respectively.
Follow-up after initial treatment is recommended to be adapted On a per-lesion basis, 75 (69%) of 108 true recurrences showed pos-
to the needs of the patient as well as the recurrence rates of the itive 18F-FDG uptake, whereas 75 (89%) of 84 positive 18F-FDG
diagnosed tumor.25,26 The Belgian guideline recommends physical uptake were confirmed to have true recurrence. The authors con-
examination and blood work every 3 months as well as CT every cluded that PET-CT might be helpful particularly in patients with a
6 months during the first year, and subsequently only annually.26 high pre-PET suspicion for recurrence.
The NCCN guidelines suggest that patients should be followed Recent developments, such as hybrid PET/CT gastrography or
systemically including physical examination every 3 to 6 months combined MR PET whole-body scanners, might improve the per-
in the first 2 years, then every 6 to 12 months during years 3 to 5 formance of nuclear medicine techniques for restaging and recur-
and annually thereafter. Complete blood count, imaging studies rence detection in gastric cancer but these techniques have not yet
and endoscopies should be done if clinically indicated.31 entered the clinical routine.
In summary, restaging of the primary tumor after neoadjuvant
therapy is not recommended but distant metastases should be Summary
ruled out prior to surgery.25 Surveillance protocols recommend
regular physical examination; whereas the Belgian guidelines rec- Nuclear medicine techniques currently play no major role in
ommend routine CT scans, the NCCN deems imaging only neces- restaging and detection of recurrence in gastric cancer patients. In
sary if clinically indicated. the case of presurgical restaging after neoadjuvant treatment, 18F-
FDG PET/CT may provide additional information to detect or rule
out distant metastases. Furthermore, it is unknown whether 18F-
Role of Nuclear Medicine FDG PET/CT has a meaningful impact on the management and
According to the most recent guidelines, there is no clear recom- outcome of patients who are re-evaluated for gastric cancer.
mendation for the routine use of 18F-FDG PET/CT and/or bone
scintigraphy for restaging, surveillance, or diagnosis of recur-
rence. However, as distant metastases should be ruled out prior to Treatment Response Monitoring
surgery, 18F-FDG PET/CT might add relevant information for
M-staging. The NCCN guideline also states that 18F-FDG PET/CT is State of the Art
useful for evaluation of recurrent gastric cancer.31,46,47 The available oncologic guidelines do not suggest which imaging
method should be used for treatment response assessments.25,26,31
Investigational Approaches However, endoscopy, EUS, and CT are the most commonly used. CT
imaging as well as changes in serum levels of tumor markers have
The data addressing a potential role of 18F-FDG PET and 18F-FDG recently been used to assess treatment responses.49,50 According to
PET/CT for detecting gastric cancer recurrence are sparse (Table the NCCN guidelines, 18F-FDG PET/CT scans are useful to predict
6.1).48 In one study, 33 patients underwent an 18F-FDG PET/CT scan response to preoperative (neoadjuvant) chemotherapy.20,21,31,46
for suspected recurrence after surgical resection with curative
intent.18 Recurrence was confirmed or ruled out histologically or by
radiologic and clinical follow-up (prevalence of recurrence 61%).
Role of Nuclear Medicine
18
F-FDG PET correctly detected recurrence in 70% (14/20) and was The currently available guidelines for the treatment of gastric cancer
false positive in four patients (specificity: 69%; 9/13). Corresponding do not provide recommendations for the role of nuclear medicine
positive and negative predictive values were 78% (14/18) and 60% techniques in treatment monitoring. Whereas the NCCN guidelines
(9/15), respectively. All of the six false-negative cases had intra- state that 18F-FDG PET/CT scans are useful to predict response to
abdominal lesions (three had generalized abdominal metastases, preoperative chemotherapy,20,21,31,46 the German S3 guidelines pro-
one liver metastasis, one local recurrence, and one ovarian metas- pose using 18F-FDG PET/CT only in the context of clinical research.25
tasis). In patients with signet-cell differentiation of the primary
tumor (n = 13, disease prevalence 62% (8/13)), 18F-FDG PET had a
sensitivity of 63% (5/8) and a specificity of 60% (3/5), respectively.
Investigational Approaches
The authors concluded that because of its poor sensitivity and low- The usefulness of preoperative treatment is still under debate and
negative predictive value 18F-FDG PET is not well suited for the fol- only few studies investigated the role of F-18F-FDG PET/CT for
low-up of treated gastric cancer patients. 18F-FDG avidity of recurrent response assessment in gastric cancer (Table 6.2). As recently sum-
lesions, however, was a predictor of poor outcome (mean survival marized by Ott et al.,51 current imaging modalities or in vitro bio-
6.9 versus 18.5; p = 0.05). markers cannot reliably predict the treatment responses in patients
In a more recent study, 18F-FDG PET/CT was evaluated in 105 with gastric cancer. Such assessments would be critically impor-
patients with clinical or radiologic suspicion of gastric cancer recur- tant to avoid unnecessary side effects of ineffective therapies and
rence. Follow-up revealed 108 recurrence sites in 75 patients.19 Sen- to provide patients with alternative treatment approaches.52
sitivity, specificity, positive predictive value, negative predictive value, The effects of neoadjuvant chemotherapy were first studied
with 18F-FDG PET in 44 patients with locally advanced gastric
cancer. Thirty-five of these had tumors with visible 18F-FDG uptake
Table 6.1 at baseline and were, therefore, assessable.20 Using a response
threshold of 35% SUVmean reduction in tracer uptake (as applied
18
f-Fdg Pet and 18f-Fdg Pet/Ct for Detection of by Weber et al.53 for patients with adenocarcinomas of the gastro-
Recurrence of Gastric Cancer esophageal junction) 2 weeks after the start of neoadjuvant treat-
ment, histopathologic response was predicted with sensitivities
and specificities of 77% and 86%, respectively (Fig. 6.4). Metabolic
Authors Year n Total Sensitivity Specificity Accuracy responders had a better median survival (not reached versus 18.9
months; p = 0.02) and a higher 2-year survival rate (90% versus
De Potter 2002 33 70 69 70
25%; p = 0.002) than metabolic nonresponders.
et al.18
Park et al.19 2009 105 75 77 75 Recently published long-term results have revealed that in
locally advanced gastric cancer, three different response patterns

Table 6. 2
18
F-Fdg Pet and 18f-Fdg Pet/Ct in Early Assessment of Response to Therapy for Gastric Cancer
Time Point of Criteria for

Response Response on
Authors Year n Total n Assessable Assessment PET Outcome Measure Design P
20
Ott et al. 2003 44 35 14 d 35% SUVmean decrease Median overall survival Retrospective 0.02
Ott et al.21 2008 71 49 14 d 35% SUVmean decrease Median overall survival Retrospective 0.037
Shah et al.22 2007 42 42 35 d 45% SUVmax decrease Disease-free survival Retrospective 0.03
exist for early response assessment after 2 weeks of neoadjuvant As up to a third of gastric carcinomas are initially 18F-FDG neg-
chemotherapy.21 Metabolic responders had a higher histopatho- ative and, therefore, not suitable for response monitoring using
18
logic response rate (69%) than metabolic nonresponders (17%) F-FDG PET,54 18F-FLT PET has also been assessed for its ability
and initially 18F-FDG-negative patients (24%). Interestingly, sur- to detect locally advanced gastric cancer39,40 and subsequently for
vival of 18F-FDG-avid nonresponders and 18F-FDG-negative treatment response monitoring.55 18F-FDG PET and 18F-FLT PET
patients did not differ significantly (24.1 months versus 36.7 were performed at baseline, 14 days after the start of treatment
months; p = 0.46), whereas for 18F-FDG-avid responders median and then again prior to surgery in 45 patients with gastric cancer.
overall survival had not yet been reached after a median follow-up No significant association between any of the PET measurements
of 56 months. The authors suggest, therefore, that although meta- and clinical or histopathologic response was found. Univariate Cox

bolic response assessment is not possible in 18F-FDG-negative regression analysis for Ki67 and metabolic parameters revealed
tumors, a therapy modification (e.g., change of chemotherapy or significant prognostic impact for survival only for 18F-FLT
immediate surgery) might be considered in this patient subgroup. SUV(mean) measurements on day 14 (p = 0.048) and Ki67 (p =
In a retrospective study of 42 patients, 18F-FDG PET responses 0.006). Multivariate Cox regression analysis (including clinical
were assessed 35 days after the start of treatment.22 A decrease in response, Lauren type, ypN category, and 18F-FLT SUV(mean) day
SUVmax of more than 45% provided the best prediction of histo- 14) revealed Lauren type and 18F-FLT SUV(mean) day 14 as the
pathologic response and outcome. Metabolic response was sig- only significant prognostic factors (p = 0.006, p = 0.002). Thus,
18
nificantly correlated with histopathologic response (less than 50% F-FLT uptake 2 weeks after initiation of therapy was the only
residual tumor; p = 0.007) and disease-free survival (p = 0.03). imaging parameter with significant prognostic impact. However,
Despite these encouraging results both groups suggested that these results must be interpreted with caution as a number of
prior to applying these parameters clinically, standardization of limitations have to be kept in mind such as the single-center trial
the imaging procedure and a prospective evaluation in a multi- study design, a relatively short follow-up, poor overall response
center trial should be performed. rates, and an unfavorable prognosis of this study population.
Summary
Nuclear medicine techniques may be useful to predict response to
preoperative chemotherapy. Even though the NCCN guideline sup-
ports the usefulness of 18F-FDG PET/CT, available data regarding
quantitative assessment of early response to chemotherapy is
from single-center studies only. Prior to routine use of 18F-FDG
PET/CT guided response assessment, standardization of the imag-
ing procedure and a prospective evaluation in a multicenter trial
should be performed.
Conclusion
The currently available NCCN guideline states the usefulness of
18
F-FDG PET/CT for predicting response to preoperative chemo-
therapy. As the only available comes from single-center studies
only, standardization of the imaging procedure and a prospective
evaluation in a multicenter trial have to be performed before 18F-
FDG PET/CT guided response assessment can be routinely used.
In clinical routine of staging, restaging, and detection of recur-
rence in gastric cancer nuclear medicine techniques play cur-
rently no significant role. However, 18F-FDG PET/CT might provide
important additional information for staging as well as presurgi-
cal restaging after neoadjuvant treatment especially regarding the
A B detection/exclusion of distant metastases. Future studies have to
address whether the inclusion of 18F-FDG PET/CT has a meaning-
Figure 6.4. A patient with biopsy-proven gastric cancer undergoing neoadjuvant chemo- ful impact on the initial staging, restaging, and detection of recur-
therapy prior to surgery. 18F-FDG PET/CT scans were performed prior to start of chemotherapy rence of patients with gastric cancer. Also alternative PET tracers
(A), and 14 days after start (B). The primary tumor was 18F-FDG avid in both scans (arrows) but
showed semiquantitatively a decrease from SUVmean 7.3 to 3.1 (SUVmean-decrease: 58%). such as 18F-FLT PET need despite initially promising results fur-
Histopathology after surgery confirmed histopathologic response. ther evaluation before being implemented into clinical routine.

Future Considerations 10. Zambon CF, Basso D, Navaglia F, et al. Increased risk of noncardia gastric can-
cer associated with proinflammatory cytokine gene polymorphisms. Gastroen-
terology. 2004;126(1):382–384.
Nuclear medicine techniques will continue to evolve with the 11. Yamaguchi N, Kakizoe T. Synergistic interaction between Helicobacter pylori
gastritis and diet in gastric cancer. Lancet Oncol. 2001;2(2):88–94.
introduction and evaluation of combined MR PET scanners, devel- 12. Baiocchi GL, Tiberio GA, Minicozzi AM, et al. A multicentric Western analysis of
opment of new PET- and SPECT-tracers and techniques beyond prognostic factors in advanced, node-negative gastric cancer patients. Ann
current PET- and SPECT-imaging such as radio-guided surgical Surg. 2010;252(1):70–73.
13. Choi MG, Sung CO, Noh JH, et al. Mucinous gastric cancer presents with more
techniques. advanced tumor stage and weaker beta-catenin expression than nonmucinous
Potential high impact of nuclear medicine modalities on the cancer. Ann Surg Oncol. 2010;17(11):3053–3058.
management of gastric cancer patients can be expected in the field 14. Park SR, Kim MJ, Ryu KW, et al. Prognostic value of preoperative clinical staging
assessed by computed tomography in resectable gastric cancer patients: A
of treatment monitoring and response assessment. If the standard- viewpoint in the era of preoperative treatment. Ann Surg. 2010.
ization of PET imaging can be achieved and prospective multi- 15. Lorenzen S, Blank S, Lordick F, et al. Prediction of response and prognosis by a
center trials confirm the impact of 18F-FDG PET/CT guided score including only pretherapeutic parameters in 410 neoadjuvant treated
gastric cancer patients. Ann Surg Oncol. 2012.
response assessment on patient survival then 18F-FDG PET/CT 16. Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edi-
will become a component in the clinical routine. Even though tion of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol.
alternative tracers such as 18F-FLT might provide relevant addi- 2010;17(6):1471–1474.
17. Washington K. 7th edition of the AJCC cancer staging manual: Stomach. Ann
tional information, we believe that 18F-FDG will continue to be the Surg Oncol. 2010;17(12):3077–3079.
most frequently used tracer for routine clinical use. 18. De Potter T, Flamen P, Van Cutsem E, et al. Whole-body PET with FDG for the
First results of combined MR PET whole-body scanners showed diagnosis of recurrent gastric cancer. Eur J Nucl Med Mol Imaging. 2002;
29(4):525–529.
that integrated whole-body PET/MR is feasible in a clinical setting 19. Park MJ, Lee WJ, Lim HK, et al. Detecting recurrence of gastric cancer: The
with high quality imaging in a short examination time.37 In the near value of FDG PET/CT. Abdom Imaging. 2009;34(4):441–447.
future, whole-body MR PET will be evaluated for staging and restag- 20. Ott K, Fink U, Becker K, et al. Prediction of response to preoperative chemo-
therapy in gastric carcinoma by metabolic imaging: results of a prospective
ing of gastric cancer. However, we believe that regarding the T- and trial. J Clin Oncol. 2003;(24):4604–4610.
N-staging it will be difficult to prove superiority over the currently 21. Ott K, Herrmann K, Lordick F, et al. Early metabolic response evaluation by
established state-of-the-art modalities endoscopy, endoscopic ultra- fluorine-18 fluorodeoxyglucose positron emission tomography allows in vivo
testing of chemosensitivity in gastric cancer: Long-term results of a prospective
sound and CT, especially with regard to cost-effectiveness. A more study. Clin Cancer Res. 2008;(7):2012–2018.
promising area appears to be M-staging but again, it will be chal- 22. Shah MA, Yeung H, Coit DG, et al. A phase II study of preoperative chemother-
lenging to prove superiority compared to 18F-FDG PET/CT. apy with irinotecan(CPT) and cisplatin(CIS) for gastric cancer(NCI 5917): FDG-
PET/CT predicts patient outcome. J Clin Oncol. 2007;25(18S):4502.
Recently, the concept of sentinel lymph node biopsy for gastric 23. Paoletti X, Oba K, Burzykowski T, et al. Benefit of adjuvant chemotherapy for
cancer has been reviewed.56 Despite not being established clini- resectable gastric cancer: A meta-analysis. Jama. 2010;(17):1729–1737.
cally, a total of 12 studies using the radiocolloid method were avail- 24. Schuhmacher C, Gretschel S, Lordick F, et al. Neoadjuvant chemotherapy com-
pared with surgery alone for locally advanced cancer of the stomach and car-
able. The overall false-negative rate was 18.5% (95% CI 9.1, 28.0) dia: European Organisation for Research and Treatment of Cancer randomized
compared to a false-negative rate for dye only of 34.7% (95% CI trial 40954. J Clin Oncol. 2010;(35):5210–5218.
21.2, 48.1). The combination of both methods was investigated in 25. Moehler M, Al-Batran SE, Andus T, et al. [German S3-guideline “Diagnosis and
treatment of esophagogastric cancer”]. Z Gastroenterol. 2011;(4):461–531.
five studies with a pooled false-negative rate of 13.1% (95% CI –0.9, 26. Peeters MLT, Lerut T, Vlayen J, et al. Wetenschappelijke ondersteuning van het
27.2). The false-negative rate of radiocolloid alone might be even College voor Oncologie: een nationale praktijkrichtlijn voor de aanpak van
further reduced by improving SLN detection through 3D tomo- slokdarm- en maagkanker. Good Clinical Practice (GCP). Brussel: Federaal
Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE Reports 75A (D/2008/
graphic imaging modalities as has been reported in breast cancer 10.273/16)
patients.57 27. Kwee RM, Kwee TC. Imaging in local staging of gastric cancer: A systematic
In summary, the field of nuclear medicine is rapidly evolving. review. J Clin Oncol. 2007;25(15):2107–2116.
28. Patel PR, Mansfield PF, Crane CH, et al. Clinical stage after preoperative chemo-
The introduction of new diagnostic methods as well as therapies radiation is a better predictor of patient outcome than the baseline stage for
might impact the future management of gastric cancer patients. localized gastric cancer. Cancer. 2007;110(5):989–995.
29. Kinkel K, Lu Y, Both M, et al. Detection of hepatic metastases from cancers of
the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR
imaging, PET): A meta-analysis. Radiology. 2002;224(3):748–756.
Acknowledgments 30. Piscaglia F, Corradi F, Mancini M, et al. Real time contrast enhanced ultrasonog-
raphy in detection of liver metastases from gastrointestinal cancer. BMC Cancer.
2007;7:171.
We appreciate the excellent contributions made by our colleagues 31. Ajani JA, Barthel JS, Bekaii-Saab T, et al. Gastric cancer. J Natl Compr Canc
PD Dr. Ambros Beer and Mrs. Christine Praus. Netw. 2010;8(4):378–409.
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ment of gastric carcinoma: Relevance for radiologic imaging.]. Rofo. 2012;
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Chapter 7
Gastric Carcinoma-II
Kemal Metin Kir • Elgin Ozkan
Introduction epithelial tumors can be subclassified according to histologic compo-

nents such as tubular adenocarcinoma (TC), papillary adenocarci-
Gastric carcinoma is one of the fourth most common cancer world- noma (PC), poorly differentiated adenocarcinoma (solid and nonsolid
wide, with 988,000 reported cases in 2008.1 It is seen more com- type), signet-ring cell carcinoma (SRC), and mucinous adenocarci-
monly in men and in several countries of the Middle East and noma (MC). Yamada et al.30 showed that cohesive carcinomas (TC,
Asia.1–3 Over the previous few decades, the incidence of gastric PC, and solid type poorly differentiated adenocarcinoma) are more
cancer has decreased, although it is the second most common detectable than noncohesive carcinomas (SRC, MC, and nonsolid
cause of cancer death after lung cancer (736,000 deaths worldwide type poorly differentiated carcinoma) (65% versus 14%, respectively).
in 2008).1 This is a consequence of a higher expression of GLUT-1 on the cell
Gastric cancer is generally asymptomatic in the early stages. It membrane of cohesive carcinomas.31,32 Alakus et al.33 reported that
is difficult to diagnose at an early stage unless there is a screening the 18F-FDG uptake in gastric cancer depended on GLUT-1 expres-
program as in countries such as Japan in which the disease is sion. SRC and MC typically have less prominent 18F-FDG uptake
endemic. When typical symptoms occur, especially in western because of high mucus content. However, GLUT-1 positive SRC has
countries, more than 80% of patients have advanced stage disease a higher degree of 18F-FDG uptake than GLUT-1 negative tumors.
with a poor prognosis.4 The cumulative 5-year survival rate of Furthermore, according to the most commonly used histologic clas-
gastric cancer remains under 20%.5–8 Early diagnosis and accurate sification, the Lauren classification, which describes the pattern of
staging of the disease can improve survival. spread of the primary tumor, there are two major types of gastric
Complete resection of a gastric tumor with lymph node dissec- tumor: Intestinal or nonintestinal (diffuse). Stahl et al.18 reported that
tion is an effective curative treatment for gastric cancer. However, nonintestinal and intestinal tumors contain intracellular or extracel-
accurate preoperative staging is critical in determining the most lular mucus approximately 81% and 11%, respectively. Increased
18
suitable therapy and in selecting curable patients for surgery. F-FDG uptake is more frequently seen in the intestinal type of gas-
Currently, computed tomography (CT) is the most common imaging tric cancer than in the nonintestinal type (83% versus 41%). The
method used for staging. Its sensitivity is limited, however, particu- cause of low 18F-FDG uptake in the nonintestinal type is explained
larly in detection of lymph node metastasis, small hematogenous by low GLUT-1 expression on the cell membrane and the abundance
metastasis, or peritoneal carcinomatosis.9,10 Endoscopic ultrasonog- of mucus content.
raphy (EUS), magnetic resonance imaging (MRI), and laparoscopic Tumor location also influences the sensitivity of 18F-FDG PET.17,18,24
diagnosis can also be used for staging.11–13 There are some limita- The detection rates of proximal and distal parts of gastric cancer
tions to these methods. Accurate detection of extent of disease and have been found to be 74% and 41%, respectively.18 This difference
hence identification of potentially curable versus incurable patients is explained by the higher incidence of the intestinal type in the prox-
by a single conventional imaging method is unlikely. imal part of stomach.
Currently, radionuclide imaging with positron emission tomogra- Tumor size and depth of tumor invasion are additional factors
phy (PET) using 2-[fluorine-18]fluoro-2-deoxy-D-glucose (18F-FDG) that affect the detection rate of primary gastric cancer. The detection
has been recognized as a useful diagnostic modality in clinical oncol- rate for early and advanced primary tumors ranges from 0% to
ogy. In this chapter, the applications of 18F-FDG PET and PET/CT 44% and from 34% to 94%, respectively.17,19,34–37 In a recent study,
scan as a radionuclide imaging method in the diagnostic workup of the sensitivity of 18F-FDG PET/CT for detection of early and advanced
gastric carcinomas are reviewed. In addition, the clinical use of bone gastric cancer was found to be 21% and 74%, respectively.38 Although
scintigraphy in gastric carcinomas is reevaluated. tumor depth is an important factor for the selection of curable
patients for surgery, it cannot be accurately evaluated by PET, because
of the limitations of resolution and physiologic 18F-FDG uptake.
Positron Emission Tomography Therefore, PET imaging is not especially useful in determining the T
stage. There is a positive correlation, however, between T stage and
Preoperative Staging of Gastric Cancer PET sensitivity (Fig. 7.2).20,24,38,39
Variable and sometimes intense physiologic 18F-FDG uptake can
Primary Tumor be seen in the gastric wall because of its high blood flow. In addition,
inflammatory mucosa secondary to gastritis is a frequent cause of
Most studies show that 18F-FDG PET is not an accurate imaging
nonspecific 18F-FDG accumulation. This accumulation may cause
technique for the primary diagnosis of a gastric tumor because of
false-positive findings or, conversely false-negative findings because
its low sensitivity despite its high specificity.14–21 Primary tumors
of weak uptake in gastric lesions.16,18,24 To prevent the low detection
are not detected by 18F-FDG PET in about 20% of patients with
rate of gastric lesions, distension of the stomach by water prior to
gastric cancer (Fig. 7.1). The sensitivity and specificity for detecting
PET imaging is recommended.40,41 Milk has been used to reduce the
primary tumors range from 21% to 100% and from 78% to 100%,
physiologic FDG uptake in the gastric wall.42 With gastric wall dis-
respectively.15,17–19,22–27
tension, malignant lesions can be observed more clearly. Some small
In 18F-FDG PET imaging, the low detection rate in primary
lesions with only mild uptake can also be detected at an early stage.
gastric tumor is a consequence of different histologic subtypes,
tumor location, tumor size, depth of tumor invasion, and background
activity in the normal gastric wall.
About 95% of all gastric malignancies are adenocarcinoma. The
Lymph Node Metastasis
remaining 5% include lymphomas, nonepithelial tumors such as The presence of lymph node metastasis in gastric carcinoma has an
gastrointestinal stromal tumors (leiomyomas or leiomyosarcomas), important role in determining the most suitable therapy and achiev-
and others.28 Gastric adenocarcinoma is a malignant epithelial tumor, ing a good prognosis. The usefulness of PET alone, in comparison
originating from the glandular epithelium of the gastric mucosa. with CT scan and hybrid PET/CT in the preoperative staging of
According to the latest Japanese classification,29 the common malignant lymph node status is shown in Table 7.1. In general, PET is less
92

Chapter 7 Gastric Carcinoma-II 93

Figure 7.1. Non-FDG–avid gastric carcinoma. The coronal PET images do not show abnormal FDG uptake in the gastric wall corresponding to
the primary carcinoma. Histopathologic examination of surgical specimen reveals signet-ring cell carcinoma.
Figure 7.2. FDG-avid gastric carcinoma. The axial CT image shows eccentric wall thickening in the distal part of stomach, and the PET image shows intense
FDG accumulation (SUV, 18.7) in this area. Histopathologic examination is consistent with T4a gastric adenocarcinoma.

Ta b l e 7 . 1
Reported Sensitivities and Specificities of PET and/or PET/CT and CT in the

Detection of Lymph Node Metastases in Gastric Cancer
Sensitivity (%) Specificity (%)

Number of
Study (Year) Patients PET CT PET CT
Yeung et al. (1998) 23 22 97

Mochiki et al. (2004) 85 23.3 65 100 77
Chen et al. (2005) 68 61 77 92 62
Yun et al. (2005) 81 35 52 97 94
Kim et al. (2006) 73 40 71 95 71
Mukai et al. (2006) 62 34.5 62.1 97 87.9
Yang et al. (2008)–PET/CT 78 37 60.5 97.2 83.3
Kim et al. (2010)–PET/CT 71 41 75 100 92
sensitive for the detection of lymph nodes, ranging from 22% to lymph nodes has been reported as 27.5% and 68%, respectively. In
61%.15,17,19,23–26,43,44 The low sensitivity may reflect the relatively addition, PET has low sensitivity (33% to 46.2%) but high specificity
poor spatial resolution of the PET system (Fig. 7.3). Hence, perigas- (91% to 100%) for the detection of N2/N3 lymph nodes.23–25,40,43,44
tric lymph nodes often cannot be distinguished from a primary The detection of distant lymph node metastases can be easier by
tumor and the normal gastric wall. CT has relatively higher sensitiv- PET because they can be distinguished from primary tumors
ity than PET for the detection of lymph nodes, ranging from 52% to (Fig. 7.5).25 CT detects both regional and distant metastases, but it
77% in same series. By contrast, 18F-FDG PET has good specificity cannot help detect cancerous involvement of normal-size nodes and
for lymph node staging of gastric cancer, ranging from 92% to 100% cannot help distinguish between reactive hyperplasia and meta-
for PET and 62% to 94% for CT (Fig. 7.4).17,19,23,24,26 static enlargement.21 PET seems to be an effective adjunctive method
The sensitivity and specificity of 18F-FDG PET variy with lymph to detect anatomically small but metabolically active foci of meta-
node staging status. The mean sensitivity of PET and CT for N1 static disease.
Figure 7.3. Non-FDG–avid lymph node. The axial CT and axial PET
images (A) as well as the axial fused PET/CT image (B) do not show FDG-
avid lymph nodes. However, after surgery, histopathologic examination
B reveals multiple metastatic lymph nodes (17/23 in the lesser curvature and
1/18 in the greater curvature).

Figure 7.4. FDG-avid lymph node. The axial CT image shows diffuse wall thickening in the greater curvature of the stomach and enlarged lymph node. Intense
FDG uptake is also detected in these regions (SUV, 31.5 in the stomach; SUV, 17.8 in the enlarged lymph node). However, no other lymph nodes are detected by PET.
Some authors have concluded that higher 18F-FDG uptake in pri- In a recent study, a statistically significant difference was found
mary gastric tumor is associated with lymph node metastasis.19,24,45 in the detection of locoregional lymph node metastasis by PET/CT

High 18F-FDG uptake of the primary tumor is associated with larger alone (43.5%), EUS alone (52.4%), and the combined use of both
tumor size and deeper tissue invasion.45 Consequently, hypermet- (67.7%).47 The hybrid imaging modality of PET/CT has low sensitiv-
abolic primary tumor and especially hypermetabolic local lymph ity (30.3%) for N staging because of the still limited spatial reso-
nodes are related to incurable surgery.46 However, regional lymph lution.38 Nonenhanced CT images of integrated PET/CT are not
node metastases from the non–18F-FDG-avid gastric carcinomas are sufficient to resolve this issue. EUS is primarily used for the evalu-
less detectable by PET/CT.15 ation of lymph nodes around the lesions. However, it has low accu-
racy and sensitivity in the N staging of gastric cancer because of
approximately half of the metastatic lymph nodes having a smaller
size than the criteria for metastatic lymph nodes.48,49 In the current
staging system, the number of pathologic nodes is important.50
However, accurate counting of pathologic lymph nodes cannot be
readily made by EUS. The combined use of modalities would seem
to be more effective for N staging in gastric cancer.
Distant Metastasis
Distant metastases from gastric cancer include solid organs, the
peritoneum, and distant lymph nodes. Solid organ metastases are
rare at the time of initial diagnosis. The main pathway for solid
organ metastases is hematogenous spread, and the most common
sites include the liver, lungs, adrenal glands, and skeleton (Fig. 7.6).
The role of 18F-FDG PET/CT to detect distant metastases is not clear,
and the overall sensitivity, specificity, and accuracy ranges from
35% to 71%, 74% to 99%, and 73% to 96%, respectively.51–54 Yoshioka
et al.51 found a sensitivity and specificity of 85% and 74% for the
detection of liver metastasis; 67% and 88% for lung metastasis; 24%
and 76% for ascites; 4% and 100% for pleural carcinomatosis; and
30% and 82% for bone metastasis, respectively.
Peritoneal carcinomatosis is one of the most common types of
spread. It has a poor prognosis. The presence of peritoneal metas-
tasis is an important factor in the decision to change treatment.
About 25% of patients with locally advanced tumors on EUS have
occult peritoneal disease that may only be identified with laparos-
copy.55 PET is of little value in the detection of peritoneal carcino-
matosis, with low sensitivity (range: 9% to 50%) and relatively high
specificity (range: 63% to 99%). The cause of low sensitivity can be
explained by extensive fibrosis with a few malignant cells in the
disseminated lesion, and the small size of peritoneal lesions may
be another reason for the low detection rate.23 Two patterns of 18F-
FDG uptake indicative of peritoneal dissemination are (a) diffuse
uptake spreading uniformly throughout the abdomen and pelvis
and (b) discrete focal uptake located within the abdomen or pelvis
Figure 7.5. Distant metastatic lymph nodes. The coronal fused PET/CT image shows high and outside expected nodal stations or solid viscera.21 Although
FDG uptake in the stomach corresponding to the primary carcinoma (SUV, 30.6). The image 18
reveals also widespread FDG accumulation in the left apical, mediastinal, and abdominal lymph F-FDG PET has lower sensitivity than CT to detect peritoneal
nodes (SUV, 24.8) consistent with the distant lymph node metastases. metastases (35% versus 77%), the specificity of PET is higher than

Figure 7.6. Distant organ metastasis. The coronal PET images show pathologic FDG uptake in the stomach and local lymph nodes consistent with
local disease. The PET examination reveals also liver metastases corresponding to the extent of disease.
that of CT (99% versus 92%).52 CT has many false-positive findings. cancer can be cured by surgical resection. Even after complete
Yang et al.54 reported the accuracy, sensitivity, specificity, positive resection of the tumor, disease recurrence occurs in 40% to 60%
predictive value, and negative predictive value of PET/CT (88%, 74%, of patients with advanced disease,57,58 and prognosis is very poor.
93%, 81%, and 91%), which are significantly higher than that of CT In fact, despite successful surgery, the 5-year survival rate is about
(78%, 39%, 94%, 72%, and 79%). A recent systematic review 35%, and even with adjuvant chemoradiotherapy, the survival
showed that ultrasound, EUS, CT, and 18F-FDG PET do not have rate is 40%.59 The most important factors for prediction of recur-
sufficient sensitivity and specificity to evaluate liver and peritoneal rence are the stage of gastric cancer, depth of tumor invasion, and
metastases of gastric cancer.56 The role of laparoscopy, PET/CT, extent of lymph node metastasis.60–63
MRI, and new PET tracers (such as 18F-FLT) to detect liver and The most common sites of recurrence include the gastric bed,
peritoneal metastases of gastric cancer needs to be studied. peritoneal dissemination, retroperitoneal lymph nodes, and hema-
togenous metastases (such as liver) (Fig. 7.7).64 Various methods,
such as tumor markers, endoscopy, and imaging modalities (CT,
Evaluation of Tumor Recurrence PET, and ultrasound) have been used, but each has limitations. For
Complete resection of the tumor with lymph node dissection is the example, tumor markers are used to detect subclinical recurrence,
only curative treatment for gastric cancer, and early stage gastric but they cannot localize the recurrence site, and endoscopy cannot


Figure 7.7. Recurrent disease in a patient who underwent surgery for gastric carcinoma. The axial fused PET/CT images show an area of intense FDG uptake
(SUV, 11.2) on the left para-aortic region consistent with recurrence.
detect extraluminal recurrence.65 CT is the most frequently used patients with confirmed recurrent gastric cancer and assessed the
conventional imaging method to detect recurrent disease in gastric impact of PET/CT results on therapy management. The overall sen-
carcinoma. It has high sensitivity for solid organ metastases such sitivity was 96% and 63% and the overall specificity was 100% and
as the liver but low diagnostic accuracy for peritoneal or lymphatic 10%, for PET/CT and CT, respectively. These results showed that
metastases. In particular, postoperative CT scan has limited value PET/CT was a highly effective modality for the detection of recur-
in differentiating postsurgical changes from local tumor recurrent gastric cancer compared to diagnostic CT. In addition, in 18
rence. In a recent study, Shim et al.66 evaluated the clinical role of (52.9%) cases, the management of the patient’s treatment was
laparoscopy as an alternative to CT and PET scans in the detection changed because of the 18F-FDG PET/CT results.
18
of gastric cancer recurrence in 12 patients. The researchers F-FDG PET also provides additional prognostic information
reported that laparoscopy might be useful to detect recurrence, par- about recurrent gastric cancer. De Potter et al.74 found a statistically
ticularly in patients with advanced (T3 or T4) gastric cancer. Despite significant difference for survival between 18F-FDG PET-negative
a severe lack of evidence for recurrence based on CT or PET, peri- and 18F-FDG PET-positive cases (18.5 versus 6.9 months). In a
toneal dissemination and malignant ascites can be confirmed by recent study, 18F-FDG uptake was found to be a significant prognos-
laparoscopy. tic factor for recurrent disease, especially TC and poorly differenti-
PET, a molecular imaging modality, provides functional infor- ated adenocarcinoma. The disease-free survival rate was 95% for
mation about the tumor, and PET/CT adds anatomical information the 18F-FDG-negative group and 74% for the 18F-FDG–positive group
to the functional evaluation. There have been some studies about (p < 0.0001).75
the role of 18F-FDG PET and PET/CT in the evaluation of gastric Although it has some limitations, 18F-FDG PET is a useful imag-
cancer recurrence after surgery. In these studies, the sensitivity ing method for the detection of recurrent gastric cancer despite low
18
and specificity of PET or PET/CT to detect recurrent disease ranges F-FDG uptake in some histologic subtypes (MC and SRC); back-
from 54% to 96% and 69% to 100%, respectively.41,67–74 In a recent ground activity in normal gastrointestinal system; and limited spatial
meta-analysis (9 studies with 526 patients), overall sensitivity and resolution for small lesions, especially for peritoneal seeding.
specificity of 18F-FDG PET was found to be 78% and 82%, respec-
tively.64 In studies in which both 18F-FDG PET and other diagnostic
tests were compared, the sensitivity and specificity of 18F-FDG PET,
Evaluation of Tumor Response
contrast CT, and combined PET and CT were 72% and 84% for As stated, the prognosis of gastric cancer is poor and cancer recur-
PET, 74% and 85% for CT, 75% and 85% for combined PET and CT, rence rates are high. To improve the outcome, (neo)adjuvant chemo-
respectively.64 PET has good but limited diagnostic accuracy in the therapy regimens have been used.76–78 However, only about 30% to
overall evaluation of recurrent gastric cancer. Kim et al.67 com- 40% of gastric cancer patients respond to chemotherapy regimens.79
pared the value of 18F-FDG PET/CT and contrast-enhanced CT in To avoid unnecessary toxic treatment, an early distinction between
28 patients with confirmed recurrent gastric cancer. The sensitivity potential responders and nonresponders is important. CT is a com-
was 54% and 64%, the specificity was 85% and 87%, and accuracy monly used imaging modality to monitor tumor response. CT-based
was 78% and 82%, for PET/CT and contrast CT, respectively. In this tumor response depends on tumor size reduction (Response Evalu-
study, PET/CT was as accurate as contrast CT in the detection of ation Criteria in Solid Tumors [RECIST] criteria). This criterion, how-
gastric cancer, except for the detection of peritoneal dissemination. ever, is a relatively late sign of response. A metabolic response could
However, PET/CT detected secondary malignancies. Sim et al.69 be detected earlier by 18F-FDG PET and has been used as an early
also reported similar sensitivity and specificity for PET/CT and sign of response in other tumors and has potential in evaluation of
contrast CT, with the exception of peritoneal seeding. Bilici et al.68 the response to chemotherapy in gastric cancer. Ott et al.79 showed
evaluated the clinical role of PET/CT and diagnostic CT in 24 that a 35% reduction in 18F-FDG uptake between prechemotherapy

and the PET scan taken 2 weeks after the initiation of therapy pre- ing group and differed significantly from the responding group. In
dicts the response to therapy with an 85% accuracy. Two other studies a recent study, Park et al.83 found that the maximal standardized
showed similar results.80,81 uptake value (SUV) of the stomach is an independent predictor for
The use of PET in monitoring therapy response also provides a progression-free survival and overall survival. In the same study,
prognostic indicator. Ott et al.79 reported significantly different sur- the low stomach (SUVmax) group had better disease control than
vival rates between the responders’ group and the nonresponders’ the high stomach (SUVmax) group. The metabolic activity of the
group (90% versus 40%). In another study, Ott et al.82 determined primary tumor evaluated by pretreatment FDG-PET can be used as
that survival was similar for the nonavid group and the nonrespond- the prognostic factor.83
Figure 7.8. Bone metastasis. A: The sagittal

PET, sagittal fused PET/CT, and MIP images
show multiple abnormal FDG uptake in the ver-
tebral column and pelvic bones. B: The bone
B scintigraphy reveals also widespread bone
Anterior Posterior metastases on the skeleton.

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44:690–699. 81. Weber WA, Ott K, Becker K, et al. Prediction of response to preoperative chemo-
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ing peritoneal metastasis on the preoperative evaluation for gastric carcinoma. imaging. J Clin Oncol. 2001;15:3058–3065.
Korean J Radiol. 2006;7:249–256. 82. Ott K, Herrmann K, Lordick F, et al. Early metabolic response evaluation by
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C h apt e r 8
Pancreatic Carcinoma
Christina Blümel • Andreas K. Buck
Introduction Detection and Staging of

With 5-year survival rates from 1% to 5%, pancreatic cancer repre-
Pancreatic Cancer
sents one of the most lethal cancers and ranks as the fourth leading
cause of cancer-related death in the United States. Approximately
State of the Art
44,000 patients are diagnosed in the United States every year.1 Sur- Sensitive detection of early cancers and lymph node metastases, dif-
gery is the only curative treatment modality but can be offered to ferential diagnosis of pancreatic cancer and chronic, mass-forming
only a limited number of patients. At initial diagnosis, most patients pancreatitis, and the assessment of tumor resectability using non-
present with an advanced stage and only 20% are potential candi- invasive imaging modalities remain challenging. Usually, clinical
dates for surgery. Despite complete resection of the primary tumor, symptoms including epigastric pain, weight loss, or jaundice raise
5-year survival rate is as low as 32% in patients without lymph node a clinical suspicion on pancreatic cancer. For the diagnostic workup,
metastases and 18% in those with such metastases.2 imaging techniques including ultrasound, endoscopic ultrasound
Most pancreatic cancers arise from ductal or acinar cells and (EUS), computed tomography (CT), and magnetic resonance imaging
related stem cells. Risk factors for pancreatic adenocarcinoma (MRI) represent the principal diagnostic tests.
include cigarette smoking, heavy alcohol consumption, and expo- In patients with newly diagnosed pancreatic tumors, the sensi-
sure to chemicals including β-naphthylamine and benzidine. Chronic tivity of spiral CT to detect pancreatic cancer is 65% to 90% and the

pancreatitis is also an established risk factor for the development of specificity is 46% to 85%. The positive predictive value (PPV) and
pancreatic cancer and is associated with a 7.2-fold increased risk. the negative predictive value (NPV) were reported to be as high as
A genetic predisposition can be assigned to a small number of 79% to 87% and 31% to 61%, respectively.5 To predict resectability,
patients (up to 10%). Mutations have been described in the CDKN2A heterogeneous results have been reported for CT with a PPV of
gene or the BRCA2, PALB2, or MSH2 genes. Neuroendocrine can- 89% and an NPV of 28%.6 Tumors are considered resectable if
cers or islet cell tumors represent rare cancers of the pancreas, there are no distant metastases and no radiographic evidence of
accounting for less than 5% of all pancreatic tumors.3 Diagnosis and encasement of the superior mesenteric artery more than 180
therapy of these tumors are discussed in the chapter on neuroendo- degrees and no aortic invasion. Also, lymph node metastases
crine tumors. beyond the area of resection are considered to render the disease
The prognosis of patients with adenocarcinoma of the pan- nonresectable. In a recent meta-analysis, Bipat et al.5 reported
creas may be improved by adjuvant or neoadjuvant chemotherapy sensitivity and specificity values from pooled data of 81% or 82%,
or chemoradiotherapy. Today, there is no accepted consensus respectively. With the availability of modern multislice CT scanners
regarding the most effective adjuvant treatment, and guidelines in using more advanced imaging protocols such as dynamic multi-
the United States and European countries vary considerably. It phase CT, the accuracy of CT imaging is steadily increasing. Using
has been generally suggested, therefore, that adjuvant or neoad- a triple-phase spiral CT technique, sensitivity for pancreatic cancer
juvant therapy should be provided within clinical trials, whenever has been reported to be as high as 97%.7
feasible. Outside of controlled clinical studies, the National Compre- Abdominal ultrasound is widely used and less costly but insuffi-
hensive Cancer Network (NCCN) practice guideline (www.nccn.org, cient for assessment of resectability. Ultrasound has a high sensitiv-
version 2.2012) suggests the use of 5-fluorouracil- or gemcitabine- ity to detect tumors of the pancreas; however, sensitivity is reduced
based protocols, with or without the addition of radiotherapy, in tumors less than 3 cm. EUS has been shown to be significantly
as adjuvant therapy. Recently, a German multicenter-controlled more sensitive. Detection rates of pancreatic cancer are reported
phase III trial (CONCO) reported a significant delay of disease between 93% and 98%.8–10 The resectability can be predicted cor-
recurrence when patients had adjuvant treatment with gem- rectly in 88% of the patients. T-Staging at EUS was reported to be
citabine, as compared to a control group receiving no further correct in 67% of cases and nodal staging in 44%. Today, EUS is
treatment after surgical resection (disease-free survival at 3 years, regarded a complementary imaging modality to CT or MRI. EUS is
23.5% versus 7.5%, respectively).4 Overall survival, however, particularly relevant to assess tumor invasion of vascular structures
was not significantly different (22.1 and 20.2 months, respectively). (e.g., the portal vein).
Regarding chemotherapy and/or chemoradiotherapy prior to sur- MRI offers superior tissue contrast compared to CT and other imag-
gery (i.e., applied in a neoadjuvant setting), no randomized trials ing modalities. Regarding detection of pancreatic cancer, MRI has
are available comparing both approaches. In principle, treatment a sensitivity of 84% to 88% and a specificity of 78%, respectively.5,8
prior to surgery may result in higher patient numbers achieving In multicenter studies, an accuracy value of 70% and a PPV of 88%
margin-negative resections and delivers treatment also to micro- have been reported for differentiation of resectable and nonre-
metastatic disease. Because no controlled trials are available, sectable pancreatic cancer. However, the corresponding NPV was as
implementation of neoadjuvant treatment is suggested only within low as 23%.6 Novel, diffusion-weighted imaging protocols have the
ongoing clinical trials (e.g., ACOSOG Z5041 trial, www.clinicaltrials.gov; potential to increase the accuracy of MRI. Recently, dedicated pan-
NCT00733746). creatic MRI has been suggested by the NCCN practice guideline as
The aim of this chapter is to report on established and investi- an equivalent alternative to CT imaging at initial workup.
gational applications of nuclear imaging techniques for differential Endoscopic retrograde cholangiopancreatography (ERCP) is
diagnosis of pancreatic tumors, staging and restaging of pancreatic regarded as a therapeutic rather than a diagnostic tool. ERCP is
cancer, and response monitoring. In the final section, an outlook especially important in case of significant biliary obstruction
on novel biomarkers potentially suitable to image pancreatic cancer needing decompression by stent placement. Patients who cannot
and novel imaging modalities, including magnetic resonance/ undergo ERCP may have magnetic resonance cholangiopancrea-
positron emission tomography, is provided. tography, or MRCP.
101

A B C
Figure 8.1. FDG PET/CT for initial staging of a 63-year-old patient with pancreatic cancer. A and B: Coronal and sagittal sections of FDG PET/CT indicate the
primary tumor in the pancreatic body (arrows ). C: Corresponding hypodense mass (arrow ) in contrast-enhanced CT (upper) and intense uptake in corresponding
axial PET (middle), and PET/CT (lower). There is no evidence of distant metastases at PET/CT.
To establish the diagnosis of pancreatic cancer, surgical histo- (e.g., nonsmall-cell lung cancer). This observation may be related
logic confirmation is not essential. A percutaneous biopsy results to increased blood sugar values, which can be frequently observed
in sensitivity and specificity values ranging between 80% to 90% in patients with pancreatic tumors (20% to 30%). In a series of
and 98% to 100%, respectively. The risk of disseminating tumor Zimny et al.,26 25% of the study collective suffered from diabetes.
cells is considered low. As recommended by the NCCN practice Whereas in patients with normal blood sugar values, 18FDG PET
guideline, EUS-guided fine-needle aspiration biopsy is preferred sensitivity was very good (98%, 46/47), and the sensitivity
to CT-guided biopsy because of better diagnostic yield and safety. dropped to 68% (17/27) in patients with hyperglycemia. Tumor
18
FDG uptake, as measured by calculation of the standardized
uptake value (18FDG-SUV), was significantly higher in patients
Role of Nuclear Medicine with normal blood glucose values (6.9 ± 3.7) compared to patients
Detection of Pancreatic Cancer and with hyperglycemia (5.5 ± 3.4). Therefore, it has been suggested
that medication with insulin should be used in hyperglycemic
Differential Diagnosis patients to increase the sensitivity of PET. Delbeke et al.13 applied
Bares and colleagues were one of the first groups to report on the insulin intravenously (2 to 10 international units) every 15 min-
feasibility of positron emission tomography (PET) to differentiate utes to achieve blood sugar values below 150 mg/dL.13 This
between benign and malignant pancreatic tumors based on an approach resulted in a sensitivity value of 80% in diabetic
increased glucose utilization in malignant lesions (Fig. 8.1). Of 13 patients. A recent Society of Nuclear Medicine (SNM) Guide-
pancreatic cancers, 12 presented with increased focal 18FDG uptake line acknowledges the use of insulin for this purpose.28 How-
(sensitivity 92%), whereas two benign tumors were negative at ever, it is recommended that injecting 18FDG should be delayed
18
FDG PET.11 Table 8.1 summarizes additional recent publications after insulin administration to reduce unspecific tracer uptake
addressing the sensitivity and specificity of PET and PET/CT for in muscle tissue.
the detection of pancreatic cancer and differential diagnosis of The second drawback of 18FDG PET in pancreatic cancer is a
pancreatic masses.12–26 For 18FDG PET without coregistration of CT frequently observed coexistence of malignant tumors and inflam-
data, meta-analyses of more than 1,000 patients report median matory processes such as acute or chronic active pancreatitis. Die-
sensitivity and specificity values of 91% and 78%, respectively. derichs et al.29 showed that the specificity of 18FDG PET significantly
However, there is a wide range of sensitivity and specificity values drops if the C-reactive protein (CRP) is elevated or the leukocyte
reported in individual studies (sensitivity, 64% to 96%; specificity count is increased. The specificity was as low as 40% compared to
64% to 94%). More recent clinical trials, including contrast- 87% in patients with normal CRP values or normal white blood cell
enhanced CT as part of PET/CT protocols, report high sensitivity count. Because of these drawbacks, 18FDG PET or PET/CT should
of 96% but also reduced specificity (67%).27 not be routinely used for the differential diagnosis of pancreatic
The performance of 18FDG PET to differentiate pancreatic tumors but can serve as a problem solving tool in patients with
tumors is somewhat lower compared to other solid tumors inconclusive findings at CT or MRI.

Chapter 8 Pancreatic Carcinoma 103
Ta b l e 8 . 1
Detection of Pancreatic Cancer and Differential Diagnosis with PET and

PET/CT (Cancer vERSUS Benign Tumors)
Number of
Patients PET Only or
Author and Year Involved PET/CT Sensitivity (%) Specificity (%)
Yao et al. (2012) 36 PET/CT 94 75

Buchs et al. (2011) 45 PET/CT 96 67
Kauhanen et al. (2009) 38 PET/CT 85 94
Farma et al. (2008) 82 PET/CT 89 88
Strobel et al. (2008) 50 PET/CT 96 82
Mansour et al. (2006) 68 PET 57 85
van Kouwen et al. (2005) 109 PET/CT 91 87
Nishiyama et al. (2005) 86 PET/CT 88 88
Heinrich et al. (2005) 95 PET/CT 89 69
Lemke et al. (2004) 104 PET 89 64
Koyama et al. (2001) 86 PET 91 76
Nakamoto et al. (2000) 47 PET 96 75
Sendler et al. (2000) 42 PET 71 64
Delbeke et al. (1999) 65 PET 92 85
Diederichs et al. (1998) 152 PET 86 78

Zimny et al. (1997) 106 PET 85 84
Inokuma et al. (1995) 46 PET 94 82
Friess et al. (1995) 80 PET 94 88
Kato et al. (1995) 24 PET 93 78
Bares et al. (1994) 40 PET 93 85
Staging Pancreatic Cancer with the therapeutic regimen was changed in 8/56 (13%) patients
18
FDG PET and PET/CT because of detection of previously unknown metastases. Heinrich
et al. reported an impact of PET/CT on therapeutic decision mak-
In patients with pancreatic cancer, detection of regional lymph ing in 16%, predominantly because of prevention of surgery in
node and distant metastases is of paramount importance to select patients with distant metastases detected exclusively by 18FDG
patients who will benefit from surgical resection (Figs. 8.2 and PET or PET/CT.16 PET/CT (including contrast-enhanced CT) was
8.3). Many studies have shown that the performance of 18FDG PET superior to contrast-enhanced CT alone in a retrospective trial of
for lymph node staging is poor with sensitivity values between Asagi and coworkers of 108 patients with pancreatic cancer.30
17% and 33%, respectively.13,16,20 Also, integrated PET/CT imaging Besides detection of lymph node and distant organ metastases,
does not lead to a significant increase in sensitivity, as recently noninvasive imaging is relevant to evaluate resectability of the
reported by Heinrich et al. and Asagi et al.16,30 Better sensitivity primary tumor. Strobel et al. recently reported that the combined
values of PET and PET/CT have been reported for the detection of use of 18FDG PET and contrast-enhanced CT is superior to 18FDG
liver, peritoneal, or extra-abdominal metastases (Fig. 8.1). In the PET or CT, interpreted separately. Using histopathology and clinical
study of Heinrich et al., the sensitivity of PET regarding detection follow-up as reference, sensitivity, specificity, and accuracy values
of liver metastases was 81% (13/16) and significantly higher to
that of contrast-enhanced CT (56%, 9/16). The specificity of CT
regarding detection of liver metastases was 95% compared to Tab l e 8 . 3
100% of PET/CT. See Tables 8.2 and 8.3 for further information.
Because of the sensitive detection of distant metastases, two M-Staging of Pancreatic Cancer with
publications reported a significant impact of PET and PET/CT PET and PET/CT
regarding patient management. In the series of Delbeke et al.,13
Number
Table 8. 2 of
Patients Imaging Sensitivity Specificity
N-Staging of Pancreatic Cancer with Author and Year Studied Modality (%) (%)
PET and PET/CT
Kim et al. (2012) 125 PET/CT 73 (32/44) —
Yao et al. (2012) 36 PET/CT 73 (8/11) 100 (25/25)
Number of Kauhanen et al. 38 PET/CT 88 (6/7) —
Patients PET Only (2009)
Author and Year Involved or PET/CT Sensitivity (%) Strobel et al. (2008) 50 PET/CT 82 (9/11) 97 (38/39)
Heinrich et al. (2005) 95 PET/CT 81 (13/16) 100 (43/43)
Kauhanen et al. (2009) 38 PET/CT 33 (5/17) Sahani et al. (2005) 34 PET 93 (28/30) —
Heinrich et al. (2005) 95 PET/CT 21 (3/14) Lemke et al. (2004) 104 PET/CT — 100 (14/14)
Lemke et al. (2004) 104 PET/CT 32 (10/31) Delbeke et al. (1999) 65 PET 81 (17/21) —
Delbeke et al. (1999) 65 PET 17 (2/12) Fröhlich et al. (1999) 146 PET 68 (15/22) 95 (138/146)
Zimny et al. (1997) 106 PET 46 (12/26) Zimny et al. (1997) 106 PET 51 (16/31) —
Bares et al. (1994) 40 PET 61 (19/31) Bares et al. (1994) 40 PET 54 (7/13) —

A C
Figure 8.2. FDG PET/CT for detection of recurrent pancreatic cancer. In a follow-up study performed 6 months after resection of the primary tumor, whole-body
view (A) and transverse PET/CT sections indicate local recurrence of pancreatic cancer (B, arrow ), and solitary liver metastasis (C, arrow ) presenting with high
focal FDG uptake.
of 96%, 82%, and 88% have been reported for 18FDG PET/CT in a curative surgery to palliative care or vice versa). The authors
series of 50 patients with pancreatic cancer.31 In a smaller series claim that PET/CT is especially helpful to detect previously
of 21 patients with pancreatic tumors, PET/CT was found to have unknown distant metastases from pancreatic cancer. However, the
a major impact on the therapeutic decision-making process.32 In numbers are small and need verification in future clinical trials
41% of the patients, extent of the disease was found to differ sig- with greater number of patients.
nificantly between PET/CT and conventional staging investigations, Cost effectiveness of PET and PET/CT has been addressed by
resulting in a major change of the therapeutic regimen (i.e., from only one study.16 Because of prevention of futile surgery, cost savings
A C
Figure 8.3. Demonstration of FDG-avid metastasis in the liver and peritoneal metastasis but no local recurrence 1 year after resection of pancreatic cancer.
A: Whole-body view with intense FDG uptake in both metastases. B: CT indicates hypodense lesion in the liver (arrow ) (left), intense FDG uptake in PET (middle), and
PET/CT (right). C: CT with small perihepatic peritoneal tumor (arrow ) (left) and corresponding FDG uptake in PET (middle) and PET/CT (right), indicating peritoneal
dissemination.

of (US) $62,900 were reported compared to the theoretical

approach of conventional preoperative staging without PET/CT.
However, additional costs for chemotherapy or chemoradiother-
apy in patients undergoing palliative treatment instead of surgery
were not calculated. The addition of functional imaging with PET
and PET/CT to the diagnostic workup of staging pancreatic cancer
has a potential for cost savings, but this issue needs to be
addressed in well-designed clinical trials, including cost for imag-
ing and therapeutic interventions also.
Summary
For differential diagnosis and staging of pancreatic cancer, no
clear role of nuclear imaging has been defined at this time, and
established algorithms do not include PET or other scintigraphic
imaging modalities into the diagnostic workup of tumors related
to the exocrine pancreas. However, keeping the limitations of PET
in mind, including a reduced sensitivity in hyperglycemic patients
and a reduced specificity in coexisting inflammatory lesions, PET/
CT, including a three-phase pancreatic CT protocol, may improve
the accuracy of noninvasive imaging. Current suggestions are
based predominantly on clinical studies reporting on the perfor-
mance of nonhybrid PET imaging or on PET/CT studies including

only low-dose CT. Superiority of state-of-the-art PET/CT imaging
awaits confirmation in future prospective clinical trials.
Diagnosis of Recurrence A B
and Restaging Figure 8.4. Response monitoring of pancreatic cancer in a 69-year-old patient using repeti-
tive FDG PET/CT. A: Intense focal FDG uptake in the malignant primary with liver metastases
State of the Art and multiple lymph node metastases (mediastinal, mesenteric, retroperitoneal); B: FDG PET/CT
after first cycle of chemotherapy (FOLFIRINOX) demonstrating partial response with decreasing
When recurrent disease is suspected, tomographic imaging (CT, FDG uptake at multiple metastatic sites.
MRI) is usually performed, followed by biopsy of the suspicious
lesion to confirm local or distant relapse. If a local recurrence is
detected, chemoradiotherapy is frequently appropriate. Second- indicate that PET/CT including a contrast-enhanced CT component
line chemotherapy should be considered in case of metastatic can serve as an accurate modality to noninvasively detect local
spread. Because of the dismal prognosis of recurrent pancreatic recurrence and distant metastases. However, the numbers are still
cancer and novel anticancer drug regimens becoming available, small and the high sensitivity and specificity values may not hold
including targeted compounds such as the EGFR-inhibitor erlotinib up in larger clinical trials. Given a dismal prognosis of patients with
or potent cytostatic drugs such as nab-paclitaxel, the NCCN prac- disease recurrence, imaging findings are less relevant in a clinical
tice guideline supports inclusion of patients in ongoing clinical scenario. However, if more therapeutic options become available,
trials (PANC-10). the relevance of nuclear imaging will likely increase.
Role of Nuclear Medicine Treatment Response Monitoring

33
Ruf et al. assessed 31 patients with a clinical suspicion on local
relapse using PET/CT. Patients were included because of increased State of the Art
tumor marker levels (cancer antigen 19–9; CA 19–9) or clinical signs Recently, the following chemotherapeutic regimens have shown
of recurrence. PET was able to detect 96% of local recurrences improvement of the time to progression and overall survival:
(22/23) which was significantly higher than CT or MRI, detecting 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX),
9/23 recurrences. Also, distant recurrence in the abdomen could be gemcitabine plus erlotinib, gemcitabine plus cisplatin, or gemcitabine
detected exclusively by PET (7/7) versus 0/7 with CT and MRI, plus nab-paclitaxel. Most recent guidelines on the management of
whereas CT and MRI performed better for detection of small liver pancreatic cancer do not suggest a specific imaging modality for
metastases (92%, 11/12 versus 42%, 5/12). A recent study reported response monitoring. In clinical trials, endoscopic techniques, includ-
on the accuracy of contrast-enhanced PET/CT in 45 patients with ing EUS, CT, and MRI are currently most widely used for this purpose
recurrent pancreatic cancer. Compared to stand-alone contrast- and response is described according to response criteria in solid
enhanced CT or PET/CT with nonenhanced CT, sensitivity, specific- tumors (RECIST 1.1).35 Data on the predictive potential of tumor
ity, and accuracy values of 92%, 95%, and 87% were reported for markers such as CA 19–9 are conflicting. Several studies report that
contrast-enhanced PET/CT.34 However, the numbers are small and a decreasing serum level of CA 19–9 correlates with survival in
the added value of PET imaging to characterize recurrent disease patients undergoing surgery.36 The NCCN practice guideline there-
needs to be addressed in a larger series. Figure 8.4 demonstrates fore recommends measuring CA 19–9 prior to surgery and at clinical
the typical PET/CT appearance of pancreatic cancer recurrence with follow-up. The most recent text version of the NCCN guideline does
multiple metastatic sites to the liver and abdomen. not comment on the utility of PET or PET/CT for this application.
Summary Role of Nuclear Medicine

Regarding detection of recurrent pancreatic cancer, there is no Several studies have indicated an association of 18FDG uptake in
clearly defined role for nuclear imaging modalities. Pilot studies malignant primary tumors of the pancreas and individual prognosis.

Every publication showed that 18FDG uptake was inversely corre- imaging will depend on the results of future clinical trials assess-
lated with overall survival. In the study of Zimny et al.,37 on multi- ing not only the diagnostic accuracy but also superiority to other
variate analysis, the tumor marker CA 19–9 and 18FDG-SUV were the well-established diagnostic modalities. Assessment of cost effective-
only independent predictors. In patients with an SUV <6.1, overall ness will also become more relevant in the future. For staging and
survival was 5 months compared to 9 months in patients with an SUV restaging of pancreatic cancer, prospective clinical trials on the
≥6.1. Lyshchik et al.38 assessed the prognostic utility of dual-phase accuracy of PET/CT should include a dedicated three-phase CT pro-
18
FDG PET in 65 patients. However, to date, only a few studies with a tocol. In addition, PET/CT should be included in clinical phase II/III
limited number of patients have been performed to assess the utility studies to predict response to novel anticancer drug regimens.
of PET or PET/CT to monitor response to treatment. As with other With the increasing availability of novel cancer biomarkers, pilot
solid cancers, molecular imaging is able to discriminate responding trials on the diagnostic utility of surrogate markers for tumor
from nonresponding pancreatic tumors at 2 months after the start of hypoxia, proliferation, integrin expression, or chemokine receptor
therapy, whereas no significant change of the tumor size was observed expression will provide interesting insights into the biology of pan-
with spiral CT.39 In another small series (of 11 patients), Maisey et al.40 creatic cancer. Nucleoside analogs such as 3′-deoxy-3′-[18F]fluoro-
assessed the effect of treatment with 5-fluorouracil in combination or thymidine (18FLT) may be used to specifically image the proliferative
without mitomycin C and identified six patients without residual FDG activity of primary cancers.43 This approach may aid in differential
uptake. Overall survival was significantly longer in patients with diagnosis of benign and malignant tumors and early response mon-
FDG-negative tumors after therapy (319 days versus 139 days, respec- itoring.44 Imidazole derivatives such as [18F]-misonidazole (FMISO)
tively). Using a decline of 18FDG-SUV ≥50%, Choi et al.41 have found can be used for specific imaging of hypoxic tumor tissue potentially
mean survival of 23.2 months in patients responding to induction leading to more efficient radiotherapy by increasing the radiation
chemotherapy followed by chemoradiotherapy. In patients with PET dose to the hypoxic fraction of tumors. The radiotracer [18F]galacto-
nonresponse, mean survival was 11.3 months. Because of the low RGD is a pentapeptide binding to the integrin ανβ3 which plays an
number of patients involved (20 patients with advanced pancreatic important role in angioneogenesis and metastasis.45 These radio-
cancer), results did not reach statistical significance. Another small pharmaceuticals quantify specific metabolic processes in vivo. Yet
series published by a Swiss group also reported a good correlation of the future role of these PET tracers for imaging pancreatic cancer
histologic response to neoadjuvant chemotherapy including gem- remains to be determined.
citabine and cisplatin.42 Histologic response was best predicted by It is also expected that the recently introduced MR/PET scanners
low metabolic activity of the malignant primary at baseline and at will enhance the diagnostic accuracy of molecular imaging.46 The
follow-up after the end of neoadjuvant chemotherapy. superior soft tissue contrast offered by MRI will complement molec-
ular information provided by PET. However, given the aggressive
nature of the disease with disseminated cancer cells present in the
Summary majority of patients, the appropriateness of imaging, especially
Until recently, only minor responses to chemotherapy and/or regarding T- and N-staging will remain challenging. M-staging
chemoradiotherapy in the adjuvant or the neoadjuvant setting have appears more promising, but it will be challenging to demonstrate
been reported. Accordingly, noninvasive imaging was of minor clin- superiority of MR/PET over the available PET/CT technology.
ical relevance and the evidence for nuclear imaging to monitor
response was low. Consequently, current practice guidelines, includ-
ing the new version of the NCCN practice guideline on pancreatic
cancer, do not report on modalities to monitor response. Given the References
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Chapter 9
Colorectal Carcinoma
Gregory C. Ravizzini • Revathy B. Iyer • Homer A. Macapinlac
Introduction presentation is often a manifestation of relatively advanced CRC.

Patients may suffer from abdominal pain, change in bowel habits,
Worldwide, colorectal cancer (CRC) is the third most commonly hematochezia or melena, or unexplained iron-deficiency anemia.9,10
diagnosed cancer in males and the second in females.1 In the There is substantial evidence that the majority of cases of CRC arise
United States, it is estimated that 143,460 new cases of CRC will from benign adenomatous polyps which grow slowly over time.11
be diagnosed in 2012, including approximately 1,030,170 colon As the polyp size increases, the risk of malignancy also increases.
and 40,290 rectal cancers.2 On an annual basis, 51,690 Americans Systematic screening of a target population of appropriate age has
die of CRC, accounting for approximately 9% of all cancer deaths. the potential to reduce morbidity and mortality of CRC by detecting
Approximately 85% of CRCs are adenocarcinomas (not otherwise asymptomatic lesions and by cancer prevention through polypec-
specified), 10% are mucinous adenocarcinomas, and the remaining tomy.12,13 The American Cancer Society recommendations for colon
are rare histologic types, such as papillary carcinoma, adenosqua- cancer screening in adults 50 years of age with average risk include
mous carcinoma, and signet cell carcinoma. The risk of developing tests to find polyps and cancer. The available diagnostic tests include
CRC is influenced by both environmental and genetic factors, with flexible sigmoidoscopy every 5 years, or double-contrast barium
the majority of cases being sporadic.3 As many as 20% to 30% of enema examination every 5 years or computed tomography (CT)
CRCs have a potentially definable inherited cause, and 3% to 5% of colonography every 5 years, or colonoscopy every 10 years.14 The
colon cancers occur in genetically defined high-risk colon cancer American Cancer Society also recommends the following screening
family syndromes such as familial adenomatous polyposis and tests to detect cancer: Fecal occult blood test (FOBT) every year, or
Lynch syndrome.3,4 fecal immunochemical test (FIT) every year, or stool DNA test (sDNA).14
Once the diagnosis is established, the local and distant extent More rigorous testing is required for patients with increased or
of disease spread will provide the scaffold for therapy planning high risk of developing CRC. Emerging technologies such as sDNA
and prognosis, with resection being the mainstay of treatment for show promise as a reasonable screening test, but to date, there are
curative intent. Following surgical exploration of the abdomen, limited data to support it as a first-line screening test. The FOBT is
histopathologic staging is performed. This will frequently include a guaiac-based test for peroxidase activity used to detect blood in the
evaluation of the grade of the tumor; depth of penetration and stool. Mandel et al.15 present evidence that the FOBT decreases mor-
extension to adjacent structures (T); number of regional lymph tality secondary to colon cancer. The sensitivity of the FOBT is in the
nodes evaluated and number involved (N); status of proximal, range of 72% to 81.8%.16,17 With flexible sigmoidoscopy, it is possible
distal, and radial margins; lymphovascular invasion; perineural to examine up to 60 cm of the colon, and thus limiting the number
invasion; and assessment of distant metastases to other organs, of detectable lesions to just 40% to 65% of all possible lesions.18
peritoneum, or nonregional lymph nodes (M).5 Symptoms of CRC are Some authors report sensitivities of 71% to 95% in the detection of
most frequently related to tumor growth into the bowel lumen or colon carcinoma with double-contrast barium enema examina-
direct invasion into adjacent structures. As a result, patients present tion.19 However, the sensitivity decreases to as low as 50% to 75% as
typically at relatively advanced stage. Among the newly diagnosed reported in prospective studies.20 Therefore, some organizations
CRCs in the United States, approximately 39% of cases are localized such as the National Comprehensive Cancer Network (NCCN) dis-
at diagnosis, and an additional 37% have locoregional metastases.2 courage the use of double-contrast barium enema for screening,
Unfortunately, nearly 20% of patients have distant metastatic disease unless patients are unable to undergo colonoscopy or if colonoscopy
at the time of presentation, most commonly to lymph nodes, liver, is technically incomplete. In the United States, colonoscopy is the
lungs, and peritoneum.2 In approximately 75% of patients presenting primary method employed for CRC screening in patients with aver-
with CRC deemed to be resectable, only two-thirds are cured by age and increased risk. Unfortunately, adherence to CRC screening
surgical intervention, whereas one-third will recur following pri- recommendations is poor, with only approximately 50% to 60% of
mary therapy. Recent data support that early diagnosis of recurrent the eligible patient population undergoing any kind of screening
disease results in more favorable outcome. Some cases of isolated examination.21 Rex et al.22 compared colonoscopic procedures in the
locoregional recurrence may be amenable to surgical resection same day back-to-back. The overall miss rate was 24% for adeno-
alone or benefit from multimodality therapy. Surgery may also have mas, 27% for adenomas 5 mm in diameter or smaller, 13% for ade-
curative potential in patients with distant metastases, such as nomas 6 to 9 mm in diameter, and 6% for adenomas 10 mm in
hepatic metastases or limited extrahepatic disease.6,7 Ablative tech- diameter or larger.
niques may be considered alone or in conjunction with surgery in More recently, CT colonography has been proposed as an alterna-
selected patients with distant metastases.8 tive noninvasive method for screening CRC. CT colonography com-
Modern imaging techniques play a critical role in the manage- bines the data from multidetector helical CT with advanced graphical
ment of patients with CRC and help in selection of patients who software to reconstruct two-dimensional and three-dimensional
would benefit most from surgical or invasive approaches. Postop- endoluminal views of the colon. Reconstructed endoluminal images
eratively, surveillance by imaging is usually performed in tandem can be viewed dynamically and interactively, simulating what is seen
with serum carcinoembryonic antigen (CEA) assays. When CEA lev- at conventional colonoscopy. Current studies have shown that CT
els rise during postoperative surveillance, imaging is performed in colonography and conventional colonoscopy show equivalent sensi-
an attempt to identify the presence and location of recurrence to tivity in the detection of polyps of 10-mm diameter or larger, that are
facilitate prompt treatment. considered to be clinically significant.13 Moreover, CT colonography
permits the complete exploration of the colonic lumen and evaluation
of eventual areas of tumor stenosis.23 Colonography can also be
Screening performed combining fluorine-18-fluorodeoxyglucose ([18F]FDG)
positron emission tomography PET/CT and magnetic resonance
The usual symptoms of CRC are typically because of tumor pene- imaging (MRI) techniques. According to Veit-Haibach et al.,24 PET/
tration into the lumen or adjacent structures. This symptomatic CT colonography showed improved T staging in patients with CRC
108

Chapter 9 Colorectal Carcinoma 109
compared with CT colonography. This study determined that PET/CT retroperitoneal chains. Those located at the rectosigmoid junction
colonography correctly localized 74% of colorectal tumors, CT and tend to spread to the perirectal lymph nodes rather than along the
PET 64% of lesions, and CT alone localized 52% of lesions. PET/CT sigmoid mesenteric chain.33
colonography helped significantly in defining TNM staging com-
pared to optimized abdominal CT staging alone, a difference mainly
based on a more accurate definition of the T stage. Consequently, Peritoneal Spread
in this study, whole-body PET/CT colonography changed therapy Peritoneal spread of disease is seen in up to 43% of patients.29
management in 9% of patients.24,25 In addition to optical colonoscopy, Tumor cells can spread throughout the peritoneal cavity and
as an all-in-one staging modality, whole-body PET/CT colonography implant on the omentum and peritoneal surfaces. This pattern of
is capable of providing an alternative to the multimodality, multistep spread is seen more commonly in the intraperitoneal portions of
staging in patients with CRC.24 The concept of whole-body PET/CT the colon, including the cecum and transverse and sigmoid colon.29
colonography demonstrated high detection rates for CRC, metastatic The ovaries are a common site of involvement by peritoneal dis-
lymph nodes, as well as distant metastases.25 semination.28 In animal models, injection of neoplastic cells into
The analysis of the differences between CT, MRI, and PET/CT the mesenteric border tend to give rise to nodal metastases
colonography shows that these techniques present both advantages whereas injection into the antimesenteric border gives rise to peri-
and disadvantages, such as the difficulty to perform MRI in patients toneal metastases, alluding to the role of tumor location to the
with pacemakers or in claustrophobic patients and the risk to per- method of dissemination.34 The presence of peritoneal involvement
form CT with iodinated contrast in patients with history of adverse predicts higher local recurrence and is strongly associated with a
reactions or renal failure.26 mucinous tumor phenotype (signet-ring feature).35 Hematogenous
spread of colonic and upper rectal tumors initially occur via the
portal circulation. The liver is often the first site of metastatic dis-
Patterns of Tumor Spread ease and may be the only site of spread in as many as 30% to 40%
of patients with advanced disease.36 Twenty percent to 25% of

Tumors spread in certain patterns: Local, nodal, and peritoneal patients will have clinically detectable liver metastases at the time
spread (well described by Tan27) of initial diagnosis and an additional 40% to 50% of patients even-
tually develop liver metastases after resection of the primary
Local Spread tumor. Approximately 20% to 30% of patients with metastatic CRC
have disease that is confined to the liver and is potentially resect-
Tumors may spread either intramurally or transmurally. Intramu- able.37 In low rectal tumors, venous drainage occurs through the
ral spread of tumor usually occurs longitudinally along the bowel systemic circulation via the iliac vessels. This may explain the
wall or superficially toward the serosa. Preferentially, tumor grows higher propensity of pulmonary metastases in low rectal cancers
in a circumferential pattern, resulting in luminal narrowing. Longi- compared with tumors from the more proximal parts of the colon
tudinal spread is not common and is generally approximately 2 cm and rectum.29 In the appropriate clinical setting, aggressive surgi-
from the primary site of disease. This supports the practice of a cal resection of distant metastases (including the liver, lung, adre-
5-cm surgical margin.28 Transmural spread is present in more nal gland, and spleen) has been shown to confer survival benefit.38
advanced disease. Lesions in the ascending colon, descending Therefore, early detection of metastastic disease by imaging proce-
colon, and rectum, which are primarily retroperitoneal in location, dures is important.
can directly invade the adjacent retroperitoneal organs such as the
kidneys and pancreas via this mode of spread. Locally advanced
rectal cancer often involves the pelvic viscera including the bladder
base, prostate gland, and vagina.29 Disease can also spread along
Diagnosis and Initial Staging of
the neurovascular structures. Extramural venous invasion is asso- Colorectal Cancer
ciated with increased metastastic burden and result in the worst
overall prognosis. Perineural spread in rectal cancer can result in Several modalities have been used in the preoperative staging of
tumor deposits along the perineural spaces more than 10 cm from CRC: CT, MRI with endorectal or phased array coils, endorectal
the primary tumor. This has been reported in as many as 35% of ultrasonography with rigid or flexible probes, and PET/CT imaging.
cases.30 Usually, a combination of these modalities provides complete stag-
ing information. Frequently, barium enema is still performed, hav-
ing the advantage of permitting the examination of the entire colon.
Nodal Spread The sensitivity of double-contrast barium enema for detecting pol-
Distant spread of disease most commonly occurs in the liver, fol- yps 1 cm or larger has been estimated to range from 50% to 90%.39,40
lowed by lymph nodes.31 Nodal spread from carcinomas of the However, the sensitivity declines with decreasing lesion size, and is
right colon follow along the marginal vessels of the cecum and less sensitive than colonoscopy for identifying smaller lesions.41 CT
ascending colon and then along the ileocolic vessels to the root of imaging is routinely used in the staging of CRC, permitting the visu-
the superior mesenteric artery. Tumors of the proximal transverse alization of the entire abdomen and pelvis. Most protocols involve
colon tend to spread along the marginal vessels on the mesocolic the administration of iodine-containing intravenous contrast, which
side of the colon. These marginal vessels in turn drain to the right gives information on perfusion and the relationship of tumors to
or middle colic vessels and to the root of the mesocolon, anterior blood vessels. In addition, intravenous contrast frequently makes
to the head of the pancreas. Lymphatics from the distal transverse metastases easier to discriminate from background tissues. Iodine-
colon and splenic flexure follow the left middle colic vessels to the or barium-containing oral contrast is often used to highlight loops
inferior mesenteric vein just caudal to the body and tail of the of bowel, allowing a higher degree of diagnostic certainty when
pancreas. Cancers of the descending colon and sigmoid colon evaluating adjacent soft tissue masses. CT is useful for identifying
spread to nodes along the left ascending colic and sigmoidal ves- the primary tumor, local and distant lymph nodes, and the presence
sels that can then be followed to the origin of the inferior mesen- of liver and lung metastases.42
teric artery.32 Proximal rectal tumors spread cranially via the Based on the American Joint Committee on Cancer (AJCC) stag-
superior hemorrhoidal nodes antegrade to the inferior mesenteric ing system, the T stage of CRC is determined by degree of involve-
lymph nodes. The more distal rectal tumors spread laterally along ment of the bowel wall, whereas that of the anus is determined by
the internal iliac lymph nodes antegrade to the common iliac and the size of the primary tumor. Also, the N stage of CRC is defined by

the number of involved nodes, as opposed to the location of nodes unveiled a solution, which involves a 3-tesla MR and a high reso-
in anal cancer. T-staging accuracy of 59% to 88% has been reported lution PET scanner with a rotating table that transfers the patient
for MRI in CRC and was similar to that reported for CT imaging.43–45 from one machine immediately into the other. The system com-
The improvement in T-staging accuracy of CRC to 71% to 91% was bines time-of-flight technology with state-of-the-art 3-tesla MRI in
achieved after development of endorectal coils.46,47 As is common a whole-body footprint for sequential imaging acquisition. The PET
with other modalities, the primary staging inaccuracy of MRI occurs gantry was redesigned to introduce magnetic shielding for the pho-
in differentiating T2 from T3 lesions. Because of the desmoplastic tomultiplier tubes, which ensured their operation in “normal” flux
reaction seen adjacent to tumors, MRI typically overstages T2 levels close to the Earth’s magnetic field. Siemens addressed the
lesions,48 thus making it difficult to determine whether an irregular mentioned challenging issues by developing a new electro-optical
outer border of the rectal wall represents perirectal fat being invaded readout scheme for a PET scintillation detector module that relays
by inflammation alone or a combination of tumor and peritumoral the signals using optical telecommunications grade lasers and
fibrosis. Difficulties of N staging in CRC occur mainly by the fact that fibers rather than shielded coaxial or high-density ribbon cables,
micrometastases could present as normal-sized lymph nodes.49,50 while preserving the high detector signal-to-noise ratio and signal
Even though MRI may localize nodes as small as 2 to 3 mm in size, integrity of the PET.59 In the Siemens 3-tesla hybrid system, named
morphologic criteria alone are a poor predictor of whether a node Biograph mMR (m = molecular), the photomultipliers were replaced
is reactive or metastatic. Consequently, the N-staging accuracy of with APDs that are only a fraction of the size of electron tubes.
MRI has been highly variable, ranging from 39% to 95%.43,44,51,52 Even though the APDs measure an electron flow that is caused by
Diffusion-weighted MRI (DW-MRI) can provide unique informa- photons, this takes place within a semiconductor layer system that
tion, as contrast is dependent on the molecular motion of water, does not suffer much interference from external magnetic fields.
which may be substantially altered by disease. The method was This technology permits fast simultaneous imaging acquisition in
introduced into clinical practice in the mid-1990s, but because it an integrated system.
requires high-performance magnetic field gradients, it has only
recently undergone widespread dissemination.53 For instance, in
the application of CRCs, DW-MRI improves the detection rate of
PET/CT for Initial Staging
metastases in normal-sized lymph nodes from 7% to 76% by calcu- PET with [18F]FDG is widely used for diagnosing, staging, restag-
lation of the apparent diffusion coefficient.54 Another MRI tech- ing, and assessing the therapeutic response in a number of tumors
nique, dynamic contrast-enhanced MRI (DCE-MRI), has become an (Fig. 9.1).60
attractive modality for evaluating response to therapy. Rapid acqui- Two different patterns of colorectal [18F]FDG uptake have been
sition of images is performed before and after intravenous contrast defined on PET examination: Focal and nonfocal.61 Nonfocal uptake
administration, providing information about tumor neovasculariza- of [18F]FDG is generally correlated with physiologic uptake by
tion by calculating the different fractions of tumor perfusion.55 smooth muscles of the gastrointestinal tract or with radiotracer
A study by Gore et al.56 suggests that quantitative DCE-MRI could excretion and intraluminal concentration, whereas there is evi-
be helpful for differentiating benign from malignant breast tumors dence from the literature that focal uptake of [18F]FDG can be asso-
and could assess the effects of antiangiogenic medications. The ciated with endoscopically detectable lesions.62 A study by Treglia
combination of DWI, magnetic resonance spectroscopy, and DCE- et al.62 evaluated 6,000 patients and recommends the use of colo-
MRI data with PET, has become an interesting research topic noscopy for further characterization of incidental focal colorectal
recently. Further attempts were made to combine MRI and FDG uptake of [18F]FDG, given the high incidence of malignant and pre-
PET, by means of software fusion, for primary staging of CRC. In malignant lesions (Fig. 9.2).
the study by Kam et al.,57 23 patients were evaluated with MRI of One of the challenges of older generation dedicated [18F]FDG
the pelvis, whole-body 18F-FDG PET, and MRI-PET fusion. All PET systems in the detection of tumors in the abdomen was related
patients subsequently underwent anterior resection. In T staging, to the poor ability to properly localize the lesions. Bowel has vari-
MRI correctly staged 14 of 22 T2/T3 tumors. MRI-PET identified able uptake that can be sometimes intense. Even though physio-
metastases in three patients, but provided little additional value over logic activity within the bowel most often has a linear pattern, focal
CT. Indeed, CT was more useful in identifying comorbid conditions activity is not rarely seen in normal patients (Fig. 9.3).63 In addition,
(such as an abdominal aortic aneurysm).57 In lymph node assess- physiologic radiotracer activity along the colon can easily obscure
ment, MRI-PET fusion had a sensitivity of 44%, with a specificity primary lesions in patients with CRC.64 It has been shown that
and positive predictive value (PPV) of 100%, and thus, MRI-PET patients treated with metformin have significantly increased [18F]
fusion added little to conventional investigations for staging colorec- FDG PET uptake in the colon and to a lesser extend in the small
tal carcinoma. intestine. This increase is typically intense, diffuse, and continuous
along the bowel wall and lumen and may mask underlying malig-
nant lesions. Stopping metformin before PET/CT imaging signifi-
PET/MR Systems cantly decreases this unwanted uptake, especially in the colon, and
The development of PET/MR scanners has been restricted because should be considered in patient undergoing scans for the evaluation
of the mutual incompatibilities between PET and MRI systems. To of CRC (Fig. 9.4).
combine these two systems, several technical challenges had to be Other sources of misinterpretation with dedicated PET scanners
solved. The PET detectors needed to be able to function within a were related to excreted radiotracer in the genitourinary tract.
high static magnetic field as well as with quickly changing gradi- Urinary activity can be confounding, particularly if focal retention
ent fields and radiofrequency signals from the MRI scanner. Sim- in the ureters is misinterpreted as nodal involvement. Diuretics and
ilarly, techniques to prevent degradation of the MR image quality hydration have been suggested to decrease urinary activity but
by inhomogeneities in the magnetic field and electromagnetic are not invariably successful and seldom used.64 Hybrid [18F]FDG
interference caused by the PET detector needed to be created. One PET/CT imaging, providing precise anatomical landmarks, has per-
ingenious solution was the replacement of the traditional photo- mitted better localization of suspicious colorectal uptake, and has
multiplier tubes in the PET detector with avalanche photo diodes been a useful guide to direct further investigations with endoscopy
(APDs).58,59 PET detectors were also integrated between the MRI and biopsy.62 However, there are several limitations for detection of
body coil and the gradient coils, thus rendering simultaneous small tumors with PET/CT. The main disadvantage is the inherent
acquisition of PET and MRI possible. Siemens AG and Philips limited spatial resolution of PET/CT imaging.65 In addition, certain
Healthcare recently launched PET/MR scanners for clinical exam- types of tumors such as mucinous adenocarcinomas do not dem-
inations, which use very different engineering approaches. Philips onstrate significant metabolic activity. There is still a lack of data


B
C D
Figure 9.1. A 39-year-old female with newly diagnosed moderately to poorly differentiated adenocarcinoma of the rectosigmoid undergoing PET/CT
for initial staging. Axial PET (A), CT (B), fused PET/CT (C), and MIP (D) images demonstrating a hypermetabolic mass in the rectosigmoid region with
an SUVmax of 12.6, compatible with the known primary tumor (arrows ). The MIP image also demonstrates bilobar liver metastases (arrowheads ).
supporting the usefulness of [18F]FDG PET/CT imaging in the rou- data were compared with findings from surgical excisions and dis-
tine staging of patients diagnosed with primary CRC. In a study that section.67 If a threshold of nodal maximum axial diameter of lymph
included 37 patients, Gearhart et al.,66 were able to identify [18F]FDG nodes was set for ≥10 mm, tumor detection with [18F]FDG PET/CT
PET/CT involved nodes within the mesorectal fascia that were not had a sensitivity of 30% (95% CI: 19% to 44%) and a specificity of
seen with standard imaging. In particular, in low rectal tumors, 95% (95% CI: 90% to 97%).67 When the optimal cutoff value of
where frequently, iliac and inguinofemoral nodes were involved. 1.5 SUVmax was analyzed, the sensitivity of [18F]FDG PET/CT was
This resulted in patient management changes in 27% of cases, and 53% (95% CI: 39% to 66%) and the specificity was 90% (95% CI:
thus improved the accuracy of pretreatment staging.66 In addition, 84% to 94%). With increased SUV value to 2.5, the sensitivity of [18F]
two studies by Tsunoda et al.67 and Tateishi et al.68 suggest that FDG PET/CT was 38% (95% CI: 26% to 53%) and the specificity was
[18F]FDG PET/CT is able to identify N-stage disease remote from the 94% (95% CI: 89% to 97%), and, at a threshold of 3.5, the sensitivity
primary site suggesting that [18F]FDG PET/CT should be considered was 24% (95% CI: 15% to 38%) and the specificity was 100% (95%
in the preoperative staging of primary rectal cancer. In proximal CI: Not calculable).67
nodal staging, based on analysis with an SUVmax threshold of 1.5, As mentioned earlier in this chapter, most protocols for CT
[18F]FDG PET/CT demonstrated a sensitivity of 51% (95% CI: 36% imaging involve the administration of iodine-containing intrave-
to 66%) and a specificity of 85% (95% CI: 72% to 92%). For distal nous contrast for detection of CRCs. Similarly, PET/CT can be per-
nodal staging (lymph node metastases of CRC) using an SUVmax formed with intravenous contrast to improve diagnostic accuracy
threshold of 1.5, the sensitivity of [18F]FDG PET/CT was 62% (95% without significant artifacts from attenuation correction.69 There
CI: 30% to 86%) and specificity was 92% (95% CI: 84% to 96%). [18F] is also the possibility to use iodine-based or diluted barium oral
FDG PET/CT was found to have a sensitivity of 28% (95% CI: 18% contrast to better delineate loops of bowel and thus improve the
to 42%) and specificity of 92% (95% CI: 87% to 96%) when used for visibility of soft tissue masses. Tateishi et al.68 reported improved
nodal staging of proximal and distal lymph nodes (n = 176), and accuracy in diagnosing N staging by adding contrast enhancement

C D
Figure 9.2. A 55-year-old male with head and neck squamous cell carcinoma undergoing initial staging. Axial PET (A), CT (B), fused PET/CT (C), and MIP
(D) images demonstrating an incidental hypermetabolic lesion (arrows) in the left colon (SUVmax 9.3). Follow-up colonoscopy revealed an ulcerated colonic
mass compatible with moderately differentiated adenocarcinoma of the colon.
to the [18F]FDG PET/CT with sensitivity of 85% (95% CI: 69% to represent approximately 17% of colonic tumors.70 These tumors
93%) and a specificity of 42% (95% CI: 23% to 67%) in 53 patients. contain clear, gelatinous fluid (mucin), which may be intracellular
They reported accuracy of contrast-enhanced [18F]FDG PET/CT or extracellular. In one study, [18F]FDG PET detected mucinous
was 85% (95% CI: 69% to 93%) and 68% (95% CI: 46% to 84%). carcinoma in only 13 of 22 patients, resulting in an unusually high
However, the accuracy data to support the use of [18F]FDG PET/CT percentage of false-negative results (41%).71 Further studies with
or contrast-enhanced [18F]FDG PET/CT in the preoperative stag- [18F]FDG PET/CT imaging confirmed that the technique is not
ing for primary CRC are very limited because of the small number sensitive in detecting mucinous colon cancers and can be a cause
of patients involved in the study. Contrast-enhanced [18F]FDG of false-negative results.72
PET/CT was favorable in imaging all lymph nodes. For imaging of
pararectal nodes, contrast-enhanced [18F]FDG PET/CT increased
sensitivity to 90% (95% CI: 76% to 97%) and specificity to 76%
PET/MRI for Initial Staging
(95% CI: 55% to 89%) compared to nonenhanced [18F]FDG PET/ PET/MRI systems are now available with only a limited number of
CT, where is reported sensitivity of 75% (95% CI: 57% to 87%) and studies describing its potential clinical applications.73,74 MR imag-
a specificity of 52% (95% CI: 32% to 71%).67,68 Imaging of internal ing combined with PET may provide unique information for stag-
iliac nodes with contrast-enhanced [18F]FDG PET/CT demon- ing of CRC. This new approach may enhance the T-staging
strated 75% sensitivity (95% CI: 50% to 90%) and 86% specificity accuracy in those tumors that could not dispense with MRI and
(95% CI: 72% to 94%); a sensitivity of 31% (95% CI: 14% to 55%) the N-staging and M-staging performance in body compartments
and specificity of 81% (95% CI: 66% to 90%) for [18F]FDG PET/CT. that are superiorly depicted by PET.75 However, current evidence
Obturator node detection had a sensitivity of 67% (95% CI: 39% to indicates that PET/MR technique provides no significant addi-
86%) and a specificity of 95% (95% CI: 84% to 99%) for contrast- tional value in the preoperative staging of patients with rectal can-
enhanced [18F]FDG PET/CT in comparison to sensitivity of 67% cer, compared with pelvic MRI in conjunction with abdominal CT
(95% CI: 39% to 86%) and a specificity of 61% (95% CI: 46% to and chest radiography.57 In a study of 23 patients, MRI localized
74%) for [18F]FDG PET/CT.67,68 100% of all rectal tumors; however, it was insufficient for the
[18F]FDG is limited in the evaluation of mucinous tumors, par- determination of tumor stage, because 11 out of 23 patients were
ticularly in hypocellular lesions with abundant mucin. Mucinous overstaged. Based on the results of a recent meta-analysis, the
carcinomas are commonly found in the gastrointestinal tract and sensitivity and specificity of MRI for the T staging of rectal cancer


B
C D
Figure 9.3. A 30-year-old female with sarcoma involving the mediastinum. Axial PET (A), CT (B), fused PET/CT (C), and MIP (D) images demonstrate a
focus of increased [18F]FDG activity (SUVmax 6) in the right colon (arrows ). On the follow-up PET/CT scan obtained 2 months later (not shown), the previously
seen focal activity in the right colon resolved, suggesting it was physiologic in nature.
are 87% and 75%, respectively (Figs. 9.5 and 9.6) in locally advanced metastasis was detected when [18F]FDG and MRI/CT were com-
colon cancer.76 As previously published, [18F]FDG PET does not add bined; the sensitivity, specificity, PPV, and NPV of combined MRI and
to the accuracy of T staging in rectal cancer.77 It remains to be deter- [18F]FDG PET/CT were 94%, 83%, 89%, and 91%, respectively.
mined if PET/MRI will be superior to MRI alone in the assessment However, these initial experiences with PET/MRI still reflect inac-
of local tumor extent in CRC patients.78 curacy of lymph node micrometastasis localization with any imaging
A study by Kam et al.57 reported only 44% sensitivity of PET/MRI modality.
for the detection of lymph node metastases in preoperative rectal For accurate quantification and clinical presentation of PET/MRI
carcinoma patients.57 The same study also reported a specificity of systems, appropriate attenuation-correction algorithms needed to
100%, a PPV of 100%, and a negative predictive value (NPV) of 74%. be developed. A study of Marshall et al.80 describes the use of MRI
The authors reported that PET was never positive in the absence of to infer patient-specific attenuation coefficients to be applied to aug-
positive lymph nodes on MRI; the pathologically determined size of ment whole-body MRI-based attenuation μ-maps. This technique
metastases within lymph nodes rated positively on MRI ranged from has been shown to improve the quantitative fidelity of PET images.
8 to 17 mm in that study.57 In a meta-analysis by Al-Sukhni et al.,76 Although μ-map choice did not influence quantification in soft
they reported a sensitivity of 77% and a specificity of 71% on the tissue or bone when averaged over the whole thorax, it did affect
diagnostic performance of MRI for the metastases N stage.76 It was structures near the lungs, notably the vena cava and peripheral left
expected that a combination of anatomical MRI or CT and functional ventricle. This could be especially useful for staging and imaging of
[18F]FDG PET would increase the diagnostic accuracy in N staging. recurrences, but because of the dearth of published data, the clini-
A confirmation came from Kim et al.,79 where 90% of lymph node cal use of PET/MRI in CRC remains to be explored.

C D
Figure 9.4. A 73-year-old female with diabetes mellitus type 2 and lymphoma status post chemotherapy undergoing restaging. Axial PET (A), CT
(B), and fused PET/CT (C), and MIP (D) images demonstrate diffusely increased [18F]FDG activity throughout the colon compatible with patient use of
metformin.
Imaging of Recurrence and Restaging patients who were disease free and remained at a median follow-
up of 42 months, presented a greater decrease in SUVmax after
PET/CT neoadjuvant treatment than patients who eventually developed
recurrence. Therefore, [18F]FDG PET/CT may provide crucial data
[18F]FDG PET/CT has an established role in restaging patients for the development of strategies for long-term monitoring of post-
before surgical resection of locally recurrent cancer and metasta- operative patients who have an increased risk of recurrence.
ses and in the assessment of residual masses after treatment Since the recurrence rate of CRC is generally high, it is impera-
(Figs. 9.7 and 9.8). It is also accurate for detection of hepatic and tive to closely monitor patients, particularly those at an increased
extrahepatic tumors (Fig. 9.9). risk.86 In the relatively short follow-up period of 2 to 3 years, up to
PET/CT has provided significant improvement in comparison 40% of patients will have recurrent disease.87,88 The location of
with PET alone, especially in patients with hepatic recurrence con- recurrent tumors typically is in the liver or lungs but also can occur
sidered for surgical resection, because PET may demonstrate at the site of the previous tumor. Local recurrence of colon cancer
uptake not only in tumors, but also in inflammatory changes, which is less common than recurrent rectal cancer, because the surgical
include postoperative healing scars and postradiation therapy.81 A removal of primary tumors of the colon involves extensive lymph
number of studies have indicated a possible role of [18F]FDG PET/ node dissection.89 In general, hepatic metastases are the first pre-
CT for prediction and evaluation of treatment response,81–83 as sentation of recurrence in 20% to 40% of patients,89 and in two of
metabolic alterations in tumor cells may occur before changes in the studies90,91 metastases were detected in patients suspected of
tumor size.55 In a study by Capirci et al.,84 the accuracy of PET was recurrence. A sensitivity and specificity of detection of local recur-
determined as 81% for the detection of residual rectal cancer after rences is relatively high with [18F]FDG PET/CT (the sensitivity of
neoadjuvant CRT (using a response index cutoff of 65% for defining [18F]FDG PET/CT was 93% [95% CI: 70% to 99%] and the specificity
response to the therapy). Guillem et al.85 showed that rectal cancer 98% [95% CI: 89% to 100%]) as reported by Bellomi et al.90 This


B
Figure 9.5. A 54-year-old male with newly diagnosed

rectal cancer. Axial PET (A), CT (B), and PET/CT (C), and
PET sagittal (D) images demonstrate a hypermetabolic rec- C D
tal mass (SUVmax 9.8) extending to the anal canal (arrows ).
Figure 9.6. Axial (A) and sagittal

(B) T2-weighted images demonstrate
a locally advanced rectal cancer
involving the distal rectum abutting the
posterior wall of the prostate gland A B
(asterisks ).

Figure 9.7. A 59-year-old male with rectal

cancer status post low anterior resection. Axial
PET (A), CT (B), and fused PET/CT (C) images
as well as a PET sagittal image (D) obtained
2 years after the initial resection demonstrate
a hypermetabolic presacral mass (SUVmax 7.1)
C D at the anastomosis (arrows), compatible with
local recurrence.
group demonstrated that in 67 patients, the accuracy of detection (95% CI: 57% to 85%) in the detection of pelvic recurrence of
of distant recurrence of resected rectal cancer is even higher with rectal cancer. In general, as reported in multiple studies, [18F]FDG
multidetector CT, where sensitivity was 100% (95% CI: Not calcu- PET/CT was repeatedly more accurate in preoperative staging
lable) and the specificity was 98% (95% CI: 90% to 100%).90 than [18F]FDG PET alone.92–94 If patient-level analyses are consid-
In the detection of extra-abdominal recurrence of CRC, data by ered in the detection of recurrent CRC, the study by Votrubova
Kim et al.92 showed a sensitivity of 100% (95% CI: 70% to 100%) et al.94 on 84 patients reported a sensitivity of 89% (95% CI: 76%
and a specificity of 97% (95% CI: 86% to 99%) for the accuracy of to 95%) and a specificity of 92% (95% CI: 80% to 97%) for [18F]FDG
[18F]FDG PET/CT whereas [18F]FDG PET alone had lower sensitiv- PET/CT, whereas the corresponding [18F]FDG PET sensitivity was
ity of 78% (95% CI: 45% to 93%) and a specificity of 86% (95% CI: 80% (95% CI: 66% to 89%), and specificity was 69% (95% CI: 53%
72% to 94%), respectively. With regard to the accuracy of staging to 81%). A study by Kim et al.92 reported patient-level analyses
pelvic recurrence, a study by Even-Sapir et al.93 demonstrated on on 51 patients, where [18F]FDG PET/CT sensitivity was 83% (95%
62 patients that a sensitivity of 98% (95% CI: 88% to 99%) and a CI: 64% to 93%) and specificity was 93% (95% CI: 76% to 97%). In
specificity of 97% (95% CI: 85% to 99%) for [18F]FDG PET/CT were contrast, for [18F]FDG PET alone, sensitivity was 67% (95% CI:
higher than for [18F]FDG PET alone, where lesion-level data had a 47% to 82%) and specificity was 74% (95% CI: 60% to 86%). A
sensitivity of 88% (95% CI: 69% to 95%) and a specificity of 70% third study reporting patient-level analysis was conducted by

A B
Figure 9.8. Axial (A) and sagittal (B) T2-weighted MR images of the same patient demonstrate a presacral soft tissue mass (arrows ), consistent with
tumor recurrence.

A
B C
Figure 9.9. A 66-year-old male with history of moderately differentiated adenocarcinoma of the rectum status post low anterior resection. PET/CT scan
obtained 2 years after the initial diagnosis for restaging. Axial PET (A), CT (B), and MIP (C) images demonstrating a large hypermetabolic mass centered
in the left hepatic lobe (arrow ), compatible with liver metastasis. Additional hypermetabolic metastases are also seen in the right hepatic lobe and in the
lungs bilaterally (small arrows ).

Even-Sapir et al. They presented [18F]FDG PET/CT sensitivity of specificity from 74% to 83% for conventional MRI, and an increase
96% (95% CI: 80% to 99%) and specificity of 89% (95% CI: 76% to of diagnostic performance by adding functional MRI information
96%) compared to sensitivity of 87% (95% CI: 69% to 96%), and (DWI) has been reported.101 Residual tumor or locally recurrent
specificity of 74% (95% CI: 58% to 80%)93 using [18F]FDG PET tumors are sometimes difficult to identify on the basis of mor-
alone. A study by Schmidt et al.95 compared [18F]FDG PET/CT with phologic criteria. This is in part because of potential postsurgical
whole-body MRI and reported equally high sensitivities and spec- changes or alterations related to chemoradiation that can lead to
ificities in the detection of all recurrent lesions in 24 patients with scar tissue or desmoplastic reactions.102 In this case, metabolic
CRC. Lesion-level analyses for the detection of nodal recurrence information of [18F]FDG activity should be considered for correct
reported by the same group had greater accuracy for [18F]FDG restaging. It is also known that tissue in process of regeneration
PET/CT with a sensitivity of 93% (95% CI: 78% to 98%) and a and inflammation may present with increased [18F]FDG uptake.
specificity of 100% (92% to 100%) compared to whole-body MRI, This is a real limitation of [18F]FDG PET/CT in prediction of histo-
where sensitivity and specificity were 62% (95% CI: 44% to 77%) pathologic tumor response after chemoradiation when scanning is
and 91% (95% CI: 80% to 96%), respectively.95 performed shortly after therapy.102 The reported sensitivity, speci-
The benefits of PET/CT over PET appeared to be more marked ficity, accuracy, PPV, and NPV of [18F]FDG PET/CT for the detection
for the evaluation of extrahepatic disease, both intra-abdominal of local CRC recurrence were 84%, 88%, 87%, 76%, and 92%,
and extra-abdominal, than for liver evaluation. In these regions, respectively.103 PET/MRI integrates the advantages of MRI and [18F]
better localization of [18F]FDG avid lesions is potentially more FDG PET and thus may evolve as the first-line restaging modality
beneficial.72 Interesting results were presented by Kula et al.,96 in CRC patients with suspected tumor relapse or newly developed
where detection possibility of CRC was compared between serum metastases.78
levels of CEA and [18F]FDG PET/CT imaging in 120 patients. Data
revealed [18F]FDG PET/CT to be more accurate for detection of
recurrent colorectal tumors than the blood test for CEA levels. The DCE-MRI
sensitivity of 98% (95% CI: 90% to 100%) and specificity of 95%
(95% CI: 82% to 99%) were reported for [18F]FDG PET/CT; for CEA The utility of DCE-MRI has already been explored in animal exper-
levels, sensitivity of 68% (95% CI: 55% to 79%) and specificity of iments104–107 as well as in several clinical trials,99,108,109 and it was
82% (95% CI: 64% to 92%) was presented for recurrence.96 In suggested that DCE-MRI is useful as a pharmacodynamic bio-
another study, Strunk et al. looked at comparing [18F]FDG PET/CT marker.110,111 A study by De Bruyne et al.55 compared the role of
with CT in patients with an unexplained elevated CEA levels with DCE-MRI and [18F]FDG PET/CT for evaluation of response and for
suspicion of recurrent CRC. This study demonstrated that, [18F]FDG prediction of long-term outcome in patients with potentially resect-
PET/CT had a sensitivity of 79% (95% CI: 69% to 86%) and a spec- able colorectal liver metastases treated with bevacizumab before
ificity of 83% (95% CI: 61% to 94%) whereas CT had a sensitivity surgery. In this study, the area under the enhancement curve (AUC)
of 85% (95% CI: 76% to 92%) and a specificity of 76% (95% CI: 55% and initial AUC (iAUC) were calculated from 19 patients diagnosed
to 89%), based on lesion-level data.91 Another, more recent study with mCRC who underwent treatment with FOLFOX/FOLFIRI and
by Ozkan et al.97 followed 69 patients with elevated CEA compared bevacizumab followed by surgery. Microvessel density (MVD) and
to the [18F]FDG PET/CT in the detection of CRC recurrences. They proliferation index were also measured. After the fifth treatment
showed there was no correlation between patient serum CEA cycle, DCE-MRI and [18F]FDG PET/CT were performed. [18F]FDG
levels and lesion’s SUVmax. In the evaluation of separate patient PET uptake was evaluated by calculating SUVmax. A major finding
groups, the sensitivity and specificity values of [18F]FDG PET/CT from this study was the delineation of a potentially important role
were different: In the group whose CEA-level elevation was less of DCE-MRI in predicting outcome, both early during treatment
than twofold (5 to 9.9 ng/mL), the sensitivity and specificity were and after treatment.55 Both AUC and iAUC were significantly
100% and 60%, respectively. The sensitivity and specificity were decreased following bevacizumab therapy (median change of 22%
100% and 75% in the group with CEA elevation less than threefold [p = 0.002] and 40% [p = 0.001] for AUC and iAUC, respectively).
(10 to 14.9 ng/mL) and least in the group, where elevation was Progression-free (PF) survival benefit was shown for patients with
more than threefold (≥15 ng/mL), the sensitivity and specificity more than 40% reduction in Ktrans (p = 0.019). An increase in Ktrans
were 95% and 62%. The sensitivity and specificity of [18F]FDG PET/ (the endothelial transfer constant) of at least 40% after one cycle of
CT were computed as 98% and 85% in the lesion-based evaluation. bevacizumab-containing chemotherapy directly correlated with
The sensitivity and specificity of contrast-enhanced CT were 73% worse progression-free survival (PFS). Other studies presented
and 86%, respectively. These studies indicate that [18F]FDG PET/CT similar results.108,112 Baseline [18F]FDG PET on the other hand,
is a safe imaging method that should be used in the determination could predict the probability of an objective response according to
of CRC recurrence in patients with elevated CEA levels, regardless De Bruyne et al.,55 and did not predict the probability of a meta-
of the degree of CEA elevation.97 bolic response. However, they demonstrated that higher [18F]FDG
uptake at follow-up scan correlated with worse PFS (p = 0.012), as
was observed also by Riedl et al.113 Pathology confirmed median
MRI and PET/MRI Imaging MVD as 10.9. PFS was significantly shorter in patients with an MVD
The biggest advantage of combined PET/MRI is expected in the greater than 10, compared with patients with lower MVD (10 months
assessment of therapeutic response and tumor relapse. Evaluation compared with 16 months, p = 0.016).55 Altogether, their data indi-
of 68 patients with rectal cancer demonstrated that the tumor-free cate that after neoadjuvant chemotherapy, high [18F]FDG uptake in
margin on preoperative MRI is predictive of tumor recurrence and liver metastases of CRC is a negative prognostic marker. This study
patient survival.98 MRI was shown to be reliable for the assessment also reflects that no correlation between DCE-MRI parameters and
of tumor-free distance to the mesorectal fascia, with reported sen- the standardized [18F]FDG uptake value was found. The lack of cor-
sitivity of 77% and specificity of 94%.76 MR DWI may predict the relation between DCE-MRI parameters, anatomical tumor response,
tumor clearance of the mesorectal fascia in locally advanced rectal and SUVmax suggests that tumor blood flow, tumor shrinkage, and
cancer99 and was reported to provide an imaging biomarker for tumor glucose metabolism are potentially independent predictors of
tumor invasiveness. Lower apparent diffusion coefficient values outcome and that both imaging techniques may provide comple-
correlated significantly with more aggressive tumor profiles, includ- mentary information.55 In conclusion, if a decrease in Ktrans, low
ing high grades, high frequency of lymph node metastases, and SUVmax on follow-up PET scan, complete metabolic response, and
invasion of the mesorectal fascia.100 In patients with clinically sus- low MVD are observed, then these parameters provide for a favor-
pected local recurrence, sensitivity ranged from 84% to 100% and able prognosis for mCRC patients.

A B C
Figure 9.10. A 65-year-old male with colorectal cancer and lung metastases. Axial PET (A), CT (B), and fused PET/CT (C) images demonstrate a pleural-based
nodule (arrows ) with only mild [18F]FLT activity (SUVmax 3.1), compatible with viable malignancy.
Other Radiopharmaceuticals for tases of CRC such as brain, lung, and bone metastases, with less

interference from background activity.120
Imaging of Colorectal Cancer
18
CEA Scan F-FLT
18
CEA is a cell surface 180-kDd glycoprotein overexpressed in a vari- F-fluoro-3′-deoxy-3-L-fluorothymidine ([18F]FLT) permits the
ety of cancers.114 To date, few compounds utilizing radiolabeled assessment of tumor proliferative activity, a key feature of malig-
monoclonal antibodies (mAbs) and fragments directed against CEA nancy. Uptake of [18F]FLT reflects proliferation by reporting the
have been developed for single photon emission imaging. The most activity of thymidine salvage, a mechanism that provides dividing
promising, CEA-Scan (arcitumomab; Immunomedics, Morris Plains, cells with DNA precursors from the extracellular environment. On
New Jersey) is an antibody (Fab′) fragment labeled with 99mTc internalization, [18F]FLT is monophosphorylated by the cytosolic
pertechnetate, previously approved for imaging of recurrent colorec- enzyme thymidine kinase 1 (TK1), resulting in intracellular trap-
tal tumors in patients with rising CEA levels.115,116 Because of its ping and accumulation.121 Recently published data by Yamamoto
relative small size and rapid renal excretion, imaging could be per- et al.,122 reported on 26 patients with newly diagnosed CRC com-
formed within 5 hours after administration. The fragment was paring [18F]FLT and [18F]FDG PET. The mean (± SD) values of
derived from a murine antibody, but elicited lower rates of human [18F]FLT SUV in colon cancer (5.4 ± 2.4) and in rectal cancer (5.6 ±
antimouse antibody (HAMA) in comparison to intact mAbs.115 Even 1.3) were significantly lower than the corresponding values of [18F]
though results from clinical trials indicated that the 99mTc anti-CEA FDG SUV (12.4 ± 6.3 and 12.5 ± 4.7, respectively) (P < 0.003).122
Fab′ agent was suitable for the diagnosis of local recurrence of Two other studies described that primary tumors were well
colorectal carcinoma, [18F]FDG PET is clearly superior in the detec- depicted using [18F]FLT;123,124 however, in 17 patients with 50 pri-
tion of distant metastases (liver, bone, and lungs).117 Therefore, in mary or metastatic CRC lesions, [18F]FDG revealed on average
2005, the marketing authorization of CEA-Scan was withdrawn at twice the uptake of [18F]FLT.123 For visualization of extrahepatic
the request of Immunomedics, Inc. lesions, [18F]FLT PET and [18F]FDG PET demonstrated comparable
sensitivities. However, of the 32 liver lesions present, only 11 were
11 visualized with [18F]FLT. The poor sensitivity of [18F]FLT for detec-
C-Choline PET/CT tion of hepatic lesions is probably because of high physiologic
Choline is a marker of phospholipid synthesis. 11C-choline has been background activity seen in the liver, secondary to the metabolism
considered as a potential PET radiopharmaceutical for tumor detec- of [18F]FLT via glucuronidation. The prognostic implications of
tion since Hara et al.118 reported on the usefulness of 11C-choline PET [18F]FLT imaging need to be further investigated, particularly in
for detection of brain tumors. Ramírez de Molina et al.119 reported regard to the assessment of response to therapy and ultimately,
that choline kinase, which catalyzes the phosphorylation of choline, patient survival (Fig. 9.10).123
is upregulated in lung, prostate, and CRCs. Therefore, 11C-choline
PET may be a reasonable approach for detection of CRC. Terauchi
et al.120 reported a single case of a patient who underwent surgical
resection for advanced colon cancer depicted by 11C-choline PET. A
Radioimmunotherapy in Colorectal
50-year-old woman presented with melena and abdominal discom- Cancers
fort. The colonoscopy showed an elevated lesion in the sigmoid
colon. Abnormal uptake of 11C-choline was observed in the sigmoid Radioimmunotherapy (RIT) utilizes radiolabeled mAbs or anti-
colon, corresponding to an area of wall thickening. In this case, body fragments against tumor-specific antigens to deliver targeted
lymph node metastases were not detected by 11C-choline PET, prob- radiation to cancer cells. Currently, there are two Food and Drug
ably because of their small size (less than 10 mm in diameter). Even Administration approved RIT agents, 90Y-Zevalin (Spectrum Phar-
though further studies are necessary, the authors hypothesized that maceuticals, Inc., Irvine, CA) and 131I-Bexxar (GlaxoSmithKline,
11
C-choline PET/CT might be useful for the detection of the primary Research Triangle Park, NC), both for the treatment of non-
lesions. Because of the high level of physiologic 11C-choline activity Hodgkin lymphoma. However, RIT has not produced sufficient evi-
in the liver, the visualization of hepatic metastasis is challenging. dence of efficacy in the treatment of more radioresistant solid
However, 11C-choline PET might be useful for detecting other metas- tumors to be considered a major therapeutic option.

Anti-CEA Radioimmunotherapy tyrosine kinase receptor overexpressed in certain human cancers,

including approximately 75% of CRCs. To date, two HER1 targeted
As a cell surface epitope overexpressed in patients with CRC, CEA mAbs are currently used as second- or third-line therapy for
presents as an interesting target for RIT. Early publications inves- metastatic CRC: Cetuximab (ImClone, Somerville, NJ), an IgG1 chi-
tigated the use of 131I-labeled anti-CEA antibodies and fragments meric mAb, and panitumumab (Amgen, Thousand Oaks, CA), a
in xenograft models of metastatic CRCs. These studies revealed fully humanized IgG2 antibody.
that 131I-labeled anti-CEA successfully inhibited the growth of Imaging HER1-positive tumors utilizing optical imaging as well as
colon cancer xenografts in a rodent model in a dose-dependent single photon and positron emitting probes has proved to be a fea-
manner. Moreover, the absorbed dose to the tumor dose was sible approach to evaluate the extent of disease in the preclinical
inversely proportional to the size of the tumor. Thus, treatment of settings. Therefore, the development of an imaging surrogate may
larger tumors was ineffective, but promising for micrometasta- help select and screen patients for subsequent HER1-targeted
ses.125–128 Early clinical trials with murine 131I-A5B7 anti-CEA RIT.140–143 Panitumumab specifically binds to the extracellular domain
antibody and neutrophil proteinase-4 (131I-NP-4), a murine IgG1 of EGFR.144–146 A critical factor in screening patients for targeted
antibody presented only modest results in regard to treatment therapy is evaluating the presence and amount of the specific target
response.129,130 in the tumor and its relevance to the disease state. To date, antibody-
More recently, Juweid et al.,131 described a new murine IgG mAb based imaging has been limited by high background levels related to
against CEA (MN-14), which has greater affinity for the antigen than slow clearance, making such imaging challenging. Therefore, smaller
NP-4. Subsequently, a radiolabeled form of this MAb (188Re-MN-14) molecules such as antibody fragments are extremely appealing. The
was investigated in a phase I trial and determined to have less toxic average molecular weight of intact panitumumab is 147 kD. In
effects than seen with 131I-labeled antibodies. However, two of the comparison, the panitumumab F(ab′)2 fragment is approximately
patients from that study developed human anti-murine antibodies 110 kDa. Wong et al.147 evaluated the preclinical properties of pani-
(HAMAs). A humanized version of MN-14 (hMN-14) was later inves- tumumab F(ab′)2 fragment and successfully assessed its utility as a
tigated in two clinical studies. In both, 42% to 45% of patients devel- targeting agent in radioimmunodiagnostic and radioimmunothera-
oped mixed or minor responses.132,133 peutic protocols. Therefore, their preliminary results confirm that the
smaller panitumumab F(ab′)2 fragment is more effective in tumor
Antiglycoprotein Radioimmunotherapy penetration and HER1 targeting. The rapid clearance of the F(ab′)2
from the blood compartment results in a higher signal-to-noise ratio
Tumor-associated glycoprotein 72 (TAG-72) is a cell surface and at earlier time points, permitting optimal patient imaging and more
secreted antigen expressed in more than 80% of CRCs and is favorable dosimetry.
another potential candidate for targeted RIT. Radiolabeled mAbs The smaller size and rapid clearance of antibody fragments
against TAG-72 (131I-CC49) was investigated in several studies by such as F(ab′)2 should also lower their immunogenicity potential,
Divgi et al.134 and Murray et al.,135 resulting in minor responses in reducing the risk of patients developing a humoral response against
20% to 25% of patients but with significant development of HAMA the conjugate, and potentially permitting repeated treatment of
response. Epithelial cellular adhesion molecule (Ep-CAM) is patients.148 Noninvasive imaging and later RIT using panitumumab
another interesting contender for RIT, because antibodies binding F(ab′)2 fragments may prove to be a powerful tool for the treatment
to Ep-CAM tend to be rapidly internalized into the cell, leading to of patients with metastatic colorectal carcinoma.
excellent intratumoral retention of the antibody.136 NR-LU-10 is a
murine IgG against Ep-CAM, which has been evaluated in the
phase I setting of 15 patients with no objective responses and with
all patients developing HAMAs.137 The chimeric version of this
antibody (NR-LU-13) labeled with 186Re, also demonstrated signifi-
Conclusions
cant immunogenicity in patients, despite the chimeric nature of the Imaging plays an important role in screening, initial staging, and
antibody.138 restaging of patients with CRC. Combined PET/CT and PET/MRI
merge advantages of functional and anatomical techniques. To this
Pretargeting Radioimmunotherapy day, data supporting the usefulness of [18F]FDG PET/CT imaging in
the routine staging of patients diagnosed with primary CRC is insuf-
Pretargeting is a novel concept in RIT, whereas an unlabeled ficient. Similarly, the clinical use of PET/MRI in CRC is yet to be
immunoconjugate is first used to target cancer cells and later fol- explored. PET/CT has an established role in evaluating tumor
lowed by a radiolabeled compound with high affinity for the immu- recurrence in the setting of rising CEA levels. PET/CT significantly
noconjugate that prelocalized to the tumor. In a phase I trial, improves localization of lesions in patients with hepatic recurrence
Kraeber-Bodéré et al.139 investigated the antitumor efficacy of tar- and is recommended for monitoring response to treatment. The
geted preradioimmunotherapy using anti-CEA, hMN-14 × m734 biggest advantage of combined PET/MRI is expected to be in the
bispecific antibody (BsmAb), followed by the injection of 131I- assessment of therapeutic response and tumor relapse or in identi-
di-diethylenetriamine pentaacetic acid (DTPA)-indium hapten. fication of newly developed metastases.
Toxicity and tumor response rates were assessed in 20 patients
with CEA overexpressing tumors (medullary thyroid carcinoma,
and colorectal, stomach, esophagus, pancreas, gallbladder, breast,
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C h a pte r 1 0
Liver Tumors
Scarlett Lewitschnig • Saabry Osmany • Imene Zerizer • Gary Cook
Introduction s ensitivity of 81% and a specificity of 97%.5 The typical appear-

ance is of increased activity compared to the background on 1 to
A wide range of clinical investigations are available to assess benign 2 hours delayed imaging (Fig. 10.1). Giant cavernous hemangio-
and malignant liver lesions. Contrast-enhanced CT, US, and MRI are mas can demonstrate heterogeneous uptake, with areas of
all of considerable importance in the evaluation of liver lesions but increased and decreased activities.
SPECT and PET nuclear medicine techniques frequently allow addi-
tional or complementary information to be collected that help direct
patient management. Nuclear medicine has an increasing role in Malignant liver lesions
the management of primary liver tumors including hepatocellular
carcinoma (HCC) and cholangiocarcinoma (CCA). Liver metastases Malignant liver lesions include CCA, HCC, and liver metastases
are a more frequent clinical problem than HCC or CCA and nuclear from other primary tumors which are particularly common in pri-
medicine has an important role in this application also. On occa- mary gastrointestinal malignancies and neuroendocrine tumors
sion, benign lesions such as focal nodular hyperplasia (FNH) and (Table 10.2).
hemangiomas can be difficult to assess with other imaging tech-
niques and nuclear medicine imaging can improve specificity.
Cholangiocarcinoma
BENIGN LIVER LESIONS Cholangiocarcinomas arise from the epithelial cells of the bile
ducts and are associated with poor prognosis. The overall median
Benign focal liver lesions are common and include cysts, FNH, survival of patients with unresectable disease is 6 to 12 months.6
hepatic adenomas, cavernous hemangiomas, and abscesses Approximately 60% occur at the hepatic duct bifurcation and only
(Table 10.1). US and CT play an important role in characterizing 5% to 15% within the liver. The best treatment option remains
liver lesions but MRI can often add sensitivity and specificity in surgical excision as the response rate for chemo- or radiotherapy
problematic cases and is probably the most accurate imaging is limited.7 Accurate preoperative staging is essential to detect
modality for hepatic adenomas and FNH. early metastatic disease. MRI is the gold standard to evaluate the
FNH is believed to be a hyperplastic response to an anomalous extent of local disease.
artery with no malignant potential. Since FNH contains hepatic
cells, it can be imaged with 99mTc-iminodiacetic acid (HIDA) and its
derivatives as well as with 99mTc sulfur colloid. HIDA is taken up by
Conventional Nuclear Medicine Imaging
99m
hepatocytes and the typical appearance of FNH with HIDA is Tc sulfur colloid can be used to demonstrate CCAs. Approximately
increased flow followed by prompt uptake and delayed clearance 85% of intravenously injected 99mTc sulfur colloid accumulates in the
compared to the surrounding normal liver tissue. This characteris- liver because of reticuloendothelial cell uptake. Intrahepatic CCAs are
tic pattern is seen in 90% of cases and is, therefore, more accurate seen as cold lesions. Specificity is low as reduced uptake is seen in
than 99mTc sulfur colloid imaging, which has a sensitivity of around most benign and malignant liver lesions including abscesses. This
40% to 70%.1–3 FNH shows equal or greater colloid uptake com- technique helps in localizing the lesions when they are larger than
pared to the surrounding liver, where the mechanism of uptake is 2 cm but is now rarely used since the advent of MRI.
via the Kupffer cells. A recent report suggests a possible role of
18
F-fluorormethylcholine PET/CT in differentiating FNH from hepa- 18
tocellular adenoma where FNH has been reported as more avid.4
F-FDG PET and PET/CT
Hepatic adenomas are benign epithelial liver tumors with the The literature on 18F-FDG PET and PET/CT to image CCA is sparse
rare potential to rupture and cause bleeding or to transform to with small numbers of patients in most series. The largest prospec-
HCC. Hepatic adenomas contain only hepatocytes, but do not take tive study was conducted by Kim et al.8 who reviewed 123 patients
up HIDA but show normal blood flow on early imaging. 99mTc sulfur with suspected CCA. Sensitivity, specificity, positive predictive value
colloid imaging is not helpful in the diagnosis of hepatic adenomas (PPV), negative predictive value (NPV), and accuracy of 18F-FDG
as most of these tumors do not take up colloid (although some do). PET/CT in primary tumor detection were 84%, 79.3%, 92.9%,
Therefore, neither 99mTc sulfur colloid imaging nor HIDA scans are 60.5%, and 82.9%, respectively. It was concluded that 18F-FDG PET/
helpful in distinguishing adenomas from other intrahepatic lesions. CT demonstrated no statistically significant advantage over CT and
Hepatic hemangiomas can be accurately assessed with 99mTc- MRI/MRCP in the diagnosis of primary liver tumors. According
labeled red blood cell scanning using SPECT with a reported to different morphologic characteristics of CCA, 18F-FDG PET/CT
Tabl e 10.1
Ta b le 1 0 . 2
Some Benign Liver Lesions where Radionuclide
Imaging may Contribute to Management Some Malignant Liver Lesions where Radionuclide
Imaging may Contribute to Management
Hepatic cysts
Focal nodular hyperplasia Cholangiocarcinoma
Hepatic adenoma Hepatocellular carcinoma
Hemangioma Solid organ liver metastases
Abscess Neuroendocrine tumor metastases
124

Chapter 10 Liver Tumors 125

Figure 10.1. A 99m
Tc-labeled red blood cell scan
showing a hypoperfused area in the dome of the liver
on the 5-minute images (left), which “fills in” on the
2-hour images (right) in keeping with a hepatic
hemangioma.
showed no significant difference in detecting the mass-forming, these infections. In Southeast Asia and Africa, hepatitis B virus
periductal-infiltrating, and intraductal-growing types. infections are common, whereas in the Western world, hepatitis C
Petrowsky et al.9 found a sensitivity of 93% to detect intrahe- infections and alcoholic liver disease lead to liver cirrhosis and
patic CCA with a specificity of 80%. Sensitivity and specificity to HCC. It is thought that the incorporation of viral DNA into the HCC
detect distant metastases, however, were 100%.9,10 18F-FDG PET genome results in the transformation into HCC. The prognosis of
appeared to be very poor to accurately determine local lymph HCC is poor. Early detection and correct staging, therefore, is cru-
node metastases, with a reported sensitivity of 12%, but a specific- cial for successful management.
ity of 96%. Breitenstein et al.10 also confirms a higher sensitivity
for intrahepatic CCA compared to extrahepatic CCA where the
sensitivity drops to 60%. Imaging in Hepatocellular Carcinoma
Kim found conflicting results in the lymph node assessment
compared to previous studies. He described a significantly higher US is used to screen patients with chronic liver disease for HCC as
accuracy over CT in the diagnosis of regional lymph node metas- it is readily available. However, US cannot reliably distinguish
tases (75.9% versus 60.9%, p = 0.004) and distant metastases HCC from other solid tumors.
(88.3% versus 78.7%, p = 0.004). Jadvar et al.11 focused on tumor Contrast-enhanced CT examinations have a high sensitivity
recurrence and confirmed the high detection rate for distant CCA and allow the detection of hypervascular HCCs as small as 3 mm.13
metastases, with a sensitivity of 94% and a specificity of 100%. Triple phase CT can visualize tumors that are isoattenuated on the
Kluge et al.12 directly compared the accuracy of 18F-FDG PET/ arterial and portal phases, increasing the sensitivity.14 Triple
CT against MRI in detecting CCA in 26 known cases and found a phase CT scans of the liver during contrast injection, include an
sensitivity of 92.3% for 18F-FDG PET/CT. Poor sensitivity for detec- arterial phase shortly after injection, a portal phase, and a delayed
tion of lymph node involvement was reported, with positive lymph phase. The arterial phase will highlight arterial lesions whereas
nodes detected in 2 out of 15 patients. the portal phase will show lesions that primarily enhance from the
portal vein. The portal phase shows the liver during higher paren-
chymal enhancement and allows depiction of most lesions with a
Hepatocellular Carcinoma greater lesion to liver ratio. The delayed phase of helical CT is
performed 5 to 10 minutes post contrast and has been reported to
This primary liver tumor usually develops in a background of show higher liver HCC contrast than does the portal venous phase,
chronic liver disease, most commonly caused by hepatitis B or C. thus improving the rate of detection of well-differentiated hypo-
Therefore, its global distribution is related to the prevalence of vascular HCCs.14

The sensitivity of MRI to detect HCC is similar to helical CT; imaging shows “filling in” within the HCC with further tracer
however, it is more sensitive and specific in differentiating regen- washout by the normal liver tissue. The pattern is very specific;
erative nodules from HCC in the cirrhotic liver.15,16 however, poorly differentiated HCC may not demonstrate filling in
on delayed imaging.
Limitations of Conventional Imaging
for Response Assessment Functional Imaging Biomarkers
The current standard method to assess response of unresectable
To meet the clinical need to be able to predict response and strat-
primary and metastatic HCC is by contrast-enhanced CT using
ify patients at an early stage of treatment, functional imaging bio-
response evaluation criteria in solid tumors (RECIST) criteria17 but
markers have been of considerable interest. Potential methods
it is recognized that this is a relatively insensitive and nonspecific
include PET tracers such as 18F-FDG, 18F-Fluorodeoxygalactose
method. In a Phase III study of sorafenib in HCC, only 2% of sub-
(18F-FDGal), 11C-acetate (11C-Act), 11C or 18F-choline (11C-Cho,
jects demonstrated an RECIST response to the drug, despite an 18
F-Cho), and 18F-Fluorothymidine (18F-FLT) to assess metabo
improvement in overall survival.18 As a consequence, a beneficial
lism, lipogenesis, cellular membrane metabolism, and prolifera-
tumor effect may be unrecognized in some patients who do not
tion, respectively.23
show a reduction in tumor volume and, in contrast, some patients
may continue to receive treatment that is not beneficial until there
is unequivocal evidence of progression. This may result in unneces- 18
sary treatment-related toxicity.
F-FDG PET/CT
Given the limitations of RECIST size change criteria for moni- Most of the existing literature comes to the conclusion that the
toring HCC, alternative methods to assess response have been uptake of 18F-FDG in HCC is variable, with more uptake demon-
proposed.19,20 With CT, this has depended on the measurement of strated in poorly differentiated carcinomas. The false-negative
viable enhancing parenchyma which provides a better correlation rate is high in well-differentiated HCCs.24 Wu et al.25 showed sen-
with survival.21,22 but still suffers from some of the same limitations sitivity for 18F-FDG in well and moderately differentiated HCCs is
as RECIST criteria for response assessment in that these criteria as low as 35%, but 83.3% in poorly differentiated HCC. The high
still rely on the measurement of size change, albeit of lesions iden- level of FDG-6-phosphatase activity in well-differentiated HCCs
tified as visible in the arterial phase of contrast-enhanced imaging. appears to be responsible for the high false-negative rate as FDG-
6-phosphate is not trapped in the cell.25
Conventional Nuclear Medicine Imaging Despite these limitations 18F-FDG PET has proven to be
useful to detect postoperative tumor recurrence, response to
of Hepatocellular Carcinoma liver-directed therapy, including radiofrequency ablation and
Imaging with HIDA shows characteristic findings for HCCs. There to predict tumor recurrence post liver transplant for HCC
is reduced flow on initial imaging. Two to four hours delayed (Fig. 10.2).26
Figure 10.2. The liver lesions of a 69-year-old man

with a history of hepatocellular carcinoma post transarte-
rial chemoembolization and radiofrequency ablation, with
a rising alpha feto protein (AFP). The peripheral portion of
the mass in segment II/III of the liver is both 18F-FDG (top)
and 11C-acetate-avid (bottom). This is indicative of a
recurrent metabolically active disease.

11
C-Choline [11C-Cho] and 18
F-Fluorocholine [18F-Cho] patients with extrahepatic disease and no uptake in seven patients
without HCC.37
Choline is one of the components of phosphatidylcholine, a phos-
pholipid found in cell membranes. In carcinoma, rapid cell dupli-
cation results in active uptake of choline.27
11
C-Cho is more sensitive than 18F-FDG in the detection of well-
Liver Metastases
differentiated HCC. Wu et al.25 investigated the advantage of com- Metastases are the most common malignant liver lesions and
bined 18F-FDG and 11C-Cho imaging in 76 patients diagnosed with account for 95% of all liver lesions seen in clinical practice. Metas-
HCC. 11C-Cho scans were positive in 71.4% (20/28) of patients who tases can result from various tumors; however, the most common
had a negative 18F-FDG PET scan. Similar results were found in a are colorectal, breast, melanoma, and lung.38
small study by Yamamoto et al.,28 reviewing 12 patients that
showed a sensitivity of 75% for 11C-Cho versus 42% for 18F-FDG in
the detection of moderately differentiated HCC lesions. In well- Ultrasonography
differentiated HCC lesions, 11C-Cho PET showed a sensitivity of Comparative studies between CT, MRI, and US without contrast
66.7% versus 35.7% for 18F-FDG. None of these comparisons demonstrate a high specificity but a low sensitivity of 55% for
reached statistical significance, most likely because of small numbers ultrasound.39,40 Intraoperative ultrasound is the most accurate
reviewed (12 patients with 16 lesions). The same study also found a imaging technique to detect liver metastases at the time of primary
poor sensitivity for 11C-Cho to detect poorly differentiated HCC. tumor resection.39,41
11
C-Cho has several disadvantages: High background stan-
dardised uptake value (SUV) (approximately 13) within the normal
liver parenchyma and a short half-life (20 minutes) limit its use to CT and MRI
institutions with an on-site cyclotron. 18F-Cho has a longer physical MRI imaging techniques include T1, T2, and diffusion-weighted
half-life of 110 minutes and appears, therefore, to be a more con- imaging (DWI) and post-contrast acquisitions. Contrast agents used

venient alternative to 11C-Cho. Direct comparison of 18F-Cho and include gadolinium and tissue-specific MR contrast agents, such as
11
C-Cho by Kolthammer et al.29 in a woodchuck model found that mangafodipir (Mn-DPDP), a hepatocyte-specific agent, and iron
they perform similarly. The Eastern woodchuck in the US harbors oxide particles.42 Mn-DPDP is taken up by hepatocytes but not
a DNA virus, the woodchuck hepatitis virus (WHV), that is similar metastases, which therefore appear hypo-intense on T1W images.
in structure and life cycle to the HBV (human hepatitis B virus). Iron oxide particles are taken up by Kupffer cells within the normal
WHV infects the liver causing acute and chronic hepatitis and leads liver parenchyma and not by metastases and therefore iron oxides
to the development of HCC. increase the liver-to-lesion ratio and can improve detection.43
Talbot et al.27 compared 18F-Cho with 18F-FDG and found that Motosugi et al.44 reviewed 94 patients with colorectal cancer
18
F-Cho is more sensitive to detect well-differentiated HCCs than using contrast-enhanced MRI and triple-phase CT for the evalua-
18
F-FDG, 94% versus 59%, respectively. tion of small hepatic metastases below 2 cm.
At this stage, 18F-FDG PET/CT in combination with 11C-Cho or The same sensitivity of 61% was found for both CT and MRI.
18
F-Cho PET/CT seems to be the most effective approach to detect The mean positive predictive value of triple phase CT was inferior
HCC. A negative study, however, should still be interpreted with to that of MRI (82% versus 91%, respectively).44 Helical CT has a
caution. reported sensitivity of 64.7% to detect liver metastases regardless
of size and 1.5-T MRI has a sensitivity of 75.8%.40
11
C-Acetate [11C-Act] PET
99m
In the woodchuck HCC model, 11C-Act uptake is associated with Tc Sulfur Colloid Imaging
de novo tumoral lipogenesis and fatty acid synthase activity. The As with most other benign and malignant liver lesions, metastatic
sensitivity of 11C-Act to detect HCC has also been shown previously deposits present as a photopenic defect on 99mTc sulfur colloid
in the woodchuck HCC model.30 11C-Cho and 11C-Act detected imaging. With SPECT, the sensitivity and specificity to detect liver
17/17 and 16/17 tumors compared to 7/13 with 18F-FDG. The metastatic disease is 90%. Although this was a common method
same study showed that lipid-related genes were upregulated. In to assess and monitor metastases in the past, it has no routine
man, previous studies have established the value of 11C-Act PET to role in modern imaging.
detect primary and metastatic HCC31–35 with sensitivities up to
87% in the liver and 77% for a metastatic disease. 18
Although 11C-Act PET appears to be one of the most sensitive F-FDG PET
modalities to detect HCC and its metastases, studies have observed Two large meta-analyses found 18F-FDG PET to be the most sensi-
a complementary relationship between 18F-FDG and 11C-Act imag- tive imaging modality for liver metastases assessment in patients
ing in HCC whereby 18F-FDG PET is often positive in the few patients with colorectal, gastric, and esophageal cancer.40,45 Lai et al.46 also
who are 11C-Act negative with 83% of primary tumors and 86% of found a high sensitivity of 94% of 18F-FDG PET to detect liver
metastases being detected in one study by the dual tracer tech- metastases. Similar results were found by D’Souza et al.,47 who
nique.32 In another study, 98% of metastatic lesions were detected evaluated 45 patients with suspected hepatic metastases in a pro-
by the dual tracer technique (Fig. 10.2).33 spective study. The authors reported a sensitivity and specificity of
97% and 75%, respectively for 18F-FDG PET.
18-Fluoro-3 ′-Deoxy-3′-L-Fluorothymidine (18F-FLT PET) Most of the published data evaluating the benefit of 18F-FDG PET
for the assessment of liver metastases are studies from staging
18
F-FLT uptake has also been investigated as a proliferation colorectal carcinoma; since 50% of patients with CRC develop liver
marker and although the degree of uptake seemed to predict over- metastases (Fig. 10.3).38 Patients with solitary liver metastases are
all survival, only 69% of primary lesions were detectable.36 amendable for surgical intervention. If there are extrahepatic
involvement or disseminated liver metastases, however, palliative
chemotherapy is frequently the more appropriate management.48,49
2-[18F]fluoro-2-Deoxy-D-Galactose (18F-FDGal)
Accurate preoperative staging is essential to reduce the num-
In a feasibility study, 18F-FDGal showed promising results with 22 ber of futile operations. The ability of 18F-FDG PET to detect occult
of 23 tumors showing uptake before treatment, including nine metastatic disease has been demonstrated in multiple studies. In

Figure 10.3. Multiple 18F-FDG avid liver metastases in

a patient with disseminated malignancy.
150 preoperative patients, Ruers et al.50 found that CT staging sive lesions had a lower tumor-to-liver ratio after 4 to 5 weeks of
alone resulted in 45% futile operations, (defined as any laparot- treatment.
omy that did not result in complete tumor treatment, revealed After radiofrequency ablation (RFA) therapy of hepatic lesions,
benign disease, or did not result in a disease-free survival period surveillance with conventional CT may be difficult, as a contrast-
longer than 6 months), whereas only 28% of 18F-FDG PET-staged enhancing rim is often demonstrated on contrast CT.55 Veit et al.56
patients had a futile operation. The relative risk reduction of futile showed that 18F-FDG PET/CT is more accurate than contrast-
operations, therefore, was 38% with 18F-FDG PET staging. Grassetto enhanced CT to detect recurrence after RFA (65% versus 22%). Choi
et al.51 evaluated 43 patients with known solitary liver metastases evaluated treatment response to RFA with 18F-FDG PET/CT and
prior to surgical intervention with 18F-FDG PET/CT. In 28% of found that within 3 weeks of therapy, most lesions became photope-
patients (12/43), 18F-FDG PET/CT resulted in restaging and change nic on 18F-FDG PET. Those lesions demonstrating persistent 18F-FDG
of management. The authors concluded that 18F-FDG PET/CT can uptake after 3 weeks were associated with local recurrence. The 18F-
have a significant impact on staging and selecting patients for FDG negative lesions did not recur during 18 months of follow-up.57
surgical intervention.
A meta-analysis by Patel et al.,52 reviewing the diagnostic accu-
racy of 18F-FDG PET/CT for colorectal liver metastases, found that Neuroendocrine Tumors
PET/CT is more sensitive than CT alone to detect extrahepatic dis-
ease (75% to 89% versus 58% to 64%) with a similar specificity (95% These groups of tumors, deriving from endocrine cells, have the
to 96% versus 87% to 97%). 18F-FDG PET/CT was also more sensitive capacity to produce biogenic amines and polypeptides and fre-
and specific for detecting hepatic disease: 91% to100% versus 78% quently spread to the liver.
to 94% and 75% to 100% versus 25% to 99%, respectively. 18F-FDG In conventional nuclear medicine, In-111-labeled pentetreotide
PET/CT also was found to have a high sensitivity and specificity to (OctreoScan) is used for the diagnosis and staging of neuroendo-
detect local recurrence when compared to CT: 93% to 100% versus crine tumors. It was found to be the single most sensitive imaging
0% to 100% and 97% to 98% specificity for both modalities. method compared to CT, MRI, and US.58
Problems arise following treatment with neo-adjuvant chemo- In terms of PET/CT imaging, 18F-FDG can be used; however, it is
therapy. The sensitivity of 18F-FDG PET was reduced to 49% fol- not taken up by indolent well-differentiated neuroendocrine tumors
lowing neo-adjuvant chemotherapy.53 This is not only because of with a low metabolic turnover but 18F-FDG may be taken up by
reduced metabolic activity, but also reduction in tumor size below poorly differentiated tumors. Scans using alternate tracers such as
11
PET resolution. Although sensitivity may be impaired to detect C-hydroxytryptophane (HT), 18F-dihydroxyphenylalanine (DOPA),
small volume residual but viable metastases following chemother- or 18F-fluorodopamine in PET imaging are being utilized.59 Kayani
apy, 18F-FDG PET has been shown to be helpful to assess treat- et al. 60 found that 18F-FDG and 68Ga-DOTA-tate combined, increases
ment response of liver metastases. Findlay et al.54 used 18F-FDG sensitivity in accurate tumor staging (66% 18F-FDG alone, 82%
68
PET to evaluate tumor response to fluorouracil and found respon- Ga-DOTA-tate alone, and 92% combined, respectively) (Fig. 10.4).


Figure 10.4. Multiple 68Ga-DOTATATE avid hepatic
lesions in a patient with a metastatic neuroendocrine
tumor with no significant interval change demonstrated
over an 5-month period.
Radionuclide Therapy of Liver Tumors administered activity is trapped in liver tumors and a proportion
remains in normal liver tissue.63–65 Major arteriovenous shunts
Intra-arterial radionuclide treatment is becoming a well-established are a contraindication to treatment.62 Slight pulmonary uptake is
treatment modality in the management of unresectable liver possible as a result of arteriovenous shunting in the liver after
tumors. Since normal liver parenchyma receives the majority of its release of 131I-Lipiodol bound to nontumoral liver. Other possible
blood supply from the portal vein and malignant liver tumors derive complications include gastrointestinal uptake when 131I-Lipiodol is
95% of their blood supply from the hepatic arteries,61 it has become administered into arteries supplying the gastrointestinal tract or
evident that targeted therapies delivered directly into the hepatic because of reflux.
artery can selectively treat tumors sparing healthy liver tissue. Side effects are rare and the treatment can be repeated 2, 5, 8,
and 12 months after the first administration.62
Intra-Arterial Radiolabeled Lipiodol

(131I-Lipiodol) Therapy Intra-Arterial Radiolabeled Microsphere Therapy
131 ®
I-Lipiodol (Lipiocis , IBA, Brussels, Belgium) is the oldest radio- Because of the undesirable properties of 131I and its increased
nuclide compound used for the treatment of unresectable HCC.62 radiation burden to healthy tissues, other treatment options have
It is prepared from ethiodized oil which is a 38% iodine-rich fatty been developed. This includes Y-90 radioembolization which is
acid ethyl ester derived from poppy seed oil. Its stable 127I is substi- increasingly becoming a well-established treatment for HCC and
tuted with 131I using a simple exchange reaction. 131I is a β-emitting liver metastases. It involves the administration of radiolabeled
radionuclide with a physical half-life of 8.04 days and a maxi- microspheres which are available in two forms for commercial use.
mum and mean soft tissue range of 2.4 and 0.9 mm, respectively. The microspheres are either made of glass beads (TheraSpheres)
131
I also emits a γ-photon of 364 keV which can be used for or resin beads (SIR-Spheres), with a mean diameter of 20 to 30
imaging. and 30 to 40 microns respectively.66 They are usually labeled with
131
I-Lipiodol is supplied in a solution for use at room tempera- Yttrium-90 (90 Y), which emits β-radiation with a maximum range
ture. Its viscous properties offer high resistance to syringe dis- of 11 mm (mean range: 2.5 mm) inducing damage to the nearby
pensing and catheter injection.63 tumor cells.37 The half-life of 90Y is 64.2 hours providing effective
The treatment is administered via the hepatic artery using an treatment duration of 92.3 hours. 90Y also produces x-rays (Brems-
implanted catheter with a port or through a femoral catheter strahlung) and has positron emission that can be utilized to image
under fluoroscopy guidance which is the preferred method of the distribution of the delivered therapy dose using a standard
administration. Administration of a fixed activity of 2.22 GBq γ-camera for Bremsstrahlung imaging and a PET/CT scanner for
(60 mCi) leads to a mean dose in the liver of approximately 50 Gy.62 positron emission.
Once in the hepatic circulation, 131I-Lipiodol migrates toward liver The delivery of 90Y-microspheres into the hepatic artery and the
tumors because of increased vessel permeability and has slow liver is done angiographically in two interventional sessions. The
clearance because of the lack of lymphatic vessels and Kupffer first is for initial assessment of hepatic as well as gastrointestinal
cells.63–65 Twenty-four hours post administration, 75% to 90% of the arterial circulation and calculation of hepatic–pulmonary shunt.

Angiography of the abdominal aorta and its branches is per- overall survival (67 weeks in responders versus 43 weeks in nonre-
formed and any vessels that can potentially deliver microspheres to sponders) whereas response on CT/MRI could not predict sur-
nontarget organs leading to complications are embolized. During vival.72 The authors also found that a pretreatment SUVmax > 20
this procedure, the hepatic to pulmonary shunt is also calculated was a poor prognostic indicator (overall survival [OS] 20 weeks
which is used to adjust the activity delivered to avoid radiation versus 57 weeks in patients with SUV < 20). The above studies have
pneumonitis. assessed response at 3 months but there has been an interest in
The second angiographic procedure is usually undertaken 1 to predicting response earlier at 6 to 8 weeks so that a different treat-
2 weeks afterward to deliver 90Y-microspheres. Patients are usu- ment approach can be adopted. A study by Szyszko et al.73 evalu-
ally discharged the following day. The treatment is generally well ated the role of 18F-FDG PET in comparison to RECIST in early
tolerated in experienced centers with limited side effects, the response assessment post 90Y-radioembolization in 21 patients. The
majority of which are treated conservatively such as transient authors demonstrated that an early 18F-FDG PET performed at 6
radiation fever and pain. weeks showed a decline in SUV in 86% of patients whereas CT
demonstrated a decline in size in only 13% of patients. In one
patient, the decline in 18F-FDG uptake was significant to downstage
Role of PET/CT in Y-90 Radioembolization the patient and as a consequence underwent surgical resection.
It has recently been shown that a minor branching fraction in the Recently, Zerizer et al.74 evaluated the role of early 18F-FDG PET/CT
decay chain of 90Y results in the emission of a positron (+β).67 This performed at 6 to 8 weeks in predicting a progression-free survival
has opened new frontiers in imaging the distribution of 90Y-micro- after 90Y-radioembolization of colorectal liver metastases in com-
spheres in the liver using PET/CT. Lhommel et al.68 evaluated the parison to RECIST and tumor density criteria (CHOI criteria). The
feasibility of imaging the positron emissions of 90Y with a PET/CT authors found that patients with a metabolic partial response on
scanner in the preclinical setting and in a patient following Y-90 PET/CT had longer progression free survival (PFS) compared to
radioembolization using a high-end time-of-flight (TOF) PET/CT. nonresponders (12 months versus 5 months, respectively). RECIST
The study showed that PET images correlated reasonably well and tumor density criteria assessed on contrast-enhanced CT at 6
with the baseline pretherapy 18FDG PET images despite the differ- to 8 weeks failed to demonstrate treatment response and did not
ences in the mechanism of uptake and reflected more accurately predict PFS. Response on PET/CT also highly correlated with
the tumor heterogeneity compared with the traditional Brems- response in tumor markers (CEA and Ca 19-9).
18
strahlung imaging using single photon emission tomography. Ini- F-FDG PET /CT is a more accurate imaging biomarker of
tial results in clinical practice also demonstrated a high-resolution treatment response to 90Y-radioembolization and is a prognostic
absorbed dose distribution and showed that 90Y dosimetry corre- indicator.
lated very well with tumor response.68 The authors also used a
copper filter (2.5 mm) to prevent saturation and dead time losses
of the detector because of the effect of other energy interactions Summary
such as the Bremsstrahlung. However, subsequent work con-
ducted by Werner et al.69 suggested that good quality 90Y PET/CT Despite increased usefulness of CT and MRI, there remain a num-
can be obtained without the need for additional copper ring or ber of situations where functional imaging with SPECT or PET
advanced TOF. More recently, a study by D’Arienzo et al.70 has tracers can be complementary to, or can add to, diagnostic accu-
shown that 90Y-PET provided very good quality images of liver racy. The ability to image several aspects of liver physiology and
tumors 2 hours after Y-90 radioembolization which correlated tumor biology with nuclear medicine techniques means that these
with 18F-FDG uptake in the target lesions on the pretreatment will remain part of the required imaging algorithms for both
PET/CT. The Y-90 PET/CT images were used to calculate the target benign and malignant tumors of the liver.
dose using voxel-based dosimetry. More importantly, the authors
have shown that the calculated dose to target lesions on the Y-90
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Chapter 11
Breast Carcinoma
Cumali Aktolun • Muammer Urhan • Umut Elboga
Introduction tumor foci in the breast as small as 2 to 3 mm in diameter. In

addition to diagnostic evaluation in women and preoperative
Breast cancer, the second leading cause of cancer-related death in planning for some patients with known breast cancer, breast MRI
women throughout the world, is often curable when the disease is may be used to evaluate the lesions obscured by breast implants,
local and diagnosed at an early stage.1 Mammographic screening assessing palpable masses following surgery or radiation therapy,
programs allow for diagnosis at an early stage resulting in occult breast cancer in patients with axillary nodal metastasis
increased detection of low-risk cancers, premalignant lesions, and detected by mammography or ultrasonography. In addition to its
ductal carcinoma in situ (DCIS). use as a diagnostic tool, MRI is more sensitive than screening
Breast cancer is a histopathologically, genetically, and clinically mammography in selected patients. It can be used as a screening
heterogeneous malignancy. The most common histopathologic test for women with a high risk of breast cancer who are BRCA
types include invasive ductal carcinoma, invasive lobular carci- 1/2 mutation carriers, or have a strong family history of breast
noma, and DCIS. Based on the molecular and genetic features, cancer, or other genetic syndromes such as Li-Fraumeni or
many subtypes of these major histologic types of breast cancer Cowden disease.7 Although rare, serious side effects associated
have been described. with commonly used MR contrast agents including nephrogenic
Imaging is still the key technology for screening, initial diagno- systemic fibrosis are a source of concern.8 In addition, MRI is
sis, and evaluation of the disease extent. Mammography that uses more expensive than any other morphologic imaging modality. Its
ionizing radiation to image breast tissue is the most commonly specificity ranges from 37% to 97%, as contrast-enhancing foci
used screening method for early breast cancer detection which can also be frequently seen in healthy breasts. Women who are
has been effective in reducing breast cancer mortality in certain screened with MRI thus have more negative surgical biopsies.
populations. It relies on differentiation of the normal breast from Ultrasonography is useful for diagnostic evaluation of palpable
abnormal by delineating patterns of density differences and calci- or suspicious lesions detected on mammography rather than serv-
fication in the breast tissue that may be the sole evidence for ing as a primary screening modality. Unlike mammography, its
malignancy. The examination is performed by compressing the use in breast cancer screening and diagnosis is complementary.
breast firmly between two plates to spread overlapping tissues Although it is widely used, its indications vary greatly from one
and reduce the amount of radiation exposure. For routine pur- site to another. Nevertheless, the number of unnecessary biopsies
poses, mammographic images are usually taken in both mediolat- decreased significantly with the advent of the newest transducer
eral oblique and craniocaudal projections that include breast technology and the use of ultrasonography in combination with
tissue from the nipple to the pectoral muscle. Its limitations mammography.
include low specificity and false-negative results especially in Radionuclide imaging techniques using tumor-seeking agents
women with radiographically dense breasts and breast implants. with penetrating γ-rays are not affected by dense breast tissue and
The sensitivity of mammography is lower in women with radio- breast implants. They have the potential of confirming or exclud-
graphically dense breasts and a significant percentage of young ing the presence of malignant tissue in a given lesion detected by
women (depending on age, race, and ethnicity) have dense breast mammography. Currently, biopsy is routinely performed on a
tissue.2,3 breast lesion before any surgical procedure is planned. Any diag-
Breast radiation absorbed dose (mean glandular dose) asso- nostic test including radionuclide imaging would thus be helpful
ciated with standard two-view mammography is about 3.91 mGy in avoiding unnecessary biopsies.
for digital mammography and 4.98 mGy for screen-film mam-
mography.4 The radiation risk associated with mammography is
acceptable for diagnostic purposes, but the radiation dose Radionuclide Imaging of the Primary
absorbed by the breasts during multiple mammographic screen-
ing procedures throughout the years has been a continuous Tumor at Initial Diagnosis
topic of debate both in the medical community and the general
public. Starting from the late 1980s, many tumor-seeking radiopharma-
One of the major criteria for abnormality detected on mam- ceuticals have been used in the efforts to detect primary breast
mography is calcification that may also be seen in many benign cancer. In addition, thanks to the advances in imaging technology,
conditions resulting in high false-positive rate and low specificity. breast imaging methods that had been unknown before have been
Almost two-thirds of abnormal findings detected on mammogra- developed using these radiopharmaceuticals labeled with
phy are benign. Hence, in current clinical practice, women with γ-emitters and positron emitters (Table 11.1).
abnormal mammographic findings must undergo additional diag-
nostic procedures including ultrasonography, magnetic resonance Breast Scintigraphy Using Gamma
imaging (MRI), and/or tissue sampling (fine-needle aspiration,
core biopsy or excisional biopsy). Although mammography is the
Camera Imaging
gold standard procedure for breast cancer screening, its low spec- Breast scintigraphy, also known as scintimammography, is a diag-
ificity often leads to a large number of unnecessary interventions nostic imaging method that utilizes tumor-seeking radiopharma-
performed to evaluate suspicious mammographic breast lesions.5,6 ceuticals to detect the primary tumors of the breast. A large
Supplemental screening with breast MRI is recommended in number of radiopharmaceuticals have been used for breast scin-
women with selected high- and intermediate-risk factors while tigraphy, but technetium-99m methoxyisobutylisonitrile (99mTc-
screening with breast ultrasonography is an option for women in sestamibi, also known as 99mTc-MIBI) is the most widely used
these risk groups who cannot undergo breast MRI. radiopharmaceutical for this purpose. 99mTc-MIBI is avidly taken
MRI may have an additional role in the diagnostic work-up as up by many malignant tumors9 and is currently the radiopharma-
it is quite sensitive especially detecting multifocal/multicentric ceutical of choice for breast scintigraphy.
132

Chapter 11 Breast Carcinoma 133
Table 11.1 dular and whole-body radiation dose. 99mTc-MIBI breast imaging
should not be considered as an alternative to biopsy.
Radionuclide IMAGING METHODS in Breast Cancer The time necessary to complete the imaging session can be as
long as 40 minutes. This is another challenge in competition with
Radiopharmaceutical mammography in diagnostic setting. In their recent study com-
paring the diagnostic performance of molecular breast imaging
I. Detection of Primary Tumor (MBI) performed with standard 10-minute-per-view acquisitions
and half-time 5-minute-per-view acquisitions, with and without
Single photon imaging
wide beam reconstruction processing, Hruska et al.13 focused on
Breast scintigraphy reducing the time needed for imaging and reported comparable
Prone imaging 99m
Tc-MIBI results with 10-minute- and 5-minute-per-view MBI, resulting in
Molecular breast imaging 99m
Tc-MIBI substantial agreement in the final assessment. In an era when
99m
more efforts are focused on reducing the injected 99mTc-MIBI activ-
Breast-specific gamma imaging Tc-MIBI ity for a more favorable radiation dose to the breast and the whole-
Positron emission imaging body, reducing imaging time unavoidably requires injection of a
PET and PET/CT 18
F-FDG higher activity which is less likely to gain acceptance clinically.
18 The interval between injection of radiopharmaceutical and
Dedicated PET F-FDG
imaging has been a topic of investigation in some studies.14 In a
99m
Intraoperative lesion detection Tc MIBI standard protocol, 10 to 15 mCi of 99mTc-MIBI is injected into the
II. Detection of Recurrence/Metastasis and Staging arm opposite the breast with the suspected lesion. Both breasts
should be imaged for the purpose of comparison during interpre-
Axillary involvement
tation. One hour after intravenous injection of 99mTc-MIBI, patients
99m
Supine SPECT imaging Tc-MIBI are positioned supine with the arms raised up to allow evaluation

PET/CT 18
F-FDG of the axilla and the breast. Some departments prefer starting the
acquisition as early as 5 minutes after injection and perform
Sentinel lymph node detection and imaging
99m
imaging as late as 90 minutes after injection.14,15
Sentinel lymph node lymphoscintigraphy Tc colloids In their original study, Aktolun et al.9 preferred supine planar
Intraoperative sentinel lymph node detection 99m
Tc colloids and single photon emission tomography (SPECT) imaging, but
Distant metastasis prone technique for patient positioning has gained wider accep-
18
tance throughout the world.11 Most authors suggested placing the
PET/CT F-FDG patients in prone position using a table with a cutout to fit the
Bone metastasis breast. Breasts are placed as close as possible to the detector to
Whole-body bone scan 99m
Tc-MDP increase the sensitivity and lesion detectability. Two lateral breast
18 images are obtained for 10 minutes (Fig. 11.1). A supine image is
PET/CT F-FDG, 18F-flouride
also recommended to cover the axillae. If patients cannot be posi-
III. Assessment of Response to Antineoplastic Treatment tioned in the prone position, an anterior supine view with the
Breast scintigraphy 99m
Tc-MIBI arms up is obtained to evaluate two breasts and axillary region
18 simultaneously.
PET F-FDG
SPECT may provide additional information about primary
18
Novel agents (research tools) F-FES, 18F-FPTP, C-11 MET, breast cancer and the axilla.16,17 For SPECT imaging, the patient
18
F-FLT, radiolabeled integ- is usually positioned in the supine position to obtain sufficient
rins (18F-galacto RGD αυβ3 counts for high-resolution images. All images must be meticu-
integrin), 18F-annexin-V PET
lously reviewed, particularly in patients with fibroglandular
changes as false-positive findings may be seen.
99m
Tc-MIBI was originally used to evaluate myocardial perfu- The sensitivity of scintimammography is higher for palpable
sion. Aktolun et al.9 were the first to show that 99mTc-MIBI can be breast tumors than nonpalpable lesions because of the limited
used to detect the primary tumor in patients with breast cancer. It resolution of gamma camera technology.18 In patients with a rela-
has the advantages of 99mTc which offers low radiation burden and tively high number of fibrocystic lesions, false-positive findings
high photon flux suitable for gamma camera imaging. MIBI is a may be obtained whereas in patients with small malignant lesions
positively charged lipophilic molecule that accumulates in the faint or no activity (false-negative) may be seen.
negatively charged mitochondria in rapidly proliferating tumor
cells.10 The mechanism of accumulation in the tumor is multifacto- Breast Scintigraphy Using Dedicated
rial and does not depend on the presence of architectural distor-
Breast Imaging Devices
tion or local or diffuse density variation in the breast. There is a
positive correlation between energy demand and increased mito- Breast scintigraphy as described above can be performed using a
chondrial activity of tumor cells. general purpose gamma camera that is available in all Nuclear
The amount of 99mTc-MIBI activity used for breast scintigraphy Medicine departments, but the ability of these devices to detect
was originally defined as 10 mCi,9 but activities as high as 25 mCi small tumors is limited. The breasts are about 15 cm away from
have been reported in studies published subsequently.11 Most of the collimator and the region of interest may be up to 25 cm away
the dosimetric studies performed for comparison of breast scintig- from the collimator. In addition, only the lateral and anterior/
raphy with mammography were based on the figures obtained posterior views can be acquired with general purpose cameras.
from the radiation absorbed dose after the injection of these high Side-by-side correlation with the standard craniocaudal and
amounts of 99mTc-MIBI which unnecessarily placed this technique mediolateral oblique views acquired in routine mammography are
in a less favorable position compared to mammography. In recent almost impossible to obtain. Dedicated breast imaging devices
studies, however, the amount of activity has been reduced to 8 to overcome these problems by reducing the size of the detector and
10 mCi.12 It should be noted that, with the current strategies using integrating it with a breast compression device. The breast is
99m
Tc-MIBI activities greater than 10 mCi, breast scintigraphy is pressed against the collimator/detector face while the patient is
not indicated for breast cancer screening because of the high glan- imaged in a seated position.

A B
Figure 11.1. Breast scintigraphy performed using a general

purpose gamma camera. Invasive ductal carcinoma (red arrow) in
a woman with dense breast parenchyma and a metastatic lymph
node in the right axilla (blue arrow) seen on mammography (A).
99m
Tc-MIBI uptake by the primary tumor was seen on both projec-
tions in prone and right anterior oblique positions (B, C; red
arrow), whereas metastatic lymph node in the axilla was more
apparent only in right anterior oblique position (C; blue arrow).
C Note that according to color scala, body part over a certain count
rate was seen as a white region (B; thick red arrow).
99m
Dedicated imaging devices with small field of view (FOV) and Tc-MIBI imaging with this device increased compared to con-
higher resolution have revealed more favorable results than previ- ventional breast scintigraphy imaging. Using this technique, malig-
ously obtained.19 These devices produce images of the breast nant breast lesions <1 cm were detected with 86% sensitivity.
parenchyma in the same projections comparable to mammogra- Brem et al.20 used a breast-specific gamma camera to evaluate
phy (Fig. 11.2). The axillae are not included in these images which 94 women considered at high risk of breast cancer despite normal
may result in missing important findings. With this technology, mammographic findings. They reported 100% sensitivity and 85%
breast scintigraphy has evolved to MBI and breast-specific gamma specificity for BSGI.
imaging (BSGI). A recent study compared the results of semiquantitative BSGI
MBI is performed through a matched, solid-state cadmium zinc with an uptake ratio cutoff of 1.5 to breast ultrasonography and
telluride (CZT) detector in a dual-head configuration in which each mammography and found that BSGI with visual and semiquantita-
CZT detectors are used as individual pixel elements. By contrast, tive analyses had a significantly higher specificity than BSGI with
BSGI uses a single detector head with pixelated sodium iodide visual analysis alone, mammography, and ultrasound (all, p < 0.01).21
scintillator technology and an array of position-sensitive photo- Small breast lesions still pose a problem as they may have a ratio less
multiplier tubes. Hurska et al. developed a semiconductor-based than the designated threshold because of the volume averaging.
gamma camera system to detect malignant breast lesions <2 cm Sensitivity of BSGI compared to that of traditional gamma cam-
and labeled this technique MBI.12 The sensitivity and specificity of era breast scintigraphy methods improved from 85% to 92% for


Figure 11.2. A patient referred for BSGI imaging
due to suspicious microcalcification in the left
breast. In the left craniocaudal and left medial lateral
images, a well-defined focus of increased 99mTc-
MIBI activity is identified (red arrows). The final diag-
nosis made through core biopsy and lumpectomy
was moderately differentiated invasive carcinoma,
1.5 cm in size. (Images courtesy of Stanley J. Gold-
smith, MD, The New York Presbyterian Hospital,
Weill Cornell Medical Center, NY, USA.)
lesions >1 cm and from 47% to 67% for lesions <1 cm.22 A more Its influence on surgical management was comparable to breast
recent study reported 96.4% and 59.5% sensitivity and specificity, MRI.
respectively, for BSGI.23 In a retrospective review of BSGI, mammography and breast
A recent retrospective study reviewing 1,480 BSGI studies ultrasonography in 121 patients with 153 breast lesions, Kim
demonstrated that in comparison with breast MRI, BSGI is a cost- et al.27 reported the overall sensitivity and specificity of BSGI as
effective and accurate imaging modality for the evaluation of 92.2% and 89.3%, whereas these values were 53.6% and 94.7%
tumors in patients with dense breast tissue.24 BSGI had a sensitiv- and 91.5% and 53.3%, for mammography and breast ultrasonog-
ity of 92%, specificity of 73%, positive predictive value (PPV) of raphy, respectively (p < 0.0001 and p < 0.0004). In breast lesions
78%, and negative predictive value (NPV) of 90%. The correspond- ≤1 cm, the sensitivity and specificity of BSGI were 80.6% and
ing figures for breast MRI were 89%, 54%, 67%, and 83%. The 91.5%, which were different from mammography and breast
accuracy of BSGI was higher, at 82%, versus MRI, at 72%, while ultrasonography, respectively (p < 0.0001 and p < 0.0003).
the cost was almost one-fourth of the breast MRI cost ($850 In patients with DCIS, BSGI performed slightly better than
versus $3381). mammography; the sensitivity was 93.9% for BSGI and 90.9% for
Rechtman et al. has recently confirmed that BCGI is not mammography whereas the combined use of mammography and
affected by dense breast tissue.25 By studying the performance of scintigraphy achieved 100% sensitivity.28
BCGI in women with dense breast (BI-RADS density 3 and BI- In a study assessing the ability of MIBI to predict early response
RADS density 4) in comparison to that in women with nondense to neoadjuvant chemotherapy, Mitchell et al.29 found that the
breast. They found no significant difference in BSGI breast cancer changes in tumor-to-background (T/B) ratio on MBI images at 3 to
detection and parenchymal breast density and concluded that 5 weeks following initiation of neoadjuvant chemotherapy were
BSGI has high sensitivity for the detection of breast cancer in accurate at predicting the presence or absence of residual disease
women with dense and nondense breasts (sensitivity 95.8% and after neoadjuvant chemotherapy completion. Diagnostic perfor-
95.1%, respectively). In conclusion, BSGI is an effective adjunct mance of BSGI in the assessment of residual tumor after neoadju-
imaging modality in women with both dense and nondense vant chemotherapy has also been studied in 122 breast cancer
breasts. patients.30 Excluding luminal and/or HER2 subtypes, the diagnostic
In terms of its influence on surgical management of patients performance of BSGI was comparable to MRI but more accurate
with breast cancer, BSGI changed surgical management to mas- than MRI in the assessment of residual tumor extent. Both modali-
tectomy in a substantial proportion of patients believed to be eli- ties underestimated the tumor size in luminal and/or HER2 sub-
gible for breast conserving surgery following standard imaging.26 types, most probably because of the low cellularity in these entities.

Rhodes investigated the performance of BSGI, mammography, from imaging studies is greater for women at high risk of breast
and the combination of the two modalities in 936 asymptomatic cancer, whether or not they are more radiosensitive, because they
women with heterogeneously or extremely dense breasts on prior generally start screening at a younger age and therefore have a
mammogram, as well as additional risk factors including BRCA longer postradiation experience.
mutations and personal history of breast cancer.31 Overall sensi-
tivity was 82% for BSGI, 27% for mammography, and 91% for 18
F-Fluorodeoxyglucose Positron Emission
both combined. The specificity was surprisingly high: 93% for
BSGI, 91% for mammography, and 85% for both. The number of
Tomography (18F-FDG PET/CT) Imaging
18
breast cancers diagnosed per the number of biopsies performed F-FDG is taken up by primary and metastatic breast tumor cells
was 28% for BSGI and 18% for mammography. in proportion to the rate of glucose metabolism. Positron emission
These results suggest that radionuclide breast imaging has a tomography detecting 18F-FDG uptake has been investigated for
clinical role as a second-line diagnostic tool to be used after mam- the detection of primary breast tumors at the initial diagnosis, but
mography in the evaluation of patients in whom the sensitivity of it has been studied more widely to detect recurrent and metastatic
mammography is low because of the density of the breast paren- breast cancer as well as to assess the response to antitumor ther-
chyma. Detection of small-sized tumors is still a serious problem apy (Fig. 11.3).38,39
associated with all breast scintigraphy techniques as tumor detec- At initial diagnosis, the histology and the size of the tumor play
tion is not dependent on tumor type, but rather on tumor size. the most important role in 18F-FDG uptake. Cumulative experience
Sensitivity is the lowest for tumors less than 5 mm in diameter. showed that the diagnostic performance of 18F-FDG PET imaging in
BSGI and MBI have been suggested for a variety of clinical appli- primary tumors less than 1 cm is not as good as that in larger
cations in practice guidelines.32–34 Despite the fact that 99mTc-MIBI tumors as a consequence of volume averaging. 18F-FDG PET has
was suggested for breast imaging as early as 1992,9 none of these poor sensitivity in noninvasive breast tumors but invasive breast
breast imaging techniques have yet gained clinical acceptance as a cancers including infiltrating ductal and infiltrating lobular carcino-
routine procedure because of the low sensitivity, especially in small mas show high 18F-FDG uptake. Infiltrating ductal carcinoma has
lesions, and high radiation burden associated with these techniques. even more avid uptake of 18F-FDG and hence higher sensitivity than
Developing a breast dedicated SPECT and SPECT/CT and using new infiltrating lobular carcinoma, possibly because of multiple biologic
99m
Tc-labeled molecular probes may increase the sensitivity and variants including glucose transport-1 expression, hexokinase I
specificity of this technique overcoming current efficacy problems. activity, tumor microvessel density, amount of necrosis, number of
Decreasing the amount of injected radioactivity is essential to lymphocytes, tumor cell density, and mitotic activity index.40
decrease the radiation burden to the breast and the entire body. A study comparing prone 18F-FDG PET and MR breast scans in
A major disadvantage of radionuclide breast imaging is that all 31 patients who underwent MR and 18F-FDG PET scanning
body organs are irradiated because of circulating radionuclide showed that the PPV increased from 77% in MR alone to 98%
while fibroglandular breast tissue is the only radiosensitive tissue when fused with 18F-FDG PET, and the specificity rose from 53%
exposed to ionizing radiation in mammography.35 Although the to 97% (p < 0.05). The false-negative rate on 18F-FDG PET alone
use of BSGI or MBI has been proposed for women at high risk of was 26.7%, and after fusion with breast MR, this figure was
breast cancer, there is controversy and speculation over whether reduced to 9%.41
some women, such as those with BRCA mutations, have higher Despite the high sensitivity and specificity in these breast
radiosensitivity.36,37 The risk associated with ionizing radiation tumors, because of its insufficient spatial resolution resulting in
Figure 11.3. Metabolic flare demonstrated in a 28-year-old female with meta-

static breast carcinoma. Findings at presentation were axillary lymphadenopathy and
a 1.1-cm solid lesion in the left breast. Diagnosis of invasive ductal breast carcinoma
was made with true-cut biopsy. There were only a few foci of bone marrow invasion
in the lumbar vertebrae (blue arrows) and multiple hypermetabolic lymph nodes
(thick red arrow) as well as the primary tumor in the left breast (thin red arrow) seen
on the first 18F-FDG PET/CT MIP whole-body image (A). The patient was treated with
chemotherapy and then referred for a repeat 18F-FDG PET/CT to assess the response
to treatment (B). Despite the decrease in the metabolic activity of the axillary lymph
nodes (SUVmax 15.9 versus 7.9) additional lesions in the skeleton (blue arrows) and
a hypermetabolic lymph node in the mediastinal area (green arrow) appeared on
18
F-FDG PET/CT performed after six cycles of chemotherapy (B). Initial interpretation
was “disease progression.” The oncologist in charge of the patient disagreed with
the diagnosis as the lump in the axilla decreased in size on palpation and blood CA
15–3 levels dropped significantly (from 307 ng/dL to 101 ng/dL). The final decision
was that the metastatic lesions not seen on the initial 18F FDG PET/CT scan became
A B visible on the second 18F PET/CT scan as the uptake in the axillary lymph nodes
decreased in response to chemotherapy (metabolic flare?).

failure to detect early-stage breast cancers, 18F-FDG PET/CT has 92%, and area under the receiver-operating characteristic curve
not gained universal acceptance and is not approved to determine 0.949 when interpreted with mammographic and clinical find-
extent of disease at the time of initial diagnosis of primary breast ings. It was concluded that 18F-FDG PEM had high diagnostic
cancer. It has a potential clinical role in the diagnostic work-up of accuracy for breast lesions, including DCIS.49
selected cases including patients with dense breasts and breast The sensitivity of PEM was investigated in relation to pathologi-
implants. The motivation to exploit this avid F18 F-FDG uptake and cally confirmed tumor size.51 A total of 113 breast lesions from 101
to overcome the difficulties associated with general purpose PET/ patients were included in the analysis. The patients underwent 18F-
CT scanners has led to more focused efforts using dedicated small FDG PEM and whole-body PET/computed tomography (CT) before
FOV PET imaging systems with higher resolution that are designed surgical resection, and images were analyzed visually and quanti-
solely for breast imaging. tatively using the tumor-to-normal-tissue uptake ratio (TNR).
Tumors were classified into four groups based on size using patho-
18 logic results. The sensitivity of PEM and PET/CT were compared in
F-FDG Positron Emission Mammography the overall subjects and in each group. By visual analysis, PEM
Thompson et al.42 first proposed a prototype PEM device in 1994, showed significantly higher sensitivity than PET/CT (95% versus
and the first clinical 18F-FDG PEM study appeared as early as 87%; p = 0.004), which was more remarkable in the groups with
1996.43 Doshi et al.44 created a breast imaging system consisting small tumor. By quantitative analysis, the TNR of PEM was signifi-
of two 15- × 15-cm2 arrays of 3- × 3- × 20-mm3 cerium-doped, cantly higher than that of PET/CT in the small tumor groups
lutetium oxyorthosilicate detector elements coupled with arrays of whereas no difference was found in the overall group. With a cutoff
position-sensitive photomultiplier tubes. After several versions of TNR of 2.5, PEM showed significantly higher sensitivity than PET/
small FOV systems, positron emission mammography (PEM) with CT in the overall and small-tumor groups. In conclusion, PEM had
a full breast size scanner that utilizes two sets of linearly scanning higher sensitivity for tumor detection than PET/CT, particularly in
planar detectors has become commercially available. A typical small tumors. Based on these findings, the authors of this study
PEM system consists of at least one pair of planar scintillation suggested that PEM can be used for diagnosis and characterization

detectors in coincidence. The breast is placed between these of small lesions as a supplementary imaging modality for PET/CT.51
detectors to permit either limited angle or full three-dimensional Schilling et al.52 compared in 208 women the performance char-
(3D) tomographic reconstruction if data are acquired from multi- acteristics of PEM with breast MRI as a presurgical imaging and
ple angles. planning option for index and ipsilateral lesions in patients with
Initial clinical trials using PEM reported sensitivity in the range newly diagnosed, biopsy-proven breast cancer. Of these patients,
of 80% to 86% in depicting primary breast cancer in patients with 26.4%, 7.1%, and 64.2% were pre-, peri-, and postmenopausal,
palpable or nonpalpable but highly suspicious mammographic respectively; and 48.4% had extremely or heterogeneously dense
lesions.45–49 With the recent developments in technology, new ver- breast tissue, whereas 33.5% had a history of hormone replace-
sions of PEM have revealed considerably higher detection rates ment therapy (HRT). Each patient underwent MRI, PEM, and whole-
(96%).50–52 body positron emission tomography (WBPET) within 10 days. A
The efficiency of PEM scanner is about 10 times higher than direct comparison between PEM, PET, and MRI showed that the
regular PET systems, especially in small tumors.51,52 Considering sensitivity of PEM was 93% for known index lesions and 85% for
that intraductal cancer represents more than 30% of reported unsuspected additional lesions.52 The sensitivity values for PEM
cancers and is the breast cancer with the highest probability of were significantly higher than those of PET and comparable to
achieving surgical cure, it is likely that the use of PEM would com- those of MRI, whereas PEM also had higher specificity than MRI for
plement anatomic imaging modalities in the areas of surgical the detection of unsuspected lesions (74% versus 48%). Further-
planning, monitoring high risk patients and choosing patients for more, in this study, PEM successfully depicted invasive tumors mea-
minimally invasive therapy. Clinical trials with a full breast PEM suring as small as 3 mm, and exhibited 100% and 85.7% sensitivity
device showed high clinical accuracy in characterizing lesions for T1a (>1 mm but ≤5 mm) and T1b (>5 mm but ≤10 mm) IDC
identified as suspicious on the basis of conventional imaging or lesions, respectively.52 In addition, the authors reported that breast
physical examination (sensitivity 93%, specificity 83%), with high density, hormone replacement therapy, and menopausal status did
sensitivity preserved (91%) for intraductal cancers.47 A subse- not interfere with lesion detection with PEM. These factors are
quent study in patients with biopsy-confirmed breast cancer with known to affect the glandular tissue of the breast and make inter-
a median size of 22 mm reported 89% sensitivity of PEM in the pretation of classic imaging modalities (mammography and MRI)
detection of malignancy.48 In this study, the PEM scan also revealed challenging as far as cancer detection is concerned. Thus, with its
an additional, mammographically occult, DCIS lesion measuring 2 ability to overcome certain limitations of MRI, PEM using 18F-FDG
to 3 mm in width.48 has been proposed as an appropriate alternative to MRI in the pre-
In a multicenter trial, PEM imaging demonstrated 90% sensi- surgical management of breast cancer patients.52
tivity and 86% specificity in detecting breast malignancy in 94 A recent study comparing detection rates of additional ipsilat-
patients who were either undergoing a breast biopsy or were eral lesions using either PEM or MRI reported comparable sensi-
recently diagnosed with breast cancer.49 PEM results were corre- tivity for each moduality, but, higher specificity for PEM.53
lated with histopathology for 92 lesions in 77 women with 48 Furthermore, increased cancer detection was reported when PEM
malignant lesions, of which 42 are index lesions, 3 ipsilateral and MRI were combined compared to MRI alone. These findings
lesions, and 3 contralateral malignant lesions. Of these 48 can- indicate an additional potential role for PEM in presurgical plan-
cers, 16 (33%) were clinically evident; 11 (23%) were DCIS, and 37 ning, as it can provide an accurate estimation of tumor size and
(77%) were invasive (30 ductal, 4 lobular, and 3 mixed; median focality. As a result, the extent of the disease can be more precisely
size 21 mm). PEM depicted 10 of 11 (91%) DCIS and 33 of 37 defined, and unnecessary additional biopsies in women with newly
(89%) invasive cancers. Overall, the sensitivity of PEM was for diagnosed breast cancer could be avoided. Contrary to these initial
detecting cancer was 90%, specificity 86%, PPV 88%, NPV 88%, encouraging results, in a recent study, however, PEM has been
accuracy 88%, and area under the receiver-operating characteris- found to be less sensitive than MRI in identifying contralateral
tic curve 0.918. In three patients, cancer foci were identified only malignancies in women with newly diagnosed breast cancer.54
on PEM, significantly changing patient management.49 Excluding Despite its obvious advantages, a few limitations apply for PEM
eight diabetic subjects and eight subjects whose lesions were scans. First, the specificity of a PEM scan can be attenuated
characterized as clearly benign with conventional imaging, PEM because of high 18F-FDG uptake in other medical or physiologic
sensitivity was 91%, specificity 93%, PPV 95%, NPV 88%, accuracy phenomena.55 Benign breast lesions, such as fibroadenomas in

the rapid growth phase and acute or chronic inflammatory pro-

cesses (e.g., fat necrosis) are known to result in increased focal
Radionuclide Imaging for the
18
F-FDG uptake56; however, these conditions can often be differen- Evaluation of Axillary Involvement
tiated from malignancy by conventional imaging.
During a PEM scan, proper positioning of the breast is essen- Locoregional staging includes axillary and internal mammary lymph
tial because noninclusion of the malignancy in the FOV can result node evaluation. Axillary lymph node status is a major prognostic
in false-negative results. Interpretation of PEM scans can also be factor for determining the survival in patients with newly diagnosed
challenging, especially in lesions that are in close proximity to the breast cancer. Internal mammary lymph nodes are not commonly
chest wall, as well as in larger breasts. included in routine staging. Axillary involvement is found in 10%
Increased breast density has also been reported to result in to 30% of patients with T1 (<2 cm) tumors, in 45% for T2 tumors
significantly higher 18F-FDG uptake57; however, no confirmatory (2.1 to 3 cm) and 55% to 70% for larger tumors (> 3 cm).60
study has addressed this issue with PEM.52 Finally, a few cases of
lobular carcinomas (known to be a source of false-negative results Breast Scintigraphy
on both PET and MRI because of their decreased vascularity and
metabolic activity) are not visualized with PEM.49 Thus, a negative Axillary involvement is revealed by physical examination in less
PEM scan should not exclude the use of further investigation for than 50% of patients and usually not identified by mammography.
the lesions that appear suspicious either clinically or on conven- CT and MRI have a limited role in detecting metastatic lymph
tional imaging. nodes harboring breast cancer as the specificity of morphologic
Integration of Computed Tomography with Positron Emission imaging is relatively low. In addition to its ability to detect the
Mammography. Raylman et al. proposed a model integrating the primary tumor, breast scintigraphy using 99mTc MIBI performed in
PEM–tomography imager and biopsy system (called PEM–PET) supine position using general purpose gamma cameras, especially
that utilizes large area (15 × 20 cm2) rotating detectors to produce with the addition of SPECT and SPECT/CT, is potentially useful in
tomographic images of radiotracer concentration by the lesion in the detection of metastasis in the axillary lymph nodes (Fig. 11.1).
the breast. They reported that reconstructed transaxial and axial The sensitivity of breast scintigraphy using general purpose
spatial resolutions of that scanner are less than 2 mm and the gamma cameras is low in the detection of metastatic axillary
PEM–PET scanner also enables image-guided biopsy of suspicious lymph nodes, and 20% of the patients with metastatic involvement
lesions in the breast.55,58 Their proof of concept study in five would be missed.61 Breast dedicated imaging devices have cur-
patients showed that the PEM/PET system which has a resolution rently no role in the evaluation of the axilla.
of about 2 mm in all three dimensions is capable of producing In studies reported up to 1998, the sensitivity of breast scintig-
good quality breast-PET images compared standard methods and raphy to detect axillary lymph node metastases is 77% and the
identifying some lesions not visible in standard mammograms.58 specificity 89%.61,62 A recent meta-analysis reviewed 45 studies
The diagnostic efficacy of another integrated 18F-FDG PET/CT and reported an average sensitivity of 83% and specificity of
mammography (mammo-PET/CT) was compared in a 2013 study 85%.63 Scintigraphy is still not accurate enough to replace axillary
with conventional torso PET/CT (supine-PET/CT) and MR-mammog- lymph node biopsy or surgical nodal dissection.
raphy for the initial assessment of breast cancer in 40 patients.59 Comparative studies showed that SPECT significantly improves
Each patient underwent supine-PET/CT, mammo-PET/CT, and MR- the sensitivity and accuracy of breast scintigraphy to detect axil-
mammography. The size of the tumor, the distance between the lary lymph node involvement compared to planar imaging, espe-
tumor and the chest wall, and the tumor and the skin, volume of cially when lymph nodes are nonpalpable and small in size.64,65 In
axillary fossa, and number of metastatic axillary lymph nodes selected cases, SPECT in combination with radio-guided sentinel
between supine-PET/CT and mammo-PET/CT were noted. The dif- lymph node (SLN) biopsy could provide additional information.64
ference of focality of primary breast tumor and tumor size in The NPV of breast scintigraphy increases with SPECT imaging;
mammo-PET/CT and MR-mammography was also compared. Their however, false-negative results might be seen because of the small
results revelead that significant differences were found in the tumour size of lymph nodes and/or to partial or micrometastatic involve-
size (supine-PET/CT: 1.3 ± 0.6 cm, mammo-PET/CT: 1.5 ± 0.6 cm, ment.64 The performance of SPECT imaging can be improved by
p < 0.001), tumor to thoracic wall distance (supine-PET/CT: 2.2 ± 0.9 using a pinhole collimator (pinhole SPECT).65 This procedure
cm, mammo-PET/CT: 2.2 ± 2.1 cm, p < 0.001), and tumor to skin reveals more lymph nodes in the axillary region and thus provides
distance (supine-PET/CT: 2.1 ± 0.8 cm, mammo-PET/CT: 2.1 ± 1.4 important prognostic information even in series with nonpalpable
cm, p < 0.001).66 The volume of axillary fossa was significantly wider lymph node metastases.64 Furthermore, although SPECT was
in mammo-PET/CT than supine-PET/CT (21.7 ± 8.7 cm versus 23.4 highly accurate and had a good NPV, only pinhole SPECT provided
± 10.4 cm, p = 0.03), and mammo-PET/CT provided more correct information on the number of involved nodes and the correct
definition of the T-stage of the primary tumor than did supine-PET/ patient classification for prognostic purposes.65
CT (72.5% versus 67.5%) while there was no significant difference in
the number of metastatic axillary lymph nodes detected by both
modalities. Compared with MR-mammography, mammo-PET/CT
Radionuclide Localization of Occult Lesions
provided more correct classification of the focality of lesion than did Fifteen percent to 20% of occult breast lesions are malignant and
MR-mammography (95% versus 90%). In the T-stage, 72.5% of frequently are detected in asymptomatic women with mammo-
patients with mammo-PET/CT and 70% of patients with MR-mam- graphic screening programs.66 The occult lesion should be marked
mography showed correspondence with histologic results.59 They before breast-conserving surgery which is currently the surgical
concluded that mammo-PET/CT provided more correct definition of technique of choice. In some centers, those lesions are removed by
the T-stage and evaluation of axillary fossa might also be delineated placing a marker (Kopans wire) with the aid of ultrasonography;
more clearly than with supine PET/CT, and the mammo-PET/CT however, the wire may be misleading as it can be displaced during
indicates similar accuracy with MR-mammography for the determi- surgery. Furthermore, migration or rupture of the wire may lead
nation of T-stage of primary breast tumor and more correct than to pneumothorax although this risk is small when the procedure
MR-mammography for defining focality of lesion. was performed by an experienced team.67 The procedure is asso-
Using more specific tumor-seeking radiopharmaceuticals and ciated with significant discomfort to the patients and may even
advances in imaging technology including integrating breast ded- cause injuries to the surgical team and pathologists.66
icated positron emission tomography with MR may help this tech- The widespread use of radio- and ultrasound-guided biopsies
nique to gain acceptance in breast cancer imaging in future. for nonpalpable breast lesions has resulted in the increased

demand for accurate preoperative localization of lesions and axil- Tab l e 1 1 . 2

lary lymph node assessment.67,68 Radionuclide occult lesion local-
ization (ROLL) is still considered a significant innovation.68–70 Colloids Used for Sentinel Lymph Node Imaging
Thus, in the last decade, radionuclide-guided excision of breast and Detection in Breast Cancer
tumors has gained acceptance throughout the world.69,70 It is a
practical technique for the localization and resection of nonpal- Radiopharmaceutical Size (in nm)
pable breast lesions, but requires experienced nuclear medicine
staff. ROLL is performed after injecting a small activity of 99mTc- 99m
Tc Human serum albumin <4
labeled macroaggregated albumin (MAA) (∼10 MBq) into the 99m
Tc Antimony sulfide colloid 15–50
breast tissue adjacent to the lesion under the guidance of ultraso- 99m
nography or stereotactic mammography. Using a hand-held Tc Nanocolloid (albumin colloid) 80
99m
gamma probe, the surgeon can remove the suspected “hot” lesion Tc Sulfur colloid (filtered) >50
with a reduced excision volume, better cosmetic results and a 99m
Tc Albumin microcolloid (unfiltered) 200–1,000
higher percentage of tumor-free margins.71,72
Radio-guided sentinel lymph node (SLN) biopsy and radio-
guided occult lesion localization can be performed in combination Data from three major studies (ALMANAC trial; the National Surgical
(SNOLL) for either infiltrating cancers or high-grade intraductal Adjuvant Breast and Bowel Project [NSABP] B-32 trial; the American
atypia.73,74 The combined procedures gained further acceptance College of Surgeons Oncology Group [ACOSOG] Z0010 trial) showed
because of their higher diagnostic accuracy in addition to excel- that the overall risk of allergic reaction is close to 1% for both dyes,
ling in assessment of surgical margins compared to the hook-wire with an approximately 0.1% risk of severe reactions.78,80,81,83 Despite
technique. The SNOLL procedure allows real-time verification of a risk of allergic reactions to blue dye, most teams favor the combina-
resecting the tumor lesion and the SLNs. The absence of radioac- tion of radiocolloid and Blue dye for mapping procedure.
tivity in the surgical bed after excision confirms the excision of the Colloids. The choice of tracer is often guided by local availabil-

tumor. The success of the resection can be further confirmed by ity (Table 11.2). 99mTc-labeled colloids of human serum albumin
demonstrating the high count rate in the resected material. With are often used in Europe whereas 99mTc-sulfur colloid is used in
stereotactic ROLL, duration of surgery is shortened by executing the United States and 99mTc-antimony trisulfide in Australia.
SLNB first, then resecting the primary lesion.75 Size of Colloid. Several studies have been conducted investigat-
Sentinel Lymph Node Biopsy. SLN biopsy is a minimally inva- ing the effect of colloid size. Smaller particles are believed to be
sive procedure performed for the investigation of potential nodal better taken up by lymphatic channels and accumulate better in
involvement.76 Its principle is based on the assumption that meta- SLNs while reducing the amount of radioactivity at the injection
static invasion starts from the tumor site in an orderly progression. site. This reduction of the radioactivity at the injection site makes
According to this principle, the nodal basin is free of malignancy if the SLN identification easier because it decreases the “shine
the SLN is not involved. Patients with SLN metastasis undergo through” effect. On the other hand, proponents of larger particles
lymph node dissection. Compared to diagnostic axillary lymph believe that smaller particles may migrate so rapidly and diffusely
node dissection, complications are reduced with the SLN biopsy.77 into the secondary regional lymph nodes that identification of
The current standard of axillary lymph node staging in early-stage SLNs becomes difficult. Mariani et al.84 suggest that 99mTc-labeled
breast cancer is SLN biopsy. In the Axillary Lymphatic Mapping colloids with most of the particles in the 100- to 200-nm size
Against Nodal Axillary Clearance (ALMANAC) trial, more than range are best for sentinel node biopsy in breast cancer. Linehan
1,000 patients were randomized to undergo either axillary lymph- et al.85 retrospectively compared unfiltered sulfur colloid with fil-
adenectomy or sentinel node biopsy.78 Lymphedema was present tered sulfur colloid and demonstrated that unfiltered sulfur colloid
in 13% of the axillary lymphadenectomy group and in 5% of the was superior to filtered colloids in SLN localization.
sentinel node group 12 months after surgery. By contrast, Lloyd et al.86 evaluated the SLN identification rate
Many centers use sentinel node biopsy only in patients with a with filtered versus unfiltered radionuclide and found no difference
unifocal tumor smaller than 3 cm, whereas others have extended between filtered and unfiltered colloids. De Cicco et al.87 studied
the application to patients with large T2 or T3 (>5 cm) tumors, 382 breast cancer patients with three different size ranges of radio-
multifocal/multicentric carcinomas or to patients who have received labeled colloids and concluded that SLN identification was most
neoadjuvant chemotherapy.79 Currently, the sentinel node biopsy accurate with large-sized (2- to 1-μm) radiolabeled colloids. Small-
procedure is recognized as the standard procedure for stages I sized (200- to 400-nm) particles were however found to be superior
and II.80,81 In these stages, this approach has a positive node rate to regular-sized (400- to 1,000-nm) particles in the intraoperative
similar to those observed after lymphadenectomy. There is no sig- identification.88 The mean radioactive counts of the hottest nodes of
nificant difference in the success rate of sentinel node biopsy the small-sized tin radiocolloid were significantly higher than those
according to clinical tumor size or clinical nodal status. of the regular-sized tin radiocolloid.88 This increased uptake of
radiocolloid made intraoperative SLN identification with a hand-
held gamma probe accurate and easy to perform.
Sentinel Lymph Node Mapping
Injection Methods. The optimal injection approach has been the
A radiotracer, blue dye, or combination of both is used for sentinel subject of active debate in recent years (Table 11.3). Peritumoral
node imaging to identify the lymph node. Radiopharmaceuticals injection was the first injection method proposed for lymphatic map-
used for SLN imaging are colloids labeled with 99mTc (Table 11.2). ping in breast cancer and has proved to be very effective for this
These radiocolloids allow sentinel node visualization with a purpose.89 Different injection techniques have been advocated. These
gamma camera before surgery as well as intraoperative detection injection techniques can be classified into two categories: deep injec-
with a hand-held gamma probe. Controversies exist with regard tion and superficial injection. Deep injection techniques, also referred
to the selection of agents, the size of the particles of the radiocol- as subcutaneous injection or parenchymal injection include peritu-
loids, the optimal route for injection, time to scintigraphy and moral (PT), subtumoral (ST) and intratumoral (IT) injection tech-
intraoperative detection, and whether or not extra-axillary lymph niques. Superficial injection techniques, also referred as epidermal
nodes should also be considered.82 (ED) or dermal injection include intradermal (ID), subdermal (SD),
Dyes. Blue dyes will color lymph nodes blue as they pass slowly periareolar (PA) and subareolar (SA) injection techniques.90
through the lymphatics. Isosulfan blue is most frequently used in the Generally, satisfactory results of SLN detection have been
United States whereas Patent blue V is used frequently in Europe. reported for all of the different injection sites. In most cases, the

Table 11.3 Although both deep and superficial injection approaches are
valid techniques and are complementary, the combination of both
Injection Techniques for Sentinel Lymph Node injection techniques (either PT and SA/PA injections107 or SD/PT
Imaging and Detection injection100) may improve detection accuracy and decrease the
false-negative rate. It is recommended that at least some of the
Deep injection • Subcutaneus/parenchymal radiocolloid or dye be injected via the PT route to avoid missing
• Peritumoral those SLNs not located in the ipsilateral axilla.90 In addition, there
• Subtumoral is good agreement that injection of a combination of radiotracer
• Intratumoral and blue dye using both superficial and deep injections enhances
Superficial injection • Epidermal/dermal detection of SLN.90,91 This is also supported by a recent study on
• Intradermal the breast lymphatic anatomy, which showed that in some cases
• Subdermal there exists alternative lymphatic drainage in the breast, although
• Periareolar the majority of the superficial lymph vessels of the breast drain to
• Subareolar only one sentinel node.101
Since PT injection with radiotracer provides additional infor-
mation about the internal mammary nodes (IMNs), the best com-
SLNs detected by deep or superficial injections are the same.91–93 bination is likely PA/SA injection with blue dye plus PT injection
Multiple studies support the notion that the location of the injec- with radiotracer. It should be noted that if IMN or other extra-
tion does not significantly affect the identification of SLN. It axillary nodes need to be detected, or if the patient has had prior
appears that there is preferred drainage to the same few axillary breast surgery or biopsy, deep injection with radiotracer and pre-
SLNs for most of the breast tissues and its overlying skin. Thus, operative scintigraphic imaging should be performed.
accurate identification of these nodes is not affected by the injec-
tion location.92,94,95 However, others argue that the superficial Preoperative Scintigraphic Imaging and
method including intradermal or PA/SA injections has the highest
Intraoperative Gamma Probe Detection
detection rate for SLN.
Many studies have shown equivalent rates for detection of SLN, The combination of preoperative scintigraphic mapping with
whereas a few have shown that PA and SA injections are slightly intraoperative probe detection is a widely used protocol for iden-
better than PT injection, with one study96 showing a relatively tifying SLN in patients with breast cancer. In most cases, after
large difference between superficial and deep injections. Blue dye injection of 99mTc colloid, scintigraphic images of the neck and
injection was used more often with PT injection, probably because chest are acquired to evaluate the distribution of radiotracer in
a larger injection volume is feasible with deep injection. As stated the patient. The skin overlying each detected radioactive focus is
above, blue dye injection has a slightly lower rate for detection of marked to indicate the location of the possible SLN. The images
SLN which may partially explain why PT injection has lower and marks on the skin provide the surgeon with a map of the
detection rate than SA/PA injection. Noguchi et al.91 recently rean- distribution of the radiotracer. Preoperative scintigraphic imaging
alyzed multiple studies and found that the use of radiotracers results in more efficient intraoperative searches for all SLNs and
results in a higher SLN identification rate than the use of blue more SLNs removed.102 It is especially helpful if a node of interest
dyes, regardless of the injection method (PT or SA/PA). is located close to an injection site or if the uptake in a node of
So far, only two randomized prospective clinical trials have interest is only slightly greater than that of neighboring tissue. In
been published,97,98 and the results are inconclusive. Povoski et al. addition, if extra-axillary SLNs need to be explored (e.g., to evalu-
compared the outcomes following injection by different routes ate the status of IMN, or in patients with prior breast surgery),
(including intradermal, intraparenchymal, and SA) of 99mTc sulfur then preoperative scintigraphic imaging is crucial.
colloid in 400 patients with breast cancer. The intradermal injec- The timing of preoperative scintigraphy is determined by the
tion route demonstrated a significantly better SLN identification particle size of the radiotracer. For commonly used radiocolloids, the
rate and less time to first localization on preoperative lymphoscin- movement of radiotracer within lymphatic channels is rapid, with
tigraphy. The intraoperative identification of SLN for intradermal, SLNs frequently seen at 15 minutes, and the vast majority of SLNs
intraparenchymal, and SA injections were 100%, 90%, and 95%, identified by 90 minutes. The location and number of nodes detected
respectively, with decreased time to harvest the first SLN during scintigraphically in patients with breast cancer are not affected by
surgery, and with greater radiotracer uptake in the SLN.113 How- imaging time after injection of 99mTc nanocolloid or sulfur colloid,
ever, these findings were not confirmed by other prospective ran- that is, whether the imaging was performed early (15 minutes to 4
domized multicenter study, which revealed a similar intraoperative hours after radionuclide injection) or delayed (18 to 24 hours after
SLN detection rate for PA injection as compared with PT injection radionuclide injection).103–105 For intraoperative gamma probe
(99.11% in both cases).98 detection, surgery can be done up to 16 to 18 hours after injection
Other factors should be considered when deciding on the with radiocolloids of 200 to 1,000 nm.106 For smaller-sized radiocol-
injection technique. One major advantage of superficial injection loids, reinjection of radiotracer may be needed just before surgery.107
is that it is easy to perform and results in less interference with Intraoperative gamma probes detect more SLNs than preop-
scintigraphic imaging. In addition, there is no need for ultra- erative scintigraphy.108,109 Even in lymphoscintigraphy-negative
sound guidance for the injection, even with nonpalpable breast patients, SLNs can often be detected intraoperatively by gamma
cancer. Intradermal or subdermal injection is more painful. The probing.108,109 It has been suggested that the addition of intraop-
addition of pH-balanced 1% lidocaine to the radiocolloid solution erative imaging may enhance the potential of node detection, but
has been reported to improve patient comfort without compro- this is still under investigation, and needs to be confirmed in
mising SLN identification.99 Deep injection may be difficult to per- larger series of patients.
form if the tumor is nonpalpable, and ultrasound guidance may SPECT/CT. There are limited data on the use of hybrid SPECT/
be needed. Important advantages of deep injection are the CT in lymphatic mapping in patients with breast cancer. It has
improved detection of extra-axillary nodes (as discussed below) been shown that SPECT/CT can detect additional nodes not visu-
and the possibility of a larger injection volume. For tumors in the alized on planar images and is especially useful in visualization of
upper outer quadrant, radiotracer injection may cause shine- SLNs outside the axilla or nodes close to the injection site.110 How-
through activity which interferes with detection of SLN on preop- ever, the current approach with combined injection of markers,
erative scintigraphy. preoperative planar scintigraphic imaging, and intraoperative

probing has proven very successful with SLN detection rates over metastatic tumor deposits less than 1 cm.39,114,115 Introduction of
95%, so the need for SPECT/CT imaging will be limited. PET systems integrated with an anatomical imaging system (CT or
Nucleic Acid Amplification: Some molecular methods have MRI) have significantly improved the diagnostic performance of
been used previously for sentinel node diagnosis but have shown PET for the assessment of axillary lymph nodes. Compared to con-
lack of reproducibility, longer time for the intraoperative assess- ventional imaging modalities, functional imaging with 18F-FDG
ment, and inability to study the whole lymph node. A new molecu- PET/CT is more sensitive to detect axillary lymph node metastases
lar method has been developed recently, based on a one-step resulting in significant changes in patient management (Fig.
nucleic acid amplification (OSNA) method. This procedure is in the 11.3).116–118 Recent studies, however, noted that the sensitivity of
18
phase of validation in some centers, while some others routinely F-FDG PET/CT in the assessment of axillary nodes is lower than
apply this method.102 initially reported, likely because of the increased detection rate of
In one multicenter study, the false-negative rate of scintigraphic micrometastases in the axilla in up to 45% of the patients studied
SLN detection was 17.7% if only one node was resected, 10% if 2, using the newest immunohistochemical staining methods.119–121 In
6.9% if 3, 5.5% if 4, and 1% if 5 or more.99 These results should recent studies, the sensitivity of 18F-FDG PET/CT has been reported
not imply removal of multiple nodes, but all identified hot or blue to be between 20% and 43% for axillary lymph node staging in
nodes should be resected. Careful palpation by the surgeon of the primary breast cancer.122–124
operative field is also required to identify any suggestive large, Furthermore, false-positive results with 18F-FDG PET are seen
hard, nonblue, and nonradioactive nodes.99 because physiologic 18F-FDG uptake is observed in inflammatory
The American Society of Clinical Oncology Guideline empha- sites which make distinguishing metastatic lymph nodes from
sized that a multidisciplinary team should aim at a sentinel node reactive lymph nodes difficult.125 Dual time-point imaging may be
identification rate of 85% with a false-negative rate of 5% or less of clinical value for lesion detectability and differentiating inflam-
to abandon axillary dissection.111 False-negative cases may result matory lesions from malignant lesions.126–128 In a study by Choi
from massive involvement of the real sentinel node, a circum- et al.,129 the sensitivity and specificity of dual time-point 18F-FDG
stance that interferes with the uptake of both radiocolloid and dye PET to detect ALN metastasis were reported to be 60.3% and

and lymph flow that goes to a node other than the true sentinel 84.7%, respectively. Numerous past reports showed that the sen-
node.111,112 sitivity of 18F-FDG PET/CT for ALN metastasis detection was lower
Interpreting Images. Major criteria to identify lymph nodes as in T1 breast carcinomas compared to T2 or T3 tumors.130–132
sentinel nodes are the visualization of lymphatic ducts, the time of Despite these advances and superiority to morphologic imaging
appearance, the lymph node basin, and the intensity of lymph modalities, currently, 18F-FDG PET is not sensitive enough to
node uptake. Following these criteria visualized radioactive lymph detect small metastasis in axillary lymph node. Further refine-
nodes may be classified as follows111: (i) Definitively sentinel nodes: ments in technology and radiopharmaceuticals to increase speci-
This category involves all lymph nodes draining from the site of ficity and sensitivity are necessary in order for 18F-FDG PET/CT
the primary tumor through an own lymphatic vessel, or a single imaging to be accepted as a reliable clinical tool for axillary lymph
radioactive lymph node in a lymph node basin. (ii) Highly proba- node staging in breast cancer patients.
ble sentinel nodes: This category includes lymph nodes appearing
between the injection site and a first draining node, or nodes with
increasing uptake appearing in other lymph node stations. (iii)
Less probable sentinel nodes: All higher echelon nodes may be Radionuclide Imaging for
included in this category. Distant Metastasis
The use of these categories to characterize radioactive lymph
nodes is also helpful for clinical decision making.111–113 Lymph 18
F-FDG PET/CT in the Diagnostic Work-Up
nodes of the first two categories (definitively sentinel node or
highly probable sentinel node) are the nodes recognized by the
of Distant Metastases
18
nuclear physician and that must be removed at the operation F-FDG PET/CT with its whole-body imaging feature is superior
room by the surgeon. Less probable sentinel nodes may some- to conventional imaging modalities to localize distant metastatic
times be removed depending on the degree of remaining radioac- tumor.133 Whole-body 18F-FDG PET/CT imaging detects not only
tivity measured by the gamma probe during the control of the the primary breast tumor and axillary lymph node metastases, but
surgical field.111–113 also skeletal and visceral metastases (Figs. 11.3 and 11.4).134–136
By contrast, distant breast cancer metastases are generally char-
18
F-FDG PET/CT in the Evaluation of Axillary, acterized by significantly increased metabolic activity compared
Internal Mammary, and Mediastinal Lymph to normal breast tissue. 18F-FDG PET/CT with significant meta-
bolic information is often more sensitive than conventional imag-
Node Metastases ing for the detection of distant metastases, particularly in the
The degree of apparent 18F-FDG uptake in breast cancer varies recurrent setting. The reported rates of sensitivity and specificity
with size of the tumor focus, at least in part because of volume of 18F-FDG PET for the detection of distant metastases range from
averaging. This can result in low sensitivity of 18F-FDG PET imag- 80% to 100% and 50% to 97%, respectively.136 Mahner et al.137
ing particularly in the detection of small breast carcinomas, reported the sensitivity and specificity of 18F-FDG PET 87% and
locoregional micrometastases, and nonenlarged tumor-infiltrated 83%, respectively, whereas the corresponding figures for com-
lymph nodes. Axillary or mediastinal lymph node metastases are bined conventional imaging modalities were 43% and 98%.
18
one of the most important prognostic factors for survival in F-FDG PET detected more metastatic lesions than other imaging
patients with breast cancer. There was no efficient and reliable modalities including CT.
noninvasive imaging modality to assess axillary lymph node Groheux et al.138 also reported that 18F-FDG PET/CT detected
metastasis until the introduction of 18F-FDG PET imaging into unexpected metastasis changing the clinical stage in 52% of
clinical practice of breast cancer.114 Surgical dissection had, there- patients. They also found that 18F-FDG PET/CT is particularly
fore, been the sole modality to confirm or exclude the presence of more accurate and efficient in the detection of distant metastasis
metastatic involvement of the axilla. The utility of 18F-FDG PET in inflammatory locally advanced breast cancer (LABC) than non-
imaging as a noninvasive method was therefore investigated in inflammatory LABC. The additional sensitivity of 18F-FDG PET/CT
the evaluation of axillary involvement as early as 1991.39 Initial for regional nodes and distant disease may be particularly impor-
studies using PET systems revealed low sensitivity, especially in tant in staging for LABC.

A B
D E
C
Figure 11.4. Multiple foci of distant metastases in the liver (green arrow) and the skeleton (some of them designated with blue arrow) in a 64-year-old woman (A: 18F-FDG PET MIP image; B:
Transaxial PET; C: transaxial CT; D: PET/CT fusion). On the second 18F-FDG PET/CT performed after six cycles of chemotherapy, lesions in the liver have significantly disappeared, but the tracer uptake
in the skeleton has become more prominent (E: 18F-FDG PET MIP image).
18
Some patients with LABC quickly develop distant metastases F-FDG PET/CT and 18F-Fluoride PET/CT
despite appropriate therapy. The detection of distant metastases Imaging in Bone Metastases
in the patients with LABC is therefore crucial to determine treat-
ment options. 18F-FDG PET imaging has been found to be superior PET imaging offers the opportunity for functional evaluation of bone
to conventional imaging modalities including CT in the detection lesions or the local skeletal response to metastasis (Fig. 11.3). In
of internal mammary and mediastinal nodal involvement which the context of skeletal relapse, although 18F-FDG PET outperforms
were not visible on conventional imaging modalities.139–142 Based the bone scan for detection of predominantly lytic bone disease, its
on these reports, it is evident that 18F-FDG PET/CT can improve use to evaluate sclerotic bone metastasis remains controversial.144–146
staging and alter therapeutic options in patients with LABC and In recent publications, it has been reported that both lytic and scle-
locoregional recurrence. In addition to confirming distant meta- rotic bone lesions are identified as well or better than a 99mTc-MDP
static disease, 18F-FDG PET/CT reveals more metastatic sites and bone scan using combined 18F-FDG PET/CT.146–148
18
has an impact on management for a major change in treatment in F-fluoride is a highly sensitive bone-seeking PET tracer used
patients with recurrent breast cancer.143 to detect skeletal abnormalities. It has a high and rapid uptake in

the bone with rapid blood clearance, producing a high bone-to- CT was 73% and 80% in breast cancer, 79% and 73% in lung can-
background ratio in a short time. Uptake of 18F-fluoride is an indi- cer, and 72 and 65% in prostate cancer. Specificity and PPV of
18
cator of blood flow and bone remodeling. The uptake mechanism F-FDG PET/CT were 100% in lung and prostate cancers and
of 18F-fluoride is similar to that of 99mTc-MDP with better pharma- 97% and 96% in breast cancer. Compared to the 99mTc-MDP bone
cokinetic characteristics including faster blood clearance and two- scan, all parameters were superior for 18F-fluoride PET/CT in
fold higher uptake in bone. These pharmacokinetic superiorities prostate and breast cancer but sensitivity and NPV were equal in
combined with the 3D sectioning ability of PET scanner, 18F-fluo- lung cancer. 99mTc-MDP bone scan had superior sensitivity and
ride PET imaging is an attractive alternative to 99mTc-MDP. The NPV compared to 18F-FDG PET/CT but had low specificity and
tracer preferentially accumulates at skeletal metastatic sites PPV.
18
reflecting increased local blood flow, osteoblastic activity, and F-fluoride PET imaging also provides an opportunity to image
bone mineralization. Thus, in contrast to other tracers, 18F-fluo- therapy response with high sensitivity and a rational mechanism
ride images the osseous response to a metastatic focus rather than for quantitative measurement that may provide a clinically useful
the tumor itself. High uptake in comparison with normal bone has method to assess changes in bone turnover as a result of therapy.155
been demonstrated in both lytic and sclerotic breast cancer metas-
tases suggesting that even in predominantly lytic disease 18F-fluo- Whole-Body Bone Scan in the Diagnostic
ride is able to usefully report an accompanying osteoblastic
reaction.148–150 The diagnostic role of 18F-fluoride PET for skeletal
Work-Up of Bone Metastases of Breast Cancer
staging is supported by data from a number of primary cancers Bones are the most common site of breast cancer metastases
including breast cancer, and prospective comparison with the con- either before the initial diagnosis or at any stage during the clini-
ventional bone scan has demonstrated superior diagnostic accu- cal course.144,156–158 Whole-body bone scans are used as a meta-
racy for both individual lesions and whole-patient comparisons in static survey tool in most patients with breast cancer (Fig. 11.5).
metastatic breast cancer.150,151 Techentium-99m methylene diphosphonate (99mTc-MDP) is the
Initial results proved 18F-fluoride PET imaging to be highly most commonly used radiotracer for whole-body bone scanning.

99m
accurate in demonstrating a very early bone reaction when small Tc-MDP bone scintigraphy images the osteoblastic response to
bone marrow metastases were present. This allows accurate bone destruction by tumor cells. Unlike cross-sectional imaging,
detection of breast cancer bone metastases and results in signifi- radionuclide bone scans permit evaluation of the entire skeleton.
cant effect on clinical management, compared with the effect on Despite the high frequency of false-positive uptake in benign
management with conventional bone scan.150 In skeletal metasta- lesions with increased bone turnover, such as fracture or degen-
ses arising from a variety of primary cancers, the diagnostic spec- erative changes, bone scintigraphy has high diagnostic sensitivity
ificity for both lytic and blastic bone diseases has been improved (87% to 88%).159 In experienced hands, with suitable correlative
by combined functional and morphologic evaluation using 18F-flu- imaging protocols, bone scintigraphy can also have good specific-
oride PET/CT.152,153 ity particularly when supplemented with SPECT or SPECT/CT.
Damle et al.154 compared the role of 18F-fluoride PET/CT, 18F- However, malignant skeletal involvement in relapsed breast can-
FDG PET/CT, and 99mTc-MDP bone scans in the detection of bone cer may result in lytic, blastic, or mixed lesions and full evaluation
metastases in patients with breast (72 patients), lung, and pros- typically requires additional morphologic tools to guide clinical
tate carcinomas. The sensitivity and NPV of 18F-fluoride PET/CT management using plain radiographs, CT, and MRI, depending on
was 100% in all three malignancies, whereas that of 18F-FDG PET/ lesion location and clinical context. Although this multimodality
Figure 11.5. Most bone metastases in primary breast

cancers are mixed (lytic and sclerotic) type, but, in a
subgroup of patients, they are only sclerotic. A: A pho-
topenic lesion (red arrow) was clearly seen in the right
lateral margin of the sternum on whole-body bone scin-
tigraphy in a 59-year-old patient with breast cancer.
This patient had undergone right radical mastectomy
4 years earlier because of invasive breast carcinoma
(2.9-cm tumor). The lesion is lytic (red arrow) on CT A B
scan (B).

approach is effective in establishing fracture risk or confirming pretherapy PET scans. A positive correlation was also found
spinal cord compression, its ability to differentiate between active between the histopathologic response and the level of 18F-FDG
and inactive diseases in those receiving treatment remains uptake after the first and second cycles of chemotherapy but
problematic.160 no defined SUV threshold was clearly superior for the
Radionuclide bone scans can be affected by antineoplastic optimal separation of responders and nonresponders during
therapy. An initial increase in osteoblastic activity in responding chemotherapy.
lesions can mimic disease progression on serial bone scans. This In a prospective multicenter trial in which 272 18F-FDG PET
is known as the “flare response” in which known lesions appear scans were performed in 104 patients, it was confirmed that the
more active and previously undetectable lesions become visible.161 greater the reduction in tumor metabolic activity early in the
There is a time lag of up to 6 months from the start of therapy course of therapy, the more likely the patient would achieve a
before reliable assessment of response to therapy using bone histopathologic response.169 In patients who showed a histopatho-
scan. This complexity of assessment has resulted in skeletal dis- logic response, the SUV decreased by 50.5% ± 18.4% (mean ± SD)
ease being generally regarded as nonmeasurable. Detailed corre- after the first cycle of primary chemotherapy; in comparison, the
lation with plain films or CT may improve the ability to SUV decreased by 36.5% ± 20.9% in nonresponders. Patients who
differentiate between responders and nonresponders.162 did not show a histopathologic response were identified with an
NPV of 89.5% after the first cycle of therapy when a relative
decrease in the SUV of less than 45% was used as a cutoff. The
Assessment of Response to NPV after the second cycle of therapy was 88.9% when the cutoff
Antineoplastic Therapy was a 55% decrease in the SUV. A metabolic response after one
cycle of therapy predicted outcomes in patients regardless of
18
F-FDG PET/CT in Monitoring the whether they continued to receive a combination of epirubicin
and paclitaxel or received a planned switch to epirubicin followed
Response to Treatment by paclitaxel. A high NPV is essential for clinical decision making
The concept of using 18F-FDG PET to predict a therapeutic to ensure the continuation of treatment in all patients potentially
response is based on early changes in tumor glucose utilization responding to therapy.169 An important observation from this
and the close correlation of changes in 18F-FDG uptake with the study is that 18F-FDG PET identified patients with low tumor met-
effectiveness of treatment.163,164 There are several potential clini- abolic activity before treatment as not achieving histopathologic
cal applications for the PET-based prediction of a response to response. Twenty-four of 104 breast carcinomas (23%) had a
treatment with primary chemotherapy. First, metabolic imaging baseline SUV of less than 3, and none responded to chemotherapy.
could identify breast cancer with low tumor metabolic activity These tumors were more likely to be well differentiated and estro-
before treatment; patients with such tumors might be more suit- gen receptor (ER) positive. These findings suggest that breast can-
able candidates for surgery or hormone therapy (Figs. 11.3 and cers with low metabolic activity identified by 18F-FDG PET before
11.4). Second, patients for whom PET predicts a poor response treatment are not likely to respond to primary chemotherapy.
after the first cycle of chemotherapy could be switched to alterna- Therefore, for patients with such tumors, it is possible that initial
tive therapies earlier. management should be different; for example, if the tumor is
At least two sequential 18F-FDG PET scans are currently neces- operable, the patient should undergo surgery immediately or per-
sary to predict a treatment response; one is obtained before treat- haps should have primary hormonal therapy.
ment to serve as a baseline, and the other is obtained after the The main rationale for primary chemotherapy is to test chemo-
initiation of chemotherapy; for example, after the first or second sensitivity, allowing for subsequent changes in the chemotherapy
cycle. Some studies confirmed a more pronounced decrease in regimen, with the aim of designing a more individualized treat-
18
F-FDG uptake in patients showing a histopathologic response ment plan. In the trials in which early changes in primary chemo-
than in nonresponders.165–167 therapy were implemented, the clinical response was used to
In an early study by Smith et al.,165 30 breast cancer patients guide treatment decisions.170–172 It is still unclear which patients
received eight cycles of primary chemotherapy. The mean reduc- would benefit most from an early change in treatment, such as a
tion in 18F-FDG uptake after the first cycle was significantly higher switch to a noncross-resistant or second-line chemotherapy regi-
in lesions with a partial, complete macroscopic or complete micro- men because there was no advantage to a change for most nonre-
scopic response than in nonresponding lesions. Dose Schwarz sponders. Nevertheless, patients showing a clinical response to
et al.166 evaluated the use of sequential 18F-FDG PET to predict primary chemotherapy benefited from either the addition of a
response after the first and second cycles of standardized chemo- noncross-resistant chemotherapeutic agent (such as a taxane) or
therapy for metastatic breast cancer. Among a series of 17 meta- prolonged treatment.172,173 For the establishment of therapy mod-
static lesions responded, all responders were correctly identified ifications based on response assessments during chemotherapy, a
after the first cycle of primary chemotherapy by a decrease in the tool more suitable than the clinical response is desirable. Meta-
SUV of greater than 72% compared with the baseline.166 In a more bolic 18F-FDG PET criteria could serve as a method for this pur-
recent report, 64 breast cancer patients underwent 18F-FDG PET pose and thus provide a clinically useful surrogate endpoint.
after the first, second, and third cycles of chemotherapy.167 Rela- There are significant differences between the goals of primary
tive changes in tumor 18F-FDG uptake were superior to alterations systemic therapy of newly diagnosed breast cancer and the goals
in tumor size to monitor treatment response. A decrease in 18F- of treatment of metastatic disease. Generally, a few chemothera-
FDG uptake of 40% predicted a histopathologic response with an peutic regimens are used for primary systemic therapy but many
accuracy of 77% after the first cycle of chemotherapy and 87% palliative treatment options are available for metastatic disease.
after the second cycle.167 Histopathology is used as a surrogate endpoint for the validation
McDermott et al.168 investigated whether there is an optimal of primary chemotherapy, but in most of the patients there are no
method to define tumor volume and an optimal imaging time to tissue specimens available from metastatic breast cancer for the
predict pathologic response in patients with large or locally evaluation of a response.
advanced breast cancers during anthracycline-based chemother- Only a few studies have reported on the clinical utility of
apy. They found that 18F-FDG PET is efficient to predict the patho- sequential 18F-FDG PET in patients with metastatic disease. In a
logic response of most primary breast tumors throughout the study by Gennari et al.,174 a rapid decrease in tumor glucose
duration of a neoadjuvant chemotherapy regimen. This technique, metabolism was observed after the first cycle of therapy in 6 of
however, was ineffective for tumors with low image contrast on 9 responding patients but there was no substantial decrease in

nonresponding patients. Specht et al.175 retrospectively reviewed Novel Agents for Radionuclide
28 patients who underwent serial 18F-FDG PET during systemic Imaging in Breast Cancer
therapy for bone-dominant metastatic breast cancer. The treat-
ments were varied including endocrine therapy, chemotherapy, Molecular characterization of cellular activities in the tumor
biologic therapy, and bisphosphonates. Smaller relative microenvironment with novel agents offers new opportunities for
decreases in the SUV were associated with a shorter time to the diagnosis and treatment of breast cancer. Measurement of key
progression. A patient with no change in the SUV was twice as tumor parameters is possible through molecular imaging that pro-
likely to progress as a patient with a 42% median decrease in vides valuable information on prognosis, optimal therapeutic
the SUV.175 strategies, and response to treatment. Using a variety of probes to
Dose Schwarz et al.176 confirmed previous observations on the study different molecular targets, information obtained from
predictive value of early changes in glucose metabolism in meta- molecular images can also provide anatomic localization of tumor
static breast cancer. Compared with the baseline PET data, the foci.
18
F-FDG uptake in responding metastatic lesions decreased to Recent efforts have focused on developing new PET imaging
72% ± 21% after the first cycle of chemotherapy and to 54% ± 16% tracers to provide specific information on the molecular activities
after the second cycle. By contrast, the 18F-FDG uptake in metas- in the tumor microenvironment including hormone receptor
tases not responding to chemotherapy declined only to 94% ± 19% expression, tumor cell proliferation, membrane phospholipid syn-
after the first cycle of chemotherapy and to 79% ± 9% after the thesis, angiogenesis, apoptosis, and hypoxia. Information obtained
second cycle. 18F-FDG PET correctly predicted the responses in all from imaging studies can help developing targeted anticancer
patients after the first cycle of chemotherapy and was more accu- drugs by identifying patients likely to benefit from such treatment
rate than conventional imaging procedures after the third cycle of by showing the expression of a relevant receptor or protein. Loss
chemotherapy. As discussed earlier, patients would potentially of the cells that previously displayed these targets documents effi-
benefit most from the early identification of ineffective treatments, cacy of treatment and indicates the merits of continuation of ther-
particularly in cases of metastatic breast cancer, because various apy. Clearly, modulation of the imaging target could reflect either

alternative treatment options are available. In addition, patients extermination of the relevant cells or development of resistance
could be spared the toxicity of ineffective treatments.176 In patients through loss of protein expression. Combined assessment using
with metastatic breast cancer, sequential 18F-FDG PET allowed multiple imaging probes is likely to lead to more precise assess-
prediction of response to treatment after the first cycle of chemo- ment of tumor biology and more accurate prognostic stratifica-
therapy. The use of 18F-FDG PET as a surrogate endpoint for mon- tion. Once the target and an appropriate probe are determined,
itoring therapy response has the potential of offering improved molecular therapeutic agents labeled with a radionuclide emitting
patient care by individualizing treatment and avoiding ineffective α- or β-particles can be developed for molecular targeted radionu-
chemotherapy. clide therapy.
The pattern of changes in glucose metabolism depends on
the type of therapeutic agent. For example, a transient increase
Hormone Receptor Imaging
in glucose metabolism followed by a decrease in 18F-FDG uptake
has been observed for tumors responding to hormone therapy Endocrine therapy targeting steroid receptors is still the most
with tamoxifen. Mortimer et al.177 investigated in 40 patients effective form of systemic therapy in breast cancer. Hormone
with biopsy-proved advanced ER-positive breast cancer receptor expression can vary between primary tumor and its
whether 18F-FDG PET and the estrogen analog 16-α-[18F-] recurrent disease in 30% or more of the cases.181–184 Targeting
fluoroestradiol-17-β (FES), performed before and after treat- hormone receptors in breast cancer tissue provides new perspec-
ment with tamoxifen, could be used to detect hormone-induced tive in the diagnostic work-up of these cancers. Investigation of
changes in tumor metabolism (Fig. 11.3) and changes in levels hormone receptors using either radiolabeled analogs or antago-
of ER. nists reveals new information on the biologic behavior of these
The same group of investigators confirmed their initial findings receptors. This information can be exploited for several clinical
in 51 postmenopausal women with advanced ER-positive breast purposes including assessment of response to hormone therapy
cancer using 18F-FES PET and 18F-FDG PET at baseline and repeat as well as providing a basis for developing new antireceptor
18
F-FDG PET after 30 mg estradiol, and found that baseline tumor drugs. Two major hormone receptors, estrogen and progesterone
18
F-FES uptake and metabolic flare after an estradiol challenge receptors (PRs), have been targeted so far, and promising results
were both predictive of responsiveness to endocrine therapy in ER have been reported but the number of human studies and the
positive breast cancer.178 number of subjects in these studies have been limited.
The critical issue in the use of 18F-FDG PET to monitor and Estrogen Receptor Imaging. 16-α-[18F]-fluoro-17-β-estradiol
predict a response to treatment in the setting of metastatic dis- (FES) is a radiolabeled estrogen analog. Its uptake reflects the
ease is the accurate identification of ineffective treatment. For functional status of tumor ER in breast cancer.182–184 Whole-body
example, if a threshold of a 20% decrease in the SUV after the imaging of ER expression with 18F-FES PET can be a valuable
first cycle of therapy is used to identify ineffective therapy, then diagnostic modality when the standard work-up is inconclu-
serial 18F-FDG PET will not identify all nonresponding patients sive.185–189 Dehdashti et al. found interesting correlations between
because some tumors might exhibit an initial decrease at or just the therapeutic response to endocrine treatment and 18F-FES
below this level in 18F-FDG uptake. uptake: Patients who were responding to tamoxifen treatment
The current use of 18F-FDG PET to monitor treatment in breast showed higher initial 18F-FES uptake than nonresponders (and
cancer varies among institutions as well as different practices in also “metabolic flare” phenomenon with 18F-FDG tracers after the
various countries. Generally, baseline 18F-FDG PET before sys- initiation of the therapy).177,186,190,191 Linden et al.192 found similar
temic therapy provides an accurate assessment of the extent of results after 6 months of hormonal treatment (i.e., tamoxifen), but
disease, and 18F-FDG PET approximately 6 weeks after the com- the connection between 18F-FES uptake and response to treat-
pletion of therapy accurately reflects the response to treatment. ment was higher in patients with luminal A molecular subtype
Despite recently published highly encouraging results,131,179,180 (only ER-positive) tumors than with luminar B (both human epi-
prediction of the therapeutic response by 18F-FDG PET after the dermal growth factor receptor 2 [HER2] and ER positive) ones.
first or second cycle of therapy as well as early changes to alterna- With tamoxifen and fulvestran treatment, the eventually detected
tive therapies in patients not showing a metabolic response have decline of 18F-FES caused by the treatment was higher than the
not yet universally accepted and approved. treatment-related decline because of estrogen-depleting aromatase-

inhibitor therapies.193 Despite these promising initial results, clin- protein 90 (HSP 90) inhibitors.209 Despite encouraging results, no
ical confirmation of the diagnostic efficacy is still necessary. definitive conclusion on the clinical role of HER2 imaging has
Progesterone Receptor Imaging. The presence of the PR is been made to date.
associated with increased likelihood of hormone responsiveness
whereas PR-negative tumors are less likely to respond to therapy.
This suggests that the presence of PR is essential for an adequate Tumor Cell Proliferation Imaging
therapeutic response. Furthermore, this relationship between ER 18
F-FDG is a highly sensitive agent to study increased glucose
and PR suggests that the estrogen response pathway may not be metabolism and detection of viable tumor tissues in the body. To
functional in these tumors. measure the exact proliferation of tumors, more specific tracers
21-[18F]-fluoro-16-α-ethyl-19-norprogesterone (FENP) and are also under investigation. Some special tracer molecules are
4-[18F]-fluoropropyl-tanaproget (FPTP) have been developed to currently available to study therapeutic response and tumor pro-
characterize the PR status of breast cancer patients.194 Clinical liferation by measuring the rate of the cell membrane synthesis or
studies with18F-FENP were not successful because of high and increased amino acid and nucleic acid utilization.
rapid metabolism of this tracer but new agents, such as 18F-FPTP, Radionuclide Imaging of Amino Acid Metabolism. The initial
may overcome these difficulties.195,196 Tanaproget is a nonsteroidal model for these molecules was carbon-11 (C-11) methionine,210 an
progestin, binding with high specificity and sensitivity to PRs; thus essential amino acid molecule used by every cell of the human
it is a potentially useful agent for PET imaging. Zhou et al.197 body, especially enhanced protein synthesis in tumor cells. C-11
investigated this agent in in vitro and in vivo studies. Their initial methionine is incorporated into newly synthesized proteins, pav-
results indicated that the use of 18F-FPTP is feasible for PR imaging way to image the increased protein metabolism of cancers. Its
ing.198 Moreover, Dehdashti et al.199 also studied the uptake of uptake correlates with tumor proliferation in patients with breast
21-18F-fluoro-16α,17α-[(R)-(1’-α-furylmethylidene)dioxy]-19-nor- cancer. This can be exploited in the assessment of therapeutic
pregn-4-ene-3,20-dione (FFNP) and obtained promising results response. Initial reports have demonstrated changes in amino
confirming safety and sensitivity to assess PR status of women acid metabolism after anti-neoplastic therapy using C-11 methio-
with newly diagnosed breast cancer. nine PET imaging to assess the response to therapy.211,212
Insulin-like growth factor receptor imaging. Type 1 insulin-like In association with glutamine and glutamate metabolism of the
growth factor receptor (IGF-1R) is a transmembrane tyrosine tumors, the cystine/glutamate exchanger (xCtransporter, xCT) is
kinase receptor which plays an important role in signaling cell also a potential target for radiotracer imaging. Koglin et al.213
survival and proliferation. Preliminary studies showed that IGF- found excellent tumor visualization and high tumor-to-background
1R–targeted therapy in breast cancer can be potentially monitored ratios using (4S)-4-(3-[18F]fluoropropyl)-L-glutamate (BAY 94–9392,
by radionuclide imaging of IGF-1R expression.188,189 also named 18F-FSPG) in preclinical tumor models. Baek et al.214
successfully studied 18F-FSPG in the detection of breast tumors.
Human Epidermal Growth Factor The number of patients (n = 5), however, is small, limiting the
value of these results. 18F-FSPG has also been evaluated to quan-
Receptor 2 Imaging tify glutathione-based drug resistance and oxidative stress-
HER2 is a protein involved in tumor cell survival, proliferation, induced signaling pathways in which system xCT plays an
maturation, metastasis, and angiogenesis, and has antiapoptotic important role by exchanging and transporting cysteine to the
effects. Overexpression of HER2, the result of the HER2 gene cell.214
amplification, is present in 25% to 30% of breast cancer Radionuclide Imaging of DNA Synthesis. Radiolabeled pyrimi-
patients.200,201 The expression of HER2 is regulated by signaling dine analogs such as carbon-11 (C-11) thymidine and 18F-fluoro-
through ERs. Trastuzumab is a recombinant IgG1 monoclonal deoxy-L-thymidine (18F FLT) have been used to study DNA
antibody targeting the extracellular domain of HER2. It is widely synthesis, cellular proliferation rate, and enhanced nucleic acid
used clinically in patients with HER2 overexpressing breast can- utilization in tumor cells. Because of the limited availability of
cer. Trastuzumab is cardiotoxic and expensive and therefore C-11, thymidine PET imaging using C-11 has not attracted signifi-
should be restricted to HER2-positive breast cancers only. HER2 cant interest. 18F-FLT PET imaging, however, was found to be suit-
tumor expression can vary during treatment and can differ in able for the visualization of breast cancers and assessment of the
metastatic lesions within a patient.202–205 Methods that are able to early response after chemotherapy.215,216 18F-FLT uptake was seen
assess the HER2 status noninvasively would be helpful for deci- in 8 out of 10 primary breast tumors and some large axillary
sion making within antineoplastic therapy protocols. HER2 testing lymph node metastases but small axillary lymph node metastases
using radionuclide imaging can potentially be helpful to assess were not detected.216 In another report, slightly better results were
noninvasively the HER2 status in vivo. seen in 12 patients where 13 out of 14 primary breast tumors and
Currently available HER2-targeted ligands include full-length 7 out of 8 axillary lymph node metastases could be detected.217 Pio
monoclonal antibodies, Fab fragments, F(ab)2 fragments, diabod- et al.218 showed that 18F-FLT PET imaging was a reliable imaging
ies, minibodies, affibodies, scFv-Fc, and peptides. Full-length HER2 method to assess early response after one cycle of chemotherapy.
monoclonal antibodies have been labeled with iodine-131 (131I), They also found that 18F-FLT imaging correlates with long-term
indium-111 (111In), and 99mTc for HER2 SPECT imaging, and efficacy of antineoplastic therapy by showing correlation with the
iodine-124 (124I), yttrium-86 (86Y), bromine-76 (76Br) and zirco- late changes of tumor markers. Lubberink et al.219 compared the
nium-89 (89Zr) for HER2 PET imaging. The smaller HER2-targeting effectiveness of tumor-to-whole blood ratio (TBR) measurements
antibody fragments, proteins, and peptides were also labeled with with the semiquantitative SUV results in locally advanced breast
131
I, 111In, and 99mTc for HER2 SPECT imaging and with 18F, cancer patients treated with neoadjuvant chemotherapy.
gallium-68 (68Ga), copper-64 (64Cu), 124I, and 76Br for HER2 PET.206 18
F-FDG and 18F-FLT PET imaging for the assessment of tumor
Perik et al.207 performed 111In-labeled trastuzumab planar scin- response to chemotherapy were compared in 14 patients with pri-
tigraphy and SPECT in 15 HER2-positive metastatic breast cancer mary or metastatic breast cancer.218 A strong correlation was
patients. Forty five percent of single tumor lesions were shown found between the percentage decrease in 18F-FLT tumor uptake
and new tumor lesions seen on PET imaging using Zr-89 trastu- 2 weeks after initiation of chemotherapy and late size changes as
zumab.208 Preliminary data showed excellent tumor uptake and determined by CT scan. No correlation was found between 18F-
successful detection of HER2-positive breast cancer metastases FDG uptake changes over the first 2 weeks and late size measure-
noninvasively. HER2 PET imaging may also be useful for the eval- ments.218 Similar results were obtained when 18F-FLT PET was
uation of HER2 downregulating therapies including heat shock performed 1 week after initiation of chemotherapy.219 These

results suggest that 18F-FLT PET may be useful to predict response clearly identified. 18F-galacto RGD PET represents a combination
to therapy in breast cancer patients but further investigations are of tracer binding to activated endothelial cells and tumor cells
needed to validate the clinical utility in larger groups of patients. expressing variable levels of αυβ3 integrin.229
Phospholipid Synthesis Imaging. C-11 choline PET imaging
has been investigated in breast cancer to detect clinically aggres-
sive tumor phenotypes in patients with ER-positive breast cancer;
Apoptosis Imaging
the tumor-to-background ratio was high and the choline uptake There are two principle methods of cell death in tumor cells; immedi-
correlated well with tumor grade.220 These results were confirmed ate cell death (necrosis) or programmed delayed cell death (apopto-
by Kenny et al.221 who showed that tumor response to trastu- sis). Cell division and cell destruction are in balance in the majority
zumab therapy could be early assessed by C-11 choline PET imag- of tumors; but in some tumors, failure of cell destruction can occur
ing only after 1 month following antineoplastic treatment. leading to cell immortality and growth of the cancer. Most effective
Contractor et al.222 also found significant correlation between cancer treatments including radiation therapy and chemotherapy
tumor proliferation and choline uptake on PET scans. C-11 cho- involve the induction of apoptosis. Once this process has started, it is
line uptake was also correlated with the proliferation measured irreversible and cell death in about 10 days is inevitable.230
by 18F-fluoro-thymidine PET. Tateishi et al.223 also examined the Annexin imaging. During apoptosis, there is blebbing of the
correlation between FDG uptake and C-11 choline uptake in affected cell wall surface and reversal of some components of the
breast cancer patients. Although C-11 choline showed higher cell membrane. This results in some antigens such as membrane-
specificity for the detection of aggressive disease, both FDG and associated phosphatidylserine (PS) being exposed to annexin V, a
choline had similar uptake profile.223 naturally occurring human protein. Annexin V binds avidly to PS
which is normally found only on the inner leaflet of the cell mem-
brane double layer. PS is actively transported to the outer layer as
Angiogenesis Imaging an early event in apoptosis and becomes available for annexin
Angiogenesis is the physiologic process of new blood vessel for- binding. Annexin also gains access to PS as a result of the mem-

mation which is the key index for tumor growth. It should there- brane fragmentation associated with necrosis.
fore be a potential target for PET imaging. Annexin V has been labeled with both single photon and posi-
VEGF-receptor. VEGF is an important downstream protein pro- tron emitting radionuclides. Initial studies showed that pro-
duced as a result of multiple processes including hypoxia, activa- grammed cell death caused by radiation and chemotherapy using
99m
tion of growth factor receptors (EGFR, HER2), and intracellular Tc EC-annexin could be quantified in vitro and in vivo.231 It was
proteins (HIF-1a, mTOR etc.). Radiolabeled anti-VEGF and Fab demonstrated in an animal model that 18F-annexin-V PET imag-
fragments were studied with the aim of antiangiogenesis imaging. ing accurately measures the internal levels of apoptosis noninva-
Imaging of VEGF using specific tracers is of great interest to select sively with high image contrast between healthy and dying tissues
patients who could benefit from VEGF-targeted therapies, and to within 1 hour after injection of 18F-annexin V.232 Its potential role
assess the response to new treatment regimes. Several radiola- in breast cancer management has not yet been fully discovered.
beled probes including anti-VEGF antibodies and Fab fragments
have been investigated for the development of VEGF imaging
probes.224 In metastatic breast cancer, the addition of bevaci-
Hypoxia Imaging
zumab, a humanized monoclonal antibody which neutralizes all There are two types of tumor hypoxia; chronic and acute.233
isoforms of VEGF-A, to paclitaxel leads to an increased response Chronic (diffusion-limited) hypoxia is defined as cells exposed to
rate and increased progression-free survival.225 low-oxygen levels for longer than 24 hours, which frequently
Increased vascularization is present in all preinvasive lesions, occurs in poorly vascularized regions. Acute (perfusion-limited)
ductal as well as lobular, and increases with lesion severity. Also, hypoxia involves transient exposure of cells to hypoxia, ranging
immunohistochemically determined VEGF expression in normal from minutes up to 24 hours. This typically involves cells located
glandular structures is lower than malignant lesions, with the near capillaries exhibiting transitory interruptions in blood flow
highest levels found in ductal lesions.226 The presence of high (e.g., as a result of functional changes in vascular stability). Tumors
VEGF levels in the extracellular matrix can increase the tumor with high hypoxic volumes tend to have a poor prognosis as they
uptake and may well make detection of small lesions possible. are associated with an aggressive phenotype and increased risk of
More efforts are needed to assess the usefulness of radionuclide metastasis,234 and often respond poorly to radiotherapy and/or
imaging of VEGF probes in the management of breast cancer. chemotherapy.235 Approximately 25% to 40% of all invasive breast
Integrin Imaging. Integrins are transmembrane receptors cancers contain hypoxic regions.236,237 Preclinical studies have
which are important in the cell-to-cell interactions. It was shown reported correlation between 18F-FDG uptake and tumor hypoxia
that αυβ3 integrin is strongly related to tumor angiogenesis, and detected with pimonidazole or 18F-fluoromisonidazole (18F-FMISO),
it is overexpressed on both endothelial and tumor cells in breast a PET tracer designed to identify hypoxic cells. Initial clinical stud-
cancer. Integrin imaging originally based on the use of arginine– ies have confirmed the correlation between FDG and FMISO
glycine–aspartic acid (RGD)-based radioligands. McParland et al.227 retention.238–241 In a recent study, 18F-FMISO PET/CT showed that
tested first the [18F]-fluciclatide, also named [18F]-AH111585 tumor-to-background ratio at 4 hours ≥1.2 is an optimal cutoff
(AH111585 is a cyclic peptide containing RGD motif that binds that highly suggests resistance to hormonal therapy.242
directly to integrin receptors such as αυβ3 with high affinity) in
healthy volunteers to assess the safety and biodistribution of inte-
grin tracers.They found that [18F]-AH111585 is a safe PET tracer Conclusion
with a dosimetry profile comparable to other common 18F-PET
tracers. High 18F-galacto-arginine–glycine–aspartic acid (18F-galacto) 99m
Tc-sestamibi breast scintigraphy and 18F-FDG PET imaging are
RGD uptake was found in lesions of squamous cell cancer of the two main radionuclide methods widely investigated in the diag-
head and neck, melanoma, breast cancer, osteosarcoma, and soft nostic work-up of primary breast cancer. Recent technical refine-
tissue sarcoma with a significant correlation of αυβ3 integrin ments including the development of small FOV imaging devices
expression.228 Beer et al.229 examined the tumor uptake of αυβ3- (MBI, BSGI, PEM) have improved the diagnostic performance of
selective PET tracer 18F-galacto RGD in 16 patients with primary gamma cameras and PET scanners. Low specificity, failure to
tumors (primary tumor in 12 and metastatic breast cancer in 4 detect small lesions, and high radiation burden are three main
patients), and found that all primary tumors and metastases were problems associated with current techniques of radionuclide

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C h apt e r 1 2
Pulmonary Carcinoma
Pietro Muto • Maria Luisa De Rimini • Cinzia Landolfi • Abdul Jalil Nordin
Introduction is the most prevalent form of lung cancer in younger men (<50 years)
and in women of all ages, in never-smokers, and in former smokers.
Lung cancer continues to rank first in mortality statistics in many Lung neuroendocrine tumors (NETs) present as well-differenti-
areas of the world. Although there has been a decrease in the over- ated tumors in 80% to 90% of cases. They rarely metastasize (5%
all lung cancer burden in the United States and the rest of the to 20%). Less frequently, they present as atypical forms with poorer
world, reflecting the success of preventive strategies, it remains a prognosis (5-year survival of 44% to 78% versus 87% to 89% for
critical public health problem in much of the developed world. The typical forms).8
epidemiology of lung cancer consistently reinforces a major theme:
Lung cancer is a consequence of the widespread addiction to ciga-
rette smoking throughout the world, although there has been some
success recently in reduction of exposure to occupational carcino-
Histology
gens in developed countries.
The majority of lung cancers usually present as a peripheral lung
nodule or mass; 80% are NSCLC; the remaining 20% are small cell
lung cancer (SCLC).5 The new World Health Organization (WHO)
Epidemiology classification of lung tumors is summarized in Tables 12.1 and 12.2.

Lung cancer is the leading cause of cancer deaths in the United
States, with an estimated 222,520 new cases and 157,300 deaths
expected to be reported in 2010—approximately 28% of all cancer
deaths.1. Although tobacco smoking is widely known as a causative Tab l e 1 2 . 1
agent, there are other causes as well, some acting synergistically to
increase risk. For example, the radioactive gas radon in indoor envi- World Health Organization/International
ronments is now considered as the second leading cause of lung Association for the study of Lung Cancer
cancer in the United States. The list of human occupational causes Classification of Lung Cancer
of lung cancer includes arsenic, asbestos, chromates, chloromethyl
ethers, nickel, polycyclic aromatic hydrocarbons, radon progeny, Malignant epithelial tumors Papillary
and other agents.2 For many of the worker groups exposed to these Clear cell
agents, there are substantial increments in risk. The risk of devel- Small cell
oping lung cancer increases with increased exposure to asbestos Squamous cell carcinoma Basaloid
either directly, as a carcinogen, or through indirect mechanisms, Small cell carcinoma Combined small cell carcinoma
such as causing chronic inflammation that has been linked to can- Adenocarcinoma Adenocarcinoma, mixed subtype
cer.3 Cigarette smoking may increase the lung cancer risk associ- Acinar adenocarcinoma
Papillary adenocarcinoma
ated with asbestos exposure by enhancing the retention of asbestos
Bronchoalveolar carcinoma
fibers.4 Nonmucinous
“Traditional” epidemiologic approaches have conclusively estab- Mucinous
lished the carcinogenicity of tobacco smoke, and molecular epide- Mixed or indeterminate
miology has characterized the sequence of molecular and cellular Solid adenocarcinoma with mucin
changes as a nonmalignant cell becomes malignant. Genetic factors Fetal adenocarcinoma
have been identified that may determine susceptibility to tobacco Mucinous “colloid” carcinoma
smoke. Lung cancer is now also a major women’s health issue. As Mucinous cystadenocarcinoma
a result of historical cigarette smoking patterns, the epidemic of Signet ring adenocarcinoma
lung cancer started later in women than in men. The rate of lung Clear cell adenocarcinoma
cancer among women has substantially increased over the past two Large cell carcinoma Large cell neuroendocrine carcinoma
decades and is only now starting to plateau. Combined large cell neuroendocrine carcinoma
Basaloid carcinoma
The prevalence of the various histologic subtypes of non–small
Lymphoepithelioma-like carcinoma
cell lung cancer (NSCLC) has changed in recent decades.5 The his-
Clear cell carcinoma
tologic characteristics of lung cancer in developed countries, includ- Large cell carcinoma with rhabdoid phenotype
ing the United States, have also changed in the past few decades Adenosquamous carcinoma
such that the frequency of adenocarcinoma has risen and that of Sarcomatoid carcinoma Pleomorphic carcinoma
squamous cell carcinoma has declined. According to Surveillance, Spindle cell carcinoma
Epidemiology, and End Results Program data collected from 2002 Giant cell carcinoma
to 2006, adenocarcinoma accounts for 43% of NSCLC, squamous Carcinosarcoma
cell carcinoma accounts for 23%, and the remaining 34%, other Pulmonary blastoma
unspecified subtypes.6 In contrast, the database used for the origi- Carcinoid tumors Typical carcinoid
nal tumor, node, metastasis (TNM) staging manual contained 1,712 Atypical carcinoid
cases of NSCLC, of which 30% (521 cases) were adenocarcinoma Salivary gland tumors Mucoepidermoid carcinoma
and 58% (996 cases) were squamous cell carcinoma; the majority Adenoid cystic carcinoma
of these patients were men. Differences in tobacco smoking habits Epithelial–myoepithelial carcinoma
(filters, light tobacco cigarettes, profound inhalation) seem to favor
Adapted from: Travis WD, Brambilla E, Muller-Hermelink HK, et al., eds. Pathology and Genetics
the development of distal bronchiolar and alveolar carcinogenesis at of Tumours of the Lung, Pleura, Thymus and Heart. World Health Organization Classification of
the expense of proximal squamous cell carcinoma.7 Adenocarcinoma Tumors. Lyon, France: IARC Press; 2004, p. 10.
153

Table 12.2 transcription factor 1, which is an adverse prognostic marker for

the likelihood of metastases.
2011 International Lung Adenocarcinoma NETs have several histologic subtypes, from low grade, typical
Histopathologic Classification (Bronchoalveolar carcinoid to intermediate atypical carcinoid, to high-grade large cell
Carcinoma)a neuroendocrine carcinoma and small cell lung carcinoma. These
subclassifications have a strong prognostic significance in terms of
Histopathologic Computed Tomography survival. The diagnosis of neuroendocrine carcinoma requires at
Findings Findings least one specific immunohistochemical marker.16,17 The category of
SCLC is limited to tumors with pure SCLC histology. Any tumor mass
Adenocarcinoma A small (<3 cm), nonin- Nonsolid with at least 10% of SCLC is called SCLC combined. Although the
in situ vasive lepidic growth TNM descriptors are not commonly used in clinical practice to stage
Minimally invasive A small (<3 cm) and Mainly nonsolid, may have a SCLC, the current (seventh) edition of the TNM staging system sug-
adenocarcinoma predominantly lepidic central solid component of gests its use for NSCLC as well as SCLC, because increasing stage
growth that has 5-mm up to approximately 5 mm correlates with decreased survival times in patients with either
or smaller invasion tumor.18 SCLC is distinct from the more common NSCLC because of
Lepidic, predominant Invasive adenocarcinoma Usually part solid but may be its rapid doubling time, high growth fraction, early development of
nonmucinous with predominantly nonsolid or occasionally widespread metastases, and dramatic initial response to chemo-
adenocarcinoma lepidic nonmucinous have cystic components
therapy and radiation.19 Despite high initial frequency of responses
growth
Invasive mucinous Lepidic growth as its Varies widely from solid to to therapy, most patients die of recurrent disease.
adenocarcinoma predominant mostly solid to part solid to Large cell carcinoma and NETs include other rare tumor types
component nonsolid; may be single or such as lymphoepithelioma-like carcinoma, clear cell carcinoma,
multiple (when multifocal, and large cell carcinoma with rhabdoid phenotype. Basaloid carci-
formerly called multicentric noma is a variant of large cell carcinoma presenting with relatively
bronchoalveolar carcinoma) small cells, forming a lobular pattern with a high rate of mitosis. It
a
is also known as giant cell carcinoma and clear cell carcinoma.
Obtained to overcome the previous bronchoalveolar carcinoma, several subcategories of varying NSCLC and basaloid carcinomas may display neuroendocrine his-
histopathologic, radiologic, and prognostic clinical importance.
Adapted from: Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of tochemical markers. Apart from morphologic appearance, the pres-
Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary ence of cytokeratins can differentiate basaloid tumors from large
classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244–285. cell neuroendocrine carcinoma.
Carcinoma with pleomorphic or sarcomatous elements is poorly
differentiated NSCLC containing sarcoma or sarcoma-like elements.
An international tumor classification system for lung cancer is They are rare tumors, and their classification depends on the pres-
necessary for consistency in applying treatment protocols. The ence of cytokeratin expression.
WHO/International Association for the Study of Lung Cancer (WHO/
IASLC) classification is based on the histologic appearance on light
microscopy.9,10 In considering therapeutic approaches, lung cancer TNM-7 Staging System
is generally divided into SCLC and NSCLC.11 To minimize the num-
ber of unclassified lesions, immunohistochemistry and electron The seventh edition of TNM classification on cancer staging by the
microscopy findings are also used in the system to classify or sub- joint committee of the American Joint Committee on Cancer (AJCC)
classify lung tumors from surgical or needle biopsy. and International Union Against Cancer (UICC) has made recom-
Atypical adenomatous hyperplasia (AAH) has been regarded as mendations for the classification of NSCLC, SCLC, and carcinoid
a precursor of adenocarcinoma, mainly based on the fact that it is tumors of the lungs.20 Sarcomas and other rare tumors are not
often found near or within the same adenocarcinoma site. AAH included. The T-stage has been redefined in this edition (Table 12.3).
is also a known precursor for nonmucinous bronchoalveolar carci-
noma (BAC). It is not present, however, in every patient with adeno- Tab l e 1 2 . 3
carcinoma. It is found in 2% of young individuals without cancer
and in up to 23% in those with cancer. AAH is defined as an atypical Summary of Changes in the Seventh TNM
proliferation of minimally atypical cuboidal cell type II pneumo- Classification
cytes, measuring <5 mm. Lesions can be further defined as mild,
moderate, or severe dysplasia on the basis of severity according to This staging system is now recommended for the classification of both non–small
the thickness, anisocytosis, and pleomorphism, with little matura- cell lung cancer and small cell lung cancer and for carcinoid tumors of the lung.
tion and abnormally oriented nuclei. Further changes involving full The T classifications have been redefined:
thickness are seen in carcinoma in situ. Atypical alveolar hyperpla- • T1 has been subclassified into T1a (<2 cm) and T1b (>2–3 cm)
sia and diffuse idiopathic pulmonary neuroendocrine cell hyperpla- • T2 has been subclassified into T2a (>3–5 cm) and T2b (>5–7 cm)
sia are associated with changes in the bronchoalveolar epithelium. • T2 (>7 cm) has been reclassified as T3
• Multiple tumor nodules in the same lobe have been reclassified from T4 to T3
As stated, adenocarcinoma is the most common form of lung
• Multiple tumor nodules in the same lung but in a different lobe have been
cancer.12–15 Histologically, this tumor is highly heterogeneous with a reclassified from M1 to T4
mixed pattern leading to difficulty in classification. Adenocarci- No changes have been made to the N classification. However, a new international
noma of mixed type with a predominantly bronchoalveolar pattern lymph node map defining the anatomical boundaries for lymph node stations has
is categorized as BAC. Nonmucinous-type BAC usually presents been developed (Mountain CF, Dresler CM. Regional lymph node classification for
as a solitary nodule. Clinically, it has a good prognosis, whereas lung cancer staging. Chest. 1997;111:1718–1723).
mucinous-type BAC tends to spread and form satellite tumors with The M classifications have been redefined:
consolidation and a poor clinical prognosis. • M1 has been subdivided into M1a and M1b
There are several variants of adenocarcinoma in the new WHO/ • Malignant pleural and pericardial effusions have been reclassified from T4 to M1a
• Separate tumor nodules in the contralateral lung are considered M1a
IASLC classification system, including well-differentiated fetal ade-
• M1b designates distant metastases
nocarcinoma, colloid carcinoma, mucinous cystadenocarcinoma,
signet ring adenocarcinoma, and clear cell adenocarcinoma. Eighty- Adapted from: Edge S, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed.
five percent of primary lung adenocarcinomas express thyroid Springer; 2010:253–270.

Chapter 12 Pulmonary Carcinoma 155
Findings with a diameter smaller than 30 mm are defined radio- alkaloids, epipodophyllotoxins, colchicine, and actinomycin D) accu-
logically as nodules, whereas those with a diameter greater than mulation. It also recognizes 99mTc-MIBI, with its lipophilic cationic
30 mm are defined as masses. Both pose challenges for the diagnosis properties, as a suitable transport substrate. It is now known that
99m
of lung cancer. No changes have been made to the N-stage classifica- Tc-MIBI is excluded from the cytosol against its concentration
tion, but the M-stage has also been redefined. gradient via the Pgp mechanism. Piwnica-Worms et al. have
On computed tomography (CT) examination, lymph nodes mea- reported that 201Tl is not recognized as a substrate by Pgp. Decreased
suring 1 cm or more in the short axis are considered significant in uptake of 99mTc-MIBI on scintigraphy is important from the clinical
size and suspicious for metastatic disease, although the predictive point of view.28 Imaging Pgp expression by scintigraphy with 99mTc-
accuracy of this criterion is limited. Two lymph node maps are cur- MIBI is an example of functional imaging. This information is in
rently in use: The Naruke map, which is used by the Japanese Lung combination with the fact that a patient will fail to respond to che-
Cancer Society, and the Mountain–Dresler—American Thoracic motherapy after the first cycle (such failure is observed in 15% of
Society map.21,22 To reconcile the differences between these two patients with SCLC).29 This implies the presence of Pgp-mediated
systems, existing nodal stations have been grouped into six ana- MDR in the tumor that limits 99mTc-MIBI concentration by acting as
tomic zones: Upper, aortopulmonary, subcarinal; lower, hilar, and an efflux pump. The absence of 99mTc-MIBI uptake on scintigraphy
peripheral. The hilar and peripheral zones represent N1 disease, may have an impact on the selection of the therapy, necessitating
and the upper, aortopulmonary, subcarinal, and lower zones repre- a more aggressive protocol or the augmentation of response by
sent N2 disease. Lymph nodes on the side opposite the primary involving radiotherapy. In summary, 99mTc-MIBI scintigraphy may
tumor, and all significantly large lymph nodes in the ipsilateral or be utilized to monitor “acquired” drug resistance induced by che-
contralateral supraclavicular or scalene regions, are considered motherapy. However, 99mTc-MIBI uptake in a tumor in the absence
stage N3 disease. In recent years, nodal skip metastases, particu- of MDR1 expression does not necessarily indicate that a cancer is
larly the presence of N2 disease in the absence of N1 disease, are sensitive to drugs associated with the MDR phenotype because there
thought to occur most frequently in the presence of upper lobe are various other mechanisms for resistance to multiple drugs, for
tumors and are reported to have a more favorable outcome.23,24 example, changes in the activity of enzymes such as glutathione

Nearly one-half of newly diagnosed lung cancers already have S-transferase (which is involved in glutathione detoxification) or
metastasized to the lung, brain, liver, adrenal gland, and osseous alterations in topoisomerase II. Resistance also can be induced by
structures. Any metastatic disease is automatically designated stage overexpression of multidrug resistance-associated protein (MRP
IV disease and, with a few exceptions, is surgically unresectable. 190 kDa) in multidrug-resistant cell lines derived from SCLCs, but
Because of differences in prognosis, the M category is now subcatego- a direct interaction between MRP and drugs or 99mTc-MIBI as a sub-
rized into intrathoracic metastasis (M1a) and disseminated disease strate has not been demonstrated.30 Prospective studies are being
involving extrathoracic spread (M1b), with the former having a better conducted to determine the significance of scintigraphic imaging of
prognosis.25 Stage M1a disease includes malignant pleural effusions, Pgp expression in tumors to predict the response to therapy.
pleural dissemination, pericardial disease, and pulmonary nodules in
the contralateral lung. Stage M1b disease involves spread to the liver,
18
adrenal gland, brain, bone, and other locations away from the chest. F-FDG PET And PET/CT
Malignant pericardial and pleural diseases are now considered to be
metastatic (M1a) disease, rather than stage T4 disease.26 Traditionally, imaging modalities such as CT and positron emission
In patients with low T-stage tumors and N0 disease, skip metas- tomography (PET) have been applied sequentially in the diagnosis,
tases are reported as synchronous cerebral metastases.24 staging of disease, and monitoring the effects of therapy. Neverthe-
less, the use of separately acquired CT and 18F-fluorodeoxyglucose
(18F-FDG) PET interferes with lesion characterization. Since their
Using Radiotracers to Image introduction in 2001, PET/CT systems have gained wide acceptance
primarily because of their inherent ability to combine functional and
Lung Carcinomas structural information about the underlying disease state of the
patient in a single imaging session. The combined imaging tech-
Historically, a fair number of nonspecific tracers have been used in nique has the advantage of shorter total imaging time, which reduces
nuclear medicine to image lung cancer of all types. 67Gallium (Ga) patient anxiety and image blurring because of patient motion. PET/CT
is taken up by more than 90% of lung cancers but is of limited systems have replaced dedicated PET systems as the imaging
value in lesion characterization because it does not distinguish modality of choice for the diagnostic evaluation of oncology patients
malignant pulmonary masses from benign inflammatory processes. in general. The use of the glucose analog, 18F-FDG, reports cellular
201
Thallium chloride (TlCl), a cardiac potassium analog imaging processes in tumors such as glucose metabolism with precise ana-
agent, has been used to investigate lung lesions, with similar non- tomical localization when acquired on a PET/CT instrument. The
specificity. Since the late 1980s, when technetium-99m-labeled extensive implementation of 18F-FDG PET/CT has allowed more
methoxyisobutyl isonitrile (99mTc-MIBI) was introduced as a myo- accurate detection of both nodal and distant forms of metastatic
cardial imaging agent, there have been many descriptions of 99mTc- disease.31 Other PET radiopharmaceuticals also show remarkable
MIBI uptake in tumors, including lung and breast adenocarcinoma, potential in management of patients with malignant tumors.
18
lymphoma, mediastinal and pulmonary metastases from thyroid F-FDG is a glucose analog in which the oxygen atom at carbon
cancer, peripheral soft tissue and bone sarcomas, as well as undif- number 2 is replaced by the radionuclide fluorine-18. 18F-FDG enters
ferentiated mesenchymal tumors.27 99mTc-MIBI accumulates within cells and is then phosphorylated to glucose-6-phosphate by mito-
mitochondria and the cytoplasm of cells on the basis of transmem- chondrial enzymes that are increased in rapidly growing malignant
brane electrical potentials. Since malignant tumors maintain a tumors. Metabolism beyond the fluorodeoxyglucose-6-phosphate
more negative transmembrane potential because of their increased step does not occur because the altered molecule is an unsatisfactory
metabolic requirements, there is an increased accumulation of substrate for the enzymatic processes beyond that point.
MIBI in malignant tumors. Initially, it was thought that 99mTc-MIBI In addition to imaging the relative glucose metabolism and local-
uptake, like that of 201thallium (Tl), is a reflection of blood flow, viabil- izing it to anatomic structures, PET/CT has the additional advantage
ity, and tumor mitochondrial activity. In cell cultures, P-glycoprotein of attenuation correction of the PET signal (Fig. 12.1A and B), ren-
(Pgp), a 170-kDa cytoplasmic membrane protein encoded by the dering PET/CT capable of quantitative imaging. The new integrated
MDR (multiple drug resistance) gene, has been identified. This system is capable in delivering higher quality images with improved
protein results in decreased cytotoxic drug (anthracyclines, vinca resolution.

Figure 12.1. Coronal, sagittal, and axial views (left to right) of PET images in grayscale showing uncorrected images (top row ) and attenuation-corrected
images (bottom row ). These demonstrate poor resolution of the nonattenuation-corrected image (A) and improved resolution and normalization of the attenuation-
corrected image (B) using CT parameters. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
The widely recommended protocol for a PET study is the intra- more time to complete the base of skull and thigh protocol as com-
venous injection of 370 to 740 MBq (10 to 20 mCi) of 18F-FDG (for pared with shorter individuals. This recommended technique is
an adult patient) after obtaining a fasting blood sugar to confirm adopted with minor variation from one institution to another
that the blood glucose level is at an acceptable level to proceed. depending on camera specification and workload.
Specific recommendations, precautions, and potential sources of
error for PET or PET/CT scans are provided in Tables 12.4 and Implication of 18F-FDG PET/CT for the
12.5. Prior to intravenous administration of the radiotracer, the
weight of the patient should also be recorded. These essential
Radiation Dose
parameters are important for the accurate calculation of the stan- The eyes to thigh protocol during PET/CT examinations incurs an
dardized uptake value (SUV), a recognized method to semi-quantify increased patient exposure compared with an individual CT or
the tumor glucose metabolic rate. PET/CT image acquisition usu- PET examination. Recent advances in CT equipment provide high-
ally starts 45-minute post injection to ensure good FDG uptake and resolution imaging of smaller anatomical structures but resulting
distribution in the body. Image acquisition starts with a low-dose in higher radiation dose delivered to the patients. Increasing con-
CT scanogram to plan the study. For patients being evaluated for cern over radiation dose has been addressed by vendors through
potential or proven lung malignancy, this is followed by a CT scan technical improvement of x-ray tubes.
examination from base of skull to thigh. Subsequently, PET study The average effective patient dose from whole-body 18F-FDG
will commence. PET images are acquired in two-dimensional (2D) PET/CT examinations is approximately 25 mSv regardless of the
or three-dimensional (3D) mode with 2 to 3 minutes per bed posi- acquisition protocol used. Although whole-body PET/CT scanning
tion ending with 5 to 7 bed positions, depending on the dose has improved accuracy in clinical staging and treatment monitoring
administered and size of the patient. Tall patients may require of patients with lung cancer, the technique is also accompanied by

Ta b l e 1 2 . 4
18
F-FDG PET/CTa
Recommended activity Adults: 370–740 MBq (10–20 mCi)

Administration Intravenous
Patient preparation
Before arrival Patients are not allowed to consume any food or sugar for at least 6 h before FDG injection (e.g., for a
morning PET study, do not eat after midnight and preferably have a light meal—no alcohol—during
the evening before the study; for afternoon PET, a light breakfast before 8.00 am).
All patients must avoid extreme exercise for at least 6 h before the PET study to minimize muscle FDG
accumulation. Medication can be taken as prescribed.
Before injection It is good practice to check the patient’s blood glucose level (BGL) on arrival (not too low or high). Most
institutions reschedule the patient if the BGL is >150–200 mg/dL. Reducing the BGL by administering
insulin can be considered, but 18F-FDG administration should be delayed after insulin.
Adequate prehydration is important to ensure a sufficiently low FDG concentration in urine (fewer arti-
facts and for radiation safety, e.g., 1 L of water in 2 h before injection). In addition, the infusion used
to administer intravenous prehydration must not contain any glucose.
Parental nutrition and intravenous fluids containing glucose should be discontinued at least 4 h before
the PET/CT examination.
During the FDG injection and the subsequent uptake phase, the patient should remain seated or
recumbent and silent to minimize FDG uptake in muscles.
18
F-FDG brain PET: Injection should take place in a darkened and quiet room, and the patient should stay
there for the subsequent uptake phase to avoid areas of enhanced uptake because of brain activation.

The patient should be kept warm starting at 30–60 min before FDG injection and throughout the
following uptake period, to minimize FDG accumulation in the brown fat (especially relevant if the
room is air conditioned).
Recommendations for Type 2 DM controlled by oral medication
patients with diabe- • Preferably perform the PET study late in the morning
tes mellitus (DM) • Fasting rules indicated above
• Continue oral medication to control the patient’s BGL
Type 1 DM and insulin-dependent type 2 DM
• Ideally, it is suggested to make an attempt to achieve normal BGL before the PET study
• The PET study should be scheduled for late morning
(e.g., normal breakfast at 7.00 am); inject the normal amount of insulin; thereafter, only prescribed
amount of water
In case of continuous insulin infusion, scheduled, if possible, the PET study early in the morning.
The insulin pump is kept on the “night setting” until after the PET study. The patient can have break-
fast after the PET study. There is no reason for routine administration of sedatives.
• FDG PET study can be performed if BGL <7 mmol/L (or <120 mg/dL)
• FDG PET study must be rescheduled if BGL >7 mmol/L (or >120 mg/dL)
Pregnancy (suspected or confirmed):
A clinical decision is necessary considering the benefits against the possible harm of carrying out any
procedureb
CT scan The effective CT dose could range from 1 to 20 mSv and may be even higher for a high-resolution
diagnostic CT scan
PET/CT scanner Preferably using a tomograph capable of 3D mode acquisition
Timing image acquisi- The recommended interval between FDG administration and the start of acquisition is 60 min after the
tion intravenous injection
Whole-body scan From the head to middle of the upper leg
Reconstructions CT- Iterative reconstruction algorithm implemented in the system and with the system settings. Include all
based regular corrections such as normalization, attenuation correction, dead time, decay correction, and
model-based scatter correction
a
According to Procedure Guideline for Tumor Imaging with 18F-FDG PET/CT. March 10, 2006. http://www.snm.org/guidelines.
b
Pregnancy and breast-feeding: See the Society of Nuclear Medicine Procedure Guidelines for General Imaging.
Guidelines FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging. Eur J Nucl Med Mol Imaging. 2009. http://www.eanm.org/
publications/guidelines/index.php?navId=37.
substantial radiation dose and theoretical cancer risk. “Diagnostic” urinary collecting system and bladder. Depending upon the dura-
CT performed during a PET/CT study ultimately gives the same result tion of fasting and other metabolic factors, the left ventricular
as a “diagnostic” CT performed alone. Importantly, avoiding duplica- myocardial may or may not be visualized, independently of
tion of studies also reduces the overall radiation exposure. In the coronary artery disease comorbidity. The liver and the spleen
evaluation of patients known to have cancer, although cancer risks will demonstrate intermediate-intensity uptake (see Fig. 12.1B).
from radiation may be of less significance, the information is still of Aside from qualitative interpretation of the 18F-FDG distribution
interest and relevant to patients.32 in a whole-body PET/CT study, the intensity of 18F-FDG uptake
can be quantified as the SUV. The SUV is a parameter that cor-
rects absolute radioactivity per gram of tissue for the amount of
Normal Distribution of FDG in PET/CT radioactivity administered, radioactive decay, and the size of the
A patient who has fasted overnight will demonstrate a low-level individual.
background activity throughout the body, with intense physio- To a certain extent, this semiquantitative scale of 18F-FDG accu-
logic FDG uptake in the brain as well as activity in urine and the mulation in tissue helps distinguish between benign and malignant

Table 12.5
18
FDG PET/CT: Image Interpretation: Potential
Sources of Errora
False positive
Physiologic Physiologic uptake is seen in normal structures such as sali-
uptake vary glands and lymphoid tissues in the head and neck,
thyroid, brown adipose tissue, thymus, especially in chil-
dren, lactating breast areola, skeletal and smooth muscles
(e.g., neck or paravertebral; hyperinsulinemia), and gastro-
intestinal (e.g., esophagus, stomach, or bowel)
Urinary tract structures (containing excreted 18F-FDG), female
genital tract (e.g., uterus during menses or corpus luteum cyst)
Inflammatory Postsurgical inflammation, infection, or hematoma; biopsy site;
processes or amputation site
Postradiation (e.g., radiation pneumonitis) or postchemother-
apy; local inflammatory disease, especially granulomatous
processes (e.g., sarcoidosis, fungal disease, or mycobacte-
rial disease); ostomy site (e.g., trachea or colon) and drain-
age tubes; injection site; thyroiditis; esophagitis, gastritis, or
inflammatory bowel disease; acute and occasionally chronic
pancreatitis; acute cholangitis and cholecystitis; osteomyeli-
tis; recent fracture sites or joint prostheses; lymphadenitis
Benign Pituitary adenoma, adrenal adenoma, thyroid follicular ade-
neoplasms noma, salivary gland tumors (e.g., Warthin’s tumor or pleo-
morphic adenoma), colonic adenomatous polyps and villous
adenoma, ovarian thecoma and cystadenoma, giant cell
tumors, aneurysmal bone cyst, leiomyoma
Hyperplasia or dysplasia
Graves disease, Cushing disease, bone marrow hyperplasia
(e.g., anemia or cytokine therapy), thymic rebound hyperplasia
(postchemotherapy), fibrous dysplasia, Paget disease
Ischemia
Hibernating myocardium
Artifacts
Misalignment between PET and CT data can cause attenuation
correction artifacts. PET images without attenuation correction
and fusion images can be used to help identify these artifacts
Inaccuracies in converting from polychromatic CT energies to
the 511-keV energy of annihilation radiation can cause arti-
facts around metal or dense barium, although these artifacts
are less common with newer conversion algorithms
False negative Small size (less than two times the resolution of the system)
Tumor necrosis, recent chemotherapy or radiotherapy, recent Figure 12.2. A 56-year-old woman whom presentation was suspicious for a recurrent ovar-
high-dose steroid therapy, hyperglycemia and hyperinsu- ian carcinoma (hairline) underwent 18F-FDG positron emission tomography (PET)–computed
linemia, some low-grade tumors (e.g., sarcoma, lymphoma, tomography (CT). FDG PET (coronal) revealed incidental findings of faint FDG uptake of a benign
or brain tumor), tumors with large mucinous components, sarcoid-like lesion in the hilar regions mimicking metastatic lymph nodes (arrows ). (Image cour-
some hepatocellular carcinomas, especially well-differentiated tesy of Peter MacCallum Cancer Centre, Melbourne, Australia.)
tumors; some genitourinary carcinomas, especially well-
differentiated tumors; prostate carcinoma, especially well-
differentiated tumors; some neuroendocrine tumors, sensitivity of 18F-FDG PET/CT to detect tumor sites, some malig-
especially well-differentiated tumors; some thyroid carcino- nancies do not vigorously accumulate 18F-FDG (i.e., BAC or carci-
mas, especially well-differentiated tumors; some bronchoal- noid tumors). False-positive lesions (i.e., granulomatous diseases
veolar carcinomas such as tuberculosis, fungal infections, or sarcoid-like lesions) may
Some lobular carcinomas of the breast; some skeletal create problems for an inexperienced interpreter (Fig. 12.2).
metastases, especially osteoblastic or sclerotic tumors; Small pulmonary lesions may have a low 18F-FDG SUV, which
some osteosarcomas does not reflect the glucose metabolism because of partial volume
a artifact.33,34 For a small volume of pulmonary nodules, qualitative
According to Procedure Guideline for Tumor Imaging with 18F-FDG PET/CT. March 10, 2006.
http://www.snm.org/guidelines. analysis of the lesion might be more reliable, perhaps by com-
Guidelines FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging. Eur J Nucl parison to the mediastinal blood pool (Fig. 12.3).35,36
Med Mol Imaging. 2009. http://www.eanm.org/publications/guidelines/index.php?navId=37.
Standardized Uptake Value in Lung Carcinoma

lesions and the degree of aggressiveness of tumors using the max- The use of Response Evaluation Criteria in Solid Tumors (RECIST)
imum standardized uptake value (SUVmax). In general, a cutoff 1.1 criteria to assess a lesion has many limitations. The established
SUV of around 2.5 is useful to separate benign from malignant assessment of lung nodules with conventional imaging techniques
processes, but some malignant tumors can have an SUV of less is based on size and morphologic changes, which do not assess
than 2.5 whereas active inflammatory processes have SUVs higher intracellular metabolic changes that are important to identify
than 2.5. During qualitative or visual interpretation of an 18F-FDG malignant cells or determining the response to treatment. It should
PET/CT study, the pitfalls and physiologic uptake must be consid- be revised to include assessment of intrinsic metabolic changes.37,38
ered to avoid false-positive interpretations. Despite an overall high Other limitations of structural imaging in NSCLC are well known.


Figure 12.3. Reconstructed axial images in
(bottom left and moving clockwise) posi-
tron emission tomography (PET), computed
tomography (CT), fused PET/CT (in lung win-
dow setting), and multiplanar image projection
(MIP) demonstrating an irregular mass with
high FDG uptake in the right lung. Two subcen-
timeter nodules are seen in the anterior seg-
ment (black arrow ), which are non-FDG avid.
Poor spatial resolution of PET camera can lead
to false-negative interpretation of small lesions
below the camera’s resolution. (Images cour-
tesy of Pusat Pengimejan Diagnostik Nuklear,
Universiti Putra Malaysia, Serdang, Malaysia.)
Tumors may be obscured by atelectasis and, after radiotherapy, sites of disease, whereas stable metabolic disease is defined as lack
may be indistinguishable from radiation pneumonitis.39 In addi- of change.
tion, lymph nodes larger than 1 cm are denoted as containing The SUV, despite being a unitless metric, is the preferred param-
tumor based on CT imaging without reference to the metabolic eter to assess therapeutic response. The SUV is determined by divid-
characteristics that precede morphologic changes. 18F-FDG SUV ing the measured radioactivity in tissue by the total activity
exhibits a change in cellular metabolism earlier than change in administered to the patient’s weight after synchronization of correc-
tumor size and is complementary to the high-resolution structural tion factors. High 18F-FDG uptake denotes an increase in the utiliza-
imaging data available from CT or magnetic resonance imaging tion rate of glucose (MRGlu). SUVmax has been shown to be more
(MRI).40 accurate than SUVmean and tumor volume–corrected SUV. Regard-
In a meta-analysis of 13 studies in patients with NSCLC, less of the methodology used, a reduction in 18F-FDG uptake in
Berghmans et al.41 reported that the primary tumor SUV measure- lesions implies a favorable response to treatment. The utility of
ment was found to have a prognostic value. 18F-FDG SUV PET is 18
F-FDG PET has been influenced by the observation that resolution
useful in the initial assessment of lung nodules and masses and in of metabolic activity has a good prognosis. Nevertheless, the exact
the assessment of treatment response. timing for a repeat 18F-FDG PET/CT scan is important as the early
Assessment of the metabolic response by 18FDG PET, however, changes of the lesion posttreatment are crucial in determining the
has no clear guidelines, but it can be assessed by qualitative or efficacy of treatment instituted. An evolving new guideline looking at
semiquantitative methods.42,43 MacManus et al.44 have recom- the metabolic changes as a yardstick for posttreatment evaluation of
mended a scheme based on the visual interpretation of a tumor a solid tumor has been suggested (i.e., PET response evaluation of a
response on 18F-FDG PET. solid tumor). However, additional work is necessary before this new
A complete metabolic response is defined as a return of 18F- criterion is accepted.45 RECIST, however, has the potential to char-
FDG SUV in previously documented lesions to a level of equivalent acterize tumor cell metabolism and is basically different from that
to or lower than the activity in normal tissue. Partial metabolic based solely on anatomic imaging.
response constitutes a significant reduction in 18F-FDG PET uptake In 73 patients, evaluated with both PET and diagnostic CT
in tumor sites on visual analysis (Fig. 12.4). Progressive metabolic scans, before and at a median interval of 70 days after treatment,
disease is determined by an increase in the extent of metabolic an early, posttreatment 18F-FDG PET scan is a better predictor of
abnormality suggestive of the tumor growth, or evidence of new survival than CT response, stage, or pretreatment performance

Figure 12.4. Examples of discordant positron emission tomography (PET) and computed tomography (CT) results. Upper panels show pretreatment CT (left) and
posttreatment CT (right) images of a mediastinal lymph node, which did not regress in size on the follow-up study after 2 months. CT indicated partial response.
Lower panels show corresponding PET images before and after radical chemoradiation; PET showed complete response. (Images courtesy of Pusat Pengimejan
Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
status.46 In a prospective study of 105 patients with NSCLC, 18F- operative chemoradiotherapy in locally advanced NSCLC as assessed
FDG PET scanning changed or influenced management decisions by pathologic examination of tumors obtained at thoracotomy.
in 70 patients (67%) with NSCLC (Fig. 12.5). Selected patients with NSCLC have a chance for long-term survival
Because of the limitations of CT scanning, 18F-FDG PET/CT scan- and even cure with radical radiotherapy, provided distant metastases
ning may also have a role in response assessment after induction are absent.48 Although results have been improved by combining
therapy prior to surgery, particularly for stage IIIA NSCLC. Choi et al.47 chemotherapy with radiotherapy, survival has remained poor.49,50
found that the residual metabolic rate of glucose (MRglc) as mea- A study evaluating serial changes in the SUV during chemother-
sured using FDG PET was strongly correlated with response to pre- apy for NSCLC in 16 patients demonstrated that a 50% or greater

Tab l e 1 2 . 6
Factors Influencing Standardized

Uptake Valuea
Physiologic
Body composition
Blood glucose level
Renal function
Diabetes mellitus
Physical
Partial volume effect
Respiratory motion
Movement
Procedure
Dose administration
Waiting time
Extravascular injection
Image manipulation and process
Reconstruction and smoothing
Region of interest
Calibration
a
Standardization of the imaging protocol is the key answer to accurate reading of 18F-FDG PET/

Figure 12.5. Computed tomography (CT) and positron emission tomography (PET) coronal
images. A 54-year-old man had completed radiotherapy of the right lung for a recurrent non– CT study.
small cell lung cancer. The images show a typical dome-shaped consolidative change in the
right upper lobe with increased FDG accumulation in radiation pneumonitis. (Images courtesy of
Peter MacCallum Centre, Melbourne, Australia.)
PET/CT Evaluation of Lung Nodules
18
F-FDG PET and CT have been found to be promising tools to dif-
reduction in the SUVmax between studies performed after 1 and ferentiate benign from malignant pulmonary nodules.16–18 More
3 weeks of therapy was predictive of the survival of patients for than 150,000 solitary pulmonary nodules (SPNs) are identified
more than 6 months, whereas patients with a less marked SUV each year on conventional chest radiographs,13 and the number of
reduction died within 6 months.51 A similar study of 15 patients indeterminate SPNs is becoming larger because widespread use of
receiving radiotherapy demonstrated that the peak residual 18F-FDG low-dose CT for lung cancer screening.55,56 Suspicious SPNs are
activity and qualitative response obtained during treatment corre- biopsied to determine the diagnosis.
lated with the overall response obtained 3 months after treatment. Malignant pulmonary nodules demonstrate higher 18F-FDG
18
F-FDG PET/CT may have wide application in measuring treat- uptake in PET and PET/CT studies than benign nodules (Fig. 12.6).
ment response in oncology. Because prognostic information can be During qualitative assessment of pulmonary nodules, the intensity
obtained at a relatively early time point, therapies could potentially of 18F-FDG uptake should be compared with the mediastinal blood
be tailored depending on information obtained from the complete- pool. The specificity of this approach to detect malignant nodules is
ness of PET response. CT scanning alone may underestimate the found to be 76% as compared with using the SUV, considering 2.5
activity of novel antitumor agents, and this could lead potentially to the cutoff value of the SUVmax to distinguish malignant from
mismanagement and risk of treatment toxicity or futile surgery. benign nodules57,58 or to proceed to a more invasive approach. The
As mentioned above, the SUV is a semiquantitative method for sensitivity and specificity of an 18F-FDG PET to characterize SPNs
evaluating a lesion’s metabolic rate. Its efficacy in lesion character- was found to be higher (96.8% and 77.8%) than contrast-enhanced
ization, prognostication, and monitoring treatment response has CT, albeit well-established CT features of benign and malignant
been documented.52 A number of physiologic, physical, and proce- nodules have been described.
dural factors, however, can influence the SUV (Table 12.6). Besides One CT criterion is the size of nodule (>1 cm in diameter). This is
dose administration, uptake time, body composition, blood glucose an inclusion criterion rather than exclusion as subcentimeter nod-
level, and renal function should be monitored consistently to achieve ules have been found to demonstrate 18F-FDG avidity in PET studies.
accurate results especially when comparison is made between scans However, other benign CT features of pulmonary nodules can be
and to monitor disease progression. The traditional cutoff value of exploited in excluding malignancy such as visual evidence of cal-
SUVmax of 2.5 should be used with caution. It is known that there cium deposits where CT value using a Hounsfield unit can suggest
may be a 15% to 20% variation in the rate in the SUV in primary lung the nature of pulmonary nodules. The sensitivity of CT in detecting
cancer among different centers and different PET/CT equipment. malignant nodules is 100%. The higher specificity of 18F-FDG PET
These differences may cause erroneous conclusions in follow-up of (76%) than CT (26%) can ultimately lead to reduced number of
patients with SCLC at different centers. Ilker et al.53 reported PET/CT biopsies and surgical interventions avoiding unnecessary, high-risk
and mediastinoscopy and/or thoracotomy performed in 337 con- invasive procedures.
secutive patients from four different centers, with a known or sus- Although the functional status of lung nodule assessment in PET
pected diagnosis of NSCLC, who were found to have the optimal SUV claims several advantages over morphologic imaging in CT, there
cutoff of 2.75 in their study, with 88% accuracy. The group concluded are two limitations of 18F-FDG PET to detect malignant lung nodules.
that this value is compatible with the traditional SUV of 2.5. Thus, the The current PET scanner technology has limited intrinsic resolution.
SUV is valuable for comparing centers and is especially useful in This limitation results in false-negative results when assessing
the evaluation of larger nodules (>1 cm), with minimal or no value smaller nodules. Because 18F-FDG is a nonspecific tracer, nodules
in the evaluation of smaller nodules of less than 1 cm in diameter.54 that originate from chronic granulomatous inflammatory and infec-
In clinical practice, it is highly recommended to adhere to strict tious conditions are well-known sources of false-positive interpreta-
acquisition and analysis protocols with regular quality assurance to tion in 18F-FDG PET and PET/CT studies. Thus, in the evaluation of
maintain SUV reproducibility in a given patient over time. pulmonary nodules, a thorough combined interpretation of results

Figure 12.6. Reconstructed multiplanar view in coronal, sagittal, axial, and multiplanar image projection of a patient diagnosed with non–small cell lung cancer
(left to right). There is a lung nodule seen in the left upper lobe. The nodule demonstrates high FDG uptake. Apart from malignant lung lesions, chronic granulo-
matous lesions such as active tuberculosis infection and fungal infection potentially lead to false-positive interpretation of FDG-avid lesions, mandating tissue
diagnosis for confirmation. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
obtained during a contemporaneous PET/CT study is strongly rec- mediastinal invasion. 18F-FDG PET images are limited by poor ana-
ommended to overcome the limitations of low CT specificity and tomical resolution, making assessment of tumor extension unreli-
limited PET sensitivity. This can save cost and time and optimize the able. Higher spatial resolution of multidetector CT scan during an
use of both modalities in a single seating. Detailed morphologic integrated PET/CT study can provide useful information by delineat-
characterization of pulmonary nodules on CT and MR should be ing low-attenuation fat planes, separating the tumor mass from
taken into consideration in the assessment of suspicious malignancy structures in the vicinity. Invasion may be excluded by demonstra-
where nodules found with negative SUVmax or less than the blood tion of the preserved fat plane. Advanced T3-stage malignant vascu-
pool are recommended for subsequent workup. lar invasion of large arteries and veins can be demonstrated by an
intraluminal filling defects on CT. These CT features are added value
to PET-derived information to identify tumors suitable for surgical
PET/CT in Evaluation of Lung Masses resection during a contemporaneous PET/CT study, including mor-
phologic evidence of circumferential contact of mass to thoracic
An integrated 18F-FDG PET with a CT study performed for the aorta. By optimizing information acquired from the integrated con-
diagnostic investigation can provide more information in the over- temporaneous study, the exact demarcation of the tumor outline
all staging of NSCLC than either study performed separately.12,14,15,59 potentially improves T3 and T4 staging.
18
F-FDG PET/CT improves lesion localization during staging and
restaging, thus improving accuracy. The “one-stop-shop” concept of 18
PET/CT investigation allows a complete TNM staging, with a whole-
F-FDG PET/CT for T Staging of Lung Cancer
body protocol adopted during the study, which covers from the CT is the predominant modality to stage patients with NSCLC.
eyes to the thigh. The surgical resectability decision depends on the Advances in clinical staging techniques also have affected the accu-
extension of the primary malignant mass. racy of staging with the advent of endoscopic ultrasonography (US),
There are several challenges to determine tumor resectability endobronchial US, endoscopic US-guided fine-needle aspiration,
based on initial staging with either modality alone. The tumor out- and endobronchial US-guided transbronchial needle aspiration for
line is an important consideration. Tumor masses should be differ- the evaluation of mediastinal disease, which has made minimally
entiated from distal atelectasis, which is often seen as peritumoral invasive tumor staging possible.60 However, 18F-FDG PET and PET/
opacities in CT images. These accompanying changes in lung paren- CT have become more established and are widely available and
chyma can overestimate the tumor size. This important information cost-effective alternatives for preoperative staging.61 18F-FDG PET
is responsible for the planning of radiotherapy where it can poten- has assumed an integral role in the staging of NSCLC in patients who
tially influence the targeted radiation field. Integrated dual-imaging may be eligible for surgery, with pooled sensitivity and specificity
modality PET/CT using 18F-FDG as a biomarker has been shown to values of 74% and 85%, respectively.62 Integrated PET/CT also pro-
be an excellent tool to demonstrate a hypermetabolic malignant vides better metabolic and anatomic information for tumor staging
lesion from surrounding normo- to hypometabolic peritumoral atel- than does isolated CT and FDG PET and provides even greater accu-
ectasis (Fig. 12.7). Thus, 18F-FDG PET/CT is helpful in planning racy.59 Results from 18F-FDG PET in lung cancer staging, a multi-
radiotherapy portals and in reducing radiation toxicity to surround- center randomized trial, indicated that PET is able to depict intra- and
ing normal tissues. extrathoracic metastases, findings that prevent unnecessary thora-
On the other hand, a peripheral tumor mass may invade the cotomy in 20% of patients.63 In this way, it better responds to the
pleura, ribs, and intercostal muscles. A mass arising from the medi- requirements of the seventh edition of the TNM classification system
astinum needs careful assessment to exclude invasion into vital which includes a number of revisions, including subdivision of
structures. PET has no real advantage over CT for chest wall or tumor categories on the basis of size, differentiation between local


Figure 12.7. Multiplanar reconstructed images of positron emission tomography (PET) (lower row), computed tomography (CT), and fused PET/CT (upper row)
in a patient diagnosed with non–small cell lung cancer demonstrating an irregular heterogeneous mass in the left upper lobe, abutting against the posterior thoracic
wall. The outline is well defined and separated from the adjacent rib. There is a “tail” connecting the mass to the mediastinum. On PET and fused PET/CT, there is
no FDG uptake within the “tail” (red arrow on CT image) as compared with intense FDG uptake within the tumor mass. Peritumoral atelectasis often causes over-
estimation of tumor size and extension on CT images. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)
intrathoracic and distant metastatic disease, recategorization of negative results particularly in cases where the nodal size is below
malignant pleural or pericardial disease from stage III to stage IV, the system’s highest resolution, possible micrometastasis or close
reclassification of separate tumor nodules in the same lung and proximity of involved nodes to a large tumor mass. Therefore, nega-
lobe as the primary tumor from T4 to T3, and reclassification of tive 18F-FDG PET findings should be interpreted in the light of the
separate tumor nodules in the same lung but not the same lobe as patient’s pretest probability of mediastinal metastasis and whether
the primary tumor from M1 to T4. the CT reveals enlarged mediastinal lymphadenopathy. A meta-
Traditionally, the TNM staging classification has not been analysis involving 14 studies showed 5% pretest probability of N2
applied to lung NETs. Because TNM has been recently found to be disease for nodes measuring 15 mm or less on CT with negative FDG
useful to assess NETs, the IASLC has recommended that the TNM PET result. This group of patients is recommended for thoracotomy
be applied to pulmonary NETs.64 because the yield from mediastinoscopy is expected to be very low.72
For patients with a mediastinal node measuring 16 mm and
18 above on CT and negative 18F-FDG PET findings, the result of pre-
F-FDG PET/CT for N Staging of Lung Cancer
test probability for N2 disease is 21%. Mediastinoscopy is recom-
Accurate mediastinal staging is crucial in NSCLC. The N stage is an mended for this group of patients.15 Taken together, mediastinoscopy
important determining factor for prognosis and selection of treat- is required in all patients without evidence of distant metastases,
ment. Despite poor sensitivity and specificity in identifying medias- with a cutoff transaxial nodal diameter of 1.5 cm.
tinal metastasis, small mediastinal lymph nodes found on CT scan Lower accuracy of 18F-FDG PET/CT in mediastinal staging is
have been proven to harbor metastatic disease.65 Before 18F-FDG also expected in countries with high prevalence of inflammatory
PET/CT was available, cervical mediastinoscopy using the modi- lung lesions such as tuberculosis.73 In these cases, the major prob-
fied Mountain–Dresler map was performed in patients with NSCLC lem with PET/CT is inadequate specificity for mediastinal staging,
for histopathologic evidence of malignant involvement.66 although the modality is more efficient than CT. Anthracosis, fol-
Alternatively, transbronchial, transesophageal, or transtracheal licular hyperplasia, and granulomatous inflammation are other
fine-needle aspiration procedures can be performed. Because the lat- common etiologies accounting for these false-positive lymph nodes.
ter techniques are found to have a lower sensitivity and negative Recent studies have reported that the dual-phase 18F-FDG PET/
predictive value, mediastinoscopy remained the gold standard in the CT protocol improves the diagnostic efficacy to differentiate benign
evaluation of N stage in patients with NSCLC, with a sensitivity rate from malignant lesions.74,75 According to this end, authors assessed
of 90% and specificity of 100%, if nodal stations were accessible. An lesion SUV at first and delayed scan (respectively at 1 hour and
exception to this are patients with evidence of metastases and stage 3 hours). They reported the utility of index retention SUV (RI SUV)
N0 where 18F-FDG PET replaced mediastinoscopy because the pro- evaluation, that is based on the SUVs values obtained for each
cedure is noninvasive and was found to give a high negative predic- phase, by using the following equation:
tive value (93%) in primary mediastinal staging.67 It is generally
accepted that 18F-FDG PET/CT shows higher accuracy to stage lymph RI SUV (%) = (SUV [delayed scan] - SUV [early scan])
nodes in NSCLC than any of CT or PET study performed alone. × 100/SUV (early scan)
A meta-analysis involving 570 studies found 18F-FDG PET more
accurate than CT for mediastinal staging in patients with NSCLC.68–71 18
The sensitivity of CT is about 59% and the specificity is 79%, lower
FDG PET/CT for M Staging of Lung Cancer
than that of 18F-FDG PET (81% and 90%, respectively). However, 18
F-FDG is the most commonly used tracer with a PET or PET/CT
18
F-FDG PET is not perfect either. The study is prone to give false- system in initial staging of lung cancer. NSCLC without distant

Figure 12.8. Transaxial computed tomography (CT) and fused positron emission tomography (PET)–CT images in a patient diagnosed with lung cancer showing
a left suprarenal mass (arrow ) with high FDG uptake in keeping with distant metastasis. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra
Malaysia, Serdang, Malaysia.)
18
metastases is potentially curable. The likelihood of metastases F-FDG activity. Thus, in cases with suspected cerebral metastases,
increases with higher T stage, in patients with laboratory evidence additional MRI or contrast CT is appropriate.
of metastatic disease and with histology of adenocarcinoma. The Adrenal metastases can occur in up to 20% of patients at presen-
most common metastatic sites are the brain, bones, adrenal glands, tation.71 On PET/CT imaging, finding of 18F-FDG activity higher than
lung, and liver. However, virtually any organ can be the site of meta- the liver is a sign of metastatic disease. The overall diagnostic accu-
static disease. racy is 92%. False-positive findings can be found in adrenal adeno-
In a study involving 170 patients with NSCLC, preoperative mas, and a false-negative result can be seen in smaller metastases
staging with 18F-FDG PET/CT and cranial imaging identified more (Fig. 12.8).
patients with mediastinal and extrathoracic disease than conventional Bone metastases are found in 20% to 30% of patients at initial
staging, thereby sparing more patients from stage-inappropriate diagnosis of lung cancer, and they are usually osteolytic lesions.
surgery. In another study, 18F-FDG PET reduced the number of Planar bone scintigraphy has moderate sensitivity to detect bone
futile thoracotomies from 46% (using conventional workup) to 25% metastases and often gives a false-negative result especially in the
in clinical stage I to II tumors and from 29% to 11% in patients with spine and pelvis. Nevertheless, the technique is better than MR to
clinical stage III tumors.70,76 detect metastases involving the skull and the ribs. 18F-FDG PET/CT
Brain metastases are found in up to 18% of NSCLC cases, but is excellent to detect osteolytic lesions but not osteoblastic metasta-
physiologic FDG uptake in brain parenchyma can obscure abnormal sis (Fig. 12.9). PET using 18F-fluoride as sodium fluoride is highly
Figure 12.9. Reconstructed transaxial images at the level of pubic bone (top row ) and right shoulder (bottom row ) in two settings: Computed tomography (CT)
(left) and fused positron emission tomography (PET)–CT (right) demonstrating well-defined lytic lesions (white arrow ) corresponding with high 18F-FDG uptake.
Glycolytic process is markedly raised in osteolytic bone metastases translated into high FDG uptake at these sites. Morphologic changes on CT validate the PET
findings and vice versa. (Images courtesy of Pusat Pengimejan Diagnostik Nuklear, Universiti Putra Malaysia, Serdang, Malaysia.)

sensitive to detect both types of metastatic lesions. The diagnostic However, some cancers have a very low doubling rate and there-
accuracy of 18F-FDG PET/CT and 18F-labeled sodium fluoride to fore may not demonstrate appreciable enlargement for months and
detect bone metastases in NSCLC is the best technique to detect even years, whereas many aggressive cancers may grow in weeks.
both types of bone metastases. 18F-fluoride has higher diagnostic These circumstances confound the optimal timing of follow-up
accuracy than 99mTc bone scintigraphy. The accuracy of 18F-FDG to imaging and potentially lead to residual disease being unrecognized
detect bone metastases is 96% compared with bone scintigraphy. until it is too late for salvage therapy. Conversely, slow regression in
Thus, bone scintigraphy can be eliminated if 18FDG PET/CT is per- lesion size after treatment may lead to the mistaken belief that
formed for staging.77 there has been a poor response and prolong treatment or even to
18
F-FDG PET is an improved method in the diagnosis of malig- substitute more aggressive therapy.
18
nant pleural effusion with better results, eliminating high-risk inva- F-FDG PET/CT imaging is increasingly used for response assess-
sive thoracotomy procedures. The diagnostic accuracy of 18F-FDG ment in lung cancer.84 Several reports have documented changes in
18
PET imaging to detect pleural metastases has a high sensitivity (92% F-FDG uptake.85 18F-FDG PET/CT has significantly higher accuracy
to 100%) and negative predictive value (100%) but only a specificity than CT or stand-alone 18F-FDG PET to assess response. 18F-FDG
of 67% to 71% and a positive predictive value of 63% to 79%.78 uptake in the primary tumor is predictive of long-term survival and is
Overall, 18F-FDG PET imaging has been found to improve stag- a better predictor of therapeutic response than the volume change as
ing in NSCLC, leading to major changes in the treatment plan. In a measured with CT scans. SUVmax is a reproducible parameter and
prospective study involving 24 patients with NSCLC, 18F-FDG PET has therefore become the preferred parameter to assess the thera-
imaging upstaged 8.3% of patients with sensitivity and specificity peutic response. One of the concerns regarding the use of the SUVmax
for metastatic disease of 100% and 95.5%.79 as a parameter for response assessment is that it ignores changes in
the distribution of a tracer within a lesion and in the extent of meta-
bolic abnormality.
18 The optimal timing of 18FDG PET/CT scanning during a course of
F-FDG PET/CT in Therapy Response radiotherapy or concurrent chemotherapy has not been established.

Assessment The earlier during treatment that scans are obtained, the more likely
a change in therapy can be considered. When 18F-FDG PET scans
Treatment options for lung cancer and lung metastases include sur- are performed late during therapy, the 18F-FDG PET scans may be
gical resection, external beam radiotherapy, chemotherapy, tar- falsely positive because of radiation-induced inflammation, render-
geted therapies (such as tyrosine kinase inhibitors), and thermal ing it difficult to determine whether the treatment was effective. If
18
ablation procedures, such as radiofrequency ablation (RFA). Radio- F-FDG PET imaging is delayed and the tumor progresses, an
therapy is one of the main treatment modalities for lung cancer. For opportunity to modify treatment has been lost.86
locally advanced NSCLC and for nonmetastatic SCLC, fractionated In contrast to NSCLC, SCLC generally responds very quickly to
radiotherapy combined with chemotherapy is the standard option. concurrent chemoradiotherapy. In a prospective study, van Loon
Approximately two-thirds of patients with SCLC have extensive et al.87 showed that both early CT and 18F-FDG PET response were
disease with hematogenous metastatic disease at the time of presen- predictive of survival. Residual 18F-FDG uptake after radiotherapy
tation. Only chemotherapy is suitable for these patients. Patients treatment is correlated with worse outcome.
with tumors limited to one hemithorax, regional lymph node metas- Hypofractionated treatment schedules used in stereotactic body
tases involving hilar, ipsilateral, or contralateral mediastinal and radiotherapy, with fractional doses ranging from 7.5 to 20 Gy, may
supraclavicular lymph nodes, and ipsilateral pleural effusion (regard- lead to a false-positive finding on the posttreatment 18F-FDG PET
less of positive or negative findings) are treated with chemotherapy scan.
and radiotherapy. In a pilot study involving 15 patients receiving induction chemo-
In locally advanced NSCLC, imaging during treatment with ade- therapy or radiotherapy,88 seven patients with persistently elevated
18
quate diagnostic tools such as CT with intravenous contrast, or even F-FDG uptake in the mediastinum developed early systemic dis-
better with 18F-FDG PET/CT scans, has been performed.80,81 CT ease and died, whereas seven of the eight patients with negative
imaging is the standard method for response assessment, but with mediastinal 18F-FDG PET results remained free of extracerebral
the new targeted therapies and chemotherapeutic drugs, assess- relapse. Even with the small number of patients studied, it was
ment of tumor volume might not reflect an adequate treatment observed that patients with 18F-FDG PET downstaging had signifi-
response. Furthermore, CT-based assessment is often not sensitive cantly longer cumulative survival than patients with a persistent
for early response evaluation. Because of fibrosis, the tumor diam- mediastinal nodal abnormality, whereas a partial response on CT
eter might not reflect the true reduction in viable tumor volume. was not predictive of outcome.
Therefore, functional imaging is viewed as a suitable method to There is no confirmed value for the degree of 18F-FDGmax reduc-
assess tumor response, frequently preceding morphologic changes tion that is a reliable prognostic indicator. In a population of patients
seen on CT imaging.82 with stage III NSCLC, a postradiotherapy SUVmax reduction of 72%
Assessment of the therapeutic response in NSCLC is primarily or more has been reported to have better overall survival and longer
based on changes in the measured dimensions of lesions identified disease-free survival than those showing less than 72%. Although
on CT. These changes are graded on the basis of definitions detailed the pretreatment SUVmax has not been associated with survival
in RECIST,38 which are modifications of earlier WHO response outcome, reduction in the SUVmax was associated with disease con-
criteria.83 Both include definitions for a complete response, a partial trol after radiotherapy for locally advanced NSCLC, observing that
response, stable disease, and progressive disease, which are based the greater the decrease in the SUVmax in the lesion (primary
on the percentage change in lesion dimensions. tumors or lymph nodes) with the highest SUVmax at diagnosis, the
Response assessment with CT is especially unreliable in lung longer the overall survival. Currently, the American College of Radi-
cancer because of the inaccuracy of initial lymph node staging. For ology Imaging Network 6668/RTOG 0235 trial is prospectively eval-
the primary tumor, the confounding effects of atelectasis and of uating whether the primary tumor 18F-FDG SUVmax shortly after
radiation pneumonitis and subsequent fibrosis compromise the definitive chemoradiation can predict long-term survival in inoper-
definition of the dimensions of the primary lesion before and after able stage II or III NSCLC. Greene et al.89 proposed that a complete
treatment, respectively. Some of these limitations are compensated response after high-dose radiotherapy, or concurrent chemoradio-
for by the use of serial CT during treatment. Further regression therapy, is defined as the complete disappearance of all evidence of
at a later time point is generally accepted as evidence of a thera- malignant disease or residual radiographic abnormalities at 3 and
peutic benefit, whereas an increase in size represents progression. 6 months after completion of radiotherapy, which remains stable for

an additional 6 months or more. A recent Dutch study confirmed the Many experiences have been reported regarding interpretation
validity of metabolic response assessment up to 6 months after criteria, as the capability of local tumor regrowth is likely when the
radiotherapy as a surrogate of survival. Timing of the first 18F-FDG reduction in SUV from baseline to follow-up study at 2 months after
PET scan as early as 3 months after radiotherapy was reported to RFA is less than 60%. On the other hand, it seems reasonable to
predict survival and obtain information helpful in identifying assume that minor reductions in SUV between the preablation and
patients who are at high risk for recurrence and to design additional postablation scans indicate incomplete ablation of the lesion. In
salvage treatment.90 addition, the postablation SUV, by itself, has been hypothesized a
18
F-FDG PET/CT has allowed more accurate detection of both better predictor of recurrence-free survival, in particular when per-
nodal and distant forms of metastatic disease. This advance has sisting or increasing during follow-up. Such a pattern is suggestive
been complemented by improved methods for sampling mediasti- of regrowth of viable tumors rather than chronic post-RFA inflam-
nal nodes, including endoscopic ultrasound-guided biopsy, with mation. Response criteria such as RECIST fail in this situation
many such studies providing complementary information. The con- because they rely solely on size in a situation in which the postablation
sequences of more sensitive detection of metastatic disease are that mass is almost always larger than the original lesion. Some groups
fewer patients are likely to undergo futile thoracotomy and that have used an arbitrary time interval of 6 months after ablation, after
more patients will be identified as requiring aggressive locoregional which any size increase is considered indicative of regrowth.99
or systemic treatment. Molecularly targeted therapies are now Moreover, reliable assessment of post-RFA findings at 6 months
increasingly being used for cancer. Inhibitors of epithelial growth may be too late because the opportunity for successful retreatment
factor receptor signaling are already in widespread use, and clinical declines with time.
studies are in progress to evaluate tumor glucose utilization to pre-
dict treatment response following epidermal growth factor receptor
kinase inhibitors.91–94
RFA of lung lesions has gained increasing acceptance as a viable
Other Challenges of PET/CT Imaging
alternative for the treatment of pulmonary malignancies in patients in Lung Cancer
who are unable to undergo surgery or for palliation of patients’
symptoms. In lung cancer, the challenges in multimodality imaging are mainly
Okuma et al.95 have shown a decrease in tumor 18F-FDG uptake because of motion artifact and the false-negative PET lesion of
to the background level at 1 day after RFA treatment. Inflammation, some NSCLC. The standard technique adopted by many PET users
including the migration of inflammatory cells into tissue surrounding is the acquisition of the emission images during normal shallow
the ablation zone, is a process that takes several hours. breathing. Nevertheless, there is still a debate as to whether opti-
Dual-time-point 18F-FDG PET imaging has been suggested as a mal attenuation maps are provided by obtaining CT scans during a
method to better differentiate between cancer and inflammatory breath-holding technique or during normal breathing.100 Respira-
changes.96 The underlying hypothesis is that cancer tissue is charac- tory motion results in inaccurate image fusion on PET/CT localiza-
terized by a continued increase in 18F-FDG uptake, whereas inflam- tion of lesions at the base of the lungs or the dome of the liver in
matory cells show either no significant change or some tracer about 2% of patients.101
washout between the first and second scans. Coaching patients to hold their breath at end-tidal volume during
Singnurkar,97 in his retrospective study, evaluated 68 consecutive a CT examination can minimize artifacts from misregistration.
patients with 94 lung lesions, including metastases and primary Breath holding during maximum inspiration or maximum expiration
lung cancers, who underwent RFA and in whom 18F-FDG PET/CT is not recommended because doing so will increase the degree of
was performed at baseline before therapy or during follow-up. 18F- misregistration artifacts. A gated respiratory system has been used
FDG PET/CT may be useful to assess treatment response to RFA and to mitigate the breathing motion that blurred off the image acquisi-
to predict the likelihood of local recurrence. Pretherapy and post- tion.102 The system allows better localization of abnormalities near
therapy imaging features associated with local recurrence were the borders between organs such as lung and liver, as well as for the
identified. Among pretherapy findings, tumor size is a significant detection of very small lesions that are “blurred” into the background
predictor of suboptimal treatment response with RFA, showing a activity by respiratory motion. Time-of-flight systems have increased
lower recurrence-free survival in patients with tumors greater than sensitivity and may make it possible to reduce acquisition time suf-
3 cm. However, this trend may be more a reflection of current tech- ficiently to improve single breath image acquisitions.103,104
nical limitations of RFA, rather than of tumor biology. In addition, as In fact, in image coregistration, technical limitations are gener-
a factor not independent of lesion size, high pretherapy SUV has ally attributed to organ motion inducing image blurring and arti-
been observed as a predictor of local recurrence. Indeed, because facts. These pitfalls can be improved by adoption of shallow
partial-volume effects cause an underestimation of the true activity breathing techniques during the sequential PET and CT scanning or
concentration in smaller lung tumors, lesions with greater size (in improvement in the PET software systems. The shallow breathing
particular, greater than twice the resolution of the PET camera) tend techniques have been popular in practice in many PET/CT centers
to have higher SUVs.98 For these technical reasons, successful RFA to reduce the artifacts generated at the diaphragm–lung interface.
is more difficult to confirm in larger lesions. Nevertheless, a nondependent patient approach via 4D PET/CT
Postablation scans may reflect various patterns of 18F-FDG technique based on product features is preferable over regulating
uptake: Diffuse, focal, heterogeneous, rim, and rim plus focal, with patient breathing.
focal uptake either at a site of original disease or at another site. However, in 4D PET/CT image acquisition, the patient needs to be
Rim uptake has been previously shown as a favorable indicator of coached in order to relax in and breathe at a consistent rate. CT data
normal postablation inflammation around the treated tumor. Other are acquired first, followed by PET acquisition. The scanner acquires
favorable uptake patterns included diffuse, heterogeneous, and rim images at one phase of the patient’s respiratory cycle. The prospec-
plus focal uptake when the focal uptake did not correspond to the tive gating creates a single volumetric image collected at a specific
original tumor nodule. On this basis, the combination of rim plus respiratory segment. In retrospective gating, the scanner acquires
focal uptake deserves further comment: A rim of 18F-FDG uptake data continuously during all phases of the breathing cycle. The data
with a superimposed hypermetabolic nodule, whose location cor- are retrospectively assigned to a respiratory cycle phase and hence
responds to the original tumor nodule, indicates local recurrence, to the corresponding image in the respiratory cycle.
whereas superimposed focal uptake at a noncorresponding site The impact of the 4D PET/CT has been shown in assessment of
more likely indicates heterogeneous inflammation around the a small pulmonary nodule. In pulmonary lesions >1 cm, respiratory
ablated site. gating changed the SUVmax by 22.5%, without compromising the

lesion size.105 4D PET/CT has also been used in radiotherapy plan- Tab l e 1 2 . 7
ning for which the target lesion in question warrants an accurate
111
localization for an effective treatment. Its use has facilitated the In-Pentetreotide Somatostatin Receptor
visualization of respiratory movement and reduces the tumor Scintigraphy
margins in the treatment beam.97
In the assessment of a smaller lesion, synchronized PET and CT Recommended Adults: 222 MBq
data confer essential benefits to patients, whereby a small-volume activity Children: 3 MBq/kg
lesion appears to be more conspicuous with profound increase in Administration Intravenous—it should not be injected into lines used for, or
the SUVmax.106 In addition, as mentioned above, improvement together with, solutions for total parenteral nutrition
in the PET detector technology such as the TOF may reduce motion Patient preparation Discontinue prior administration of “cold” octreotide acetate therapy
artifacts and hence better characterize small lesions.107 and precautions Pregnancy (suspected or confirmed)
Another challenge in 18F-FDG PET/CT imaging is the relative To minimize radi- Good hydration before and for at least 1 d after tracer injection
nonspecificity of increased glucose metabolism for malignancy. The ation exposure
Impaired renal As the rate of tracer excretion may be much slower than that
dilemma of delineating a non–18F-FDG–avid lung tumor (i.e., BAC or
function in normal patients, the use of 111In-pentetreotide should be
carcinoids) is at times problematic when one has to differentiate considered. In patients on dialysis, interpretable images
between a less aggressive lesion (i.e., benign tumor) and a low-grade may be obtained after dialysis
malignant lesion. There are also active inflammatory diseases that Chest planar Routinely acquired at 24 h
can have high 18F-FDG avidity where dual-time-point 18F-FDG PET imaging 4- and 48-h postinjection imaging: Optional
imaging has been recommended to differentiate between the latter Large-field-of-view γ-camera fitted with a medium-energy
two.108,109 collimator. Symmetric 20% energy windows centered over
PET tracers that demonstrate an increased rate of cellular prolif- both photopeaks of 111In (173 and 247 keV) and the data
eration are likely to be particularly helpful in the setting of thera- is summed; 512 × 512 or 256 × 256. Images are best
peutic monitoring because they are less likely to be taken up in viewed using computer display with individualized physician-

directed optimization of intensity and contrast
inflammatory conditions. The search for proliferation markers has
Whole-body Dual-head camera, anterior and posterior images acquired
been active with most attention to thymidine analogs. To date, the imaging into 2048 × 512 or 1024 × 256 matrices
most promising of proliferation tracer for clinical application appears SPECT Iterative reconstruction with ordered subset expectation maxi-
to be 18F-fluorothymidine (18F-FLT).110 There is evidence that 18FLT mization (OSEM) is the recommended reconstruction algo-
uptake is closely correlated with cellular proliferation, with correla- rithm, as it may eliminate some of the artifacts seen with
tion between the intensity of uptake as measured by SUV with pro- filtered back projection in areas near intense tracer activity.
liferation indices such as Ki-67 staining in suspected lung cancer Specific parameters depend on vendor recommendations.
lesions undergoing resection.111 Three-dimensional rendering of the SPECT data and its
In addition, 18FDG PET/CT uptake is related to epidermal growth review in cinematic display is encouraged
SPECT-CT Check SPECT-CT alignment and then fuse CT images for
factor receptor mutations, in predicting tumor response to treat-
attenuation correction and combined interpretation
ment, which is a new advancement in clinical application of molec-
ular imaging in personalized treatment delivery in patients with
lung cancer.112 111
In-pentetreotide
111
Indium pentetreotide (OctreoScan®) is [111In-DTPA-D-Phe]-
Labeled Peptide Scintigraphy octreotide, a standard somatostatin analog. The amount of pente-
treotide injected per dose of OctreoScan® is 10 μg, with no clinically
[111Indium-DTPA-d-Phe1]-octreotide scintigraphy and 99mTc-depreo- significant pharmacologic effect.
tide have been used to detect and evaluate patients with known or In patients with NETs, 111In-octreotide somatostatin receptor scin-
suspected NSCLC and thoracic NETs including SCLC. High-affinity tigraphy (SRS) can be used to localize and staging primary tumors
somatostatin receptors (SSTRs), in particular subtype 2 (SSTR2), and to select patients for peptide receptor radionuclide therapy
have been demonstrated in vitro in a variety of human malignancies, (Tables 12.7 and 12.8), but it has low specificity and differentiation
including SCLC.113–124 Traditionally, SCLC has been hypothesized to
originate from the so-called Kulchitsky normal cells with neuroendo- Tab l e 1 2 . 8
crine characteristics found in the tracheobronchial mucosa,125 making
it likely that tumor expresses SSTRs. 111
In-Pentetreotide Somatostatin Receptor
In some studies that explored the value of SSTR of different NETs, Scintigraphy Image Interpretation: Potential
evidence was obtained that part of the normal immune system in the Sources of Error
surrounding tissue and “activated” leukocytes, lymphocytes, and
macrophages126 and labeled octreotide to tissue surrounding the
False positive Respiratory infections: Accumulation in the nasopharynx and
tumor in NSCLC. Two mechanisms may be responsible for this: (1) A
pulmonary hilar due to the accumulation in the lymphocytes.
variety of white blood cells, but especially activated lymphocytes, Diffuse pulmonary or pleural tracer uptake after radiation
shown to possess SSTRs,127,128 and (2) proliferation of neuroendo- therapy to the lung or bleomycin therapy
crine cells of the lung, leading to the formation of “tumorlets.”129 111In- Tracer uptake in normal structures (pituitary, thyroid, liver,
octreotide is not specific for SCLC; it is positive for many other spleen, kidneys, bowel, gallbladder, ureters, bladder,
tumors, granulomas, and autoimmune disease involvement.130 SCLC stimulated adrenal glands) and in multiple nonneoplastic
cells possess both amine precursor uptake and decarboxylation disorders must be kept in mind
(APUD) characteristics and represent the so-called APUD cells. The Caution must be used to avoid interpreting physiologic gall-
catecholamine analog meta-iodobenzylguanidine (MIBG) has a high bladder activity as hepatic metastasis
In breast-feeding women, physiologic uptake may be seen in
affinity for adrenergic neurons. As this characteristic has been
the breast
exploited in other APUD tumors, it has been postulated that this
might be of value in scintigraphic imaging and staging of SCLC. False negative Presence of unlabeled somatostatin, as a result of octreotide
Indeed, Nakajo et al.131 observed accumulation of iodine-131 labeled therapy and absence of somatostatin receptor subtype 2,
variable tumor differentiation, and receptor expression also
MIBG in such a tumor, but other studies failed to reproduce this
influences tumor detectability
result both for the primary tumor and for metastases.132

between SCLC and NSCLC is not possible. There is a correlation showed favorable comparison with the results of a prospective
between SSTR expression and prognosis; patients with NETs with trial with FDG-PET in SPNs evaluation.130 The trial evaluated 114
positive SRS have a better response to treatment with somatostatin patients with SPNs; the diagnosis of all these patients was subse-
analogs.133–136 quently confirmed by tissue analysis; the sensitivity of 99mTc-depre-
SRS is the procedure of choice to image NETs and serves as a otide scintigraphy was 96.6% and the specificity was 73.1%.114
prognostic parameter to predict therapeutic response (surgery, Malignant lesions correctly identified by 99mTc-depreotide scintigra-
radiotherapy, chemotherapy, or somatostatin analog one). SRS sen- phy (SPECT/CT) ranged from 0.8 to 6 cm. 18F-FDG PET in a previ-
sitivity depends on both lesion size and the expression of SSTR ous series had failed to identify this tumor type.130 The tracer,
subtypes 2 and 5, and it is between 82% and 95%, higher than CT however, is no longer available.
and MRI.137–139 However, in a study of 27 patients,140 helical CT
appeared to be more sensitive than SRS to detect extrahepatic 78
metastasis from NETs and to have a similar sensitivity, specificity, Ga-DOTA–Conjugated Peptides
and accuracy in detecting primary NETs and hepatic metastasis.
Although SRS octreotide is not useful to differentiate SCLC from The PET tracers most commonly employed to assess thoracic
other lung disease, it should be included in the staging procedure NETs are 68Ga-DOTA-peptides (68Ga-DOTA-TOC, -NOC, -TATE) and
18
of SCLC because it provides early detection of metastases, especially F-DOPA. 18F-FDG provides valuable information in selected cases.
to the brain, in both limited disease and extensive disease. As stated Because well-differentiated NETs have a slow proliferation rate
previously, 60% of the patients already have extensive disease at and low glucose consumption, FDG is not suitable to stage well-
the time of initial diagnosis. Common sites of metastatic disease differentiated NETs but is valuable in highly proliferating undif-
include liver (22% to 28%), bone (38%), bone marrow (17% to 30%), ferentiated tumors.150,151
68
central nervous system (8% to 15%), and retroperitoneum (11%). Ga is of great interest because of its suitable physical proper-
The influence of various sites of distant metastases on survival ties; it decays by positron emission (89%) and electron capture
has been analyzed in several studies, but it seems that prognosis is (11%)152–155 (Tables 12.9 and 12.10). The long half-life of 270.8 days
related more to an increase in the number of sites than to specific of the parent 68Ga allows the use of the generator for up to 1 year
sites. Following this, Richardson et al.141 suggested that no further or longer. 68Ga-DOTA-TOC is not yet available for routine clinical
diagnostic procedures are necessary once extensive disease has use. There are several 68Ga-DOTA–peptides (TOC, NOC, TATE). The
been demonstrated unequivocally. This would also improve the most relevant difference among these compounds relies in a vari-
cost-effectiveness of pretreatment evaluation. In this respect, 111In- able affinity to SSTRs subtypes: All can bind to sst2 and sst5, but
octreotide scintigraphy has been suggested as a (single) tool to only DOTA-NOC presents a good affinity also for sst3, and DOTA-
stage the patient suffering from SCLC. Nevertheless, to date, the TATE has a predominant affinity for SST receptor 2.156 SCLC (mainly
results obtained with 111In-octreotide in the staging of SCLC are still primary tumors) has high expression of SST receptors and can be
inconclusive. In two studies with only a small number of patients, a visualized with 68Ga-DOTA–conjugated peptide PET/CT.157,158
sensitivity of 45% and 50% was found. In patients with a solitary In the management of NETs, 68Ga-DOTA–conjugated peptide
metastasis, there is a high likelihood of understaging. The low sen- PET/CT is used to localize primary tumors and to stage and follow-
sitivity may be because planar techniques were used for the detec- up of patients with known disease as well as to detect residual,
tion of metastases. recurrent, or progressive disease (restaging) and to identify patients
Li et al.142 described a sensitivity of 100% for bone marrow scin- likely to respond to octreotide and SST receptor radionuclide ther-
tigraphy and 91% for bone scintigraphy to detect skeletal metasta- apy with 177Lu or 90Y-DOTA-peptides.159 68Ga-DOTA-TOC PET has a
ses. Because MRI seems to be more sensitive than bone scintigraphy
to detect metastases in the spine, pelvis, and sternum, this modality Tab l e 1 2 . 9
might be performed in patients with NETs with a normal bone scin-
tigram.143 In 50% of the patients with known skeletal metastases, 68
Ga-DOTA–Conjugated Peptides (DOTA-TOC,
O’Byrne et al.144 demonstrated 111In-octreotide uptake, but there DOTA-NOC, DOTA-TATE)
was a discrepancy between findings on bone and octreotide scintig-
raphy. In view of the high sensitivity and low cost, it seems logical
Recommended Adults: To obtain a good-quality image is at least 100 MBq
to use bone scintigraphy as the first step. With this modality, one-
activity
third of the patients with extensive disease will be correctly identi-
Administration Intravenous
fied at an early stage during the initial diagnostic workup. Patient preparation Discontinue prior administration of “cold” octreotide acetate
Limitations of SRS include the evaluation of organs with higher therapy. No need for fasting before injection
physiologic uptake (e.g., liver) and the detection of small lesions.145,146 Precautions Pregnancy (suspected or confirmed)
SRS has other potential sources of error such as physiologic uptake A clinical decision is necessary considering the benefits
in the liver, spleen, kidneys, and bowel contents secondary to biliary against the possible harm of carrying out any procedure
excretion (see Tables 12.7 and 12.8). In addition, the visualization To minimize radia- Good hydration before and for at least 1 d after tracer injection
of brain metastases may not represent expression of SSTRs but tion exposure
rather a disturbance of the blood–brain barrier. Octreotide is a PET-CT scanner Preferably using a tomograph capable of three-dimensional
polar substance and does not sufficiently penetrate the intact bar- mode acquisition
Timing image It depends on the analog used, range 45–90 min after the
rier to allow accumulation at possible receptors.
acquisition intravenous injection
Single-photon emission computed tomography (SPECT)/CT Best results are reported with image acquisition at 60 min
combines functional and anatomical data and improves sensitivity Whole-body scan From the head to middle of the upper leg
of detection.135,147,148 Attenuation correction of SRS SPECT data by Reconstructions Iterative reconstruction algorithm implemented in the system
SPECT/CT further improves the sensitivity.149 CT-based and with the system settings. Include all regular corrections
such as normalization, attenuation correction, dead time,
99m decay correction, and model-based scatter correction
Tc-depreotide Tumor detection 68
Ga-DOTA–conjugated peptide uptake evidence. Its relation to
99m
Tc-depreotide, a 99mTc-labeled somatostatin analog, depreotide, histology and expression/density of somatostatin receptor
which was introduced clinically several years ago, had affinity for subtypes and the knowledge of normal tissue accumulation
of tracer are to be taken into consideration as potential
SSTR2 (expressed in NETs such as SCLC) but had greater affinity
sources of false-negative and false-positive results
for SSTR3. The 99mTc depreotide false-negative rate in this study

18
Table 12. 10 F-FDG, confirming 11C-4DST PET/CT as a useful noninvasive
modality to image DNA synthesis by NSCLC. 11C-4DST to evaluate
68
Ga-DOTA–Conjugated Peptides (DOTA-TOC, lymph node metastases, however, is difficult. Relatively low accu-
DOTA-NOC, DOTA-TATE) Image Interpretation: mulation of 11C-4DST results in failure to detect some lesions. This
Potential Sources of Error is also seen with 18F-FLT.170,171 As a result, 11C-4DST PET may be
best to predict patient prognosis rather than detection or staging of
False positive Intense accumulation of radioactivity is seen in normal struc- cancers. Minamimoto et al.168 reported a double-tracer protocol, by
tures (spleen, and accessory spleens if present, kidneys, and obtaining 18F-FDG scans after the 11C-4DST one, for most of the
pituitary) patients included in their study. 18F-FLT is receiving greater interest
Caution must be used to avoid interpreting physiologic gall- because it is an analog of thymidine; thus, it reflects cellular prolif-
bladder activity as hepatic metastasis eration and correlates better with proliferation of lung tumors than
Variable tracer uptake is frequently found in the pancreas 18
F-FDG.172–174
because of the physiologic presence of somatostatin recep- Tian et al.175 recently conducted a randomized multicenter clin-
tor scintigraphy (SST) receptor 2
ical trial with dual-tracer PET/CT using 18F-FLT and 18F-FDG. Fifty-
False negative Octreotide therapy or the endogenous production of SST (by five patients in six imaging centers, using the same models of
the tumor) may interfere with tumor detection, reducing or equipment and standardized protocols, were evaluated. The diag-
enhancing tumor detectability nostic accuracy to assess pulmonary nodules improved over 18FDG.
In general, the uptake of 18F-FLT by a pulmonary lesion is lower
than that of 18F-FDG. The higher uptake by liver and bone marrow
significantly higher detection rate compared with conventional SRS of vertebrae and ribs makes the detection of small lesion(s) by 18F-
and diagnostic CT, with a clinical impact in a considerable number FLT more difficult. 18F-FLT was developed to reflect the prolifera-
of patients, even if the combined use of PET and CT shows the high- tion rate of the lesions and to characterize malignant tumor growth.
est overall accuracy.160,161 The current dual-tracer study was designed to prove the following

Wherever available, 68Ga-PET/CT has become a routine imag- assumptions: (a) 18F-FDG and 18F-FLT provide information related
ing modality to assess patients with NET lung cancer. 68Ga-DOTA- to different aspects of tumor biology; (b) 18F-FDG and 18F-FLT, dual
TOC PET is more accurate than 111In-DTPA-octreotide SPECT and tracer imaging, are complementary to each other and increase
SPECT/CT. Although the sensitivity of 111In-DTPA-pentetreotide diagnostic confidence; and (c) the criteria in dual-tracer PET/CT
SPECT to detect NETs in the lung approaches 100%, the use of image interpretation are objective, accurate, and easy to use. 18F-
PET combined with a diagnostic CT further improves the value of FDG PET detected more lesions than 18F-FLT, and the image quality
68
Ga-DOTA-TOC in these patients. of 18F-FDG was superior with higher SUVs. The better image quality
18
F-DOPA is another PET tracer that is useful to detect NETs. It was believed to be due primarily to its comparatively lower back-
serves as a substrate for the synthesis of dopamine in tumors man- ground and more uniform tissue distribution. However, nonspecific
ifesting the APUD pathway.162 A potential advantage of 18F-DOPA uptake has been noted in a number of benign lesions, especially in
over 68Ga-DOTA peptides is the detection of lesions with low tuberculosis. In comparison with 18F-FDG, 18F-FLT images are
expression of SSR as frequently observed in patients with undif- “noisy.” The positive bone marrow of the thoracic cage may inter-
ferentiated tumors. fere with the evaluation of intrathoracic lesions. The uptake of
18
In general, 68Ga-DOTA-NOC is superior to 18F-DOPA for the F-FLT is lower than that of 18F-FDG, which is in accordance with
detection of the primary tumor site in nonoperated cases and other reports. For example, Buck et al. reported that 18F-FLT uptake
detects more lesions in the liver, lymph nodes, and lung.163 The was only 50% of 18F-FDG uptake in positive nodal metastases of
greatest discordance is in the pancreas because of the high physi- NSCLC. In the study, 18F-FLT had better specificity (76.92% versus
ologic uptake of 18F-DOPA. 58.97%), but the increased 18F-FLT uptake was not “related exclu-
It is debatable whether the use of carbidopa, an inhibitor of sively to malignant tumors.” The uptake of 18F-FLT was present to
DOPA decarboxylase, as premedication increases the sensitivity of various degrees in many tuberculous and other benign lesions. This
18
F-DOPA PET for the detection of NET lesions.164 was not entirely unexpected because false-positive 18F-FLT PET
had been reported.176 The mechanism of false positive is poorly
understood considering, for example, that the extent of 18F-FLT
Other PET Tracers accumulation in positive benign lesions did not correlate with gran-
ulomatous tissue. Similar results occurred in a case of interstitial
Radiolabeled methionine has been investigated extensively in can- pneumonia with a Ki-67 of 15% and inflammatory cells with a
cer imaging with PET. The normal biodistribution of C-11 methio- slightly increased Ki-67.
nine (MET) includes relatively intense tracer accumulation in the
pancreas, liver, stomach, and intestine and moderate tracer local-
ization in the bone marrow, tonsils, and the salivary glands, which Lung Perfusion Scintigraphy
does not interfere with evaluation of tumors in the thorax. 11C-
MET may have a specificity advantage over 18FDG by improving Although surgical resection of lung cancer remains the best thera-
the differentiation between cancer and inflammation. peutic option, only one in four patients presents with a resectable
Thymidine labeled with 11C at the methyl group (methyl-11C- disease. Prediction of postsurgical pulmonary function is crucial to
thymidine) makes possible PET imaging of cellular proliferation.165 limit morbidity and mortality after lung resection in patients with
Toyohara et al.166,167 developed 4′-thiothymidine labeled with 11C at ventilatory obstruction, making accurate preoperative evaluation the
the methyl group (4′-[methyl-11C]-thiothymidine [11C-4DST]) as a key to successful outcome.177–181 Measurement of ventilation indices,
new candidate tracer for cell proliferation imaging, which is resis- including forced expiratory volume in 1 second (FEV1), diffusing
tant to degradation by thymidine phosphorylase and is incorpo- capacity of the lungs for carbon monoxide, and maximal oxygen
rated into DNA. uptake, usually represents the first step of this evaluation process.
Recently, Minamimoto et al.168 studied 18 patients with NSCLC Spirometry-based pulmonary function tests have become the
with 11C-4DST. All malignant lesions showed focal increases in gold standard of preoperative functional assessment of lung func-
uptake of 11C-4DST and 18F-FDG.169 All NSCLC specimens con- tion, but the constant need for more accurate evaluation tools led to
tained Ki-67-positive cells. 11C-4DST showed a higher correlation the use of perfusion or ventilation lung scintigraphy, or both, to
with cell proliferation evaluated by the Ki-67 index in NSCLC than provide a regional assessment of lung function and thus offer the

Table 12.1 1 them is more effective for estimating FEV1ppo in lobectomies than
in pneumonectomies. At the same time, it has been observed that
Lung Perfusion Scintigraphy integration of SPECT with CT can provide more precise anatomic
information.
99m SPECT estimation of FEV1ppo is more accurate than planar
Radiotracer Tc macroaggregated albumin (MAA)
scintigraphy. In addition, Wu and colleagues found quantitative CT
Recommended activity Adults: MAA 40–150 MBq
Administration After having the patient cough and take several deep scanning to be an adequate tool. It is now routinely performed
breaths, 99mTc MAA must be injected slowly intrave- during the preoperative workup for lung cancer surgery.185–187
nously during three to five respiratory cycles with the Errors may be large with perfusion scintigraphy, and the accu-
patient in the supine position racy is not improved by the combined use of ventilation scintig-
Precautions A well-flushed indwelling line can be used if venous raphy.188 Nevertheless, patients undergoing lobectomy with a
access is difficult quantitative CT-predicted FEV1ppo of about 40% or less should also
Do not administer in the distal port of a Swan–Ganz undergo a perfusion scintigraphy. The technique has been used
catheter or any indwelling line or port that contains a extensively to predict lung function after resection and is still the
filter (e.g., chemotherapy line) simplest and most reliable method, even if it can underestimate post-
Imaging is preferably performed in the upright position to
increase chest cavity size and to minimize diaphrag-
operative measured FEV1 values. Conversely, CT-based methods
matic motion require more postprocessing and are limited by the need for scanner
If necessary, images can be obtained in the supine or calibration, the dependence of lung density on the inspiratory effort,
decubitus position and the x-ray beam collimation.189,190 Furthermore, Mineo et al.177
Planar acquisition Images should be obtained in multiple projections includ- showed that, although results achieved by planar lung scintigraphy
ing anterior, posterior, both posterior oblique, both and SPECT were comparable, SPECT accounts better for spatial
anterior oblique, and both lateral projections (1 million overlapping of the pulmonary lobes and differences in their size or
counts each). Either the anterior oblique or the lateral perfusion and better estimates hypoperfused areas/segments in can-
projections can be omitted. It may be possible to didates for lobectomy or pneumonectomy with no additional cost.
obtain only limited views in some patients
SPECT can assess the amount of pulmonary emphysema in
SPECT Acquisition over 36 nm (matrix 12.8 × 12.8, 0.3-nm
angle steps, 25 s/frame), by using a dual-head variable-
specific regions of the lung, without loss of accuracy by the super-
angle γ-camera, equipped with high-resolution low- position of lung tissues. Operable patients tolerate a pulmonary
energy collimators resection of a nonfunctional part of the lung without increased
It can be used to obtain a three-dimensional evaluation risk of respiratory failure during the postoperative period if deter-
of the perfusion, and is recommended by some inves- mined to be operable by SPECT.191
tigators Planar scintigraphy and SPECT lung perfusion scintigraphy
Image analysis before pulmonary surgery for lung cancer accurately predict postoperative FEV1ppo and can therefore be
Quantify differential Each lung is generally divided into three equal rectangu- considered reliable tools to establish operability of patients with
pulmonary function lar regions of interest on anterior and posterior views— lung cancer and ventilatory obstruction.
top, middle, and bottom Pulmonary function can also be investigated by MRI.192
The activity in the six regions of interest is reported for
perfusion or for both ventilation and perfusion
SPECT A semiquantitative analysis of planar and SPECT lung
perfusion scintigraphy images can be preoperatively
Malignant Pleural Mesothelioma
performed to estimate postoperative predicted FEV1
(FEV1ppo)
Malignant pleural mesothelioma (MPM) is the most frequent pri-
mary tumor of the pleura characterized by a poor prognosis. The
Adapted from: Society of Nuclear Medicine Practice Guideline for Lung Scintigraphy 4.0. Pub- pleural form is the most common of the three typical forms of the
lished online January 26, 2012. Copyright 2012 by the Society of Nuclear Medicine, Inc. Avail- disease —pleural, peritoneal, and pericardial—in about 75% of
able at http://www.snm.org/guidelines. cases. Once considered to be rare tumors, malignant mesotheli-
oma is now seen in increasing numbers. Death rates in the United
possibility of estimating postoperative pulmonary function by Kingdom are some of the highest in the world, at around 30 cases
means of the predicted postoperative FEV1 (FEV1ppo).182,183 In par- per million per year, similar to Australia and Belgium.193 In the
ticular, an FEV1 >2 L or >60% of the predicted value usually accounts United States, the annual incidence of malignant mesothelioma is
for a feasible pneumonectomy, with the values lowered to >1.5 L or approximately 2,500 to 3,000 cases.194,195
>40% of the predicted value for a lobectomy. These cutoff values The major etiologic factor for MPM is exposure to asbestos fibers,
exclude a considerable number of subjects who have a resectable particularly crocidolite.196 The long gestation period, up to 50 years
disease but whose pulmonary function appears too compromised of exposure to asbestos dust or fiber inhalation before the appear-
for them to successfully undergo lung resection. ance of asbestosis symptoms, can often mean that a diffuse MPM has
Lung perfusion scintigraphy with Tc-labeled macroaggregates of reached an advanced stage and spread to tissues of other organs.
albumin is the currently recommended protocol to estimate the Various approaches have been used in the treatment of MPM.
FEV1ppo (Table 12.11). Preoperative and postoperative assessment Radiotherapy alone is generally used for palliation. Patients who
by means of perfusion scan with planar acquisition (PA) and SPECT undergo chemotherapy have shown limited response, without sig-
has been evaluated. It has been suggested that surgical candidates nificant change in survival time.197 Aggressive surgical resection
with preoperative FEV1 <60% should always undergo lung perfu- (extrapleural pneumonectomy or radical pleurectomy/decortica-
sion scintigraphy to achieve accurate postoperative outcome pre- tion) used alone has also yielded disappointing results, with a
diction with an estimated FEV1ppo >40%, indicating an acceptable median survival time of less than 1 year.198 However, multimodality
surgical risk. Postoperative FEV1 estimation by perfusion SPECT therapy consisting of surgery followed by chemotherapy and
demonstrates good correlation with spirometrically measured radiotherapy has been shown to prolong survival.
FEV1. In this study, FEV1ppo, estimated by planar scintigraphy or
SPECT acquisition, was similar compared with spirometry-measured
postoperative FEV1.
Histopathology
No significant difference between either planar or SPECT scans On the basis of histopathology, it is possible to distinguish three
was reported by Piai et al.,184 who also suggested that each of types of mesothelioma: Epithelioid, sarcomatoid, and biphasic.193,199

Epithelioid mesothelioma is the most common type of asbestos with rare hematogenous spread even in the late stages of untreated
cancer. Approximately 50% to 70% of all mesothelioma cases are of disease. Even after aggressive local control measures, locoregional
this variety. The cell structure is similar to other diseases that man- recurrence is the fate of a majority of patients.
ifest in the tissue lining. The most notable one is adenocarcinoma. Many diagnostic modalities are used to identify patients with
Because of the similarities in cellular appearance, a misdiagnosis of MPM. Surgical staging consists of bronchoscopy, mediastinoscopy,
epithelioid mesothelioma is very common. Diagnostic problems can and/or laparoscopy with peritoneal lavage to rule out abdominal
be categorized into several groups. Determining whether a biopsy involvement. Before surgery, actually, there is no consensus as to
specimen is benign or malignant presents problems in two main which single modality should be used to confirm diagnosis prior
areas: (1) distinguishing between reactive mesothelial hyperplasia to surgery, but it is evident that imaging plays an essential role in
and epithelioid mesothelioma and (2) distinguishing between reac- the evaluation of MPM. Each imaging modality, particularly CT,
tive pleural fibrosis and sarcomatoid or desmoplastic mesotheli- MRI, and nuclear imaging, has its advantages and limitations, but
oma. Having decided that malignancy is present, the distinction their combined use is crucial in determining the most appropriate
must be made between epithelioid mesothelioma and metastatic treatment options for patients with MPM, allowing to select those
carcinoma, particularly in patients who have a history of malig- patients who may benefit from aggressive therapy.
nancy or atypical radiology, and between sarcomatoid mesotheli-
oma and other types of malignant connective tumors that may 18
F-FDG PET and PET/CT: Role in the
occasionally involve the pleura primarily.
Sarcomatoid is the least common type of mesothelioma, occurring
Actual Imaging Scenario
in approximately 10% to 15% of all cases. In relation to epithelioid The increasing role of nuclear imaging is because of 18F-FDG PET/
cancer cells, sarcomatoid cells feature a less uniform structure. Singu- CT, which plays a crucial role in the assessment of patients with
lar cells are more oval than they are cubed. In addition, the nucleus of known or suspected MPM. However, surgical or radiologic pleural
each cell is less distinct when viewed under a microscope. Like epithe- biopsy still provides the most accurate definitive diagnosis in MPM,
lioid, sarcomatoid mesothelioma can be difficult to diagnose because although it is a more invasive procedure than 18F-FDG PET/CT.

other disorders exhibit similar cell structures. For example, desmo- CT is the primary imaging modality used for the diagnosis and
plastic sarcomatoid mesothelioma, a subtype, has a rather innocuous staging of MPM, with signs such as pleural effusion, diffuse pleural
appearance, which may be dismissed as benign fibrous tissue. Pulmo- thickening with frequent nodularity, interlobar fissure thickening,
nary sarcomatoid carcinoma and sarcomatoid cancer are also fre- growth typically leading to tumoral encasement of the lung, and
quently misdiagnosed in individuals who suffer from sarcomatoid calcified pleural plaques. However, although some findings are
mesothelioma. The distinction between reactive fibrosis, sarcomatoid quite characteristic, none is pathognomonic for the disease; for
mesothelioma, or desmoplastic mesothelioma can be very difficult and example, enlarged nodes alone do not prove nodal involvement,
depends largely on the recognition of cellular atypia.200 so CT accuracy remains suboptimal.201 CT can also lead to under-
Biphasic mesothelioma, occurring in 20% to 40% of all cases, is estimation of the extent of disease in early chest wall involvement
the second most prevalent form of cancer. Unlike the more distinct and peritoneal studding.202,203 Despite these limitations, CT remains
cell structures of epithelioid and sarcomatoid, biphasic mesotheli- the imaging study of choice for initial evaluation of patients with
oma exhibits a more varied structure. In fact, biphasic mesotheli- or suspected for MPM, because it is superior to conventional chest
oma is named as such because both epithelioid and sarcomatoid radiography, even more in delineating the optimal site for biopsy
cells are present. The structure of such intermingled cells can vary and providing a tremendous amount of anatomic information
from one case to another. Sometimes, individual epithelioid and sar- about the stage of the disease.204–206
18
comatoid cells mix together in true patchwork form. Other times, F-FDG PET/CT is a useful diagnostic tool to identify and stage
each type of cell assembles in larger clusters. Because of the com- MPM and differentiate it from benign pleural disease. Mesotheli-
bined nature of biphasic mesothelioma, extreme precision is again oma, in fact, is 18F-FDG avid (Fig. 12.10), and initial studies sug-
necessary in the diagnosis process. gested that 18F-FDG PET/CT may be useful in the assessment of
Several factors have been shown to correlate with survival: prognosis and in the staging of patients with MPM.207–209
Intrathoracic lymph node metastases, distant metastatic disease, Increased 18F-FDG uptake is not uncommon in inflammatory
and the initial extent of pleural involvement. Patients affected with and infectious processes, and also radiation-induced pneumonitis is
mesotheliomas of the epithelial subtypes tend to survive longer a known cause of false-positive findings in PET/CT.210 The other one
than those with mixed or sarcomatoid subtypes. false-positive case can consist of an intense linear focus of uptake,
MPM diagnosis in the early stages is often limited by unspecific extending to the right chest wall because of bronchopleural fistula
symptoms, which mimic other illnesses and diseases, including with empyema. Nevertheless, MPM is a malignancy in which the
allergies, some cardiac conditions, immune system failures, and prognostic information provided by 18F-FDG PET imaging could be
persistent pneumonia of unknown etiology. Often, at onset the of value. Although most MPMs are highly FDG avid, lack of tracer
radiologic pattern is characterized by pleural effusion. Exudative uptake was previously reported in the epithelial subtype.211 The
effusion, typical of mesothelioma, is caused by the inflamed pleura. excellent sensitivity of 18F-FDG PET in detecting and staging MPM,
Thoracentesis can be used to extract pleural fluid for analysis. combined with the prognostic information of this method, can
Protein-rich fluid indicates transudative effusion. Biopsy and immu- make this imaging modality a useful adjunct to conventional evalu-
nohistochemistry findings plays a major role in helping to make ation. As known, PET with coregistration of anatomic and func-
the diagnosis, but they should be interpreted with due regard to the tional imaging data (PET/CT) improves the localization of regions
clinical setting and radiologic features, and with knowledge of with increased FDG uptake and accuracy of MPM staging. It is effec-
the wide morphologic variations seen in mesothelioma. tive for highlighting MPM metastases, which may not appear on
Mesothelioma is known as a particularly aggressive cancer, with other conventional imaging scans. By revealing the stage of the can-
a range of development rates. Although the genetic changes that cer, PET scans can also project survival of a patient with MPM.
lead to the disease’s initial development can take decades, mesothe- Because these scans help visualize a mesothelioma tumor’s volume
lioma grows quickly and spreads to other parts of the body within a and level of metabolic activity, theoretically it can be used to predict
matter of months. Because it is not generally diagnosed until its later how quickly the cancer will spread and how positive the patient’s
stages (usually stage III or stage IV), metastatic disease is common prognosis will likely be.
at the time of diagnosis. Mesothelioma progression normally affects Mesothelioma staging is a crucial diagnostic step that influences
the organs around the lungs ipsilateral to the side of the original the course of treatment and the patient’s prognosis. Several staging
tumor. It has shown a natural history of relentless local progression systems are in use. The IASLC and the International Mesothelioma

Figure 12.10. Axial computed tomography

(CT) and axial, coronal, and sagittal FDG posi-
tron emission tomography (PET)–CT fusion
images, illustrating the patterns of FDG uptake
in malignant pleural mesothelioma. Pattern of
intense FDG uptake corresponding to circum-
ferential pleural thickening seen on CT. (Images
courtesy of Nuclear Medicine–PET/CT Center
Azienda dei Colli, Monaldi, Naples, Italy.)
Interest Group (IMIG) previously developed a TNM staging system Although the IMIG staging system for MPM emphasizes the
that has been accepted by the UICC and the AJCC. The most widely importance of local tumor invasion in determining respectability,
used and most comprehensive system is the TNM system associ- these imaging techniques often fail to detect nonresectable tumor
ated with the IMIG, which emphasizes the importance of local invasion in the chest wall, mediastinal structures, or the diaphragm
tumor invasion in determining respectability.212 Patients’ diseases (T4).216 A consequence of the increasing use of TNM staging is that
are staged according to the IMIG TNM staging system by combin- accurate determination of the anatomic extent of disease is impor-
ing the information obtained from the CT and PET scans, whereas tant in selecting patients for potentially curative resection. CT plays
mediastinoscopy is the standard method for obtaining preopera- an important role in the assessment, diagnosis, and staging in
tive histologic evaluation of tumor involvement in mediastinal patients who are being considered for resection. CT features can also
lymph nodes, although the nodes in the para-aortic and aortopul- be used to preclude surgery in patients with obviously unresectable
monary window are inaccessible.213 Further evaluation of medias- tumors (e.g., diffuse extension of tumors into the chest wall, medias-
tinal node involvement together with histologic verification of tinum, or peritoneum or distant metastasis), whereas EPP is the sur-
local tumor spread is obtainable by the surgical procedure of gical procedure of choice for patients with resectable disease.217,218
extrapleural pneumonectomy (EPP). This distinction guides the choice of treatment options and implies
Although the current AJCC/UICC staging system and the methods significant differences in survival. Although CT is the most commonly
available for clinical staging represent advances made in the man- used modality for the evaluation of lymph node groups, its accuracy
agement of MPM during the past decade,214 they are imperfect. The remains suboptimal because enlarged nodes alone do not prove
IASLC database represents the largest, multicenter, and interna- nodal involvement.219 PET scans are highly effective in revealing can-
tional database on MPM to date. Analyses not only demonstrate that cerous activity in the lymph nodes, which implies a later stage of
the proposed TNM staging system effectively distinguishes the T and cancer in the traditional TNM staging system and the optimal thera-
N categories but also highlight areas for potential revision in the peutic strategy considering, for example, that disease can also spread
future. Further studies to improve the accuracy of staging in MPM to N2 mediastinal lymph nodes, which in many centers is considered
are warranted. to be a sign of inoperability, or N3 glands that may be missed. The
MRI can provide additional staging information. The excellent TNM system emphasizes criteria used to determine the extent of
contrast resolution of MRI imaging can allow improved detection of local tumor and lymph node involvement, both of which factors have
tumor extension, especially to the chest wall and diaphragm, and been shown to be related to the overall survival rate in MPM.220
better prediction of overall resectability. Anatomic and morphologic So, currently CT and PET scanning provide the most accurate
MRI features, similar to those seen on CT, are used to establish local information, whereas MRI does not appear to add significantly to
invasion of MPM. Loss of normal fat planes, extension into medias- PET/CT combined and should be used selectively. Video-assisted
tinal fat, and tumoral encasement of more than 50% of the circum- thoracoscopic surgery can provide some additional information
ference of a mediastinal structure are some of the MRI imaging about T status, transdiaphragmatic tumor invasion, and perito-
features that suggest tumor extension. Perfusion MRI is the most neal metastases. Currently available data in solid tumors indicate
promising technique for the assessment of the tumor microvascula- that PET/CT is more sensitive and specific than either of its con-
ture. In MPM, therapeutic effects of chemotherapy can be moni- stituent imaging methods alone.
tored with perfusion. Both CT and MRI are helpful in identifying the With locally advanced tumors, it is important to distinguish
location and extent of the involved area.215 between T3 (potentially resectable) and T4 (technically unresectable)

disease. This distinction guides the choice of treatment options and the metabolic activity in primary lesions of patients with metastases
implies significant differences in survival. The presence of N3 nodal was significantly higher than in those without metastases. These
disease or distant metastasis also precludes surgery. Although surgi- findings, later confirmed by Lee et al.,228 tend to support the hypoth-
cal staging is often required in patients with potentially resect- esis that tumors with high metastatic potential have higher energy
able lesions, CT, MRI, and PET have proved helpful in further requirements, suggesting that the observed increased glycolytic
delineating the extent of disease and can aid in choosing whether activity in primary lesions might be a necessary precondition for
to treat MPM surgically, medically, or both, as reported in some the acquisition of metastatic potential.229 The number of systemic
studies221,222 regarding the use of 18FDG PET/CT in the evaluation sites of relapse was lower in those patients who had received more
of patients with MPM. However, it is important to note that PET aggressive treatment. Patients with extrathoracic metastases had a
alone lacks the spatial resolution to detect transdiaphragmatic significantly higher SUV in the primary pleural lesion at all stages
extension of tumors. Some authors, for T4 disease, obtained as a of disease and shorter survival than those with nonmetastatic dis-
result the sensitivity, specificity, positive predictive value, nega- ease. The treatment process is similar to all types of mesothelioma.
tive predictive value, and accuracy of PET/CT, which were 67%, However, the rate of survival and expected survival time varies
93%, 86%, 82%, and 83%, respectively.223 For the purpose of from one type to another. Epithelioid mesothelioma offers the best
evaluating the ability of PET/CT compared with conventional chances for survival. Individuals with this type of cancer have an
preoperative CT to detect inoperable stages of MPM in order to expected survival rate of approximately 8.5 months. Sarcomatoid
avoid futile surgery, Sørensen et al.224 demonstrated that PET/CT mesothelioma offers slightly reduced expectations, with a mean
improves the accuracy of preoperative staging in MPM as com- survival time of 7 months. Biphasic mesothelioma is the most dan-
pared with CT alone in 29% of patients (caused by either distant gerous, with diagnosed patients expected to survive 6 months.
metastases or T4 disease). On the other hand, when comparing Surgical procedures for MPM can range from a pleurectomy/
PET/CT with the final histologic results obtained on all patients decortication for those patients with early stage disease to more
referred to surgery and by the surgical–pathologic results from aggressive procedures. In most cases, surgery alone can be inad-
EPP by mediastinoscopy and surgical–pathologic results together, equate because of residual disease and a high rate of relapse, and

the following results were obtained: Sensitivity of 50%, specificity is followed by chemotherapy and/or radiotherapy. Despite effective
of 75%, positive predictive value of 50%, negative predictive value of treatment, changes in tumor size can be minimal in tumors such
75%, positive likelihood ratio of 5, and negative likelihood ratio of as lymphomas, sarcomas, hepatomas, mesotheliomas, and gastro-
0.67. PET scan was found to be useful in the prediction of survival, intestinal stromal tumors. PET/CT is a functional measure of tumor
determination of mortality risk, and detection of metastases and metabolic activity, which is potentially more sensitive in detecting
recurrent disease. Erasmus et al.223 in their study noted that PET/CT change to therapy than anatomic measurements. PET/CT has been
did not detect the metastases in some patients with pathologic N1 demonstrated to be useful in the prediction of response to chemo-
disease because of the presence of confluent adjacent primary tumors therapy in several solid tumors, with the reduction in 18F-FDG
or absence of increased FGD uptake in the hilum and detected the uptake often preceding radiologic changes.230 There are no formal-
metastases in only two of the eight patients with N2 disease. Although ized guidelines for the measurement of response to chemotherapy
this may affect prognosis, it did not affect surgical management. using 18F-FDG PET in solid tumors. Visual analysis is challenging,
Furthermore, PET/CT inaccurately staged MPM as N3 (nonre- particularly in mesothelioma, because of the extent and distribu-
sectable) disease in three patients. In two of these patients, false- tion of disease.
positive increased FDG uptake in the N3 nodes was attributable to The most common semiquantitative parameter used is the SUV-
inflammation on histopathologic examination. Because of the max within a tumor.231,232 Mesothelioma is poorly suited to SUVmax
implications for management, authors advocate sampling of all measurements because it is often diffuse and heterogeneous. Defin-
FDG-avid N3 nodes in patients with MPM and also for N3 lymph ing the site to apply a representative SUVmax measurement is dif-
nodes that are enlarged according to CT criteria and are not FDG ficult and potentially unreliable. In addition, a measure that defines
avid, in patients considered for surgery. The authors concluded change on the basis of only 1 pixel within such a complex tumor
that the use of integrated PET/CT in patients with MPM increases mass is likely to be an oversimplification. There is an emerging
the accuracy of the overall staging and significantly improves the interest in volume-based measures for response assessment with
PET/CT selection of patients for EPP and suggested that whole- PET/CT, and volume-based 18F-FDG PET tumor assessment has
body integrated PET/CT should be the preferred modality for stag- been performed also for other tumors.233,234 Theoretically, this tech-
ing in patients with MPM. The sensitivity, specificity, positive nique can be particularly effective in MPM, as a predominantly con-
predictive value, negative predictive value, and accuracy of PET/CT tiguous tumor encasing the pleural space and defining the tumor
in lymph node staging in patients with N2 disease have been volume manually is laborious and unreliable.
reported as 38%, 78%, 60%, 58%, and 59%, respectively. Most published methods used fixed threshold techniques. Fixed
Flores225 observed higher SUVs in N2 disease (8.6 ± 3.4) than in threshold techniques are poorly suited to mesothelioma because of
N0/N1 disease (5.3 ± 2.1). The area under the receiver operating the plaque-like tumor mass and the problems associated with dif-
curve of the SUV was a strong predictor of N2 disease (78% ± 10%). ferentiating tumors from adjacent normal tissue, such as chest wall,
An SUV of <4 was associated with a longer survival than an SUV of mediastinum, liver, and heart. Therefore, Francis et al.235 have
>4 (24 months versus 14 months; p < 0.04), with the latter having developed a novel software that semiautomatically defines the 3D
a hazard ratio for death of 3.3 ( p = 0.03).225 boundaries of the tumor on 18F-FDG PET scans. This results in a
PET/CT has been demonstrated to detect extrathoracic metasta- measure of the total glycolytic volume (TGV), which is a composite
ses that are not suspected after routine clinical and conventional of tumor volume and total metabolic activity. The authors used this
radiologic evaluation. In fact, a well-documented advantage of 18F- methodology to compare the response to one cycle of chemother-
FDG PET over anatomic imaging modalities is its greater accuracy apy, as assessed by serial CT scans, with changes on serial 18F-FDG
for the detection of systemic metastases.207,226 As shown by Erasmus PET scans in patients with MPM. They observed the role of serial
and colleagues,223 18F-FDG PET/CT improves extrathoracic staging 18
F-FDG PET in assessing the response to chemotherapy after one
by detecting lesions missed in conventional imaging or by correctly cycle. Patients with a partial response had a lower median total
characterizing equivocal lesions. These authors indicated that pre- glycolytic volume (TGV: A volume-based measure of total glycolysis)
operative 18F-FDG PET/CT detected extrathoracic metastases not (30% versus 71% of baseline) compared with those with stable disease.
identified by conventional imaging in 24% of patients with MPM. Reduction in TGV was predictive of improved survival ( p = 0.015).
Gerbaudo et al.227 described that, at initial staging of MPM, met- We do not know what change in total lesion glycolysis is required
astatic failure sites were more FDG avid than primary lesions and for a response. Because the dynamic range is larger, a suggested

figure of 40% for a response should be considered on the basis of the csr/1975_2008/, based on November 2010 SEER data submission, posted to
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and quantitative changes in global tumor glycolysis using PET-FDG imaging:

Chapter 13
Renal Carcinoma
Antonija Balenovic • Jasna Mihailovic • Katherine Zukotynski
Introduction including partial nephrectomy have emerged as an alternative to

radical nephrectomy, particularly in patients with early stage
Renal cell carcinoma (RCC) accounts for approximately 3% of all tumors, poor renal reserve, or the absence of a normal functioning
adult cancers1 although the incidence has been slightly increasing contralateral kidney.6,11 Of note, prospective randomized studies
in recent years.2,3 It is estimated that over 50% of RCC cases are have not shown a benefit for patients receiving radiation therapy
found incidentally on diagnostic imaging studies performed for before or after surgery if RCC is confined to the kidney and/or
other reasons. The average age at diagnosis is 60 years and men renal vein.4,12
are more commonly affected than women, with a ratio of 1.5:1. A For patients with metastatic RCC, palliative nephrectomy can
number of environmental, occupational, hormonal, cellular, and relieve pain, hemorrhage, hypertension, or hypercalcemia. Pallia-
genetic factors have been associated with the development of tive radiation therapy is effective in relieving symptoms in patients
RCC.4 The most frequent symptom associated with RCC is hema- with metastatic disease, especially those with bone and brain
turia, which can be either microscopic or gross in advanced dis- metastases.4,13 Chemotherapy has not produced significant results
ease. Other signs and symptoms include flank pain, a palpable in advanced stage RCC. Conventional cytotoxic therapies as well
abdominal mass, systemic paraneoplastic syndromes, or symp- as hormonal and immunotherapies have had low response rates.
toms from metastatic disease. Primary RCC is highly angioinvasive In the past, cytokine therapies such as interferon alpha (IFN-α)
and is associated with hematogenous and lymphatic metastases. and interleukin (IL-2) were the main systematic treatments avail-

Malignant spread of disease can occur via local infiltration through able for advanced RCC.14,15 However, recent advances have led to
the renal capsule, by growth along the venous channels to the the development of agents that target specific biologic pathways.
renal vein or vena cava or by drainage along lymphatic vessels. Tyrosine kinase inhibitors (multiple TKIs) that target the vascular
The right kidney drains predominantly into the paracaval and endothelial growth factor receptors (VEGFRs) such as sunitinib,
interaortocaval lymph nodes whereas the left kidney drains to the sorafenib, and pazopanib and inhibitors of the mammalian target
para-aortic lymph nodes.5 Lymph node metastases occur with an of rapamycin (mTOR) such as temsirolimus and everolimus, are
incidence of 9% to 27% and most often involve renal hilar, para- now available and have revolutionized the treatment of RCC.16,17
aortic, and paracaval lymph nodes.6 The most common sites of These new developments have made it necessary to find novel
RCC metastatic disease are the lungs (75%), soft tissue (36%), bone biomarkers to predict prognosis and to identify patients in such
(20%), liver (18%), skin (8%), and the central nervous system a way that optimal targeted therapy can be administered.13,18–20
(8%).7 The most lethal of all urologic malignancies, it is estimated One such approach involves development of novel radiotracers for
that 25% to 30% of patients with RCC present with metastatic positron emission tomography (PET)/computed tomography (CT).20
disease.3 The prognosis following a diagnosis of metastatic RCC is
extremely poor, regardless of the site of disease.6,8,9 Moreover, it is Initial Diagnostic Workup and Staging
thought that 20% to 40% of patients develop metastases following
nephrectomy.7,10 of Renal Cell Carcinoma
Renal lesions are common findings on anatomic imaging. Although
the majority are benign (e.g., renal cysts and angiomyolipomas
Pathologic Classification [AMLs]), if a malignant neoplasm is suspected, ultrasonography
(USG), contrast-enhanced computed tomography (CECT) or mag-
There are several histopathologic subtypes of RCC. The most netic resonance imaging (MRI) can be helpful for further evalua-
common subtype is clear cell carcinoma, accounting for approxi- tion. USG and CECT remain the initial imaging modalities of
mately 70% to 75% of cases.10 Other less common subtypes choice for the accurate assessment of renal lesions.13 Though
include papillary RCC (10% to 15%) and chromophobe RCC (5%). MRI is usually not the initial imaging modality of choice, it has a
The sarcomatoid variant of RCC (1% to 6%) is associated with a higher sensitivity compared to CT for the evaluation of compli-
significantly poorer prognosis.8 Malignant tumors arising in the cated cysts. Also, MRI provides additional diagnostic value in the
upper urinary tract (renal pelvis and ureter) account for approxi- evaluation of lesions with minimal amounts of fat or with intra-
mately 1% to 7% of all renal neoplasms. Since the mucosal sur- cellular fat.21
faces of the renal pelvis, the ureter, and the bladder have the In most cases once the diagnosis of RCC is made, a staging
same embryologic origin, many of the etiologic factors as well as evaluation should be undertaken, which includes a clinical history,
the natural history and general management of these tumors also physical examination, blood work, urinalysis, and imaging such as
apply to tumors of the urinary bladder. Therefore, these tumors a chest x-ray and CT or MRI of the abdomen and pelvis.13 Patients
will be described together in the chapter on cancer of the urinary with symptoms suggestive of bone metastases can be further eval-
bladder. uated with skeletal scintigraphy and CT or MRI of the brain can
be performed if the physical examination suggests brain metasta-
ses. Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) PET/CT, although
routinely used in the assessment of malignant disease,22–24 is not
General Management of Renal a standard tool for the diagnosis or follow-up of patients with RCC,
Cell Carcinoma Patients according to the National Comprehensive Cancer Network (NCCN)
and European Society for Medical Oncology (ESMO) guidelines.13,25
The standard therapy for nonmetastatic RCC has long been radi- The use of FDG PET/CT is limited in the evaluation of genitouri-
cal nephrectomy in which the malignant tumor is removed along nary lesions by significant physiologic FDG activity in the kidneys,
with the kidney, the adrenal gland, and the perinephric fat collecting system, and urinary bladder26 and often low activity at
enclosed within Gerota’s fascia. Regional lymph node dissection is sites of pathology. Therefore, close attention must be paid to both
performed routinely. More recently, less aggressive interventions the PET and CT portions of the study to effectively characterize
179

Figure 13.1. A 71-year-old male post left

nephrectomy for renal cell carcinoma. A: PET/
CT performed 3 months after radiotherapy of a
left iliac bone metastasis (and prior to planned
cardiosurgery), shows a large heterogenous
FDG-avid lytic expansile mass in the left iliac
bone. FDG activity is seen throughout the
mass, most intense in the medial part of the
lesion (SUVmax range 3.5 to 8.6). B: Follow-up
PET/CT performed 8 months later shows pro-
gression of the FDG-avid left iliac bone mass
(SUVmax 11.7). No additional sites of meta-
B static disease were seen (FDG activity in the
sternal region was related to cardiac surgery).

Chapter 13 Renal Carcinoma 181
renal lesions.27 Despite these concerns, the role of FDG PET/CT in the last dose of chemotherapy and the follow-up FDG PET/CT
patients with suspected RCC has increased over the last few however, data in genitourinary malignancy is limited.
years.28 FDG PET/CT can be used to characterize indeterminate
cysts, detect both primary and metastatic disease and may be use-
ful for preoperative disease characterization/staging RCC and for Standardized Uptake Value in Renal
postoperative surveillance of advanced RCC27,28 (Fig. 13.1). In Cell Carcinoma
addition, recent advances have led to the use of PET radiophar-
The maximum SUV (SUVmax) represents the highest radioactiv-
maceuticals other than FDG in the evaluation of RCC patients,
ity concentration in one voxel within the region of interest (ROI)
although this remains to a large extent still in the realm of
and is often used as a semiquantitative measure of FDG uptake
research.29–31
or glucose utilization in an ROI. The SUVmax can serve as a
biomarker, providing prognostic information or quantifying
FDG PET/CT in the Initial Evaluation and Staging therapy response between baseline and follow-up FDG PET/CT
studies.
of Renal Cell Carcinoma Patients There is no specific (or “cut-off ”) SUVmax that suggests a
The most widely used PET radiotracer in genitourinary oncology is diagnosis of RCC. According to published reports, the SUVmax of
FDG, although it is well known that because of its urinary elimina- biopsy-proven RCC, either primary or metastatic, demonstrates a
tion, FDG is not an ideal radiotracer for this purpose32 (Table 13.1). broad range.33,34 Further, there is no definite correlation between
To minimize this limitation, FDG PET/CT studies in renal and blad- SUVmax and RCC histopathologic subtype,34 although a correla-
der cancer patients are occasionally modified by using diuretics and tion has been seen between SUVmax and lesion size, with lesions
performing bladder catheterization. Otherwise, patient preparation larger than 5 cm demonstrating increased FDG activity.35 There
and study acquisition is the same as in other cancer patients. In are mixed results regarding the analysis of glucose transporter
general, patients are asked to avoid strenuous exercise for 24 hours GLUT-1 expression and RCC FDG avidity. For example, a study by

and to fast for 4 to 6 hours prior to radiotracer administration. It is Miyakita et al. suggested there was no correlation of GLUT-1
also recommended that the level of glucose in the blood at the time immunoreactivity and FDG-PET positivity;35 however, positive
of radiotracer administration should not exceed 10 mmol/L (ideally GLUT-1 expression was seen in larger tumors. Lidgren et al.36
8 mmol/L). In adults, an empiric dose of FDG is injected intrave- showed that RCC was associated with high GLUT-1 expression
nously, typically ranging from 185 to 555 MBq (5 to 15 mCi). Imag- and that there was a significant difference among different histo-
ing is performed after an uptake period of 60 ± 10 minutes. First a logic subtypes of RCC. Specifically, in 187 patients GLUT-1 expres-
scout CT is performed, followed by a low-dose CT for PET attenu- sion was significantly higher in clear cell RCC compared with
ation correction and anatomical correlation. PET data acquisition papillary RCC or chromophobe RCC. However, in clear cell RCC,
follows, usually with the whole body scanning from the skull base GLUT-1 expression had no correlation with clinicopathologic
to the thighs, requiring a total of 7 to 10 bed positions at 1 to tumor stage. In the subgroup with low GLUT-1, there was a trend,
4 minutes per bed position, depending on the scanner type and the although it was not significant, to improved survival in patients
desired image quality. CECT may be performed either in conjunc- with either the clear cell or the papillary RCC subtypes.36 Several
tion with the PET/CT, as a separate study or not at all, depending studies have explored the prognostic significance of an SUVmax
on the clinical indication and pre-existing contraindications, if index. In general, patients with RCC and a high SUVmax index
present.24 have poor prognosis.20,33
The timing of the PET/CT study should be coordinated with FDG is sensitive for the detection of RCC metastases and it is
other procedures which could alter FDG uptake in the affected estimated that FDG activity is seen in over 95% of metastases
region such as surgery, radiotherapy, or chemotherapy. For exam- diagnosed by CT.20,37 There is no definite relationship between the
ple, increased FDG uptake can be seen in tissue after radiation SUVmax of the primary tumor and the SUVmax of metastatic dis-
therapy and it is therefore recommended to wait at least 8 weeks ease or between different sites of metastatic disease in the same
after external beam radiation before evaluating (or re-evaluating) patient. Although the lungs are the most frequent site of metasta-
the irradiated area for residual disease. For patients on chemo- ses, certain anatomic sites which are rarely affected by RCC meta-
therapy, the timing of follow-up FDG PET/CT is variable. It has static disease (uterus, pancreas, muscle metastasis) can present
been suggested that at least 4 weeks be allowed to elapse between with the most intense FDG accumulation.20
Table 13. 1
PET Radiotracers in Renal Carcinomas
Radiotracer by tumor type Biologic analog Function Measured effect Indication for PET/CT
18
F-FDG Glucose Glycolysis Aerobic and anaerobic glycolyses; Staging; assessment of metastatic disease and
glucose consumption therapy response
18
F-FMISO NA Measures hypoxia Tumor hypoxia Local staging
18
F-FLT Thymidine Cell proliferation Activity of enzyme TK1 Predicting treatment response/failure and the
physiologic effects of VEGFR TKI
11
C-acetate Acetate Fatty acid syntheses Lipid synthesis Staging, restaging, evaluation of salvage
therapy
124
I-cG250 Monoclonal chimeric Targeting antigen Expression of CAIX in RCC cell— Identification of RCC
131
I-cG250 G250 antibody CAIX, expressed in marker of poor prognosis Local radioimmunotherapy
RCC cells
FDG, Fluorine-18-fluoro-2-deoxy-D-glucose; PET, positron emission tomography; CT, computed tomography; 18F-FMISO, Fluorine-18-fluoromisonidazole; NA, not applicable; TK1, thymidine kinase
1, VEGFR TKI, vascular endothelial growth factor tyrosine kinase inhibitors; 18F-FLT, Fluorine-18-3-deoxy-3-fluorothymidine; 11C-acetate, Carbon-11 acetate; 124I-cG250, 124-Iodine-labeled chimeric
form of monoclonal antibody G250; 131I-cG250, 131-Iodine-labeled chimeric form of monoclonal antibody G250; CAIX, carbonic anhydrase IX.

Figure 13.2. A 62-year-old male with an

FDG-avid renal cell carcinoma. PET/CT shows
multi-focal radiotracer activity in both kidneys
related to physiologic urinary excretion. Axial
nonenhanced CT shows a small left renal cor-
tical nodule (green arrow), which was hyper-
vascular on contrast enhanced images (red
arrow) and intensely FDG-avid on PET (green
arrow).
FDG PET/CT in Characterization

cally shows FDG uptake comparable to normal renal paren-
of Renal Lesions
chyma; however, FDG uptake can be heterogeneous depending
Detection and characterization of incidental renal lesions on on the subtype and the size of the tumor. Although RCC can be
PET/CT can be challenging because of the presence of physio- incidentally detected on FDG PET/CT, many incidentally detected
logic FDG activity in urine and limited FDG activity at sites of renal lesions are benign and it is important to be aware of the
disease. The importance of viewing both the PET and CT compo- imaging features that suggest specific pathology. Several causes
nents of a PET/CT study to characterize renal lesions as benign of focal FDG accumulation in the kidney on PET/CT are summa-
or malignant cannot be overemphasized (Fig. 13.2). RCC typi- rized in Table 13.2.
Table 13.2
FDG PET/CT in Renal Pathology
Renal Pathology Findings on CT Findings on FDG PET Role of FDG PET/CT
Renal Cell Cancer Nonenhanced CT: Hypo, iso- or hyperdense. Variable FDG uptake. Limited role in diagnosis and staging of primary
CECT: Significant postcontrast enhancement disease.
particularly with clear cell carcinoma, although Useful in restaging, detection of metastases, and
can be heterogeneous caused by tumor assessing treatment response.
necrosis.
Renal Angiomyolipoma Detection of macroscopic fat on CT is a Variable FDG uptake. Limited role.
characteristic finding.
Renal Oncocytoma Indistinguishable from RCC. Variable FDG uptake. Limited role. Not useful for differentiation from RCC.
Renal Lymphoma Multiple masses or solitary mass or diffuse renal Typically FDG uptake is intense at Useful to detect metabolically active renal disease as
infiltration. May be associated with disease sites of disease. May be associ- well as additional sites of disease elsewhere.
elsewhere or may be an isolated finding. ated with anatomic change on the Useful for follow-up of therapy response, detection of
accompanying limited CT. residual and/ or recurrent disease.
Renal Leukemia Diffuse renal infiltration with nephromegaly or focal Limited data with variable FDG Can be useful as a nonnephrotoxic imaging
masses. uptake. Often moderately to modality.
intensely FDG-avid.
Renal Metastases Solitary or multiple renal masses involving one or Often intensely FDG-avid. Moderate role. Lesions can be clearly detected if
both kidneys. peripherally located.
Renal Cysts Simple cysts: Homogeneous, water density, sharp No FDG uptake/ photopenic. No role for assessing simple cysts.
border with the adjacent renal parenchyma. No FDG uptake except in infected Useful for noninvasive characterization of complicated
Complicated cysts: Wall thickening, nodularity, solid cysts. cysts or for localization of infected cysts.
components in the cystic lesion.
FDG, fluorine-18-fluoro-2-deoxy-D-glucose; PET, positron emission tomography; CT, computed tomography; SUV, standardized uptake values; CECT, contrast-enhanced CT; RCC, renal cell cancer;
GLUT-1, glucose transporter 1.

A B

Figure 13.3. A 50-year-old male post right
nephrectomy for renal cell carcinoma. A: Non-
enhanced CT shows a left renal cyst which is
photopenic on PET (cursor ). B: Nonenhanced
CT shows small retroperitoneal lymph nodes
that are not significantly FDG-avid on PET
(cursor ).
Renal Cysts RCC frequently contains calcification and may infrequently contain
a small amount of adipose tissue as well, the presence of calcium
The prevalence of several benign renal lesions, such as cysts, and fat suggests the diagnosis of RCC rather than AML. There is
increases with age, male gender, renal dysfunction, and hyper- controversial and limited data on the role of FDG PET/CT in the
tension.38 The typical appearance of a simple cyst on PET/CT is a diagnosis of AML, since AML lesions demonstrate variable FDG
well-defined, thin-walled, low attenuation (0 to 20 Hounsfield uptake.27
units (HU)), photopenic lesion.39 Simple cysts do not require fur-
ther follow-up (Fig. 13.3). Complex cysts often have suspicious fea-
tures such as wall thickening, nodularity, or irregular peripheral
calcifications and may be multilocular with multiple enhancing Renal Oncocytoma
septa or nodularity. PET/CT may provide additional characteriza- The renal oncocytoma is typically an asymptomatic solid benign
tion and precise localization of complex cysts. For example, in renal tumor that presents as an incidental finding at the time of
autosomal dominant polycystic disease a benign appearing FDG imaging. On CT, oncocytomas are often isodense or hypodense
PET/CT study in conjunction with a negative cyst aspiration can compared to normal renal parenchyma with homogeneous
be helpful and avoid additional imaging/intervention.39 Even enhancement. On FDG PET/CT oncocytomas often have low-level
though USG, CT, or MRI with or without tissue sampling is pre- activity comparable to adjacent normal renal parenchyma; how-
ferred for the characterization of cystic renal lesions with solid ever, intense FDG uptake has also been reported.27,44,45 Renal
components,40 FDG PET/CT can help prevent unnecessary inter- oncocytomas are indistinguishable from RCC on imaging. Also,
vention and optimal management of suspicious lesions in certain although oncocytomas are considered benign lesions, there are
cases.41,42 reported cases of local recurrence and metastases following
resection.44 It has been postulated that oncocytomas could reflect
a form of malignant chromophobe cell tumor, such as RCC. Tissue
Renal Angiomyolipoma
sampling is needed for a definitive diagnosis.
The renal AML is the most common benign tumor of the kidney.
Most AMLs are found incidentally on imaging studies performed to
investigate hematuria and contain variable amounts of blood ves-
sels, adipose tissue, smooth muscle, and rarely calcification. The
Renal Lymphoma
presence of macroscopic fat on imaging suggests the diagnosis.43 Primary renal lymphoma is rare and commonly associated with
Usually asymptomatic, AMLs can be associated with life-threatening disseminated non-Hodgkin lymphoma. Typical radiologic pat-
hemorrhage and therefore may require surgical resection. Since terns of disease are seen in renal lymphoma, including multiple

renal masses, perirenal disease, renal invasion from contiguous positive CT for local relapse in one patient and identified all bony
retroperitoneal disease, and diffuse renal infiltration. On CECT, metastases, whereas skeletal scintigraphy had two false negatives.
renal disease is typically of low attenuation compared with nor- Conventional imaging methods had higher sensitivity and lower
mal renal parenchyma. Large retroperitoneal masses can specificity compared to FDG PET/CT (94.7% versus 89.5% and
invade and displace the renal hilum. FDG PET/CT can detect 80% versus 83.3%, respectively), but the overall accuracy of both
metabolically active renal lymphoma although careful attention methods was the same (85.7%).
must be paid in order to distinguish FDG-avid renal lymphoma Generally, there is a wide disparity reported in the overall accu-
from physiologic activity in the collecting system.46–48 Primary racy of FDG PET/CT for RCC. Reports of sensitivity range from
renal leukemia is rare and there is little published data 31%35 to 95%.20 Data from published reports are summarized in
on the imaging features of leukemic involvement of renal Table 13.3.
parenchyma.48,49 In a study by Safaei et al.,52 36 patients with advanced RCC
referred for restaging had FDG PET and the sensitivity and speci-
ficity of lesions detected with FDG PET later biopsied were 88%
Renal Metastases and 75%, respectively. In a series of 53 patients who had FDG PET,
35 patients for characterization and staging of a suspicious renal
Renal metastases are rare and are often clinically occult. These
mass and 18 patients for restaging after surgery, PET produced a
can present with a solitary renal mass or with multicentric disease
high rate of false-negative results (sensitivity, specificity, and accu-
involving one or both kidneys. Typically intensely FDG-avid on
racy were 47%, 80%, and 51%, respectively). However, PET
FDG PET/CT, the most common primary malignancies associated
detected all sites of metastatic disease identified by CT and an addi-
with renal metastases are lung, breast, and colon.48,50
tional 8 sites, leading to an accuracy for metastatic disease of 94%
versus 89% for CT.53 In a series of 66 patients who had FDG PET
for suspected or known RCC, FDG PET had a sensitivity of 60%
Role of PET/CT in Postoperative (compared to 91.7% for CT) and was less sensitive in detecting
Surveillance of Advanced Renal primary tumors, retroperitoneal lymph node metastases, and dis-
tant metastases.54 The discrepancy in the reported FDG PET sen-
Cell Carcinoma sitivity may be partly caused by the increasing knowledge gained
over the years resulting in better image interpretation and signifi-
According to the ESMO Recommendations and the NCCN Guide- cant improvement in equipment.
lines,13,25 imaging examinations following surgery for advanced The strength of whole-body PET/CT in postoperative surveil-
RCC should be symptom driven and dependent on the specific lance for RCC is the ability to image the entire body for sites of
clinical situation. Accordingly, there are no definite recommenda- metastatic disease (Fig. 13.4). This is important since a solitary
tions on the use of FDG PET/CT in the surveillance of patients with metastasis, if treated aggressively, might result in alleviation of
RCC. Recent results in the literature suggest that imaging surveil- symptoms and prolonged survival. Ramdave et al.56 reported that
lance can detect early disease recurrence so that optimal salvage in eight patients referred for evaluation of local recurrence and/or
therapy can be administered. This is particularly important in RCC, metastatic disease, FDG PET changed management in four
where surgical resection might be the patient’s best option for patients (50%), namely the disease was up-staged in three and
cure. It is thought that RCC recurs locally in approximately 5% of recurrence was excluded in one. In addition, in six patients (35%)
patients after radical nephrectomy and that if diagnosed early, who would have had a radical nephrectomy after initial conven-
these recurrences are treatable.51 FDG PET/CT and CECT may be tional imaging, FDG PET altered the proposed treatment; in three
complementary in the diagnosis of recurrent disease, either locally cases, surgery was avoided because of the interpretation of benign
or distant. In a study by Park et al.,37 63 RCC patients were evalu- pathology or detection of unsuspected metastatic disease. Another
ated after surgical treatment for an average of 24.3 months of issue, also affecting treatment decisions in RCC patients, is the
follow-up; 51% of these patients developed a local recurrence or detection of incidental second primary cancers. Overall, 5% to
distant metastases. Among 12 patients with local recurrence, 5 had 10% of patients on whom FDG PET/CT is performed are found to
isolated local recurrence and 7 had distant metastases as well. All have a second primary tumor. FDG is a highly sensitive method
were diagnosed by abdominal CT; FDG PET/CT was falsely nega- in this regard with a reported sensitivity of over 90% and positive
tive in one. However, FDG PET/CT correctly diagnosed a false- predictive value (PPV) of 69%.57
Table 13.3
FDG—Published Studies on Positron Emission Tomography in Renal Cell Carcinomas
Studies (References) PET Tracer Purpose Patients (n) Sensitivity (%) Specificity (%)
Goldberg et al.39 [F-18]-FDG Staging 26 90 100

Safaei et al.52 [F-18]-FDG Staging 36 88 75
Miyakita et al.35 [F-18]-FDG Staging and GLUT-1 expression 19 31 NA
Aide et al.53 [F-18]-FDG Staging 53 47 80
Majhail et al.26 [F-18]-FDG Staging 24 64 100
Kang et al.54 [F-18]-FDG Staging 66 60 100
Park et al.37 [F-18]-FDG Staging 63 90 83
Namura et al.20 [F-18]-FDG Impact of SUV on survival 26 95 NA
Kayani et al.55 [F-18]-FDG FDG as a biomarker of therapy response 44 87 95
Ueno et al.34 [F-18]-FDG Assessment of early therapy response 35 89 NA
PET, positron emission tomography; [F-18]-FDG, fluorine-18-fluoro-2-deoxy-D-glucose; NA, not applicable; GLUT-1, glucose transporter 1.


A
B
Figure 13.4. A 56-year-old male post left nephrectomy for renal cell carcinoma.
A: PET/CT performed 1 month after the nephrectomy shows an intensely FDG-avid
retroperitoneal lymph node (size 1 cm, SUVmax 6.2). B: Because of postoperative
complications (thrombosis), systemic therapy was postponed and a repeat PET/CT
performed 4 months later shows multiple intensely FDG-avid and enlarged lymph
nodes (SUVmax 9.3). A single site of focal FDG uptake in the left supraclavicular region
corresponds to a small lymph node on CT (SUVmax 3.8). C: Follow-up PET/CT per-
formed 9 months after sunitinib and sorafenib therapy shows FDG-avid metastatic
C disease involving lymph nodes above and below the diaphragm, the lungs, and liver
consistent with disease progression.

PET/CT Assessment of Treatment Other PET Radiotracers used

Response in Renal Cell Carcinoma
For decades, treatment options for patients with metastatic RCC Radionuclides used in PET typically have short half-lives and are
have been limited. Increasing knowledge of the underlying biology incorporated to form radiopharmaceuticals that can be divided
of RCC, however, has identified pathways for targeted therapy, into two groups: Tracers that follow a particular metabolic path-
implying an increasing need for surrogate markers to assess early way or tracers that target a specific receptor. The most widely
tumor response.58 There are several criteria that can be used to used radiopharmaceutical is 18F-FDG, a radioactive glucose ana-
categorize disease response such as Response Evaluation Criteria log. Other radiotracers, that follow metabolic pathways and are
in Solid Tumors (RECIST),59 RECIST 1.1, the Choi criteria, the not excreted in the urine, are currently being investigated in RCC
modified Choi criteria, and the Size and Attenuation CT (SACT) patients. Radiotracers that target specific receptors such as
18
criteria. However, these criteria are anatomically based and sev- F-labeled sunitinib and 89Zr-labeled bevacizumab are also being
eral new drugs (sunitinib, sorafenib, temsirolimus, etc.) result in investigated.
disease stabilization, rather than substantial tumor regression.
Therefore, treatment with those drugs is associated with a low
response rate, according to the anatomic-based criteria, but with
Fluorine-18-Fluoromisonidazole PET/CT
improvement of overall survival (OS).58 Therefore, in early evalua- An important mechanism of RCC growth involves overexpression
tion of patients, anatomic-based criteria such as RECIST does not of a hypoxia-inducible factor and increased secretion of vascular
discriminate patients with stable disease (SD) from patients who endothelial growth factor (VEGF) leading to angiogenesis, neoan-
have progressive disease (PD) or partial response (PR). In addi- giogenesis, tumor proliferation, and metastatic spread.66 These
tion, treatment-induced changes in tumor density, which may be newly formed tortuous immature vessels have increased permea-
the result of response to therapy could be incorrectly interpreted bility resulting in elevated interstitial pressure, impaired oxygen
as disease progression.60,61 These limitations have led to the intro- diffusion, and tumor hypoxia. Tumor hypoxia can be imaged with
duction of new criteria based on functional imaging such as fluorine-18-fluoromisonidazole (FMISO) PET/CT.29 FMISO diffuses
dynamic contrast-enhanced MRI (DCE-MRI), dynamic contrast- across cell membranes. When the tissue oxygen partial pressure is
enhanced USG (DCE-USG), FDG PET/CT. Data analyses of DCE- less than 10 mm Hg and the cells are viable, FMISO is reduced by
MRI and DCE-USG are promising but complex. These imaging nitroreductase at which point it is trapped in the cell and accumu-
modalities are dependent on acquisition protocols and the indi- lates. Intracellular retention of FMISO observed 1 hour after radio-
vidual interpretation of results; consensus has not yet been tracer administration is thought to be specific for cellular hypoxia.
reached. Also, DCE imaging has risks associated with contrast The identification of hypoxia in RCC and its impact on tumor biol-
media, which can jeopardize patients with renal insufficiency.58 ogy and prognosis is an area of ongoing research.67–70 A study by
The role of FDG PET/CT in evaluating response to targeted Hugonnet et al.29 evaluated initial tumor hypoxia in metastatic
therapy in RCC is expanding. Several prospective studies have RCC, the change in hypoxia following sunitinib treatment, and the
suggested FDG PET/CT could serve as a biomarker of response to possible prognostic value of these parameters. Fifty-three antian-
sunitinib or sorafenib.29,30,33,34,55,62 A significant decrease of FDG giogenic naïve patients with metastatic RCC were prospectively
uptake has been seen in treated patients after only one treatment enrolled; metastatic targets were defined by CT before initiation of
cycle with sorafenib or sunitinib. The most interesting finding is therapy and assessed at 1 and 6 months after the initiation of
that patients with decreases in SUV can, simultaneously, have an therapy, using RECIST. Pretreatment target uptake of FMISO was
increase in tumor size. Since patients with decreases in tumor compared with uptake at 1 month. The relationship between base-
SUV have had a long progression-free survival (PFS), the change line and follow-up tumor hypoxia, with OS and PFS were assessed.
in tumor size is explained as probably caused by necrosis.63 In a There was an association between baseline tumor and PFS with
study by Ueno et al.,34 the effect of sunitinib or sorafenib therapy increased hypoxia suggesting shorter PFS. After 1 month of suni-
on long-term outcome was assessed with FDG PET. Patients pre- tinib therapy, FMISO uptake significantly decreased in target
senting with a high baseline SUVmax had shorter PFS and OS, metastases that were initially hypoxic, but did not significantly
where baseline SUVmax ranged from 2.3 to 16.6 (mean 9). Patient decrease in baseline nonhypoxic metastases. OS was not signifi-
whose SUVmax decreases less than 20% after therapy (cut-off for cantly different between hypoxic and nonhypoxic disease at
response in this study) had a worse prognosis, where SUVmax baseline and reduction in tumor hypoxia following therapy did not
after therapy ranged from 3.7 to 5.5 (median 7.1).34 In another correlate with either OS or PFS. Interestingly, tumor hypoxia as
study, patients who had a response to therapy, 20% reduction in assessed by FMISO uptake in metastatic RCC was less frequent and
SUV after 16 weeks, had better OS, whereas SUV reduction less pronounced than initially suspected. Further studies with pro-
observed after only 4 weeks was not prognostically significant.62 longed follow-up are needed to evaluate the prognostic significance
Discrepancy between FDG PET and CT in the evaluation of treat- of tumor hypoxia on PFS and OS.29,71
ment response after two courses of sunitinib was observed in a
study by Revheim et al.33 FDG PET showed PD in 3 of 12 patients
whereas CT detected progression in only one; PR was observed in
Fluorine-18-3-Deoxy-3-Fluorothymidine PET/CT
6 patients (no responders on CT), whereas SD was observed in 4 Fluorine-18-3-deoxy-3-fluorothymidine (FLT) is a PET tracer used
(compared to all 12 on CT). These results suggest that evaluating for imaging tumor proliferation.72,73 FLT is a thymidine analog
metabolic tumor response with FDG PET may provide additional that is trapped in the cytosol after being monophosphorylated. It
important information (Fig. 13.5). enters the exogenous DNA pathway via the action of thymidine
New PET tracers such as F-18-labeled sunitinib and Zr-89- kinase 1 (TK1), where TK1 is an enzyme synthesized when prolif-
labeled bevacizumab provide a unique opportunity for personal- erating cells enter the S-phase in the salvage pathway of DNA syn-
ized treatment planning64,65 and might give insight into drug thesis. The accumulation of FLT is tightly linked to TK1 enzyme
uptake during treatment as well as information on the develop- activity, which is closely associated with cellular proliferation. The
ment of tumor resistance. At the present time, PET is not incorpo- Ki-67 protein is required for cell proliferation through the synthe-
rated in commonly used response evaluation criteria; however, it sis of ribosome during the cell cycle and its expression phase in the
is accepted as an adjunct study in the evaluation of the progression cell cycle parallels that of TK1. Indeed, a direct correlation between
of disease.59 FLT uptake and proliferation as assessed by Ki-67 labeling index


A
1 2 3
Figure 13.5. A 66-year-old male post

nephrectomy for renal cell carcinoma, surgery
for metastatic disease to the right adrenal
gland, and 2 years of sinitinib and sorafenib
therapy. A: PET/CT shows increased FDG
avidity in the right adrenal fossa (SUVmax
5.3). B: PET/CT performed 3 months later
shows progressive disease in the right adrenal
fossa (SUVmax 6.9) and multiple FDG-avid
subcutaneous nodules (cursors) throughout
the torso and in both lower extremities B
(SUVmax 3.6).

(Ki-67 LI) has been observed.74 It has already been validated that by a scout infusion. External imaging permitted assessment
tumor proliferation assessed by Ki-67 is an important prognostic of tumor dosimetry, whereas serial measurements of blood
factor in nonsmall cell lung cancer.75 Further, the intensity of radioactivity permitted quantification of whole body and marrow
tumor FLT activity (SUV) is significantly correlated with Ki-67.76 In radiation absorbed dose. The maximum tolerated dose (MTD) of
131
RCC patients, FLT PET/CT has been used to characterize and I-cG250 is thought to be 2220 MBq/m2,86 with hematologic tox-
quantify changes in tumor proliferation during sunitinib exposure icity being the dose-limiting factor. The use of dose fractionation
and temporary sunitinib withdrawal.30 FLT PET/CT scans were and the effect of two sequential high doses of 131I -cG250 have
obtained 60 minutes after the injection of FLT: At baseline, during been investigated. A fractionated schema was much less likely to
sunitinib exposure and after sunitinib withdrawal. Plasma levels be immunogenic than a schema where there was a 3-month or
of VEGF and sunitinib were assessed at the same time points. greater interval between treatments. It thus appeared that a
Sixteen patients were evaluated and nearly all had some initial shorter interval between administrations of xenogenetic protein
reduction in tumor proliferation as measured by FLT PET/CT after was more likely to result in tolerance, whereas longer intervals
4 weeks of sunitinib treatment. During the treatment break, resulted in an immune response. Although patients achieved sta-
patients with a relative increase in FLT uptake suggesting an bilization of their disease lasting up to 12 months, there was no
increase in tumor proliferation (withdrawal flare) also had decrease in the burden of disease. 131I has a relatively “soft”
increased levels of plasma VEGF and comparatively worse out- β-minus emission, limiting radiation dose to contiguous normal
come than those who did not have or had a more limited with- tissue. Its gamma emissions, although relatively high energy,
drawal flare. nonetheless permit external imaging and quantification. Attach-
ment of radioiodine to protein is easily accomplished by estab-
11
C-Acetate PET/CT lished direct iodination methods. Iodinated antibodies, however,
suffer from disadvantages, particularly when the antibody under-
Carbon-11-acetate is a PET radiotracer, which is not eliminated goes cellular internalization into lysosomes. This usually results in
via the urinary tract and therefore may be of interest for evalu- prompt dehalogenation of the radioiodinated antibody with rapid
ation of RCC patients. Although Shreve et al.77 reported that RCC clearance of the (now unbound) radioactivity.
accumulates more 11C-acetate than normal kidney parenchyma, Studies have demonstrated that in internalizing systems,
this was not confirmed in a subsequent study by Kotzerke radiometal-labeled antibodies accumulate to a greater extent in
et al.78 tumor than do radioiodinated antibodies. Other radionuclides that
can be combined with cG250 in order to optimize cG250 RIT
Iodine-124 (124I)-cG250 PET/CT include 177Lu and 90Y.87 Medium-energy β-emitters 131I and 177Lu are
thought to be more effective for the treatment of small tumors,
Monoclonal antibody (MAb) G250 binds to carbonic anhydrase IX whereas in larger tumors 90Y may be a better option. The results of
(CAIX), a transmembrane protein that is overexpressed in primary an in vivo study has suggested that, compared to the other conju-
and metastatic clear cell renal cell carcinoma (ccRCC).31 Of note, gates, 177Lu- and 90Y-cG250 in combination may be the best option
G250 is thought to be absent in normal kidney parenchyma. A for RIT. Preliminary results have shown excellent tumor targeting
chimeric form of G250 (cG250) labeled with iodine-124 (124I) has of RCC lesions and stabilization of previously progressive meta-
recently been used for imaging RCC. Human clinical trials using static RCC disease with 177Lu-cG250 therapy.88 It is becoming clear
124
I-cG250 have shown high sensitivity, specificity, positive predic- that solid tumor RIT will be most useful in small volume disease,
tive values, and negative predictive values in the detection of pri- with an inverse correlation between tumor mass and absorbed
mary RCC and in metastatic disease.79–81 In 26 patients with renal dose being observed. RIT will therefore be most promising as part
masses, Divgi et al. found that 124I-cG250 PET/CT accurately identi- of a multimodality therapeutic strategy.
fied 15 of 16 ccRCC patients whereas all nonclear cell renal masses
were negative for tracer uptake.81 Sensitivity, specificity, positive
predictive values, and negative predictive values were 94%, 100%, Conclusions
100% and 90%, respectively. In future, 124I-cG250 may prove to be
a valuable tool in diagnosing metastases in patients with a G250 As the quality of diagnostic imaging has improved, the presenta-
positive primary tumor and in the work up of unknown renal tion of RCC has changed from that of a large palpable symptomatic
masses. Further, the favorable targeting properties of antibodies mass to that of an “incidentaloma.” Since small renal masses are
combined with radionuclides (124I-cG250) may also have therapeu- often benign, urologists are faced with a new dilemma: Perform a
tic potential for targeted radionuclide therapy (TRT) of RCC.82 nephrectomy on a potentially benign mass, or watch a potentially
aggressive tumor progress. As such, the need for an accurate non-
invasive method of characterizing renal lesions has become
Radioimmunotherapy increasingly important. Also, since surgery is often the only treat-
ment that is curative for RCC patients, accurate staging is very
Monoclonal antibodies targeting tumor-associated antigens have important. Although sensitive diagnostic imaging is necessary to
been developed for RCC and are being increasingly used for the avoid futile surgical intervention, a highly sensitive imaging modal-
treatment of metastatic RCC in investigational settings. In particu- ity could limit treatment options because of false-positive findings.
lar, the cG20 antibody that targets the CAIX antigen has been used FDG PET/CT is complementary to anatomic imaging for the char-
for both diagnosis and therapy.79–81 In a study by Divgi et al.,83 acterization of indeterminate incidental renal lesions and for stag-
escalating doses of 131I-G250 were administered to patients with ing and follow-up in patients with RCC. However, accurate
metastatic RCC. Fifty-two percent of patients showed stabilization interpretation of FDG PET/CT findings depends on a detailed
of disease progression. However, all patients developed a HAMA knowledge of the benign diseases that involve the kidney, RCC
reaction to the murine antibodies that were used. The excellent pathophysiology, and the effects of therapeutic intervention.
targeting and the SD population, however, suggested that repeat Although prospective PET/CT studies in RCC patients have been
therapies of a nonimmunogenic G250 may have promise in meta- the focus of scientific research for several years, many clinical
static ccRCC therapy. Therefore, chimeric form of G250 (cG250) questions remain unanswered, for example, why do patients even-
has also been tested in clinical radioimmunotherapy (RIT) tually progress on antiangiogenic therapy or become resistant to
trials.84,85 RIT with cG250 was well tolerated and generally safe. therapy? Perhaps the use of different PET radiotracers to evaluate
Kinetics of a therapeutic administration of RIT could be predicted cell proliferation and tumor hypoxia, thought to be implicated with

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C h apt e r 1 4
Bladder Carcinoma
Antonija Balenovic • Jasna Mihailovic • Katherine Zukotynski
Introduction t ransurethral resection (TUR) of the primary site of disease. It is

thought that 15% to 25% of new bladder cancers have associated
Urinary bladder carcinoma (UBC) was the fourth most common muscle invasion at the time of diagnosis with an additional 40%
cancer type in men in the United States in 2012, accounting for of patients who initially presented with superficial disease devel-
an estimated 7% of all new cancer cases, and the eighth most oping muscle invasion, usually after unsuccessful conservative
common cause of cancer-related death in men, accounting for an therapy. Perineural, lymphatic, and blood vessel invasion is com-
estimated 3% of all cancer-related mortality. It is three times mon after the tumor has invaded the muscle. Lymphatic drainage
more common in men than women.1 Based on long-term trends is to external iliac, internal iliac, and presacral lymph nodes. The
in cancer incidence and death rates, the incidence rate for UBC incidence of pelvic lymph node metastases is related to the depth
has remained relatively stable with a slow/gradual increase,1 of tumor invasion into the bladder wall and is in the range of 5%
possibly as a result of population aging. Rarely diagnosed in for T1 to 50% for T4 stage disease.3 The most common sites of
individuals below the age of 40 years, the median age of diagno- distant metastases are the lungs (23%), followed by the bones
sis is 65 years. (17%), soft tissues (8%), liver (7%), adrenal glands (4%), and kid-
Symptoms may include gross, painless hematuria, bladder irri- neys (3%) (Fig. 14.1).4,5
tability, or obstruction. Approximately 75% to 85% of all bladder
cancers are superficial tumors in situ (Tis), or T1 stage disease at

presentation. Because of the similarities in symptoms and cysto- Pathologic Classification
scopic appearance, diffuse Tis may be mistaken for interstitial
cystitis, especially if the bladder is distended at the time of cysto- More than 90% of urothelial tumors originate in the urinary blad-
scopic examination. Although most patients have solitary tumors, der, 8% originate in the renal pelvis, and the remaining 2% origi-
about 25% have multifocal disease.2 If multifocal or diffuse Tis are nate in the ureter and urethra. Urothelial (transitional cell)
present, involvement of the distal ureters, prostatic urethra, and carcinomas, the most common histologic subtype, may develop
periurethral prostatic ducts is common, which may account for anywhere transitional epithelium is present, from the renal pelvis
the high incidence of local recurrence following successful to the ureter, bladder, and proximal two-thirds of the urethra. The
Figure 14.1. An 80-year-old male with

newly diagnosed transitional cell carcinoma
of the bladder. FDG PET/CT shows an FDG-
avid hypodense liver lesion (SUVmax 4.2) as
well as FDG-avid metastatic disease in the
L2 vertebra (SUVmax 7.3) and in para-aortic,
right external iliac, and left axillary lymph
nodes (SUVmax 2.7 to 4).
191

distal third of the urethra is dominated by squamous epithelium Doppler. Although USG can be used to assess UBC, it is not a rou-
and squamous cell tumors, which represent 3% of all urinary tinely used method to stage UBC.12
tumors, are found predominantly in this location. Other histologic CT is both sensitive and specific for the detection of bladder
subtypes include adenocarcinoma (2%), small cell carcinoma cancer, with sensitivity ranging from 79% to 98%, and specificity
(1%), and rarely sarcoma.4 Appropriate histologic classification is of 91% to 95%.10,11 CT is often performed before TUR because it
important since patient management differs depending on the cell can provide information on pelvic and retroperitoneal lymph
type. For example, the chemotherapy regimens used to treat uro- nodes and liver lesions that can change management. On CT, the
thelial transitional cell tumors are ineffective for nonurothelial primary site of malignancy may appear as a papillary, sessile,
histology; therefore, patients with adenocarcinoma, small cell car- infiltrating, or mixed lesion involving the bladder wall. CT cannot
cinoma, or sarcoma are best treated according to protocols for determine the depth of tumor invasion.10 As the tumor grows, cir-
those cell subtypes. The presence of mixed histologic features at cumferential wall thickening may be seen, with enhancement
TUR suggests locally aggressive disease.6 similar to normal bladder. TUR can cause linear or focal enhance-
ment of the bladder wall, which may limit the specificity of CT. The
accuracy of CT for local bladder staging varies but is thought to be
Management of Patients with Urinary approximately 60% and for the detection of lymph node involve-
ment ranges from 73% to 92%.11–13 CTU has been recently pro-
Bladder Carcinoma posed as a method to evaluate the entire urinary system, including
the renal pelvis. Compared with IVU, CTU is faster, provides supe-
Besides the differences in histology which affect patient manage- rior anatomic detail, and permits better evaluation of the collect-
ment, the clinical spectrum of UBC can be divided into three catego- ing system, particularly when this is obstructed. Although virtual
ries that differ in prognosis, management, and therapy.4 The first cystoscopy, obtained by manipulating a three-dimensional recon-
category consists of nonmuscle-invasive tumors where the primary struction of CTU data, has potential for the detection of bladder
goal of therapy is to reduce the risk of recurrence and prevent pro- mucosal lesions, this is still considered a supplementary examina-
gression to a more advanced stage. The second group includes the tion and is limited by high radiation exposure.14
muscle-invasive lesions where the goal of therapy is to determine if MRI has several advantages over other imaging modalities,
bladder resection is needed and if the patient is at high risk for dis- because of its superior soft tissue characterization and ability to
tant spread of disease requiring systemic chemotherapy. In the third provide detailed imaging of the bladder dome, trigone, prostate,
group, that is, patients with metastatic disease, the goal of therapy is seminal vesicles, and other adjacent structures. MRI is generally
to prolong overall survival and to provide good quality of life. considered superior to CT for staging the site of primary bladder
TUR is the initial treatment for UBC. In muscle-invasive disease, cancer.15 Although the reported accuracy of MRI for UBC staging
the goal of TUR is to correctly identify the disease stage; therefore, varies from 60% to 85%, it is higher for local staging (73% to 96%)
bladder muscle must be included in the resection biopsies. In lower- and staging extravesical extension or differentiating superficial
grade tumors, intravesical therapy may be recommended for pro- from invasive disease (73% to 100%).15 Overstaging is the most
phylactic therapy (Bacillus Calmette–Guérin, BCG) or adjuvant therapy common error on MRI, occurring in up to 40% of cases.15,16 Of
(chemotherapy, usually with mitomycin C).4 If muscle invasion is note, this is also a significant problem in CT. In a recently pub-
identified on TUR, additional therapy may include radical cystectomy, lished prospective study by Vargas et al.16 of 16 patients with his-
partial cystectomy, bladder-preserving resection, neoadjuvant or tologically confirmed bladder cancer who had MRI, CECT, and
adjuvant systemic therapy, and chemotherapy for advanced meta- 11
C-acetate PET/CT prior to radical cystectomy and pelvic lymph
static disease. The most frequently used chemotherapy agents include node dissection, MRI overstaged 38% of patients (6/16), CT 44%
methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) or cis- (7/16), and PET/CT 12.5% (2/16). The limitation of imaging for
platin, methotrexate, and vinblastine (CMV) and gemcitabine and accurate staging was thought to be due, at least in part, to prior
cisplatin (GC). In elderly patients, the choice of chemotherapy regi- intravesical and/or systemic chemotherapy. However, since TUR
men is often limited by hepatic or renal dysfunction or other comor- and/or intravesical and/or systemic chemotherapy is often unavoid-
bid conditions. Currently, radiotherapy is used predominantly for able prior to imaging, a more accurate imaging approach is
palliation, that is, to reduce symptoms such as pain or bleeding. needed for patients with UBC.
However, with the prospect of developing three-dimensional treat-
ment planning with precise delivery of radiation therapy, this may
play a larger role in the treatment of UBC patients in the future.7 Hybrid Imaging
According to the latest NCCN and ESMO guidelines for bladder can-
Initial Diagnostic Work Up and Staging cer, PET/CT is not recommended for routine staging or follow-up
in bladder cancer patients.4,17 However, the currently used routine
of Urinary Bladder Carcinoma imaging modalities are limited in this regard. Once a urothelial tumor
Accurate staging is critical for appropriate management of patients has been diagnosed, accurate staging is needed. Furthermore, the
with UBC. If characteristic symptoms like hematuria, urinary tract patient is at high risk for developing new sites of malignancy either
obstruction, or bladder irritability are present, cystoscopy is typically at the same location as the site of primary disease or at a different
performed. However, imaging of the bladder alone is not sufficient. location. Also, it is thought that additional sites of primary malig-
Cystoscopy and TUR are helpful for staging the site of primary dis- nancy are relatively common, incidence of 7%.18 Therefore, there is
ease and determining tumor grade. Since urothelial cancer is a pan- a clinical need for imaging that can guide management, assess treat-
urothelial disease and may be associated with metastases, imaging ment response, and determine prognosis. It has been postulated that
is needed to detect tumor extension, lymph node involvement, and/ PET/CT could be helpful. Several PET tracers have been assayed in
or distant metastases.8,9 Intravenous urography (IVU), although pre- patients with bladder cancer. The most common include 18F-FDG,
11
viously used for the evaluation of the upper urinary tracts, has now C-acetate, 11C-choline, and 18F-choline (Table 14.1).
been largely replaced by CT, computed tomography urography (CTU),
MRI, and ultrasonography (USG).10 Dual-Phase PET/CT in Urinary
USG has a diagnostic accuracy approaching 95% for tumors
over 0.5 cm on the posterior or lateral bladder walls.11 These
Bladder Carcinoma
tumors often appear as polypoid or plaque-like, hypoechoic lesions Because of urinary excretion of FDG and radiotracer accumula-
projecting into the bladder lumen, with increased blood flow on tion in the bladder, FDG PET/CT is not ideal for the assessment of

Chapter 14 Bladder Carcinoma 193
Table 14. 1
Positron Emission Tomography Radiotracers in Bladder Carcinomas
Radiotracer by
Tumor Type Biological Analog Function Measured Effect Indication for PET/CT
18
F-FDG Glucose Glycolysis Aerobic and anaerobic glycolyses, glucose Local staging, recurrence/residual
consumption disease and metastasis evaluation
11
C-choline Choline Choline kinase Cell membrane metabolism, tumor proliferation Initial staging and restaging
18
F-fluorocholine Choline Choline kinase Cell membrane metabolism, tumor proliferation Initial staging and restaging
11
C-acetate Acetate Fatty acid syntheses Lipid synthesis Initial staging, and restaging
18
F-FDG, fluorine-18-fluoro-2-deoxy-D-glucose; PET, positron emission tomography; CT, computed tomography; 11C-acetate, carbon-11 acetate; 11C-choline, carbon-11 choline; 18F-fluorocholine,
fluorine-18 fluorocholine.
urologic malignancy. However, FDG is still the most widely used diagnostic TUR performed a few weeks prior to the PET/CT. In a
and investigated radiotracer in bladder cancer today.19–22 Washing study by Anjos et al.,25 in addition to standard FDG PET/CT,
out the excreted FDG by forced diuresis with furosemide and imaging was performed after furosemide injection, oral hydra-
acquiring postvoid images are considered to be crucial for over- tion, and voiding in 17 patients with UBC and resulted in
coming the above-mentioned disadvantage.23–27 improved detection of locally recurrent or residual bladder can-
The first attempts to empty FDG accumulated in the bladder cer. Indeed, in this study, 100% sensitivity and 100% specificity

prior to imaging were reported by Kosuda et al.28 who used ret- were achieved and 7 of 17 (41%) of patients were upstaged as a
rograde saline urinary bladder irrigation. This did not reduce result of delayed imaging. In a study by Harkirat et al.26 of 29
radiotracer activity to background levels and there was a 40% patients, 87% sensitivity and 100% specificity were achieved by
false-negative rate for the detection of recurrent or residual FDG PET/CT, compared to a sensitivity of 54% and a specificity
tumor in the bladder. Indeed, continuous bladder irrigation and of 54% for CT. In this study, 59% of patients had more accurate
immediate postvoiding imaging have not been found to be effec- staging caused by the delayed postdiuretic imaging. In seven
tive in reducing intravesical activity possibly because of continu- bladder wall lesions, hypermetabolism on PET was the only
ous renal function that results in radiotracer accumulation in the abnormality with no wall thickening discernable on the corre-
bladder. Recently, a prospective study on 19 patients compared sponding CT images.26
the results of FDG PET/CT in primary bladder cancer detection There are papers suggesting a high accuracy for FDG PET/CT
using four different protocols: (1) Empty bladder, (2) empty blad- in local and distant UBC staging, even if a diuretic protocol is not
der after flushing, (3) filled bladder (retrograde) with 50 mL used.5,32 In these cases, PET and CT images were carefully
saline, and (4) filled bladder (retrograde) with 100 mL saline.29 reviewed and compared (Fig. 14.2). Also, a recent study has sug-
UBC was detected in 16 patients, and the sensitivity of the pro- gested amending the dual imaging protocol so that patients
tocols with an empty bladder was lower (38%) than with retro- receive oral hydration, void frequently prior to initial imaging, and
grade filling (63%). However, bladder catheterization and subsequently hold back urine so that an additional pelvic image
retrograde filling are invasive procedures that increase the risk can be obtained. Of 12 patients with recurrent UBC, 11 were cor-
of urinary tract infection and could result in increased radiation rectly detected by PET/CT and of those, 5 (45.5%) were detected
exposure. Although Garcia-Vicente et al.,30 used a modified filled only after the delayed pelvic images were acquired. The sensitiv-
bladder technique and achieved good results for the assessment ity, specificity, and accuracy of PET/CT were 92%, 87%, and 89%,
of residual malignancy within the bladder (sensitivity 100% and respectively.33 Overall, forced diuresis with furosemide and the
specificity 83%), there have been no additional published series acquisition of postvoiding images may be helpful in imaging
using this protocol, possibly caused by the inconvenience for patients with UBC and has led to reconsidering the role of FDG
both patients and staff. PET/CT for staging and detecting recurrent disease in this popula-
Initial attempts using furosemide and oral hydration gave tion (Table 14.2).
poor results.23,24 More recently, however, a dual-phase protocol
has been suggested, with oral hydration, forced diuresis, and FDG PET/CT in Staging and Detecting Residual
postvoid imaging 2 to 3 hours after FDG administration.25,26 In
the dual-phase protocol, initial whole-body PET/CT is performed
or Recurrent Urinary Bladder Carcinoma
60 minutes following FDG administration. Subsequently, 60 to As with other malignancies, there is no cut-off SUVmax on FDG
120 minutes after the FDG injection, furosemide is injected. Also, PET/CT above which a diagnosis of bladder cancer can be defi-
1 hour after the injection of diuretic, a second PET acquisition is nitely made, although an SUVmax over 4 is suggestive of malig-
performed. This dual protocol produces excellent urinary radio- nancy.5,25,26 Interpretation of FDG PET/CT depends on both the
tracer washout, reducing bladder activity to background levels. appearance of the abnormality on PET and on CT.
Although this protocol is not effective in patients postcystectomy Local staging for UBC is commonly performed with TUR; how-
and urinary diversion, it is fortunate that bladder diversion walls ever, the presence of lymph node involvement (N) and distant
are an extremely uncommon site for tumor recurrence.31 Several metastases (M) associated with invasive bladder cancer is a major
studies evaluating FDG PET/CT for the detection of residual or determinant of survival and must be identified in order to plan
recurrent local disease using a furosemide dual-phase protocol appropriate management. FDG PET/CT has moderate to high sen-
have shown promising results. Lodde et al.27 reported FDG PET/ sitivity and specificity for staging UBC (see Table 14.2). One of the
CT had higher sensitivity for the detection of primary UBC than early prospective studies conducted in 70 patients with bladder
CT (85% versus 77%, respectively) but lower specificity (25% ver- cancer reported the sensitivity of lymph node staging was only
sus 50%, respectively) in 44 patients with UBC imaged prior to 57%, although this was better than the reported CT sensitivity of
radical cystectomy. The low specificity was thought to be, at least 33% in the same patient group. PET detected three of nine patients
in part, associated with inflammation of the bladder from the with metastasis to a solitary lymph node, all of which were missed

Figure 14.2. A 73-year-old male with

recurrent transitional cell carcinoma confined
to the bladder. FDG PET/CT shows thickened
bladder walls and a polypoid mass which are
FDG-avid (A), with FDG-avid disease best
seen after adjusting the images to decrease
B the intensity of physiologic radiotracer accu-
mulation in the bladder (B and C).


Figure 14.2. (Continued ) C
by CT.27 The specificity of both tests was 100%. Results by specificity of 94% for metastatic disease involving bone. The accuracy
Drieskens et al.,23 suggested all patients with metastasis to a soli- of PET/CT was superior to that of MRI or CT in 40% of patients,
tary lymph node were detected by PET and missed by CT. Patients as confirmed on post-PET follow-up. PET/CT changed clinical
with metastases, even if only to a solitary lymph node, have poor management in 68% of patients; 40% of which were understaged
survival and the improved sensitivity of PET/CT over CT alone for by CT or MRI and 18% of which were overstaged by CT or MRI.
the detection of disease can have significant impact on patient Almost 20% of patients thought to have organ-confined muscle-
management (Fig. 14.3). In a study comparing MRI and PET/CT in invasive UBC were found to have metastatic disease, and required
patients who were preoperatively referred for staging, the specificity systemic chemotherapy.5 In a retrospective study by Jadvar
for PET/CT and MRI were 93% and 80%, respectively.34 PET may et al.32 of 35 patients previously treated for UBC, FDG PET/CT
also have higher sensitivity and specificity for bone disease. A few improved imaging evaluation and altered clinical management in
reports have suggested that PET is superior to skeletal scintigraphy 17% of patients.
for the detection of bone disease.27,38 Apolo et al.5 performed a pro- Although pathologic confirmation of suspected metastatic disease
spective study of 57 patients and found a sensitivity of 81% and a remains the gold standard, biopsy is not always possible because of
Table 14. 2
Published Studies on Positron Emission Tomography in Bladder Carcinomas
Studies (References) PET Tracer Purpose Patients (n) Sensitivity (%) Specificity (%)
28
Kosuda et al. [F-18]-FDG Staging 12 NA NA
Drieskens et al.23 [F-18]-FDG Staging 55 60 88
Anjos et al.25 [F-18]-FDG Local and distant staging 17 100 100
Jadvar et al.32 [F-18]-FDG Staging 35 NA NA
Kibel et al.24 [F-18]-FDG Staging 43 70 94
Apolo et al.5 [F-18]-FDG Staging 57 81 94
Harkirat et al.26 [F-18]-FDG Local staging 29 87 100
Lodde et al.27 [F-18]-FDG Local staging 44 85 25
Garcia-Vicente et al.30 [F-18]-FDG Local staging 38 100 83
Jensen et al.34 [F-18]-FDG Lymph node staging 48 33 93
Yang et al.18 [F-18]-FDG Staging 60 87 90
Picchio et al.35 [C-11]-choline Staging 27 96 NA
Maurer et al.36 [C-11]-choline Staging 44 58 66
Schöder et al.37 [C-11]-acetate Staging 17 80 NA
Vargas et al.16 [C-11]-acetate Staging 16 78 NA
[F-18] FDG, fluorine-18-fluoro-2-deoxy-D-glucose; [C-11]-choline, carbon-11 choline; [C-11]-acetate, carbon-11 acetate; NA, not applicable.

Figure 14.3. A 41-year-old male with blad-

der cancer post cystectomy, lymphadenec-
tomy, uretherectomy and construction of an
ileal conduit. FDG PET/CT following four
cycles of methotrexate, vinblastine, doxorubi-
cin, and cisplatin (MVAC) shows two FDG-avid
retroperitoneal lymph nodes, suspicious for
malignant disease, despite normal size on CT
(A). Follow-up FDG PET/CT performed
3 months later shows multiple FDG-avid retro-
peritoneal lymph nodes consistent with disease
progression (B). Systemic chemotherapy was
changed to a different protocol regimen (gem-
citabine and cisplatin). Follow-up FDG PET/CT
performed 8 months after the conclusion of
systemic chemotherapy (gemcitabine and cis-
platin) shows resolution of the previously seen
FDG-avid lymph nodes. A residual retroperito-
B neal lymph node that is not significantly FDG-
avid is depicted by the arrow (C).


Figure 14.3. (Continued ) C
11
the risk involved with accessing lesions deep in the body that may be C-Acetate PET/CT
adjacent to vascular structures or because of the other medical con-
traindications. PET/CT may serve as an acceptable substitute to Acetate is a metabolic substrate of β-oxidation and a precursor of
assess distant disease or detect recurrent disease when present. amino acid and sterol. 11C-Acetate PET/CT has been performed in
patients with cancer, most notably in the brain, nasopharynx, liver
and prostate gland.41 Although 11C-acetate is removed from the
Other PET Radiotracers used blood by glomerular filtration, it is reabsorbed by active transport
in the proximal convoluted tubule and excreted mainly thorough
in Urinary Bladder Cancer the biliary system. Because of the absence of urinary excretion,
11 18 improved detection of malignancy within the bladder was expected.
C-Choline and F-Fluorocholine PET/CT However, studies using 11C-Acetate PET/CT in bladder cancer
Choline can be labeled with carbon-11 (11C) or with fluorine-18 (18F). patients are few.16,37 In a study by Vargas et al., 11C-acetate PET/CT
Choline is a substrate for the synthesis of phosphatidylcholine, a cell had better sensitivity and specificity compared to MRI and CT. In a
membrane phospholipid. It has been hypothesized that uptake of study by Schöder et al.,37 11C-Acetate PET/CT showed moderate
radiolabeled choline reflects proliferative activity by providing an sensitivity for bladder lesions (8/19 patients true positive), but
indication of membrane lipid synthesis. Choline is cleared quite rap- false-positive uptake occurred in 14 lymph node regions, possibly
idly from the blood, which allows imaging as early as 3 to 5 minutes caused by the granulomatous disease following intravesical BCG
after radiotracer injection. Physiologically, increased radiotracer therapy. A prospective study of 14 patients comparing 11C-choline
uptake is seen in the salivary glands, liver, kidney, pancreas and faint and 11C-acetate PET/CT in UBC reported 11C-acetate and 11C-cho-
uptake is seen in normal bone marrow.39 This is important to remem- line were equivalent in the preoperative evaluation. The study also
ber because it means the sensitivity of the study to detect metastatic confirmed the previously reported high negative predictive value
disease in those regions, especially the liver which is a common site of both methods for lymph node involvement.42 However, further
of a metastatic disease in UBC, can be limited (Fig. 14.4). studies are needed to assess the utility of 11C-acetate and 11C-cho-
Early studies of 11C-choline PET/CT in bladder cancer patients line in UBC patients.
were optimistic, suggesting a higher accuracy compared to CT
alone for the detection of local disease (96% versus 85%) and
lymph node staging (62% versus 50%).35 Further studies, however, Radioimmunotherapy
have reported mixed results although few have been done in
patients with bladder cancer.40 In a recent study of 44 UBC patients Overexpression of the human epidermal growth factor receptor-2
referred for 11C-choline PET/CT prior to radical cystectomy, the (HER2) is known to contribute to cell proliferation and is commonly
sensitivity, specificity, and accuracy of 11C-choline PET/CT were found in breast cancer. Indeed, the HER2 gene is amplified in
58%, 66%, and 81%, respectively, whereas for CT alone these were approximately 30% of breast cancer patients.43,44 Trastuzumab, a
75%, 56%, and 86%, respectively.36 recombinant humanized monoclonal antibody to the extracellular

Figure 14.4. An 18F-fluorocholine PET/CT in a 56-year-old male with prostate carcinoma infiltrating the urinary bladder. The prostate gland carcinoma infiltrating
the bladder wall shows increased radiotracer activity (SUVmax 5). There is also radiotracer uptake in a left acetabular metastasis (SUVmax 7.4). Please note that
physiologic radiotracer activity in the liver, pancreas, and kidneys reduces the sensitivity of this study for the detection of disease in these areas.
domain of HER2, has dramatically changed the treatment of HER2- problems remain with the development of targeted radionuclide
amplified breast cancer patients in both the adjuvant and meta- therapy.51
static setting. Studies on urothelial carcinoma examining HER2
expression have reported 5% to 80% of invasive urothelial carcino-
mas express HER2.45–47 In a study by Gårdmark et al.,46 72% of Conclusion
patients with HER2 positive primary UBC had HER2 positive metas-
tases and there was a decrease in HER2 positivity with increasing Patients with carcinoma or the urinary bladder have an increased
distance from the site of primary disease: 74% of regional metasta- lifelong risk for recurrent disease throughout the urinary tract and
ses and 47% of distant metastases were HER2 positive. Random- recurrence in the upper urinary tract can occur more than 5 to 10
ized multicenter trials of chemotherapy combined with trastuzumab years after radical cystectomy. Unfortunately, conventional imag-
in UBC patients are underway.48 ing in patients with UBC frequently fails to detect all sites of dis-
Trastuzumab has been labeled with radionuclides suitable for ease and despite routine surveillance, it is estimated that over
targeted therapy. It has been postulated that HER2-targeted 75% of upper urinary tract recurrences are detected after symp-
therapy could be helpful in the future treatment of metastatic toms have developed. FDG PET/CT can detect metastatic disease
UBC. For example, a study of 177Lu-labeled trastuzumab on HER2 and local recurrence, and is often more accurate than conven-
positive microxenografts suggested promising results for the tional imaging. However, imaging protocols should be adjusted to
treatment of HER2 positive micrometastases.49,50 The major lim- optimize the diagnosis of bladder cancer and to meet the clinical
itation of this therapy in animal studies is that in order to deliver needs of the patient. Today, the accuracy of FDG PET/CT to detect
sufficient radioactivity to the site of malignancy unacceptably metastatic disease in UBC is comparable to that of other malig-
high doses of radioactivity are also delivered to critical organs, nant diseases, for which PET/CT already has become a standard
particularly bone marrow. To improve the tumor-to-nontumor of care. Therefore, FDG PET/CT may be helpful as a diagnostic
dose ratio, smaller antibody fragments derived from a new class tool in advanced bladder cancer and should be considered in the
of affinity proteins called “affibody molecules,” have been used to surveillance of patients receiving chemotherapy for advanced dis-
bind to HER2. However, this approach has resulted in increased ease. Further, targeted radio-immunotherapy has the potential to
radiation exposure to the kidneys. Additional studies conducted have a high impact on the outcome of UBC patients. The potential
with affibody molecules attached to albumin although effective in involvement of HER2 in urothelial carcinoma has led to the initia-
reducing renal toxicity, increased radiation exposure to the blood tion of anti–HER2-targeted therapy protocols in advanced disease.
and bone marrow. Although imaging of HER2 expression in However, the design of tumor targeting radiopharmaceuticals is a
tumor xenografts has been performed, significant toxicity complex problem which requires further consideration.

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urological tumors. Curr Opin Oncol. 2010;22:274–280.

Chapter 15
Prostate Carcinoma
Marina Hodolic̆ • Stanley J. Goldsmith
Prostate carcinoma is the most common life-threatening cancer to a urologist, endorectal US, and biopsy. In addition to providing
affecting men in the Western world. In the United States, it is esti- a diagnosis of malignancy, biopsy material provides a means to
mated that almost 250,000 new cases are diagnosed annually and assign a Gleason grade. The Gleason scoring system is based upon
that approximately 1 in 10 will ultimately die of the disease the microscopic architecture which provides a measure of the
despite improved methods of early diagnosis, evaluation, and degree of aggressiveness of the malignant tissue and serves as a
management. Prostate cancer is the second highest cause of can- prognostic indicator, thus assisting in determining management
cer-related death per year, second only to bronchogenic carci- strategy. The grades range from 1, with small closely packed, rela-
noma in the United States.1 Rates of detection vary widely, with tively orderly pattern, to 5, with larger poorly differentiated cells,
the incidence in South and East Asia less frequent than in Europe lack of glandular architecture, and considerable disarray. The sum
and United States.2 Prostate carcinoma tends to develop in men of the two most common patterns provides the overall Gleason
over the age of 50; it is diagnosed in 80% of men by the age of 80. score from 2 to 10. Higher Gleason scores (i.e., a Gleason score of
Recently, there has been recognition that the disease in older men 7 and above) are associated with poorer prognosis.
may not merit the same vigorous intervention as in younger men. With the widespread availability of serum PSA, patients are
This insight evolves from greater understanding of the complex now seen early in the course of disease where many patients will
biology and clinical course of this tumor. not have obvious findings of pelvic or distal involvement. Treat-
In the development of prostate cancer, many factors have been ment in these cases is focused on the prostate gland. This involves
implicated: genetics and diet among them. The American Dietetic either surgical prostatectomy or external beam radiation or
Association and Dieticians of Canada report a decreased incidence brachytherapy (insertion of radioactive seeds directly into the
of prostate cancer in men who follow a vegetarian diet.3 However, prostate). In recent years, other techniques to remove tumor with-
there is no established relationship between any environmental fac- out sacrificing the entire prostate gland (such as cryosurgery)
tor and the incidence or aggressive nature of prostate carcinoma. have become available but they are not widely used. Improved
In the majority of cases, in the early stages, prostate cancer is mapping of the intraprostatic distribution of tumor and character-
harmless and symptom free. This leads to the assumption that ization of the degree of aggressiveness of the tumor would enable
appropriate and sensitive diagnostic procedures are crucial for a better informed decision making and perhaps modify surgical and
good survival rate. The serum marker prostate specific antigen (PSA) subsequent clinical management. These options may be accompa-
provides an early clue to the presence of prostate carcinoma but it is nied by hormonal therapy; that is, elimination of androgen hor-
a nonspecific biomarker. It is increased in the serum of men as they mones that have a stimulating or supportive effect on prostate
age and the prostate enlarges, as well as in patients with prostatitis. tissue and tumors. It is no longer necessary to surgically castrate
Nevertheless, an elevated PSA value should lead to other diagnostic these patients; the hormonal suppression of testosterone is suffi-
procedures such as digital rectal examination, endorectal ultrasound cient to be considered pharmacologic castration. The serum PSA
(US) and biopsy resulting in earlier detection of malignancy than had value falls to very low or undetectable levels and is measured peri-
been the case prior to the availability of PSA determinations. The odically. In approximately one of three patients, after a quiescent
earlier and improved detection of prostate carcinoma has contrib- period up to 5 years after initial treatment with no biochemical
uted to an apparent increase in the incidence of prostate malignancy. (PSA) evidence of disease, a rise in the serum PSA is detected. If
Nevertheless, clinical management remains complex including the the PSA level rises, the next challenge is to identify the location
choice of therapeutic intervention. This depends somewhat on the and extent of the source:
age of the patient at the time of detection as well as the nature
(degree of aggressiveness) and extent of disease. In recent years, a • prostate bed recurrence and/or
variety of imaging modalities have become available: US, computed • pelvic lymphadenopathy and/or
tomography (CT), and magnetic resonance imaging (MRI) improve • distal osseous and/or
detection of disease within the prostate gland but they do not identify • soft tissue involvement
nodal or distant metastases early in the course of the disease nor do
Obviously, if the patient has not undergone surgical prostatec-
they characterize the degree of aggressiveness of the tumor. Identifi-
tomy, the assessment of recurrent disease in residual prostate
cation of lymph node involvement by either CT or MRI is based pri-
gland tissue is another challenge.
marily on size criteria; nor do these modalities determine the degree
Each of these possibilities, from extent of disease at presenta-
of aggressiveness of the tumor, a feature that would be useful to
tion to the reappearance of PSA in the treated patient, presents
guide therapy. In summary, the following represents needs that are
many decisions and choices for the patient and urologist or oncol-
not satisfied by conventional imaging methods (CT, MRI).
ogist. Until recently, US, CT, MRI, and 99mTc methylene diphospho-
• Early detection and localization of tumor within the prostate nate [99mTc-MDP] bone scintigraphy were the only imaging
gland (to avoid false-negative biopsies) procedures available to assess the extent of disease in patients
• Characterization of the degree of aggressiveness of the tumor with prostate carcinoma. Radionuclide bone scintigraphy, of
foci (to avoid under- or overestimating therapeutic options) course, was only useful to determine if bone metastatic disease
• Early detection of lymph node metastases was present. Regardless of whether it was positive or negative, it
• Early detection of distal metastases did not exclude soft tissue involvement. In the United States,
In-111 pendetide caproate [Prostascint], a radiolabeleled mono-
Clinical Features of Prostate clonal antibody, has been approved for its use to determine the
extent of disease in newly identified patients who were at high
Carcinoma risk for early metastatic disease based on the Gleason score of
biopsied tissue and to identify the source of rising PSA values in
Early disease is detected by elevation of a serum PSA value lead- patients who had undergone surgical prostatectomy. The tech-
ing to a workup that involves a digital rectal examination, referral nique, however, has had limited utility.
200

Chapter 15 Prostate Carcinoma 201
Diagnostic Imaging tomography (PET). Single photon emitters have been used to obtain
planar images for many years but for the past 25 years, instrumen-
The conventional imaging methods used to assess and localize tation that can provide tomographic images from single photon
disease burden in patients with known or suspected prostate emitters has been available. Single photon emission computed
carcinoma are limited to CT and traditional radionuclide bone tomography (SPECT) and PET imaging are currently used to best
scintigraphy with 99mTc-methylene diphosphonate. A number of advantage in combination with CT acquisition and image fusion.
new imaging techniques are at various stages of clinical investiga-
18
tion. Some are currently used regularly in specific medical centers F-FDG
that have access and are in locales that provide reimbursement.
MRI has evolved and now has available many additional pulse Although not tumor specific, 18F-FDG PET/CT is currently the
sequences that provide further insight into the biology of the most widely available and widely used nuclear medicine proce-
changes observed in the image provided. Nevertheless, there is no dure to identify primary and metastatic cancers. The utility of
18
consensus about the optimal imaging technique or the criteria for F-FDG is based upon the increased anaerobic glucose metabo-
the use of MRI in patients with suspected or proven prostate car- lism present in most tumors. In early stages, prostate cancer is
cinoma. MRI quality improves with the use of an endorectal coil. not characterized by a significant increase in the metabolic activ-
It is likely, though not yet confirmed that 3T magnets will outper- ity on 18F-FDG PET/CT imaging. Based on the low overall sensi-
form 1.5T systems. Apparently the reliability of results (sensitivity) tivity for the detection of prostate carcinoma in early clinical
varies with the location of lesions within the prostate; more super- studies, the general impression evolved that 18F-FDG is not use-
ficial lesions detected and characterized more consistently than ful to image prostate cancer or that its use is limited to the most
lesions deeper in the prostate. There is high signal intensity on aggressive cancers.5–9 The conclusion that 18F-FDG is not useful
T2-weighted images in the peripheral zone of the gland whereas is certainly not the complete picture. 18F-FDG has poor overall
deeper foci of prostate carcinoma have decreased signal intensity. sensitivity for the detection of prostate carcinoma early in the
course but it is sensitive to detect aggressive tumors and hence,

The sensitivity of the technique is less reliable in the transition
zone or the anterior portion of the prostate gland (further from the it is useful to characterize the degree of aggressiveness of the
endorectal coil). Nevertheless, there is no consensus about the tumor. Furthermore, both primary and metastatic prostate car-
optimal criteria for the use of MRI in patients with suspected or cinomas have been detected as an incidental finding in men
proven prostate carcinoma. undergoing 18F-FDG PET/CT for nonprostate disease or on fol-
Nevertheless, there is no consensus about the optimal criteria low-up of other abdominopelvic tumors (Fig. 15.1).10 Low-grade
for the use of MRI in patients with suspected or proven prostate prostate carcinoma has a low metabolic rate and low levels of
carcinoma. the glucose transport protein, Glut-1 and consequently, relatively
There has been persistent interest in the potential use of MR low levels of anaerobic glucose metabolism and 18F-FDG uptake.
spectroscopy to assess regional metabolic differences in prostate Certainly, when the tumor is more aggressive (higher Gleason
tissue. Although the spatial resolution of MR spectroscopy is sig- scores), glucose utilization is increased and 18F-FDG images are
nificantly less than MRI, some data has emerged, likely compro-
mised, however, by volume averaging of the metabolic data. MR
spectroscopy can identify relative levels of citrate and choline. The
normal prostate tissue has relatively high levels of citrate whereas
malignant tissue has higher levels of choline and relatively reduced
citrate levels. This may reflect the increased choline utilization
involved in membrane synthesis associated with tumor growth.4
Nuclear medicine imaging has evolved also in recent years and
numerous single photon and positron emission radiopharmaceuti-
cals have been developed (Table 15.1). There are two broad groups
of radiopharmaceutical imaging agents: positron-emitting tracers
and single photon emitters. Because of the coincident nature of the
signal associated with positron emitter, imaging always provides
transaxial tomographic images; hence the term positron emission
Table 15. 1
Radiotracers Used to Image Prostate Carcinoma
Nonspecific Tumor Imaging

18
F-Fluoro Deoxy Glucose [18FDG]
18
Fluorocholine and 11C-Choline
11
C-Acetate
11
C-Methionine
Prostate Tumor-Specific Imaging
111
In-anti-PSMA (capromab pendetide [Prostascint ])
111
In-anti-PSMA [J591]
177
Lu-anti-PSMA [J591]
123
I-PSMA ligand antagonists (heterodimers)
99m
Tc-PSMA ligand antagonists (heterodimers)
68
Ga-PSMA ligand antagonists (heterodimers)
18
F-Fluorodehydrotestosterone Figure 15.1. A 69-year-old man who is presented with anemia unresponsive to therapy; referred
68
Ga-anti-PSMA [J591] with diagnosis of aplastic anemia. The whole-body maximal intensity projection (MIP) image reveals
18
68
Ga-anticellular PSA F-FDG focal uptake in the prostate gland right posterior quadrant (black arrow ). 18F-FDG activity also
identifies a right inguinal lymph node (white arrow).

revealed. Since 18F-FDG uptake correlates with the degree of that the SUVmax was higher in lymph node and bone metastases
tumor aggressiveness, identification of metastatic prostate cancer compatible with the suspicion that more aggressive metastatic
with 18F-FDG indicates a poor prognosis. In comparison with lesions had a higher rate of glucose utilization and hence higher
radiotracers like 11C-Choline or 18F-FCH, 18F-FDG sensitivity is SUVmax values.9 In a later study, Oyama evaluated the SUVmax,
better associated with the Gleason score; that is, tumors identi- PSA, and prostate size in 10 patients with moderately aggressive
fied on 18F-FDG PET imaging are more apt to have higher Glea- disease prior to therapy and 1 to 5 months later after a 28-day
son scores whereas 18F-FCH is, in general, equally positive in course of antiandrogen therapy with an LH–RH agonist (goserelin).
both high and low Gleason score foci. Since 18F-FDG is insensitive The 18F-FDG SUVmax decreased in all cases with decreases in
to prostate carcinoma in general, a negative 18F-FDG does not serum PSA and prostate gland size. In addition, although there was
reliably exclude tumor. Accordingly, 18F-FDG is generally viewed an occasional unexplained exception, there was a decrease in SUV-
neither as a screening tool nor as the imaging agent of choice. max in metastatic lymph nodes and bone lesions.11 By contrast, Liu
Nevertheless, nuclear medicine physicians should be alert to the et al. found no correlation between Gleason scores and 18F-FDG
finding of focal increased 18F-FDG in the prostate as it may iden- uptake in patients with prostate carcinoma confined to the pros-
tify prostate carcinoma in men undergoing 18F-FDG PET/CT for tate.12 In 2002, Morris reported that 18F-FDG PET was useful to
other reasons. Moreover, in aggressive disease, 18F-FDG imaging discriminate osseous metastases with active tumor from quiescent
can be used to assess tumor response to chemotherapy. boney lesions, Of 134 lesions in 17 patients identified as positive on
Glucose (and hence 18F-FDG) enters the cell via glucose trans- 18
F-FDG and/or bone scintigraphy, only 95/134 (71%) were subse-
port proteins. In tumor cells, this is most commonly the Glut-1 quently determined to be active lesions. All lesions seen on 18F-FDG
transporter which is underexpressed in prostate cancer in its PET were subsequently determined to be active tumor sites demon-
early stages (low Gleason scores) but increases in primary pros- strating that 18F-FDG was more specific than bone scintigraphy for
tate adenocarcinomas with higher Gleason scores and in meta- the detection of active tumor foci in the skeleton.13
static disease when it becomes androgen (or castrate) independent. In patients with the so-called biochemical failure or PSA relapse,
Aside from the variable biology of prostate carcinoma, imaging of that is rising PSA after surgical or radiation prostatectomy, 18F-FDG
the prostate itself is compromised somewhat by its proximity to PET (PET/CT) has frequently identified the site or sites of recur-
the bladder. Finally, in assessing tracer sensitivity, characteriza- rence with a reasonable degree of accuracy, that is, most positive
tion of any tracer is complicated by the question being asked: findings are true positive (Fig. 15.2).14–16 Depending on the PSA
values and PSA doubling time, there are various levels of sensitivity
• detection of disease within the intact prostate
since the utility of 18F-FDG PET depends upon the degree of aggres-
• detection of residual or recurrent disease in the prostate bed
siveness of the tumor. Obviously, since alternate imaging methods
• detection of tumor in pelvic or distal lymph nodes
(bone scans, CT, MRI) failed to identify sites for biopsy, the overall
• detection of disease in bone marrow and/or bone
sensitivity and validity of negative 18F-FDG PET scans cannot be
Each of these specific indications involves site-specific issue assessed because there are no findings for comparison or identifi-
including the sufficiency of blood flow and tissue perfusion, the cation of a site to biopsy. Schoeder et al. found that 18F-FDG PET
tumor-to-background tissue perfusion and metabolic activity. was most useful in patients with a PSA >2.4 ng/mL or a PSA dou-
Nevertheless, despite early random observations that prostate bling time >1.3 ng/mL/yr.16
carcinoma, in general, was not 18F-FDG avid, reports of successful By 1999, reports began to appear comparing 18F-FDG to other
identification of prostate cancer with 18F-FDG began to appear in tissue substrates such as 11C-Methionine,17,18 11C-Acetate [11C-
the 1990s.5–9 Initial reports with mixed patient populations, mean- Ac],19–24 11C-Choline [11C-Ch], 18F-Fluorocholine [18F-FCH] and
ing patients at various clinical stages with various disease burdens, more recently to prostate tissue-specific PET and SPECT tracers.
had a wide range of sensitivities, some as low as 4% and others as By far, the most widely investigated substrate has been 11C-Choline
high as 81%. This suggests that the populations studied were very and 18F-Fluorocholine [18F-FCH].24–66
heterogeneous with some patients with early stage disease and oth-
ers with clinically more aggressive disease. Shreve et al., for exam- 11
ple, reported a sensitivity of 65% for bone metastases whereas Yeh
C-Methionine
et al. reported only an overall 20% sensitivity in a small group of The increased amino acid transport and metabolism associated
patients.7 Oyama reported that 18F-FDG SUVs appeared to be some- with tumor growth can be assessed with the positron-emitter–
what proportional to the Gleason score of the primary tumor and labeled amino acid 11C-Methionine. As might be expected,
A B C
Figure 15.2. The same patient as in Figure

15.1.18F-FDG uptake in metastatic prostate can-
cer lesions: PET/CT (A, D), CT (B, E), PET (C,
F). A–C: transaxial slices at level of the prostate
gland revealing 18F-FDG avid focus in right pos-
terior quadrant of intact prostate gland (black
arrow). D–F: transaxial slices, slightly cephalad
D E to prostate gland revealing 18F-FDG avid meta-
F
static focus in right iliac bone (open arrow).

11
C-Methionine identifies more tumor sites in patients with meta- that 11C-Acetate PET “may have significant potential for the detec-
static prostate tumor than 18F-FDG but 18F-FDG identifies the tion of recurrent prostate cancer.” One of the advantages being
more aggressive metastatic sites.17 In a study of patients with mul- that PET offers a single technique to assess local prostate gland/
tiple likely metastatic sites identified on conventional imaging, bed recurrence, regional and distal lymph nodes, and possible
11
C-Methionine PET imaging identified 72% of the sites whereas skeletal metastases.22 In the most extensive study reported to
18
F-FDG PET imaging identified only 48%. In fact, it was suspected date, Haseebuddin et al. performed 11C-Acetate PET/CT imaging
that the negative 11C-Methionine sites may have been due to on 107 men with intermediate- or high-risk disease based on
tumor necrosis and that rather than being false-negative sites on Gleason scores comparing treatment failure and failure-free sur-
11
C-Methionine imaging, the data actually demonstrated false- vival in patients who were PET-positive and PET-negative. The
positive findings on bone scintigraphy.18 median treatment-failure free survival of PET-positive patients
was 1.3 months whereas PET-negative patients had a median
value of 31.5 months. Interestingly, patients who were false posi-
11
C-Acetate tive on PET/CT (compared to subsequent biopsy evaluation) had
a worse treatment–failure-free interval than patients who were
Low levels of GLUT-1 transporters are characteristic of normal
true negative suggesting that 11C-Acetate PET/CT correctly identi-
and malignant prostate cells. Hence, 18F-FDG has limited utility as
fied disease that was missed on subsequent hostopathologic
a diagnostic imaging tracer for detection and extent of disease in
evaluation.23
patients with prostate cancer. Whereas citrate is usually produced
In 2007, Morris and Scher reviewed most of the published
by the tricarboxylic cycle (TCA) in prostatic epithelium and is 11
C-Acetate PET imaging studies published to that time, comment-
present in excess in normal cells perhaps because of the relatively
ing on the results in a total of 154 patients. They stressed that
quiescent metabolism of these cells, malignant prostate cells oxi-
there is a need for a consistent imaging protocol to include com-
dize citrate as an energy source. Since glucose transport in pros-
parison with traditional bone scintigraphy and CT scans. Fore-
tate carcinoma cells is limited, acetate can serve as an alternate
most in their recommendation, in addition to a call for studying a

substrate for the TCA cycle.
larger number of patients, was defining a specific prostate carci-
Based on these observations, Oyama et al. reported on the util-
noma patient population: untreated patients; postinitial treatment
ity of 11C-Acetate as an imaging agent to identify prostate carci-
with rising PSA but no evidence of tumor recurrence on tradi-
noma.19 Using a 740 MBq (20 mCi) dose of 11C-Acetate, PET
tional imaging; extent of disease in patients with known metasta-
showed primary lesions within the prostate prior to treatment in
ses; response to therapy (presumably antiandrogen).24
22 of 22 patients (100% sensitivity) with histopathologically con-
firmed prostate carcinoma. 18F-FDG PET detected tumor in 15 of
18 evaluable patients (83% sensitivity) in the same patient group.
In general, 11C-Acetate uptake was greater than18F-FDG uptake
Choline and Choline Analogs
and tumor foci were more readily detectable. Five patients had By far, 11C-Choline and 18F-Fluorocholine aside from 18F-Fluoro-
lymph node metastases, all readily detected with 11C-Acetate deoxyglucose have been the most extensively reported radio-
whereas only 2 of 5 were detectable with 18F-FDG. Similarly, in tracers used for the detection of prostate carcinoma. Choline
bone metastases, 11C-Acetate was positive in all but one lesion was discovered in 1864 by the German chemist, Adolph Strecker.
detected on bone scintigraphy whereas 18F-FDG PET only identi- It was chemically synthesized in 1866 and over 100 years later
fied a subset of patients. In addition, 11C-Acetate activity was not in 1998, it was classified as an essential nutrient by the Food
observed in the urine. There was no correlation between Gleason and Nutrition Board of the Institute of Medicine in the United
score and uptake of either 18F-FDG or 11C-Acetate although States in 1998.25 As a component of cell membrane phospholip-
patients with advanced clinical stage disease showed higher 18F- ids, choline when labeled with a PET tracer such as 11C is an
FDG uptake than patients with earlier stage disease.19 excellent biomarker to assess increased proliferation and malig-
Kotzerke et al. investigated the utility of 11C-Acetate to detect nant transformation.26
recurrent disease in patients with increasing PSA following a Many cancers show alterations in choline metabolism: The
“complete” prostatectomy. Patients were imaged 5 minutes after increased choline uptake in tumor tissue is associated with mod-
an IV injection of 800 MBq 11C-Acetate. The results were com- ulation of enzymes that control anabolic and catabolic pathways.
pared to transurethral ultrasound (TRUS) followed by biopsy. The increased level of choline-containing compounds is associ-
11
C-Acetate PET demonstrated local recurrence in 15 of 18 ated with increased synthesis of phospholipids in cellular
patients identified by TRUS and biopsy. No focal prostate bed membranes.
activity was identified in 13 patients with subsequent negative
biopsies. Lymph node involvement and bone metastases were 11
identified in five patients each.20
C-Choline
Fricke et al. reported similar results in 25 patients suspected of Initially, choline was labeled with 11C (11C-CH). Radiolabeled cho-
relapse or metastatic disease following primary treatment. line is indistinguishable from natural choline. In vitro experiments
11
C-Acetate detected prostate tumor in 20/24 patients (83%) demonstrated that radiolabeled choline is incorporated into tumor
whereas 18F-FDG detected only 10/15 malignant lesions in local cells by active transport and subsequently phosphorylated in the
recurrences or lymph node metastases. Observing that 18F-FDG cells and integrated into phospholipids.
11
was more accurate in the detection of distal, presumably more C-CH is primarily eliminated by the liver which is advanta-
aggressive, metastases, Fricke et al. proposed combined geous since there is little radioactivity in the urinary tract. The
11
C-Acetate/18F-FDG PET imaging in the follow-up of prostate car- 20-minute half-life of 11C limits its utility at sites without a cyclo-
cinoma patients.21 tron and PET radiochemistry facilities.
Albrecht et al. performed 11C-Acetate PET in 32 patients with Since choline itself is a natural component of human diets and
evidence of early relapse; that is, rising PSA after initial treatment. has been demonstrated to be safe when ingested, the 11C-Choline
Seventeen of the patients had been treated with radiotherapy and tracer has been approved by the FDA in the United States as an
15 were treated surgically. The PET scans were coregistered with imaging agent “that helps detect prostate cancer.” The Mayo Clinic
separately acquired CT scans. A subset of 12 patients underwent in Rochester, MN is the first facility to receive specific approval.
endorectal MRI and 9 patients had MR spectroscopy. The results Because of its short half-life, it is not likely to become commer-
were similar to those reported by others. The authors conclude cially available.

Figure 15.3. PET maximum intensity images (MIP) of 18F-FCH biodistribu-

tion at 1 minute (lower) and 45 minutes (upper) after administration in a
patient with metastatic prostate cancer (Gleason score 9, PSA 500 ng/mL).
18 18
F-Fluorocholine Physiologic Distribution of F-FCH
18 18
The advantages of the longer-lived radionuclide, F (half-life: 110 Physiologic F-FCH uptake is noted in salivary glands, liver, pan-
minutes), led Hara et al.27 to synthesize the fluorocholine analog, creas as well as renal parenchyma and urinary bladder. Faint
2-[18F]-fluoroethyldimethyl-2-hydroxyethylammonium (FEC). The uptake is seen in spleen, bone marrow, and muscles. Bowel activ-
rates of FEC phosphorylation were low and the phosphorylation ity is variable (Fig. 15.4).
step is crucial for PET imaging. In 2000, DeGrado synthesized no-
carrier-added choline analog [18F]-fluoromethyl-dimethyl-2- 18
hydroxyethylammonium (FCH) and evaluated it in a murine PC-3
Patient Preparation and F-FCH PET/CT
human prostate cancer xenograft model. Both compounds showed Acquisition Protocols
similar properties with minor differences (later peak uptake for Patients should fast 6 to 10 hours prior to the scan and should
FEC).28 be well hydrated. The influence of androgen deprivation therapy
The longer half-life of 18F provides 18F-Choline analogs allow to on choline uptake in patients with prostate cancer disease has
be distributed to centers lacking an on-site cyclotron and makes it not yet been clarified. Nevertheless, most patients continue their
possible to perform repeated (dynamic) imaging. The shorter pos-
itron range of 18F, also provides better spatial resolution and bet-
ter imaging quality.29 18F-Choline analogs, however, are eliminated
via the kidneys which is a disadvantage since urinary activity can
be mistaken for malignant tissue in the pelvis. This effect is mini-
mized with early dynamic imaging, prior to tracer appearance in
the bladder, and delayed imaging, after voiding.
18
Biokinetics and Dosimetry of F-FCH
The distribution of radioactivity varies in various organs. Based
on the biokinetic compartmental model in prostate cancer
patients, dosimetry of 18F-FCH has been calculated. The highest
radioactivity has been found in the kidneys (reference patient,
0.079 mGy/MBq; individual values, 0.033 to 0.105 mGy/MBq)
and liver (reference patient, 0.062 mGy/MBq; individual values,
0.036 to 0.082 mGy/MBq).30 A large amount of radioactivity
appears in urine after a time lag of 5 minutes. The reference
patient received between 0.017 and 0.030 mGy/MBq dose to the
wall of the urinary bladder, depending on frequency of voiding.
Blood clearance is rapid and in 1 minute, blood level is minimal.
The uptake in prostate cancer tissue is rapid with significant
uptake after 1.5 minute (Fig. 15.3). The effective whole-body dose
equivalent from administration of 4.07 MBq/kg (0.110 mCi/kg) is
approximately 0.01 Sv.31 Figure 15.4. Physiologic distribution of 18F-FCH.

antiandrogen therapy prior to choline-PET/CT acquisition. 18F-FCH Choline uptake in inflamed tissue as well as in cancer cells is
PET/CT in patients with prostate cancer is most frequently per- resulting in suboptimal specificity. Suboptimal sensitivity is mainly
formed using a dose of 2.5 to 4 MBq/kg of 18F-FCH intravenously. due to limited spatial resolution of PET/CT systems (detection of
At present, there is no standardized 18F-FCH PET/CT acquisi- lymph node micrometastases, extracapsular extension, seminal
tion protocol. Many nuclear medicine departments incorporate vesicle involvement). The role of 18F-FCH PET/CT to detect regional
late imaging with early (dynamic) imaging, to avoid interference lymph node metastases varies among reports. In a large study
from bladder accumulation. Dynamic acquisition over the pelvis involving 912 lymph node samples (in 130 patients with interme-
immediately after injection of the tracer (0 to 15 minutes) allows diate- or high-risk prostate cancer), greater sensitivity to detect
visualization of the pelvic disease without interference from phys- lymph node involvement was found in the lymph nodes equal or
iologic filling of urinary activity in the bladder.31–36 Whole-body greater than 0.5 cm in size. Sensitivity and specificity were 66%
acquisition is usually performed 45 to 60 minutes later. Late and 96%, respectively.44 By contrast, in a study of patients with
acquisition allows better sensitivity for distal disease.37–44 Fused intermediate-risk prostate cancer disease (Gleason score >6 and
PET/CT images of early and late acquisitions, and coregistered CT PSA >10 ng/mL), a sensitivity of only 10% and a specificity of 80%
data are used for interpretation. were observed in patients where sentinel lymph nodes were iden-
tified and pathologic choline uptake was compared with histol-
ogy.45 FCH PET/CT showed very good results for the early detection
Clinical Application of 18F-FCH PET/CT of bone metastases in men at initial staging of prostate cancer
18
disease.46,47 Some bone metastases have no detectable morpho-
F-FCH PET/CT imaging has been investigated for a variety of logic changes on CT—probably due to bone marrow involvement,
indications in prostate cancer patients: but they are positive on 18F-Fluorocholine scans.
• Initial staging of prostate cancer disease (high-risk prostate Despite different conclusions in various studies, 18F-FCH PET/
cancer patients) CT appears to have a role in the initial staging in patients with
• Restaging of prostate cancer disease (biochemical evidence of biopsy-proven high-risk prostate cancer (Fig. 15.5).

recurrence)
• Localization of prostate cancer (elevated PSA level and negative Restaging of Prostate Cancer Disease
biopsy)
(Biochemical Evidence of Recurrence)
• Treatment monitoring of prostate cancer disease
• Therapy planning of prostate cancer disease The greatest contribution of 18F-FCH PET/CT in patients with
prostate cancer disease is in the evaluation of patients with evi-
Initial Staging of Prostate Cancer Disease dence or suspicion of recurrent disease. This modality provides
information about locoregional as well as distant sites of recur-
(High-Risk Prostate Cancer Patients)
rence (Figs. 15.6 and 15.7). Thus, 18F-FCH PET/CT helps to deter-
18
F-FCH PET/CT is a useful imaging modality that characterizes mine appropriate treatment (radiation therapy, antihormonal
extent of disease in the entire body, both soft tissue and the skel- treatment, salvage surgery, chemotherapy, or combination of
eton especially in high-risk prostate cancer patients. these) in patients with recurrent prostate cancer.
Figure 15.5. 18F-FCH PET/CT scan in initial staging in a patient with prostate
cancer (Gleason score 9, PSA 10 ng/mL): positive left iliac lymph node.

Figure 15.6. 18F-FCH PET/CT scan in a patient with recurrent prostate

cancer disease (Gleason score 7, PSA 4 ng/mL): local recurrence in pros-
tatic bed.
Figure 15.7. 18F-FCH PET/CT in a patient with recurrent prostate cancer

disease (Gleason score 9, PSA 1.3 ng/mL): recurrence in right pubic bone.

After radical prostatectomy, a confirmed PSA value >0.2 ng/mL prostate cancer, but because the tracer is not specific, it cannot be
represents recurrent prostate cancer disease—biochemical generally recommended as the primary procedure for the local-
relapse.48 Following radiation therapy, a confirmed PSA value ization of prostate cancer. A study of 20 patients with elevated PSA
>2 ng/mL represents recurrent prostate cancer disease.49,50 Approx- level and negative biopsy showed that 18F-FCH PET/CT correctly
imately 19% to 53% patients initially treated with radical prostatec- identified prostate malignancy in 25% of the patients.62
tomy or radiotherapy will have recurrent disease.51,52 Currently,
there are no guidelines regarding imaging procedures in patients
with biochemical relapse; CT and bone scintigraphy are sensitive at
Treatment Monitoring of Prostate
PSA levels >20 ng/mL.52 MRI showed good results in the evaluation Cancer Disease
of prostatic bed but it is not routinely recommended.52,53 In patients receiving antiandrogen treatment, conventional imaging
Several studies showed that 18F-FCH PET/CT is sensitive to modalities very often do not show any significant morphologic
detect recurrent prostate cancer disease if PSA is greater than changes in involved lymph nodes or other sites of tumor involve-
2 ng/mL.54,55 In patients with PSA <2 ng/mL, the detection rate is ment. In these patients 18F-FCH PET/CT has a potential role to dem-
30% to 40%.56 PSA doubling time (PSA DT) is an independent onstrate metabolic response to hormonal therapy (Fig. 15.8).
predictor of choline PET/CT results.57 In another study, 81% of 18
F-FCH PET/CT has a sensitivity of 96%, specificity of 96%, positive
patients with PSA DT <3 months had positive 11C-CH PET/CT predictive value 99%, and a negative predictive value 81% for the
scan. Also, PSA DT, but not PSA alone, distinguished patients detection of bone and soft tissue metastases in castrate-resistant
with pathologic tracer uptake in the skeleton versus patients patients.63 False-positive results can be due to inflammatory changes
with pathologic tracer uptake in prostatic bed.57,58 Gleason score (e.g., after radiation therapy); false-negative results can be due to
is another important factor that can influence sensitivity of small size of the lymph nodes. Nevertheless, 18F-FCH PET/CT is use-
18
F-FCH PET/CT in evaluation of recurrent prostate cancer dis- ful for the detection of prostatic recurrence, lymph node, and skel-
ease. In a study of 100 patients with biochemical relapse,59 etal lesions especially with high-risk prostate cancer patients with
Cimitan et al. concluded that 18F-FCH PET/CT is not likely to PSA value >4 ng/mL during antiandrogen therapy.64

have a significant impact in the therapeutic care until PSA
increases to >4 ng/mL in patients with Gleason score 7 or <7.60
In conclusion, in patients with recurrent prostate cancer disease, Therapy Planning of Prostate Cancer Disease
the overall sensitivity of 18F-FCH PET/CT seems to be higher Most patients with prostate cancer have one or two dominant
among patients with higher PSA, higher initial Gleason score, intraprostatic lesions. Due to gastrointestinal and genitourinary
and shorter PSA DT. toxicity of external irradiation, definition of volumes for focal
radiotherapy, in primary or recurrent prostate cancer disease, is
Localization of Prostate Cancer (Elevated crucial. In a study of 66 patients, intraprostatic lesions were iden-
tified in all patients, mostly in the periphery of the prostate, within
PSA Level and Negative Biopsy) 5 to 10 mm of the bladder or rectal wall.65 In a study of 183
The false-negative biopsy rate in patients with prostate cancer is patients after radical prostatectomy, Gleason score >7 and PSA
20%.61 Radiolabeled choline uptake seems to be similar in benign <1.5 ng/mL, who were considered for local salvage radiotherapy,
changes like prostatitis and prostatic hypertrophy as well as in Cimitan et al. found that 18F-FCH PET/CT showed distant metas-
prostate cancer. This is the main limitation for the use of radiola- tases in one-third, making radiotherapy inappropriate.60
beled choline to identify primary prostate tumor. In patients with In 16 European countries, 18F-Fluorocholine has been approved
repeatedly negative biopsies, 18F-FCH PET/CT is able to localize and is widely used to image patients with prostate cancer. With
Figure 15.8. 18F-FCH PET/CT in a patient with prostate cancer before (down)
and after (up) hormonal treatment (Gleason score 9, PSA before hormonal
treatment 2,646 ng/mL).

the approval of 11C-Choline in the United States for this purpose, able imaging techniques. Increasing PSA levels following prosta-
a large-scale clinical trial of 18F-FCH PET/CT with standardized tectomy without identification of a metastatic site on conventional
18
F-FCH PET/CT protocols should be considered.66 imaging is known as biochemical failure and represents an oppor-
tunity and need for prostate-specific radiolabeled imaging agents
18 to identify the location of recurrent disease. The patient with bio-
F-Fluoro (Dihydro)Testosterone chemical failure is also an appropriate candidate for targeted
Since the androgen receptor is vigorously expressed in prostate radionuclide therapy.
tissue and is involved in the catalytic release of PSA from the There is no doubt that serum PSA assays detect many men
larger tissue molecule from which circulating PSA is derived, it with prostate cancer who would have not been identified until the
might be worthwhile to image the androgen receptor utilizing a disease had become more advanced and widespread. However,
radiolabeled testosterone analog, dihydrotestosterone which is currently the US Preventive Services Task Force does not recom-
known to be the primary ligand for the androgen receptor. Utiliz- mend PSA screening as it may result in “overdiagnosis” and over-
ing an 18F-radiolabeled testosterone derivative (16β-18F-fluoro-5- treatment” which involves risks of complications.70 Since PSA
α-dihydrotestosterone), a group at MSKCC in New York performed assays identifies malignant tissue in the prostate of so many men,
a feasibility study in seven patients with metastatic prostate can- it has become more important to better characterize the degree of
cer. Although the labeled preparation underwent considerable tumor aggressiveness and intraprostatic tumor mapping to guide
metabolism and serum protein binding of metabolites, tumor decision making and choice of therapy.
uptake was observed in 46 of 59 lesions observed by conventional PSA itself has not been a suitable target for radionuclide imaging
imaging; 18F-FDG was positive in 57 of 59. The average SUVmax and/or therapy. PSMA offers another potential target that distinct
was 5.22. On repeat imaging following testosterone treatment, the from both PSA and prostate mucin antigen (PMA). PSMA is a trans-
18
F-dihydrotestosterone uptake was decreased. Unfortunately, the membrane, 750 amino acid glycoprotein which has an enzymatic
synthesis takes at least 100 minutes and is a challenging one. role in cell physiology as folate hydrolase I or glutamate carcoxy-
Furthermore, the rapid conversion to metabolites renders quanti- peptidase II. It is abundant in prostate epithelium (with some
tative studies even more challenging. No further studies using this expression in other secretory tissues) and has increased expression
tracer have been published.67 in prostate carcinoma. The degree of expression is somewhat pro-
portional to tumor aggressiveness; that is, greater expression of
PSMA on more aggressive tumors. It has been recognized as an
Prostate-Specific Tracers antigen with an extra- and intracellular component. These epitopes
are distinguishable by specific monoclonal antibodies and can serve
Over 30 years ago, Goldenberg et al. demonstrated that antibodies as a target for prostate cancer imaging and therapy.
could be developed against tumor-associated antigens.68 These
antibodies can then be radiolabeled and serve as relatively tumor-
specific radiolabeled markers of tumor location. Since that time, the PSMA Antibody Imaging
use of immunoglobulins as tumor-specific carriers of radionuclides (Radioimmuoscintigraphy)
(or other signaling agents or therapeutics) has been aided by the Multiple antibodies to PSMA have been developed and character-
development of monoclonal antibody technology, thus allowing pro- ized, two of which, 7E11 and J591, have been extensively evaluated
duction of large quantities of a specific immunoglobulin with well- as either a vehicle for diagnostic imaging or targeted radionuclide
characterized sensitivity and specificity. Subsequently, investigators therapy.71
have identified many tumor-associated antigens that have been
used to produce antibodies to serve as radiodiagnostic or radioim-
munotherapeutic agents. Several PSAs have been identified and 7E11 (Antibody to Intracellular
while present in normal prostate tissue, these antigens are Epitope of PSMA)
expressed in increased amount in prostate carcinoma: PSA, pros-
tate mucin antigen and prostate-specific membrane antigen (PSMA). 7E11 recognizes the intracellular component of PSMA raising the
PSA is a glycoprotein enzyme that has peptidase properties. It issue of whether an intact immunoglobulin can gain access to the
is secreted by the prostate into the seminal fluid but also appears intracellular component of a transmembrane protein. In cell sus-
in small quantities in the serum. In fact, the circulating PSA is a pensions, 7E11 bound to 95% of prostate cancer tissue samples
fragment of a larger molecule within the prostate cell membrane. tested. The success in identifying PSMA in tissue samples gener-
Although the expression of the tissue PSA and the cleavage of the ated impetus for the development of a radiolabeled preparation
circulating component are influenced by androgen stimulation of that could be imaged in intact patients. Because of the slow clear-
the androgen receptor, there is considerable variation among indi- ance of immunoglobulins from plasma, 111In was chosen as the
viduals and not all of the factors that influence the level of circulat- tracer to allow sufficient time for plasma and extracellular fluid to
ing PSA are understood.69 Antibodies to the circulating component clear as the detection of tumor foci depends upon both the tumor
of PSA make possible a widely used, sensitive and specific immu- uptake and the contrast with background activity.
noassay for the detection of PSA in serum. Serum PSA has become
the essential clinical biomarker to assess diseases of the prostate 111
gland, both benign and malignant. PSA values rise gradually with
In-Capromab Pendetide
111
age reflecting prostatic enlargement and bursts of PSA activity are In is linked to the murine immunoglobulin via GYK DTPA, a
observed in prostatitis. PSA is also a marker of prostate cancer. chemically stable linker that is covalently attached to the immuno-
Despite the nonspecific reasons for PSA elevation, an accelerated globulin prior to combination with 111In. GYK DTPA serves as a
rise in PSA, not associated with prostatitis, raises suspicion for chelator to bind the radiometal. Following clinical trials, 111In-
prostate carcinoma leading to further evaluation including tran- capromab pendetide was approved by the Food and Drug Admin-
srectal biopsy followed by decision making in terms of selection istration (FDA) and marketed in the United States as Prostascint.
and extent of therapy. Following prostatectomy, the PSA falls to As a murine immunoglobulin, 7E11 has the potential to lead to
very low levels. Subsequent, post prostatectomy monitoring of the development of human antimurine antibodies (HAMAs) which
serum PSA levels provides a practical means to detect recurrent have been observed after a single infusion in about 8% of the
disease. In fact, a significant number of patients will have elevated patients and up to 19% after repeat infusions. (Package Insert)
PSA levels without detectable tumor recurrence on currently avail- Although serious adverse reactions have not been reported, the

presence of HAMA precludes normal biodistribution and limits In a comprehensive review of the early Prostascint imaging
tumor access to radiolabeled antibody as it is rapidly cleared from experience, Blend and Sodee reported sensitivities for the detec-
the blood stream following conjugation with HAMA. tion of pelvic and abdominal lymph node metastases from 62% to
The initial FDA approval of 111In-capromab pendetide Prostas- 92% in various studies compared to CT and MRI with sensitivities
cint was for two indications: from 4% to 52%.73 In these early studies, compared to surgical
sampling of pelvic lymph nodes, SPECT imaging with Prostascint
• Preoperatively, to assess extent of disease for high-risk patients
had a sensitivity of 62% and a specificity of 72% for the detection
based on a high Gleason score identified on biopsy material.
of tumor involvement. In general, the technique was insensitive to
• Identify location and extent of disease recurrence following sur-
detect involvement in lymph nodes <1.5 cm. Although the overall
gical prostatectomy who after a period of low PSA values have
accuracy in the pelvis, therefore, is not great, it provided addi-
experienced a rise in serum PSA.
tional information to guide the extent of surgical intervention. The
Prostascint was introduced prior to the routine use of digital technique performed better at extrapelvic sites with positive and
displays and certainly before the use of fused SPECT and either negative predictive values of approximately 80%. There is no
separately acquired or sequential CT or MR imaging. The initial doubt that the addition of hybrid imaging that provided fused
protocol involved planar whole-body images and SPECT acquisi- SPECT/CT images markedly improves the sensitivity and specific-
tion of the pelvis and other areas if suspicious. The transaxial ity of this technique. With SPECT/CT, Schettino et al. excluded 74
radionuclide distribution was challenging to interpret as the of 161 suspicious foci identified on nonfused images. Nodal metas-
radiolabeled antibody remained in the vascular spaces, specifi- tases were excluded in 25 of 58 patients.74 At the New York-Pres-
cally the femoral and iliac vessels and the bone marrow sinuses. byterian/Weill Cornell Medical Center, SPECT/CT of Prostascint
Some activity was often seen in the bladder urine and there was significantly reduced imaging time; that is, patient time on the
some secretion of activity into bowel contents. The strategy was to imaging table as well as technologist time involved in image
image on day 0, approximately an hour or 2 after infusion of the acquisition and processing and finally, nuclear medicine physician
111
In-capromab pendetide and to reimage 3 to 5 days later. Inter- involvement in interpretation. SPECT/CT fusion images had

pretation was based upon identification of a focus or foci on the greater credibility with referring physicians who could more read-
delayed images that was not present on the earlier acquisition. ily comprehend the anatomical location of identified foci when the
Since patients had usually undergone radionuclide skeletal imag- SPECT data were fused with even nondiagnostic CT images. Even
ing prior to referral for Prostascint, the foci of interest were usu- recurrent intraprostatic foci were confidently and accurately iden-
ally in the region of the prostate bed indicating local recurrence or tified in several instances in which the prostate had not been
the lymphatic drainage which was particularly challenging removed as the patient was treated with brachytherapy or cryo-
because the lymph nodes ran along the great vessels and had to therapy (Fig. 15.9). Finally, the correlation of disease mapping
be distinguished from the nearby vascular activity. with anatomic detail provided a basis for utilization in field plan-
Subsequently, the technique was modified to include 99mTc ning in radiotherapy. Jani et al. reported significant changes in the
labeling of red blood cells on days 3 to 5 when the patient appeared clinical target volume based on the immunoscintigraphic defined
for imaging. Simultaneous acquisition of the upper 111In peak and extent of disease.75,76 The technique facilitated improves mapping
the 99mTc peak was performed. This provided direct comparison of of treatment fields, boosting radiation doses to tumor, and reduc-
transaxial activity distribution and eliminated the need to image on ing or eliminating exposure of nearby normal tissue.77,78
the day of infusion. The application of SPECT/CT, however, was the
greatest advance to image acquisition and interpretation. Patients
were imaged on days 3 to 5. The Prostascint images were read J591 (Antibody to Extracellular Epitope of PSMA)
alongside as well as fused with the CT images. At about the same
Since the 1990s, a group led by Dr. Neil Bander, a urologist at Weill
time, software was developed that fused separately acquired trans-
Cornell Medical College with additional training and experience in
axial images (CT or MR) with the radiopharmaceutical distribution
laboratory and clinical immunology, have performed extensive
using intrinsic anatomical markers as the basis for anatomic cor-
laboratory and clinical assessments of the monoclonal antibody,
relation. These techniques significantly reduced patient-scanner
J591. J591 binds with high affinity and specificity to the extracel-
time, technologist processing time, and physician interpretation
lular component of the membrane enzyme, PSMA. The antibody–
time. Moreover, the interpretations based on fusion imaging had
antigen complex is subsequently internalized. As an extracellular
greater credibility with referring physicians who could “see” the
epitope, it is more readily exposed to the extracellular fluid (and
foci considered significant for themselves.72 This led to the addition
its contents) than 7E11 and has therefore been of interest to sev-
of new applications beyond those approved by the FDA:
eral groups of investigators.71 In a “nonimmunogenic” (human-
• external beam radiation therapy and ized) form, it has been evaluated for over a decade as a
• assess local or metastatic disease involvement in patients who radioimmunotherapy agent. More recently, humanized J591 has
had not undergone surgical prostatectomy (such as those treated been evaluated as a SPECT and/or PET imaging agent to identify
with brachytherapy or other prostate in situ interventions) tumor expression of PSMA in an effort to explain the variations in
Figure 15.9. 111In-capromab pendetide

(Prostascint) SPECT/CT; transaxial slices, left to
right: CT, SPECT/CT, SPECT demonstrating
intraprostatic focus in a patient who declined
surgery and EBRT.

therapeutic response and to assess the degree of expression of

PSMA to identify patients who are more apt to benefit from J591
radioimmunotherapy. Because of the relatively long plasma half-
life of the labeled J591, it is necessary to image after an interval
of 3 to 5 days following administration of the labeled antibody.
The physical half-lives of 99mTc, 123I, 18F, and 11C are too short to be
utilized as tracers. Accordingly, imaging has been performed with
either 111In-labeled J591 or by imaging the γ-component of the
therapeutic preparation Lutetium-177 [177Lu]-DOTA-J591. Planar
and SPECT/CT imaging has been performed with these tracers.
More recently, J591 has been labeled with Zirconium-89, a posi-
tron emitter with a 78-hour half-life.
J591 Imaging
Whereas it would be useful if scintigraphic or conventional imag-
ing accurately determined the extent and location of prostate
malignant tumor, in many instances there is biochemical evidence
of relapse without positive image findings. Detection of tumor with
scintigraphy and/or effective targeted radionuclide therapy
depends upon the tracer receptor (or epitope) affinity, the physical
characteristics of the radionuclide, the lesion size, the absolute
amount of the radiolabeled tracer within the primary tumor or
metastatic focus, and the tumor-to-background contrast. Hence,
the initial radioimmunoscintigraphy studies utilizing 111In-DOTA-
J591 were performed to obtain pharmacokinetic data for dosimet-
ric calculations and, if possible, to confirm targeting of lesions,
particularly during an early trial of 90Y-labeled J591 since 90Y did
not have a γ-emission that would make external imaging and
quantitation possible. In studies using 177Lu, it was possible to
perform radioimmunoscintigraphy which has been used to assess
the degree of J591 binding to determine if the variation in radio-
immunotherapy responses were due to the degree of expression
of PSMA. In both cases (111In-J591 and 177Lu-J591), whole-body
and, when deemed appropriate, SPECT/CT imaging were per-
formed from 2 to 5 days following injection of appropriate doses
of 111In-J591 or 177Lu-J591.
111
In-DOTA-J591 Imaging
There is not a great deal of 111In-J591 imaging data. 111In-J591
was initially used in a 90Y-J591 radioimmunotherapy trial to dem-
onstrate that the antibody did indeed bind to metastatic lesions. It
had previously been demonstrated in nude mice that the pharma-
cokinetics (plasma clearance) and biodistribution of 111In-DOTA-
J591and 90Y-DOTA-J591 were similar, thus justifying the use of the Figure 15.10. 177
Lu-DOTA-J591 and 99mTc-MDP whole-body images revealing large right
111
In-DOTA-J591 as a proxy molecule for 90Y-DOTA-J591. Of 29 sacroiliac lesion with vigorous uptake of both tracers. In clinical trials, vigorous uptake of
177
patients in the trial who initially received 185 MBq (5 mCi) of Lu-DOTA-J591 at sites of osseous metastases correlated with a good (albeit temporary)
111 therapeutic response. 177Lu images are possible because of the γ-emission component of 177Lu
In-DOTA-J591 (total protein: 20 mg), 19 patients had focal
which has been studied as a radioimmunotherapy agent at Weill Cornell Medical Center in New
lesions on skeletal scintigraphy and 13 had soft tissue lesions on York for over a decade. 111In-DOTA-J591has served as a proxy molecule for 177Lu-DOTA-J591
conventional imaging. Seventeen of the 19 patients (89%) with in dosimetry studies and others evaluating PSMA expression prior to infusion of 177Lu-DOTA-
skeletal foci and 9 of 13 patients (69%) with soft tissue lesions J591 for therapy.
localized 111In-DOTA-J591. Of course, it is now recognized that
tumor-specific tracers may be more accurate than bone scintigra-
phy because of their specificity since focal uptake on skeletal phy to determine the degree of variability in the percent targeting.
imaging is nonspecific and may represent the osseous response 177
Lu-J591 planar images were scored on a 4-point scoring system;
from nonviable tumor, trauma, or degenerative changes.79,80 “0” if the known site had no detectable activity, “1” if faint tumor
activity was seen, “2” if the activity was prominent but not equal to
177 the liver intensity, and “3” if the tumor activity was approximately
Lu-DOTA-J591 Imaging
equal to the liver activity (Fig. 15.10). In addition, a more quantita-
Although 177Lu-J591 is an investigational agent for targeted radio- tive scoring system, the so-called tumor targeting index (TTI) was
nuclide therapy, it emits a 210-KeV γ-ray with an 11% abundance, also determined in which the ratio of background corrected tumor
making planar and SPECT imaging possible in patients receiving counts/area was compared to the whole-body counts/area. With
doses of approximately 1.4 GBq (40 mCi) or more. Since the clini- both indices, a greater fraction of patients with higher scores had
cal trials usually began at 0.7 GBq/m2, the photon flux is sufficient either stabilization or reduction of the PSA levels than the patients
to image but diagnostic imaging with 177Lu-J591 was not a realistic with lower scores. In conclusion, 177Lu-J591imaging is useful to
possibility. In radioimmunotherapy trials, imaging was performed assess fractional uptake of the dose administered as a therapeutic
to compare targeting with lesions identified on skeletal scintigra- but has no role as a diagnostic agent.81

89
Zr-J591 minant of tumor aggressiveness. An antibody, 5A10, has been
developed that selectively binds fPSA at an epitope adjacent to the
As stated previously, image resolution and lesion detection are catalytic cleft of fPSA from which “complexed” PSA is released into
improved with PET technology; a consequence of the abundant the circulation.69 Using desferroximine B as a chelator, 89Zr was
photon flux and coincidence circuitry localization of events. In conjugated to 5A10 and in vivo studies were obtained in a male
general, PET imaging has been performed with short-lived posi- mouse model bearing subcutaneous xenografts of a PSA-positive
tron tracers. Imaging of a large molecule like immunoglobulins prostate cancer cell line that overexpresses the androgen receptor
requires sufficient delay after administration to allow for back- (LNCaP-AR). A high degree of specific binding to the tumor tissue
ground clearance. Hence, 11C and 18F are not appropriate tracers was observed, confirmed by lack of binding to tumor implants that
for intact or large fragments of immunoglobulins. 89Zr is a posi- did not express PSA or the androgen receptor. Furthermore, there
tron-emitting radiometal with a relatively long half-life (t1/2 78 was minimal localization of a nonspecific immunoglobulin. Testos-
hours). Accordingly, 89Zr is of increasing interest as a tracer for terone stimulation of the androgen receptor resulted in significant
immuno-PET; PET imaging using a radiotracer linked to specific increases in intratumoral PSA and in the binding of 89Zr-5A10.
immunoglobulins. Since the binding chemistry of 89Zr is suffi- Finally, administration of an antiandrogen inhibited tumor growth,
ciently different from 111In and 177Lu, the usual DOTA moiety is fPSA expression, and radiotracer localization. Although no direct
unsatisfactory to chelate 89Zr. A group at Memorial Sloan-Ketter- comparison has been made to date between 89Zr-5A10 and 89Zr-
ing Cancer Center in New York conjugated desferrioxamine B J591, the authors point out that PSMA expression is neither spe-
(DFO) to the humanized J591 immunoglobulin that had been cific for cancer nor is the effect of antiandrogen therapy on PSMA
extensively studied initially as a radioimmunotherapy agent expression known.69
labeled with 177Lu (or less frequently 90Y) and more recently to
image PSMA positive tumors when labeled with 111In or 177Lu. The
DFO-J591 conjugate was subsequently labeled with 89Zr and
Small Molecule Imaging
injected into mice previously prepared with either PSMA+ or Although PSMA was initially utilized as an antigen and antibodies

PSMA– tumors. The immunoreactive fraction was determined to that had high affinity for various epitopes of PSMA have been
be 0.95+/–0.03 and the radiolabeled preparation remained active exploited for both scintigraphy and targeted therapy, more
for 7 days. High tumor-to-background tissue contrast was observed recently attention has focused on PSMA as a transmembrane pro-
with tumor-to-muscle ratios greater than 20 in the mice with tein with enzymatic activity. PSMA is specific peptidase found in
LNCaP xenografts. Based on these encouraging findings in labora- high concentration in prostate tissue and to a lesser extent in
tory animals, the group is currently assessing the use of this tracer other secretory epithelium. As an enzyme, PSMA binds specific
for clinical assessment of patients with prostate carcinoma. To molecules with high affinity. Various analogs have been developed
date, there is no published data but localization of 89Zr-J591 at including molecules that bind to the enzyme to such a high degree
metastatic sites has been identified in a patient with soft tissue that they effectively serve as inhibitors of the enzymatic activity.
and osseous metastases. The degree of 89Zr-J591 uptake corre- These molecules are described as heterodimers; the essential core
lated with the qualitative assessment of subsequent 177Lu-J591 being two amino acids linked by a urea moiety. The glutamate–
uptake on planar and SPECT imaging.82 urea–lysine complex has a high degree of affinity and specificity
for the external component of the complex PSMA molecule.83
89 Based on this specific and high affinity, it was recognized that
Zr-5A10
these heterodimers could serve as carriers of radionuclides. After
89
Zr has also been used to perform immuo-PET using an alternate preliminary studies involving animal models bearing human pros-
prostate cancer target, the precursor of the circulating marker tate carcinoma successfully imaged implanted tumors, initial
PSA. Circulating PSA itself is not a satisfactory target for radioim- imaging studies were performed in patients with metastatic pros-
munoscintigraphy or radioimmunotherapy. Serum PSA is actually tate carcinoma comparing two 123I-radioiodinated compounds
a component of a larger molecule within the cell membrane that with glutamate–urea–variable amino acid cores. The side chains
functions as a serine protease. A portion is catalytically released of these compounds were modified to provide differences in their
from the larger molecule (“free” PSA or fPSA) into the circulation biodistribution and mode of excretion. In a “First-in-Man” publi-
in a noncatalytic form (the so-called “complexed” PSA). Since cation, both 123I-iodinated compounds had similar biodistribution
androgen receptor signaling more directly augments expression of although one had greater renal clearance and therefore cleared
the intact PSA molecule, it was postulated that direct assessment the plasma more rapidly. Tracer uptake was seen in the liver,
of the intact tissue PSA may be a more meaningful determination bowel, kidneys, lacrimal, salivary, and parotid glands. In the case
to assess the degree of androgen receptor expression as a deter- of slower plasma clearance, more activity was seen in organs and
Figure 15.11. 123I-labeled heterodimer [Glu-Urea-Lys] with demonstrated high affinity for PSMA. Minimal uptake is seen in the normal prostate (left); well-defined
uptake in prostate gland with a confirmed as yet untreated prostatic adenocarcinoma.

Figure 15.12. Left to right: Anterior and posterior whole-body scans (99mTc-MDP, 123I-PSMA antagonist [MIP-1072], and 111In-capromab pendetide). Bone scan
demonstrates lumbar spine metastases that are not seen on 111In-capromab pendetide scans. 123I-labeled heterodimer (PSMA antagonist) demonstrated lumbar
spine lesions as well as multiple soft tissue metastases. There is a suggestion of tracer accumulation in the left medial groin on the 111In-capromab pendetide
images. p.i., postinfusion.
metastatic lesions. Nevertheless, uptake and background clear- were imaged with SPECT/CT within 3 hours after receiving 10 mCi
ance was sufficient to detect most metastatic lesions within 2 of the 99mTc-PSMA ligand heterodimer. A previously scheduled rad-
hours after dose administration. Some uptake was seen in the ical prostatectomy was performed within 2 weeks. The prostates
prostate gland of normal volunteers but in patients with prostate were removed, stained for PSMA and analyzed on a 6-sector grid
cancer, foci of increased uptake could be identified (Figs. 15.11 (right and left, 40 of the 48 sectors were positive for PSMA-express-
and 15.12). ing prostate carcinoma albeit not all with Gleason scores ≥7. Imag-
Although these 123I-labeled small molecules were apparently ing overall had a sensitivity and specificity of 62.5%). The intensity
successful to image metastatic prostate carcinoma, it was recog- of tracer localization appears to correlate with Gleason scores of 7
nized that a 99mTc-labeled tracer would be more useful since it or above (Fig. 15.15).85
could be made available in a kit form so the tracer could be pre- As with the 123I-labeled agents, the 99mTc-labeled heterodimers
pared in clinical nuclear medicine units and the γ-emission would identified metastatic disease including lymph node involvement
be even more abundant. In fact, 99mTc-labeled versions have been prior to initial surgery although findings could not be confirmed
developed and evaluated in normal subjects and prostate cancer as the protocol did not include sampling of lymph nodes based on
patients (Figs. 15.13 and 15.14).84 The 99mTc-heterodimers pro- image identification. In a 71-year old patient with a rising PSA
duce images of good contrast and biodistribution in normal sub- following prostatectomy, both 99mTc agents identified multiple foci
jects similar to the 123I heterodimers. As with the 123I compounds, of metastatic disease that had not been seen on a bone scan per-
slight variations in the chemical side groups affected the route by formed 2 months earlier. Three months later, repeat bone scintig-
which the tracer is eliminated (kidneys versus liver). Two 99mTc- raphy confirmed the presence of multiple osseous metastases.84
radiolabeled versions with different degrees of renal excretion The quality of the 99mTc-heterodimer images is so impressive that
were evaluated. it would be expected that this agent might be useful to identify the
The agent with the preferential renal clearance excreted 37% of extent of regional disease prior to initiation of therapy and modify
the injected dose within 4 hours whereas the other agent elimi- initial surgery to include harvesting of lymph nodes that might not
nated a greater fraction of the administered dose via the liver. With otherwise be retrieved. Initial studies, in patients prior to surgery,
either agent, it was possible to image the intact prostate and have demonstrated excellent resolution capable of identifying intra-
identify the intraprostatic distribution of multiple tumor foci. In prostatic tumor foci and distinguishing the degree of PSMA expres-
preliminary studies, the mapping correlated with subsequent sion among several foci. The degree of uptake has correlated with
immunopathologic staining following removal of the intact prostate the Gleason score of the individual foci. This is indeed exciting if
gland. Patients with a Gleason score ≥7 on 3 or more biopsy cores confirmed with further clinical studies, it suggests that would be

hours after injection of 52 to 212 MBq of the 68Ga-PSMA ligand.

The ligand localized in normal tissues in a pattern similar to the
123
I- and 99mTc-labeled heterodimers. Activity appears promptly in
the urine; it is advisable to have the patient empty the bladder
before imaging. Thirty-one of 37 prostate carcinoma biochemical
failure patients had at least one suspicious lesion. The detection
rate was 60% at PSA values below 2.2 ng/mL and 100% in patients
with PSA exceeding 2.2 ng/mL.87
Prostate Sentinel Lymph

Node Identification
Sentinel lymph node identification is a technique that involves
injection of a radiocolloid into an organ of interest or in or near a
known tumor followed by imaging to determine the lymphatic
drainage pattern. The sentinel lymph node or nodes is the node
receiving the initial drainage from the area of interest. It is not
necessarily the closest lymph node. In patients with melanoma and
breast carcinoma, sentinel lymph node dissection has been dem-
onstrated to be of great value, reducing the morbidity as a sentinel
lymph node resection is considerably less traumatic than a regional

lymh node dissection in which relatively large areas are resected.
Furthermore, in a patient without obvious lymph node metastases,
it is more accurate as the pathologic examination is more rigorous
with less tissue to examine. Finally, of course, an unexpected
drainage pattern is readily identified.
Identification of pelvic lymph node involvement in prostate car-
cinoma patients is challenging. Although such involvement would
have a significant impact on the choice of therapeutic options,
resection of the multiple lymph node basins draining the prostate
is not a standard of practice component because of the complica-
tion rate. In recent years, a limited number of medical centers have
evaluated the potential of intraprostatic radiocolloid injection to
identify the sentinel lymph node or nodes. In a relatively recent
study, 35 patients with intermediate or poor prognosis who under-
went extensive pelvic lymph node dissection had intraprostatic
injections and were imaged shortly thereafter. The surgical proce-
dure followed from 5 to 24 hours after injection. A radiation detec-
tion probe was available in the operating suite. In a review
Figure 15.13. 99mTc-anti-PSMA heterodimer (MIP-1404) whole-body scans demonstrating published by the European Association of Urology, Willem Mein-
focal accumulation just below the bladder activity on the left. hardt concludes that the sentinel lymph node identification tech-
nique is as reliable a diagnostic tool as extended pelvic lymph node
dissection and occasionally more sensitive since it may identify
possible to noninvasively identify and map the location of the foci of relevant lymph nodes outside of the usual area resected.88,89
highest Gleason score and greatest concern in terms of aggressive- The standard radiopharmaceutical used in Europe is albumin
ness and prognosis; features that certainly would have an impact on nanocolloid. Veermeeren reported using a standard dose of
choice of therapy. Currently, there is a great deal of discussion as to 225 MBq in 0.4 mL. Planar images are obtained at 15 minutes and
whether, given the potential consequences of a total prostatectomy, 2 hours. In addition, SPECT/CT was performed; an intraoperative
it is necessary to resect the entire prostate regardless of Gleason probe was used at surgery and a portable γ-camera was available.
score or other evidence of the lack of tumor aggressiveness. This In a study comparing the detection rate with 0.1 mg to 0.2 mg of
concept has not yet been subjected to a controlled clinical trial but nanocolloid, more lymph nodes were identified with the greater
data of this sort might provide a basis selection of appropriate amount of nanocolloid (2 to 2.6 lymph nodes, respectively). In
patients for partial resection rather than total prostatectomy.85,86 patients receiving the lesser amount of nanocolloid (but the same
total activity), 84% of the lymph nodes were detected as were
68 detected with the greater amount of nanocolloid.90 In a study of
Ga-PSMA Ligand Heterodimers over 1,200 patients, Winter et al. found that sentinel lymph node
Gallium-68 [68Ga] is a positron-emitting radiometal with a 68-min- pathology examination identified involvement in 3.2% of the low-
ute half-life. Since the small molecule heterodimers with high risk patients (as categorized by the European Guideline nomo-
affinity for PSMA provide good contrast between targeted tumor gram), 14.8 % in the intermediate-risk group, and 37.4 % in
and background within a relatively short timeframe, physicians high-risk patients. In total metastatic lymph node involvement
and biomedical scientists at the University of Heidelberg labeled would have been missed in 16% of the patients based on the cur-
the glutamine–urea–lysine heterodimer with 68Ga using the het- rent nomogram. They proposed a revision to include sentinel
erobifunctional agent N,N’-bis[2-hydroxy-5-(carboxyethyl)benzyl] lymph node as a component of the assessment of risk in patients
ethylenediamine-N,N’-diacetic acid [HBED-CC]. This agent was with the diagnosis of prostate carcinoma.91 In another study,
used because it complexed 68Ga3+ much faster than DOTA at Weckermann et al. reported that positive lymph nodes were found
ambient temperatures. PET images were obtained at 1 and 3 in 207 men (∼20 % of the total assessed). In this study, in 63.3%

A B
Figure 15.14. The same patient as in Figure 15.13. A and B:

Coronal and transaxial slices through prostate gland demonstrat-
ing tumor avidity with localization to the left side of the enlarged
C D prostate gland. C and D: Coronal and transaxial slices of a small
presacral lymph node with PSMA+ tumor.
Figure 15.15. Whole-body and transaxial SPECT/CT slices if a patient with a large, Gleason 9 tumor in the right hemiprostate gland. There is a second less FDG
avid focus in the left anterior region of the prostate that correlates with histopathologic mapping of a Gleason 7 tumor focus.

of the men, at least one lymph node was outside of the region of next step would be to re-treat but this required a new protocol.
standard lymphadenectomy. The frequency of nodal involvement Rather than wait for patients to relapse, a trial was designed giving
was greater than predicted from existing nomograms but was less than the single MTD but repeating the dose 2 weeks after the
more likely in patients with higher PSA values and T stage. They initial dose. With this protocol, the MTD for divided doses was
conclude that if lymph node dissection is considered based on risk determined to be 1.48 GBq (40 mCi)/m2) × 2 for a total dose of
factors, sentinel lymph node identification should be performed 2.96 GBq (80mCi)/m2. Clinical responses at this level based on sta-
since positive lymph nodes are identified beyond the usual extent bilization of the serum PSA level as a biomarker revealed more
of the dissection although in some cases, the sentinel lymph node responders than the single dose 177Lu-J591 trial where patients
was not the only involved metastatic site.92 received 370 MBq less.96
Currently, based on the promising results in patients with cas-
trate-resistant metastatic disease, multiple protocols have been
Targeted Radionuclide Therapy designed to evaluate the therapeutic potential of 177Lu-DOTA-J591
Metastatic prostate carcinoma appears to be an appropriate tar- as well as 90Y-DOTA-J591:
get for radionuclide therapy as the disease is often multifocal.
• As adjuvant therapy
Recurrent disease may present prior to the time when lesions are
• Combination with chemotherapy
large enough to be seen by traditional or even novel imaging
• Substitution with an α-emitter
methods. Until recently, there has been no well-defined chemo-
therapy option particularly when hormonal manipulation is no 7E11, the murine monoclonal antibody that recognizes the
longer effective. Targeted radionuclide therapy of prostate carci- intracellular epitope of PSMA (and when labeled with 111In is mar-
noma has been largely pursued with radiolabeled monoclonal keted as Prostascint as an imaging agent). 7E11 has been also
“humanized” immunoglobulins to the external epitope of the labeled with Yttrium-90 [90Y] and evaluated as a radioimmuno-
membrane protein PSMA. Recently, however, there has been activ- therapeutic agent. In a trial to evaluate the potential as a radioim-
ity utilizing molecules that inhibit the PSMA enzyme activity by munotherapy agent, 90Y-7E11 was insufficiently effective to be

high affinity binding. considered further.97,98 Although exposure of the intracellular por-
tion of PSMA in necrotic cells might provide a basis to image tumor
foci, it would not be expected to serve as an effective basis for a
Radioimmunotherapy radioimmunotherapy agent.
Radioimmunotherapy of prostate carcinoma, the use of appropri-
ately labeled immunoglobulins to deliver targeted radiation to dis-
persed prostate tumor foci has been actively pursued in clinical
Small Molecule Targeted Radionuclide Therapy
trials for over a decade by a multidisciplinary team at the New Following the demonstration that urea-linked peptides (such as
York-Presbyterian Hospital and Weill College of Medicine of Cornell glutamate-urea-lysine) have a high affinity for the enzymatic func-
University in New York City. Although studies continue, a rather tion of PSMA and the successful demonstration that the molecule
complete summary of results to date was recently published.93 could be radiolabeled with 123I as well as other halogens and 99mTc
as well as other radiometals as imaging agents, investigators in
several laboratories replaced the diagnostic γ-emitting radionu-
Lu-177 J591 clides with β-emitters like 177Lu and 131I.
As described in the imaging section, the antibody utilized for radio- When the external epitope of the PSMA moiety binds an anti-
immunotherapy investigations is J591, a monoclonal antibody that body, the epitope–antibody complex is internalized, the iodinated
recognizes the extracellular epitope of the membrane protein amino acid within the immunoglobulin is labile and elutes from
PSMA. The antibody has been “humanized,” that is rendered non- the cell. By contrast, either the radioiodinated high affinity enzyme
immunogenic by enzymatically cleaving a large nonspecific portion antagonist molecules are not internalized but remain bound to the
of the murine IgG and fusing the immunorecognition portion with PSMA-expressing cells or the radioiodine labeling of the amino
the appropriate component of human IgG. To date, with more than acid–urea heterodimers produces an iodinated molecule that is
100 patients studied, there has been no evidence of HAHA or more stable than the usual iodotyrosine-labeled immunoglobulin
altered pharmacokinetics on repeated dosing. The chelating agent as the iodine has remained at the targeted lesion rendering these
decatetraacetic acid (DOTA) is covalently linked to the antibody. On molecules potentially useful for radioimmunotherapy.
the day of infusion, the DOTA J591 is incubated with the chosen Using a 177Lu-labeled heterodimer, Jiang et al. demonstrated
radiometal. The DOTA preparation has been used to bind 111In for tumorocidal effects in mice engrafted with human prostate can-
biodistribution studies and to either Yttrium-90 or Lutetium-177 cer.99 The nuclear medicine group in Heidelberg, Germany have
for radioimmunotherapy.94–96 Because of the likelihood that many administered 5.55 GBq of 131I-labeled heterodimer in patients
patients might have small metastatic lesions in the bone marrow, with metastatic prostate cancer with dramatic results. In one
the 177Lu-labeled preparation was selected for most studies based patient with a markedly elevated PSA, the PSA value declined over
on the improved absorption fraction of lower-energy β-particles. In 2 months to barely detectable levels and the whole-body scan that
studies using the classic FDA clinical trial design, patients received had demonstrated multiple metastases virtually normalizing.
escalating doses of 177Lulabeled antibody; three patients at each Although no classic clinical trial has been reported to date, the
doses and observed for toxicity before moving the dose to be results in terms of normalization of serum PSA and lesions identi-
administered to the next level. Patients were observed for toxicity. fied on scintigraphy are dramatic and have been repeated in other
The principal toxicity, as expected, was hematologic with a nadir patients although the duration of the response has not yet been
of platelets and white blood cells at approximately 4 weeks. From reported.100
these studies, it was determined that a single administration of
2.88 GBq (70 mCi)/m2 was a maximal tolerated dose (MTD). Fur-
thermore, using stabilization or decline of the PSA values as evi- Conclusion and Future Considerations
dence of antitumor activity, it was observed that there was a
striking difference between 2.68 GBq (65 mCi)/m2 and the MTD After many years in which nuclear medicine’s role in the evalua-
suggesting that even greater doses might be advantageous. The tion and treatment of patients with prostate carcinoma was lim-
usual course among responding patients was stabilization of the ited in terms of diagnostic imaging to nonspecific bone scintigraphy
PSA for several months and then a gradual PSA rise. An obvious to identify and monitor bone metastatic, there have been great

strides toward development and clinical applications of advances uation of 123I- and 99mTc-labeled anti-PSMA heterodimers was only
using SPECT and PET imaging agents with excellent sensitivity possible because of the access to these agents and the involvement
and specificity. The first of these advances, an 111In-labeled anti- of John Babich, PhD and the dedication of Anatasia Nikolopoulou,
PSMA antibody, had limited access and application. Although PhD and Shankar Vallabhajosula, PhD. Dr. Vallabhajosula is also
prostate carcinoma was sometimes identified with FDG PET, it responsible for the development of the DOTA labeling of the anti-
was found not to be sufficiently sensitive to detect all foci. Cur- PSMA antibody, J591 and the subsequent labeling, pharmacoki-
rently, the most sensitive agent for the detection of intraprostatic netic and dosimetry studies of this immunoglobulin with 177Lu and
tumor, lymph node, and distal involvement appears to be 18F-Flu- other radionuclides. Neil Bander, MD and Scott Tagowa, MD have
orocholine [18F-FCH] although it is not specific for PSMA nor does guided many studies and have mentored one of us (SJG) in the
it differentiate between aggressive, higher Gleason score foci and biology and clinical aspects of prostate cancer for many years. To
less aggressive disease. Since it 18F has a 2-hour half-life, it can be all of these individuals, we express our appreciation and gratitude.
prepared in regional centers and distributed similar to FDG. In
fact, 18F-FCH is commercially available in Europe. In the United
States, 11C-Choline has been approved by the FDA on a site-by-site References
basis. Approval of 18F-FDG is a more complex issue but it is cer-
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C h apt e r 1 6
Uterine and Cervical Carcinoma

Berna Degirmenci Polack
Introduction stage 1 disease, the tumor is confined to the corpus uteri with no,
or less than half thickness, of myometrial invasion (stage IA), inva-
Uterine carcinoma is one of the most common cancers in women. sion equal to or more than half of the myometrium (stage IB). In
In this chapter, endometrial and cervical cancers are discussed in stage II, tumor invades the cervical stroma, but does not extend
detail with different perspectives such as epidemiology, diagnostic beyond the uterus. Stage III indicates that the tumor spreads locally
imaging methods, staging, therapy monitoring, and prognosis. and the involvement of pelvic and para-aortic lymph nodes (PALNs).
Related up-to-date literature has been reviewed and summarized The likelihood of LN involvement is related to the histologic grade
on this subject. The case examples are presented to facilitate of the tumor, and the presence of deep myometrial and cervical
learning. In parallel with increasing use of 18F-FDG PET or PET/ invasion. Distant metastases most commonly involve the lungs,
CT imaging in oncology, the role of nuclear medicine has recently inguinal and supraclavicular nodes, liver, bones, brain, and vagina.
gained acceptance in management of patients with uterine endo- The vast majority of patients presents with early stage of disease
metrial and cervical carcinomas. and undergo hysterectomy and bilateral salpingo-oophorectomy.
Ideally, staging should be done by total hysterectomy, bilateral
salpingo-oophorectomy, as well as assessment and sampling of pel-
vic and PALNs. The tumor is generally confined to the uterus at the
Endometrial Carcinoma time of diagnosis, with only 10% to 20% of surgically staged patients

having LN metastases at the time of surgery. In relatively older
Epidemiology patients and those with comorbid diseases, unnecessary LN sampling
may increase operation duration and may cause postoperational
Endometrial cancer, a tumor of the endometrial lining of the uterus,
complications. For this reason, the patients who should undergo LN
is the most common genital tract cancer and the fourth most com-
sampling should be chosen before their operation.
mon malignancy in women in developed countries worldwide.1
According to the American Cancer Society’s reports, there will be
approximately 49,560 new cases of and 8,190 deaths from endo-
metrial cancer in the United States in 2013.2 Endometrial cancer Imaging Modalities in Staging
is associated with excess estrogen levels, either from endogenous Magnetic Resonance Imaging and
or exogenous sources. Obesity and diabetes are linked to increased
levels of circulating unbound endogenous estrogen, and with the
Computed Tomography
epidemic of obesity, the incidence of this cancer is expected to Magnetic resonance imaging (MRI) appears to be superior imaging
increase. Over 80% of endometrial cancer is typical adenocarcino- modality compared to computed tomography (CT) for the staging
mas and are also known as endometrioid. Other less common of endometrial cancer. The extent of myometrial invasion and LN
types of endometrial cancer are squamous cell and undifferenti- metastases can be evaluated by MRI. Recent guidelines for the
ated carcinoma. Endometrial cancer can be graded on the basis of staging of endometrial cancer with MRI involve a protocol includ-
its histopathologic characteristics: Grade 1 tumors have 95% or ing at least two T2-weighted turbo spin echo (TSE) sequences with
more of the cancerous tissue forming glands; grade 2 tumors have high resolution in the sagittal, transversal (short uterine axis) and
between 50% and 94% of the cancerous tissue forming glands; coronal (long uterine axis) planes and the high resolution, contrast-
grade 3 tumors have less than half of the cancer forming glands. enhanced T1-weighted sequences. To evaluate cervical invasion,
Grade 1 and 2 tumors are known as low-grade tumors; grade 3
tumors are known as high-grade tumors. Tab l e 1 6 . 1
Diagnosis and Staging Staging of Endometrial Cancer

The majority of endometrial cancer cases occur in postmenopausal
women. Uterine bleeding is the most frequent clinical presentation Endometrial Cancer FIGO TNM
of endometrial cancer causing early diagnosis of the patients. Well-
Tumor confined to the corpus uteri I T1
differentiated endometrial (grade 1–2) cancers are generally No or less than half myometrial invasion IA T1a
localized to the surface of the endometrium, whereas poorly dif- Invasion equal to or more than half of the myocardium IB T1b
ferentiated tumors (grade 3) show myometrial invasion. The diag- Tumor invades the cervical stroma, but does not extend II T2
nosis of endometrial cancer is made by endometrial biopsy or beyond the uterus
uterine dilatation and curettage (D&C), with or without hysteros- Local and/or regional spread of the tumor III T3
copy. These procedures are indicated if a woman complains of Tumor invades the serosa of the corpus uteri and/or adnexa IIIA T3a
unexplained postmenopausal bleeding, has abnormal glandular Vaginal and/or parametrial involvement IIIB T3b
cells on the patient’s Papanicolaou (Pap) smear, or an ultrasono- Metastases to pelvic and/or para-aortic lymph nodes IIIC N1
gram shows a thickened endometrial stripe. A meta-analysis has (a) Positive pelvic lymph nodes IIIC1 —
shown that the 5-mm endometrial stripe as a threshold is 96% (b) Positive para-aortic lymph nodes with or without IIIC2 —
sensitive for detecting cancer, but has a 4% false-negative rate and positive pelvic lymph nodes
Tumor invades the bladder and/or the bowel mucosa, IV —
a 50% false-positive rate.3
and/or distant metastases
The patients who are diagnosed with endometrial cancer are Tumor invasion of bladder and/or bowel mucosa IVA T4
staged according to International Federation of Gynecologist and Distant metastases, including intra-abdominal metastases IVB M1
Obstetricians (FIGO) staging system (Table 16.1).4 Staging is based and/or inguinal lymph nodes
on the extent of the primary tumor, regional lymph node (LN)
involvement and the presence or absence of distant metastasis. In FIGO, International Federation of Gynecologist and Obstetricians; TNM, tumor, nodes, metastasis.
219

Table 16.2 women were 5 ± 3.2 and 3.7 ± 0.9 during the menstruating and
ovulating phases, respectively, and 2.6 ± 1.1 and 2.5 ± 1.1 during
Figo Stages and Corresponding Mri Findings the proliferative and secretory phases, respectively. They also
in Endometrial Cancer reported that the mean endometrial SUV of postmenopausal
women receiving hormonal therapy was 1.7 ± 0.7 (range: 1.1 to
FIGO Stages MRI 2.6) and that hormonal therapy in postmenopausal women was
not associated with a significant alteration in endometrial 18FDG
Stage I — uptake. Increased 18FDG endometrial uptake in postmenopausal
IA The endometrial mass is confined to the endometrium or invades women may indicate the malignancy.
<50% of the myometrial wall with disruption of the JZ Benign endometrial lesions, such as uterine leiomyomas, ade-
IB Mass invades ≥50% of the myometrium with a preserved nomyosis, and endometrial hyperplasia generally show mild 18F-
stripe of enhancing outer myometrial wall FDG uptake. Uterine leiomyomas sometimes may show intense
18
Stage II Disruption of the low-signal intensity inner cervical stroma (T2) F-FDG uptake. Chura et al.11 reported leiomyomas showing very
Disruption of the cervical epithelium enhancement (CE T1) high SUVs in three patients: One case was an ordinary leiomyoma
Stage III — of 13 mm (SUVmax: 16), the second was a cellular leiomyoma of
IIIA Disruption of continuity of the outer myometrium or presence 33 mm (SUVmax: 9.3), and the third was a stromomyoma of
of nodules on the peritoneal surface or adnexa 10 mm (SUVmax: 6). The exact mechanism responsible for high
IIIB Tumor extension into upper vagina and/or parametrium FDG uptake in leiomyomas is unclear. The FDG uptake in leiomyo-
IIIC Enlarged pelvic and/or para-aortic lymph nodes (cut-off value: mas would be related to several factors including hormonal depen-
>10 mm for short-axis diameter) dency, cellularity (the number of viable tumor cells), vascularity
IIIC1 Enlarged pelvic lymph nodes (microvessel density), tumor cell proliferation (the expression of
IIIC2 Enlarged para-aortic lymph nodes
growth factors such as basic fibroblast growth factor, transforming
Stage IV — growth factor β, granulocyte-macrophage colony-stimulating fac-
IVA Tumor extension into bladder/rectum with disruption of the tor, and Ki-67 and their receptors), expression of glucose trans-
hypointense signal of bladder or rectal wall porter 1 (GLUT-1) and hexokinase, the existence of endometrial
IVB Distant (hematogenous) metastases to the lung, bones, or liver
tissue, and the presence of inflammatory cells (12–14). Leiomyo-
Distant lymph node metastases
mas with FDG uptake are more common in premenopausal women
FIGO, International Federation of Gynecologist and Obstetricians; JZ, Junctional zone; T2, than postmenopausal women. Nishizawa et al.12 reported that the
T2-weighted images; CE T1, contrast-enhanced T1-weighted images. incidence of 18FDG uptake in premenopausal women with leiomyo-
mas (10.4% of 164 women) was higher than that in postmeno-
pausal women with leiomyomas (1.2% of 338 women). They also
an additional section perpendicular to the axis of endocervical reported that leiomyoma in premenopausal women tends to show
channel is also recommended.5,6 The reported results for a higher uptake during a luteal phase than during menstrual flow
contrast-enhanced MRI in the assessment of myometrial invasion and the follicular and per ovulatory phases. In their study, degener-
ranged from 59% to 100% for accuracy, 33% to 100% for sensitiv- ated leiomyomas showing high signal intensity on T2-weighted MR
ity, and 72% to 100% for specificity. The detection of cervical images tend to show higher FDG uptake than nondegenerated leio-
stroma invasion preoperatively is very important in selecting high- myoma showing low signal intensity on T2-weighted MR images.
risk patients eligible for radical hysterectomy including pelvic However, Kitajima et al.13 showed that nondegenerated leiomyoma
lymphadenectomy. The reported accuracy, sensitivity, and the can often show high uptake. Adenomyosis and endometrial hyper-
specificity values for MRI in the evaluation of cervical invasion of plasia generally show mild FDG uptake in premenopausal women.
endometrial carcinomas ranged from 46% to 98% for accuracy, Higher 18F-FDG uptake during the menstruating and ovulating
19% to 100% for sensitivity, and 87% to 100% for specificity.7 phases can be seen in adenomyosis.
Table 16.2 summarizes MRI findings in different FIGO stages of
endometrial cancer.7 CT is more useful to evaluate stage IV patients Initial Staging with 18
F-FDG PET or PET/CT
with distant LN or solid organ metastases such as liver, lung, and 18
Compared to MRI, F-FDG PET/CT has a limited diagnostic role
bone than MRI. in the local staging of endometrial cancer. 18F-FDG PET/CT is a
useful imaging modality in assessing LN involvement and dis-
18 tant organ metastases. In a recently published meta-analysis, it
F-FDG PET-CT in Endometrial Carcinoma
has been reported that the overall pooled estimates of sensitivity
Primary endometrial cancer usually shows an increased 18F-FDG and specificity of FDG PET or PET/CT scan in the detection of
uptake. The reported mean SUVmax for primary tumors in the pelvic lymph node (PLN) and/or PALN metastasis were 63%
studies was between 4.5 and 17.6. The SUVmax of 18F-FDG PET/ (95% confidence interval (CI), 48.7% to 75.7%) and 94.7% (95%
CT in endometrial cancer increases with FIGO grade, the expres- CI, 90.4% to 97.4%), respectively. The positive likelihood ratio
sion of GLUT-1 transporters, and the maximum tumor size. Glu- (LR+) was 10.465 (95% CI, 5.646 to 19.396) and the negative
cose consumption in endometrial cancer, as determined by likelihood ratio (LR−) 0.399 (95% CI, 0.284 to 0.560). The overall
18
F-FDG PET/CT, provides valuable information about tumor activ- diagnostic accuracy (Q* index) was 89.5%. The authors con-
ity and histology. The higher primary tumor’s SUVmax of 18F-FDG cluded that the high positive likelihood value confirms the reli-
PET/CT in endometrial cancer may be associated with aggressive ability of a positive FDG PET or PET/CT to detect PLN and/or
biologic characteristics in endometrial cancer.8–10 PALN metastasis in patients with untreated endometrial cancer.
Small malignant tumors or malignant tumors with low cellular According to this meta-analysis, the surgeons may use FDG PET/
density may have lower SUVmax values because of volume averag- CT when selecting appropriate patients on whom to perform
ing and limited spatial resolution of the system. It is also important lymphadenectomy.14
to be familiar with the variable physiologic uptake of 18F-FDG in Kitajima et al. compared the three different imaging modali-
the normal endometrium and benign endometrial lesions. Physio- ties such as contrast-enhanced 18FDG PET/CT scan with low-
logic endometrial uptake can be seen around the time of the first dose CT (ldCT), followed by full-dose CT with IV contrast, and
3 days of menstruation phase and the ovulatory phase of the contrast-enhanced CT (ceCT) in detecting PLN and/or PALN
menstrual cycle of the premenopausal women. Lerman et al.8 metastases in endometrial cancer patients. They investigated 358
reported that the mean endometrial SUVs in premenopausal LNs in 40 patients. They reported the sensitivity, specificity, and

Chapter 16 Uterine and Cervical Carcinoma 221
accuracy of PET/ceCT were 61.4%, 98.1%, and 93.6%, respectively, with endometrial cancer indicating that 18FDG PET/CT cannot
whereas those of PET/ldCT were 52.3%, 96.8%, and 91.3%, respec- replace surgical staging. In LN staging, the main reason for false-
tively, and those of enhanced CT were 40.9%, 97.8%, and 90.8%, negative results is the size of the LNs. The sensitivity of detecting
respectively by region-based analysis. In this study, PET/ceCT had LNs metastases increases with the size of LNs. The LNs that are
the best sensitivity among the three imaging modalities, a signifi- less than 5 mm in diameter can be missed by FDG PET/CT imag-
cant difference was observed only between PET/ceCT and ing. The major benefit of 18FDG PET/CT in staging endometrial
enhanced CT. Although PET/ceCT had better sensitivity and accu- cancer is to detect distant organ metastases which may alter sub-
racy than PET/ldCT, the differences between the two imaging sequent patient management.
methods did not reach statistical significance.15 In Figures 16.1 and 16.2, 18F-FDG PET/CT demonstrated dis-
MRI and PET/CT findings in 53 patients with endometrial can- tant metastases which could not be found in MRI. The PET/CT
cer who underwent preoperative work up were compared by Park findings changed the staging of these patients.
et al.16 They obtained T1-weighted spin-echo, T2-weighted trans-
verse fast spin-echo, and contrast-enhanced MRI images. FDG Recurrence Detection and Restaging with
18
PET/CT images were obtained using ldCT imaging protocol. In F-FDG PET or PET/CT
their study, they histopathologically examined all the primary Although endometrial cancer is very common, there is still no con-
tumors and 1,464 LNs from 137 LN areas. They found that for the sensus about the follow-up for patients after therapy. Most institu-
primary tumors, MRI and 18FDG PET/CT showed no differences in tions have their own follow-up strategies such as physical
sensitivity (91.5% versus 89.4%), specificity (33.3% versus 50.5%), examination, Pap smear, tumor marker assays, chest x-rays, CT,
accuracy (84.9% versus 84.9%), positive predictive value (PPV) and MRI. The common sites of endometrial cancer recurrence are
(91.5% versus 93.3%), and negative predictive value (NPV) (33.3% the vagina, pelvic and PALNs, the peritoneal cavity, and lungs.
versus 37.5%). 18FDG PET/CT had better sensitivity in detecting Other sites of hematogenous spread, such as bone, liver, and
LN metastases than MRI but the significance did not reach the brain, can occur but are uncommon. Vaginal recurrence of this
statistical significance. The sensitivity, specificity, accuracy, PPV, cancer is the most common site, occurring in approximately 7% of

and NPV of MRI for detecting metastatic LNs on LN area-by-area cases. Vaginal recurrence is detected by the occurrence of bleed-
analysis were 46.2%, 87.9%, 83.9%, 28.6%, and 94%, respectively; ing and is apparent on vaginal examination. Vaginal recurrence
but the corresponding figures for 18FDG PET/CT were 69.2%, can be successfully treated in 50% to 75% of cases. Other sites of
90.3%, 88.3%, 42.9%, and 96.6%, respectively. In the study, 18FDG recurrence, with the exception of isolated PLNs, are rarely sal-
PET/CT showed high sensitivity, specificity, accuracy, PPV, and vaged. To manage treatment in patients with recurrence, it is
NPV for detecting distant metastases such as 100%, 93.8%, 92.5%, important to describe whether the recurrence is either local or
62.5%, and 100%, respectively. disseminated. For the patient who has an isolated site of recur-
18
FDG PET/CT has moderate sensitivity, specificity, and accu- rence, surgery and/or radiotherapy may be curative or provide
racy in detecting primary tumors and LNs metastases in patients palliation, but with disseminated recurrent disease only palliative
Figure 16.1. A 68-year-old woman with pathologically proven endometrial carcinoma. 18FDG
PET/CT was performed to evaluate the stage of the disease. Computed tomography (CT) shows
a large mass in the uterus and multiple pelvic lymph nodes (PLNs) which are less than 1 cm in
diameter (A). Magnetic resonance imaging shows a uterine mass which is 7.5 × 4 cm in diam-
eter causing distortion at cavity of the uterus and suspicious PLNs (arrows ) next to the uterus on
the right side (B). 18FDG PET/CT demonstrates increased 18FDG in the mass of the uterus (arrow-
C head ) and pelvic multiple PLNs (arrows ) which are consistent with a malignant uterus mass and
PLN metastases (C). (continued )

D E
F G
Figure 16.1. (continued ) 18FDG PET/CT also demonstrates metastatic bone disease in left ischium (D) which is not clearly seen in CT (E). Whole-body 18FDG PET
(F) and 18FDG PET/CT (G) images show para-aortic lymph nodes and liver metastases.
treatment can be considered. The early detection of recurrence of the patients showing no evidence of recurrent disease in FDG PET/
the tumor in especially asymptomatic patients may have a signifi- CT images were free of recurrence. The sensitivity, specificity, accu-
cant effect on survival.17–20 racy, PPV, and NPV of FDG PET or PET/CT in asymptomatic
18
F-FDG PET or PET/CT is a promising imaging modality in patients without evidence of recurrence based on tumor markers
detecting recurrent disease in patients with endometrial cancer. and/or CT have been reported as 100%. The optimum time to
There are published studies investigating the diagnostic role of image in the asymptomatic patients is still uncertain. Kitajima et al.26
18
F-FDG PET or PET/CT in detecting recurrent disease in the lit- compared contrast-enhanced FDG PET/CT (PET/ceCT) and low-
erature. Table 16.3 shows the summary results of the studies. The dose nonenhanced FDG PET/CT (PET/ldCT) to evaluate the diag-
sensitivity, specificity, and accuracy of 18F-FDG PET or PET/CT to nostic value of the two tests in detecting recurrence disease. The
detect recurrent disease in endometrial cancer are all almost 90% sensitivity, specificity, and accuracy have been reported as 90%,
and more. The 18F-FDG PET or PET/CT studies have an impact on 97% and 95% for PET/ceCT and 83%, 94% and 91% for PET/ldCT,
clinical decisions in between 22% and 73% of the patients. Park respectively. Although there was no statistically significant differ-
et al.25 showed that 18F-FDG PET/CT especially revealed true posi- ence between the two tests, four equivocal regions (local recur-
tive studies in elevated tumor markers and negative CT findings. In rence, pelvic LN metastasis, liver, and muscle metastasis) in PET/
this study, 18F-FDG PET/CT showed recurrence in 3 out of 64 asymp- ldCT were correctly interpreted by PET/ceCT. Kitajima et al.
tomatic patients without evidence of tumor recurrence. The rest of claimed that PET/ceCT is an accurate imaging modality for the

A B

E
Figure 16.2. A 48-year-old woman complaining of excessive bleeding from her uterus and pathologically proven
endometrial carcinoma. Computed tomography (CT) shows thickening uterine wall and pelvic lymph nodes which
are 1 cm in diameter (A). Magnetic resonance imaging (MRI) demonstrates a lesion starting from the endocervical
channel and extending to the endometrium with a 3 cm in length (B). 18FDG PET/CT shows markedly increased
18
FDG uptake in the lesion of uterus and bilateral external and internal iliac lymph nodes (C). Bilateral common iliac
lymph nodes, left para-aortic lymph nodes, and left axillary lymph nodes (D, E). The patient was staged as IIIC1 for
FIGO and N1 for tumor, node, metastases (TNM) with MRI. After PET/CT findings the patient was evaluated as stage IVB
for FIGO and M1 for TNM staging.

Table 16.3
The Validity and Clinical Impact of 18F-FDG PET or PET/CT in Posttherapy Surveillance of Endometrial Cancer
Number of
Patients/Imaging Impact on
Reference Studies Imaging Modality Sensitivity Specificity Accuracy PPV NPV Clinical Decision
Belhocine et al.21 34/41 PET 96 78 90 89 91 35

Saga et al.22 21/20 PET 100 88.2 93.3 — — 33
Chao et al.23 49/60 PET 87 97 96 — — 73.1
Sironi et al.24 25 PET/CT 92 100 96 100 91.7 —
Park et al.25 24a /25 PET or PET/CT 100 83.3 96 95 100 21.9
64b /74 PET or PET/CT 100 100 100 100 100
Kitajima et al.26 100 (55c + 45d ) PET/ceCT 90 97 95 — — —
— — PET/ldCT 83 94 91 — — —
a
24 patients with suspected tumor recurrence in tumor marker or CT.
b
64 asymptomatic patients without evidence of recurrence.
c
Uterine cervical cancer.
d
Endometrial cancer.
PET/ceCT, PET/full-dose IV contrast-enhanced CT; PET/ldCT, PET/low-dose nonenhanced CT.
assessment of uterine cancer recurrence, and PET/ceCT reduces high SUVmax in the primary tumors were significantly lower than
the frequency of equivocal interpretations. those of patients who have low SUVmax. Even in the advanced
Figure 16.3 shows a patient who was diagnosed as stage IIIA FIGO stage patients, DFS and OS were significantly lower in the
endometrial carcinoma. 18F-FDG PET/CT was used to restage and patients who have high SUVmax in the primary lesion than those
monitor the treatment of the patient. In this particular case, 18F-FDG of the patients who have low SUVmax. In Nakamura’s report, SUV-
PET/CT demonstrated metastatic focus in the abdomen of the patient. max was an independent factor for OS in the patients with endo-
18
F-FDG PET/CT also showed the inefficacy of the chemotherapy at metrial cancer. Chung et al.29 reported on the prognostic value of
the early phase of chemotherapy and caused a change to the chemo- SUVmax in 61 patients who had prior surgery and/or chemoradio-
therapy regime. After changing chemotherapy regime, the patient therapy. Posttreatment SUVmax and serous adenocarcinoma his-
showed complete response to treatment. In this patient, 18F-FDG tology were significantly associated with the recurrence and
PET/CT has played a very important role in the patient management. inversely correlated with DFS.
Prediction of Prognosis of Endometrial Carcinoma

with 18F-FDG PET/CT Cervical Cancer
The most important factors in predicting recurrence and death in
patients with endometrial cancer are Epidemiology
• advanced FIGO surgical stage Carcinoma of the cervix is the third most common cancer of gyne-
• a nonendometrioid surgical subtype cologic malignancies. According to American Cancer Society Statis-
• poorly differentiated histology tics, 12,340 new cases of invasive cervical cancer will be diagnosed
• invasion of more than half of the myometrium and about 4,030 women will die from cervical cancer in 2013.30
• larger tumor size Cervical cancer was once one of the most common causes of cancer
• presence of LN metastasis death in American women. The death rate declined up to 2003 with
• lymphovascular space invasion increased use of Pap test as screening procedure. The most impor-
tant risk factor for cervical cancer is infection by Human Papilloma
These parameters are dependent on comprehensive surgical virus (HPV). Certain types of HPV such as HPV16, HPV18, HPV31,
staging of the patients. Preoperative prediction of tumor aggres- HPV33, and HPV45 are high-risk types because they are strongly
siveness and prognostic information about the patients are useful linked to cervical cancer. Smoking, immunosuppression, chlamydia
in patient management. infection, long-term oral contraceptive usage, family history of can-
18
F-FDG PET/CT might be useful noninvasive imaging modality cer, multiple full-term pregnancies, low fruit and vegetable diet,
in predicting recurrence of the endometrial cancer in preoperative diethylstilbestrol exposure, increased number of sexual partners,
phase of the patients. Kitajima et al.27 evaluated the prognostic value early age of first coitus, and low socioeconomic status are the other
of SUVmax of primary endometrial cancer in 57 patients with stage risk factors for cervical cancer.
I–IV endometrial cancer. In their study, a total of 57 patients with The most common histologic subtype of cervical carcinoma is
stage I–IV endometrial cancer were included. The median follow-up squamous cell carcinoma which occurs in 90% of cases. Squamous
period was 33 months. They found that SUVmax in primary tumor cell carcinomas arise from the squamocolumnar junction near the
was statistically higher in patients with higher FIGO stage, higher external orifice of cervix in younger patients, resulting in exophytic
tumor histologic grade, myometrial invasion, LN metastasis, and lesions. As the squamocolumnar junction migrates toward the uter-
larger tumor size. Univariate analyses of the data showed that ine body in older women, these tumors grow from the endocervix
SUVmax in primary tumor, FIGO stage, histologic grade, myometrial and may become quite large before they are diagnosed. Adenocar-
invasion, LN metastasis, and larger tumor size are associated with cinoma and adenosquamous carcinoma account for about 10% of
the recurrence of the disease. However, multivariate analysis showed cervical cancer cases; sarcoma and lymphoma are quite rare.
that only SUVmax in primary tumor was significantly related to
tumor recurrence. In this study, the patients with a high SUVmax
(≥12.7) had a significantly lower disease-free survival (DFS) rate
Diagnosis and Staging
than those with a low SUVmax (<12.7). Nakamura et al.28 also Clinical, vaginal, and colposcopic examinations of the cervix,
showed that the DFS and overall survival (OS) of patients who have bimanual palpation of the parametrial area, cytologic smears,

A B
C
D

E
Figure 16.3. A 61-year-old woman who was operated on 4 years ago because she had grade
2 endometrium cancer. The patient was staged as IIIA pathologically. During the follow-up, she
had a history of pulmonary metastases 2 years after the diagnosis. Pulmonary metastases were
resected and she underwent chemotherapy. On the follow-up after chemotherapy, tumor mark-
ers of the patient increased 1 year after the completion of chemotherapy. The patient was
referred to our nuclear medicine department to evaluate recurrence/metastatic disease. Com-
puted tomography (CT) shows a lesion 1 cm in diameter in her abdomen in the pericecal region
(arrow) (A). 18FDG PET/CT demonstrates increased 18FDG uptake at the lesion which is consis-
tent with a metastatic disease (B). The patient once again received chemotherapy. However,
because she had multiple infectious episodes, the chemotherapy could not have been given to
the patient precisely according to chemotherapy scheme. 18FDG PET/CT was performed to
evaluate chemotherapy response and shows progression of the lesion in terms of size and
metabolic activity (C and D). After 18FDG PET/CT findings, her chemotherapy regime was
changed. The last 18FDG PET/CT was performed to evaluate the efficiency of the new chemo-
therapy after the chemotherapy was completed. At this time, 18FDG PET/CT shows no evidence
of metastatic disease (E).
and biopsies are mandatory in diagnosing cervical cancer. Fol- The most important parameter of staging in patients with
lowing a preinvasive stage, the cancer invades the cervical stroma cervical cancer is to evaluate parametrial spread. Once a diag-
and then spreads by direct invasion into the parametrium, uterus, nosis of invasive cervical cancer is made, accurate staging is of
and vagina. Adjacent organs in the pelvis such as the bladder and great importance for treatment planning. When the tumor is
rectum may be involved in more advanced disease. As the disease confined to the cervix and the overall tumor volume is small,
advances, the tumor spreads via lymphatic channels toward the surgical management can be curative and radical hysterectomy
pelvic, para-aortic, and supraclavicular LNs. Hematogenous is typically performed. As tumor size increases and spread
spread to the lungs, liver, or any other distant organ may occur beyond the cervix into the parametrial tissues occurs, definitive
at any stage, but it is unlikely to occur in the early stages of the radiotherapy and chemotherapy are generally used. FIGO
disease. staging has been used for the staging of patients with cervical

Table 16.4
The Figo and Tnm Staging and Corresponding Mri Findings for Cervical Cancer
Cervical Cancer FIGO MRI Findings TNM
The carcinoma is strictly confined to the cervix (extension to the I — T1

corpus would be disregarded)
Invasive carcinoma which can be diagnosed only by microscopy, IA No evidence of tumor T1a
with deepest invasion 5 mm and largest extension 7 mm
(a) Measured stromal invasion of 3 mm in depth and horizontal IA1 T1a1
extension of 7 mm
(b) Measured stromal invasion of >3 mm and not >5 mm with IA2 T1a2
an extension of not >7 mm
Clinically visible lesions limited to the cervix uteri or preclinical IB Intermediate SI mass against low SI of the background T1b
cancers greater than stage IA cervical stroma
Clinically visible lesion ≤4 cm in greatest dimension IB1 T1b1
Clinically visible lesion >4 cm in greatest dimension IB2 T1b2
Cervical carcinoma invades beyond the uterus, but not to the II — T2
pelvic wall or to the lower third of the vagina
Without parametrial invasion IIA Loss of the normal low SI of the vaginal fornix or wall, usually T2a
contiguous with the primary cervical tumor mass
(a) Clinically visible lesion 4 cm in greatest dimension IIA1 T2a1
(b) Clinically visible lesion >4 cm in greatest dimension IIA2 T2a2
With obvious parametrial invasion IIB Breach of the low SI ring of the cervical stroma T2b
The tumor extends to the pelvic wall and/or involves the lower III — T3
third of the vagina and/or causes hydronephrosis or
nonfunctioning kidney
Tumor involves the lower third of the vagina, with no extension to IIIA Loss of the normal low SI of the vaginal wall in the lower third T3a
the pelvic wall of the vagina
Extension to the pelvic wall and/or hydronephrosis or IIIB Presence of tumor within 3 mm of internal obturator, levator T3b
nonfunctioning kidney ani, and piriformis muscles or iliac vessels. Additional
signs include increased SI and/or retraction of pelvic
muscles, presence of hydronephrosis owing to ureteral
obstruction at the level of the primary tumor or nodal
metastases
The carcinoma has extended beyond the true pelvis or has involved IV — T4
(biopsy proven) the mucosa of the bladder or rectum. A bullous
edema, as such, does not permit a case to be allotted to
stage IV
Spread of the growth to adjacent organs IVA Tumor nodules protruding into the bladder/rectal lumen T4a
Spread to distant organs IVB Tumor involving organs outside the true pelvis, includes the M1
para-aortic and inguinal nodes
FIGO, International Federation of Gynecologists and Obstetricians staging system; SI, signal intensity; TNM, tumor, nodes, Metastasis classification system.
Adapted from Brocker AK, Alt CD, Eichbaum M, et al. Imaging of female pelvic malignancies regarding MRI, CT, and PET/CT. Strahlenther Onkol. 2011;187:611–618 and Liyanage SH, Roberts CA,
Rockall AG. MRI and PET scans for primary staging and detection of cervical cancer recurrence. Women’s Health. 2010;6(2):251–269.
cancer.31 Table 16.4 shows FIGO and TNM staging for cervical delineation and multiplanar capability, MRI is the ideal diagnostic
cancer. imaging tool in patients with cervical cancer. MRI protocols vary
from institution to institution but the recommended standard pro-
Imaging Modalities in Cervical Cancer tocol in MRI includes T2-weighted TSE sequences with high spatial
resolution (matrix 512) in the sagittal and transversal oblique
Imaging is an important tool in the evaluation of tumor size,
(short cervical axis) planes in addition to a T1-weighted TSE
detection of parametrial invasion, and assessment of the involve-
sequence in the transversal plane.31 Dynamic multiphase contrast-
ment of the pelvic sidewall and adjacent organs, as well as the
enhanced MRI (DCE-MRI), which is a T1-weighted sequence, may
assessment of nodal involvement and distant metastasis. Nodal
improve detection of small tumors and distinguishing recurrent
involvement is not part of the FIGO staging classification. Never-
tumors from radiation necrosis.33,34 The sensitivity of DCE-MRI has
theless, nodal stage has marked prognostic implications and may
been reported 92% compared to 23% with T2-weighted MRI in
alter the extent of radiotherapy field. Tumor grade and histologic
detecting small lesions with depth stromal invasion between 3.1
subtype, patient age, intratumoral oxygenation, tumor vascularity,
and 5 mm.
DNA ploidy, distant metastasis, and the presence of HPV infection
The overall staging accuracy of MRI ranges from 77% to 90%.35–39
are additional prognostic factors.32
MRI performance has been reported better than CT in the depic-
tion of parametrial invasion and overall staging accuracy. A recent
Magnetic Resonance Imaging prospective multicenter study performed by the ACR Imaging Net-
Although transvaginal and abdominal ultrasonography can be work (ACRIN) and the Gynecologic Oncology Group (GOG) compar-
used for diagnosis and staging, because of its superior soft tissue ing MRI with CT in patients with early invasive cervical cancer

reported that MRI was equivalent to CT for overall preoperative with stage IA–IIA, <4 cm cervical cancer. Overall patient-based sen-
staging. However, MRI performed significantly better for visualiza- sitivity, specificity, PPVs, and NPVs of 18F-FDG PET/CT for detection
tion of the primary tumor and detection of parametrial invasion. In of PLN disease were 32.1%, 96.9%, 69.2%, and 87%, respectively.42
addition, CT had much greater interobserver variability when The low sensitivity in this group of patients was probably because
compared with MRI.39 Table 16.4 shows FIGO and TNM staging of nodal micrometastasis which is typical in the early stage of cer-
and corresponding MRI findings in cervical cancer. vical cancer. Micrometastasis, less than 5 mm could not be detected
with FDG PET/CT because of its limited spatial resolution. Other
18
18 F-FDG PET/CT studies in patients with early cervical cancer
F-FDG PET or PET/CT in Cervical Cancer showed the low (10% to 73%) sensitivity in detecting PLN involve-
Initial Staging ment.43–48 Table 16.5 summarizes the results of the studies in early
Almost all the primary tumors greater than 0.7 cm in diameter stage of cervical cancer. Although NPVs are good at depicting LN
demonstrate increased 18F-FDG uptake. In cases of tumor exten- metastasis in patients with early stage cervical cancer, 18F-FDG
sion superiorly to the uterus and inferiorly to the vaginal cuffs, PET/CT seems to have minimal clinical impact on patient manage-
18
F-FDG PET/CT may be helpful in delineation of the tumor mar- ment. The benefit gained is limited from additional 18F-FDG PET/
gins. However, MRI is more effective than 18F-FDG PET/CT to eval- CT after negative MRI/CT at primary staging in patients with early
uate primary tumor size and extensions. Integrated PET/MRI stage cervical cancer.
technique may well become the preferred method to evaluate pri- The second group includes patients with locally advanced cervi-
mary tumor and extension, but at present there is no sufficient cal cancer. In this group of patients, determining PALN involve-
data. ment is a very important prognostic parameter because the
The evaluation of LN involvement is an important parameter patients with PALN have lower OS, DFS, and survival after recur-
for defining prognosis and therapy in cervical cancer. MRI and CT rence.49–52 Accurate assessment of PALNs metastasis is also crucial
have poor diagnostic accuracy in evaluating LN metastasis to determine radiotherapy field planning because PALNs are
because LN metastasis is basically based on the enlargement of beyond the standard radiotherapy planning field. Therefore, surgi-

size in both the imaging techniques. Using the size criteria, the cal staging has been recommended as a gold standard procedure
sensitivity of MRI detecting LN metastasis ranges from 29% to to evaluate PALN involvement. The routine use of surgical staging
86%.40 A meta-analysis comparing the diagnostic efficiency of CT, before radiotherapy in locally advanced cervical cancer patients
MRI, and PET or PET/CT showed that PET or PET/CT has the increases adverse effects and morbidities resulting from surgery.
highest pooled sensitivity (82%) and specificity (95%), whereas CT Imaging methods in this group of patients, therefore, are useful to
has 50% and 92%, MRI has 56% and 91%, respectively in patient evaluate PALNs metastases. A meta-analysis indicates that both CT
data analyses. In region- or node-based data analysis, sensitivities and MRI have low sensitivity (57.5% and 55.5%, respectively). Both
of CT (52%) and PET or PET/CT (54%) were higher than that of MRI and CT had an LR− greater than 0.5, meaning these tests can-
MRI (38%), respectively, whereas specificities of MRI (97%) and not be used to confirm the absence of nodal metastasis.52 Kang
PET or PET/CT (97%) were higher than that of CT.41 et al. published a meta-analysis investigating the diagnostic value
The diagnostic value of 18F-FDG PET/CT in detecting LN metas- of 18F-FDG PET for evaluation of PALN metastases in patients with
tases in cervical cancer should be discussed in two different groups cervical carcinoma. They analyzed data from 385 patients in 10
of patients with cervical cancer. The first group is early stage cervi- studies. The overall sensitivity, specificity, LR+, and LR− were 34%,
cal cancer patients. In this particular patient group, the treatment 97%, 12.49, and 0.68, respectively. When the studies were divided
is radical hysterectomy and pelvic lymphadenectomy (RH-PLND). into two different prevalence groups such as low (≤15) and high
The diagnostic role of 18F-FDG PET/CT to determine PLN involve- (>15) prevalence of PALN metastases, the sensitivity of the 18F-FDG
ment in early stage cervical cancer is still controversial. Signorelli PET decreased in low-risk group up to 5%, but it increased to
et al. investigated the effectiveness of 18F FDG PET/CT in patients 73% in high-risk group. In both low- and high-risk groups, specific-
with early stage disease. In this study, they included the patients ity were 99% and 93%, respectively. The LR− was 0.95 in low-risk
Ta b l e 1 6 . 5
Literature Review of the Diagnostic Accuracy of 18F-FDG PET or PET/CT in Detecting

Lymph Node Involvement in Early Stage of Cervical Cancer
Number
of Positive
Authors Patients Stage Imaging Nodes (%) Sensitivity Specificity PPV NPV
43
Park et al. 36 IB1–IB2– PET 39 43 100 100 73
IIA
Wright et al.44 59 IA2–IB1– PET 32 53 90 71 80
IB2–IIA
Chou et al.45 60 IA2–IB1– PET 17 10 94 25 84
IB2–IIA
Sironi et al.46 47 IA2–IB1– PET/CT 32 73 97 92 89
IB2
Goyal et al.47 80 IB1–IB2– PET/CT 30 58 93 78 84
IIA
48
Chung et al. 83 IB1–IB2– PET/CT 33 29 84 47 70
IIA–IIB
Signorelli et al.42 159 IB1–IIA PET/CT 18 32 97 69 87
PPV, positive predictive value; NPV, negative predictive value.

group, whereas it was 0.29 in high-risk group. Nevertheless, established using SUVmax, which was demonstrated to be a sen-
Kang et al. suggested that in the low prevalence group, PALNs sitive biomarker of treatment response and prognosis for patients
showing high 18F-FDG uptake should be histologically confirmed in with cervical cancer. The OS rates at 5 years were 95% for an
terms of metastases because the false-positive rate was 21.9% in SUVmax 5.2, 70% for an SUVmax ranging from 5.2 to 13.3, and
this group. However, when 18F-FDG PET or PET/CT is positive for 44% for an SUVmax more than 13.3 (p < 0.0001). Increasing
PALN metastases in high-risk group, the finding is likely indicative SUVmax was associated with persistent abnormal FDG uptake in
of metastatic involvement.53 the cervix on 3-month FDG PET studies in 238 patients who
Leblanc et al. recently reported a study that included 125 received curative chemoradiation.
patients with locally advanced cervical cancer (stage IB2 and Yen et al.59 analyzed 70 patients with untreated squamous cell
IVA). The sensitivity, specificity, PPV, and NPV of the PET/CT for cervical cancer and PLN or PALN metastasis detected by CT/MRI.
the detection of microscopic PALN metastases were 33.3%, 94.2%, All patients had 18FDG PET for primary staging. SUVmax greater
53.8%, and 87.5%, respectively. These results were greatly influ- than 3.3 at a PALN is predictive of poor outcome in patients with
enced by the size of metastatic node; for metastasis ≥5 mm, the primary squamous cervical carcinoma and LN metastasis on CT/
sensitivity and PPV were 42% and 38%, respectively. But the sen- MRI as measured by adverse 5-year recurrence-free survival
sitivity and PPV decreased to 22% and 15% when metastasis size (HR = 4.52, 95% CI, 1.73 to 11.80) and 5-year OS (HR = 6.04, 95%
was <5 mm. When PLN and PALN were negative in 18FDG PET/ CI, 1.97 to 18.57).
CT, they found a 10% false-negative rate for detection of PALN Recently, Chung et al.60 studied with a metabolic tumor volume
microscopic metastases. By contrast, PLN was positive, but PALN (MTV) measured by 18F-FDG PET/CT to determine its prognostic
was negative in 18FDG PET/CT, PALN metastases were confirmed value in patients with cervical cancer primarily with radical hyster-
histopathologically in 20% of the patients. When PLN is positive ectomy. They enrolled 63 patients with stage IB to IIA and evaluated
in 18FDG PET/CT, the probability of microscopic metastases of the relationship of MTV to DFS in this study. MTV was found to be
PALN increases.54 They concluded that laparoscopic staging is correlated with LN metastasis, parametrium involvement, FIGO
necessary in patients with locally advanced cervical cancer with stage, and SUVmax. In univariate analysis, MTV ≥23.4 mL (HR
negative 18FDG PET scan who are candidates for definitive con- 1.017, 95% CI 1.005 to 1.029, p = 0.004), SUVmax ≥9.5 (HR 5.198,
current chemoradiotherapy or pelvic exenteration. Similar find- 95% CI 1.076 to 25.118, p = 0.04), LN metastasis (HR 12.338, 95%
ings were reported by Ramirez et al.55 in an analysis of 60 patients CI 1.541 to 98.813, p = 0.018), parametrium involvement (HR
with locally advanced cervical cancer. They performed laparo- 14.274, 95% CI 1.785 to 114.149, p = 0.012), and lymphovascular
scopic extraperitoneal lymphadenectomy from the common iliac space invasion (HR 8.871, 95% CI 1.104 to 71.261, p = 0.04), were
vessels to the left renal vein. Given the results of the study, 14 related to DFS. In multivariate analyses, age (HR 0.748, 95% CI
(23%) patients had histopathologically positive para-aortic nodes. 0.587 to 0.952, p = 0.018) and MTV ≥23.4 mL (HR 49.559, 95% CI
Of the 26 patients with negative PLN and PALN on PET/CT, 3 1.257 to 1953.399, p = 0.037) were determined to be independent
(12%) had positive PALN on histopathology. Of the 27 patients prognostic factors of DFS.
with positive PLN but negative PALN on PET/CT, 6 (22%) had
18
histopathologically positive PALN. The sensitivity and specificity F-FDG PET/CT in Monitoring the Response
of 18FDG PET/CT in detecting positive PALN when nodes were to Treatment and Detection Recurrence
negative on CT or MRI were 36% and 96%, respectively. Eleven Disease in Cervical Cancer
(18.3%) patients had treatment modifications based on surgical Recurrence may occur in approximately one-third of cervical can-
findings. The authors concluded that laparoscopic extraperitoneal cer patients. The majority of the recurrence occurs within first 2
para-aortic lymphadenectomy should be discussed with patients to 3 years after completion of therapy. The amount of tumor
with locally advanced cervical cancer scheduled to undergo regression during the course of extension beam radiotherapy is
chemoradiation, particularly if preoperative 18FDG PET/CT shows an important predictor factor for both local recurrence and sur-
positive pelvic nodes and negative PALN as a safe and feasible vival. Lin et al.61 analyzed the physiologic tumor volume response,
surgery method. using 18FDG PET, during radiotherapy and brachytherapy treat-
Two case examples are presented in Figures 16.4 and 16.5. ment in 32 patients with cervical cancer. Patients with no residual
18
These two patients had locally advanced cervical carcinoma and FDG uptake at 3-month posttreatment had better 5-year recur-
positive PLN but negative PALN in 18FDG PET/CT. After chemora- rence-free survival (83%) than the patients with evidence of 18FDG
diotherapy, both patients showed complete response to treatment PET residual disease within the cervix. Grigsby et al.62 reported
with a 2-year follow-up without recurrence or metastatic disease. similar results to this study. In this retrospective study of 152
patients, posttherapy 18FDG PET was performed 1 to 12 months
18
Pretreatment Prognostic Value of F-FDG PET/CT (mean: 3 months) after completion of treatment. Five-year cause-
in Cervical Cancer specific survival was 80% for patients with no abnormal 18FDG
Although increased 18FDG uptake has been found to correlate uptake, 32% for those with persistent uptake, and 0% for those
positively with tumor aggressiveness in many cancers, the prog- with new uptake on posttreatment imaging.
nostic value of PET is still under investigation. Miller and Grigsby56 Schwarz et al.63 demonstrated that 3-month posttherapy 18FDG
reported that the three-dimensional volume of the primary tumor uptake was predictive of survival of 92 patients who were treated
by 18FDG PET was predictive for both progression-free survival with external irradiation, brachytherapy, and concurrent chemo-
(PFS) and OS in patients with advanced cervical cancer. The pres- therapy. Posttherapy whole-body 18FDG PET was performed 2 to
ence of SUVmax of more than 3.3 in PALNs was significantly 4 months (mean: 3 months) after completion of treatment, show-
associated with both 5-year disease recurrence (Hazard Ratio ing a complete metabolic response in 65 patients (70%), a partial
[HR] = 4.52, 95%, CI 1.7 to 11.8) and 5-year mortality (HR = 6.04, metabolic response in 15 (16%), and progressive disease in 12
95%, CI 1.97 to 18.57). Xue et al.57 reported that a pretreatment (13%). The 3-year PFS rates were 78%, 33%, and 0%, respectively.
baseline SUVmax less than 10.2 in primary cervical cancers The HR for risk of recurrence based on the posttherapy metabolic
was associated with a better prognosis in patients receiving defin- response showing progressive disease was 32.57 (95% CI, 10.22
itive radiotherapy than in patients whose tumors had higher to 103.82). A partial metabolic response had an HR of 6.30 (95%
values. CI, 2.73 to 14.56).
Kidd et al.58 assessed pretreatment SUVmax and its association Chung et al.64 recently demonstrated the diagnostic accuracy of
with treatment response and prognosis in 287 patients with stage posttherapy 18F-FDG PET/CT to detect recurrent disease and prog-
IA2 through IVB cervical cancer. Three prognostic groups were nosis of the 276 patients with cervical cancer in a retrospective

A B

E
Figure 16.4. A 55-year-old woman with pathologically proven squamous cell carcinoma of the
cervix. 18FDG PET/CT was performed for staging of the disease. A cervical mass invading the
rectum showed markedly increased 18FDG uptake as seen in CT and PET/CT images (A and B).
There was also left internal iliac lymph node showing increased 18FDG uptake which is consistent
with metastatic disease (arrow) (C). The patient was evaluated as having locally advanced cervi-
cal cancer. Radiotherapy and chemotherapy were applied. After 6 months of completion of a
therapy regimen, the patient was imaged with 18FDG PET/CT for therapy evaluation. 18FDG PET/
CT shows marked regression of the lesion both in size and metabolic activity (D). The internal
iliac lymph node is not visible at this time (E). The findings were evaluated as a complete therapy
response.
study. 18F-FDG PET/CT scans were performed under several The overall sensitivity, specificity, PPV, NPV, and accuracy of
circumstances. posttreatment 18FDG PET/CT to detect recurrent disease were
94.7%, 87.8%, 80.4%, 97%, and 90.2%, respectively. The 18FDG
• Patients had symptoms suspecting recurrence PET/CT scan modified both the diagnostic or treatment plan in 67
• A new lesion in other surveillance imaging studies patients (24.3%). The patients were divided into two groups based
• Elevated tumor markers with or without abnormal imaging studies on SUVmax value established on the basis of ROC analysis (<5.25
• Abnormal physical examination findings versus ≥5.25). They found a significant difference in OS between
• Clinician concern for unspecified reasons groups (p = 0.001). They reported that the 5-year PFS and OS

B
A
Figure 16.5. A 72-year-old woman with biopsy proven squamous cell cervical carcinoma.
Magnetic resonance imaging (MRI) shows a 6 × 3 cm in diameter lesion starting from cervix and
extending halfway through the uterus (A). There was no suspicion of metastatic disease in MRI.
18
FDG PET/CT was performed for initial staging. There was markedly increased 18FDG uptake in
the lesion (B). 18FDG PET/CT images show a tiny right internal iliac lymph node showing moderate
FDG uptake with SUVmax: 3.1 which is suspicious of metastatic involvement of the lymph node
(arrow) (C). The patient was treated with radiotherapy which was planned to cover primary lesion
of cervix and suspicious lymph node. Six months after radiotherapy, 18FDG PET/CT was performed
to evaluate the response of the treatment. 18FDG PET/CT shows no evidence of residual and
metastatic disease (D and E). MRI also confirmed no residual disease at the cervical region (not
shown). With these findings, the patient was accepted as a complete response to treatment.
rates of patients with a negative PET/CT scan for recurrence were scan after completion of treatment is still controversial. In most
significantly better than those with a positive PET/CT (98.62% studies, the median follow-up FDG PET/CT scan is 3 months after
versus 17.83%, p < 0.0001 for PFS, 99.31% versus 85.38%, p = completion of therapy. In some studies, a 6-month interval is rec-
0.0015 for OS). ommended especially after radiotherapy to decrease false-positive
Figure 16.6 shows a patient who had disseminated metastatic identification of an inflammatory reaction.
disease as documented by 18F-FDG PET/CT after 18 months of rad-
ical chemotherapy and brachytherapy. In this case, metastatic LNs Pitfalls and Limitations of 18F-FDG PET or PET/CT
and bone metastases are well documented with 18F-FDG PET/CT. in Imaging of Endometrial and Cervical Cancer
According to the literature, posttreatment PET/CT scan is a Physiologic accumulation of 18FDG in bowel and urinary bladder
sensitive and accurate surveillance modality, and provides prog- may interfere with evaluation of the primary tumor and LN
nostic information in cervical cancer. Optimum time for PET/CT involvement. These issues should always be kept in mind; careful


A B
Figure 16.6. A 51-year-old woman with stage IIB

cervical cancer. She had radical chemotherapy and
brachytherapy. Eighteen months after her treatment
was completed, a full-dose contrast-enhanced thorax
computed tomography (CT) showed pleural thickening
and pleural nodules, enlarged lymph nodes in medias-
tinum, bilateral hilum, and bilateral para-aortic region.
18
FDG PET/CT was performed to restage the patient.
18
FDG PET/CT shows increased FDG uptake in the
lymph nodes of the bilateral cervical chain of the neck,
multiple stations of the mediastinum and bilateral
hilum. Para-aortic lymph nodes and pelvic lymph nodes
C
also showed high 18FDG uptake (A and B). There is
also increased 18FDG uptake in the corpus and pedicle
of the ninth vertebra which is consistent with meta-
static bone disease (C).
review and clinical correlation are required for accurate interpre- lism, but neither of the imaging methods can detect such tiny
tation. To avoid the bladder problem, patients are asked to empty lesions. The recent introduction of instrumentation with greater
off their bladder at the beginning of the examination; alternately, sensitivity, however, may alter these limitations somewhat.
a urinary catheter can be placed in the bladder to drain bladder
activity continuously or using hydration with 1 L of intravenous
normal saline along with diuretics.65
One of the other limitations of 18FDG PET/CT imaging in cancer
Future Perceptions and Research
imaging is the accumulating of 18FDG in inflammatory lesions. Areas of PET in Endometrial and
This may cause false-positive interpretations of the lesions, espe-
cially in differentiating recurrence lesions from postoperative
Cervical Cancer
changes. This problem may be solved by as PET/MRI becomes
available.
Other PET Tracers
18
F-FDG PET/CT has a limitation to identify the lesions <1 cm Although 18F-FDG is the most commonly used tracer in oncology
and especially in lesions smaller than 5 mm because of the limited imaging, tracers other than 18FDG are under investigation. These
spatial resolution leading to false-negative evaluation of the LN new tracers that potentially address the complexities of tumor
metastases. 18F-FDG PET/CT can also detect lesions with a certain biology may provide information that will result in patient-specific
amount of malignant cells sufficient to change glucose metabo- treatment and reliable prognostic information. Tracers other than

18
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18
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165. irrigation in patients with uterine and ovarian tumors. J Nucl Med. 2003;44:353–358.
49. Nelson JH Jr, Boyce J, Macasaet M, et al. Incidence, significance, and follow-up 66. Lapela M, Leskinen-Kallio S, Varpula M, et al. Imaging of uterine carcinoma by
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50. Berman ML, Keys H, Creasman W, et al. Survival and patterns of recurrence in cancer by positron emission tomography with 60Cu-ATSM: Relationship to
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CMAJ. 2008;178:855–862. FDG PET. J Nucl Med. 2009;50:1598.

Chapter 17
Ovarian Carcinoma
Marie Lacombe • Thomas Eugène • Jean-François Chatal • Françoise Kraeber-Bodéré
Introduction resolution, and safety. Many clinical studies using this technique for
the detection of malignant ovarian lesions report sensitivities and
Ovarian cancer is the seventh most frequent cancer in women specificities of 25% to 100% and 52% to 100%, respectively.6–12
worldwide, and is the leading cause of death from gynecologic MRI, used in addition to ultrasound for the characterization
malignancies in most western countries. Because of insidious proof an ovarian mass of unknown origin, has sensitivity and spec-
gression and lack of suggestive symptoms, these types of malignan- ificity for malignancy of 100% and 94%, respectively.13 Although
cies are most often discovered at an advanced stage. Hence, about useful in cancer detection, its value lies in its specific character-
60% of ovarian cancers present an International Federation of ization of benign lesions.14 Indeed, MRI is useful to characterize
Gynecology (FIGO) stage III or stage IV, at diagnosis. The prognosis undetermined lesions on ultrasound, such as the extraovarian
is significantly modified depending on the spread of the disease but cystic lesions (viz., hydrosalpinx, paratubal cysts, pseudocysts,
5-year survival remains poor for most patients (Table 17.1). peritoneal inclusion cysts) especially when the ipsilateral ovary
Initial treatment of advanced ovarian cancer consists of is not seen and the solid component of the lesion requires fur-
platinum-based cytotoxic chemotherapy after primary cytoreduc- ther characterization (i.e., dermoid cysts, fibrothecomas).
tive surgery. Even if the overall response rate after primary therapy Finally, MRI is a valuable tool to characterize complex ovarian
is about 80%, approximately two-thirds of the patients experience masses like endometrioma and to detect rare signs of malignant
disease recurrence.1,2 degeneration.
Ovarian cancer usually spreads to the local lymph nodes, PET/CT provides precise localization of increased 18FDG uptake,
implants on the peritoneum, and less frequently disseminates which is particularly useful to characterize adnexal masses.
hematogenously.3 Lymph node metastases mostly involve pelvic, In a study by Fenchel et al.,15 99 patients with a suspicious
para-aortic, retroperitoneal, or inguinal chains. Common sites of adnexal mass on ultrasound underwent an 18FDG PET/CT of the
peritoneum implantation are the pelvis, right hemidiaphragm, abdomen, 1 week before an exploratory laparoscopy. 18FDG PET/
liver, right paracolic gutter, bowel, and omentum. Pleural effusion CT correctly detected 7 of 12 malignant ovarian lesions and 66
and parenchymal liver lesions are the most frequently observed of 87 benign lesions. The sensitivity and specificity were 58%
distant metastases.4 76%, respectively. There were five false negatives in patients
Before the introduction of positron emission tomography (PET) with cystadenocarcinomas, classified pT1a (tumors of low malig-
imaging in routine practice conventional scintigraphy had no real nancy). Moderate accumulation of 18FDG in the pelvis was related
place in management of this tumor. The increasing use of positron to intestinal activity or benign ovarian lesions in 21 of the
emission tomography/computed tomography using 18F-fluorode- 27 false-positive results. In 2007, Castellucci et al.16 studied
oxyglucose (18FDG PET/CT) for more than a decade has proven to 50 patients with pelvic masses scheduled for surgical exploration
be quite useful and has become standard in the management of based on ultrasound criteria, CA 125 serum level, and clinical
ovarian cancer. examination. Focal increased 18FDG uptake with an SUVmax >3
in the ovary was classified malignant, whereas SUVmax <2.7
was classified as benign lesion. At surgery, 32 patients had a
Initial Diagnosis and Staging malignant lesion; the remaining 18 patients had a benign ovar-
ian lesion. The sensitivity, specificity, NPV, PPV, and accuracy
were 87%, 100%, 81%, 100%, and 92%, respectively. Two of the
Characterization of Adnexal Masses four false-negative results involved patients who had ovarian
Adnexal masses which have benign features on imaging can undergo tumors less than 5 mm.
simple resection, or continued imaging surveillance. If a mass has Risum et al.17 studied 97 patients with a risk of malignancy
malignant characteristics, however, radical cytoreductive surgery index (RMI) greater than 150, based on CA 125 serum level, ultra-
is indicated as there is evidence that it improves outcome.5 The sound, and menopausal status. 18FDG PET/CT was considered
current approach to assess an adnexal mass is based on imaging positive in 57 patients with ovarian malignancy and negative in 37
studies. Transvaginal ultrasound (TVUS) is the most widely used of 40 patients with benign lesions. Sensitivity and specificity were
technique for initial evaluation because of its availability, good 100% and 92.5%, respectively.
Ta b l e 1 7 . 1
Five-Year Stage-Specific Relative Survival Rates, Adults (AGES 15–99)
% of all 5-Year Relative 5-Year Relative

Stage at Diagnosis Casesa Survival (%)a % of All Casesb Survival (%)b
Stage I Limited to the ovaries 29 92 15 91.5

Stage II Extent into pelvis 4 55.1 17 71.9
Stage III Spread beyond pelvis 45 21.9 61 26.9
Stage IV Distant involvement 15 5.6
Unstaged 6 27.6 7 22
All stages 100 43.5 100 43.7
a
Data derived from Anglia Cancer Network, 2004–2008, from 1,443 cases.
b
Data derived from SEER Cancer Statistics Review, 2002–2008, from 33,667 patients.
234

Chapter 17 Ovarian Carcinoma 235
Ta b l e 1 7 . 2
FDG PET/CT in The Detection of Ovarian Cancer: Principal Results from The Literature
Number of
Authors Year Patients % Sens. % Spec. % PPV % NPV % Acc.
Fenchel et al.15 2002 99 58.3 75.9 25 93 73.7

Castellucci et al.16 2007 50 87 100 81 100 92
Risum et al.17 2007 97 100 92.5 95 100 96.9
Yamamoto et al.18 2008 30 100 85 76.9 100 90
Nam et al.19 2010 133 97.9 73.7 90.2 93.3 86.7
Sens., sensitivity; Spec., specificity; PPV, predictive positive value; NPV, negative predictive value; Acc., accuracy.
In 2008, Yamamoto et al.18 conducted a prospective study on The first study of this indication, by Yoshida et al.24 in 2004
30 patients suspected of epithelial ovarian cancer (EOC) based reported a correlation between 18FDG PET/CT staging and surgi-
on morphologic (ultrasound and MRI) and biologic (elevated CA cal staging in 13 of 15 patients (83%) versus 8 of 15 patients (53%)
125) data. The sensitivity and specificity of 18FDG PET/CT to dif- based on CT. Castellucci et al.16 in 2007 reported similar results
ferentiate malignant lesions from borderline lesions were 71.4% with 18FDG PET/CT staging concordant with surgical staging in 22
and 81.3%, respectively. The SUVmax of borderline lesions were of 32 patients (69%) whereas CT staging was concordant in 17 of
lower than that of malignant lesions but not significantly differ- 32 patients (53%). CT classified as stage III, four of the six patients

ent from benign lesions. In this report, the sensitivity and spec- with distant involvement and did not detect liver, pleural, or medi-
ificity of 18FDG PET/CT to differentiate malignant from benign astinal and supraclavicular lymph node metastases, that were cor-
lesions were 100% and 85% respectively. Three false positives rectly detected by 18FDG PET/CT. Kitajima et al.,25 in 40 patients
were observed in two patients with a fibroma and one patient with ovarian carcinoma (OC), showed CT and 18FDG PET/CT stag-
with a fibrothecoma. The four false-negative results were related ing concordance in 22 of 40 (55%) for surgical staging and 30 of
to borderline lesions (Table 17.2). 40 (75%) cases for 18FDG PET/CT, respectively (Table 17.3).
18
Based on these results, 18FDG PET/CT should be included in FDG PET/CT classified 27/87 (31%) patients as stage IV versus
the diagnostic assessment of adnexal masses, in addition to TVUS, only two with surgery based on FIGO criteria.26 Extra-abdominal
CT, and MRI (Fig. 17.1). lymph nodes and distant metastases were found in 23 (85%) and
14 (52%) patients classified as stage IV by 18FDG PET/CT. In 2010,
Nam et al.19 compared 18FDG PET/CT and CT or 18FDG PET/CT and
Staging of Ovarian Cancer MRI for the detection of extraovarian lesions in the abdomen and
It is widely accepted that optimal debulking surgery has a survival pelvis. The sensitivity, specificity, PPV, and NPV of FDG PET/CT
benefit.20–22 In 30% of cases, however, initial laparotomy underes- were respectively 94.6%, 82.8%, 87.5%, and 92.3% against 94.1%,
timates the disease stage, mainly because of technical difficulties 71.4%, 94.1%, and 71.4% with CT. For the detection of locoregional
and spread of the disease outside of the pelvis.23 Although many lymph node metastases (bilateral pelvic lymph nodes and para-
studies have investigated the value of 18FDG PET/CT to characterize aortic), sensitivity, specificity, PPV, and NPV were 83.3%, 92.6%,
ovarian lesions, fewer studies have studied its value in the staging 81.6%, and 93.6%, respectively for 18FDG PET/CT against 62.5%,
situation. 83.6%, 60%, and 85% for CT or MRI. In this study, the correlation
Figure 17.1. FDG PET/CT at initial staging of

an ovarian serous papillary adenocarcinoma:
Tumor mass of 13 cm, including both ovaries.

Table 17.3 determined prior to initial surgery in 60 patients with stage II or IV

ovarian cancer. The prognostic value of SUVmax was determined
Comparison Between PET/CT and CT Staging Versus prior to the initial surgery in 60 patients with stage III or IV ovarian
Surgical Staging cancer. There was no correlation between initial SUVmax and an
incomplete cytoreduction at the time of initial surgery or survival.
Number of At the present time, more prospective clinical studies in large
Authors Year Patients PET/CT CT numbers of patients are needed to determine the added value of
18
FDG and 18FDG PET/CT as a prognostic indicator.
24
Yoshida et al. 2004 15 13/15 (83%) 8/15 (53%)
Castellucci et al.16 2007 32 22/32 (69%) 17/32 (53%)
Kitajima et al.25 2008 40 30/40 (75%) 22/40 (55%) Detection of Recurrence
Early detection and complete localization of relapse is important
of staging with 18FDG PET/CT versus surgery was also studied. A to select appropriate second-line treatment, and improve survival.
concordance was observed in 71 of 91 patients (78%). Also, 14 of Cytoreductive surgery and additional chemotherapy and radiation
91 (15.4%) patients were overclassified by 18FDG PET/CT and 6 therapy which may prolong survival largely depend on accurate
(6.6%) underclassified. determination of the extent of disease.3,30
18
FDG PET/CT may contribute to staging of OC with an impact Recent National Comprehensive Cancer Network guidelines
on survival. recommend that the disease status be monitored with regular
In total, 18FDG PET/CT is particularly useful in the accurate physical and pelvic examinations, contrast-enhanced CT, magnetic
staging of EOC due to its high sensitivity to detect extra-abdominal resonance imaging (MRI), and measurement of serum CA-125 lev-
spread of disease and therefore to influence therapeutic strategy. els, and 18FDG PET/CT.31
CA-125: Approximately 80% of all ovarian cancers present
18 with elevated CA-125 expression.32 In those patients, persistently
FDG PET/CT as a Prognostic Indicator rising serum CA-125 levels after first-line treatment have a high
Three recent clinical studies have reported on the potential interest positive predictive value (>95%) for recurrent disease, but poor
of 18FDG SUVmax to serve as a prognostic indicator. negative predictive value (50% to 60%).33
Chung et al.27 conducted a retrospective preoperative 18FDG CT and MRI have comparable performance with sensitivity,
PET/CT study in 55 patients with disease recurrence. The distri- specificity, and accuracy for CT being 40% to 67%, 93% to 100%,
bution of SUVmax was divided into two regions, above and below and 66% to 85%, respectively and 62% to 91%, 40% to 93%, and
the umbilicus. An SUV ratio was defined as the sum of SUVmax of 59% to 90%, respectively for MRI.34 Those techniques are chal-
lesions located above the umbilicus divided by the sum of SUVmax lenged by small-volume recurrence or metastasis (CT sensitivity =
of lesions located below the umbilicus. In univariate analysis, an 25% to 50% for lesion <1 cm) and lymph node involvement (sensi-
increased SUV ratio was significantly associated with recurrence tivity = 40%). In addition, they have limitations for differentiating
risk. In multivariate analysis, increased SUV ratio was associated tumor recurrence from postoperative and postradiation changes.35–37
with histologic type and an increased risk of recurrence. In this Several studies investigated the role of 18FDG PET/CT for post-
study, stage of disease according to FIGO classification was not a therapy surveillance of patients (Table 17.4). In a recent meta-
significant prognostic indicator for recurrence; probably caused analysis, Gu et al.48 showed that 18FDG PET/CT had an area under
by the low number of patients included and the initial staging the receiver operating characteristic curve of 0.96 for detection of
(45 patients; 55 were classified as stage III). recurrent ovarian cancer, which was the best result of all tested
Nakamura et al.,28 in a prospective study including 51 patients, techniques: CT = 0.88; CA-125 = 0.92; MR = 0.8. In studies using
showed that a high SUVmax of the primary ovarian lesion was sig- clinical follow-up as gold standard, FDG PET/CT performance was
nificantly associated with FIGO stage and histologic type. Survival very high with 74% to 100% sensitivity, 80% to 100% specificity,
was the shortest in patients with the highest SUVmax suggesting that and 83% to 100% accuracy on patient-based analyses.38–43,49
a high SUVmax in the primary tumor is an important factor identify- However, when the gold standard was histopathology, the diag-
ing patients at risk of poor prognosis. Risum et al.29 provides contra- nostic accuracy of PET/CT tended to be poorer (because of the
dictory evidence on SUVmax. The prognostic value of SUVmax was microscopic disease not visualized by any imaging modality) and
Ta b l e 1 7 . 4
FDG PET/CT in Detection of Recurrent Ovarian Cancer
Number of Gold
Authors Year Patients % Sens. % Spec. % Acc. % PPV % NPV Standard
Kitajima49 2008 132 74 91 83 NA NA Follow-up

Hauth38 2005 19 100 100 100 NA NA Follow-up
Chung39 2007 77 93 97 94 98 91 Follow-up
Thrall40 2007 51 95 100 NA NA NA Follow-up
Sebastian41 2008 53 97 80 92 93 80 Follow-up
Garcia42 2007 80 87 79 85 92 68 Follow-up
Bilici43 2010 60 95 93 95 98 88 Follow-up
Bristow44 2003 22 83 NA 82 94 NA Histopathology
Sironi45 2004 57 78.05 75.00 77 89.00 57.00 Histopathology
Bristow46 2005 14 41 94 72 83 69 Histopathology
Sens., sensitivity; Spec., specificity; PPV, predictive positive value; NPV, negative predictive value; Acc., accuracy.

Figure 17.2. FDG PET/CT at restaging of an ovarian serous papillary adenocarcinoma: Pathologic peritoneal uptake not depicted on CT scan (red arrows).

sensitivity, specificity, and accuracy of patient-based analysis were and 82.8%, respectively, despite a weak sensitivity of 40.7%.46
41% to 83%, 75% to 94%, and 72% to 82%, respectively.44–46 In a Moreover, the increasing use of PET suggested a reassessment of
retrospective study of 60 patients with suspected recurrent ovar- the classical pattern of lymphatic spread of disease by highlighting
ian cancer, Bilici et al.43 showed superiority of PET/CT over CT a significant number of supradiaphragmatic lesions not depicted
with 95.5% versus 55% sensitivity, 93.3% versus 66.6% specificity, by conventional imaging (Fig. 17.4).19,51,52
and 95% versus 58.3% accuracy. Distant metastases are less common, even at restaging. How-
For recurrences localized in abdomen and pelvis, 18FDG PET/ ever, the high sensitivity and whole-body examination of 18FDG
CT is limited not only by physiologic uptake in the bladder and PET/CT proved to be very useful to determine the correct extent
bowel loops, but also by post-treatment (i.e., surgery, radiother- of disease.
18
apy) inflammatory changes in pelvis. Hence, sensitivity for detec- FDG PET/CT not only contributes to the diagnosis of recur-
tion of such lesions is lower than that of MRI (73% versus 93% on rence but also to subsequent therapeutic management in 40% to
patient-based analysis), but PET/CT has slightly higher specificity 60% of patients by depicting otherwise undetected recurrence site
(91% versus 86%).47 Peritoneal metastasis outside the pelvis seems or guiding site-specific treatment.40,44,53–56 In a prospective study
to be a more favorable situation for PET, with a sensitivity, negative to assess the impact of 18FDG PET-CT on the management of
predictive value, and diagnostic accuracy values of PET/CT patients with suspected recurrence and to determine the incre-
significantly better than those of MRI particularly for lesions <2 cm mental information provided by PET-CT, Fulham et al.57 showed
(Figs. 17.2 and 17.3).50 that at least 168 additional sites of disease in 61 patients (68%),
Visualization of lymph node involvement by conventional not identified by conventional imaging, were identified by PET-CT.
imaging may be difficult because of the inability to distinguish In 77% of cases, the additional lesions were located below the
nodal metastases from inflammatory or fibrotic nodes. 18FDG diaphragm and most of them were nodal or peritoneal. PET-CT
PET/CT appears to be useful, particularly in retroperitoneal lymph changed management in 60% (49% high, 11% medium impact). In
nodes with high specificity and positive predictive values of 94% another recent study, treatment modifications induced by 18FDG
Figure 17.3. FDG PET/CT at restaging of an ovarian serous papillary adenocarcinoma: Obvious peritoneal metastasis on FDG PET (green arrow ) and pathologic
peritoneal uptake not depicted on CT scan (red arrow ).

Figure 17.4. FDG PET/CT at restaging of an ovarian serous papillary adenocarcinoma: Pathologic lymph node, doubtful on CT scan (red arrows).
PET/CT consisted in : previously unplanned chemotherapy or sur- Interestingly, protocols for CT image acquisition varied much
gery in 61.2%, and cancellation of diagnostic or therapeutic pro- more than PET because of different system capacity and role
cedures in 38.8%.43 In addition, Du et al.53 proved very recently assigned to CT (anatomic localization only or codiagnostic image).
that 18FDG PET/CT can help guide radiotherapy in treatment of In the majority of published studies, the main limitation of
18
recurrent ovarian by improving the delineation of gross tumor FDG PET/CT was the detection of small or microscopic lesions,
volume and potentially improve clinical outcome. because of the spatial resolution of 4 to 6 mm for currently avail-
able systems and insufficient 18FDG uptake in small lesions. The
inability to detect lesions <1 cm led to a false-negative rate of 5%
Response Assessment to 10%.58 However, a recent study by Sanli et al.50 showed that
PET/CT was similar to conventional MRI for the detection of
Neoadjuvant chemotherapy followed by surgical debulking seems recurrence and even better for the detection of small-to-medium-
to improve outcome but only in patients with complete or nearly sized (<2 cm) peritoneal implants. Further is necessary.
complete response to neoadjuvant therapy.54 CT and MRI are lim- Other pitfalls are related to physiologic 18FDG concentrations.
ited in detecting response early after the initiation of therapy Normal activity in the urinary system and bladder can interfere with
because anatomic changes take time. A few studies are available image interpretation in the pelvis. Thus problem can be reduced by
regarding the role of 18FDG PET/CT to monitor therapy. administering 20 mg of Furosemide 20 minutes before imaging and
Avril et al.55 demonstrated that after one and three cycles of having the patient empty her bladder just before the start of image
chemotherapy, 18FDG PET/CT was more accurate for response recording. Another approach to limiting the urinary artifact is to
evaluation to therapy than conventional clinical or CA-125 criteria. have the patient drink 500 mL of water 1 to 2 hours prior to image
A higher rate of complete tumor resection was achieved in meta- acquisition and to void just before image acquisition.59
bolic responders (defined as >20% reduction in SUVmax after the Focal activity in bowel loops and misregistration caused by
first cycle and >50% after the third cycle) than in nonresponders. bowel peristalsis may lead to over or underestimate extent of the
In addition, metabolic responders had a longer median overall sur- disease. In a recent study, Kitajima et al.59 showed that contrast-
vival than nonresponders. With a threshold for SUVmax decrease enhanced CT reduces frequency of equivocal interpretations and
from baseline of 20% after the first cycle, median overall survival improves confidence for assessing ovarian cancer recurrence.
was 38.3 months in metabolic responders, compared to 23.1 Oral contrast allows more accurate identification of the bowel and
months in metabolic nonresponders. Using a threshold of 55% facilitates the interpretation of abdominal and pelvic CT studies
decrease in SUV after the third cycle, median overall survival was and improves image quality.39
38.9 months in metabolic responders, compared to 19.7 months in In the evaluation of recurrence, posttreatment inflammatory or
nonresponders. In 21 gynecologic cancer patients (uterine cancer, fibrotic changes may lead to equivocal interpretations. Caution is
n = 13; ovarian cancer, n = 8), 18FDG PET/CT performed at the end necessary when 18FDG PET/CT is performed within 6 months of
of chemotherapy, SUV was significantly lower in responders than surgery. Detailed knowledge of previous treatment and other
that in nonresponders.56 Based on these preliminary data, 18FDG imaging results improves interpretation. False-negative 18FDG
PET/CT is promising to predict response to chemotherapy. PET/CT results may also occur in patients with cystic or necrotic
lesions or lesions with copious mucinous collections.60
Considering these pitfalls, careful review and correlation with
Pitfalls or Limitations of 18FDG the conventional imaging findings and patient’s history are required
PET/CT in Ovarian Cancer for accurate interpretation.
18
FDG PET protocols vary in multiple studies investigating this
modality in ovarian cancer. Injected 18FDG activity ranged from Targeted Radionuclide Therapy
200 to 740 MBq.48 Patients fasted at least 4 hours (more often,
6 hours), and blood glucose level was controlled before intrave- The prognosis for patients with advanced disease remains poor
nous injection. Whole-body imaging was acquired 1 hour after with a 5-year survival rate of less than 40%. There is a need for
18
FDG injection. The early studies assessed 18FDG PET alone, innovative treatment modalities. After primary standard treatment
whereas the most recent ones used an integrated PET/CT system. combining debulking surgery and chemotherapy using platinum

and paclitaxel, frequency of relapses is up to 50%. These relapses Integrated PET/MRI

are generally confined to the peritoneal cavity and may be ame-
nable to intraperitoneal (IP) therapy. PET/MRI in ovarian cancer is a new hybrid imaging modality that
For the last 20 years, several phase I/II IP radioimmunother- would provide an alternative to a PET/CT scanner for whole-body
apy clinical trials have been performed using different antibodies imaging for the detection, staging, characterization, and func-
labeled with different radionuclides including iodine-131, tional therapy monitoring of ovarian cancers. At this time, no
yttrium-90, lutetium-177 and, more recently, astatine-211.61–67 studies are available.
Two studies were limited to evaluation of toxicity. The other phase
I/II studies included a total of 92 patients.61,63,64,67 Transitory
tumor regression was observed in 14 patients, in small-volume Conclusion
tumors of less than 5 mm.
Finally, a randomized phase III trial has been performed in The role of nuclear medicine in ovarian cancer management is
447 patients using yttrium-90-labeled anti-MUC1 antibody currently limited to 18FDG PET/CT. Although 18FDG PET/CT value
(HMFG1) murine antibody.68 Those patients had a macroscopi- in the characterization of adnexal masses and the initial assess-
cally negative second-look laparoscopy and so were assumed to ment of ovarian cancer remain controversial, there is now strong
have a microscopic residual disease that is the optimal indication evidence to support its use for early detection and restaging of
for radioimmunotherapy (RIT). Unfortunately, this large, prospec- recurrent disease. Its contribution is particularly important in
tive trial failed to demonstrate significant improvement in overall patients with rising CA-125 levels and negative morphologic
survival. This lack of efficacy confirmed an earlier limited phase II imaging results to improve treatment selection but also for patients
trial with a rigorous systematic histologic evaluation.65 The proto- with normal CA-125 level and abnormal CT scan to avoid unnec-
col included second-look surgery to assess the extent of the dis- essary procedures. 18FDG PET/CT has to be carefully interpreted
ease and third-look surgery to assess the response to RIT. This with other imaging and clinical information. 18FDG PET/MR may
protocol was very demanding for patients which accounts for the improve the detection and staging of ovarian cancer.

limited number of six enrolled patients. There was no evidence of
efficacy.
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C h apt e r 1 8
Testicular Germ Cell Tumors

Christoph Oing • Carsten Bokemeyer • Karin Oechsle
Introduction are designated as having CS I disease if no lymphatic spread or

distant metastases can be detected.2 Prognostic factors for stage I
Malignant testicular germ cell tumors (GCTs) are relatively rare GCT differ between the two histologic subtypes. For CS I semi-
types of cancer accounting for 1% to 3% of all cancers in cauca- noma, tumor size ≥4 cm and infiltration of the rete testis have been
sian males in Western countries. But, GCTs are the most common proposed as independent predictors of an adverse outcome15
malignancy among young men in most European populations.1,2 Recently, this risk stratification model could not be validated in a
The worldwide incidence of testicular tumors is increasing and multivariate analysis. Therefore, at the present time, no distinctive
has more than doubled over the past 40 years.2,3 In contrast, tes- risk factors can be defined for early stage seminoma.16
ticular cancer mortality has markedly declined in a number of In CS I nonseminoma, the presence of vascular invasion (VI), is
European countries since the mid-1970s likely related to the the most important prognostic factor for occult metastatic disease.
introduction of platinum-based chemotherapy and best-practice It is mandatory that it is assessed in every patient.17 Forty-eight
tumor management schemes.1 percent of VI positive patients will develop metastases if adjuvant
GCTs account for more than 95% of all testicular malignancies.4 treatment is not administered.18,19
Histologically and clinically, GCTs are classified into seminomatous In advanced GCT, treatment decision is based on prognosis but
and nonseminomatous germ cell tumors (NSGCTs).5,6 The majority not on the CS alone. In a cooperative retrospective database analy-
of seminomas are diagnosed among men aged 30 to 45, whereas sis including data of a total of 5,202 patients, independent adverse

most of the NSGCT patients are between the ages of 20 and 35.7 factors were the following: Mediastinal primary site; degree of
The cause of GCTs is unknown but established risk factors for serum tumor marker elevation (α-fetoprotein, AFP; beta-subunit of
GCT development are cryptorchidism or maldescended testes, a human chorionic gonadotropin, b-HCG; lactate dehydrogenase,
previous contralateral GCT, and a family history of testicular can- LDH); and presence of nonpulmonary visceral metastases. For
cer, particularly among siblings and in case of affected first-degree seminoma, the predominant adverse feature was the presence of
relatives.8,9 Furthermore, the Klinefelter syndrome appears to be nonpulmonary visceral metastases.20 Based on these risk factors,
a predisposing factor for the development of tumors arising from the International Germ Cell Cancer Collaborative group (IGCCCG)
the testis and mediastinum.10 classification was established (Table 18.2).
Histology of Germ Cell Tumors

GCTs comprise a heterogeneous group of neoplasms that originate Tab l e 1 8 . 2
from cells belonging to the germ cell lineage.6,11 Male GCTs com-
monly occur in the testes, and in different extragonadal sites along Risk stratification according to the International
the midline of the body; the retroperitoneal and mediastinal regions, Germ-Cell Cancer Collaborative Group classification
as well as the midline of the brain, that is the hypothalamus–pineal
gland region.12 Prognosis Seminoma Nonseminoma
As stated, testicular germ cell tumors (TGCTs) can be divided
into two main types: Seminomas and nonseminomas. The latter Good (5-y Any primary location Testis or primary extragonadal retroperi-
type may harbor one or more histologically different components survival No nonpulmonary toneal tumor
90%) visceral No nonpulmonary visceral metastases
of embryonal carcinoma, teratoma, polyembryoma, choriocarci-
metastases Low markers
noma, or yolk sac tumor.13 Pure seminomas comprise about 50% Any marker level AFP <1,000 ng/mL
of TGCTs, and nonseminomas account for 30% of cases. The b-HCG <5,000 IU/L
remaining tumors consist of a mixture of cell types containing both LDH <1.5 × normal level
seminomatous and nonseminomatous components.12
Intermediate Any primary location Testis or primary extragonadal retroperito-
(5-y Presence of non- neal tumor
Staging and Classification of survival
75%)
pulmonary visceral
metastases (liver,
No presence of nonpulmonary visceral
metastases
Germ Cell Tumors CNS, bone, Intermediate markers
intestinum) AFP 1,000–10,000 ng/mL
The definition of the clinical stage (CS) of patients with gonadal Any marker level b-HCG 5,000–50,000 IU/L
LDH 1.5–10 × normal level
GCT is based on the UICC TNM classification (Table 18.1).14 Patients
Poor (5-y Does not exist Primary mediastinal GCT with or without
Table 18. 1 survival testis
50%) Primary retroperitoneal tumor
Clinical Stage of Germ Cell Tumors at Primary Diagnosis Presence of nonpulmonary visceral
metastases (liver, CNS, bone, intestine)
High markers
Seminoma (%) Nonseminoma (%) AFP <10,000 ng/mL
b-HCG >50,000 IU/L
Clinical stage I 60 80 LDH >10 × normal level
Clinical stage II 20 15
Clinical stage III 20 5 AFP, α-fetoprotein; HCG, human gonadotropin; LDH, lactate dehydrogenase.
Adapted from Krege S, Beyer J, Souchon R, et al. European consensus conference on diagnosis
Adapted from Horwich A, Shipley J and Huddart R. Testicular germ-cell cancer. Lancet 2006; and treatment of germ cell cancer: A report of the second meeting of the European Germ Cell
367:754–765. Cancer Consensus group (EGCCCG): Part I. Eur Urol. 2008;53:478–496.
241

Table 18.3 In CS I NSGCT, there also exist three different treatment options
following orchiectomy. These are active surveillance, one or two
Diagnostic Tools for Assessment of the cycles of chemotherapy (BEP), or nerve-sparing retroperitoneal
Extent of Germ Cell Tumors lymph node dissection (RPLND). For low-risk patients, active sur-
veillance is the recommended treatment strategy. In contrast, high-
Markers mandatory risk patients defined by VI should preferably receive adjuvant
Seminoma/nonseminoma → AFP, b-HCG chemotherapy.24–26
Metastatic disease → LDH in addition to AFP and b-HCG Detection of patients with CS IIA caused by retroperitoneal
Imaging procedures lymph nodes ≤2 cm is problematic, because of difficulties in pre-
Testicular ultrasonography (7.5-MHz transducer) dicting malignancy of a suspicious lymph node based on a CT scan.
Chest x-ray Nerve-sparing RPLND is an established option if tumor marker
CT scan of abdomen and pelvis levels are normal, and offers the opportunity for accurate patho-
Chest CT scan (not mandatory for seminoma clinical stage I ) logical staging. Patients with CS IIA/B and elevated tumor markers
MRI of chest and abdomen: Only if contraindication for CT scan should be treated systemically with chemotherapy.26
(e.g., contrast media) Patients with seminomatous or nonseminomatous advanced
MRI (if unavailable: CT) of central nervous system in advanced disease or disease require cisplatin-based combination chemotherapy poten-
in presence of symptoms
tially followed by secondary salvage surgery to resect residual
Bone scan: Only in presence of symptoms
Fertility investigations (should be offered): Total testosterone, LH, FSH, semen masses. The chemotherapy regimen of choice depends on the risk
analysis, sperm banking category according to the IGCCCG risk stratification model.20 It is
recommended that low-risk patients receive three cycles of BEP, or
AFP, α-fetoprotein; CT, computed tomography; FSH, follicle-stimulating hormone; b-HCG, beta- if bleomycin has to be abandoned, four cycles of PE, alternatively. All
subunit of human chorionic gonadotropin; LDH, lactate dehydrogenase; LH, luteinizing hormone; intermediate-risk or high-risk patients should primarily receive four
MRI, magnetic resonance imaging. cycles of BEP. Four cycles of cisplatin, etoposide, and ifosphamide
Adapted from Krege S, Beyer J, Souchon R, et al. European consensus conference on diagnosis
and treatment of germ cell cancer: A report of the second meeting of the European Germ Cell (VIP) are equally effective but cause more acute myelotoxicity and
Cancer Consensus group (EGCCCG): Part I. Eur Urol. 2008;53:478–496. are therefore not recommended as standard therapy.25,26 Further-
more, in two randomized phase III trials, a primary treatment
approach including high-dose chemotherapy (HD-CTX) slightly
improved treatment outcome among patients with metastatic poor-
Diagnosis of Germ Cell Tumors risk disease, but the improvement did not reach statistical signifi-
cance. Estimation of serum marker decline during the first two
The diagnostic procedure in GCT patients consists of clinical exam- cycles of induction chemotherapy has been shown to be valuable for
ination, palpation and high frequency ultrasound (7.5 MHz) of the predicting the outcome of primary treatment. Delayed tumor marker
testes, determination of serum tumor markers prior to surgery decline during induction therapy predicts for adverse outcome with
(AFP, b-HCG, LDH), and primary orchiectomy. Postoperative rou- a significantly shorter progression-free survival and overall sur-
tine assessment of disease extent is mandatory with chest x-ray vival.27,28 Therefore, HD-CTX is currently not recommended as part
and computed tomography (CT) of the abdomen and pelvis.21 A CT of primary treatment in all poor-risk GCT patients, but may be a
of the chest should be performed if the chest x-ray is abnormal or valuable option for selected patients with special risk characteristics.
abdominopelvic CT shows metastatic disease.22 Brain imaging is
indicated if suspicious clinical symptoms are present.2 Bone scin-
tigraphy is recommended if clinical signs of bone metastases are
Salvage Treatment
present.21 However, bone metastases are rare and only present in In contrast to the primary treatment, salvage strategies after
about 5% to 10% of patients with advanced metastatic disease at relapse are less well established. The majority of relapses occur
initial diagnosis (Table 18.3).23 within 2 years after completion of the initial treatment. Even in the
salvage situation, an overall rate of 40% to 50% long-term remis-
sions can be achieved.29
Treatment of Germ Cell Tumors Chemotherapeutic treatment regimens in the salvage setting
are the following combinations: VIP, or paclitaxel, and ifosphamide
Seminomas are highly sensitive to both radiation and chemother- with or without cisplatin (TI or TIP) for second-line, as well as
apy whereas nonseminomas are less susceptible to radiotherapy. gemcitabine, oxaliplatin preferably together with paclitaxel (GOP)
NSGCTs, except for mature teratomas, are highly sensitive to plat- as third or further line option for truly refractory patients. In the
inum-based chemotherapy. Mature teratomas are insensitive to absence of randomized trials, no salvage chemotherapy regimen
both radiation and chemotherapy and have to be surgically has shown unequivocal superiority.26,30,31 In patients with poor
resected to prevent transformation.12 prognosis, phase II trials have suggested an improvement in sur-
In CS I seminoma, three different treatment approaches are vival using HD-CTX with subsequent autologous stem cell trans-
available. Because the risk stratification model introduced by plantation but the role of HD-CTX remains to be defined by
Warde et al.15 in 2002 could not be validated prospectively, treat- prospective phase III trials.
ment guidelines are progressively favoring active surveillance The results of a retrospective analysis of a large international
following orchiectomy, rather than adjuvant chemotherapy (one database of approximately 1,600 patients who relapsed after
cycle carboplatin AUC7) or retroperitoneal irradiation of the para- platinum-based first-line treatment by Lorch et al. indicate a clear
aortic lymph nodes.21,24,25 advantage of HD-CTX given as first salvage treatment. Patients
At present, the recommended treatment standard for CS II, have been allocated to five different prognostic categories accord-
especially CS IIA seminoma according to the NCCN and EGCCCG ing to the prognostic model previously identified by the Interna-
consensus guidelines is radiotherapy. The target volume includes tional Prognostic Factors Study group. Of interest, the advantage
the para-aortic and ipsilateral iliac lymphatics. Overall survival fol- of HD-CTX was significant for all categories, except for patients
lowing this treatment is approaching 100%. In CS IIB, chemother- with low-risk factors.32,33 Thus, HD-CTX with subsequent autolo-
apy with either three cycles of cisplatin, etoposide, and bleomycin gous stem cell support seems to be a promising salvage treatment
(BEP) or four cycles of cisplatin plus etoposide (PE), if contraindica- option, which needs further prospective validation particularly in
tions for bleomycin are present, are approved alternatives.25,26 the salvage setting.

Chapter 18 Testicular Germ Cell Tumors 243
Residual Masses Post Chemotherapy undertreatment if CS is underestimated.48 CT scans of the abdo-

men and pelvis based on morphology and size alone may yield
In about 40% of GCT patients, indeterminate residual masses per- false-negative results in 20% to 30% of cases, where pathologic
sist in CT scans after completion of chemotherapy and tumor lymph nodes will be found at RPLND.21,48 The differentiation
marker normalization.34 between CS I and IIA is fault-prone, if both AFP and b-HCG are
In pure seminomatous GCTs, residual masses presenting after normal.21,49,50 Regardless of risk factors, about 5% to 20% of CS I
chemotherapy do not have to be resected necessarily, irrespective seminoma patients, and approximately 15% to 50% of patients
of their size but should be followed closely by radiographic imag- with CS I NSGCT undergoing a surveillance strategy suffer relapse
ing and determination of serum tumor markers. Residual masses, of germ cell cancer, mostly during the first year of follow-up, indi-
not larger than 3 cm in size should routinely be observed without cating an important number of patients being understaged.19,51
any further local or systemic treatment as the risk for persistent Because improved detection of patients with metastatic disease
viable tumor cells is only about 0% to 10%.35–37 In patients with requiring chemotherapy would be of clinical value, it would be use-
residual lesions of >3 cm in size, the incidence of recurrence is ful if 18F-FDG PET scans detected small metastases, particularly if
approximately 25% to 30% and treatment decision should be standardized staging including CT and serum tumor markers are
based on 18F-fluoro-2-deoxy-D-glucose PET/CT.38 negative.48,52 In a small series of 31 patients (13 seminomas, 18
After treatment of an NSGCT, there is an increased risk of NSGCTs) Hain et al.48 reported a comparably high rate of false-
residual mature teratoma, if teratomatous histology was present negative results with 5 out of 16 negative 18FDG PET scans (31%)
in the initial tumor orchiectomy specimen. Mature teratoma is for the use of 18F-FDG PET for primary staging. The high rate of
chemotherapy-resistant, can grow locally and might undergo relapses in initially 18FDG PET-negative patients suggests that
malignant transformation into teratocarcinoma. After surgical small (diameter <0.5 cm) and microscopic lesions may be missed.
resection of residual masses >1 cm in NSGCT patients, histologic Moreover, mature teratoma of any size was missed on 18F-FDG
examination shows necrosis and/or fibrosis in 40%, mature tera- PET, as well. Even in high-risk CS I patients, in the TE22 trial of the
toma in 40% to 50% and persistent viable tumor tissue in 10% to Medical Research Council (MRC), 18F-FDG PET was not sensitive

20% of cases.34,39 Therefore, surgical resection is generally recom- enough to predict early metastatic disease in a statistically signifi-
mended for all NSGCT residues >1 cm, if technically feasible.40 cant proportion of patients.53
Thus, approximately 40% of patients with persisting residual 18
F-FDG PET has not conclusively been proven to significantly
masses after chemotherapy unnecessarily undergo overtreatment improve the sensitivity of staging compared to routine CT imaging,
by surgery. This could be avoided if viable residual tumors could even in high-risk CS I germ cell cancer. CT and 18FDG PET rather
be excluded noninvasively.41 Unfortunately, both routine radio- seems to be equivalent for primary staging in a number of studies.
logic imaging (e.g., CT and MRI), and serum tumor marker moni- 18
F-FDG PET, however, may be a useful diagnostic tool when the
toring are unable to determine the viability of a residual tumor, CT scan is equivocal.53–55 Furthermore, 18F-FDG PET provides no
sufficiently.42 There are only a few distinct markers that allow the further information in addition to ultrasound at primary diagnosis
prediction of pure necrosis with almost 90% certainty in patients of a testicular tumor.45 As a result, the routine use of 18F-FDG PET
with retroperitoneal or pulmonary residual masses. These are for primary staging of GCT cannot be recommended at present.
combinations of tumor shrinkage measured radiographically,
initial histology lacking mature teratoma, and normal tumor marker
values (AFP and HCG) prior to chemotherapy.43 FDG PET Evaluation of Residual Masses
Post Chemotherapy
Positron Emission Tomography Seminoma
in Germ Cell Tumors Management of postchemotherapy residual masses in seminoma
patients remains a challenge, with the primary dilemma being
To date, 18F-fluoro-2-deoxy-D-glucose (18F-FDG) is the only PET whether to resect or simply observe these lesions.56 In patients
tracer approved for routine imaging, primary diagnosis, and for with pure seminoma and residual lesions after completion of che-
the evaluation of treatment response/residual masses post chemo- motherapy of >3 cm in size, the risk for persistent viable tumor
therapy in GCT patients. In the last few years, however, there has cells is approximately 25% to 30%. In patients with persistent via-
been some effort to investigate the use of other tracers (e.g., 18F- ble tumor cells, further chemotherapy or complete resection of all
fluorothymidine (18F-FLT) for GCT treatment response evaluation)44 lesions is necessary. Conventional radiographic imaging (e.g., CT),
Physiologically, 18F-FDG uptake is detected in normal testicular however, does not distinguish between necrotic or fibrotic tissue
tissue. This activity declines slightly with increasing age. Physiologic and viable tumor remnants. A prospective multicenter German–
18
F-FDG uptake in the testis should not be confused with pathologic Austrian trial (SEMPET) was conducted to determine the value of
accumulation.45 GCTs are generally characterized by high 18F-FDG 18
F-FDG PET for viability assessment of seminomatous GCT post-
uptake. In testicular GCT, pure seminomatous lesions show a sig- chemotherapy residues. In a total of 37 patients, 41 residual lesions
nificantly increased 18F-FDG uptake compared to nonseminomatous >1 cm after completion of chemotherapy were identified by
tumors.41 Cells of mature teratoma have a relatively low metabolic 18
F-FDG PET scans. The results were compared to clinical outcome
activity as they are usually well differentiated like normal tissues during follow-up. Nine patients underwent secondary surgery of
which makes the detection of teratoma as well as its differentiation the lesions so that direct comparison between 18F-FDG PET results
from normal tissue by 18F-FDG PET scanning difficult.22,46 and histology was possible. Viability of residual masses was cor-
At the present time, PET/CT has become the standard of PET rectly assessed by 18F-FDG PET in all 14 patients presenting with
imaging in GCT patients because it provides both CT and PET lesions sized >3 cm, and in 22 of 23 patients (96%) with lesions
images simultaneously, thus identifying the exact anatomic loca- ≤3 cm. There was only one false-negative 18F-FDG PET result. In
tion of a tumor or suspicious lesion as small as 5 mm.47 the SEMPET study, in patients with pure seminoma 18F-FDG PET
had a sensitivity of 100% and a specificity of 89% for all residual
18 lesions and 100% for lesions sized >3 cm. The positive and negative
FDG PET for Staging at Primary Diagnosis
predictive values were 100% and 97%, respectively. Therefore,
18
Selection of patients with true CS I disease and a consecutively low F-FDG PET was judged to be a clinically useful tool to identify viable
risk of developing disease recurrence or metastases is important to tumor in postchemotherapy residues of pure seminoma, especially
reduce the burden and toxicity of overtreatment and to avoid those bigger than 3 cm.57 In an update of this trial, 56 18FDG PET

Table 18.4 Tab l e 1 8 . 5
Impact of 18F-FDG PET on The Assessment of Size of Residual Masses of Seminoma and its
Residual Masses in Seminoma Impact on Diagnostic Imaging
Detection of Viable Detection of Viable Positive Negative

Tumor by 18F-FDG PET Tumor by Size (≥3 cm) Predictive Predictive
Mode Sensitivity Specificity Value Value
Specificity (95% CI) 1 (0.92–1) 0.74 (0.58–0.85)
Sensitivity (95% CI) 0.80 (0.44–0.95) 0.70 (0.34–0.90) All lesion PET 0.67 0.82 0.42 0.93
Positive predictive value 1 0.37 sizes CT 0.67 0.44 0.19 0.87
Negative predictive value 0.96 0.92 Lesions PET 0.43 0.83 0.27 0.91
<3 cm CT 0 1 — 0.87
Adapted from De Santis M, Becherer A, Bokemeyer C, et al. 2-18fluoro-deoxy-d-glucose positron Lesions PET 0.79 0.81 0.50 0.94
emission tomography is a reliable predictor for viable tumor in postchemotherapy seminoma: An ≥3 cm CT 1 0 0.19 —
update of the prospective multicentric SEMPET trial. J Clin Oncol. 2004;22:1034–1039.
Adapted from Bachner M, Loriot Y, Gross-Goupil M, et al. 2-18fluoro-deoxy-d-glucose positron
emission tomography (FDG PET) for postchemotherapy seminoma residual lesions: A retrospec-
scans of 51 patients were assessed and the results of the first anal- tive validation of the SEMPET trial. Ann Oncol. 2012;23:59–64.
ysis were confirmed. Viability was correctly assessed in 100% of
residues >3 cm in size, and in 95% of lesions ≤3 cm, respectively
(Table 18.4).38 Based on these studies, 18F-FDG PET is the best at Indiana University Hospital showing the association between a
predictor of viable residual tumor in postchemotherapy seminoma negative 18FDG PET scan and a low likelihood of persistent semi-
residues and is recommended as a standard diagnostic tool for noma in a residual mass (Fig. 18.2).56
clinical decision making in this patient group (Fig. 18.1).21,38 A smaller prospective study of 29 patients, however, was subse-
However, following the more frequent use of PET scans, a quently conducted at Indiana University Hospital. This study failed
higher than expected number of false-positive scans was reported, to confirm a benefit of 18FDG PET to detect viable tumor, both after
for example, up to 45% in a small prospective trial including 20 first-line, and after salvage chemotherapy caused by an increased
patients with residual mass or recurrent seminoma.58 Therefore, number of false-negative results in patients who subsequently
a retrospective trial was conducted by the Austrian–German study relapsed. Four patients relapsed despite a negative PET scan result:
group to evaluate the current PET recommendations in a larger One had a 3 cm residual mass, two had a residual mass <3 cm, and
patient cohort (SEMPECON trial). A total of 125 seminoma patients in one, the size was undetermined.60
were eligible. Thirty-seven patients (30%) underwent subsequent Nevertheless, the current recommendation is that at 6 to
secondary surgery of residual masses. Viable tumor was found in 8 weeks after completion of chemotherapy, 18F-FDG PET is a valu-
8 of 37 patients (22%) whereas relapse was detected on radiologic able tool for clinical decision making that spares patients unneces-
or clinical follow-up in 14% of the remaining patients. False- sary additional therapy.59
positive PET results were obtained in eight studies (15%) in lesions
<3 cm, and in lesions sized ≥3 cm 11 false-positive results (15%)
Nonseminoma
occurred (Table 18.5).59 As a result, in the SEMPECON trial, the high
specificity, sensitivity, and negative predictive value of 18F-FDG PET In residual masses of NSGCT after first-line chemotherapy vital
to evaluate postchemotherapy seminoma residues was confirmed.59 carcinoma and mature teratoma are present in 40% to 60% of
Similar results have been obtained in a small retrospective series patients despite normalization of tumor markers. CT scans and
A B
Figure 18.1. PET of a 22-year-old male with refractory seminoma 4 months after finishing first-line chemotherapy with three cycles of cisplatin, etoposide, and
bleomycin (PEB). Subsequently, the patient underwent salvage chemotherapy based on the shown PET/CT scan. A: Whole body PET signalling with enhanced signal-
ing of brain, heart, bladder and a tretroperitoneal refractory seminomatous tumor residue. B: PET/CT slices of the residual viable mass.

A B

Figure 18.2. PET of a 36-year-old male with seminomatous germ cell tumor showing a PET-negative residual tumor in the retroperitoneum after chemotherapy
with three cycles of cisplatin, etoposide, and bleomycin. During follow-up no relapse occurred until now, confirming the high negative predictive value of a negative
PET scan of residual lesions after curative chemotherapy of seminomas. A: Whole body PET signaling without presentation of the residual mass. B: PET/CT of the
PET-negative retroperitoneal tumor residue.
measurement of serum tumor markers do not sufficiently distin- false-positive results in patients with mature teratoma and inflam-
guish between the presence of necrotic or fibrotic tissue, viable matory components. Of interest, 11 of all 12 patients with a true-
tumor residues, and/or mature teratoma.42 In patients with NSGCT, negative 18FDG PET result did not have mature teratoma in their
therefore, complete resection of all residual masses >1 cm is rec- primary tumor. Therefore, 18F-FDG PET was considered to be useful
ommended today. Consequently, approximately 45% of patients to predict fibrotic residual masses in NSGCT without mature tera-
with necrotic residuals unnecessarily undergo secondary surgical toma in the primary histology.55 Based on the results mentioned
resection after completion of chemotherapy.41 above, 18FDG PET once was recommended to accompany both CT
In the 1990s, several small studies evaluated 18F-FDG PET to and tumor marker determination during follow-up of NSGCT.
detect viable tumor residues after completion of chemotherapy in Nonetheless, in subsequent years a prospective multicenter
NSGCT. Results were heterogeneous.61–63 Hence, reliable differen- trial was thought to determine the value of 18F-FDG PET in NSGCT
tiation between vital undifferentiated tumors and teratomatous patients presenting with a residual mass >1 cm in size in a CT
lesions remains challenging. scan. In this trial, secondary surgery was mandatory to obtain
In a retrospective single-center analysis of 85 residual masses in histologic validation of PET results. After inclusion of 121 patients,
45 patients, Kollmannsberger et al.64 described additional informa- an interim analysis revealed that the study did not achieve the
tion by applying 18FDG PET scans together with the standard fol- primary objective anymore, which was to demonstrate an accu-
low-up CT and tumor markers after completion of chemotherapy in racy of 18FDG PET imaging of 80%. Consequently, the study was
metastatic NSGCT. The 18FDG PET results were validated either by prematurely closed. The accuracy for the prediction of residual
histologic examination of resected tumor or biopsy samples (n = 28 tumor histology of all three diagnostic methods was nearly identi-
lesions), or 6-months clinical follow-up (n = 57 lesions). The results cal, with 55% for CT and 56% for both 18F-FDG PET and serum
of 18F-FDG PET alone were correctly positive in 34%, false positive tumor markers (Table 18.6).66
in 4%, correctly negative in 39%, and false negative in 23%. Assessed The lack of specificity for CT in this study is explained by the
together, the results of PET, CT, and tumor markers indicated that positive CT scan in all patients as residual masses in CT scan
39 residual masses (45%) could be correctly defined as viable represented the main study inclusion criterion. Direct comparison
tumor/mature teratoma. The remaining 46 lesions were interpreted
as necrotic or fibrotic tissue. This resulted in 14 false-negative cases
(16% of all lesions). Excluding patients with mature teratoma from
the analysis did not further improve the results. Tab l e 1 8 . 6
In a subsequent trial including 60 residual tumors in 28 patients
who had undergone HD-CTX because of primarily poor-risk Diagnostic Value of 18F-FDG PET Versus Routine
advanced disease or relapse after first-line treatment, similar Diagnostics to Detect Residual Nonseminoma
results were obtained. Positive 18FDG PET results were highly cor-
18
related with the presence of viable tumor, but residual masses with F-FDG PET CT Serum Tumor Markers
negative 18FDG PET findings still required secondary resection
caused possibly by remaining mature teratoma. In cases of tumor Sensitivity 0.70 1 0.40
progression diagnosed by CT and elevated tumor markers, 18F-FDG Specificity 0.48 0 0.73
PET scans did not improve results.65 Positive predictive value 0.59 0.55 0.61
In another retrospective trial, 38 18F-FDG PET scans (28 NSGCT Negative predictive value 0.51 0 0.50
patients, 10 seminoma patients) after completion of chemotherapy
Adapted from Oechsle K, Hartmann M, Brenner W, et al. [18F]Fluorodeoxyglucose positron
were validated by histology (20 patients) or clinical follow-up. 18FDG emission tomography in nonseminomatous germ cell tumors after chemotherapy: The German
PET revealed true-positive results in 30% of patients and also 30% multicenter positron emission tomography study group. J Clin Oncol. 2008;26:5930–5935.

Ta b l e 1 8 . 7
Comparison of 18F-FDG PET Versus 18F-FLT PET for Response Assessment
Positive Negative
Timing of PET Imaging PET Tracer Sensitivity Specificity Predictive Value Predictive Value
18
After one cycle of CTX F-FDG 0.60 0.33 0.43 0.50
18
After one cycle of CTX F-FLT 0.60 0.80 0.75 0.67
18
After completion of CTX F-FDG 0.20 1 1 0.60
18
After completion of CTX F-FLT 0 1 0 0.50
CTX, chemotherapy.
Adapted from Pfannenberg C, Aschoff P, Dittmann H, et al. PET/CT with 18F-FLT: Does it improve the therapeutic management of metastatic germ
cell tumors? J Nucl Med. 2010;51:845–853.
between 18F-FDG PET and serum tumor markers demonstrated and necrotic tissue found at the RPLND histology may identify a
that PET did not add further significant information for assess- subgroup of patients who could be spared further surgery at other
ment of viability in residual masses post chemotherapy despite sites. This would be of interest, if surgical resection is not feasible
the low sensitivity of tumor marker measurements. Mature tera- to better predict a patient’s risk of relapse, as well as to guide deci-
toma had previously been suspected to be a reason for false- sion making regarding the operative procedure in patients with
negative PET results. Excluding patients with teratoma from the lesions suitable for surgery.39 In this regard, Kollmannsberger et al.
analysis did reduce the rate of false-negative PET results from found that if PET results were uniformly positive or negative for all
17% to 6%, but increased false-positive results from 27% up to lesions within a single patient, the clinical behavior of the multiple
54%. In contrast to previous studies, this prospective trial, which residual masses was uniform, which means remission or progres-
to date is the only one with histologic confirmation in all patients, sion at all locations. Consequently, a uniformly positive 18FDG PET
demonstrated that 18FDG PET is unable to yield significant addi- result was a strong predictor of viable GCT. Hartmann et al. found
tional information compared to the standard diagnostic proce- histology results to be different after secondary resection of mul-
dures, CT and serum tumor markers, in the prediction of tumor tiple lesions at different anatomic localizations in approximately
viability in residual masses.66 The diagnostic value of 18FDG PET, 30% of patients who underwent salvage surgery. In patients who
however, was not worse than these methods either. underwent resection of a necrotic lesion at a single localization and
More recently, 18FLT PET has been used to evaluate the treat- who previously had PET-negative results uniformly for all lesions,
ment response of GCTs. Eleven patients (10 NSGCTs, 1 seminoma) the probability of necrosis at the remaining nonresected lesions
were consecutively staged with both 18F-FDG and 18F-FLT PET clearly was >90% (negative predictive value of a quantitatively
prior to onset of treatment and after each chemotherapy cycle for assessed PET was 67% in this study).64 Accordingly, a subgroup of
metastatic GCT in addition to standard staging procedures. Seven patients with multiple residual lesions may benefit from PET scan-
patients underwent secondary salvage surgery, so that Ki-67 ning after incomplete resection by sparing them further, potentially
immunostaining was performed and compared to 18F-FLT PET harmful and dispensable surgery.
result.44 The results are summarized in Table 18.7.
Both patients with teratomatous tumor components had negative
PET results with both 18F-FDG and 18F-FLT. Furthermore, 18F-FLT
FDG PET for Evaluation of GCT at Relapse
uptake was lower in GCTs as compared to 18F-FDG. PET-negative Identification of recurrence after completion of prior treatment of
residual masses post chemotherapy still require secondary surgical testicular cancer remains a relevant problem in patients with
resection, because the low negative predictive value of 18F-FDG PET continuously rising serum tumor markers but without morpho-
for viable tumor is not improved by application of 18F-FLT.44 logically correlating tumor in CT scan results.52,69 It is unclear if
18
False-positive PET results post chemotherapy have been shown FDG PET scans add useful information in the early detection of
in most of these studies in germ cell cancer patients. 18F-FDG is not relapse or the search of a tumor manifestation. As part of a ret-
a tumor-specific tracer. Accumulation in benign tissue frequently rospective analysis, 23 PET studies of patients with rising tumor
occurs if increased glucose metabolism is present (Fig. 18.3). markers during follow-up were evaluated. Among the patients
Extensive tracer uptake is caused by inflammatory and granu- with elevated markers but normal or long-term stable results on
lomatous tissue with increased macrophage activity which is CT during follow-up, in three of four with a rapidly progressive
found in granulation tissue surrounding abscesses as well as non- relapse, the localization of relapse was identified by 18FDG PET
neoplastic cellular elements in the tumor mass. Furthermore, scan. The positive predictive value of 18F-FDG PET in this cohort
increased 18F-FDG uptake can be related to the effects of irradia- of patients at relapse was 92%, but the negative predictive value
tion and chemotherapy.41,67,68 False-positive 18FDG PET results are was only 50%.69
caused by persisting inflammatory reaction with macrophage Another clinically relevant issue would be the identification of
accumulation post chemotherapy.68 In the prospective trial with patients who are more likely to relapse after primary treatment
histologic confirmation, 61% of false-positive residual lesions of for CS I NSGCT. In a study conducted by Lassen et al., in 46
NSGCTs were caused by persisting inflammation at the time of his- patients with normal tumor makers and inconspicuous follow-up
tologic examination.66 Therefore, a minimal time interval of about CT result after orchiectomy for CS I GCT, 18F-FDG PET scans were
6 weeks after completion of chemotherapy is recommended for performed within 1 month. Subsequently, patients were solely fol-
the evaluation of residual masses of a metastatic seminomatous lowed by active surveillance even in cases with a positive PET
GCT.21,24,25,62 In this study the rate of false-positive PET results was result. 18FDG PET results were true positive in 70% of patients
significantly higher in thoracic masses as opposed to abdominal relapsing within 2 months. The negative predictive value of 18FDG
residual tumors (41% versus 12%).66 PET in this study was 92%, implying that adjuvant treatment
Furthermore, for patients with multiple residual masses, it may could be avoided in patients with CS I NSGCT, who have a negative
be assumed that the combination of a negative PET scan at all sites PET scan during follow-up.22,52

A B

Figure 18.3. PET of a 33-year-old male with nonseminomatous germ cell tumor showing
a PET-positive residual tumor after first-line chemotherapy. The patient underwent subse-
quent surgical resection. The histologic examination revealed sarcoidosis in the tissue sam-
ples, which represents an interesting finding proving the difficulties in distinguishing tumors
from otherwise metabolically active tissue by PET imaging alone. A: Whole body PET signaling
C showing several PET-positive nodular lesions of the mediastinum. B and C: PET/CT slices
detecting multiple enlarged PET-positive mediastinal lymph nodes.
To confirm these findings in a larger patient cohort, a subse- treatment to avoid further toxic treatment or to potentially reduce
quent study of 111 patients with high-risk CS I NSGCT was per- the dose intensity in case of a very good response. In this regard,
formed by the MRC. After a median follow-up of 12 months, 33 of a prospective trial was conducted to evaluate whether 18F-FDG
the 87 initially PET-negative patients on surveillance relapsed PET scans could add additional information to predict treatment
(1-year relapse-free rate 63%). For that reason, the trial was outcome early in 23 patients with relapsed GCT who were sched-
closed prematurely.53 In conclusion, 18F-FDG PET does not reliably uled to undergo salvage HD-CTX. Treatment consisted of three
detect CS I patients at risk of relapse, because even PET-negative cycles standard-dose chemotherapy (TIP) followed by one cycle
results do not conclusively rule out an increased risk of relapse. HD-CTX (thiotepa, etoposide, carboplatin) with subsequent autol-
ogous stem cell transplantation. 18F-FDG PET imaging was per-
formed before the start of induction standard-dose chemotherapy
FDG PET to Predict Treatment Outcome and again within 8 days prior to HD-CTX. Baseline 18FDG PET
A large international database analysis found that patients with prior to the start of chemotherapy was positive in all lesions eval-
relapsed germ cell cancer receiving salvage HD-CTX may achieve uated in this study. Results of the second PET scan were corre-
an improved outcome compared to standard-dose chemotherapy. lated to the histologic findings of the residual mass if a secondary
Treatment intensification, however, is potentially associated with resection after completion of chemotherapy was done. If no resec-
higher toxicities.70 Therefore, it would be helpful to identify both tion was performed, the clinical course of the patient over the next
responding and nonresponding patients at an early time point of 6 months was used for correlation. The clinical course of disease

Table 18.8 Other Nuclear Medicine Procedures

Early Prediction of HD-CTX Response By F-FDG PET 18 in Germ Cell Cancer
Versus Routine Staging Procedures
In the diagnosis and treatment of TGCTs, 18F-FDG PET is the only
18 nuclear medicine procedure evaluated in large clinical trials and
F-FDG PET CT/MRI Serum Tumor Markers
has earned a role in daily clinical practice. 18F-FLT PET failed to
Sensitivity 1 0.43 0.15 consistently correlate with proliferation or to significantly improve
Specificity 0.78 0.88 1 the results obtained with 18F-FDG PET.44,72–74
Positive predictive 0.88 0.86 1
value
Negative predictive 1 0.47 0.42
value Conclusion
18
Adapted from Bokemeyer C, Kollmannsberger C, Oechsle K, et al. Early prediction of treatment F-FDG PET has been evaluated in different diagnostic settings in
response to high-dose salvage chemotherapy in patients with relapsed germ cell cancer using patients with TGCTs but an enduring impact of 18F-FDG PET was
[(18)F]FDG PET. Br J Cancer. 2002;86:506–511. demonstrated in only a few indications.
18
F-FDG PET has no relevant impact for primary staging of
GCT and does not reliably detect CS I patients at risk of relapse.
after HD-CTX was correctly predicted by 18FDG PET imaging dur- The most relevant clinical role of 18F-FDG PET is to detect viable
ing chemotherapy in 21 of the 23 patients (91%). Interestingly, tumor in postchemotherapy residual tumor masses in patients
none of the patients with negative 18FDG PET after induction che- with pure seminoma. In patients with NSGCTs, a prospective trial
motherapy relapsed after HD-CTX. Of the patients who still had a with histologic confirmation demonstrated that 18F-FDG PET was
positive 18FDG PET prior to HD-CTX, 88% either relapsed within not useful to identify viable tumor in postchemotherapy residues.
6 months or the histology of the resected residual tumor mass Patients with multiple residual lesions may benefit from 18FDG
after HD-CTX still revealed viable GCT components. Overall, the PET scans for staging because a negative PET result accompanied
outcome of HD-CTX was correctly predicted by 18FDG PET, CT by necrosis or fibrosis in RPLND or single lesion histology may
scan, and tumor markers in 91%, 59%, and 48%, respectively.71 predict a low likelihood of relapse at other locations in a subgroup
Sensitivities and specificities to predict failure of HD-CTX are of NSGCT patients without a teratoma component in the primary
summarized in Table 18.8. 18F-FDG PET scans conducted early tumor.
18
in the course of salvage treatment may help to identify patients F-FDG PET has a relevant positive predictive impact in the
with an overall unfavorable outcome despite intensified treatment detection of recurrence in patients with rising serum tumor mark-
(Fig. 18.4).71 ers without tumor progression on CT scans but the negative pre-
Moreover, a more reliable evaluation of tumor response during dictive value is limited. Therefore, the use of 18F-FDG PET in this
the course of chemotherapeutic treatment and thus the sensitivity indication should be restricted to special questions on an indi-
to chemotherapy, for example, by the use of PET scanning, would vidual patient basis. Furthermore, 18F-FDG PET scans early in the
be of great value to detect subgroups of patients, who may be course of dose-intensified salvage chemotherapy in relapsed GCT
applied a decreased dosage of chemotherapy while maintaining patients identifies patients with worse prognosis. But, because
the excellent cure rate of GCTs. To elucidate this issue further pro- HD-CTX does not represent a standard approach, this cannot be
spective evaluation in clinical trials is necessary. recommended as a standard diagnostic procedure.
A B
Figure 18.4. PET of a 22-year-old male with “poor prognosis” nonseminomatous germ cell tumor showing a residual viable tumor after the first cycle of first-line
high-dose chemotherapy (cisplatin, etoposide, and ifosphamide regimen). The patient underwent additional surgery of the thoracic tumor manifestation followed by
two further cycles of high-dose chemotherapy and remained free of disease during follow-up until now. A: Whole body PET signaling showing a big, inhomoge-
neously PET-positive tumor of the mediastinum. B: PET/CT slices showing the inhomogeneously PET-positive NSGCT in detail.

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C h apt e r 1 9
Tumors of the Adrenal Glands

Shinji Yamamoto • Per Hellman • Anders Sundin
Introduction current high-resolution imaging techniques, mainly computed

tomography (CT), incidental findings of adrenal tumors, so-called
The adrenal glands are small but because of the hormones they incidentalomas, are common and are found in up to 1.8% to 7.1%
produce, they are essential for maintaining life. Located adjacent to of all abdominal and thoracic CT examinations that include the
the upper and medial aspects of both the right and left kidneys, they adrenals in the field of view.2 Radionuclide evaluation was intro-
weigh about 4 g and are composed of an outer, lipid-rich adrenal duced in 1970s to analyze the functional status of these tumors, as
cortex and an inner medulla. The cortex has three histologic layers: well as anatomic location and eventual metastases of malignant
Zona glomerulosa (ZG), zona fasciculate (ZF), and zona reticularis tumors. The past decade has seen rapid developments in radionu-
(ZR). Hormone production in the adrenal cortex is regulated by the clide imaging of adrenal tumors: Indeed, some of the tracers that
adrenocorticotropic hormone (ACTH) in the hypothalamic– have been previously described are now out of date and have been
pituitary–adrenal (HPA) axis, and the renin–angiotensin system replaced by new, potent, and effective tracers (Table 19.1).3 Techni-
(RAS) mainly through angiotensin II. The adrenal cortex produces cal innovations include better spatial resolution. Radionuclide
the steroid hormones aldosterone (in ZG), cortisol (in ZF), and the imaging has progressed from classic scintigraphic planar imaging
androgens (in ZR).1 The adrenal medulla is derived from the neuro- to single-photon emission computed tomography (SPECT) and
ectoderm and contains chromaffin cells and is therefore part of the positron-emission tomography (PET), leading to better image clar-
sympathetic nervous system. These cells produce catecholamines ity and more precise diagnosis. Moreover, the integration of ana-

(epinephrine and norepinephrine) and secrete them into the blood. tomic and radionuclide imaging is currently achieved using
Adrenal tumors arise from both the cortex and medulla. In many combinations with CT in hybrid systems, SPECT/CT and PET/CT
cases these tumors are functional and produce hormones that, in and recently, PET/magnetic resonance imaging (PET/MRI). Radio-
excess amounts, give rise to various symptoms. Some patients seek nuclide therapeutic modalities have also advanced and are now
medical attention for these symptoms, where hypertension is a used in many institutes worldwide.
common finding regardless of which hormone is in excess. With
Clinical Problems Associated

Table 19. 1 with Adrenal Imaging
Radionuclide Agents for Imaging of Adrenal gland imaging is associated with several problems related
Adrenal Tumors to the clinical questions. The adrenal glands are small and when
searching for functioning adrenal tumors, such as in the case of
Radionuclide Agent Uptake Mechanisms to the Tumors primary aldosteronisms (PAs) where a micronodular disease or a
small adenoma may be present, there is a risk that these tumors
Adrenocortical tumors — may be below the detection limits of conventional imaging methods
PET — such as CT or MRI.
11
C-Metomidate Adrenocortical steroid enzyme Nevertheless, the overall CT sensitivity to detect intra-adrenal
(11-β-hydroxylase) inhibitor. tumors >0.5 cm is 93% to 100%.4 However, patients who present
2-[18F] Fluoro-2-deoxy-D-glucose Glucose analog. Enhanced uptake via GLUT-1 with the clinical symptoms of adrenal disease are rare compared to
(18F-FDG) transporter. those who are diagnosed with an incidentaloma—an adrenal tumor
Scintigraphy — diagnosed when the patient has undergone radiologic imaging,
123
I-Metomidate usually CT, for reasons other than the suspicion of adrenal disease.
Adrenal medullary tumors — The incidence of incidentalomas increases with age. A multicenter
PET — study in south-western Sweden, comprising 3,801 randomly selected
2-[18F] Fluoro-2-deoxy-D-glucose — CT examinations, showed 4.5% mean frequency of adrenal inciden-
(18F-FDG) taloma (range: 1.8% to 7.1% between centers).2 These tumors are
18
F-Fluorodihydroxyphenylalanine Precursor of endogenous catecholamines. almost always benign when there is no cancer history and, con-
(18F-DOPA) Uptake via the large amino acid transporter
versely, malignant in up to about half of cancer patients,5,6 although
(LAT) system.
11
C-Hydroxy-ephedrine Norepinephrine analog. Uptake in catecholamine- this high proportion has recently been questioned.
producing cells via the plasma membrane
norepinephrine transporter (NET) and
the intracellular vesicular monoamine Characterization of Adrenal
transporter (VMAT).
18
F-6-[18F]-Fluorodopamine Dopamine analog. Uptake via the plasma Incidentalomas
(18F-FDA) membrane NET and the intracellular VMAT.
11
C-Epinephrine Radiolabeled epinephrine. Binds to epineph- The work up of the incidentaloma patient should aim at excluding
rine receptors on cell membranes. hormonal overproduction and malignancy. The biochemical work-
Scintigraphy — up is usually performed by an endocrinologist, whereas a radiolo-
123/131
I-Metaiodobenzylguanidine Guanethidine and noradrenaline analog. gist needs to characterize the adrenal mass according to predefined
(MIBG) Uptake via the plasma membrane NET criteria. Before starting to characterize an incidentaloma, the
and the intracellular VMAT.
111 patient’s previous imaging studies should be requested and
In-DTPA-Pentetreotid, Somatostatin analogs. Bind to somatostatin
68
Ga-DOTA-TOC, 68Ga-DOTA- receptors on the cell membrane.
reviewed. Frequently, the incidentaloma may be found in a previ-
NOC, 68Ga-DOTA-TATE ous CT or MRI that includes the adrenal region, although it may not
have been reported. According to the Swedish National Guidelines,
251

and delayed (D) phases 15 minutes after injection. The “absolute

wash-out” is calculated according to the formula (E – D)/(E – U)
where in daily clinical practice, the cut-off 0.6 is applied. A wash-out
>0.6 indicates a benign lesion and <0.6 indicates that the tumor
may be malignant.
The imaging work up and follow-up for most incidentalomas is
adequately managed by CT and MRI. Further characterization is
needed for a minority of these tumors and several molecular
imaging techniques are available for these patients.
According to the Swedish National Guidelines, adrenal inciden-
talomas characterized as benign adrenocortical adenomas by
their benign morphologic appearance and shown to contain cyto-
plasmic fat by a CT attenuation ≤10 HU or measuring less than 3
to 4 cm in transaxial diameter generally require no further imag-
ing or radiologic follow-up. However, the relevant routines vary in
different countries. In order not to misdiagnose a simple cyst
(attenuation approximately 0–15 HU) as a benign adrenocortical
adenoma, it should, however, be confirmed that the lesion is con-
trast enhancing. Similarly, there is generally no need for further
imaging in some larger lesions >4 cm that are apparently benign,
for example, in a myelolipoma or a cyst. The significance of con-
Figure 19.1. Transverse intravenously contrast-enhanced CT image showing a myelolipoma trast medium wash-out varies between centers. According to the
in the right adrenal gland. The tumor is predominately fat attenuating (–100 HU) and containing current Swedish Guidelines, lesions with >10 HU precontrast
small higher attenuating areas and is somewhat dislocating–compressing the liver. The finding
of macroscopic fat within the tumor is typical for a benign myelolipoma.
attenuation with a benign appearance based on contrast medium
wash-out (>0.6) are nevertheless subjected to follow-up imaging
in 1 year.
incidentalomas that have remained unchanged in size and internal

structure for a year may be disregarded. Seen during morphologic
imaging, generally CT, a benign adrenal lesion is typically small
Diagnosis, Staging, and Follow-Up
with a rounded to oval shape. The internal structure in a benign of Adrenocortical Carcinoma
incidentaloma is homogeneous, well defined and sharply delineated
from the surrounding retroperitoneal fat. Malignant masses are Patients with adrenocortical carcinoma (ACC) usually present when
often larger with a heterogeneous internal structure. They may be the tumor is large. They can already be at a locally advanced stage
lobulated and diffusely delineated and are sometimes seen to and may have metastasized.17 Approximately 50% of the tumors
invade adjacent organs and tissues. An area of macroscopic fat is are functioning18 but hormonal symptoms and signs such as amen-
typical of a benign myelolipoma (Fig. 19.1). In this instance, varia- orrhea and virilization, or Cushingoid habitus and skin changes,
tions are large and this area of macroscopic fat may either be may initially be overlooked by both the patient and the physician.
restricted to a very small region or comprise almost the whole of By the time the CT is performed, the tumor is generally round to
the tumor. oval, frequently lobulated and fairly often calcifications are found.
Attenuation measurement in nonenhanced (native) CT exami- Loss of a fat plane between the tumor and surrounding tissues sug-
nations is important in assisting the characterization of adrenal gests invasion, most often to the kidney and liver. A tumor throm-
incidentalomas. A region of interest (ROI) positioned in the fatty bus extending into the inferior vena cava is not an infrequent
part of the myelolipoma will typically show –100 Hounsfield units finding. Metastases are most often found in lymph nodes, liver,
(HUs). On the other hand, the most frequent incidentaloma, the lungs, and bones.19 Staging of ACC is shown in the American Joint
adrenocortical adenoma is composed of cytoplasmatic fat. This will Committee on Cancer manual.20 The decision regarding surgical
decrease the attenuation, if the lesion measures ≤10 HU it can be versus nonsurgical management of patients with a nonfunctioning
considered to be a benign adrenocortical adenoma with 71% sen- incidentaloma was previously governed primarily by its size. All
sitivity and 98% specificity.7 The attenuation should be measured lesions larger than approximately 4 cm were removed because of
in a large ROI (diameter 2/3–3/4 of the tumor) but avoiding partial the risk of a malignant tumor. Today, this decision is increasingly
volume effects from the surrounding retroperitoneal fat. A recent influenced by the imaging characterization of the incidentaloma as
study confirms this almost maximum specificity for attenuation mentioned above.
measurements in the precontrast CT examination and reports 65% Before a biopsy of an adrenal tumor is performed, pheochro-
sensitivity and 99% specificity.8 The sensitivity to detect cytoplas- mocytoma needs to be ruled out biochemically. A localized ACC is
matic fat is comparably high with MRI using in- and out-of-phase generally not biopsied because of the risk of tumor cell seeding.
sequences.9,10 Therefore imaging characterization is important and PET/CT
Some of the adrenal incidentalomas measuring >10 HU may with 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) or 11C-metomidate
be confirmed as benign lesions by characterizing their wash-out may be used for this characterization and to stage the disease.
of IV contrast media at CT performed before (precontrast) and When an adrenal metastasis is suspected, core needle biopsy or
after IV contrast enhancement in the venous phase and after 10 to fine needle aspiration cytology may be a more appropriate diag-
15 minutes.11–16 Malignant tumors are generally hypovascular and, nostic procedure than further imaging. A patient with a single
compared to normal tissues, they have a larger interstitial space in metastasis in the adrenal may be operated on but 18F-FDG PET/
which high pressure impedes the contrast enhancement and delays CT can help to confirm that there are no additional lesions.
the contrast medium wash-out. By contrast, benign lesions are gen- If the ACC is hormonally active, the clinical and biochemical
erally well vascularized; they contrast enhance rapidly and have a follow-up is significant for detecting recurrent disease after surgical
fast contrast medium wash-out. To calculate the contrast medium intervention and to monitor medical therapy. Conventional radio-
wash-out, the attenuation of the incidentaloma is measured (ROI) in logic imaging, mainly CT or MRI, is also performed periodically.
the precontrast (unenhanced, U), contrast-enhanced (enhanced, E) Functional imaging by PET/CT with 18F-FDG or 11C-metomidate is

Chapter 19 Tumors of the Adrenal Glands 253
valuable, especially when radiologic imaging is inconclusive. In the Tab l e 1 9 . 2

case of nonfunctioning ACC, no biochemical parameter can be used
and CT and MRI are the primary methods for follow-up after treat- Adrenal Neoplasms
ment. In these patients, 18F-FDG PET/CT or 11C-metomidate PET/CT
are probably even more helpful for the detection of recurrent Neoplasms in adrenal cortex
disease. Hyperplasia (unilateral/bilateral)
Adrenocortical adenoma (unilateral/bilateral, functional/nonfunctional)
Aldosteronoma, Cushing adenoma, androgen-secreting adenoma
Diagnosis, Staging, and Follow-Up Adrenocortical cancer (unilateral/bilateral, functional/nonfunctional)
Metastatic adrenocortical cancer (unilateral/bilateral)
of Pheochromocytoma Neoplasms in adrenal medulla
Hyperplasia (unilateral/bilateral)
The diagnosis of pheochromocytoma is usually biochemical Pheochromocytoma/paraganglioma (unilateral/bilateral, benign/malignant)
(increased normetanephrine, metanephrine, epinephrine, or nor- Neuroblastic tumors (unilateral/bilateral)
epinephrine in plasma or urine) in patients with sympathomimetic Neuroblastoma, ganglioblastoma, ganglioneuroma
symptoms such as palpitations, sweating, headache, and hyperten- Other adrenal neoplasms
sion. In hereditary syndromes, mainly multiple endocrine neoplasia Metastatic tumors
type 2 (MEN2) or von Hippel–Lindau (VHL), but also neurofibroma- Lymphoma
tosis type 1 (NF1) or the syndromes associated with paraganglio- Hemangioma
mas (with mutations in SDHD, SHDB, or SDHC), biochemical or Lipoma
functional imaging may indicate the development of pheochromo- Myelolipoma
cytoma. Morphologic imaging (CT and MRI) shows the tumor to be Angiomyolipoma
Sarcoma
rounded, sometimes with calcifications and with varying internal
Angiosarcoma

structure (homogeneous to heterogeneous). Necrosis and cystic Leiomyosarcoma
changes may be found centrally. Pheochromocytomas are generally Myofibrosarcoma
hypervascular and therefore, well contrast-enhancing lesions. Adrenal cyst
Radionuclide imaging of these tumors consists of methyl- Cystic hamartoma
iodobenzylguanidine scintigraphy, somatostatin receptor (SR) imag- Tuberculoma
ing, and PET/CT using 18F-FDG and more specialized tracers such
as 18F-dihydroxyphenylalanine (18F-DOPA), 11C-hydroxy-ephedrine,
and 18F-6-[18F]-fluorodopamine (18F-FDA).
Malignant pheochromocytoma is diagnosed by the presence of Tumors in the Adrenal Cortex
metastasis (in liver, lungs, bones, brain, lymph nodes, etc.), signs The tumors that may arise in the adrenal cortex are listed in
of invasive primary tumor, or recurrence after surgical resection. Table 19.2. Benign adrenocortical adenomas are divided into func-
Detection of recurrent tumor is performed by monitoring of symp- tional adenomas (hormone-producing adenomas) and nonfunctional
toms, biochemical parameters, and follow-up with morphologic adenomas. Functional adenomas include aldosterone-producing
and radionuclide imaging. adenomas (APAs), or adenomas secreting cortisol giving rise to Cush-
ing syndrome. Very rarely, occasional androgen-producing adeno-
mas have been described.
Indication for Radionuclide Imaging
of Adrenal Glands Primary Aldosteronism
CT and MRI are the gold standards for morphologic imaging of adre- PA is caused by (1) APA, (2) aldosterone-producing carcinoma (APC),
nal tumors. Functional evaluation by radionuclide imaging is added (3) bilateral idiopathic hyperaldosteronism (IHA), and (4) unilateral
in some cases. Indications for radionuclide imaging are as follows: adrenal hyperplasia (UAH), or familial aldosteronism types I to III.
(1) Biochemically and radiologically suspected adrenal tumors, According to the Clinical Guidelines Subcommittee (CGS) of The
where CT/MRI is inconclusive, (2) incidentalomas with/without bio- Endocrine Society, iodocholesterol scintigraphy (NP-59) is not rec-
chemical parameters, not characterized as benign tumors by CT/ ommended for the diagnosis of PA. The method has low sensitivity
MRI, (3) patients with hereditary diseases which are known to cause and has generally been abandoned. Diagnosis and evaluation of
pheochromocytomas, (4) follow-up after surgery/medical therapy of adrenal hypersecretion of aldosterone is laborious and suffers
adrenal malignant tumor. from low sensitivity. Adrenal venous sampling and subsequent hor-
monal analysis is currently the standard procedure for lateraliza-
tion, but this is a difficult procedure, especially sampling from the
right adrenal gland. The results are very operator dependent. Addi-
Indication for Radionuclide Therapy tional methods to guide the clinician in this setting are needed but
for Adrenal Gland Diseases are currently unavailable. Other tests such as the posture stimu-
lation test, NaCl infusion and the florinef test are all generally
The first option for the management of adrenal tumors is surgical unsatisfactory. Recently, 11C-metomidate PET/CT has been used,
intervention. The indications for radionuclide therapy in adrenal after suppression of the ACTH axis by pretreatment with dexa-
disease are as follows: (1) Nonresectable adrenal tumors, which methasone. This procedure has been found to visualize APAs with
include invasive tumors with or without metastases, (2) multiple higher tracer uptake (standardized uptake values, SUV) than to
11
recurrences or metastases of malignant adrenal tumors previ- C-metomidate PET/CT without cortisone pretreatment.21,22
ously treated surgically, with chemotherapy or radiologically by
locally ablative procedures (e.g., intra-arterial embolization/
chemo-embolization, radiofrequency ablation). In all cases, the
Cushing Syndrome
type of tumor should be confirmed, thus indicating which type of Cushing syndrome is caused by excessive circulation of glucocorti-
therapy is needed. No prophylactic or adjuvant radionuclide ther- coids, giving rise to a classical range of signs and symptoms. Diag-
apy is currently used in cases of R0 resections. nosis is easier than for PA and is made by 24-hour urinary cortisol

measurements or by performing a dexamethasone suppression one metastasis, one mesenchymal tumor, and two cysts) showed
test. The most common etiology is Cushing disease, caused by pituitary low or no uptake.29 Physiologic accumulation of 11C-metomidate is
hypersecretion of ACTH, generally by a pituitary micro-adenoma, generally seen in normal adrenals and in gastric juice into which
which causes bilateral adrenocortical hyperplasia. Adrenal scintigra- the tracer and/or its metabolites were transported. From time to
phy with 131I-norcholesterol (NP-59) was previously used to image time, patients display high radioactivity concentrations in the gall
hyperplasia. Functioning ACC causes the Cushing syndrome. The bladder. The uptake in the liver is intermediate and may some-
tumor, as well as eventual metastases, can be identified with times interfere with the depiction of adrenocortical tumors in the
11
C-metomidate PET/CT or with 18F-FDG with slightly lower sensitivity. right adrenal. A comparative study on 11C-metomidate PET and
CT of adrenocortical cancer, consisting of 13 examinations in
11 patients, visualized all viable tumors with a high tracer uptake.
Radionuclide Imaging of Two lesions that were missed by CT were adequate.30 It is interest-
ing to note that three completely necrotic adrenocortical cancer
Adrenocortical Tumors lesions were false negative at 11C-metomidate PET; that the tracer
uptake in the ACC lesions showed a high uptake with the peak
131
I-norcholesterol (NP-59) and SUV ranging from 5 to 32, and that treatment with adrenal steroid
6b-[75Se]-Selenomethyl-1 g-Norcholesterol inhibitors and chemotherapy was found to decrease the tracer
(Scintadren Scintigraphy) accumulation in the tumors. An example of 11C-metomidate PET/
CT in ACC is shown in Figure 19.2.
Iodocholesterol scintigraphy with 131I-19-iodocholesterol and an In a comparison of 11C-metomidate and 18F-FDG, 21 patients
improved agent, NP-59, was introduced in 1970s. These tracers underwent PET with both tracers. 11C-metomidate uptake was
had been used for scintigraphy including SPECT mainly to preop- highest in the ACCs, followed by the functioning adenomas and
eratively localize APAs (Conn adenomas) in PA.3,23 Drawbacks of nonfunctional adenomas, and was lowest in the noncortical
the technique were the limited spatial resolution of planar imaging tumors.31,32 18F-FDG PET detected two out of the three malignant
and SPECT, making small tumors difficult to visualize, and a high adrenal lesions; the nonmalignant adrenal lesions were negative.
radiation dose to the patient (30 mSv or even more). NP-59 is no Another comparative study based on 16 patients who had PET
longer available either in the United States or in most European imaging with 11C-metomidate and 18F-FDG (1 adrenal metastasis,
countries because the production of the tracer was terminated. one adrenocortical cancer, one malignant pheochromocytoma, ten
In the past, scintigraphy with 6β-[75Se]-selenomethyl-1 g- adenomas, one hyperplasia, two benign pheochromocytomas). As
norcholesterol (Scintadren) was also utilized to image the adrenal with previously published results, 11C-metomidate PET differenti-
cortex and adrenal cortex–derived tumors,3 but used less often for ated the adrenocortical from nonadrenocortical tumors and also
the diagnosis of APAs caused by slow accumulation in the adrenals 18
F-FDG PET differentiated the malignant from the benign tumors.
requiring a long-lived radionuclide (t1/2 120 days). Scintadren is An interesting finding was that the 11C-metomidate uptake in the
also no longer in use in the United States or most other countries. contralateral normal adrenal was not suppressed in patients with
The discovery of an adrenal tumor during morphologic imag- Conn tumors whereas this was the case in those with Cushing
ing does not by itself suffice for preoperative localization because syndrome when a subgroup of nine patients with functioning adre-
occasionally the patient’s radiologically evident tumor can be non- nocortical tumors was considered.
secreting and a very small Conn adenoma may instead be har- A strict correlation of the histopathologic diagnosis and findings
bored in the contralateral adrenal. Thus, currently, hypertensive from 11C-metomidate PET was performed in 73 patients with 75
patients with a biochemical diagnosis of PA undergo lateralization adrenal tumors (26 adenomas, 13 adrenocortical cancers, 8 hyper-
of the Conn adenoma by selective venous sampling instead. plasia, 6 pheochromocytomas, 3 metastases, and 19 tumors of non-
adrenal origin).33 The study also included small adrenal tumors (size
11 range: 1 to 20 cm). Because of this, the sensitivity to distinguish the
C-Metomidate-PET and PET/CT and
123 adrenocortical from the nonadrenocortical lesions, compared with
I-Metomidate Scintigraphy previous studies, decreased to 89% because of false-negative obser-
Metomidate is the methyl ester of etomidate that has been used as vations in three ≤1 cm tumors. Because of a false-positive finding in
an anesthetic agent.24,25 Etomidate, the ethyl ester, and metomidate one patient, specificity was 96%. PET measurements of the tracer
are both powerful inhibitors of the two CYP11B enzymes 11β- uptake (SUV) could not distinguish benign from malignant adreno-
hydroxylase (CYP11B1, P45011β) and aldosterone synthase cortical tumors.
(CYP11B2, P450aldo) that are involved in cortisol and aldosterone The role of 11C-metomidate PET was investigated in a clinical
synthesis, respectively. Metomidate and etomidate have been setting to characterize 44 adrenal incidentalomas in 38 patients
labeled with 11C and 18F as PET tracers26,27 and metomidate has as compared to CT and MRI.22 11C-metomidate PET was found to
been labeled with 123I for scintigraphy28 and 131I for purposes of be best used as a problem-solving tool for the few patients in
therapy because of their specific adrenocortical binding properties. whom CT and MRI failed to characterize the tumor.
There are numerous studies published on the metomidate-based In two studies on patients with PA, 11C-metomidate PET was
imaging of adrenocortical tumors. Generally, these have shown that performed before and after premedication with oral dexametha-
the sensitivity and specificity to diagnose adrenocortical tumors is sone. The aim was to visualize small Conn adenomas.34,35 The
high but measurements of tracer uptake cannot be applied to dif- hypothesis was that corticoid treatment decreases ACTH secretion
ferentiate benign from malignant lesions. and thereby the 11β-hydroxylase concentrations in normal adrenal
The binding of 11C-metomidate and 11C-etomidate was initially parenchyma but not in Conn adenomas, and consequently increases
shown to be high and specific in adrenal cortical tissue from dif- the tumor to normal tissue contrast. In the first study on nine
ferent species by using frozen section autoradiography.27 Because patients with Conn adenomas and, for purposes of comparison, two
of its better radiochemical characteristics, 11C-metomidate was subjects with nonfunctioning lesions, the small (average: 1.7 cm;
chosen for PET in vivo and the adrenals were successfully imaged range: 1 to 2.5 cm) tumors were all visualized by 11C-metomidate
in primates. In the initial clinical study,29 of 15 patients with uni- PET in all examinations but with similar visibility and tumor to
lateral adrenal tumors, 11C-metomidate PET correctly identified normal adrenal ratios in examinations performed before and after
those of adrenocortical origin (six adenomas, one hyperplasia, two corticoid pretreatment.
adrenocortical cancers) with a high tracer uptake, whereas the [123I]-iodometomidate has recently been developed as a SPECT
noncortical lesions (one myelolipoma, one pheochromocytoma, tracer29 and has the potential advantage of much better availability


A
Figure 19.2. 11C-metomidate-PET/CT exami-

nation (transverse images) of a patient with an
adrenocortical carcinoma on the left side (A) and
regional para-aortic lymph node metastases (B). In
each panel (A and B) the noncontrast enhanced
CT is displayed upper left, the PET upper right,
the PET/CT fusion lower left and the maximum
intensity projection (MIP) of the PET volume on the
lower right. The primary tumor (A) displays a
high tracer uptake except for the ventral–lateral
part, which is probably necrotic. 11C-metomidate
is also found in the gastric juice and the radioac-
tivity in the stomach is clearly seen in the MIP
(lower right). Two regional lymph node metasta-
ses (B) are found on the left side of the aorta and
the physiologic radioactivity in the gastric juice is B
clearly seen.

than 11C-metomidate-based PET imaging. Preclinical and clinical eval- Tumors in the Adrenal Medulla
uation demonstrated high and specific uptake of [123I]-iodometomidate
in normal adrenals, in adrenocortical tumors and in ACC metasta- The tumors that may arise in the adrenal medulla are listed in
ses. Interestingly, the tracer uptake in the liver is relatively lower Table 19.2. All of these tumors are rare but patients who have
for [123I]-iodometomidate than for 11C-metomidate, potentially facili- specific hereditary diseases are particularly at risk.
tating visualization of right-sided adrenal tumors. Clinical tumor
imaging can be achieved 4 to 6 hours after [123I]-iodometomidate Pheochromocytoma/Paraganglioma
injection but the highest target-to-background ratios were reached Pheochromocytoma is derived from adrenalin-producing chromaf-
after 24 hours and the effective dose is a mere 3 to 4 mSv. Like fin cells in the adrenal medulla. Paraganglioma is a rare tumor orig-
11
C-metomidate PET, [123I]-iodometomidate SPECT is unlikely to dif- inally derived from extra-adrenal neural crest cells, the paraganglia,
ferentiate benign from malignant adrenocortical lesions. On the one regardless of its location. Pheochromocytoma/paraganglioma is
hand, SPECT imaging has lower spatial resolution than PET, which characterized by excess catecholamine secretion and sympathomi-
may be a disadvantage for the visualization of small adrenal lesions. metic symptoms. Patients with hereditary syndromes such as MEN2
On the other hand, the longer half-life of 123I-iodine may result in a (genetic mutations of the RET gene), VHL, NF1, or mutations in either
better lesion-to-background ratio than with 11C-metomidate PET. No the succinyl dehydrogenase subunits B (SDHB), SDHC, and SDHD, or
comparative study on [123I]-iodometomidate SPECT and 11C-metomi- susceptibility genes such as SDHA, MAX, TMEM127, SDHAF2,
date PET has been published to date. EGLN1/PHD2, and KIF1Bβ are all at risk of developing pheochromo-
cytoma or paraganglioma.4,42–44 Twenty percent to 30% of pheochro-
18
F-Fluorodeoxyglucose PET and PET/CT mocytomas and paragangliomas are associated with these hereditary
syndromes.45 In MEN2, approximately 50% of patients develop
PET/CT with 18F-FDG is routinely used in general oncologic imag-
pheochromocytoma following the occurrence of medullary thyroid
ing for tumor staging, diagnosis of recurrent disease, therapy
cancer, which has higher penetration than pheochromocytomas.46
monitoring, detection of occult tumors, and to differentiate malig-
Pheochromocytomas with MEN2 are usually found in the adrenal
nant from benign lesions. It may also be used for ACC.
glands. They tend to be benign; more than 50% of patients have
In a study of 28 patients with ACC, the results of 18F-FDG PET/
bilateral adrenal tumors.47 Tumors derived from chromaffin cells
CT were correlated to those of contrast-enhanced CT that was per-
express the membrane norepinephrine transporter (NET), which
formed separately because the CT in conjunction with PET was
can be the target of specific radiolabeled ligands.48 These ligands
carried out with a reduced radiation dose and used merely for
have characteristics that allow them to enter sympathomedullary
attenuation correction.36 18F-FDG PET/CT showed a 90% and 93%,
tissue through the NET system and to be marginally metabolized.
lesion-based sensitivity and specificity, respectively, and the cor-
Another means of functionally imaging these tumors is through
responding figures for CT were 88% and 82%. The two methods
receptor-mediated pathways, for example, the SRs, using 111In-
were complementary and 12% of the lesions were diagnosed only
Pentetreotide (Octreoscan). However, metastatic pheochromocyto-
by 18F-FDG PET/CT and 10% only by CT. In a patient-based analy-
mas can become dedifferentiated and lose both the NET system
sis, the methods were concordant in 25/28 patients (89%) and
and/or SRs.49–51 Excess glucose uptake, mainly via GLUT-1 receptor
showed 95% sensitivity, whereas the specificity was 83% for 18F-
is seen in various hypermetabolic tumors including pheochromo-
FDG PET/CT and 100% for CT. In a smaller study of 12 patients
cytoma; hence the glucose analog 18F-FDG can be used for func-
who underwent 18F-FDG PET to assess recurrent or metastatic
tional imaging of the tumor.52
adrenocortical cancer, the sensitivity was 83%.37
Neuroblastic Tumors
Radionuclide Therapy of The fetal adrenal cortex is penetrated by sympathogonia of neural
Adrenocortical Carcinoma crest origin that develop into the adrenal medulla. The sympatho-
gonia differentiate into chromaffin cells and ganglion cells in the
Advanced ACC has a poor prognosis. The median survival at the adrenal medulla. Neuroblastic tumors arise from primitive neural
time of diagnosis of stage IV ACC is less than 12 months.38 Even crest cells of the sympathetic nervous system from the neck, pos-
with cytotoxic chemotherapy, objective regression occurs in up to terior mediastinum, adrenal gland, retroperitoneum, and pelvis.53
25% of patients.39 Beneficial effects of radiotherapy were observed Neuroblastic tumors can be divided into three types that will be
in some reports; the consensus conference on the management of described below. Neuroblastoma is an aggressive and rare type of
ACC treatment judged radiotherapy in ACC to be effective.18 The cancer of the sympathetic nervous system that mainly occurs in
disease is very rare and thus the results of radionuclide treatment infants and very young children. The median age at diagnosis is
for ACC have only been reported by one center to date. 15 months.54 In most patients the tumor arises from neuroblasts in
the adrenal glands but tumors may also develop in other nerve
131 tissues ranging from the neck to the pelvis.53 The majority (98%)
I-Metomidate Therapy are sporadic, but familial neuroblastomas are reported.55 Progno-
Because some adrenocortical cancer lesions exhibit very high and sis depends on the age at diagnosis, and patients diagnosed before
specific uptake of [123I]-iodometomidate, the potential to treat ACC the age of 18 months are regarded as having a good prognosis.56
patients with [131I]-iodometomidate has been investigated.29,40,41 v-myc avian myelocytomatosis viral oncogene neuroblastoma
The tracer bound to adrenocortical cytochrome P450 family 11B derived homolog (MYCN) gene amplification is associated with a
enzymes and was rapidly metabolized within a few minutes, mainly worse prognosis.57 The revised versions of the International Neu-
by hepatic esterases. Whole-body elimination of [131I]-iodometomidate roblastoma Staging System and International Neuroblastoma Risk
showed a half-life of 20 hours.29,40 The clinical experiences of 11 Group Staging System are used for disease staging.56–58 Ganglio-
patients with advanced nonresectable ACC were reported.41 The neuroblastoma is very rare, of intermediate aggressiveness, and
patients received up to 20 GBq [131I]-iodometomidate. It was pos- arises from neural crest sympathogonia found commonly in the pos-
sible to achieve stable disease in five patients and even partial terior mediastinum, retroperitoneum, adrenal medulla, and neck.53
response in one patient, with ongoing disease stabilization and Ganglioneuroblastoma occurs in older children but might also
a median progression-free survival of 14 months (range: 5 to 33 occur in adults.59 The revised version of the International Neuro-
months). The treatment was well tolerated in all patients and the blastoma Pathology Classification defines prognostic subsets of
main side effects were transient thrombocytopenia and leucopenia. ganglioneuroblastoma.60 Ganglioneuroblastoma is composed of

well-differentiated elements such as ganglion cells, Schwann cells, acquisitions using SPECT, the spatial resolution is low (∼1.5 cm)
and nerve fibers, with primitive neuroblasts. This tumor is less and the detection of small lesions may therefore be difficult.
aggressive than neuroblastoma.59 Ganglioneuroma in the adrenal Recently, there have been reports on the additional value of fusion
glands is a very rare tumor and arises from ganglion cells, is well imaging by radiolabeled MIBG SPECT/CT and SPECT/MRI88 and to
differentiated, and has a benign character.53 Ganglioneuromas detect pheochromocytoma and neuroblastoma.89–91 The particular
occur in older children. Elevated urine homovanillic acid (HMA) strengths of radiolabeled MIBG SPECT/CT were the detection of
and vanillylmandelic acid (VMA) are used for the diagnosis. For local recurrences, small extra adrenal pheochromocytomas, mul-
the diagnosis, imaging by CT, MRI, and MIBG scintigraphy are per- tifocal tumors, or the presence of metastatic disease.
formed, as well as a biopsy. Functional imaging with radiolabeled When MIBG is negative in patients in whom an adrenomedul-
ligands for pheochromocytomas/paragangliomas other than MIBG lary tumor is suspected, PET/CT with specific tracers such as 18F-6-
may also be utilized. However, functional imaging studies cannot [18F]-fluorodopamine (18F-FDA), 18F-fluorodihydroxyphenylalanine
differentiate these three types of neuroblastic tumors; pathologic (18F-DOPA), or 11C-hydroxyephedrine can be utilized. When PET
evaluation is needed to establish the definitive diagnosis. with one of these tracers is negative, the tumor may have lost the
type I uptake transporter and have transferred to become malig-
nant. In these cases, 18F-FDG PET/CT or somatostatin receptor
Radionuclide Imaging of Adrenal scintigraphy (SRS) may be positive.92,93
Medullary Tumors
Somatostatin Receptor Imaging
Table 19.3 shows the sensitivity and specificity of radionuclide
imaging methods for the detection of adrenal medullary tumors. SRS with 111In-DTPA-Pentetreotid (Octreoscan) is the standard
radionuclide imaging method for patients with neuroendocrine
tumors.94–96 Pheochromocytomas mainly express the somatostatin
Metaiodobenzylguanidine Imaging receptor (SR), subtypes 2, 3, and 5. SRS has shown 89% sensitivity

Metaiodobenzylguanidine (MIBG) is a guanetidine derivative and by patient-based analysis and 69% by region-based analysis for
structural and functional analogs of norepinephrine. It enters the localizing malignant tumors or metastatic pheochromocytomas/
cell by the uptake-1 NET and/or by passive diffusion and selec- paragangliomas.67 However, only 25% to 38% of the primary
tively accumulates in the noradrenergic neurosecretory granules benign pheochromocytomas are positive at SRS with lesion/
of chromaffin tissue.61,84 Some pharmaceuticals, however, may region-based analysis.50,67 Currently 68Ga-DOTA-Tyr3-octreotide
interact with MIBG by blocking the uptake or depletion of storage (68Ga-DOTA-TOC), 68Ga-DOTA-Tyr3-octreotate (68Ga-DOTA-TATE),
vesicle contents.85 Such pharmaceuticals include antihypertensive and 68Ga-DOTA-1-NaI3-octreotide (68Ga-DOTA-NOC) are becoming
drugs (Labetalol, Reserpine, Nifedipine), tricyclic antidepressants, available for SR imaging by PET/CT and have provided high sen-
sympathomimetics and cocaine. This interaction may produce sitivity and specificity in the detection of pheochromocytomas and
false-negative results. These drugs should be discontinued prior to paragangliomas.62,78,79,97
evaluation. Free iodine accumulates in the thyroid gland and may
cause thyroiditis and thyroid dysfunction. The thyroid iodine 2-[18F] Fluoro-2-Deoxy-D-Glucose (18F-FDG)
uptake is saturated with potassium iodine used prior to perform-
ing MIBG scintigraphy. Scintigraphy with 123I-MIBG and 131I-MIBG
PET/CT Imaging
18
is used to visualize pheochromocytomas and other sympathomed- F-FDG reflects excessive glucose uptake mainly via GLUT-1 in
ullary neoplasms such as neuroblastoma, and has long been various hypermetabolic tumors.98 This uptake of 18F-FDG is nonspe-
regarded as the gold standard radionuclide imaging method to cific and 18F-FDG PET/CT is regarded as the second-line method for
detect these tumors (Fig. 19.3).86 For 131I-MIBG the sensitivity to detecting pheochromocytoma/paraganglioma (Fig. 19.4), although
detect pheochromocytomas is 77% to 90% and the specificity 95% the method has high sensitivity for metastatic tumors.99,100 In the
to 100%.50,61–67 123I-MIBG is better than 131I-MIBG with superior past, the specificity for 18F-FDG PET in non–18F-FDG metastatic
detection efficiency and a lower radiation exposure for the pheochromocytomas has been reported to be low.100 However,
patient.87 It has a sensitivity of 83% to 100% and specificity of 95% according to a recent study, the sensitivity of 18F-FDG PET is similar
to 100%.50,61,64,65,67,72–77 123I-MIBG SPECT can be performed for the to that of 123I-MIBG SPECT/CT in benign pheochromocytoma/
evaluation of these tumors. However, even with three-dimensional paraganglioma.71 For nonmetastatic tumors, the lesion-based
Table 19. 3
Sensitivity and Specificity of Radionuclide Imaging Methods for Detection of Adrenal Medullary Tumors
Sensitivity Patient- Specificity Patient- Sensitivity Lesion- Specificity Lesion-

Radionuclide Agent Based Analysis (%) Based Analysis (%) Based Analysis (%) Based Analysis (%) Referencesa
131
I-Metaiodobenzylguanidine (MIBG) 77–90 95–100 64 86 50,61–67
123
I-Metaiodobenzylguanidine (MIBG) 83–100 95–100 52–93 91–100 50,61,64,65,67–77
111
In-DTPA-Pentetreotid 29 — 25–38 — 50,67
68
Ga-DOTA-TOC 100 — 92 — 78
68
Ga-DOTA-NOC 100 86 100 86 62
68
Ga-DOTA-TATE 80 — — — 79
2-[18F] Fluoro-2-deoxy-D-glucose (18F-FDG) 58–95 100 58–88 90 52,69,71
18
F-Fluorodihydroxyphenylalanine (18F-DOPA) 85–100 88–100 81–98 100 69,74,76,77,80
11
C-Hydroxy-ephedrine 90–91 100 99 100 75,81,82
18
F-6-[18F]-Fluorodopamine (18F-FDA) 75–100 — 78–100 77 69,70,83
a
Data for nonmetastatic pheochromocytoma/paraganglioma. Some studies include both nonmetastatic and metastatic diseases and small numbers of other adrenal medullary tumors. Lesion-based
analysis include also region-based data.

Figure 19.3. 123I-MIBG scintigraphy in a patient with pheochromocytoma on the right side seen in planar images (A) frontal view (left) and posterior view
(right) and SPECT/CT (coronal reformatted images) (B).
sensitivity of 18F-FDG PET/CT and 123I-MIBG was 77% and 75%, to 18F-dopamine, which is stored in intracellular vesicles.101 18F-DOPA
respectively, and the corresponding specificity was 90% and 92%. can be used for PET imaging of benign pheochromocytomas and
For metastatic tumors, the region-based sensitivity of 18F-FDG PET/ glomus tumors.74,102 The advantage of 18F-DOPA is the lack of uptake
CT was 83%, and 50% for 123I-MIBG SPECT/CT.71 SDHB-related in the normal adrenal glands and every uptake in the anatomical
metastases were more accurately detected by 18F-FDG PET/CT than compartment of the adrenal gland could therefore be classified as
by 123I-MIBG SPECT.69 The authors emphasized that SDH- and VHL- pathologic.74 18F-DOPA had high sensitivity for both primary tumors
related tumors were all detected by 18F-FDG PET whereas 60% of and metastases.69,74,76,77,80 However, subgroup analysis showed
MEN2-related pheochromocytomas were 18F-FDG PET negative. that region-based sensitivity was high for non-SDHB (93%) metas-
The SUV was higher in SDH- and VHL-related tumors than in tases but low for SDHB-related metastases (20%) without clear
MEN2- and NF1-related tumors.71 explanation.69
18
F-Flurorodihydroxyphenylalanine (18F-DOPA) 11
C-Hydroxyephedrine PET/CT Imaging
PET/CT Imaging 11
C-Hydroxyephedrine is synthesized using 11C-methyliodine by
Dihydroxyphenylalanine (DOPA) is the precursor of all endogenous direct N-methylation of metaraminol to create a synthetic false
catecholamines. 18F-dihydroxyphenylalanine (18F-DOPA) is trans- transmitter analog of norepinephrine.103 Its mode of transmem-
ported via the amino acid transporter system. 18F-DOPA can be decar- brane transport is similar to that of norepinephrine, which is
boxylated to dopamine by the enzyme l-amino acid decarboxylase selectively and rapidly transported into the sympathetic neuron by


Figure 19.4. 18F-FDG PET/CT (transverse
images) in a patient with pheochromocytoma
on the right displaying a high tracer uptake. No
metastases were diagnosed. The noncontrast-
enhanced CT is displayed upper left, the PET
upper right, the PET/CT fusion lower left
and the maximum intensity projection (MIP) of
the PET volume on the lower right.
the NET. In contrast to norepinephrine, 11C-hydroxyephedrine 100%).82 The question of hereditary disorders was further investi-
is resistant to metabolism in the terminal endings of the sympa- gated. It was found that the sensitivity of 11C-hydroxyephedrine
thetic neuron, leading to accumulation. Moderate physiologic PET in MEN2 patients was lower (73%) but with 100% specificity.
11
C-hydroxyephedrine accumulations are seen in organs with sym- The mean SUVmax was significantly higher when sympathetic
pathetic innervation, such as the myocardium, liver, spleen, pan- symptoms were present and in metastatic sites compared to pri-
creas, salivary glands, and normal adrenal medulla.103 With these mary tumors. The SUVmax correlated significantly with plasma
characteristics, 11C-hydroxyephedrine was originally developed as normetanephrine and urinary norepinephrine. The mean SUVmax
a PET tracer to investigate the sympathetic innervations of the in 11C-hydroxyephedrine-positive primary tumors was signifi-
heart. 11C-hydroxyephedrine became the first available positron- cantly higher than in normal adrenal glands, which suggested that
emitting probe of the sympathetic nervous system suitable for the degree of 11C-Hydroxyephedrine accumulation (SUVmax) in
administration in humans.104 With excellent imaging quality, PET the tumors correlated with malignancy and biochemical data.
studies demonstrated that 11C-hydroxyephedrine accumulated at Figure 19.6 is an example of a 11C-hydroxyephedrine-PET/CT
high levels in pheochromocytomas and neuroblastomas.81,105 examination in recurrent pheochromocytoma.
There have been a few studies evaluating the effectiveness of These results suggested that 11C-hydroxyephedrine PET and PET/
11
C-hydroxyephedrine PET for pheochromocytomas/paraganglio- CT can be clinically used to localize these tumors. However, despite
mas.75,81,82,106,107 The Institute in Uppsala, Sweden, reported excel- these promising reports, this tracer has not been widely used in
lent sensitivity (92%) and specificity (100%) in 19 patients with clinical setting to detect adrenal tumors. This is because of the limited
pheochromocytomas (Fig. 19.5).106 Another group reported that availability of 11C-hydroxyephedrine and the short physical half-life
11
C-hydroxyephedrine PET demonstrated all sites of confirmed of 11C (20.4 minutes) thus requiring an in-house cyclotron and on-site
disease in eight patients with pheochromocytoma without any production of this tracer.108 By contrast, 18F-FDG is commercially
false-negative results. However, there was one false-positive case available and can be transported to PET centers lacking a cyclotron.
with medullary hyperplasia.107 In this report, 11C-hydroxyephed- Radio-iodinated MIBG scintigraphy is the established, standard
rine PET detected the tumors more accurately than 131I-MIBG, radionuclide imaging method with comparably wide availability and
especially in cases of bilateral and extra-adrenal lesions. Franzius’ with high sensitivity and specificity. In metastatic disease, when
131
group reported that in 14 patients (six neuroblastomas, five pheo- I-MIBG therapy is being considered, 123I-MIBG is regularly per-
chromocytomas, one ganglioneuroblastoma, and two paraganglio- formed to evaluate the patients’ eligibility for this treatment.
mas), 11C-hydroxyephedrine PET detected 80 of 81 tumor lesions, 11
C-Hydroxyephedrine PET/CT may be most suitable as a problem-
including bone and soft tissues, with 99% sensitivity and maximum solving tool if 123I-MIBG fails to visualize the disease.
specificity. 123I-MIBG SPECT/CT detected 75 of 81 lesions with 93%
sensitivity and maximum specificity.75 Our institute recently 18
F-6-[18F]-Fluorodopamine (18F-FDA)
reported our 11 years’ experience with 11C-hydroxyephedrine PET.
11
C-Hydroxyephedrine PET (n = 69) and PET/CT (n = 101) exami-
PET/CT Imaging
nations on 134 patients were analyzed, showing no false-positive The dopamine analog 18F-6-[18F]-fluorodopamine (18F-FDA) is a
and just six false-negative examinations (sensitivity 91%, specificity catecholamine precursor and an excellent substrate for both the

Figure 19.5. 11C-hydroxy-ephedrine-PET/

CT examination (transverse images) of a patient
with biochemical evidence of a pheochromocy-
toma but equivocal CT finding. The 11C-hydroxy-
ephedrine-PET/CT examination shows an
intermediate tracer uptake in the right adrenal
consistent with a pheochromocytoma that was
later surgically resected. The noncontrast-
enhanced CT is displayed upper left, the PET
upper right, the PET/CT fusion lower left and
the maximum intensity projection (MIP) of the
PET volume on the lower right.
Figure 19.6. 11C-hydroxy-ephedrine-PET/

CT examination (transverse images) of a
patient previously having undergone surgical
resection of a large pheochromocytoma on
the right side. Biochemical evidence of recur-
rent tumor could not be confirmed by follow-up
CT. 11C-hydroxy-ephedrine-PET/CT showed a
retro-crural lymph node metastasis on the right
side. Surgical clips are found in front of the right
kidney after surgical resection of the primary
tumor. The noncontrast-enhanced CT is dis-
played upper left, the PET upper right, the
PET/CT fusion lower left, and the maximum
intensity projection (MIP) of the PET volume
on the lower right.

plasma NET and intracellular vesicular monoamine transporter in toma because of multiple metastases/recurrence or direct invasion
catecholamine-producing cells.61 PET with 18F-FDA is reported to into other organs.111 Patients should have pretreatment evaluation
have excellent results in localizing both primary and metastatic by [123I] or [131I] MIBG scintigraphy and should have 123/131I-MIBG-
pheochromocytomas/paragangliomas.67,69,70,83,109 In 99 consecu- positive tumors if the treatment is to be efficacious. The treatment
tive studies including 26 patients with nonmetastatic pheochro- was introduced in 1983.112 but the effectiveness of [131I] MIBG ther-
mocytomas and 34 patients with metastatic pheochromocytomas, apy alone or combined with chemotherapy is still limited and the
the sensitivity and specificity for nonmetastatic pheochromocyto- outcome for malignant pheochromocytoma with this treatment
mas were 78% and 77% in a lesion-based analysis, and sensitivity remains poor. Those patients who responded to the treatment were
for metastatic pheochromocytomas was 97% in a patient-based shown to have prolonged survival (9 months longer median survival)
analysis.70 Uptake in adrenal hyperplasia and metabolically active compared to those who did not respond.112 Nevertheless, given the
brown fat were sometimes experienced.67 lack of effective alternatives [131I] MIBG treatment is still used, at least
to stabilize the disease and especially to treat metastatic disease.
11
C-Epinephrine PET/CT Imaging
11
C-Epinephrine was tested as a PET tracer in patients with pheo- Radiolabeled Peptide (Somatostatin
chromocytomas/paragangliomas but the diagnostic yield was less Analog) Therapy
than that of 123/131I-MIBG.110
Metastatic pheochromocytoma can be treated by the radiolabeled
somatostatin analog 90-Yttrium-DOTA-Tyr3-octreaotide (90Y-DOTA-
Comparison of Radiopharmaceuticals TOC), 177-Lutetium-DOTA-Tyr3-octreotide (177Lu-DOTA-TOC), and
177-Lutetium-DOTA-Tyr3-octreotate (177Lu-DOTA-TATE).113–115 In
for Visualization of some tumors, especially in neuroblastomas, binding to the SRs per
Pheochromocytoma/Paraganglioma se induces apoptosis and thereby reduces tumor volume. Radionu-
clide therapy using 177Lu- and 90Y-labeled somatostatin analogs is

In a comparative study, detection of benign pheochromocytomas by often referred to as peptide receptor radiotherapy (PRRT) and has
MIBG scintigraphy showed a sensitivity of 83% but the correspond- mainly been utilized in malignant and metastatic pheochromocy-
ing figure for 18F-FDG PET was merely 58% by patient- and lesion- tomas and paragangliomas. Twenty-eight patients with nonre-
based analysis. By contrast, in malignant pheochromocytomas, sectable, SR-positive pheochromocytomas and paragangliomas
123
I-MIBG scintigraphy showed 88% sensitivity and 18F-FDG PET received 90Y-DOTA-TOC (25 patients) and 90Y-DOTA-TOC followed
82% by patient-based analysis. The author thus concluded that by 177Lu-DOTA-TOC (three patients), and at restaging 8 to 12 weeks
uptake of 18F-FDG is found in a greater percentage of malignant after the last treatment cycle, two patients had partial remission,
than benign pheochromocytomas and that 18F-FDG PET is useful five patients had minor responses, thirteen had stable disease, two
when tumors fail to concentrate 123I-MIBG.52 In the comparative had mixed responses, and six remained progressive.115 The authors
study, it was demonstrated that 18F-FDA PET was better than concluded that the therapy seemed less effective than in gastroentero-
131
I-MIBG scintigraphy for localization of metastatic pheochromocy- pancreatic NETs and had low toxicity, mainly leukopenia and
tomas with patient-based sensitivities of 100% and 56%, respec- thrombocytopenia. From a theoretical point of view, combined
tively.109 18F-FDA PET was also compared with 123I-MIBG scintigraphy treatment with MIBG and PRRT could have synergistic effects and
and SRS with Octreoscan in nonmetastatic and metastatic pheo- might thus be considered.116
chromocytomas in 53 patients.67 The overall patient-based sensitiv-
ity for 18F-FDA PET was 90%, 123I-MIBG scintigraphy 76%, and SRS
22%. In a region-based analysis, the overall sensitivity for 18F-FDA Conclusion
PET was 75%, 123I-MIBG scintigraphy 63%, and SRS 64%. The
authors concluded that 18F-FDA PET should be used in the evalua- With the escalating use of cross-sectional imaging, mainly CT, the
tion of pheochromocytoma because of its better sensitivity. In the increasing incidence of adrenal incidentalomas creates a clinical
evaluation of metastatic pheochromocytomas, 123I-MIBG was shown problem because they represent a wide range of both benign and
to be the least informative modality.67 18F-DOPA PET was shown malignant lesions which require radiologic and endocrinologic
to be superior to 123I-MIBG scintigraphy to localize catecholamine- characterization. Most incidentalomas may be diagnosed as benign
producing tumors with lesion-based sensitivity/specificity of 98%/100%, by means of morphologic imaging, generally CT or MRI, by estab-
and 53%/91%, respectively.77 In a comparative study, 18F-DOPA, lishing that the lesion contains cytoplasmic or macroscopic fat, or
18
F-FDG, 18F-FDA PET, and 123I-MIBG scintigraphy were tested in the by calculating the intravenous contrast medium wash-out or
same patient group.69 Lesion-based sensitivities for nonmetastatic through follow-up of tumor size. Radionuclide imaging represents
tumors were 81% for 18F-DOPA PET, 88% for 18F-FDG PET/CT, 77% a range of complementary tools to distinguish between the tumor
for 18F-FDA PET/C, and 77% for 123I-MIBG scintigraphy. For meta- lesions that need to be surgically removed and those that will nei-
static tumors, the region-based sensitivity was 45% for 18F-DOPA ther require surgery nor long-term follow-up.
PET, 74% for 18F-FDG PET/CT, 76% for 18F-FDA PET/CT, and 57% Imaging of tumor metabolism with 18F-FDG PET/CT can dif-
for 123I-MIBG scintigraphy. In patients with SDHB metastatic tumors, ferentiate benign from malignant adrenal tumors with high accu-
18
F-FDA and 18F-FDG showed higher region-based sensitivities (82% racy, despite the nonspecific nature of the tracer117 and can also
and 83%) than 123I-MIBG (57%) and 18F-DOPA (20%). The author assist in the diagnosis and staging of pheochromocytoma. Target-
concluded that 18F-FDA PET/CT was the preferred method to local- ing of tissue-specific enzyme expression by 11C-metomidate PET/
ize primary tumors and to exclude metastases. CT and 18F-DOPA scintigraphy are ways of differentiating adreno-
cortical from nonadrenocortical tumors and are suitable for tumor
characterization and detection of metastatic disease when ACC is
Radionuclide Therapy for Tumors suspected.
123/131
of the Adrenal Medulla I-MIBG scintigraphy remains the gold standard for radio-
nuclide imaging of adrenal medullary tumors because of its wide
availability and because it is a means to evaluate the patients’ eli-
[131I] MIBG Therapy gibility for 131I-MIBG therapy. Because of its availability, 18F-FDG
Radionuclide therapy with [131I] MIBG is performed in patients with PET/CT also represents an alternative although it is nonspecific.
nonresectable pheochromocytoma/paraganglioma and neuroblas- PET/CT with a specific tracer such as 11C-hydroxyephedrine,

18
F-DOPA, and 18F-FDA are problem-solving tools and are recom- 8. Ozcan Kara P, Kara T, Kara Gedik G, et al. The role of fluorodeoxyglucose-posi-
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Clin Endocrinol Metab. 2009;94:4757–4767. 96. Breeman WA, de Jong M, Kwekkeboom DJ, et al. Somatostatin receptor-
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P a r t II
Malignancies Involving the Entire Body
Chapter 20
Neuroendocrine Tumors
Lisa Bodei • Mark Kidd • Irvin M. Modlin • Giovanni Paganelli
PART II • Malignancies Involving the entire Body

Introduction At this time, nuclear medicine strategies have become key ele-
ments in the diagnostic strategy to identify tumor location and
extent of metastatic disease as well as providing information as to
Neuroendocrine tumors were first described in 1907 by Oberndorfer1 the metabolic activity of the tumor (Fig. 20.1).
(1876–1944) as small tumors of the intestine that he referred to Similarly, the development of appropriate nuclear medicine
using the German diminutive for cancer, Karzinoide, and thereby therapeutic strategies to control and eradicate metastatic disease
mistakenly implying a benign tumor. It is now apparent that this as well as ameliorate symptoms has become an important compo-
class of tumors, neuroendocrine tumors, exhibit a wide range of nent of the advancing therapeutic strategy to manage this disease.
malignancy, are ubiquitous, are rapidly increasing in incidence, and
have a greater prevalence in the gut than all other neoplasia except
colon cancer.2 They have, in the past, been considered rare and Molecular and Cellular Biology
were overall little understood as scientific and clinical attention and
research resources were mostly focused on adenocarcinoma. As a Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), or
consequence of limited clinical awareness, diagnosis was usually “carcinoid” as they are often labeled, are now known as neuroen-
made late in the course of the disease when metastatic disease was docrine neoplasms (NENs) and are derived from neuroendocrine
already evident.3 cells in the pancreas and gastrointestinal tract which themselves
The recent recognition that the incidence of the disease is rapidly are derived from local tissue-specific stem cells, probably through
increasing and that its prevalence as a gastrointestinal cancer was a committed precursor cell.9
only exceeded by that of colon cancer has resulted in significant The mechanisms leading to tumorigenesis are largely unknown
clinical and scientific focus on the problem.4 It is now evident that but the majority of lesions (>95%) are sporadic. Others, notably
they behave much as do other cancers, cause severe alterations in some gastric and pancreatic types, are related to genetic defects
quality of life (QoL) because of their bioactive secretory products, such as multiple endocrine neoplasia type 1 (MEN1), neurofibroma-
and can be effectively treated if appropriately managed with the tosis (NF-1) von Hippel–Lindau (VHL), or tuberous sclerosis (TSC).10
wide array of diagnostic and therapeutic strategies that have been Overall, there are at least 13 different neuroendocrine cell types in
developed to support such patients.5 the gastrointestinal tract and four in the pancreas with distinct ana-
In contradistinction to the notion that they are benign and indo- tomical localization and secretory products (Table 20.1).
lent, they often exhibit a poor prognosis because of widespread Some of these are localized to a single organ (e.g., the gastric
metastatic disease and a low QoL caused by disabling symptoms. enterochromaffin-like [ECL] cell) and others are distributed
A key issue in limiting clinical advances in this disease has been throughout the GI tract (e.g., the enterochromaffin [EC] cell).
the paucity of information about the cells of origin and the biology Although diverse in location, neuroendocrine cells share a number
of the tumors.3 More recently, scientific advances have yielded con- of common features including (1) lineage derivation (largely neuro-
siderable information which has allowed introduction of sensitive genin 3-expressing secretory progenitor cells); (2) production of
techniques for detection of these tumors.6 In addition, a better specific proteins (e.g., chromogranin A [CgA]) involved in secretory
delineation of the molecular mechanisms of the tumors has facili- granule formation, maturation, and exocytosis11; (3) transport
tated the development of effective therapeutic agents including (vesicular monoamine transporters—VMAT1, VMAT2)12; (4) amine
somatostatin analogs, interferon, targeted drugs (mTOR kinase synthesis through specific rate-limiting enzymes (histamine and
inhibitors, antityrosine kinase agents), and peptide receptor radio- histidine decarboxylase in gastric ECL cells or serotonin and tryp-
nuclide radiotherapy (PRRT).7 Although diagnostic modalities such tophan hydroxylase—Tph1—in EC cells), and amine uptake and
as somatostatin receptor scintigraphy (SRS), positron emission decarboxylation (APUD)13; (5) electron-dense secretory granules
tomography (PET), and the combination of nuclear imaging tech- (readily visible by electron microscopy)14; (6) Calcium and ERK1/2
niques with anatomical imaging are useful in accurate and early signaling pathways for secretion15; (7) MAPK pathways for growth
diagnosis, a critical issue is the absence of a peripheral blood or factor (e.g., gastrin/TGF) mediated proliferation16; and (8) inhibi-
genetic marker to identify early disease or predict and recognize tory receptors that can be targeted, for example, somatostatin
micrometastasis.8 Apart from early diagnosis, delineation of the receptors (SRs).17,18
mechanistic and biologic basis of neuroendocrine tumor biology is The majority of these cell types can transform into tumors
necessary to develop a rational and effective therapeutic approach which, based on the cell of origin, exhibit a wide spectrum of
using targeted agents. Increased knowledge about cell biology and clinical behavior that ranges from indolent (e.g., gastric type I
genetic characteristics, therefore, is the key to the evolution of tumor or insulinomas) to highly aggressive (e.g., glucagonomas
therapy. and colon NENs3) (Table 20.2).
265

266 Part II Malignancies Involving the Entire Body
Figure 20.1. Key figures in the discovery of

radionuclides and the pathobiologic elucida-
tion of gastroenteropancreatic neuroendocrine
tumors. The central background motif repre-
sents element 71, described by Georges
Urbain (upper center) of France and Carl
Auer von Welsbach of Austria (lower center)
almost simultaneously in 1907. The element
originally called cassiopium by Welsbach was
in fact an impurity of ytterbium (discovered in
Ytterby, Sweden) and nationalistically named
lutetium (after the Lutetii tribe, founders of
Paris) by Urbain, given his precedence in the
original description. Oberndorfer (top right)
identified a series of diminutive small bowel
tumors as “Karzinoide” as opposed to Karzi-
noma (cancer) in 1907. Feyrter (bottom
right) described a linking system—the dif-
fuse neuroendocrine system that character-
izes the different cell types which he proposed
as the source of the tumors. This was further
expanded into the amine uptake and decar-
boxylation classification by Pearse (top left)
based upon his delineation of their common
cytochemical characteristics. Bloom (bottom
left) provided a clinical understanding of the
pathologic nature (top) of the tumors and
linked their immunocytochemical characteris-
tics (bottom) with their secretory characteris-
tics and symptoms.
Table 20.1 Their natural history varies from local invasion and fibrosis in
the peritoneal cavity to metastatic spread, most commonly to the
Gastrointestinal and Pancreatic Neuroendocrine liver and lungs. Their biologic characteristics (local invasion,
Cell Types and Secretory Products fibrosis, and metastatic potential) vary considerably depending on
anatomical site, neuroendocrine cell(s) of origin, and secretory
Cell Type Localization Products products. However, despite their diversity in tissue origin and bio-
logic behavior, GEP-NENs share many common features including
δ (D) Entire GI tract Somatostatin pathologically definable growth patterns, secretion of bioactive
Enterochromaffin (EC) Entire GI tract Serotonin/substance P/guanylin/ products (most commonly serotonin or peptides such as insulin,
melatonin gastrin, and glucagons), and expression of neuroendocrine mark-
Enterochromaffin-like Gastric fundus Histamine ers including CgA.
(ECL)
Gastrin (G) Gastric antrum and Gastrin
duodenum Neuroendocrine Neoplasm
Ghrelin (Gr)
I
Entire GI tract
Duodenum
Ghrelin
CCK
Classification Systems
K Duodenum/jejunum GIP
L Small intestine GLP-1, PYY, NPY The 1963 classification of GEP-NENs based on their putative embry-
Motilin (M) Duodenum Motilin ologic origin (foregut, midgut, or hindgut) by Williams and Sandler,19
Neurotensin (N) Small intestine Neurotensin although still in use, has largely been superseded by the World
Secretin (S) Duodenum Secretin Health Organization (WHO) classification system which has defined
Vasoactive intestinal Entire GI tract VIP these tumors by degree of differentiation and the tumor site of
peptide (VIP) origin.20 In this schema, tumors are described as well-differentiated
X Stomach: Fundus Amylin neuroendocrine tumors (benign behavior or uncertain malignant
and antrum potential), well-differentiated neuroendocrine carcinomas (low-
β Pancreas Insulin grade malignancy), or poorly differentiated (usually small cell) neu-
α Pancreas Glucagon roendocrine carcinomas of high-grade malignancy. The term
δ Pancreas Somatostatin “carcinoid” applies to tumors classified as “well differentiated.”
PP Pancreas PP Size, angioinvasion, proliferative activity, histologic differentiation,
metastases, and hormonal activity (association with clinical syn-
CCK, cholecystokinin; GI, gastrointestinal; GIP, gastric inhibitory peptide; GLP-1, glucagon-like
peptide 1; PYY, polypeptide YY (tyrosine-tyrosine); NPY, neuropeptide Y (tyrosine); PP, pancreatic dromes or diseases) are also taken into consideration. Histochem-
polypeptide. ical indicators of prognosis include the degree of expression of the

Chapter 20 Neuroendocrine Tumors 267
Ta bl e 2 0 . 2
Characterization and Clinical Presentation of Gastroenteropancreatic

Neuroendocrine Neoplasms
Gastrointestinal Neuroendocrine Neoplasms
Gastric Type I Atrophic gastritis-gastrin dependent

Type II (MENI-ZES) Genetic defect menin dependent-gastrin related
Type III Gastrin independent; clinically aggressive
Duodenal: Variety of different phenotypes Gastrinoma, “carcinoid,” somatostatinoma
Jejunal “carcinoid”—classic symptoms; clinically aggressive
Ileal “carcinoid”—classic symptoms; clinically aggressive
Appendiceal “Carcinoid” Usually present as appendicitis or incidental finding at laparotomy/
Goblet cell carcinoid laparoscopy; can exhibit clinically aggressive especially if
(mucinous carcinoid) goblet/mucinoid phenotype
Colonic Carcinoid symptoms are rare, presentation similar to
adenocarcinoma

Rectal Local manifestations—pain, bleeding
Hepatic >95% are metastases from GEP-NEN primary
Pancreatic Neuroendocrine Neoplasms (PNEN)
Gastrinoma (Zollinger-Ellison Peptic ulceration and secretory diarrhea; 60–90% malignant behavior
Syndrome [ZES])
Insulinoma Hypoglycemia; 5–15% malignant
Glucagonoma Skin rash, weight loss, diabetes; 60% malignant
VIPoma (Verner–Morrison) Secretory diarrhea; 80% malignant
Somatostatinoma Diabetes, gallstones; often a component of a genetic syndrome; 60% malignant
GRFoma Acromegaly; 30% malignant
ACTHoma Present as Cushing syndrome; aggressive behavior; >90% malignant
PNEN causing carcinoid Diarrhea, flushing; 68–88% malignant
syndrome
PNEN causing hypercalcemia Symptoms of hypercalcemia; 80–90% malignant
Nonfunctioning Local mass effects; 60–90% malignant
proliferation protein Ki-67 and the p53 tumor suppressor pro- Ki-67 index [proportion of cells positively stained by the antibody])
tein.21,22 Metastases are present overall in ∼35% of all GEP-NENs was used in the assessment of Hodgkin lymphoma.26 Although dis-
at presentation23 but may be as high as 60% to 80% for tumors that covered 30 years ago, the function of Ki-67 remains unclear27; there
originate in the small bowel and colon. By contrast, gastric tumors is, however, evidence that it regulates ribosomal expression rather
very rarely metastasize <10%.3 than directly contributing to cell cycle progression.28 Nevertheless,
The European Neuroendocrine Tumor Society (ENETS) group its expression has been noted in cells in all phases of mitosis26 and
and the Neuroendocrine Tumor Summit Consensus of 2009 have despite reservations as to its efficacy, it is used as a surrogate
proposed to further refine this classification to include the Ki-67 marker of proliferation. Although controversy exists as to the utility
scoring index and a TNM classification system (Table 20.3).24,25 of the Ki-67 and its general application, it is embedded in therapeu-
Historically, Ki-67 was incidentally identified as an antibody that tic decision making.29 The recent development and introduction of
bound a nuclear antigen associated with proliferation in Hodgkin a minimal data set for pathologists will add consistency and unifor-
and Reed–Sternberg cells. This measurement of its detection (the mity to the evaluation and classification of GEP-NENs.29
Ta bl e 2 0 . 3
Classification of Neuroendocrine Neoplasms
Classification of
Classification of Gastroenteropancreatic NENs Bronchial/Thymic NENs
WHO 1980 WHO 2000 WHO 2010/ENETS AJCC Classification WHO 2004
Carcinoid Well-differentiated Neuroendocrine Well differentiated Typical carcinoid <2 mitosis/

endocrine tumor Tumor G1 (Ki-67 low grade (carcinoid/ 10HPF, no necrosis
<2%), (carcinoid) islet cell tumors)
Well-differentiated Neuroendocrine Moderately differentiated Atypical carcinoid 2–10
endocrine carcinoma Tumor G2 (Ki-67, -Intermediate grade mitosis/10HPF, necrosis
3–20%) (carcinoid/islet cell tumors)
Poorly differentiated Neuroendocrine Poorly differentiated Neuroendocrine carcinoma
endocrine carcinoma G3 -High grade >10 mitosis/10HPF, vast
carcinoma/small (Ki-67, >20%) necrosis
cell carcinoma -Large cell -Large cell
-Small cell -Small cell

Figure 20.2. Incidence of neuroendocrine neoplasms by anatomical location in the US population between 1973 and 2005.
Epidemiology of Neuroendocrine Clinical Presentation of

Neoplasms Neuroendocrine Neoplasms
The Surveillance, Epidemiology, and End Results (SEER) database GEP-NENs may present a considerable diagnostic and therapeutic
(1973 to 2006), containing 48,195 NENs,30 demonstrates that in challenge as their clinical presentation is protean, nonspecific,
the United States, NENs comprise 0.66% of all malignancies and and usually late when hepatic metastases are already evident.
the incidence is increasing at a rate of 3% to 10% per year depend- Symptomatology is referable to either local tumor mass effects
ing on the subtype (Fig. 20.2). (pain, bleeding, or biliary duct obstruction), local (pain from adhe-
NENs comprised 1.25% of all malignancies in 2004 compared sions and obstruction) or distant fibrotic events (pulmonary and
to only 0.75% of all malignancies in 1994.23,30 Much of this increase right-sided cardiac), or the biologic consequences of the secretion
probably reflects the introduction of more sensitive diagnostic of bioactive amines or peptides (Fig. 20.4).
tools (topographic and immunohistochemical) as well as an overall Diagnostic delay is usually 5 to 7 years because the symptoms
increased awareness among clinicians and pathologists.31,32 The are considered as caused by other conditions as opposed to a
frequency (1.22%) of NENs in a large autopsy series also indicates tumor. The fact that they are not persistent but episodic further
that they have previously been underdiagnosed.33 In the United hinders the diagnosis because their paroxysmal nature often
States, NENs occur most frequently in the gastrointestinal tract results in the incorrect assumption of an allergy or an unreliable
(66%) with the second most common location in the broncho- patient. Thus, the diarrhea is considered as response to a food or
pulmonary system (25%), followed by considerably less frequent irritable bowel disease, whereas the sweating and flushing as anx-
locations such as the ovaries, testes, hepatobiliary, and pancreas iety, menopause, or thyroid abnormalities. Tachycardia or anxiety
(Fig. 20.3).34 is misdiagnosed as a neurotic issue and bronchospasm as allergy
In SEER (1993 to 2006), African Americans exhibited a high over- or asthma. The classical carcinoid syndrome is relatively uncom-
all incidence of 6.5/100,000 compared to 4.4/100,000 among cauca- mon (10% to 15%), typically consisting of diarrhea, cutaneous
sians. Rectal NENs were the most common lesion (1.65/100,000, flushing, bronchospasm, and right-sided heart failure.33
27%) among African Americans, followed by small intestinal BPNs represent a spectrum of tumors (benign to malignant)
(1.42/100,000, 21%) and bronchopulmonary (1.20/100,000, 18%) arising from respiratory neuroendocrine cells. They comprise ∼20%
lesions. Taking gender and ethnicity into consideration, the highest of all lung cancers and 25% of all NENs.36 BPNs present with cough,
incidence rates were small intestinal (1.83/100,000) and rectal hemoptysis, and obstructive pneumonia but this varies depending
NENs (1.81/100,000) in black males followed by bronchopulmo- on the site, size, and growth pattern. A substantial number is iden-
nary NENs (BPNs) (1.51/100,000) in white females. Despite the rela- tified serendipitously on chest radiology. Less than 5% of BPNs
tive rarity of the disease (∼1% of all tumors), the prevalence of exhibit hormonally related symptoms such as carcinoid syndrome,
GEP-NENs is substantial given the often indolent nature of the dis- Cushing, acromegaly, or SIADH. They are usually divided into four
ease process.35 subgroups: Typical carcinoid tumor (TC), atypical carcinoid tumor


Figure 20.3. Distribution of 49,012 neuro-
endocrine neoplasms (NENs) from the Surveil-
lance, Epidemiology, and End Results (SEER)
1973 to 2007 tumor registry database. Pie
charts reflect the distribution of NENs by ana-
tomical site and tumor type. Total NEN distri-
bution (top left), gastroenteropancreatic
(GEP)-NEN distribution (bottom left), and
pancreatic NEN distribution (bottom right).
Non–GEP-NENs are predominantly located in
the respiratory system (bronchopulmonary
NENs ∼70%, top right ).
(AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell exhibits a fairly good prognosis (5-year survival, ∼88%,), whereas
lung carcinoma (SCLC). Both SCLC and LCNEC progress rapidly, are this is 50% for AC and 15% to 57% for the highly malignant LCNEC
aggressively metastatic, and exhibit a poor prognosis. The TC group and SCLC (<5%), respectively.36
generally behaves in a benign/indolent fashion, whereas the atypi-
cal tumors can range from indolent to highly aggressive. SCLC is
the most common variant, whereas LCNEC is rare. The only cura-
tive treatment for BPNs is surgical resection. The slow-growing TC Diagnostic Strategies in
Clinical Aspects
A history of flushing, sweating, diarrhea, or bronchospasm
whose precise etiology cannot be satisfactorily demonstrated
within 3 months should give cause for consideration of the diag-
nosis especially in someone older than 30 years (Fig. 20.5).
Similarly, the association with intermittent abdominal pain, gas-
trointestinal bleeding, or concomitant cardiac issues should
arouse suspicion.
Biochemical Features
Urine
A 24-hour measurement of urinary 5-hydroxyindole-3-acetic acid
(5-HIAA) can be undertaken to detect serotonin (5-HT) producing
lesions. This is a somewhat useful laboratory marker but is cumber-
some in terms of collection and the onerous dietary restrictions nec-
essary to avoid false-positive diagnoses. It has 88% specificity for
serotonin-producing GEP-NENs although tryptophan/serotonin-
rich foods (bananas, avocados, plums, eggplants, tomatoes, plan-
tains, pineapples, and walnuts) can provide false elevations and
several drugs (antihypertensive agents) can result in increased or
decreased 5-HIAA levels. Higher concentrations of urinary 5-HIAA
are consistent with a worse prognosis, whereas persistently
Figure 20.4. The inner circle represents symptoms associated with the classical “carcinoid”
disease. The outer circle represents common misdiagnoses based on incorrect interpretation of low levels suggest a more favorable survival in disseminated
the symptoms. GI, gastrointestinal. disease.

Figure 20.5. Current diagnostic algorithm

for gastrointestinal neuroendocrine neoplasms
(NENs). CT, computed tomography; echo,
echocardiography; ERCP, endoscopic retro-
grade cholangiopancreatography; EUS,
endoscopic ultrasound; 5-HIAA, 5-hydroxyin-
dole-3-acetic acid; MRI, magnetic resonance
imaging; PET, positron emission tomography;
SRI, somatostatin receptor imaging; VIP, vaso
active intestinal peptide.
Blood Peptide and Amine Measurement Blood Transcript Analysis

A wide variety of peptides and amines have been proposed as bio- A key unmet need therefore is the availability of a blood test for
markers to identify NEN disease. These include histamine, gastrin, early diagnosis or surveillance. The recent demonstration of spe-
vasoactive intestinal peptide (VIP), glucagon, bradykinin, substance cific NEN transcripts in plasma suggests that this strategy may
P, neurotensin, neuron-specific enolase, pancreastatin, human cho- enable early diagnosis and detection of lesions and even provide a
rionic gonadotropin (hCG), neuropeptide K, neuropeptide L, pan- basis for prognostic determination and therapeutic recommenda-
creatic polypeptide, and 5-HT. The majority of biomarkers proposed tion.8 Recent reports indicate that measurement of neuroendocrine
for the diagnosis of these lesions have proven to exhibit a low blood transcripts is significantly more specific and reproducible
sensitivity and specificity, are difficult to measure accurately or than CgA measurement (Fig. 20.7).41
easily, and are therefore mostly of research use. Exceptions to this
are the PNENs in which measurement of the peptides gastrin,
insulin, VIP, and glucagon have been of clinical utility.
Levels of the general GEP-NEN marker, plasma CgA, are sensi-
tive (>90%) but nonspecific (elevated in other types of NENs, by
impaired kidney function and during proton pump medication).37
Currently, CgA measurements are used to confirm diagnosis and
gain insight as to tumor burden and possible location of the tumor.
Circulating CgA is elevated in the majority of patients with GEP-
NENs and is most frequently increased in subjects with gastrinomas
(100%), followed by “carcinoid” tumors (80%), and nonfunctioning
PNENs (70%).38 NonGEP-NENs including pheochromocytomas
(90%) and medullary thyroid carcinomas (50%) also express ele-
vated levels.39 Some studies have noted an association between CgA
concentrations and tumor location and it has been proposed that
plasma CgA levels are more frequently elevated in well-differenti-
ated tumors compared to poorly differentiated tumors of the mid-
gut. CgA has also been suggested to have some utility in predicting
survival40 as well as providing insight into the efficacy of therapy.
However, measurement of CgA is substantially limited by a lack of
standardization of assays and a relatively low sensitivity in some Figure 20.6. Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) biomarkers.
Chromogranin A (CgA) is the most widely used biomarker for GEP-NENs, but many others have
clinical situations. Thus, CgAs measured at different time points in
been used and some in particular have utility in identifying neoplasms with specificities that range
the disease or using different commercial assays are not compara- from high to intermediate. Thus, specific tumor types can be identified using, for example, sero-
ble or provide information that is difficult to interpret. tonin (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) for enterochromaffin cell tumors (small
Overall, individual markers like urinary 5-HIAA levels or plasma bowel NENs), gastrin for a gastrinoma, or glucagon for a glucagonoma. A variety of putative
biomarkers (left) of variable clinical utility that are occasionally used include adrenomedullin,
5-HT levels are cumbersome, insensitive, and difficult to quantify
neurokinin, and bradykinin. ANP/BNP, atrial natriuretic peptide and brain/ventricular natriuretic
whereas the most commonly used, CgA levels, varies between lab- peptide; GHRH, gonadotropin hormone-releasing hormone; hCG, human chorionic gonadotropin;
oratories and can be nonspecifically elevated (Fig. 20.6). NSE, neuron-specific enolase; PYY, peptide YY.

Amine Precursor Imaging

A principal function of neuroendocrine cells is to regulate physio-
logic functions through paracrine stimulation which is achieved by
the production of a large variety of bioactive agents, for example,
5-HT or catecholamines. The production of these aminergic hor-
mones is accomplished via APUD, features that were initially identi-
fied by the biochemist, Pearse13 (1916–2003) in 1966. This
capability to synthesize bioactive products is retained following
neoplastic transformation and has allowed for the development of
isotopic imaging techniques with amine precursors such as 5-HTP
and L-dihydroxyphenylalanine (L-DOPA) which can be internalized
into tumor cells and are then incorporated in the synthesis of pep-
tide hormones like 5-HT and dopamine.47,48 By way of example,
both tryptophan and 5-hydroxytryptophan (5-HTP) enter the cell
using L-type amino acid transporters (LATs). Thereafter, a decar-
boxylation step to 5-HT occurs through the enzyme aromatic amino
acid decarboxylase (AADC) and the resulting end product (in this

case 5-HT) is transported into storage vesicles through VMATs from
which they can be released into the extracellular environment.
Although the exact uptake mechanism and intracellular fate of these
amines and their metabolites are not precisely understood, it
appears that increased LAT activity plays a role in supporting a high
precursor turnover because of an increased metabolic pathway, for
example, 5-HT, or at least increased AADC activity in NENs. Using
this feature of the cell, PET for example, using the 11C-labeled
Figure 20.7. Receiver operating characteristic curves for a polymerase chain reaction (PCR)-
based peripheral blood fingerprint compared to chromogranin A (CgA) for the correct identifica-
serotonin-precursor, 5-HTP, has been shown to be a sensitive modal-
tion of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). The areas under the ity for imaging.49
curve (AUC) were significant in two validation sets—1 (AUC = 0.98, p < 0.0001) and 2 (AUC =
0.95, p < 0.0001) compared to CgA (AUC = 0.64, p < 0.002). Direct comparisons of the PCR
fingerprint with CgA identified performed significantly better (p < 0.0001).
Therapeutic Strategies
Despite the introduction of novel treatments including PRRT and
Conventional Imaging enzyme inhibitors (tyrosine kinase inhibitors), primary surgical
Once the biochemical diagnosis of a NEN has been made, it is nec- resection of the tumor and regional lymph nodes remains the only
essary to identify the primary site, define the extent of the locore- curative treatment available for GEP-NENs (Fig. 20.8).
gional disease, and assess metastatic spread before determining This approach, however, is usually only possible in ∼20% because
therapeutic strategy. Topographic localization using endoscopy/ of the delay in diagnosis and the presence of metastatic disease at
ultrasound, capsule endoscopy, CT, MRI, SRS, and whole-body PET the time of the initial procedure. Small, solitary noninvasive (endo-
are all variously effective depending upon equipment availability sonographically proven) lesions in the stomach, duodenum, and rec-
and user skill. No modality alone is entirely secure and overall, tum may be treated with endoscopic local resection.50,51 Somatostatin
these exhibit a sensitivity and specificity of ∼80% to 90%.42 These analogs usually induce biochemical stabilization or effective bio-
techniques are dealt with in detail later in this chapter. Of particular chemical response (∼85%) and manage clinical symptoms (∼80%) in
relevance to nuclear medicine imaging, however, are modalities patients with SR-positive tumors. More recently, the PROMID and
that utilize the SR or a variety of metabolic or amine precursors that Radiant 001 studies have indicated a positive effect of both octreo-
are unambiguously related to neuroendocrine tumor cells. More tide alone and the combination of octreotide and an mTOR kinase
specifically these include SRs and precursors of serotonin and inhibitor on tumor progression and survival.52,53 By way of example,
dopamine. in the latter study, the activity of the oral inhibitor of mTOR, evero-
limus (RAD001) in combination with octreotide LAR was investi-
gated in 60 patients with advanced low- to intermediate-grade
Somatostatin Receptor Expression as NENs.35 There were 13 (22%) with partial responses, 42 (70%) with
stable disease, and 5 (8%) patients with progressive disease. The
Target for Imaging
positive data represent increases in progression-free survival as
Neuroendocrine cells express a range of SRs. Five SR subtypes (1 opposed to an increase in life expectancy. Similar clinical data exist
to 5) have been identified in human tissues, and 70% to 90% of for an alternative agent Sutent, a receptor protein-tyrosine kinase
GEP-NENs express multiple subtypes with a predominance of inhibitor that inhibits the actions of vascular endothelial growth fac-
subtypes 2 and 5.43 It appears that most tumors originating from tor (VEGF) and is an angiogenesis inhibitor.54 A diverse array of
tissues that are physiologically regulated by somatostatin express single- or multiagent chemotherapeutic regimes have also been
a high density of SR.44 Diverse neoplasia, apart from GEP-NENs examined. Invariably, they exhibit little, short-lasting, or no effect on
and BPNs, therefore also express SR including pituitary tumors, NEN response and, in most circumstances, the associated adverse
meningiomas, medulloblastomas, medullary thyroid carcinomas, events usually exceed the efficacy of the agents.55 Novel agents,
adenocarcinomas of the breast, ovary, and colon.44 By contrast, including inhibitors of the tyrosine kinase receptor family c-kit,
poorly differentiated or undifferentiated tumors express SR less platelet-derived growth factor receptors (PDGF-R) α and β and epi-
often and at a lower density than well-differentiated (less malig- dermal growth factor receptor (EGFR) have shown modest (∼10%
nant) neoplasia. In general, SR subtypes 2 and 5 are expressed in tumor response rate) results.56,57
high density on most GEP-NENs.45,46 Receptor expression is thus Unfortunately, most patients have multiple, bilateral liver
a useful target to either detect or treat these lesions using radio- metastases at diagnosis, and ∼5% to 10% metastases are available
labeled somatostatin analogs, such as 111In-DTPA-octreotide. for “complete” resection.58 Liver transplantation may be an option

Figure 20.8. Potential therapeutic algorithm

for metastatic neuroendocrine neoplasms.
5-FU, 5-fluorouracil; CgA, chromogranin A;
chemo, chemotherapy; CT, computed tomog-
raphy; embo, embolization; MRI, magnetic
resonance imaging; PET, positron emission
tomography; PRRT, peptide receptor radionu-
clide therapy; RF, radiofrequency; STZ, strepto-
zotocin.
in highly selected patients59 but for the majority, ablative tech- more recently, PET with 68Ga-labeled octreotides, 18F-DOPA, and
11
niques including hepatic arterial embolization or radio frequency C-5-hydroxytryptophan (11C-5-HTP).3
ablation are effective in decreasing tumor load and reduce symp- Usually, a sequence including more than one examination is
toms and prolong survival with a 5-year survival of up to 50%.60 needed to obtain information on the site and extent of disease,
The strategy of reducing liver tumor bulk to 10% followed by ther- which represent the two most pertinent clinical issues. In this
apy with a somatostatin analog in conjunction with a pharmaco- regard, a combination of anatomic and functional techniques is
therapeutic strategy warrants consideration. In this respect, the routinely performed to optimize sensitivity and specificity thereby
field of radionuclide therapy via a targeting agent such as a soma- maximizing the acquisition of clinically relevant information.63,64
tostatin molecule has considerable potential given the initial early From a strictly technical point of view, imaging findings of
encouraging data.61 NENs, whether using morphologic or functional modalities, are
The 5-year survival rate for GEP-NEN disease between 1973 not necessarily indicative of tumor differentiation as lesions with
and 2005 ranged from 56.2% for colon NENs to 87.6% for rectal different grading may show common features.65
NENs. Disappointingly, the overall 5-year survival has not improved Imaging features are also not directly indicative of the secre-
appreciably over this time period.62 The 5-year survival is highly tory status of the tumor. This aspect descends from the recent
dependent on tumor stage and grade and ranges from only 4.5% reconsideration of the common biology of NENs, irrespective of
in undifferentiated NENs with distant spread to 83.4% in localized, their clinically evident functionality.66
well-differentiated tumors. However, the biologic and growth characteristics of a specific
tumor may be reflected in the appearance of the corresponding
lesions at imaging. Functional, hormonally active tumors tend to
Role of Diagnostic Imaging be diagnosed earlier, because of the recognition of a related clinical
syndrome. Nevertheless, even in the event of the recognition of a
The localization of a NEN and the assessment of the extent of dis- functional syndrome, the detection of a primary tumor may be dif-
ease are two critical requirements to ensure optimal patient man- ficult, because of its small size. In general, nonfunctional tumors
agement. As a consequence, every effort should be undertaken to are detected later unless they obstruct the common bile duct or
ensure accuracy and thereby facilitate the interface of the diagnos- pancreatic duct and present with jaundice or pancreatitis. Thus,
tic and therapeutic components necessary for disease staging and nonfunctioning tumors may grow to represent larger lesions, and
application of the appropriate therapeutic modalities. despite being asymptomatic, may have associated liver metastases
The aims of diagnostic imaging embrace a number of interre- at diagnosis.
lated areas but primarily, this is used to localize the tumor lesion In the past, despite all diagnostic efforts, in as many as 50%
and define its relation to adjacent structures as well as to evaluate of patients in some series, the primary neoplasm may remain
the extent of disease at both locoregional and distant levels (stag- undetected.3 The recent availability of more sophisticated diag-
ing). Thereafter, attention should be directed to reassessment of the nostic methodology has, however, substantially decreased this
tumor burden (restaging) and to guide the selection or stratification number.
of patients for a specific therapy or sequence of therapies. The dif- Many imaging modalities have been advocated, especially for
ferent therapeutic strategies may include either one or more com- GEP-NENs, which have lesions that often may be small and diffi-
binations of surgery, locally directed ablative therapies, bioactive cult to locate. Studies directly aimed at a rigorous comparison of
agents (somatostatin analogs/interferon), chemotherapy, and/or the various methods are limited and have been hindered by the
molecular targeted agents or PRRT. constant evolution of the available techniques at the time of the
Diagnostic strategies that are available include morphologic analysis.67 Table 20.4 reports a detailed description of morpho-
modalities such as CT, MRI, transabdominal ultrasound (US), endo- logic and functional imaging techniques in NENs, and the sug-
scopic (EUS) and intraoperative US (IOUS), and selective angiog- gested sequence for localization, staging, restaging, and therapy
raphy with or without hormonal sampling. Nuclear medicine selection. Where applicable, the impact on patient management is
imaging consists of 111In-pentetreotide (OctreoScan), 123I-MIBG, or, reported.

Table 20. 4
Morphologic and Functional Techniques for the Diagnosis of Neuroendocrine Neoplasms
Primary Localization Staging Restaging Therapy Selection % Therapy Change

68–70 71 73
Gastroenteropancreatic Pancreas -SRI (OCT ; PET -SRI + CT/MRI 63,64
-SRI + CT/MRI 63,64
-SRI: SSA, PRRT -SRI OCT74,75; PET in 76,77
functioning [PET >scintigraphy]) -11C-5-HTP49 -11C-5-HTP49 -CT/MRI: Surgery3 -FDG (prognosis)78
(except for -Endo US3,72
insulinoma) -CT/MRI65,72
-11C-5-HTP49
Pancreas -EndoUS3,72 -SRI + CT/MRI63,64 -SRI + CT/MRI63,64 -SRI: SSA, PRRT73 -SRI (OCT74,75; PET76,77)
nonfunctioning -SRI (OCT69,79,80, PET71) -11C-5-HTP49 -11C-5-HTP49 -CT/MRI: Surgery3 -FDG (prognosis)78
-CT/MRI65,72
Duodenum -SRI (OCT68,69 -SRI + CT/MRI63,64 -SRI + CT/MRI63,64 -SRI: SSA, PRRT73 -SRI (PET76,77)
PET71) -11C-5-HTP49 -11C-5-HTP49 -CT/MRI: Surgery3 -FDG (prognosis)78
-EndoUS3
Small bowel -SRI (OCT79–82, PET in71) -SRI + CT/MRI63,64 -SRI + CT/MRI63,64 -SRI: SSA, PRRT73 -SRI (OCT79,84;

-Video capsule, DB -18F-DOPA83 -18F-DOPA83 -CT/MRI: Surgery3 PET76,77)
enteroscopy34 -FDG (prognosis)78
-CT72
Gastric -EndoUS72 -SRI + CT/MRI63,64 -SRI + CT/MRI63,64 -SRI: SSA, PRRT73
-SRI5 -5
-CT5 -Endoscopy: Resection5
Colon -EndoUS72 -SRI + CT/MRI63,64 -SRI + CT/MRI63,64 -SRI: SSA, PRRT73 -SRI76,77
-SRI79 -CT: Surgery3 -FDG (prognosis)78
-CT72 -Endoscopy: Resection3
Rectum -EndoUS72 -SRI + CT/MRI63,64 -SRI + CT/MRI63,64 -SRI: SSA, PRRT73 -SRI76,77
-SRI -CT: Surgery3 -FDG (prognosis)78
-CT/MRI72 -Endoscopy: Resection3
Unknown -SRI (PET85) -SRI + CT/MRI63,64 -SRI + CT/MRI63,64 -SRI: SSA, PRRT73 -SRI76,77
-CT surgery, locally -FDG (prognosis)78
directed ablative
therapies5
Bronchial Bronchia -Bronchoscopy34 -SRI87,88 -SRI87,88 -Bronchoscopy: -SRI76,77
-SRI86 -CT87 -CT87 Resection34 -FDG (prognosis)78
-FDG89,90 -FDG89,90 -CT (MRI): Surgery87
-SRI: SSA, PRRT73
SRI, somatostatin receptor imaging with either 111In-pentetreotide (OCT) or PET/CT with 68Ga-DOTA-peptides; EUS, endoscopic ultrasound; SSA, somatostatin analogs; PRRT, peptide receptor radio-
nuclide therapy.
Morphologic Imaging Usually, primary NEN lesions appear as low echogenic masses.
Liver metastases may appear as either hypo- or hyperechogenic,
Morphologic imaging generally refers to radiologic modalities such generally with hypervascular aspects of contrast enhancement.72
as US techniques, CT, and MRI. Transabdominal US is often the US is the method of choice when there is a need to perform a
first technique utilized to study a patient with a GEP-NEN. Its value biopsy of liver metastases.
is limited by the fact that it is an operator-dependent technique Upper gastrointestinal endoscopy can detect lesions up to the
capable of producing a wide variation of sensitivity and specificity. ligament of Treitz, whereas colonoscopy can reveal colorectal
Therefore, in the vast majority of individuals with GEP-NENs, con- lesions and can visualize the terminal ileum. Flexible fiberoptic
ventional imaging with contrast-enhanced CT and MRI are the bronchoscopy is the method of choice to detect a bronchial NEN,
principal methods used for the detection of primary tumors, the which tend to present as central lesions. In some instances, endo-
delineation of the extent of metastatic disease, and as the modali- scopic maneuvers allow cytologic or histologic sampling and may,
ties to assess therapeutic response. even in certain circumstances, allow a resection of the primary
Contemporary CT utilizes multidetector CT (MDCT) scanners lesion to be undertaken.34
whereas MRI is undertaken with scanners exhibiting a field
strength of at least 1.5 T. Sequences should be evaluated with fat
suppression, to increase tissue contrast. The more recent develop-
ment of liver-specific contrast agents has significantly improved
Functional Imaging
the detection of liver and lymph node metastases.91 Both CT and Although conventional, morphologic imaging is useful in the initial
MRI should be performed as multiphasic studies.72 localization of the primary tumor and in the characterization of its
Because neuroendocrine lesions and their metastases are usu- architectural relationship with the surrounding structures, func-
ally hypervascular, they enhance after contrast medium injection tional techniques provide added information in establishing the
on CT and MRI. The degree, uniformity, and timing of enhance- receptor status (somatostatin, e.g., OctreoScan), metabolic activity
ment may vary, although vascular heterogeneity is generally con- (glucose, e.g., 18FDG-PET), and specific amine or peptide regula-
sidered a sign of malignancy, because of the related variety of tory profile (e.g., 5-HTP). In addition, they may provide further
vasculature, perfusion, and permeability.92,93 details in respect to the extent of disease and thereby facilitate
Among the morphologic modalities, US generally yields a poor more accurate staging and precise therapy.
sensitivity in localizing NENs. However, improved techniques, Nuclear medicine imaging is able to detect both the expression
including contrast-enhanced US, EUS, or IOUS have allowed for an and function of identifiable targets within a lesion. In most circum-
increase in sensitivity. stances NENs present two targets, SRs and the neuroamine uptake

system that can be utilized for imaging and therapy. In addition, in Similarly, SR imaging, which is predominantly of value in the
aggressive forms of the disease, the presence of accelerated glu- identification of GEP-NENs or bronchial NENs, may also be used
cose consumption can be traced via the glucose transporters. Con- for imaging chromaffin tumors, which also express SR in a very
versely, the absence of accelerated glucose metabolism may also be high percentage of cases.100
used to predict low-activity disease.94
Radiolabeled somatostatin analogs have been successfully used for
imaging of NENs since the early 1990s and their introduction repre-
Clinical Applications
sented a significant advance in the management of NEN disease. The specific aims of functional imaging of NENs are the localiza-
Somatostatin is a biologically active peptide present in the hypothala- tion of the disease, the staging, and the characterization of tumor
mus, brainstem, gastrointestinal tract, and pancreas that exists in lesions (as to their somatostatin expression, neuroamine uptake
either a 14-amino acid or a 28-amino acid isoform. SRs are ubiqui- mechanism, specific neuroendocrine metabolism, or glucose con-
tously expressed throughout the body and on circulating white cells sumption). In addition, these techniques are of considerable value
but their presence on cells of neuroendocrine origin is of special rel- in the restaging disease after therapy (as to the presence of tumor
evance in the identification of NENs. The receptor profile consists of residues, relapse, or progression), and guiding therapy selection
five G-protein–coupled somatostatin subtypes (sst1 to 5), all of which (in particular “cold” and radiolabeled somatostatin analogs) based
have been cloned and characterized. All five receptors bind with high upon the identification of a target, for example, SR.
affinity to native somatostatin, whereas its principal synthetic analog,
octreotide, binds with very high affinity to subtype 2 (sst2), showing
moderate affinity for sst5 and intermediate affinity for sst3. Sst2 is the Radionuclide Techniques
most frequently overexpressed receptor in NENs, and, therefore rep-
resents the optimal target for imaging, enabling primary and meta-
Somatostatin Receptor Scintigraphy
static masses to be localized by scintigraphy. Furthermore, there is The rationale of SR imaging is the receptor-mediated internaliza-
some evidence of a correlation between SR expression and prognosis, tion of the receptor–radioanalog complex and its retention in the
because patients with NENs that exhibit a positive scan profile usually cytoplasm. 111In-pentetreotide or OctreoScan represents the first
have a better response to treatment with analogs.84 approved radiopharmaceutical for NEN imaging and is the com-
In nuclear medicine imaging, octreotide derivatives are used monly used agent.
for SR imaging. 123I-labeled octreotide (123I-[Tyr3]-octreotide) was The radiopharmaceutical should be prepared in accordance
the first radiolabeled analog used for the in vivo visualization of with the manufacturer’s instructions and quality control performed
lesions overexpressing sst2 receptors. However, its relatively short with a calibrated ionization chamber. Radiochemical purity should
effective half-life and the high background of radioactivity within be checked with thin layer chromatography prior to patient admin-
the abdomen were drawbacks that limited its clinical application. istration. The amount of peptide injected in this preparation is
111
In-[DTPA-D-Phe1]-octreotide, or 111In-pentetreotide (OctreoScan), 10 μg. The recommended injected activity, to obtain a high quality
was subsequently developed and because of its stability in plasma, examination in terms of sensitivity, should be ∼200 MBq (5.4 mCi).
as well as its more favorable imaging characteristics in delayed However, lower activities can be administered if acquisition param-
images, has became the agent of diagnostic choice.95 eters are adjusted accordingly.101 At least two different sets of pla-
Other radiolabeled somatostatin analogs that have been uti- nar and/or whole-body images should be acquired to facilitate the
lized in clinical studies include the 99mTc-labeled depreotide (P829) interpretation of the examination. Commonly adopted protocols
(currently commercially available for lung cancer studies) and include scans at 4 and 24 hours or, optimally, 24 and 48 hours
99m
Tc-EDDA/HYNIC-octreotide (99mTc-N-α-[6-hydrazinonicotinoyl]- post injection. Later images can also be advantageously acquired
octreotide), and 111In-DOTA-lanreotide (MAURITIUS).96–98 Tc-labeled should the earlier images provide equivocal clinical information. A
octreotide derivatives, such as 99mTc-EDDA/HYNIC-octreotide, or γ-camera equipped with a medium-energy, parallel-hole collimator,
alternative somatostatin analogs, for example, 111In-labeled lanreo- with the window set for 20% on 111In photopeaks (172 and 245 keV)
tide have failed to supplant 111In-pentetreotide because no overt should be used to acquire planar images, either spot or whole body.
advantage over the conventional, commercially available technique To increase sensitivity it is mandatory to acquire 3D reconstructed
has been demonstrated. SPECT images, preferably after 24 hours to increase sensitivity.80
In addition to the biologic propensity to overexpress SRs, NENs The concentration of the radiopharmaceutical increases signifi-
possess the chemical capacity of decarboxylation; amino acids cantly after the first hours and it is evident that the coregistration
acquired by the cells can thus be transformed into biogenic amines. of SPECT/CT images, by means of hybrid devices that combine
This unique biochemical property was recognized in the original SPECT and multislice CT, increases the specificity of the study, by
denomination as APUD tumors. Certain types of neuroendocrine improving the anatomical localization of the areas of uptake and
cells can, in addition, synthesize catecholamines in an enzymatic therefore reducing equivocal findings.102 Laxatives are also recom-
pathway by converting the amino acid tyrosine into L-DOPA mended to eliminate nonspecific activity in the bowel. To achieve an
(L-dihydroxyphenylalanine). L-DOPA is subsequently decarboxyl- acceptable sensitivity, it is mandatory to acquire images with suffi-
ated to dopamine, oxidized to norepinephrine (NE), and methyl- cient counts per view. To obtain this, planar images should be
ated to produce epinephrine, which is transported into synaptic acquired for 10 to 15 min/image, using a 512 × 512 word matrix or
vesicles. NE transporters present on the cell membrane are then 256 × 256 word matrix, whole-body images into a 1,024 × 512
capable of presynaptic catecholamine reuptake. As a consequence word matrix or 1,024 × 256 word matrix for a minimum of 30 min-
of these biochemical features, NENs can be imaged by either utes, corresponding to a maximum scanning speed of 3 cm/min. For
18
F-DOPA PET, which accumulates within cells because of the high precise details of the detailed scanning protocol, the Society of
activity of the aromatic amino acid L-DOPA decarboxylase, or by Nuclear Medicine (SNM) or the European Association of Nuclear
metaiodobenzylguanidine (MIBG). The latter strategy relies upon Medicine (EANM) procedure guidelines for 111In-pentetreotide scin-
MIBG uptake by the cell via the NE transporter and accumulation tigraphy should be consulted.101,103
in neurosecretory vesicles by means of the vesicular catecholamine After injection, there is a rapid plasma clearance and a progres-
transporter. In this technique, expression of transporters and the sive accumulation in tissues. The kidneys are the principal route of
neurosecretory vesicles for catecholamine are the basis of imaging. elimination, followed by the hepatobiliary system.86 A normal scan
Usually, 18F-DOPA or 18F-Dopamine PET and MIBG scintigraphy clearly depicts the spleen, the liver, and the kidneys, together with
are highly effective in the detection of chromaffin tumors, but the a variable visualization of the pituitary, thyroid, urinary bladder,
isotopes can also be taken up by nonchromaffin NENs.99 and bowel. The visualization of the kidneys is mainly because of the


Figure 20.9. Normal distribution of 111
In-pentetreotide, anterior (left) and
posterior (right) whole-body images, 24 hours post injection with physiologic
visualization of liver (L), kidneys (K), spleen (S), and of the activity eliminated in
the intestine (I) and urinary bladder (B).
proximal tubular reabsorption of the radiopeptide, whereas the disease. The latter may especially occur in benign insulinomas
uptake to the spleen, pituitary, and thyroid is receptor mediated. (malignant insulinomas are usually positive) or in dedifferentiated,
Figure 20.9 demonstrates an example of a normal distribution. highly aggressive malignant NEN disease. In some cases, normal
Images should be interpreted based upon the integration of accumulation in the liver may mask isointense metastases or those
clinical information. Nevertheless, as a general rule, clearly out- with a relatively low expression of SR density.81
lined areas that show an isotope uptake higher than the normal The issue of the possible competition by unlabeled somatosta-
liver (below, if outside the liver) distribution are classified as posi- tin analogs on the uptake of the radiolabeled counterpart has long
tive for receptor expression and thus considered to represent neu- been debated and remains unresolved.101 The lack of predictable
roendocrine malignancy. There are, however, alternative behavior of these neoplasms during therapy may be ascribed to
conditions that may be associated with increased SR expression the variable sensitivity that different types of NENs exhibit to the
and hence, exhibit increased uptake. effect of chronic exposure to somatostatin analogs on intracellular
In the evaluation of a scan, it is therefore important to consider receptor trafficking and membrane redisplay.105 However, to min-
possible sources of a false-positive, namely nonNEN SR-positive imize any diminution in scan sensitivity, it is considered prudent
lesions or accumulations of isotope that represent other disease to withdraw short-acting analogs for at least 48 hours, long-acting
states or scan irregularities. These may generically be divided into formulations for 4 to 6 weeks, and to otherwise undertake scintig-
abnormal sites of isotope accumulation, areas of inflammation, or raphy just prior to the next administration.106
other tumors. As such, false positives may include areas of chronic SRS is commonly used to select patients for therapy with “cold”
inflammation (such as radiation pneumonitis, sequelae of recent and radiolabeled somatostatin analogs.73
surgery), accessory spleens, gallbladder accumulation, focal stool The sensitivity of 111In-pentetreotide scan has been well docu-
aggregation, thyroid nodules, pulmonary granuloma, diffuse breast mented.68,79–81,84,95 Given the heterogeneity of NENs, they may be
uptake, a recent cerebrovascular accident, arthritis, abscesses, and categorized into high sensitivity tumors (detection rate >75%),
urine contamination.104 Figure 20.10 shows a positive OctreoScan such as pituitary tumors, GEP-NENs, paragangliomas, SCLC, and
in a patient affected by a pancreatic NEN (A) and a false-positive intermediate sensitivity tumors (detection rate ranging between
result related to postactinic chronic inflammatory modifications in 40% and 75%), such as insulinomas, medullary thyroid carcino-
a patient affected by bronchial NEN (B). mas, and pheochromocytomas.73
In the interpretation of scans, it should be considered that pro-
longed therapy with “cold” somatostatin analogs may reduce the
physiologic uptake to the spleen and the liver.
Somatostatin Receptor PET
As opposed to false positives, the issue of false negatives is wor- The goal of an optimal protocol of 111In-pentetreotide scan is to be
thy of clinical consideration. This reflects the lack of visualization able to ensure good image quality and to provide useful clinical
of NEN lesions and is most commonly ascribed to incorrect meth- information. Nevertheless, since the beginning of 2000, the
odology. This may be a consequence of too low a dose of adminis- approach to the functional imaging of NENs has been revolution-
tered activity, too rapid (or too early) scan time, the absence of ized by the introduction of octreotide derivatives, the DOTA-
SPECT images, or lesions whose dimensions fall below the resolu- peptides, labeled with the positron emitter gallium-68. The three
tion limit of the γ-camera. Other possible causes may be competi- most commonly used analogs are DOTA-Tyr3-octreotide (DOTA-TOC),
tion for receptor uptake by recent analog therapy, alteration of DOTA-Tyr3-octreotate (DOTA-TATE), and DOTA-1-Nal3-octreotide
receptor expression by recent chemotherapy, or receptor-negative (DOTA-NOC). These analogs retain an octreotide-like affinity profile

C D
Figure 20.10. Pancreatic neuroendocrine
neoplasm (NEN) visualized by 111In-pentetreo-
tide scintigraphy. Planar abdominal imaging,
24 hours post injection (A) depicts the primary
tumor in the pancreatic head (solid arrow),
clearly visible in the corresponding computed
tomography (CT) slice (B, dashed arrow).
Bronchial NEN with previous radiotherapy. A
typical nonspecific, postactinic bilateral sym-
metrical image (dotted arrows) is visible on
the anterior (C) and posterior (D) images col-
lected 24 hours post injection. The corre-
sponding CT scan (E) shows bilateral diffuse
B E ground glass opacities related to the previous
external irradiation.
and, in particular, a high affinity for sst2. Only DOTA-NOC exhibits and body weight. To avoid possible clinicopharmacologic effects, the
a substantial affinity for sst3.107 Despite these differences in recep- amount of the injected peptide should not exceed 50 μg.113
tor affinity, a clear superiority of one compound over the others has The clearance of 68Ga-DOTA-peptides from the blood is rapid.
not been unambiguously demonstrated in clinical practice. A com- Arterial activity elimination is biexponential and no radioactive
parison of 68Ga-DOTA-TOC versus 68Ga-DOTA-TATE PET/CT in the metabolites are detected in serum and urine in the first 4 hours.
same patients, yielded comparable diagnostic accuracy for the two Maximal tumor activity accumulation is reached at 70 ± 20 minutes
radiopeptides, with a potential advantage for 68Ga-DOTA-TOC in the post injection. Excretion occurs almost exclusively via the kidneys.114
number of detected lesions and the higher SUV.108 However, a The PET/CT acquisition begins 45 to 60 minutes after the
recent comparison of 68Ga-DOTA-TATE and 68Ga-DOTA-NOC PET/ intravenous administration of the radiopeptide, by means of a
CT imaging in the same patients with NENs, showed higher SUV dedicated PET/CT scanner as a whole-body image, preferably in a
values and superiority of 68Ga-DOTA-TATE on a lesion basis, and a 3D mode. For a detailed description of the scanning protocol and
comparable diagnostic accuracy on a patient basis.109 The inconclu- image reconstruction, reference should be made to the EANM pro-
sive results on this issue as reported in the literature possibly reflect cedure guidelines for 68Ga-DOTA-peptides.113
the particular receptor configuration of the individual tumors. As in the case of conventional scintigraphy, the normal find-
Currently, these novel radiopharmaceuticals are in use only as ings at receptor-based PET include the visualization of the liver,
components of research projects, because none have yet been regis- the spleen, the pituitary, the thyroid, the kidneys, as well as the
tered for use in routine clinical practice. It is of note that PET/CT with adrenal glands, the salivary glands, the stomach wall, and the
68
Ga-DOTA-peptides offers several advantages over the conventional intestines. Figure 20.11 demonstrates an example of normal
scintigraphic technique: The synthesis of the radiopeptide from the distribution.
68
Ge/68Ga generator eluate is simple and economical and can also be The clinical interpretation of the images is easier than SRS
undertaken in centers without an on-site cyclotron, the imaging can because of the better spatial resolution and the CT coregistration.
be performed as a single day procedure, the activity in a given region As with 111In-pentetreotide, besides normal findings, clearly defined
of interest can be semiquantified as SUV, and the spatial resolution areas that show an uptake higher than that of the normal liver are
of the method is higher and allows an excellent quality of the images considered as positive for receptor expression, and thus consistent
with the detection of small lesions <10 mm. Another advantage is the with the presence of a NEN lesion.
possibility of labeling the same peptide used for radionuclide therapy When using receptor-based PET, the pancreas requires some-
(whether DOTA-TOC, DOTA-TATE, or DOTA-NOC).110,111 what different consideration as it may exhibit a variable uptake of
As a result, PET/CT with 68Ga-DOTA-peptides represents a 68
Ga-DOTA-peptides. Although SRs are located preferentially in the
major advance in the management of NEN patients and is increas- endocrine component of the pancreas, uptake at the pancreatic
ingly being utilized in specialized centers given its greater accu- head has been documented. This may represent a potential source
racy over conventional scintigraphic imaging.112 The acceptance of false-positive results that should not be ignored. Because the pan-
of the increased accuracy obtained with 68Ga-DOTA-peptides in creas and the duodenum are frequent sites of neuroendocrine malig-
NENs is further substantiated by the rapid increase in the number nancies, it is important to differentiate pathologic from physiologic
of recent publications detailing their clinical use (an in-house accumulation of the radiopeptide. In a series of 245 patients under-
PubMED search identified 228 publications relating to 68Ga-DOTA; going PET/CT with 68Ga-DOTA-NOC, nonspecific uptake to the head
51 in 2012, and 54 in the first 9 months of 2012).110 of the pancreas with a focal and diffuse pattern was identified in
The recommended activity to obtain good image quality ranges 23% and 8% of patients, respectively.115 It has recently been demon-
from 100 to 300 MBq, depending on the tomographic characteristics strated that this focal uptake is most likely to be the result of a

nonspecific phenomenon if the SUV is low and similar to the liver, with
a threshold value of the average head-to-liver SUV ratio around 1.
The precise clinical significance of the uptake in this location is still
unclear, although misalignment of PET and CT data, caused by dif-
ferent breathing phases, is a common cause.116
False-positive results occur as with conventional somatostatin
imaging and can be because of the presence of accessory spleens,
sites of inflammation with lymphoid infiltrate, or urinary contam-
ination. Figure 20.12 shows a positive 68Ga scan in a patient with
a pancreatic NEN (A); (B) shows an example of nonspecific accu-
mulation to the head of the pancreas.
As noted for scintigraphy, therapy with “cold” somatostatin ana-
logs may interfere with the uptake of 68Ga-DOTA-peptides, although
there is no consensus on this issue. In a recent series of 105
patients, 35 of whom had received chronic therapy with LAR
octreotide at various intervals between the injection and the PET
examination, treatment with somatostatin analogs did not signifi-
cantly alter the tumor uptake, in comparison to binding levels in the

normal spleen and liver.117 Nevertheless, given the pharmacokinet-
ics of the long-acting release formulations, this subject requires fur-
ther exploration in larger series of patients studied at homogeneous
intervals between the analog injection and the PET.118
Although the sensitivity of 68Ga-DOTA-TOC PET/CT for NENs is
high, it has been proposed that the use of contrast media may
further enhance detection; in standard usage, unenhanced PET/
CT is considered sufficient.119
Evaluation of the performance of 68Ga-DOTA-TOC PET has been
undertaken in a large series of 84 patients with NENs of various
origin and compared to CT scan and receptor scintigraphy. PET
exhibited the greatest sensitivity (97%) compared to CT (61%) and
SRS (52%) for the detection of NEN lesions, especially in patients
Figure 20.11. Normal distribution of 68Ga-DOTA-TOC (maximum intensity projection image) with small tumors at a nodal or bone level. PET was also able to
with physiologic visualization of the pituitary (P), thyroid (T), liver (L), adrenals (A), kidneys (K), spleen
(S), pancreatic head (PH), and of the activity eliminated in the intestine (I) and urinary bladder (B). identify small lesions in unusual locations such as the breast,
uterus, prostate, ovary, and kidney.71,120
PET/CT with 68Ga-DOTA-peptides is used to select patients for
therapy with “cold” and radiolabeled somatostatin analogs.
1 2
4
A B
Figure 20.12. A: 68Ga-DOTA-TOC PET/CT in a patient with a pancreatic neuroendocrine tumor (1, MIP, maximum intensity projection image) with visualization of
the primary (solid arrow) and liver metastases (dotted arrow). These lesions are more clearly depicted in the correspondent transaxial fused slices (2, liver metas-
tasis in the liver dome; 3, primary tumor). B: An example of focal non specific uptake to the head of the pancreas (solid arrows) at PET/CT with 68Ga-DOTA-TOC.
The MIP image (4) shows an area of focal uptake that has no anatomical reference on the correspondent fused transaxial slice (5). Moreover, the uptake is similar
to the one of the normal liver.

Ta bl e 2 0 . 5
Pharmaceutical Compounds that Reduce the Sensitivity of Scintigraphy
Drugs Mechanism of Interference Withdrawal Before MIBG
Antiarrhythmics (e.g., amiodarone) Uptake inhibition and depletion Not easily feasible
α-β-blockers (e.g., labetalol) Uptake inhibition and depletion 3d
Calcium channel blockers (e.g., amlodipine) Increased uptake and retention 1–2 d
α-2 sympathomimetics (e.g., salbutamol) Depletion of granules 1d
Vasoconstrictor sympathomimetics Uptake inhibition and depletion 1–2 d
(e.g., pseudoephedrine)
Neuroleptics (e.g., haloperidol) Uptake inhibition 1–15 d (short-acting formulations)
Antihistamine (e.g., promethazine) Uptake inhibition 1d
Opioid analgesics (e.g., tramadol) Uptake inhibition 1d
Tricyclic antidepressants (e.g., amitriptyline) Uptake inhibition 2–8 d
Psychostimulants (amphetamines, cocaine) Uptake inhibition and depletion 1–5 d
18
F-DOPA PET There are numerous drugs that reduce the sensitivity of the
18 18
scintigraphy and frequently result in false negatives; this occurs
The ligand 6-L- F-dihydroxyphenylalanine ( F-DOPA) is a sub- through interference with the uptake, intracellular transport,
strate for the LAT and is utilized in the catecholamine synthesis granule storage, or the retention of MIBG.128 To ensure optimal
pathway where it is subsequently decarboxylated by the AADC. The imaging, these pharmaceuticals should be temporarily withdrawn
resulting decarboxylated 18F-dopamine is transported by the mono- before the examination, for a time period of approximately five
amine transporters and stored in the secretory granules, where the times longer their respective half-lives (Table 20.5).129,130
radioactivity remains trapped. The enzyme, AAAD, constitutes a Although 131I-MIBG and 123I-MIBG are commercially available
hallmark of neuroendocrine cells, namely APUD, and is generally for diagnostic imaging, the former has been preferred because it
upregulated in chromaffin tumors as well as in many NENs.121,122 is more widely available and economical. The physical character-
Oral coadministration of carbidopa, a peripheral inhibitor of istics of 131I-MIBG, although not optimal for scintigraphic imaging
AADC normally used in the treatment of Parkinson disease, is rou- (γ-energy 364 keV, half-life 8 days), facilitates delayed studies.131
tinely performed during 18F-DOPA imaging to reduce the back- Alternatively, the physical properties of 123I (γ-energy 159 keV, half-
ground activity, particularly in the pancreas, and to increase the life 13.3 hours) provide better image quality, more favorable dosim-
tumor uptake.123 etry, and the possibility of performing a SPECT study, rendering it
Whole-body imaging begins 30 to 90 minutes after injection of the agent of choice.132,133 123I-MIBG has, however, recently been
at least 100 MBq. approved for US usage by the Food and Drug Administration.134
Normal findings include the visualization of the kidneys, ureter, Thyroid blockade with nonradioactive iodide or, alternatively,
and bladder, with variable uptake in the gallbladder, intermediate potassium perchlorate, is necessary to avoid thyroid uptake of free
uptake in the corpus striatum, myocardium, liver, and low uptake radioiodine and consequent potential damage. A solution of satu-
in the small intestine and muscles. There is also evidence of min- rated potassium iodide (1 to 2 mg/kg/day) is commonly used,
imal uptake in the normal adrenal medulla.121 beginning 1 day before injection and continuing for 3 to 5 days.
Administered activities are 37 to 74 MBq (1 to 2 mCi) for
131
11
C-5-HTP PET I-MIBG and 370 MBq (10 mCi) for 123I-MIBG. To avoid potential
hormonal side effects, 123I- or 131I-MIBG, should be administered
11
C-5-HTP is a serotonin precursor, which is the substrate for DOPA by slow intravenous injection.
decarboxylase.49 11C can be incorporated without changing the bio- 131
I-MIBG scan is performed using a γ-camera equipped with a
logic properties of the molecule and 11C-5-HTP is therefore able to high-energy, parallel-hole collimator. Images are collected at 24 and
define the metabolism of the neuroendocrine cell, and is thus con- 48 hours after injection. If nonspecific activity is suspected in the kid-
sidered a universal imaging method for NEN detection. Tomographic neys or bowel, delayed images can be recorded after 72 to 120 hours.
imaging is performed after intravenous injection of 370 MBq.124 Whole-body and planar images of areas of interest are collected.
Despite this obvious application in diagnosis, its short half-life and 123
I-MIBG scan is performed with a low-energy, high-resolution
the need for an on-site cyclotron have relegated the synthesis and collimator. Images are collected 6 and 24 hours after injection and,
clinical utility of 11C-labeled 5-HTP in NEN disease to specialized if needed, 48 hours post injection. Whole-body and spot images are
centers. recorded. The use of 123I-MIBG allows SPECT imaging which is usu-
ally undertaken 24 hours after administration. The use of hybrid
SPECT/CT system further improves sensitivity.133 Suboptimal sensi-
MIBG Imaging
tivity can be caused by a small lesion size and/or an extra-adrenal
MIBG is an NE analog that concentrates within secretory granules location.135 MIBG SPECT evaluated side by side with contrast-CT or
of catecholamine-producing cells. It is structurally similar to gua- MRI and/or hybrid imaging with SPECT/CT, provides an even more
nethidine. The agent has been in use either labeled with 131I or, accurate anatomic localization of areas of MIBG uptake.136
later, with 123I, since 1980 for the specific imaging of tumors that Normal findings, with either 123I- or 131I-MIBG, are the visualiza-
originate from the neural crest (chromaffin tumors and NENs).125 tion of salivary glands, heart, lungs, liver, spleen, bladder and, to
Apart from its diagnostic utility131I-MIBG has also been used (since some extent, the bowel. Normal adrenal medulla is frequently vis-
1984) in the therapy of chromaffin tumors and NENs.126 ible with 123I-MIBG but rarely with 131I-MIBG.
MIBG, like NE, is taken up by an active, sodium- and energy- Any area of uptake located outside of these sites should be
dependent amine uptake mechanism (uptake-1), inserted into the regarded as suspicious for malignancy. Figure 20.13 provides an
cell membrane of chromaffin tissues, and then transported to the example of normal distribution (A) and a metastatic pheochromo-
intracellular storage granules by an active uptake mechanism.127 cytoma (B).


Figure 20.13. A: Normal distribution of
131
I-MIBG, 6 hours after injection (S, salivary
glands; Lu, lungs; H, heart; Li, liver; K, kidneys;
B, bladder.) (Courtesy of Dr. A. Chiti, Istituto
Clinico Humanitas, Rozzano, Milan, Italy).
B: Patient affected by a right adrenal pheo-
chromocytoma. An area of intense 131I-MIBG
uptake (solid arrows) is visible in the whole-
body (left) and fused SPECT-CT (right)
images. (Courtesy of Dr. P. Erba, University of A B
Pisa, Pisa, Italy.)
Rare causes of false-positive results such as the physiologic accu- Recently, however, the utility of this modality has been reconsid-
mulation of MIBG within the urinary tract or the bowel, which can ered as a predictor of tumor assessment. Thus, in a prospective
mimic a tumor lesion, should also be considered. False-negative study of 38 patients with GEP or bronchial NENs, 18F-FDG PET
results may occur if the lesion is of small dimension or in lesions positivity was noted to be an independent predictor (irrespective of
whose uptake mechanisms have been altered by concomitant grading, based on Ki-67 index) of the progression-free survival at
usage of drugs (Table 20.5). multivariate analysis.94 Thereafter, a second study in a larger cohort
of 98 patients prospectively enrolled after surgery and scheduled
18 for various therapies, demonstrated that between 18F-FDG uptake,
F-FDG PET Ki-67, CgA, and liver metastases, the only parameter that corre-
18
F-FDG, a glucose analog, is transported into the cell via dedicated lated with prognosis was positivity at 18F-FDG PET. Of particular
glucose transporters where it is subsequently phosphorylated by the note was the observation that univariate analysis indicated that an
cytoplasmic enzyme, hexokinase. The resulting compound cannot be SUVmax >9 and a high Ki-67 index were significant predictors of
further metabolized and is thus trapped within the cytoplasm. overall survival, whereas multivariate analysis showed that an
Because many tumors, particularly those of aggressive or accelerated SUVmax >3 was the only predictor of progression-free survival.78
proliferative nature, exhibit an increased glycolytic metabolism, they Although additional concordant reports are emerging in the litera-
overexpress glucose transporters and hexokinase. This provides the ture, these observations need confirmation in larger series.
biologic basis for the use of 18F-FDG as a radiopharmaceutical to The use of 18F-FDG PET has been re-evaluated in chromaffin
detect such tumors. The process of accelerated glycolytic metabolism tumors given the observations of a study of 216 patients which
is, in addition, a phenomenon that is common to activated inflamma- reported a high sensitivity for metastatic forms (82.5%). In the
tory cells and 18F-FDG may accumulate at sites of inflammation same study it was noted that the uptake was higher in succinate
which constitutes a potential cause of false positivity for malignancy. dehydrogenase (SDH) and VHL-related tumors.139
For a detailed description of the scan methodology, reference
should be made to the specific section on this subject.
Currently, 18F-FDG PET has widespread use in oncology, par-
ticularly in staging, assessing the response to treatment and in Gastroenteropancreatic
planning external-beam radiotherapy.137
The reported sensitivity of 18F-FDG PET in NENs, however, is
Neuroendocrine Tumors
generally low. A recent prospective study in 96 patients showed a
sensitivity of only 58%. As a result, 18F-FDG PET has always been
Conventional Imaging
regarded as a secondary modality in neuroendocrine oncology, par- Pancreatic NENs typically are highly vascularized and enhance
ticularly apt for the identification of undifferentiated (aggressive/ during the arterial and venous phases on CT. Heterogeneous
high) tumors, especially in the lung, or when the SRS is negative.138 enhancement may occur in lesions of larger dimension which are

often associated with necrosis, therefore, representing an indirect Likewise, on MRI study, liver metastases show enhancement
sign of tumor aggression.140 after gadolinium. Hepatic arterial phase and fast spin-echo
The localization of a small tumor, like an insulinoma, may be T2-weighted sequences are the most sensitive method.147 Overall,
difficult and modern multiplanar CT examinations are recom- MRI is considered to provide a higher sensitivity than CT.
mended to improve the visualization of the pancreas.141 An analysis of four studies of hepatic metastases in 135 patients,
The diagnosis of a gastrinoma suggests a localization most reported 82% sensitivity and 92% specificity for CT, and 82% and
commonly in the duodenum or the pancreas. These lesions can 95% for MRI. Data on the sensitivity of US for the detection of liver
also be multifocal, especially in MEN type 1. Metastatic spread may metastases are scarce but overall are lower than CT/MRI. A study on
occur to lymph nodes in the peripancreatic area, often referred to 17 patients with 69 liver metastases reported a sensitivity of 68% for
as the “gastrinoma triangle.” unenhanced US, rising to 99% after contrast medium.148 The clinical
Pancreatic lesions appear as hypointense on fat-suppressed utility of US is most effective in providing guidance when undertak-
T1-weighted sequences, hyperintense on fat-suppressed T2-weighted ing a biopsy.72
sequences, and hyperintense on diffusion images.65 These lesions
markedly enhance after gadolinium injection, resulting in hypoin-
tense to isointense, when compared to the surrounding parenchyma.142
Functional Imaging
Despite the variability in presentation, clinically silent tumors In the two decades since its introduction, the use of SRS in GEP-
generally have larger dimensions and may have metastatized when NENs has become widespread. As illustrated below, considerable
identified. The image features are similar to functioning lesions, data have accumulated indicating a sensitivity of 75% to 100% in
namely an iso/hypodense aspect on basal CT images, which show localizing the primary tumor and, at the same time, assessing the
contrast enhancement in arterial and portal venous phases, as well extent of disease.149 Studies have demonstrated a higher accuracy
as a hypointense appearance in T1 images, hyperintense in T2 compared to conventional imaging such as CT/MRI.149,150
phase, which show enhancement after gadolinium. SRS has a central role in the tumor localization in the presence
An overview of 11 studies in 343 patients with pancreatic NENs of clinical syndromes, such as Zollinger–Ellison, where it represents
reported CT to have a mean sensitivity and detection rate of 73%, the single most sensitive method for imaging either primary or met-
with 96% specificity. Mean sensitivity and specificity for MRI are astatic liver lesions.68 The European Multicenter Trial concluded that
93% and 88% for pancreatic NENs. Transabdominal US per se has the sensitivity of SRS in locating glucagonomas was 100%, VIPomas
a poor detection rate in pancreatic lesions (mean 39%). A collation 88%, and gastrinomas 73%, whereas the diagnostic sensitivity was
of six studies noted that this modality has largely been superseded 43% for insulinomas.69 Somatostatin scintigraphy is thus considered
by EUS (90%) and IOUS (92%).72 to play a secondary role in localizing insulinomas, which generally
In a separate assessment, EUS was considered able to detect have a low expression of sst2, although a variable proportion of
45% to 60% of duodenal lesions and 90% to 100% of pancreatic benign and malignant insulinomas may show uptake.151,152 The
lesions.3 It has been reported that the combination of MDCT and nuclear medicine study of most utility in the diagnosis of insulinoma
EUS may reach 100% sensitivity in the localization of a primary is 111In-GLP-I because both benign and malignant insulinomas
pancreatic lesion.143 express the glucagon 1–like peptide.153
On CT scans, small bowel NENs usually appear as a contrast- In functioning tumors, receptor scintigraphic techniques may
enhancing spiculated mass, sometimes containing calcifications, also allow the localization of the primary tumor in anomalous
surrounded by lines of desmoplastic reactions.144 Angio-TC may sites, such as a gastrinoma of the cardiac septum, or in areas that
be useful to assess the involvement of vessels, such as the superior may be difficult to explore, such as the retroperitoneal or posterior
mesenteric vasculature or the portal venous system. mediastinal region.154
The MRI appearance of these lesions is isointense to muscle in The diagnostic accuracy of 111In-pentetreotide scintigraphy in
T1-weighted sequences and hyper/isointense in T2-weighted nonfunctioning tumors is not much different to secreting tumors,
images. Usually, they enhance on fat-suppressed T1 images. as the SR-mediated internalization of the radiopeptide is indepen-
The efficacy of endoluminal diagnostic studies such as enteros- dent of the secretory activity of the cell. However, in the absence
copy, contrast intestinal radiography, and videocapsule endoscopy of a clinical syndrome that might initiate earlier imaging, nonfunc-
is suboptimal given the difficulty in adequately accessing the small tional tumors may be larger when identified. In this case, nuclear
bowel.34 Most of the small bowel is not directly accessible, and medicine techniques may have a secondary role in locating the
videocapsule endoscopy or the more invasive double balloon primary tumor, compared to conventional imaging.
enteroscopy is the only technique that can study this area, although In a study of 131 patients with GEP-NENs comprising a sub-
their sensitivity is not high.34 CT enteroclysis has a clearly inferior group of 26 nonfunctional pancreatic lesions, the sensitivity of SR
sensitivity and specificity to videocapsule enteroscopy (50% and imaging was 79%.79
25% versus 38% and 100%, respectively for the two methods).145 Other series have demonstrated a sensitivity in locating nonin-
Endoluminal lesions, such as gastric (especially types 1 and 2), sulinoma pancreatic NENs ranging from 75% to 100%.70,79,80,155
duodenal, rectal and colonic NENs, are better diagnosed by endos- The sensitivity of 111In-pentetreotide in detecting small bowel
copy. The role of radiologic imaging, in these cases, is mainly NENs is high, and in some centers has been reported to reach
directed at staging the disease by providing anatomic evidence of 100% although it is generally somewhat less.81,82,149
the locoregional and distant involvement. In an initial study of more than 1,000 patients, 52 of which had
Colonic and rectal NENs are generally diagnosed with endos- carcinoids, SRS localized the primary tumor in 86% of patients.95 In
copy and a CT scan is used to assess the regional and distant a study in 131 patients, 87 of which were carcinoids (mainly intes-
metastases. In rectal NENs, MRI may also be used to evaluate the tinal), the sensitivity for primary tumor localization was 54%.79
invasion of the rectal wall and adjacent structures although EUS In a group of 12 patients with positive scan referred for the
is also an effective modality in delineating transmural disease and search of a primary, SPECT/CT improved the localization of the
perirectal lymph node involvement.72 primary tumor in only three of the patients.80
The most common site of NEN metastasis is hepatic and such In the evaluation of liver metastases, present in 40 of 64 patients
lesions are often like the primary, hypervascular. They appear as with GEP-NENs studied with CT, MRI, and 111In-pentetreotide, pla-
hypodense masses on CT, with rich enhancement during the arte- nar and tomographic receptor imaging exhibited the lowest sensitiv-
rial phase, and revert to hypodense during the portal phase.146 ity (204 lesions), compared to arterial phase–enhanced CT (325
Larger metastases, enclosing areas of necrosis, may appear as het- lesions), and arterial phase–enhanced T1-weighted MRI (394 lesions).
erogeneously enhanced. The median size of metastases was the only factor significantly

associated with the sensitivity of scintigraphy for the detection of In a series of 59 patients with an unknown primary studied in
liver metastases.156 an attempt to locate the primary tumor, 68Ga-DOTA-NOC was suc-
The principal limitation of SRS resides in the typical low spatial cessful in 35 (32 of which were GEP-NENs), with an overall detec-
resolution of the γ-camera. In recent times, the introduction of tion rate of 59%.159
novel somatostatin analogs labeled with positron emitters such as When seeking to establish the location of a NEN, receptor PET
68
Ga has altered the diagnostic approach to NENs. Numerous stud- should not be performed as the initial technique in patients with a
ies have demonstrated a high tumor to nontumor contrast and a suspicion of a NEN based only on increased blood markers, like
higher sensitivity of PET/CT with 68Ga-DOTA-peptides compared to CgA, or clinical symptoms. 68Ga-DOTA-NOC is more frequently pos-
conventional imaging and scintigraphy.110 Although not all studies itive when conventional imaging or when clinical and biochemical
rigorously compared the PET technique with an adequate scinti- findings suggest a NEN.85
graphic protocol, it seems probable that PET with 68Ga-DOTA-pep- Unless specifically investigated, skeletal metastases are easily
tides will replace conventional receptor imaging in the future.6,157 missed on CT. PET with 68Ga-DOTA-peptides is useful in the early
In the initial published study with 68Ga-DOTA-TOC, the sensitivity visualization of bone metastases, with a higher sensitivity, specificity,
of PET in a group of eight NEN patients, six of which were GEPs, and accuracy than a CT scan. In a study of 84 patients (116 PET-
was 100% as opposed to 85% for conventional scintigraphy.114 positive lesions), only 84 (72.5%) bone metastases were evident at
The use of 68Ga-DOTA-NOC in a group of 84 patients (62 GEPs) conventional scintigraphy and only 58 (50%) at CT scan.71 Recently,
demonstrated 97% sensitivity, compared to 61% and 52% for con- in a study of 51 patients, 35 of which were GEP-NENs, demon-
ventional imaging and scintigraphy, respectively.71 strated that PET/CT with 68Ga-DOTA-TOC performed better than

PET/CT with 68Ga-DOTA-TATE produced a positive interpreta- conventional SRS or bone scintigraphy, resulting in 97% sensitivity
tion in 87% of 47 patients with a radiologic or biochemical suspi- and 92% specificity.160 Figure 20.14 reports examples of localization
cion of NENs, mainly GEPs 79%, when conventional receptor and staging with 68Ga-DOTA-TOC of a duodenal gastrinoma in the
imaging was ambiguous. No false positive was identified.158 MEN1 syndrome (A); (B) shows an example of restaging with
1 2
1 2 3 4
Figure 20.14. A: Example of localization of a

duodenal gastrinoma in multiple endocrine
neoplasia type 1 with 68Ga-DOTA-TOC PET/CT
after a positive secretin test. A magnetic reso-
nance image (2) is silent, while both maximum
intensity projection (MIP) (1) and transaxial
fused images (3) show the duodenal lesion
(dashed arrows) with peripancreatic lymph
nodes (solid arrows). In this case the PET exam-
ination serves also as a staging technique.
B: Example of restaging with 68Ga-DOTA-TOC
PET/CT in a patient affected by multiple bone
marrow metastases from a pancreatic neuro-
endocrine tumor (1 and 2, fused sagittal and
MIP images, respectively, at basal evaluation),
undergone peptide receptor radionuclide radio-
therapy with 177Lu-DOTA-TATE (25 GBq). Follow-
up 68Ga-DOTA-TOC PET/CT performed after the
end of treatment shows a complete response
(3 and 4, fused sagittal and MIP images, B
respectively).

Figure 20.15. 18F-DOPA PET/CT in a patient

affected by diffuse bone, lymph node, liver, and
soft tissue metastases from a small bowel
neuroendocrine tumor. (Courtesy of Professor
S. Fanti, University of Bologna, Bologna, Italy.)
68
Ga-DOTA-TOC of a patient with a pancreatic NEN who had under- Similar results were obtained with 68Ga-DOTA-TATE in a group of
gone receptor radionuclide therapy with 177Lu-DOTA-TATE ( A to C). 25 patients with NENs mainly of GEP origin. SR PET yielded a
Alternative modalities of imaging GEP-NENs include 18F-DOPA clearly superior sensitivity compared to 18F-DOPA (96% versus 56%,
and 11C-HTP. 18F-DOPA PET was popular in the past decade, because respectively).
it was the first PET modality to outperform 111In-pentetreotide At this time, it may be concluded that PET with alternative
scintigraphy. It has a high sensitivity and accuracy for carcinoid tracers can be regarded as a viable second investigative modality
tumors (93% and 89%, respectively) compared to the performance when SR imaging is negative, particularly in NENs associated with
of 111In-pentetreotide in a variety of GEP-NENs.48 high plasma serotonin values.162
In a prospective cohort of 53 patients with carcinoid tumors,
18
F-DOPA PET with carbidopa pretreatment demonstrated a per
patient sensitivity of 100%, detecting more lesions than conven- Bronchial Neuroendocrine
tional scintigraphy and CT scan.47
PET/CT with 11C-HTP has been proposed as a universal imag-
Neoplasms
ing method for the detection of NENs. Compared to conventional
receptor imaging and CT, 11C-HTP was able to detect more lesions
Conventional Radiologic Imaging
than scintigraphy and CT in 58% of 42 patients with NENs, mainly Primary NENs of the lungs represent ∼25% of all NENs and are
of GEP origin. Moreover, in 84% (16 of 19 patients), 11C-HTP could the second most common presentation, after GEP, among well-
visualize the primary tumor, as opposed to 47% and 42% for differentiated forms.163 In general, they are divided in an archaic
somatostatin imaging and CT, respectively.49 fashion into typical (mostly benign) and atypical. The latter usually
The sensitivity of radiolabeled serotonin and catecholamine exhibit malignant behavior but the criteria for differentiating
precursors was studied in a group of 47 patients with GEP-NENs between atypical and typical are sometimes difficult to determine.164
(24 carcinoids and 23 pancreatic NENs) and compared to conven- Most BPNs are located close to central bronchi, although ∼40% of
tional morphologic and functional imaging. In all carcinoid patients, cases are located in the peripheral lung.165 They typically show a
the two PET techniques had a higher sensitivity than receptor scin- spherical or ovoid shape with a well-defined border, but sometimes
tigraphy (100%, 96%, and 86%, respectively). Moreover, PET with they develop along bronchi or pulmonary arteries. Punctate or dif-
11
C-5-HTP was superior to 18F-DOPA PET in pancreatic NENs (67% fuse calcifications are frequently observed on CT. Both typical and
versus 41%), whereas 18F-DOPA PET is the optimal imaging modal- atypical BPNs are usually hypervascular and demonstrate intense
ity for staging in carcinoid patients (87%). The sensitivity was fur- contrast enhancement (more than 30 HU).87 Atypical BPNs are asso-
ther increased by CT fusion (87% to 98% in carcinoids for 18F-DOPA ciated with hilar or mediastinal lymph node metastases.166 LCNEC,
and 67% to 96% in pancreatic NENs for 11C-5-HTP).83 Figure 20.15 which is a poorly differentiated and high-grade NEN, is a morpho-
illustrates an example of 18F-DOPA PET/CT. logic entity that is between the “atypical” BPN and SCLC. LCNEC and
The enthusiasm for these alternative PET techniques has been SCLC do not show any specific CT feature and are similar to other,
somewhat diminished by the increased availability of 68Ga-DOTA- more common non small cell lung carcinomas (NSCLCs). However,
peptides and the demonstration of a better performance of SR PET. CT plays a role in staging and follow-up for all BPNs.
By way of illustration, in a group of 13 patients affected mainly by CT is the modality of choice for bronchial NENs, although MRI
GEP-NENs, 68Ga-DOTA-NOC identified more lesions than 18F-DOPA can be undertaken, especially if iodinated contrast medium cannot
(71 compared to 45), especially in the liver, lung, and lymph nodes. It be used. At MRI, lesions can appear as hypointense or isointense
was also of advantage, because, unlike 18F-DOPA, it facilitated selec- in T1-weighted images.87 MRI is more sensitive than CT scan for
tion for therapy with “cold” or radiolabeled somatostatin analogs.161 the detection of liver metastases.147


Figure 20.16. Example of PET/CT with 68Ga-DOTA-TOC in a patient
affected by a bronchial neuroendocrine tumor (arrows) with liver and
skeletal metastases; A: Maximun intensity projection image; B: corre- A B
spondent fused transaxial slice.
Functional Imaging uptake because of the low proliferative index. An increased avidity
of 18F-FDG and/or decreased avidity for 68Ga-DOTA-TATE might
Molecular imaging can help differentiate the etiology of bronchial therefore be useful to identify aggressive tumors containing foci of
masses.167 SR imaging combined with CT or MRI is used for stag- possible dedifferentiation.90
ing, restaging, and treatment monitoring, thus optimizing manage-
ment strategy.87 Figure 20.16 reports an example of 68Ga-DOTA-TOC
in a patient with a bronchial NEN.
Because most thoracic NENs exhibit SRs, especially sst2 and
Chromaffin Tumors
sst5, 111In-pentetreotide scintigraphy is useful to detect most bron- Conventional Imaging
chial NENs >1 cm in diameter, including those associated with ecto-
pic ACTH or GHRH secretion.168,169 SRS is also helpful for radioguided Pheochromocytomas and paragangliomas derive from sympathetic
surgery, allowing evaluation of the tumor bed after resection to chromaffin tissue in the adrenal medulla and from the extra-adrenal
detect any residual radioisotope uptake that corresponds to the paraganglial system of the thorax and abdomen. The majority of
presence of residual tumor.170 PET/CT with 68Ga-DOTA-peptides these tumors, except for those arising from the head and neck
has the highest sensitivity in the detection of mediastinal lymph region, are associated with catecholamine hypersecretion.129 Imag-
node involvement and distant metastases.88 ing is usually initiated after the biochemical demonstration of these
PET/CT with 18F-FDG in lung NENs exhibits variable uptake, tumors, with the aim of locating the primary tumor (or the primary
depending upon the tumor proliferation (grade). A low 18F-FDG lesions associated with hereditary neoplasia) or detecting metasta-
uptake (SUVmax <2.5) is usual in bronchial NENs.89 Tumors of a ses in malignant diseases.173 CT and MRI are sensitive and specific
higher grade than typical bronchial NENs can have high 18F-FDG for detecting adrenal pheochromocytomas (77% to 98% for CT and
uptake. Atypical BPNs can be more metabolically active and usually 95% to 100% for MRI) and provide useful information for the surgi-
appear as a small pulmonary nodule associated with hilar or medical intervention. MRI is usually the preferred modality in children
astinal lymph nodes, and exhibit high SUV values. The more dedif- and young adults. However, MRI and CT have a lower sensitivity
ferentiated forms, such as LCNECs, usually have a high 18F-FDG (29% for CT) for extra-adrenal lesions or metastases from malig-
uptake and PET/CT as well as CT alone, have a high accuracy in nant pheochromocytomas.174 When metastases are suspected, par-
predicting the presence of hilar and mediastinal nodal involvement. ticularly in large lesions over 5 to 6 cm, functional techniques
However, PET/CT seems to be better than CT alone in detecting exploring the whole body may help in staging the patient.173 In
distant metastases and thus altering clinical management. An SUV- extra-adrenal lesions, the specificity may be decreased, because
max greater than 13.7 has been suggested as predictive of a short other tumors of neurogenic or mesodermal origin may resemble
survival period suggesting the use of PET/CT with 18F-FDG not only paragangliomas in both distribution and appearance. MRI is the
in staging but also as a prognostic tool in LCNEC.171 In SCLC, technique of choice for head and neck paragangliomas.175,176
18
F-FDG PET is valuable for initial staging, to distinguish localized
from metastatic disease. It has been reported that 18F-FDG PET/CT
is also useful for prognostic prediction after treatment.172
Functional Imaging
Initial data examining the combined use of 18F-FDG and Functional imaging with 123I-MIBG, is the primary choice as a
68
Ga-DOTA-TOC are encouraging. Typical BPNs, rich in SRs, exhibit nuclear medicine diagnostic.132,177,178 MIBG scintigraphy is fre-
high uptake on 68Ga DOTA-TOC PET/CT imaging, but low 18F-FDG quently used to confirm if the disclosed adrenal mass is actually a

11
pheochromocytoma. MIBG has a sensitivity and specificity of 90% C-hydroxyephedrine, 18F-dopamine, and 18F-DOPA, with sensi-
and 95%, respectively. Overall, the combined sensitivity of cate- tivities ranging from 90% to 100%. 18F-FDG was found to be of
cholamine measurements and an 123I-MIBG scan is close to moderate utility, with a sensitivity of 72%. 111In-pentretreotide can
100%.179 A whole-body MIBG scan is particularly helpful in the be of selected utility, particularly in metastatic forms.
preoperative identification of multiple primary lesions (relatively In paragangliomas, 18F-dopamine, 18F-DOPA, and SR imaging
frequent in NE secreting pheochromocytomas) or metastases from are the modalities of proven utility, whereas 123I-MIBG appears of
malignant tumors. Functional MIBG studies are also able to detect moderate utility, with 71% sensitivity.189
recurrences because the radiotracer accumulates specifically within
the tumor and is not affected by postsurgical or postradiotherapy
changes.
Impact of Functional Techniques on
Initial studies using 131I-MIBG reported 77% to 90% sensitivity Patient Management
in detecting pheochromocytomas, with a specificity of 95% to It has become apparent in numerous studies that patient manage-
100%.99 Because 123I yields a superior image quality compared to ment is significantly altered by the use of both functional and mor-
131
I, subsequent studies confirmed that 123I-MIBG exhibited a better phologic imaging. The impact of each diagnostic modality on
performance for pheochromocytoma detection with 83% to 100% therapeutic strategy is more critical than its diagnostic perfor-
sensitivity.180 mance alone. In a group of 186 NEN patients, partly studied with
Several factors such as drug administration can decrease the radiologic techniques as a first approach and partly studied with
sensitivity of MIBG scintigraphy, these are based on interference 111
In-pentetreotide, it was demonstrated that the influence of
with MIBG uptake, and thus produce false-negative results. In morphologic or functional imaging on therapy management was
addition, false-negative scans may occur because of small lesion equivalent. The authors concluded that a combination of both mor-
size, or extra-adrenal location. MIBG imaging has a sensitivity of phologic and functional imaging represented the optimal manage-
58% for extra-adrenal tumors compared to 85% for adrenal pheo- ment strategy.63
chromocytomas.135 Prior to 2000 and the advent of last generation radiologic tech-
A sensitivity of only 65% is reported in familial forms associ- niques, the impact of SRS on altering GEP-NENs management
ated with succinate dehydrogenase B (SDHB) mutations.181 strategy, ranged from 21% to 53% in a variety of studies.70,74,75,79,84
MIBG imaging is not very useful in the detection of paragan- More recently, with the introduction of newer radiologic tech-
gliomas (17% to 42%) located in the craniocervical area. Although niques, it has become evident that conventional imaging, MRI in
paragangliomas of the abdomen and thorax can be functionally primis, followed by CT scan have the greatest sensitivity for the
active (catecholamine secreting), head and neck paragangliomas detection of liver metastases.156 The principal limitation of con-
are rarely hormonally active. Such lesions were, in the past, ventional receptor scintigraphy is low spatial resolution.
referred to as glomus tumors and although of chromaffin cell ori- In most patients, however, the detection of an increased num-
gin, actually consist of a local regulatory cell system as opposed to ber of metastases, for example, in the liver, does not translate into
the endocrine functionality of adrenal lesions.182,183 a modification of the therapeutic approach. Nevertheless, the
In those settings where scintigraphic results could be affected demonstration of unsuspected metastatic deposits, local recur-
by a lack of sensitivity of MIBG (size and site of the lesions, extra- rence, the identification of the primary tumor or the demonstra-
adrenal, familial, and malignant pheochromocytomas) other tion of the absence of SRs in the lesions can alter therapeutic
radiopharmaceuticals should be considered as diagnostic strategy. Of note therefore is a recent report indicating that PET/
adjuncts. CT with 68Ga-DOTA-NOC was able to modify the stage or the ther-
SRs are overexpressed in chromaffin tumors and SR imaging is apy in more than 50% of 90 patients with NENs (62 GEP-NEN
therefore of use. The sensitivity of SRS is inferior to MIBG for the primary). Alterations included initiation or continuation of ther-
detection of benign adrenal pheochromocytomas because small apy with “cold” or radiolabeled somatostatin analogs, an indica-
lesions can be obscured by gastrointestinal activity and renal tion for exclusion from surgery or to stop somatostatin analog
excretion.184 However, 111In-pentetreotide has been reported as use.76 In a separate study, the clinical impact of PET/CT with
more sensitive than 123I-MIBG in the detection of malignant pheo- 68
Ga-DOTA-TOC compared to standard imaging was evaluated in
chromocytoma and metastatic lesions.185 SR imaging is more 52 patients. PET/CT detected several more lesions compared to
effective than MIBG in the localization of head and neck para- standard radiologic imaging and was able to modify the treatment
gangliomas, with a higher sensitivity (93% versus 44%) and image
quality.182
Tab l e 2 0 . 6
Catecholamine-based PETs with 18F-fluorodopamine, 18F-
fluorodopa, 18F-fluorodeoxyglucose, or 11C-hydroxyephedrine are
Clinical Utility of Each Nuclear Imaging
alternative functional imaging methods to 123I-MIBG or can be used
Technique in Neuroendocrine Neoplasms
as additional procedures if 123I-MIBG scanning is negative. The
reported sensitivities are 18F-dopamine (76%), 18F-DOPA (45%),
18
F-FDG (74%), and 123I-MIBG (57%).99,186 18F-FDG, the only PET Clinical Utility Imaging Technique Comment
imaging compound that is widely available, is not recommended 68 18
for initial diagnostic localization, because it is nonspecific for pheo- Primary tumor Ga-octreotide (OctreoScan) F-DOPA is optimal for small
18
localization F-DOPA intestine NENs whereas
chromocytoma and sensitivity is restricted, although it can offer 11 11
C-5-HTP C-5-HTP may be more
important prognostic information.139 effective for pancreatic NENs
Recent reports suggest that 68Ga-DOTA-TATE PET/CT SR imag- Staging, restag- 68
Ga-octreotide (OctreoScan) 18
F-DOPA is optimal for small
ing has a higher sensitivity than 123I-MIBG in patients with chro- ing, and 18
F-DOPA intestine NENs whereas
maffin tumors (pheochromocytomas and paragangliomas).187 therapy 11
C-5-HTP 11
C-5-HTP may be more
Despite the low number of published studies, there is evidence control effective for pancreatic
that 68Ga-labeled-peptides are promising agents for the diagnosis NENs
68
and management of pheochromocytomas, as well as for the selec- Selection for Ga-octreotide (OctreoScan)
tion of patients for radionuclide therapy with radiolabeled soma- treatment with
tostatin analogs.188 SSA/PRRT
68
Prognostic Ga-octreotide (OctreoScan)
Overall, it has been demonstrated that nuclear medicine tracers 18
parameter F-FDG
of proven utility in studying pheochromocytomas are 123I-MIBG,

Ta bl e 2 0 . 7
Advantages and Limitations of Nuclear Medicine Techniques in

Procedure Advantages Disadvantages
OctreoScan Whole-body technique Low spatial resolution

Gives therapeutic indications Low receptor density (insulinoma)
68
Ga-DOTA-peptides Whole-body technique Low receptor density (insulinoma)
Gives therapeutic indications Costs
Not commercially available
18
F-DOPA Explores norepinephrine (NE) metabolism Not widely available
May be an alternative when SRI is negative, No therapeutic indication
especially in carcinoids
11
C-5-HTP Explores NE metabolism Only in specialized centers
May be an alternative when SRI is negative, No therapeutic indications

especially in pancreatic NENs
18
F-FDG Gives a prognostic evaluation Not a diagnostic/staging tool (scarce sensitivity in
G1-G2 forms)
123
I-MIBG Traces catecholamine transport (specific for Low spatial resolution
chromaffin tumors)
Explores the whole body
Gives therapeutic indications
decision in almost 60% of patients, through a change in surgical Radionuclide Therapy of

or nonsurgical strategy.77 A third study with 68Ga-DOTA-TATE
PET/CT of 51 patients (37 GEP-NENs), identified more lesions
than conventional receptor scintigraphy (168 versus 27 of the 226
identified with cross-sectional imaging, namely 74% versus 12%),
Peptide Receptor Radionuclide Therapy
resulting in a management change in 36 patients (71%).158 In the past two decades a new approach to the treatment of unre-
It may therefore be inferred that SR imaging, particularly PET/ sectable or metastasized NENs based on specific receptor target-
CT with 68Ga-DOTA-peptides, can be regarded as an axiomatic or ing with radionuclides has gained acceptance in clinical practice
fundamental procedure to define management strategy. Table 20.6 in many European centers. PRRT consists of the systemic admin-
illustrates the clinical utility of each nuclear imaging technique in istration of a synthetic somatostatin analog, radiolabeled with a
NENs. suitable β-emitting radionuclide. The compound is able to irradi-
A further advantage of PET is that the SUVmax expression of ate tumors and their metastases via the internalization through
uptake, represents a prognostic tool because it is higher in well- SRs overexpressed on the cell membrane. As a result, the radio-
differentiated NENs with elevated sst2 expression which are there- pharmaceutical is concentrated in the tumor cell, where sensitive
fore predicted to be more responsive to “cold” and radiolabeled molecules, such as DNA, can be targeted. 111In-pentetreotide was
somatostatin analogs.190 Table 20.7 illustrates advantages and lim- the initial therapeutic agent utilized based upon the emission of
itations of nuclear medicine techniques in NENs. Auger and conversion electrons by 111In in close proximity to the
A further prognostic advantage of 68Ga-DOTA-TATE PET cell nucleus. A multicenter trial demonstrated some clinical ben-
regards therapy with radiolabeled somatostatin analogs because efit although partial remissions were rare.195
an early reduction of SUV correlates with a response to radiore- Further investigations led to the development and usage of
ceptor therapy with somatostatin analogs.191 radiopharmaceuticals labeled with higher-energy and longer-range
Apart from clinical issues, there is a need to consider the cost/ β-emitters, such as Yttrium-90 (Emax 2.27 MeV, Rmax 11 mm, half-life
benefit ratio of different diagnostic strategies. Previous data from 64 hours) and Lutetium-177 (Emax 0.49 MeV, Rmax 2 mm, half-life
the 1990s had noted that combining appropriate modalities 6.7 days). Subsequently 90Y-DOTA-Tyr3-octreotide or 90Y-DOTA-TOC
into rational algorithms, for example, 111In-pentetreotide and or 90Y-octreotide (with an octreotide-like pattern of affinity), was
abdomen CT scan for gastrinomas, resulted in an optimal cost- developed based upon its favorable chemical profile. This agent has
effectiveness ratio in terms of tumor localization, effect on patient since been used in a number of clinical trials.196,197 Thereafter, a
management, and financial costs. It was concluded that the rela- newer analog, DOTA-TATE, with a six- to nine-fold higher affinity
tively high cost of the scintigraphic procedure was largely out- for sst2, was synthesized. The 177Lu-labeled form, 177Lu-DOTA-Tyr3-
weighed by the invaluable information obtained.192 octreotate or 177Lu-DOTA-TATE or 177Lu-octreotate, is currently one
A more recent cost comparison analysis of 111In-pentetreotide of the most clinically used radiopharmaceuticals.198
scintigraphy and 68Ga-DOTA-TOC PET/CT for staging GEP-NENs It is now widely accepted and demonstrated by dosimetric stud-
indicated lower costs for the PET procedure. This analysis consid- ies that PRRT with either 90Y-octreotide or 177Lu-octreotate delivers
ered the cost of the materials and personnel, as well as the cost radiation doses adequate to achieve significant tumor responses.199
reduction associated with the considerable reduction of additional Patients who are candidates to receive PRRT with radiolabeled
examinations.193 Nevertheless, the need to establish a GMP certi- somatostatin analogs are those with lesions that significantly
fied laboratory and the fact that, to date, no commercial group has overexpress SRs, namely with an adequate uptake (at least equal
marketing authorization for 68Ge/68Ga generators as medicinal to that of normal liver) at OctreoScan or PET with 68Ga-DOTA-
product somewhat increases the complexity of the precise fiscal peptides. This strategy is critical, as it enables the delivery of high
evaluation.111,194 doses to the tumor, whereas sparing the normal tissues.

B C
A
Figure 20.17. Example of objective response

to peptide receptor radionuclide therapy (PRRT)
with 90Y-DOTA-TOC in a patient affected by
liver metastases from a resected ileal neuro-
endroine tumor. Basal OctreoScan imaging
shows the biggest liver lesions (solid arrows;
A, planar anterior image; B, transaxial SPECT
slice), whereas computed tomography (C [CT])
shows another small lesion in the seventh
segment. Follow-up imaging after the end of
PRRT shows a partial reduction of the disease,
both from a functional (dashed arrows on pla-
D E F nar [D] and transaxial [E] SPECT images) and
morphologic (F [CT ]) point of view.
PRRT is typically fractionated in multiple cycles. The maximum The radiopeptide most commonly utilized in the first 8 to 10 years
cumulative administrable activity depends on the irradiation of the of experience was 90Y-octreotide. All the published results derive
kidneys, which are the dose-limiting organs. The absorbed dose from different phase I/II studies and represent a heterogeneous
threshold is conventionally set at 25 to 27 Gy, or, optimally, at ∼40 Gy group in terms of inclusion criteria and treatment schemes. As a
(for a biologic effective dose [BED]).200 consequence, a direct comparison is virtually impossible at this
To reduce the renal dose, patients are coinfused with an intrave- time. Nevertheless, even with these limitations, objective responses
nous infusion of positively charged amino acids, such as lysine or (Fig. 20.17) are registered in 6% to 37% of patients (Table 20.8).
arginine. This measure reduces the renal dose by competitive inhibi- A recent study of the role of 90Y-octreotide in 90 patients with
tion of the proximal tubular reabsorption of the radiopeptides via the metastatic midgut “carcinoids,” demonstrated that symptomatic
COAL (cystine, orthinine, arginine, lysine) transporter mechanism.201 responses had an impact on survival, because progression-free
In more than 15 years of academic phase I/II trials, despite the survival was significantly longer in those who had a durable diar-
lack of homogeneity among studies, PRRT has proved to be effi- rhea improvement.207
cient and consistent in efficacy and has, ultimately, demonstrated More recently, objective morphologic and symptomatic responses
an impact on survival.73 in 1,109 patients, (821 GEP-NENs), treated with 90Y-octreotide were
Ta bl e 2 0 . 8
Clinical Results of Peptide Receptor Radionuclide Therapy in Gastroenteropancreatic

90
Y-Octreotide Patient Numbers CR + PR (%) Response Criteria Outcome
Otte et al.202 16 6 Nonspecified Not assessed

Paganelli et al.203 23 13 WHO Not assessed
Waldherr et al.204 37 27 WHO TTP >26 mos
Waldherr et al.205 36 34 WHO Not assessed
Bodei et al.201 21 29 WHO TTP 10 mos
Valkema et al.206 58 9 SWOG TTP 29 mos
Bushnell et al.207 90 4 SWOG PFS 16 mos
Imhof et al.208 821 37 RECIST Mean OS 4–60 mos
177
Lu-Octreotate Patient Numbers CR + PR (%) Response Criteria Outcome
61
Kwekkeboom et al. 310 30 SWOG PFS 33 mos
Garkavij et al.209 12 17 RECIST Not assessed
Bodei et al. (2011)210 47 32 RECIST TTP 36 mos
PFS, progression-free survival; RECIST, Response Criteria in Solid Tumors; SWOG, Southwest Oncology Group; TTP, time to progression; WHO,
World Health Organization.


A B C D
Figure 20.18. Example of objective response to peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-TATE. A: Basal anterior scan, 24 hours post injec-
tion in a patient affected by liver (solid arrows) and skin (dotted arow) metastases from a pancreatic NET (dashed arrow). B: Posttherapy scan at the last PRRT cycle,
which demonstrates the almost complete disappearance of liver metastases (solid arrows), and persistence of faint uptake at the head of the pancreas (dashed
arrow). The skin metastasis is no longer visible. C and D: The PET/CT with 68Ga-DOTA-TOC performed 6 months after the end of treatments (C, maximum intensity
projection image) confirms the disappearance of liver metastases and the persistence of a small lesion located at the head of the pancreas (dashed arrows)
(D, fused transaxial slice).
demonstrated to have an impact on survival. The best predictor of roles, in patients with metastatic GEP-NENs. The effect was more
survival was the tumor uptake at baseline.208 frequent in individuals with tumor regression, but surprisingly,
Since its introduction in 2000, 177Lu-octreotate, has gained was also evident in those with progressive disease.214 In a series
popularity, because of its higher affinity for sst2, its easier man- of 265 patients, no significant deterioration of QoL was observed
ageability, and the ability to undertake synchronous imaging. in asymptomatic patients treated with 177Lu-octreotate. On the
In a series of 310 GEP-NENs treated with 177Lu-octreotate, contrary an improvement was evident, in those treated in subop-
PRRT proved to be oncologically active (lesion shrinkage) and it is timal clinical conditions.215
likely to have an impact on survival parameters. A median overall
survival >48 months was observed in responding patients, with a
median progression-free survival of 33 months. A direct compari-
MIBG Therapy
son with the literature obtained from similar patients showed a Treatment of malignant pheochromocytomas and paragangliomas
40- to 72-month survival benefit. Although these data are not the is complex and can be difficult. Surgery is the only curative treat-
result of a rigorous randomized trial, the substantial difference in ment but in the event of unresectable or residual malignant dis-
survival is probably as a consequence of the PRRT. These data ease, the use of 131I-MIBG has been advocated since the mid-80s.
compare favorably to other treatments, such as chemotherapy, in 131
I is a β- and γ-emitter that can be used both for diagnosis and
terms of the cost/benefit and tolerability point of view.61 therapy. The γ-emission component is of diagnostic value whereas
In a prospective study on 51 patients treated with 177Lu-octreo- the high kinetic energy of the β-electrons provides a viable strategy
tate, in a subpopulation of 39 patients in progression at enrolment, for radionuclide therapy. The high sensitivity and specificity of
it was noted that stabilization and objective responses shared the MIBG for the detection of primary and secondary tumor sites has
same survival probability, thus indicating that stabilization may be facilitated the use of the 131I-labeled compound for the treatment of
regarded as a form of response (Fig. 20.18).210 malignant tumors of neuroectodermal origin.216
PRRT is generally well tolerated. Acute side effects, such as nau- Initial studies with 131I-MIBG were undertaken in 1984 in
sea or fatigue, are usually mild and self-limiting. From a hematologic patients with malignant pheochromocytomas.126 Given the success
point of view, severe (WHO grade 3 or 4) toxicity occurs in <13% of of this therapeutic modality, numerous patients with malignant
cases after 90Y-octreotide and in 9.5% after 177Lu-octreotate.73,211 chromaffin tumors have since been treated with a variety of clinical
Chronic and permanent effects on kidneys and bone marrow are protocols (single and cumulative).217 Overall, the interpretation of
generally mild if the necessary precautions, such as coinfusion of MIBG studies has been hampered by the lack of homogeneity in
positively charged amino acids and fractionation of the cumulative terms of the therapeutic scheme and by the generally low number
activity, are undertaken.212 With advances in expertise and knowl- of patients studied. Nevertheless, the clinical results in advanced
edge about PRRT, cases of severe, end-stage, renal damage are cur- disease treated with 131I-MIBG (Europe and the United States) have
rently very rare.73 Studies have demonstrated that a higher and more demonstrated that it is possible to provide a significant symptom-
persistent decline in creatinine clearance and the subsequent devel- atic response. Thus, diminution of catecholamine hypersecretion,
opment of renal toxicity were risk factors for delayed renal toxicity, consequent blood pressure control, and substantial pain control
particularly in long-standing and poorly controlled diabetics and have proved to be viable outcomes of therapy. Although tumor
hypertensives (with a lower renal BED threshold of about 28 Gy).213 responses are mainly stabilization or partial responses, complete
It is apparent that 177Lu-octreotate significantly improved the responses are rarely evident (Table 20.9).218
global health/QoL and a variety of symptom scales, particularly More recently, a comprehensive review of 116 patients with malig-
fatigue, insomnia, pain, as well as emotional, and social functional nant pheochromocytomas treated with 131I-MIBG demonstrated that

Table 20.9 a positive impact on survival.228 In more recent times, the role of
131
I-MIBG in the management of NENs has decreased as a result of
Response to 131I-MIBG in the Main Studies on the emerging efficacy of PRRT. This reflects the clinical advantages
Patients with Malignant Chromaffin Tumors that have accrued based upon the higher uptake and efficacy of
radiolabeled octreotides.229,230 In the event of renal impairment or
Number of when PRRT is not available or not feasible (e.g., sst-negative lesions)
131
Study (Year) Patients CR + PR (%) SD (%) References I-MIBG may represent a viable alternative strategy in the treat-
ment of NENs.228
Shapiro 28 2 (7%) 16 (57%) 219 Individuals most likely to benefit from 131I-MIBG are those with
et al. (1991) a significant uptake (at least 1% of the injected dose) at diagnostic
Lewington 13 2 (15%) 11 (84%) 220 imaging with either 123I-MIBG or 131I-MIBG scans. This level is con-
et al. (1991) sistent with adequate irradiation of tumor lesions, whereas spar-
Krempf 15 5 (33%) 7 (47%) 221 ing normal tissues. The bone marrow is the dose-limiting organ for
et al. (1991) 131
I-MIBG therapy.224 Thyroid blockade with potassium iodide
Fischer (1991) 13 2 (15%) 7 (54%) 222 preparations from at least 1 day before to 15 days after the therapy
Castellani 12 5 (42%) 6 (50%) 223
is mandatory to avoid unnecessary radiation exposure of the thy-
et al. (2000)
roid and, consequently, hypothyroidism.231 Observed hematologic
Bomanji 15 6 (40%) 3 (20%) 224
et al. (1993) toxicity is usually mild, and mainly consists of a transient leucope-
nia and thrombocytopenia. Severe myelosuppression is extremely
rare and generally occurs when high-dose regimens are applied.217
Occasionally, malignant pheochromocytomas and paraganglio-
symptomatic improvement could be obtained in 76% of patients, hor- mas may show an elevated uptake at OctreoScan and no uptake
monal responses in 45%, and tumor responses, mainly partial, in at MIBG. In such cases, therapy with radiolabeled octreotides may
30%. Usually, responses are more frequent in patients with limited be used and sporadic successes have been reported.43
disease and soft tissue metastases.225 Experience related to meta-
static paragangliomas treated with 131I-MIBG are more limited; the
observed results, however, appear similar.218 Tumor control is an Conclusions
important parameter in terms of the determination of survival
parameters. Thus, patients with stabilization and objective responses NENs are ubiquitous and exhibit a wide range of malignancy. Their
6 months after the completion of treatment exhibit a longer time to incidence is rapidly increasing and their prevalence in the gut
progression, compared to those not responding to 131I-MIBG (14.5 exceeds that of all other neoplasia except colon cancer. Recent sci-
versus 4.5 months).226 Although it has been reported that survival is entific advances in understanding the biology of these diseases have
prolonged in patients receiving higher cumulative activities (>500 yielded considerable novel information. This has allowed for the
mCi),227 these observations need to be confirmed in controlled studies. introduction of sensitive techniques for the detection of these tumors,
Moreover, the possible additional efficacy of treatment combinations as well as the development of effective management approaches.
with myeloablative chemotherapy require further investigation.129 The different therapeutic strategies include surgery, locally
Figure 20.19 illustrates an example of response to 131I-MIBG. directed ablative therapies, bioactive agents (somatostatin analogs/
131
I-MIBG has been used also for the treatment of nonchromaffin interferon), chemotherapy, molecular targeted agents, and PRRT.
NENs (e.g., GEP-NENs). Objective response rates, not surprisingly, Diagnostic imaging allows localization of the tumor lesion, defi-
are low (10% to 15%) and complete responses are rare. On the nition of its relationship to adjacent structures, and evaluation of
other hand, symptomatic responses are frequent (∼65%) and have the extent of disease at both locoregional and distant levels (staging).
Figure 20.19. Example of objective

response to 131I-MIBG in a patient with diffuse
peritoneal metastases by a malignant pheo-
chromocytoma. The arrows indicate the larg-
est metastatic deposits (A, basal scan,
anterior view; B, basal scan, fused SPECT/CT
images). Collected after the last cycle (C, ante-
rior view) shows the reduction of intensity and
extension of uptake as the therapeutic
A B C response. (Courtesy of Dr. P. Erba, University of
Pisa, Pisa, Italy.)

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C h apt e r 2 1
Lymphoma and Leukemia

Jasna Mihailovic • Stanley J. Goldsmith
Lymph o m a organs, either as isolated organ involvement or as disseminated

disease.1 Lymphoma is the fifth most common malignancy in the
United States and represents 5.3% of all malignancies (excluding
Introduction simple basal cell and squamous cell skin cancers) and 56% of all
blood malignancies.2,3
Lymphoma is a malignancy of the lymphatic system. The patient In general, the lymphomas are divided into two groups: Hodg-
may be asymptomatic and comes to diagnosis as an incidental kin disease (HD) and non-Hodgkin lymphoma (NHL). Thomas
finding on a physical examination or conventional imaging per- Hodgkin, in 1832, was the first to describe the form of lymphoma
formed for other reasons. It may present as a solid tumor, such as that bears his name, Hodgkin lymphoma or HD.1 Since then, other
an enlarged lymph node or as extranodal lymphoma involving forms of lymphoma have been described and grouped under sev-
eral proposed classifications. These include the Working Formula-

tion Classification,4 the Karl Lennert Classification,5 and the
Tab l e 2 1 . 1 Revised European-American Classification (REAL).6 The most
recent classification is the WHO Classification of Tumours of Hae-
WHO 2008: The Mature B-Cell Neoplasms matopoietic and Lymphoid Tissues which was published in 2008
(Table 21.1).7 The Ann Arbor staging system was developed in
Chronic lymphocytic leukemia/small lymphocytic lymphoma 1971 to describe the extent of disease based on the number of
B-cell prolymphocytic leukemia involved sites, disease location, and presence or absence of clini-
Splenic marginal zone lymphoma cal symptoms. Initially developed for HD, it has since been adapted
Hairy cell leukemia to stage NHL into one of four stages (Table 21.2).8,9
Splenic lymphoma/leukemia, unclassifiable
Splenic diffuse red pulp small B-cell lymphomaa
Hairy cell leukemia varianta Hodgkin Disease
Lymphoplasmacytic lymphoma
Waldenström macroglobulinemia Hodgkin lymphoma represents 10% to 15% of all lymphomas and is
Heavy chain diseases divided into two main groups: Classic HD accounting for 95% of HD
α-Heavy chain disease patients and nodular lymphocyte predominant HD for the remaining
γ-Heavy chain disease
5% of cases. Classic HD is classified into subgroups: nodular sclero-
μ-Heavy chain disease
Plasma cell myeloma sis which accounts for 75% of patients, 20% of mixed cellularity,
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue Tabl e 2 1 . 2
(MALT lymphoma)
Nodal marginal zone B-cell lymphoma (MZL) ANN Arbor Staging System for Hodgkin Disease
Pediatric-type nodal MZL
Follicular lymphoma
Pediatric-type follicular lymphoma Stage Definition
Primary cutaneous follicle center lymphoma
Mantle cell lymphoma I Involvement of a single lymph node region or lymphoid structure
Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (e.g., spleen, thymus, Waldeyer ring)
T-cell/histiocyte-rich large B-cell lymphoma II Involvement of two or more lymph node regions on the same side
DLBCL associated with chronic inflammation of the diaphragm (the mediastinum is a single site; hilar lymph
Epstein–Barr virus (EBV) + DLBCL of the elderly nodes should be considered “lateralized” and, when involved
Lymphomatoid granulomatosis on both sides, constitute stage II disease)
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma III Involvement of lymph node regions or lymphoid structures on
Primary cutaneous DLBCL, leg type both sides of the diaphragm
ALK + large B-cell lymphoma III1 Subdiaphragmatic involvement limited to spleen, splenic hilar
Plasmablastic lymphoma nodes, celiac nodes, or portal nodes
Primary effusion lymphoma
III2 Subdiaphragmatic involvement includes para-aortic, iliac, or
Large B-cell lymphoma arising in HHV-8-associated multicentric Castleman disease
mesenteric nodes plus structures in III1
Burkitt lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large IV Involvement of extranodal site(s) beyond that designated as “E”
B-cell lymphoma and Burkitt lymphoma More than one extranodal deposit at any location
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large Any involvement of liver or bone marrow
B-cell lymphoma and classical Hodgkin lymphoma A No symptoms
Hodgkin Lymphoma
Nodular lymphocyte-predominant Hodgkin lymphoma B Unexplained weight loss of >10% of the body weight during the
Classical Hodgkin lymphoma 6 months before staging investigation
Nodular sclerosis classical Hodgkin lymphoma Unexplained, persistent, or recurrent fever with temperatures
Lymphocyte-rich classical Hodgkin lymphoma >38°C during the previous month
Mixed cellularity classical Hodgkin lymphoma Recurrent drenching night sweats during the previous month
Lymphocyte-depleted classical Hodgkin lymphoma E Localized, solitary involvement of extralymphatic tissue, excluding
a
liver and bone marrow
These represent provisional subtypes of other neoplasms.
293

lymphocyte rich and lymphocyte depletion types, the remaining sis of lymphoma. Moreover, the clinical stage provides a basis to
5%.10 Cervical lymph nodes are the most common involved site in select the patient’s treatment course. The Ann Arbor staging sys-
60% to 80%. Extranodal involvement is rare in HD and is caused tem was established to divide patients into two groups: Those who
mainly by direct spread of disease. Hematogenous spread occurs in might be candidates for radiation therapy and others who should
the minority of cases (10% to 15%) and usually carries a poor prog- receive systemic treatment. Initially, it was based on physical
nosis. The overall cure rate is over 80% whereas the recurrence rate examination and BM evaluation.14 For many decades, staging of
is between 10% and 40%. The prognosis is directly related to the lymphoma also included patients’ history, laboratory analyses,
stage of disease and the presence of systemic symptoms.1 In 1998, and ultrasound (US). Recently, computed tomography (CT), mag-
a prognostic score index was created for advanced HD, the Interna- netic resonance imaging (MRI), and nuclear medicine procedures,
tional Prognostic Score (IPS). According to the IPS, there are seven particularly 18F-FDG PET/CT have been used to stage and restage
adverse prognostic factors at presentation: a serum albumin level lymphoma patients. Since the introduction of these methods, the
<4 g/dL, a hemoglobin level <10.5 g/dL, male gender, age ≥45 years, use of US is limited mostly for US-guided biopsy of focal lesions.15
stage IV disease by Ann Arbor Classification, leukocytosis (a white Before the era of these modern diagnostic imaging tools, laparot-
cell count ≥15,000/mm3), and lymphocytopenia (a lymphocyte count omy and lymphangiography were performed to detect lymph node
<600/mm3, a count <8% of the white cell count, or both). About 85% involvement and complete staging of lymphoma.16
of patients initially present with stage I or II disease.11 For many years, CT was the main imaging tool for detection,
staging, and follow up of lymphoma patients. CT has high sensitiv-
ity and specificity in pretreatment staging but low specificity in the
Non-Hodgkin Lymphoma evaluation of response to treatment. The assessment of lymphoma
by CT relies on size-related criteria. Nevertheless, lymphoma may
NHL accounts for about 85% of lymphomas. The clinical behavior appear with lymph node involvement without enlargement of the
includes indolent and aggressive types. Aggressive lymphomas lymph nodes. Thus, involved lymph nodes may be missed on CT
account for about 60% of NHL whereas indolent lymphomas rep- although images with good resolution will identify an increased
resent the remaining 40%.10 Diffuse large B-cell lymphoma number of lymph nodes.17–20 CT is also a good method to image
(DLBCL) is the most common histologic diagnosis among the lymphoma organ involvement in extranodal NHL.21–23
aggressive lymphomas, accounting for about 30% of all lympho- The role of MRI in the evaluation of lymphoma is also based on
mas. Localized aggressive lymphomas are usually treated with nodal size and has similar accuracy to CT. Decreased signal on
combination chemotherapy combined with radiation therapy; T2-weighted images is specific for benign lymph nodes enabling
about 85% of these patients are cured.1 Follicular lymphoma (FL) MRI to differentiate them from nodal tumor involvement in which
is the most common indolent lymphoma, accounting for 22% of the signal is not decreased. In case of micrometastases, the MRI is
NHLs worldwide and at least 30% of the NHLs diagnosed in the not specific.24 Performance of whole-body MRI including diffu-
United States. The predominant presentation for FL is painless sion-weighted imaging (DWI) in the staging of newly diagnosed
multiple site lymphadenopathy. In extranodal NHLs, liver and lymphoma has been recently described as a promising tool.25
bone marrow (BM) are commonly involved.12 Gu et al.26 stated that DWI enhanced lesion conspicuity and
Patients with FL have a 5% to 7% annual rate of histologic trans- improved diagnostic accuracy for lymphomas. More recently,
formation to DLBCL. Chronic lymphocytic leukemia may also undergo Kwee et al.27 proposed that MRI can be limited to a head/neck and
transformation to diffuse large-cell lymphoma (DLCL). Transforma- trunk imaging only instead of conventional whole-body imaging
tion usually carries a poor prognosis. DLBCL can present with either for lymphoma staging. MRI is the most sensitive diagnostic imag-
nodal or extranodal disease or both. At presentation, more than half ing tool for the detection of BM involvement.22–32
of the patients will have some site of extranodal involvement. The
gastrointestinal tract and the BM are usual sites of extranodal
involvement, each involving about 15% to 20% of patients.12 Radionuclide Imaging
In 1993, The International non-Hodgkin Lymphoma Prognostic 99m
Factors Project established the International Prognostic Index Gallium-67, Thallium-201, and Tc-sestamibi
(IPI) to predict prognosis for patients with aggressive NHL. It was In the past, the radionuclides Gallium-67 (67Ga), Thallium-201
also used to determine the best treatment based on a risk profile. (201Tl) and 99mTc-sestamibi (99mTc-MIBI) have been used as tracers
The IPI summarizes different factors at the time of diagnosis and to image lymphoma. Both 201Tl and 99mTc-MIBI are widely used for
has become an established parameter for risk stratification and myocardial perfusion but can be used for tumor detection and
determination of patient’s outcome. It includes the presence or assessment of tumor viability.33–35 For many years, 67Ga citrate
absence of five adverse prognostic factors: was probably the most widely used radionuclide for the assess-
• Age ≥60 years ment of the extent of both HL and NHL involvement. It was spe-
• Ann Arbor tumor stage III or IV cifically useful to detect the extent of disease in HD and high-grade
• >1 site of extranodal involvement NHL. 67Ga citrate is not sufficiently sensitive to detect lymph node
• Performance status 2 (ECOG) or Karnofsky ≥70 involvement in low-grade NHL. 67Ga was particularly useful to
• Elevated serum lactate dehydrogenase level detect the treatment response of the high-grade tumors, HD, and
NHL. 67Ga had some additional limitations such as nonspecific
In addition, there is a follicular lymphoma-specific IPI (FLIPI) localization in inflammatory or infectious lesions.36 Compared to
score which replaces performance status with hemoglobin level 67
Ga, 201Tl has greater tumor avidity in low-grade lymphoma
and the number of extranodal sites with the number of nodal sites involvement. In the assessment of the presence of disease and of
(more than four).12,13 site localization in patients with low-grade lymphoma, 201Tl had a
sensitivity of 100% compared to 67Ga with only 56% patient sensi-
tivity and 32% site sensitivity.37 There are several reports combin-
Imaging ing 201Tl and 67Ga scintigraphy to increase overall sensitivity.38,39
99m
Tc-MIBI has a slightly lower sensitivity and specificity than 201Tl
Conventional Imaging
to assess lymphoma: 71% and 76%, respectively.40 Several studies
Correct pretreatment staging determines the extent and spread of report on the role of 99mTc-MIBI to assess response and effective-
disease and is important in the selection of therapy. The clinical ness of chemotherapy protocols based on the association between
99m
stage, as well as the histologic tumor type, determines the progno- Tc-MIBI and multidrug resistance.41–45

Chapter 21 Lymphoma and Leukemia 295
Table 21. 3 Several studies show higher sensitivity for 18F-FDG PET than for
CT60–65 and other conventional diagnostic imaging procedures.66–69
FDG Uptake in Lymphoma In a study by Hoh et al.65 that evaluated 18F-FDG PET-based stag-
ing results compared to the patient’s clinical stage based on con-
Lymphoma Types High FDG Uptake ventional imaging tools (CT, MRI scans, and 67Ga scans), staging
by 18F-FDG PET was superior to conventional methods with a sen-
Classic HD ≥95% positive sitivity of 94% versus 83% for other methods.69 Bangerter et al.70
reported 18F-FDG PET had a sensitivity of 96% with a specificity
Lymphocyte-predominant HD Less than classic HD
of 94%. 18F-FDG PET accuracy was similar or better than CT in
DLBCL NHLs ≥95% positive determination of hilar and mediastinal involvement. Although
Transformed follicular NHLs ≥95% positive Jerusalem et al.71 detected more lymph nodes by 18F-FDG PET
than by CT and concluded that 18F-FDG PET is sensitive for the
Nodal marginal zone NHLs ≥95% positive
staging of aggressive NHLs and resulted in fewer staging changes.
Burkitt NHLs ≥95% positive Although most of the studies show a high level of concordance
T/natural killer cell NHLs High between 18F-FDG PET and CT, PET/CT as a hybrid imaging system
shows the best results.72–74 Thus, Fueger et al.72 showed that 18F-
Mantle cell NHLs High to moderate
FDG PET/CT detected more extranodal lesions than either CT or
18
Lymphoma Types Low FDG Uptake F-FDG PET and concluded that 18F-FDG PET/CT is more accu-

rate than either 18F-FDG PET or CT alone for staging and restag-
Small lymphocytic lymphoma/ Low to undetectable; ing of patients with indolent NHL.
chronic NHLs 50–70% positive As a consequence of these studies, 18F-FDG PET has become
Peripheral T-cell NHLs Low to undetectable the standard imaging tool for the staging of lymphoma (Fig. 21.1).
Extranodal marginal zone/MALT Low to undetectable to high; Most of the early literature analyzed studies using PET scanners,
NHLs ≤70% positive without attenuation correction and inaccurate anatomical local-
ization of lesions. More recently, hybrid imaging utilizing PET/CT
has been available and is a more powerful technique for the stag-
111 ing of lymphoma. PET/CT allows more accurate lesion localization
In-DTPA-Pentetreotide (Octreoscan) than PET alone.73,75–78 PET/CT performed even without intrave-
Somatostatin receptor imaging (SRI) with 111In-pentetreotide has nous contrast with low-dose CT (40 to 80 mAs) is more sensitive
also been used to image lymphoma since lymphocytes and some and specific than contrast-enhanced full-dose CT for evaluation of
of the tumors derived from lymphocytes express somatostatin nodal and extranodal lymphomatous involvement.75,76
receptors, predominantly subtype 2. Since the expression of spe- Detection of more extensive disease by PET changes staging.
18
cific receptor subtypes varies in lymphomas, SRI is not a reliable F-FDG PET makes possible detection of additional sites of lym-
method to determine the extent of disease in general but it is quite phoma in up to 30% of patients. With this aim, a large number of
sensitive to detect high-grade lymphoma including Hodgkin lym- studies have been focused on HD and aggressive NHL
phoma. The sensitivity of 111In-SRI in HD is 70% to 90%; 98% in (Table 21.5).58,60,63,64,67,72–74,79–83 Some studies showed results that
supradiaphragmatic lesions and 67% in infradiaphragmatic change stage; some reported 8%,58,60 some 15.5% to 18.2%63,79,80 of
lesions versus a sensitivity in low-grade NHLs of 62% for supra- change; others reported higher values ranging between 20% and
diaphragmatic; and 44% for infradiaphragmatic disease.46–51 29%;73,81,83,84 whereas very high changes in stage, between 40%
and 47.7%, were observed in other studies.64,67,82 18F-FDG PET
18 studies resulted more frequently in upstaging than in downstaging,
F-Fluorodeoxyglucose PET and PET/CT influenced by its advantage to detect more sites of disease with
By the end of 1990s, imaging with fluorine-18-fluorodeoxyglucose greater sensitivity.58,63,64,72,73,79–81,83 There were only a few studies
(18F-FDG) positron emission tomography (PET) based on imaging of with discordant result.67,82 In comparison to PET and CT, PET/CT
tumor metabolic activity, opened a new era in diagnosis and man- has advantage in initial staging. Thus, Fueger reported correct
agement of neoplasms in general. It was recognized quite early that stage that was determined by PET/CT, PET, and CT in 76%, 62%,
NHL and HD were readily identified by 18F-FDG. Furthermore, 18F- and 58%, respectively. PET/CT correctly upstaged 18% of patients
FDG PET, even prior to the introduction of PET/CT was being used compared to CT in 20% of patients compared to PET alone and
not only to evaluate the extent of disease but also in patient surveil- PET/CT more accurately (4%) staged patients than PET.72
lance following treatment since it was observed that in responsive Since the therapeutic protocol selected depends on the extent
patients, the previously identified lesion failed to accumulate the of lymphoma involvement, changing the stage results in alteration
tracer. It soon became apparent that the accumulation of 18F-FDG of management. Usually, patients with early-stage (stage I or II)
varied among the different histologic lymphoma types depending lymphoma are treated with involved field radiation therapy
on the proliferative activity52; some, the higher-grade lymphomas whereas chemotherapy is utilized in patients with a more
and Hodgkin lymphoma, were highly 18F-FDG-avid tumors53–55 advanced stage disease (stage III or IV). Armitage reported that up
whereas others, the low-grade lymphomas such as FL, had low to one-third of patients with FL are diagnosed with stage I and II
18
F-avidity (Table 21.3).56 Nevertheless, the low-grade lymphomas, disease, whereas 70% to 90% of mucosa-associated lymphoid tis-
for which 67Ga scintigraphy was not considered useful, could fre- sue (MALT) lymphomas are present initially with localized disease
quently be identified with 18F-FDG PET imaging.57 (stage IE to IIE).85 These patients undergo external beam radiation
therapy, whereas higher stages usually require systemic therapy.
If additional disease sites are detected, systemic therapy would be
Staging utilized.86
A comparison between several diagnostic imaging methods in the
initial staging of lymphoma is shown in Table 21.4. 18F-FDG PET
Extranodal Involvement
shows higher sensitivity than CT and other conventional staging
methods but not at the expense of the specificity. 18F-FDG PET NHL may present with extra lymph node involvement with an
shows high sensitivity (90% and 98%) in staging of patients with incidence of 10% to 58%.87–90 For the detection of extranodal lym-
NHL and HD as well as high-negative predictive value of 97.4%.58,59 phoma, 18F-FDG PET is superior to CT (Table 21.6).59,91–94

Tab l e 2 1 . 4
Comparison of diagnostic imaging procedures in initial staging
Number of Lymphoma Sens Spec Acc PPV NPV

Study Patients Type DxI % % % % %
Buchman60 52 NHL/HDa PET 99.2 100 99.9 N/A N/A
CT 83.2 99.8 96.9 N/A N/A
Stumpe61 33 NHL/HD PET 86 96 N/A N/A N/A
CT 81 41 N/A N/A N/A
Thill62 27 NHL/HD PET 100 N/A N/A N/A N/A
CT 77 N/A N/A N/A N/A
Weihrauch63 22 HD PET 88 100 N/A N/A N/A
CT 74 100 N/A N/A N/A
Partridge64 44 HD PET 100 N/A N/A N/A N/A
CT 53 N/A N/A N/A N/A
Young65 49; (11)b HD PET 100 100 N/A 100 100
CT 20 83 N/A 50 56
Altamirano66 40 aggNHL/HD PET 100 100 100 100 N/A
Ga-67 64 0 64 100 N/A
Hueltenschmidt67 25 HD PET N/A N/A 96 N/A N/A
CIM N/A N/A 56 N/A N/A
Wirth68 50 NHL/HD PET 95 N/A N/A N/A N/A
CIM 90 N/A N/A N/A N/A
Ga-67 88 N/A N/A N/A N/A
Hoh69 18 NHL/HL PET 94 N/A N/A N/A N/A
CIM 83 N/A N/A N/A N/A
Jerusalem71 60; (42)c HD PET 86 96 N/A N/A N/A
NHL PET 89 100 N/A N/A N/A
Fueger72 45 NHL/HLa PET/CT 99 100 99.8 N/A N/A
CT 70 100 94.7 N/A N/A
Hutchings73 99 HDa PET/CT 92.2 99.3 N/A 98.4 96.2
CT 82.6 98.9 N/A 97.4 92.3
Schaefer74 6 NHL/HDa PET/CT 94 100 N/A N/A N/A
Karam84 17 FL PET N/A 100 N/A N/A N/A
CT 94 100 N/A N/A N/A
15 MZL PET 71 100 N/A N/A N/A
15 SLL/CLL PET 47 100 N/A N/A N/A
CT 93 100 N/A N/A N/A
a
Nodal lymphoma manifestation.
b
Patients had confirmation by staging laparatomies (10 patients with new disease were staged, while 1 relapsed patient was restaged).
c
Study included 60 pts in total; 42 pts underwent PET for initial staging while 18 pts for disease recurrence.
CIM, conventional imaging methods.
Moog reported histologic verification in 58 biopsies of patients contrast allows better delineation and separation between lymph
with NHL or HD and obtained better results with 18F-FDG PET nodes and bowel loops.97,98 Extranodal involvement of liver and
compared to CT; 98% accuracy for 18F-FDG PET and 78% for CT. spleen may present as diffuse involvement or as a mass. Liver
18
F-FDG PET downstaged patients in 2.5% of the patients and involvement is present in 15% of NHL patients and 3% of HD
upstaged in 12% of patients with extranodal NHL malignant lym- patients at presentation whereas splenic involvement is present
phoma.95 in 30% to 40% of NHL patients and 22% of patients with HD.58,98,99
The most common extranodal sites of involvement in NHL are Moog et al.58 showed that 18F-FDG PET was better than CT in
the gastrointestinal tract and head and neck sites (Fig. 21.2). Gas- detection of spleen, liver, and bone involvement that resulted in
trointestinal lymphoma occurs in 10% to 15% of NHL patients modified staging of patients.
and 30% to 40% of patients with extranodal NHL.96 Physiologic MALT lymphoma mainly involves gastric mucosa and rarely
uptake of 18F-FDG, however, may compromise the accuracy of skin, thyroid, breast, thymus, orbit, liver, kidney, prostate, urinary
18
F-FDG PET and results in false-positive and false-negative bladder, and gall bladder.96,100,101 Approximately 25% of patients
results.58 18F-FDG PET/CT and oral contrast reduce error. Oral have multiple sites of involvement including BM.102


Figure 21.1. 18F-FDG PET/CT in the staging of extent of disease in lymphoma. Coronal images: left to right: CT, 18F-FDG PET, PET/CT fusion images illustrating
stage I, stage II, stage III, and stage IV involvement prior to treatment. Stage I, single lymph node involvement; stage II, multiple lymph node involvement in a single
region; stage III, active disease above and below the diaphragm; stage IV, active disease involving organs. Although the larger masses are detectable on the CT
images alone, the metabolic assessment demonstrating increased anaerobic metabolism is useful to identify small lymph nodes with lymphoma involvement as well
as to provide a baseline for comparison with posttreatment imaging.
Table 21. 5
FDG PET and Change in Staging
Study Lymphoma Type Number of Patients Change in Staging Upstage % Downstage % Change in Rx %
58
Moog NHL/HD 60 8 6.7 1.7 N/A
Buchman60 NHL/HD 52 8 8 0 8
63
Weihrauch HD 22 18.2 18.2 0 4.5
Partrige64 HD 44 47.7 40.9 6.8 25
Hueltenschmidt67 HD 81 40 12 28 8
Schaefer74 Agg NHL/HD 60
PET/CT N/A N/A N/A 16
CT N/A N/A N/A 5.2
Delbeke79 HD/NHL 45 15.5 11.1 4.4 13
Dortz80 NHL 45 18 18 0 N/A
Menzel81 HD 28 21 14 7 N/A
82
Schöder NHL/HD 52 44 21 23 62
Naumann83 HD 88 20 13 8 18
Hutchings73 HD 60 24 19 5 9
Karam84 NHL/FL 17 N/A 29 N/A N/A
Fueger72 NHL/HD 45
PET/CT N/A 18%,a 0%b 4%b N/A
PET N/A N/A N/A N/A
CT N/A N/A N/A N/A
a
In relation to CT scan.
b
In relation to PET scan.
FL, follicular lymphoma

Tab l e 2 1 . 6
Diagnostic Imaging in Staging of Extranodal Lymphoma
Lymphoma Number of Sens Spec Acc PPV NPV

Study Type Patients DxI % % % % %
Buchman60 NHL/HD 52 PET 100 99.4 99.4 N/A N/A

CT 80.8 99.4 97.6 N/A N/A
Hutchings73 HD 99 PET/CT 72.7 97.2 N/A 80 95.8
PET 86 96.5 N/A 78.2 97.9
CT 37 99.7 N/A 94.4 92.2
Schaefer74 NHL/HD 60 PET/CT 88 100 N/A N/A N/A
Moog95 NHL/HD 81(58)a PET 97 100 98 100 97
CT 63 93 78 91 70
a
Eighty-one patients were studied in total; 58 is number of lesions visualized that were taking into account for calculating.
DxI, Diagnostic Imaging; Sens, Sensitivity; Spec, Specificity; Acc, Accuracy; PPV, Positive Predictive Value; NPV, Negative Predictive Value.
Beal et al. reported PET/CT sensitivity of 81% in patients with Cashen et al.,113 Gigli et al.,114 and Bishu115 reported high negative
MALT lymphoma.103 Primary bone lymphoma accounts for less predictive value (NPV) of PET for restaging whereas high specific-
than 5% of all primary bone tumors but 18F-FDG accumulates in ity was reported by Bangerter, Gigli, and Bishu.59,114,115 In com-
primary bone tumors as well as in bone lymphomatous involve- parison with other imaging modalities, PET and PET/CT have
ment.104 Differentiating between the two may be difficult and significant advantages.67,80,116–122
require clinical correlation. Zinzani et al. showed that 18F-FDG PET-positive findings after
The detection of BM involvement is important since it identifies induction treatment were highly sensitive for residual disease
high-risk patients and alters management. This is usually impor- whereas negative 18F-FDG PET at restaging was a strong indica-
tant in the early stage of disease. BM involvement occurs in 10% tion of the absence of active lymphoma. They recommended his-
of newly diagnosed HD and 25% in newly diagnosed NHL and is topathologic verification in patients with residual PET-positive
an indicator of poor prognosis.91 This incidence rises to between findings.123 In fact, this observation has led to the recognition that
18
60% and 70% in low-grade NHL, mainly follicular, whereas it var- F-FDG PET can identify transformation of low-grade lymphoma,
ies from 90% to 100% in mantle cell lymphoma. In aggressive such as FL, to a high-grade lymphoma. The generalization can be
NHL, BM involvement occurs in 25% to 40% of patients.105,106 MRI made that low-grade lymphoma will generally have a standard-
provides the best imaging of BM involvement with a low T1 and ized uptake value (SUV) below 5 compared to high-grade lympho-
high short tau inversion recovery (STIR) signal. In patients with mas that generally will have SUVs of 8 or more. Although no single
negative BM biopsies, MRI findings resulted with upstaging up to SUV level is diagnostic, finding of a site with a strikingly greater
33%. In low-grade NHL, there are some reports of false-negative SUV has been found to indicate that the lymphoma has trans-
results because of microscopic infiltration of BM. Inflammation formed to a high-grade lymphoma (Fig. 21.4).124
and posttreatment changes may also compromise MRI results.1 In the posttreatment period, residual masses, mostly in the
The accuracy of 18F-FDG PET to detect BM involvement is as mediastinum, remain on CT findings in 50% to 64% of patients
high as 93%107 with a reported sensitivity of 81% and a specificity with HD, and in 20% to 60% of patients with NHL.124–127 Residual
of 100% with confirmation by BM biopsy.58 In another study, 18F- masses on CT may represent fibrosis, necrosis, or active tumor. In
FDG PET accuracy of 95% was superior to CT as well as BM 30% to 50% of residual masses in large-cell NHL patients, only 5%
biopsy because of sampling error producing false negatives.108 will have active lymphoma.127 In the past, 67Ga scintigraphy was
Jerusalem et al. reported that 18F-FDG PET was not reliable for widely performed for posttreatment evaluation of high-grade lym-
detection of BM involvement in low-grade NHL.109 In a meta-anal- phoma and HD. 67Ga was useful to detect residual viable tumor
ysis that included 26 eligible reports of 18F-FDG PET for evalua- since it differentiated between high-grade active tumor tissue and
tion of BM infiltration in lymphoma staging, Pakos et al. came to posttreatment fibrotic changes. Because of the low spatial resolu-
a similar conclusion. There was better sensitivity of HD and tion and bowel excretion of 67Ga, abdominal tumor sites were dif-
aggressive NHL than in patients with less aggressive (low-grade) ficult to evaluate.128–130 Although CT and MRI detect the size and
NHL consistent with the general observation if 18F-FDG uptake as exact anatomical location of the masses as well as morphologic
a marker of vigorous glucose metabolism in high-grade, more changes, these techniques cannot reliably distinguish between
aggressive lymphomas.110 residual active tumor and fibrotic tissue.131–136 MRI provides better
Treatment with granulocyte colony-stimulating factors (G-CSF) morphologic details but has a low sensitivity rate (45%).137,138
18
appears as diffuse increases in BM uptake but this can usually be F-FDG PET replaced 67Ga based on more accurate identifica-
identified with clinical correlation although a degree of uncer- tion of abdominal residual masses and a shorter imaging proto-
tainty remains (Fig. 21.3).111,112 Lymphoma of the CNS accounts for col. In 1987, the ability of PET to differentiate between active
2% to 4% of extranodal sites of lymphoma and 1% to 4% of malig- lymphoma and fibrosis on the basis of increased glycolysis was
nant tumors of the brain.96 described for the first time.139 18F-FDG PET has high specificity in
the differentiation between active tissue versus necrosis and
fibrosis.67,116,118–120,133,140,141 18F-FDG PET was found to play an
Restaging important role in the posttreatment evaluation because of better
Aside from its role in initial staging, 18F-FDG PET is important in evaluation of residual masses due to a positive predictive value of
restaging after initial treatment with chemotherapy. There are 100% versus 42% for CT.142
several studies in restaging patients with NHL, HD, or both NHL Cremerius evaluated the role of 18F-FDG PET in the evaluation
and HD that show 18F-FDG PET superiority over CT (Table 21.7). of residual lymphoma versus posttherapy changes. In assessing

Case I Case II Case III Case IV

A
Spleen, bones Lungs, liver, Lungs, liver, Lungs, spleen,

spleen, kidneys spleen, bones bones
Patient 1
Patient 2
Figure 21.2. Extranodal organ involvement in lymphoma. A: 18F-FDG PET maximal intensity projection (MIP) images (display of all acquired transaxial slices
reconstructed in computer memory and displayed so as to appear as a volume display). Four different patients illustrating varied and extensive extranodal involve-
ment—usually an ominous clinical finding. B: Transaxial projections, two different patients. Left to right: CT, transaxial PET, and fused image of CT corresponding
to transaxial PET. Patient 1, large solitary focus in spleen; patient 2, multiple small foci of disease involvement in the spleen in addition to several foci in the hepatic
parenchyma.

A Patient 1 Patient 2
B
Figure 21.3. Differential diagnosis of bone marrow 18F-FDG activity. A: Lower extremity 18F-FDG MIP images of patient with extensive marrow involvement with
hypermetabolic lymphoma cells. Although quite extensive, note patchy pattern. B: Whole-body MIP images of hyperplastic marrow secondary to granulocyte colony-
stimulating factor (G-CSF) administration or bone marrow rebound following completion of chemotherapy (three different patients). Left to right: diffuse hyperplas-
tic bone marrow activity, bone marrow hyperplasia, and activation of spleen (does not indicate splenic involvement with lymphoma; patient should be reimaged after
marrow recovery); diffuse marrow hyperplasia with absent marrow in T11 and L5 vertebrae. This pattern is seen when there was prior vertebral involvement or other
reasons for normal marrow replacement. It may be difficult to differentiate from diffuse, patchy bone marrow involvement. Differential diagnosis can be based on
timing of imaging in relationship to G-CSF or suspension of chemotherapy.
residual lymphoma activity, 18F-FDG PET was more accurate than

Response to Treatment
CT. 18F-FDG PET also showed higher specificity than CT, 92% and
17%, respectively. 18F-FDG PET correctly identified all biopsy- In HD, more than 80% of patients are cured after the standard
proven residual diseases in all patients.116 In 24 patients, 18F-FDG therapy regimen. Patients with aggressive NHL have a worse
PET and CT were compared with respect to detecting viable prognosis and outcome; after the first-line chemotherapy, 50% to
tumor in residual masses. Sensitivity and specificity of PET were 70% of patients achieve complete remission; one-third of patients
87.5% and 94.4% versus 25% and 56% for CT. Persistent lym- are cured whereas 7% relapse annually.1 Identifying patients
phoma disease still remains a diagnostic problem, particularly in who will be cured by a specific therapeutic regimen early in the
HD.120 course of their therapy would be most valuable. Pretherapy

Tabl e 2 1 . 7
FDG PET and PET/CT in restaging lymphoma patients after chemotherapy
Number of Lymphoma Sens Spec Acc PPV NPV

Study Patients Type DxI % % % % %
Bangerter59 58 NHL/HD PET 85.7 96.1 94.8 75 98
Cashen113 42 NHL PET N/A N/A N/A 80 92
Gigli114 42 NHL PET 75 94 N/A 75 94
Huelten- 63 HD PET N/A N/A 91 N/A 96
schmidt67 CIM N/A N/A 62 N/A N/A
Dortz80 45 NHL PET/CT 100 96.9 97.7 92.3 100
CT 100 51.5 64.4 42.8 100
Cremerius116 27 HD/NHL PET 100 92 N/A 100 96
CT 100 17 N/A 100 63

Friedberg117 36 HD PET 80 85 N/A 50 96
Ga-67 40 96 N/A 65 90
Mikhael118 33 NHL PET N/A N/A N/A 100 82
CT N/A N/A N/A 41 75
De Wit119 37 HD PET 91 69 74 46 96
CT 72 21 32 21 73
Filmont121 32 HD PET 100 86 91 79 100
CT 82 57 66 50 86
Ditmann120 24 HD PET 87.5 94.4 N/A 87.5 94.4
CT 25 56 N/A 20 62.5
Weihrauch126 28a HD PET 70 80 76 60 84
84
Karam 30 FL PET 100 91 N/A N/A N/A
16 MZL PET 89b, 85c 92b, 66c N/A N/A N/A
CT 74b, 57c 82b, 100c N/A N/A N/A
7 SLL/CLL PET 75 100 N/A N/A N/A
CT 100 33 N/A N/A N/A
Bishu115 31 NHL PET 94 93 N/A 94 93
DxI, diagnostic imaging method; CIM, conventional imaging methods; Sen, sensitivity; Spec, specificity; Acc, accuracy; PPV, positive predictive
value; NPV, negative predictive value.
a
Values resulted from 29 FDG-PET scans obtained on 28 patients.
b
Overall sensitivity/specificity.
c
Extranodal sensitivity/specificity.
FL, follicular lymphoma; MZL, marginal zone lymphoma; SLL/CLL, B-cell small-cell lymphocytic lymphoma.
c linical risk factors [International Prognostic Score (IPS) in Several 18F-FDG PET studies have shown that demonstration
advanced HD and International prognostic index (IPI) in aggres- of a metabolic response prior to completion of therapy for both
sive NHL] have been developed and are useful but have limited HD and NHL patients is more meaningful than assessment fol-
accuracy.1,11–13,143 Posttreatment evaluation would divide treated lowing completion.10 Thus 18F-FDG PET images can predict long-
patients into one of the two categories: responders and nonre- term response, progression free survival (PFS), and overall
sponders. survival (OS).
Previously, evaluation of treatment response using CT relied on Some studies were performed on mixed patient populations
tumor volume reduction. 67Ga scans were used to detect residual including NHL and HD,66,113,114,117,118,149,150–156 others on NHL patients
metabolic activity in high-grade disease and hence 67Ga scintigra- only,113,114,118,149,152,153,156,157 and others on classical HD.117,154
phy was described as a very useful functional imaging method to In 2002, Kostakoglu et al. found better correlation of PFS with
18
monitor treatment response in these patients. Some authors used F-FDG PET findings obtained after completion of the first chemo-
67
Ga to assess treatment response prior to completion of therapy, therapy cycle compared to 18F-FDG PET at completion of the treat-
after one to two cycles as well as at midtreatment and found it to ment. 18F-FDG PET was performed at baseline, after one cycle and
be a good predictor of outcome.144–148 Since 18F-FDG PET assesses again after completion of chemotherapy in patients with aggressive
tumor viability, it can also be used as an indicator of the biologic NHL or HD. Patients with positive 18F-FDG PET scans after either
changes after the initiation of therapy. 18F-FDG PET scans after one cycle or after completion of the therapy had a short PFS com-
several cycles of chemotherapy are more accurate than 67Ga scin- pared to those with negative PET scans, regardless of the immedi-
tigraphy to evaluate response to therapy. Zijlstra reported better ate posttherapy clinical response. More significantly, there was a
positive and negative predictive values for 18F-FDG PET scans significant difference in PFS between positive and negative 18F-FDG
compared to 67Ga scintigraphy after two cycles of therapy.149 Oth- PET scans obtained after one cycle and after completion of treat-
ers reported positive 18F-FDG PET scans after the third cycle of ment (p < 0.001) (Fig. 21.5). A negative scan after one cycle was
chemotherapy had a higher sensitivity for predicting the relapse more predictive than a negative scan after the full course of therapy.
compared to 67Ga scans.117 This suggests that persistent tumor metabolic activity on 18F-FDG

Figure 21.4. Transformation of lymphoma grade in a patient presenting with low-grade follicular lymphoma involving the parotid glands. Left to right: CT, 18F-FDG PET,
and PET/CT fusion images. Top row: Coronal sections. Image on far right is an MIP image demonstrating mildly increased 18F-FDG activity in bilateral parotid masses
(A) and prominent hypermetabolic masses (B) in the abdominal periaortic lymph nodes. Middle row: Transaxial sections of mildly hypermetabolic parotid masses, SUVmax
1.8 to 2.9, which were the presenting symptom and finding. 18F-FDG PET characterization of these masses is typical of a low-grade lymphoma which was confirmed on biopsy.
Bottom row: Transaxial images of periaortic lymph nodes which are markedly hypermetabolic, SUVmax 16 to 19.5. Biopsy demonstrated large B-cell lymphoma, a high-grade
variant which would not have been detected or biopsied without the high SUV finding on the 18F-FDG PET/CT.
A B
Prior to chemotherapy After three cycles
Figure 21.5. A: Pre- and Posttherapy F-FDG PET MIP images in a Hodgkin disease patient demonstrating complete metabolic response. No evidence of 18F-FDG
18
+ foci. B: Left, pretherapy 18F-FDG PET MIP image in patient with a diffuse large B-cell lymphoma (DLBCL), a high-grade lymphoma; right, 18F-FDG PET MIP image
after only three cycles of chemotherapy, approximately halfway through projected course of therapy. No evidence of 18F-FDG + foci, demonstrating prediction of a
prolonged remission.

DLCL
Baseline

PFS: >24
months
After first
cycle Complete
Remission
C
Figure 21.5. C: Coronal projections, CT, 18F-FDG PET, and PET/CT fusion in a patient with DLBCL at baseline (top row) and after the first cycle of
CHOP chemotherapy (bottom row). All evidence of tumor hypermetabolism has resolved after a single cycle of therapy. The full course of therapy,
nine cycles, was completed and at the time of imaging after 24 months, the patient continued to be free of symptoms or evidence of disease progres-
sion, confirming that it is possible to assess efficacy early in the course of therapy. DLCL, diffuse large-cell lymphoma; PFS, progression free survival.
PET after one cycle of chemotherapy identifies patients who require Hutchings et al. investigated treatment response with 18F-FDG
a more intensive regimen. Patients with a positive 18F-FDG PET PET in patients with HD after two or three cycles and compared
after one cycle had a high likelihood of relapse and a shorter inter- the findings with end-treatment 18F-FDG PET. After the comple-
val until relapse than patients with negative 18F-FDG PET scans tion of treatment, 18F-FDG PET did not add prognostic information
after one cycle of chemotherapy.150 It may be possible to alter the to early interim PET results that was clearly positive or negative.
treatment to second-line chemotherapy and stem cell transplanta- Hutchings et al. conclude that interim 18F-FDG PET is a reliable
tion without completing the full course of initial regimen, or in case tool for early prediction of a long-term remission and PFS. They
of repeated positive PET after two to three cycles and repeated found a highly significant relationship between early interim PET
tumor biopsy to change to alternative dose intense regimen. These and PFS (p < 0.0001) and OS (p < 0.03). A positive interim 18F-FDG
investigators concluded that 18F-FDG PET after one cycle is more PET was highly predictive of early relapse in patients with
accurate to predict the outcome than after completion of chemo- advanced stage HL. All patients relapsed within 2 years.154
therapy.150,151 Subsequently, they confirmed their earlier findings Mikhael et al. compared 18F-FDG PET and CT in posttreatment
and detected higher sensitivity, accuracy, and NPV after the first evaluation in aggressive NHLs. 18F-FDG PET was more accurate
cycle (100%, 96%, and 100%), than at the end of treatment (79%, than CT in assessing remission status. The relapse rate was 100%
92%, and 91%, respectively).151 In a multivariate analysis in aggres- for positive PET scans versus 14% for negative PET scans and
sive NHLs, Spaepen et al. showed that 18F-FDG PET at midtreat- 41% and 25% for positive and negative CT scans, respectively.
ment was a stronger predictor for PFS and overall survival than the They stated that compared to CT, 18F-FDG PET is a more accurate
IPI. Patient who had positive PET scan at midtreatment either rap- method of assessing remission and estimating posttreatment
idly relapsed after a temporarily achieved complete response (CR), prognosis with positive and negative predictive accuracies of
never achieved CR, or progressed during the course of therapy. In 100% and 82% for 18F-FDG PET versus 41% and 75% for CT,
contrast, almost all patients with negative midtreatment 18F-FDG respectively. The prognostic value of interim 18F-FDG PET, after
PET scan achieved a durable CR; however, some patients, neverthe- two to four cycles of chemotherapy was useful to predict treat-
less, experience progression of disease.155 For patients without an ment outcome. Positive predictive accuracy of interim PET is 88%,
early response, it may be appropriate to consider an alternative whereas the negative predictive value is 100% accurate.118
regimen.153 At present, there is no evidence to support less than Altamirano reported that 18F-FDG PET had greater prognostic
completion of a full course of their first-line treatment regimen in value than CT after the third cycle of chemotherapy and at regi-
patients with negative 18F-FDG PET results after one cycle. men completion. 18F-FDG PET after three cycles was predictive of

the outcome at 18 months in patients with intermediate and instructions on how many lesions to follow (maximum of 10 total,
aggressive NHL and HD.66 Others also found that an 18F-FDG PET maximum 5 per organ site), and unidimensional measures for
interim scan, was a good predictor of PFS in patients with aggres- overall evaluation of tumor burden. RECIST criteria have been
sive NHLs and HD.118,154,155 Nevertheless, some studies did not accepted as an appropriate guideline for treatment response by
confirm the value of interim 18F-FDG PET as a predictor of out- regulatory agencies and were widely adopted for trials where the
come.113,114 Given the large number of reports confirming the primary endpoints are objective response or progression.160 A
value of interim 18F-FDG PET assessment of lymphoma activity, it decade later, new revised criteria, RECIST guideline (version 1.1)
is difficult to understand these negative findings. Since many lym- was established. This revision defined the following:
phoma chemotherapeutic protocols include corticosteroids which
are known to interfere with glucose metabolism, it is possible that • The number of lesions required to assess the tumor burden has
the negative correlation of these few studies is a consequence of been reduced from a maximum of 10 to a maximum of 5 in total
an insufficient interval between steroid administration and 18F- (and from maximum 5 to 2 per organ); lymph nodes with a
FDG PET or PET/CT assessment. short axis of ≥15 mm are considered measurable and assess-
Most 18F-FDG PET studies are evaluated, based on visual able as target lesions. The measurement of short axis is included
observer analysis. To categorize responders and nonresponders in the sum of lesions in calculations of tumor response.
(based on 18F-FDG uptake: no 18F-FDG uptake or residual uptake), • Nodes which decreased in size to less than 10 mm in short axis
it is best to use the SUVs.156–158 Itti et al. performed semiquantifica- are considered normal.
tion of SUV values to improve the prognostic value of PET.156 • Confirmation of response is no more required for randomized
Using 18F-FDG SUV, they reported reduced false-positive 18F-FDG studies but only for trials with response primary endpoint.
PET results after the initial two cycles of chemotherapy. After four • In addition to the previous definition of disease, progression in
cycles of therapy, visual analysis was equal to SUV criteria. target disease of 20% increase in sum, a 5 mm absolute increase
is now required.
• Section of new lesions and interpretation of 18F-FDG PET scan
Response Criteria assessment is included, as well as new imaging appendix with
updated recommendations on the optimal anatomical assess-
Assessment of the change in tumor burden is an important feature ment of lesions.161
of the clinical evaluation of cancer therapeutics. Both tumor
shrinkage (objective response) and time to the development of dis- RECIST committee recommended standard criteria for lymph
ease progression are important endpoints in cancer clinical trials. node measurements to be more accurate by adopting the short
In 1981, the WHO first published tumor response criteria, mainly axis measurement thus allowing their use in response assessment
for use in clinical trials, where tumor response was the primary better aligned with clinical radiology practice.162
endpoint. These criteria presented a concept of overall assessment Since some limitations exist in anatomic imaging alone using
of tumor burden by summing the products of bidimensional lesion standard WHO, RECIST, and RECIST 1.1, Wahl et al. proposed
measurements and determined response to therapy by evaluation including functional metabolic criteria to include 18F-FDG SUV
of change from baseline while on treatment.159 response in a new guideline, PERCIST 1, for use in clinical trials
Confusion in interpretation of trial results led to a need for and in quantitative clinical reporting.163
standardization and simplifying the response criteria. Interna- There are several different response criteria created by differ-
tional Working Party that was formed in mid-1990s created a new ent cancer treatment groups who performed clinical investigations
criterion, a Response Evaluation Criteria in Solid Tumors (RECIST) in NHLs. Those guidelines were based on solid tumor criteria but
criterion. It was published in 2000. The new response criteria were quite different from each other, and subsequently resulted in
introduced definitions of minimum size of measurable lesions, confusion (Table 21.8). NHL requires separate response criteria
Tab l e 2 1 . 8
Interim FDG PET in Chemotherapy Response Assessment
Number Median
of Lymphoma F/U Sens Spec Acc PPV NPV
Authors Patients Type Cycles (mos) % % % % %
Kostakoglu150 30 Agg NHL/HD 1 19 87 87 87 87 87

Kostakoglu151 47 DBCL/HD 1 21 100 94 95.7 87.5 100
Jerusalem152 25 NHL 2–5 17.5 42 100 73 100 67
66
Altamirano 28 Agg NHL/HL 3 18 92 93 93 92 93
Spaepen153 70 Agg NHL 3–4 36 85 100 91 100 84
Zijlstra149 26 Agg NHL 2 25 64 75 69 75 64
Friedberg117 22 HD 3 24 80 94 91 80 94
154
Hutchings 77 HD 2 23 N/A N/A N/A 69 95
Mikhael118 23 Agg NHL 2–4 30 100 94 96 88 100
Haioun155 90 Agg NHL 2 24 N/A N/A N/A 44 87
Itti156 80 DLBCL 4 41 58.8 87.3 81.3 55.6 88.7
113
Cashen 50 DLBCL 2–3 15 N/A N/A N/A 25 85
Gigli114 42 DLBCL 3 15 75 76 N/A 43 93
F/U, follow-up; Sens, sensitivity; Spec, specificity; Acc, accuracy; PPV, positive predictive value; NPV, negative predictive value.

Table 21. 9
Response Criteria for NHL
Response Category Physical Examination Lymph Nodes Lymph Node Masses Bone Marrow
CR Normal Normal Normal Normala

CRu Normal Normal Normal Indeterminateb
Normal Normal >75% decrease Normal or indeterminate
PR Normal Normal Normal Positive
Normal ≥50% decrease ≥50% decrease Irrelevant
Decrease in liver/spleen ≥50% decrease ≥50% decrease Irrelevant
Relapse/progression Enlarging liver/spleen; new sites New or increased New or increased Reappearance
a
If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site. The sample on which this determination
is made must be adequate (≥20 mm biopsy core).
b
Increased number or size of aggregates without cytologic or architectural atypia.

CR, complete response; CRu, complete response unconfirmed; PR, partial response.
from solid tumors since lymphomas differ from other malignant The standardized response criteria are necessary to interpret
tumors. Standardized response criteria are important for NHLs, to and compare clinical trials and provide data for approval of new
conduct clinical research as well as individual patient manage- therapeutic agents for regulatory agencies. According to the
ment. The guidelines should facilitate interpretation, comparisons revised PET guidelines, the recommendations to use PET scans
between clinical trials, and evaluation of new therapeutic agents. include the following:
The uniform guidelines ensure a reliable analysis and comparison
• Timing of PET scans after treatment with standardized defini-
of patient groups among studies and data reproducibility. There-
tions of endpoints of clinical trials.
fore, The International Working Group (IWG) criteria for response
• Visual assessment is considered as adequate to determine if an
assessment were established in 1999 to enable comparison 18
F-FDG PET scan is positive; SUV is not considered to be nec-
between clinical trials; they were based mostly on computed
essary. A positive scan was defined as focal or diffuse 18F-FDG
tomography, without contribution of PET imaging (Table 21.9).164
uptake above background in a location incompatible with nor-
Since 18F-FDG PET was performed routinely in the evaluation
mal anatomy or physiology, without a specific SUV cutoff.
of the treatment response in lymphoma, it has become clear that
• PET is recommended in several histologic types of lymphoma,
these criteria needed to be updated. Because of the high degree of
HD, and NHL with specified timing of performance.166
accuracy of 18F-FDG PET in evaluating treatment response in
patients with DLBCL NHLs and HD, it has been incorporated into Currently, the use of 18F-FDG PET is reserved primarily for
the International Workshop Criteria to provide more accurate patients with HL and DLBCL before treatment and after therapy
response evaluation. The International Harmonization Project since the degree of 18F-FDG uptake in low-grade NHL is generally
Imaging Committee created the guidelines to interpret 18F-FDG low although 18F-FDG will identify more sites of disease than 67Ga
PET in treatment assessment in lymphoma. It was aimed to and will also detect transformation of a low-grade lymphoma to a
ensure reliability of PET interpretation for both clinical trials as higher grade (Table 21.10).
well as in routine clinical practice. The technique to perform and The criteria suggested by the International Harmonization
interpret 18F-FDG PET in lymphoma has been standardized into a Project are valid only for the end-treatment response evaluation
consensus document. The new guidelines incorporated 18F-FDG by PET. On the other hand, during the past several years, interim
PET, immunohistochemistry, and flow cytometry to define PET has a significant role in predicting the treatment outcome in
response assessment in HD and NHL in 2007.165 Hodgkin lymphoma and diffuse large B-cell non-Hodgkin
Tabl e 2 1 . 1 0
Timing of PET (PET/CT) Scans in Lymphoma Trials
Histologic Type of Baseline Midtreatment Response

Lymphoma PET PET Evaluation Follow-up PET
a
Routinely FDG avid Yes Clinical trial Yes No
DLBCL Yesa Clinical trial Yes No
b b
HD No Clinical trial No No
Follicular NHL Nob Clinical trial Nob No
MCL Nob Clinical trial No No
Variably FDG avid
- Other aggressive NHLs Nob Clinical trial Nob, c No
b
- Other indolent NHLs No Clinical trial Nob, c No
a
Recommended but not required pretreatment.
b
Recommended only if ORR/CR is a primary study endpoint (ORR, overall response rate; CR, complete remission).
c
Recommended only if PET is positive pretreatment.
Histologic types: DLBCL, diffuse large B-cell lymphoma; HD, Hodgkin disease; NHL, non-Hodgkin lymphoma; MCL, mantle cell lymphoma.

lymphoma (DLBCL NHL). A systematic review of interim PET stud- well as low-grade lymphomas despite the relatively low SUVs
ies by Terasawa et al.167 reported a sensitivity of 65% to 100% and observed in patients with low-grade lymphoma. In the symptomatic
specificity of 94% to 100% for HD; whereas 50% to 100% and 73% patient with the diagnosis of low-grade lymphoma, 18F-FDG PET/
to 100% for DLBCL NHL, respectively. Some authors state that CT serves to identify the extent of the lymphadenopathy and to
PET is better than IPI or IPS in HD and DLBCL NHL.156,168 exclude transformation to a higher grade. 18F-FDG PET/CT also
Several meetings of International Workshop on Interim-PET- serves to identify a response to therapy and is useful in surveillance
Scan under the auspices of Groupe d’Etude des Lymphomes de of patients who have responded to therapy. Further studies are
l’Adulte (GELA) was held with the aim of reaching a consensus on necessary to determine if imaging early in the course of therapy is
simple and reproducible criteria for interpretation of HD and a useful biomarker to shorten the current duration of chemother-
DLBCL NHL. A five-point visual assessment as the initial evalua- apy protocols in responsive patients as well as to provide a basis to
tion with the additional value of SUV analysis was proposed in discontinue a therapeutic course and replace it with a more aggres-
evaluation for both HD and DLBCL NHLs. The five-point scale sive alternate therapy if the 18F-FDG PET/CT biomarker indicates
assessment includes (1) no uptake; (2) uptake ≤mediastinum; (3) that the duration of response will be brief. The principal short-
uptake >mediastinum but ≤liver; (4) uptake moderately more than coming of 18F-FDG PET/CT is the occasional nonspecific finding of
liver uptake, at any site; and (5) markedly increased uptake at any foci with increased SUVs secondary to inflammation. Hence, an
site and new sites of disease.169 imaging biomarker that identifies proliferative activity rather than
just increased metabolism would be more specific for the demon-
stration of tumor activity. 18F-fluorothymidine (18F-FLT) is fluori-
Conclusions and Future nated analog of thymidine that is phosphorylated by thymidine
Considerations kinase during the S-phase of the cell cycle but not incorporated into
DNA. Nevertheless, it can serve as an imaging marker of cell prolif-
For the past decade, 18F-FDG PET/CT has served as the biomarker eration. In most cases, the findings correlate with 18F-FDG PET
of choice for the initial assessment (staging) of patients with Hodg- imaging as well as Ki-67 evidence of proliferative activity
kin lymphoma and NHL, both high-grade aggressive lymphomas as (Fig. 21.6).170–172 In an exhaustive review of the literature, Bertagna
18F-FLT
Pretreatment Posttreatment
18F-FDG
Figure 21.6. 18F-fluorothymidine (18F-FLT) and 18F-fluorodeoxyglucose (18F-FDG) in

a patient with mantle cell lymphoma (MCL). Multiple tumor sites are 18F-FDG positive
and 18F-FLT negative. Other sites are both 18F-FDG positive and 18F-FLT positive. The
18
F-FDG-positive, 18F-FLT-negative sites did not respond as well to chemotherapy
whereas the 18F-FDG-positive, 18F-FLT-negative sites are smaller and have a decrease
Pretreatment Posttreatment in SUV.

et al. identified nine publications that dealt with the value of 18F-FLT cells. The SUV is expected to be elevated but this finding has no
PET in the hematologic malignancies. In general, the results cor- impact on management. 18F-FDG PET has demonstrated extra-
related with 18F-FDG PET in terms of identifying disease activity medullary involvement that was subsequently confirmed on
and the response to therapy. Bertagna et al.173 concludes that there biopsy. In addition, 18F-FDG PET has potential to identify compli-
was no advantage compared to 18F-FDG PET except in the central cations such as Richter conversion to DLBCL as well as to identify
nervous system where there is no 18F-FLT uptake in the normal coexisting neoplasms or infection complicating the clinical course
grey matter thus providing a better lesion to background contrast. and management.174
Leukemi a 18
F-FLT PET/CT
Buck et al. evaluated the merit of 18F-FLT in ten patients with
Introduction acute myeloid leukemia (AML) prior to and following initial ther-
apy. Utilizing 18F-FLT in doses similar to those used with 18F-FDG
Leukemia is a malignancy characterized by excess, uncontrolled PET imaging, they recorded dynamic images for the initial 60
production of white blood cells which overload the BM and spill minutes. BM and spleen had the most activity with BM mean SUV
out into the circulation. The patient may be profoundly ill with of 11.5 versus 6.6 in control subjects. Spleen SUV was 6.1 versus
fever and weakness or relatively asymptomatic (at least initially) 1.1 in controls. Activity in other organs such as the brain or testes

with the disease first identified on routine blood count examina- was confirmed on biopsy to represent leukemic infiltrates.
tion. There are many variants of the disease as any of the compo- Although there was no demonstrable relationship between mar-
nents of the white blood cell lineage may give rise to a malignant row SUV and BM blast cell count, absent activity was demon-
clone. The various types cannot be identified based on clinical strated in a patient who received myeloablative therapy.175 Using
symptoms but precise diagnosis is important as it determines the a similar 18F-FLT PET imaging protocol, Eary et al. demonstrated
choice of therapy and the potential course of the disease. As a 50% and 35% decrease in BM SUV in two patients following
stated, diagnosis is based on examining the peripheral blood as therapy. In a third patient the SUV increased but no correlation
well as the BM. There are four principal groups of leukemia: Acute with the subsequent clinical course was reported.176 Vanderhoek
and chronic myelogenous leukemia and acute and chronic lym- et al.177 similarly concluded that 18F-FLT PET might be useful to
phatic leukemia. The acute designation is characterized by a pre- confirm disease control during induction chemotherapy.
dominance of immature blast cells in the BM and the peripheral Overall, nuclear imaging, including PET and PET/CT, currently
circulation whereas the chronic forms have more mature but has no role in the management of the leukemic patient. Neverthe-
excessive numbers of the cell type. As might be expected, acute less, there are findings on 99mTc-MDP imaging, 67Ga scintigraphy,
leukemia follows a more aggressive course leading to death unless and 18F-FDG PET and PET/CT that are seen in patients with leu-
remission is achieved by initial therapeutic efforts. Even when a kemia. There is a potential future role for 18F-FDG and possibly
clinical and laboratory response is achieved, most patients will other imaging biomarkers such as 18F-FLT to serve as biomarkers
relapse. Hence, the so-called consolidation therapy is usually of responsiveness to chemo- or other therapy.
employed; that is, additional therapeutic intervention despite nor-
malization of the differential blood count and BM.
Targeted Radionuclide Therapy
Diagnostic Imaging
Radioimmunotherapy of Lymphoma
Other than demonstrating splenomegaly and expanded BM cavity
activity, diagnostic imaging including nuclear scintigraphy and Over the past quarter century, the classification of both Hodgkin
PET or PET/CT has little to offer in terms of management of the lymphoma and NHL has grown increasingly complex. This insight
patient with leukemia. Nevertheless, the nuclear medicine physi- into the diverse features of this group of tumors arising from lym-
cian should recognize the findings when present although they phoid tissue has provided many benefits as recognition of specific
are usually nonspecific. markers has enabled more appropriate and patient-specific treat-
ment. In particular, the identification of specific cell surface markers
has led to the development of antibodies which have altered the
Bone Scintigraphy management of many patients with NHL. An antibody to the lym-
On skeletal imaging, there is usually diffuse increase in the radio- phocyte cell marker, CD20, is now commonly used as a component
tracer throughout the skeleton consistent with increased bone of the initial chemotherapy protocol for patients with lymphomas
mineral turnover secondary to the stress on the skeleton from the expressing CD20. This antibody, rituximab, is a chimeric immuno-
expanded and hypermetabolic BM. The bone scintigraphy find- globulin derived from the murine immunoglobulin ibritumomab
ings, however, are nonspecific and similar to the pattern seen in and is marketed in the United States as Rituxan. It is used as a
myeloid metaplasia, other causes of BM expansion such as Gau- maintenance form of therapy in many patients. Both rituximab and
cher disease, and even the superscan seen secondary to diffuse another anti-CD20 immunoglobulin known as tositumomab are
BM infiltration by metastatic soft tissue tumor. components of two different FDA approved radioimmunotherapy
regimens (Zevalin and Bexxar) for the treatment of patients with
lymphoma.
Liver–Spleen Colloid Scintigraphy
Splenomegaly is identified on any radiocolloid scan but the findings
has no significance on management decisions nor is it likely infor-
Zevalin and Bexxar
mative beyond the clinical assessment of the patient’s abdomen. Both Zevalin and Bexxar involve infusion of an unlabeled (cold)
antibody followed by the radiolabeled antibody. Zevalin consists of
18 rituximab and Yttrium-90 (90Y)-ibritumomab tiuxetan and involves
F-FDG PET and PET/CT infusion of the unlabeled at the initiation of the regimen, followed
18
F-FDG PET and PET/CT are likely to demonstrate diffuse mar- a week late by a second rituximab infusion at the same dose level
row activity as well as solid organ foci if infiltrated by leukemic after which the 90Y-ibritumomab tiuxetan is infused.

The Bexxar regimen consists of infusing the unlabeled tositu- Zevalin

momab followed by a 185 to 222 MBq (5 to 6 mCi) dose of
131
I-labeled tositumomab to perform whole-body dosimetry by Zevalin is the only commercial product currently available in
obtaining whole-body counts, usually at three time points over the Europe and the United States. Zevalin is actually a regimen: A
following 7 days. From this data, the whole-body radiation combination of the unlabeled anti-CD20 antibody, rituximab, fol-
absorbed dose per unit of radioactivity is calculated. From this lowed by an infusion of a 90Y-labeled antibody, ibritumomab. Ibri-
data, one determines the amount of radioactivity that would tumomab is a murine antibody from which rituximab, a chimeric
deliver 65 or 75 cGy to the whole body. Subsequently, this dose is antibody, is derived. The anti-CD20 portion is similar in both the
infused after an infusion of unlabeled tositumomab. Both ritux- rituximab and ibritumomab molecules. Rituximab infusion pre-
imab and tositumomab are anti-CD20 immunoglobulins. The cedes administration of the radiolabeled immunoglobulin to
labeled anti-CD20 antibody delivers a β-Emitting radionuclide to occupy the abundant CD20 binding sites on circulating B and
B-cells, combining the direct cytotoxic effect of immunoglobulin splenic B-lymphocytes. Although somewhat counterintuitive,
fixation with a delivery of a local radiation flux, thus altering the tumor uptake of the radiolabeled form of the antibody is actually
life cycle of cells even if they have not been directly bound with greater when nonradiolabeled immunoglobulin is infused prior to
antibody. The unlabeled antibody infusion prior to administration the infusion of the radiolabeled immunoglobulin. Initially, clinical
of the labeled immunoglobulin occupies a good portion of the cir- studies involved the infusion of an 111In-labeled ibritumomab pre-
culating B lymphocyte CD20 epitope, resulting in prolongation of ceded by a Rituxan infusion to obtain dosimetry data and confirm
plasma half-life and a greater fraction of the administered dose biodistribution of the radiolabeled immunoglobulin. Currently,
accumulated in tumor sites.178 within both the European and United States communities, use of
As expected, radioimmunotherapy has resulted in further the In-labeled form of the immunoglobulin followed by imaging is
improvement in clinical responses compared to immunotherapy no longer required. Nevertheless, since the initial clinical trials
alone. This is because of the added cytotoxicity of radiation in involved the infusion of a potentially therapeutic amount of
addition to the direct cytotoxic effect of the antibody augmented Rituxan (450 mg/m2), the entire regimen still consists of the initial
by the crossfire effect so that cells are irradiated even if they have infusion of the nonlabeled rituximab followed 1 week later by a
not been directly targeted by the radiolabeled antibody. repeat infusion of rituximab followed by 90Y-ibritumomab.
Both Bexxar and Zevalin were initially approved by the FDA for The dose of 90Y-ibritumomab employed is based upon the
use in patients with refractory or relapsed low-grade FL. Other patient’s weight and platelet count. 15 MBq/kg if platelets are
requirements included confirmation on biopsy material that the ≥150 K/μL; 11 MBq/kg if platelets are <150 K/μL but >100 K/μL;
tumors were CD20+, had less than 25% BM involvement, and a maximum dose 4.44 GBq. The dose of 90Y-ibritumomab employed
platelet count ≥150 K/μL. Allowance was made for patients with is based upon the patient’s weight and platelet count. BM involve-
platelets below 150 K but >100 K/μL. The principal toxicity of both ment in the nonmyeloablative setting should be <25%.182,183
Zevalin and Bexxar is hematologic with reduction of platelet count In the initial efficacy trials comparing rituximab to Zevalin in
being the greatest concern. Patients should be monitored with com- patients with indolent low-grade lymphoma who had relapsed
plete blood and platelet counts weekly after infusion. In general, the after chemotherapy, the Zevalin regimen had an overall response
platelets nadir from 4 to 7 weeks and generally return to about 80% rate (ORR) of 82% compared to rituximab alone which had an ORR
of the pretherapy level. Many patients can be managed with obser- of 33% with no complete responses (CRs). By contrast, the Zevalin-
vation alone but platelet infusions may become necessary. The treated group had 26% CR (Table 21.11).184
absolute neutrophil count also may decline to 1,000 cells/mm2. In a subsequent randomized trial comparing Zevalin to rituximab
The initial clinical trials and postapproval experience have alone in patients who had relapsed or been refractory to chemo-
been excellent but total sales of both products have suffered for a therapy but were rituximab naïve, Zevalin had an 89% ORR com-
variety of reasons that proponents of radioimmunotherapy con- pared to a 56% ORR in patients receiving only rituximab. Zevalin had
sider nonsubstantive. Nevertheless, the failure of the oncology a 30% CR compared to 16% for rituximab.185 In general, patients
community to embrace radioimmunotherapy despite the impres- with a CR have a longer PFS than patients only achieving a PR.
sive clinical results has had a negative effect on sales of the prod- A subsequent clinical trial has demonstrated the beneficial
ucts.179,180 In fact, in late 2013, the distributors of Bexxar effect of Zevalin as consolidation therapy in patients who achieved
announced that distribution of the product would be discontinued a CR or PR following initial chemotherapy such as CHOP, CHOP-R,
in February 2014. Accordingly, the remainder of this section on CVP, CVP-R, or fludarabine. Compared to the randomized control
radioimmunotherapy will be devoted primarily to Zevalin. Addi- group who did not receive consolidation therapy, there was an
tional clinical details about both Bexxar and Zevalin are described increase in the median PFS threefold (36 months versus 13
in several recent reviews.178,181 months). In patients achieving a CR, the median PFS in the group
who received Zevalin was 54 months.186
Tab l e 2 1 . 1 1
Zevalin Therapy (90Y-Ibritumomab Tiuxetan + Rituximab)
Zevalin Therapy (90Y-Ibritumomab tiuxetan + rituximab)

Overall Responders CR/CRu
Study (N) % Median DR % Median DR Range of Ongoing
(mos) (mos) Response (mos)
Phase 1-2 (51) 73 11.7 29a 23a 60+ to 66+

Phase 2 (30) 83 11.5 47 23 40+ to 42+
Phase 3 (73) 80 13.9 34 23 33+ to 48+
a
Data in patients with CR only.
N, number of patients involved; CR, complete response; CRu, complete response unconfirmed; Median DR, median duration of response.

Radioimmunotherapy of Leukemia
Although there are no radiolabeled antibodies, antibody fragments
or small molecules available clinically for the treatment of leuke-
mias, leukemic cells represent an attractive target for this therapeu-
tic approach as access to the tumor cells is readily achieved. Indeed,
there is a substantial and ongoing investigational effort to treat
various leukemias with specific immunoglobulins, both unlabeled
and labeled.189–191 At the present time, none of these are approved
for clinical use in the United States, Europe, Asia, or elsewhere. An
interesting aspect of these investigations has been the development
and evaluation of specific immunoglobulins labeled with α-emitters.
Since, in the case of leukemia, the tumor cell is circulating in the
blood pool and residing in the BM where there is ample perfusion,
the characteristic very short range of α particles (50 to 80 μm) com-
pared to β particles (0.8 to 5 mm) is satisfactory to severely damage
the tumor cells and limit radiobiologic damage to other tissues and
marrow precursors that do not express the specific epitope. Fur-

thermore, Scheinberg et al. at Memorial Sloan Kettering have devel-
oped a nanogenerator in which the immunoglobulin is labeled with
a precursor α-emitter that subsequently decays into a second
α-emitter.189 Trials in animal models have been encouraging.
Conclusions and Future

Considerations
Figure 21.7. A 49-year-old man with a history of diffuse large-cell lymphoma, diagnosed 11 Radiolabeled molecules, principally immunoglobulins have been
years earlier. At that time, patient had undergone classical chemotherapy (CHOP). Relapsed after
5 years with pleural involvement; responded after pleural resection, rituximab infusions, and two used in preclinical trials to treat lymphoma and leukemia. In the
cycles of DICE. Second relapse, 6 years later; referred for radioimmunotherapy. Left, preradio- case of lymphoma, following extensive clinical trials, two products
immunotherapy 18F-FDG MIP demonstrating large abdominal mass; right, repeat 18F-FDG MIP have been approved by the FDA in the United States. The results
5.5 months later demonstrates resolution of abdominal mass. 18F-FDG + foci in left thorax are in terms of clinical response, both complete and partial, and the
granulation tissue which persist following pleurectomy.
therapeutic–toxic ratio have been very favorable. Moreover, these
two products (Bexxar and Zevalin) have demonstrated efficacy in
a variety of clinical applications beyond the original approval.
In general, the clinical response (ORR, CR, PR) with the radioim-
Patients have tolerated the BM exposure well and fair, no worse
munotherapy agent Zevalin used for the treatment of patients with
upon relapse, and retreatment than patients who have not
CD20+ NHL who have relapsed after initial therapy are greater,
received targeted radionuclide therapy. Nevertheless, acceptance
and of greater duration, than repeat chemotherapies. In fact,
by clinicians who see the patients initially and upon whom refer-
radioimmunotherapy is safe and effective even in patients who fail
ral is dependant has been disappointing. It is likely that there will
to respond or relapse after response following immunotherapy.
be additional advances in identifying cell targets for the delivery
The CR and ORR are even better when used as first-line treatment
of radiation. Significant impact on the management of these dis-
in conjunction with chemotherapy or as “consolidation” therapy.
eases, lymphoma and leukemia, depends upon recognition and
The principle toxicity of Zevalin as a radioimmunotherapeutic is
utilization by the larger clinical community.
hematologic; secondary to BM irradiation from labeled antibody in
blood and specific deposition on tumor cells in the BM. Patients
should be followed with weekly CBC and platelet count: Supportive
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C h apt e r 2 2
Melanoma
Alice Lorenzoni • Ettore Seregni • Marco Maccauro • Andrea Maurichi • Alessandra Alessi • Flavio Crippa
Introduction The updated version of the American Joint Committee on Cancer

(AJCC) staging and classification system, which include sentinel
Cutaneous melanoma is estimated to be the seventh most common node (SN) staging, is the internationally accepted classification
malignant tumor, and a steady increase in incidence has been system (Table 22.1).4
observed over the past 30 years.1 The incidence of malignant mela- Tumor thickness thresholds were changed to reflect updated
noma varies from 3 to 5/100,000/year in European countries to 12 prognostic information (thresholds of 0.75, 1.50, and 4 mm were
to 20 in Australia, which has the highest incidence of cutaneous changed to 1, 2, and 4 mm), mitotic index was added as an indepen-
melanoma.2 Ultraviolet light exposure is only in part responsible dent prognostic factor (regardless of stage). Breslow thickness and
for the increase in incidence that is related in part to improved the presence of ulceration are the two most important independent
screening programs. Consequently, the detection of earlier lesions prognostic factors for localized melanoma, associated with an
with a more favorable prognosis is more frequent. The mortality increased risk for distant metastases and poor survival. The value of

rate is 3 to 5/100,000/year and has remained relatively stable over mitotic rate as an independent determinant of prognosis was par-
the last decade. The median survival time for patients with meta- ticularly evidenced in thin melanomas (≤1 mm in thickness).
static melanoma, however, is less than 1 year. The total number of metastatic lymph nodes influences subcat-
Risk factors include the presence of multiple atypical nevi, fam- egorization within stage III, and macroscopic nodal involvement is
ily history of melanoma, episodes of severe sunburn, and freckles. associated with worse prognosis compared to microscopic lymph
Thirty-five percent of patients with malignant melanoma will node metastases. Lung metastases have a more favorable progno-
develop another cutaneous malignancy within 5 years.3 The natu- sis compared to other distant visceral lesions (M1b versus M1c
ral history is characterized by hematogenous and lymphatic dis- disease).5 Consequently, accurate disease staging is important for
semination to regional and distant sites. appropriate patient management with melanoma.
Diagnosis and Staging Treatment

An atypical pigmented lesions suspicious for malignant melanoma Surgery with a wide excision of primary tumors is the potentially
is characterized by asymmetry, border irregularities, color hetero- curative treatment for localized melanoma. Elective lymphadenec-
geneity, dynamics (dynamics in colors, elevation or size) (“ABCD tomy or irradiation of the regional lymph nodes does not significantly
rule”). The diagnosis is based on a full thickness excisional improve the overall survival. The role of adjuvant radiotherapy (RT)
biopsy. to the primary has not been defined in clinical trials. In stage IV
Histopathologic analysis includes evaluation of tumor thick- melanoma, RT plays an important role in the treatment of brain
ness (Breslow measurement), presence of ulceration as well as of metastases and may be useful for other systemic metastases as pal-
the mitotic rate/mm2, and the involvement of surgical margins. liative treatment. The role of adjuvant whole brain RT or stereotactic
Tabl e 2 2 . 1
American Joint Committee on Cancer Staging
Regional Lymph Node Distant

Stage Primary Tumor (pT) Metastases (N) Metastases (M)
IA ≤1 mm, no ulceration None None

IB ≤1 mm with ulceration or Clark Level IV or V None None
1.01–2 mm, no ulceration
IIA 1.01–2 mm with ulceration None None
2.01–4 mm, no ulceration
IIB 2.01–4 mm with ulceration None None
>4 mm, no ulceration
IIC >4 mm with ulceration None None
IIIA Any tumor thickness, no ulceration Micrometastases None
IIIB Any tumor thickness with ulceration Micrometastases None
Any tumor thickness no ulceration Up to three macrometastases None
Any tumor thickness with/without ulceration None but satellite and/or in-transit None
metastases
IIIC Any tumor thickness with ulceration Up to three macrometastases
Any tumor thickness with/without ulceration ≥4 macrometastases, or lymph node
involvement extending beyond capsule,
or satellite and/or in-transit metastases
with lymph node involvement
IV Any T Any N Distant metastases
Reprint with permission from American Joint Committee on Cancer. Melanoma of the Skin. In: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer
Staging Manual. 7th ed. New York, NY: Springer; 2009;325–344.
313

radiosurgery is still controversial. Adjuvant therapy with dicarbazine value for the remaining nodal basin has been shown to be 95%.15
and interleukin 2 has not been shown to improve survival. Reintgen et al.16 validated the SN approach in melanoma by eluci-
dating the concept of an orderly progression of lymph node metasta-
ses in melanoma. Preoperative localization of SLN has been used to
Diagnostic Procedures identify draining nodal basins in patients with melanoma of the
trunk to perform elective lymph node dissection. When the SLNB
An extent-of-disease workup in patients with melanoma should be technique was introduced in the early 1990s, preoperative lymphos-
considered to detect clinically occult disease and to define homo- cintigraphy (LS) was of great assistance not only in identifying with
geneously staged patients for inclusion in clinical trials. certainty the draining lymph node field but also in providing pre-
The utility of imaging studies in patients with melanoma gener- cise information about the location and number of SLNs within that
ally depends on the stage of the tumor. In patients with early stage field. This led to the introduction of routine preoperative LS in
disease, all imaging methods have limited utility, with a very low patients scheduled for SLNB. It became apparent that SLNs were
sensitivity. The presence of clinical indications (e.g., suspected or sometimes in clinically unexpected locations. Even for sites from
palpable lymph nodes) should be considered for further imaging. which lymphatic drainage was thought to be completely predict-
Computed tomography (CT) imaging is not particularly helpful in able, surprising SLN locations were occasionally demonstrated.
the initial evaluation of patients with stage I or II disease because of SLN status has been shown to be the most important indepen-
the overall low frequency of patients with anatomically identifiable dent prognostic factor of melanoma stage I to II patients. In the past,
metastases.6 Neither is ultrasound (US) routine in the diagnostic elective lymph node dissection of the lymph node region draining
workup of primary melanomas. In case of clinical suspicion of met- the primary tumor site (based on Sappey’s anatomic description of
astatic adenopathy, however, US of the lymph node with fine-needle cutaneous lymphatic pattern) was used as part of the staging proce-
aspiration (FNA) or biopsy can be useful to provide an indication for dure. However, in 80% of stage I to II melanoma, there are tumor-
radical lymph node dissection. US of regional lymph nodes is able to negative lymph nodes; consequently, the elective lymph node
accurately demonstrate metastases in 65% of SN-positive patients.7 dissection associated with a significant morbidity is not an optimal
Chest x-ray is commonly used for the evaluation of pulmonary procedure.
lesions in newly diagnosed melanoma. However, this procedure has SLNB is a minimally invasive procedure for the staging of mel-
low sensitivity and specificity. In fact, in less than 1% of patients with anoma when there is no clinical evidence of regional nodal metas-
abnormal radiography, other imaging modalities confirm the pres- tases. The term SLNB includes the preoperative node localization
ence of metastatic disease.8 Patients with regional lymph node with a radiotracer, the intraoperative removal of the SLN, and
involvement (stage III) should undergo diagnostic imaging at the pathological evaluation.
time of diagnosis to detect possible distant metastasis. The detection US-guided FNA is not a sufficient alternative to SLNB as it has
rate is low particularly in patients with microscopic lymph node low sensitivity to detect micrometastasis.17 In 1992, SLN has been
involvement (stage IIIA). The use of CT in stage III melanoma can be defined as “the initial lymph node upon which the primary tumor
particularly helpful in patients with groin or cervical adenopathy.9 drains.”18 More recently, the definition of SLN has been modified to
In high-risk patients (e.g., those with thick primary tumors) or in “a node upon which a lymph vessel originating in the tumor drains
patients with suspected or known stage IV disease, diagnostic imag- directly” including all nodes in which the tumor directly drains. In
ing plays an important role. It may lead to an earlier diagnosis of fact, these nodes are at risk to receive malignant melanoma cells.
regional or systemic relapses. In this setting, CT is most useful in the The in-transit nodes (also called interval-node) are lymph nodes
evaluation of pulmonary metastases but the sensitivity in the evalua- localized on a direct drainage pathway between the primary tumor
tion of intra-abdominal and distant nodal metastases is not well and the draining lymph node basin.19 They are present in 3% to
defined.10 MRI is usually reserved for the evaluation of suspected 10% of the cases and often are localized in subcutaneous fat.20
brain metastases and suspected or known liver metastases.11 How- These nodes should also be considered as SLNs, because they
ever, the impact of radiologic examinations upon survival has not directly receive the tumor lymphatic vessels.
been demonstrated. Furthermore, no single modality is highly sensi- Interval nodes can occur anywhere between a melanoma site
tive and specific for the detection of all types of local or distant lesions. and a recognized node basin, but they are more common in the
In the past, several radiotracers such as 67Ga citrate, labeled midaxillary line on the lateral thorax and in the posterior loin area.
immunoreactive cells, or 99mTc-MIBI have been used for the detec- Other common sites for interval nodes are on the upper back toward
tion of distant metastasis but the sensitivity of these techniques was the base of the neck, in the upper arm, and over the costal margin.
limited and they were not used widely. Patients with positive SLNs have significantly decreased
disease-free survival compared with those who have negative
SLNs (5-year survival rate 72% versus 90%).21 Several factors are
Sentinel Lymph Node associated with the probability of having a positive SLN. They
include age, mitotic rate, Breslow depth, ulceration, angiolym-
The concept of sentinel lymph node (SLN) identification, the first phatic invasion, and microsatellitosis.
node to which a tumor spreads, implies that nodal metastases SN localization and excision using radionuclide methods are
progress in a nonrandom pathway explaining the pattern of meta- indicated in patients with intermediate stage (Breslow 0.76 to
static disease in not only cutaneous cancers such as melanoma 4 mm) and without clinical evidence of nodal involvement or dis-
but also other organ-specific tumors such as breast, colon, and tant disease. Melanoma with Breslow thickness greater than
endometrium. 4 mm and lymph nodes not clinically palpable have a very high risk
The relationship between the primary tumor location and the of lymph node metastases (around 50%).
metastatic spread of cancer to specific regional lymph node was SLNB can be also an option in patients with melanocytic
first described by Virchow in 1863.12 In 1955, radiolabeled colloidal tumors of uncertain metastatic potential (MELTUMP). The contra-
gold was used by Seaman and Powers to describe metastatic spread indications to SN biopsy are as follows.
to regional lymph node13 but the concept of “sentinel node” was first
used in 1960 by Gould et al.14 to describe the presence of the first 1. Extensive previous surgery in the primary tumor site with a
node in a nodal basin to be involved by cancer cells Sentinel lymph possible significant modification in the drainage pathway or
node biopsy (SLNB) provides important diagnostic data about the severe local inflammatory/infectious process.
status of the nodal basin, as a negative SN correlates with the lack 2. Presence of known metastases.
of metastatic involvement elsewhere. In fact, the negative predictive 3. Severe concurrent disease and poor patient compliance.

Chapter 22 Melanoma 315
Pregnancy is not a contraindication to SLN mapping because of a

low radiation exposure. In any case, the procedure should be modi-
fied to minimize radiation exposure to the fetus. The dose to the fetus
from an SN examination is generally below 1 mSv.22 Breastfeeding
should be discontinued prior to and 24 hours after the procedure.
SLN is evaluated with standard histological technique (hema-
toxylin and eosin staining) and immunohistochemistry (IHC). IHC,
used to identify typical melanoma-associated antigens (S-100, HMB-
45, MART-1/Melan-A), has been shown to increase the positive SLNs
rate up to 34%.23
The lymphatic pathway may be altered after a wide local exci-
sion (WLE),24 thus SLNB ideally should be performed prior to WLE
if possible. Leong et al.25 found that performing an SLNB in patients
who had a previous WLE on the extremities still provides useful
diagnostic data. Similar findings were reported by Kelemen et al.26
Lymphatic Drainage Pathway

In 1984, Sappey described lymphatic drainage pathway of the skin
suggesting that it occurs in a predictable pattern. Therefore, the
lymphatic drainage described never crossed the midline. Subse-
quently, cutaneous lymphatic pattern was found to be unpredictable
in an area 5 cm wide along the midline and a circumferential area
between the umbilicus and L2 termed Sappey’s line.27 The introduc-
tion of lymphoscintigraphy has radically changed previous descrip-
tions of lymphatic pattern, determining that the entire head and
neck area, as well as a wide area of 10 cm from the midline and
10 cm from Sappey’s line has unpredictable lymphatic drainage.
Lymphatic drainage pathway tends to be ipsilateral but the
possibility of contralateral drainage should be evaluated espe-
Figure 22.1. Lymphatic drainage pathway of trunk melanoma (whole-body anterior image).
cially in the region of the back and face. Node mapping shows the presence of sentinel nodes both in axillary and inguinal regions.
The usual drainage from the upper limb is to the axilla, as well as
the drainage from the leg and the thigh is to the groin. In some cases,
popliteal nodes draining the leg can be identified. The lymphatic drain- Several colloidal radiotracers have been used for these proce-
age patterns on different parts of the trunk are markedly variable dures, varying in different countries. In the 1950s, colloid gold-
(axillary, groin, and supraclavicular nodes) and cannot be predicted 198 was the radiopharmaceutical used in the first clinical studies
(Fig. 22.1). In posterior melanoma of the trunk, the triangular by Walker.28 This colloid (5 to 10 nm), however, has β-emission
intermuscular space, lateral to the scapula should be considered. In and a long half-life (2 to 3 days) within unacceptable radiation-
fact, in 11% of posterior upper trunk, melanoma SLN is localized in absorbed dose. Thus, a 99mTc-radiocolloid was developed.
this area. Lymphatic vessels after passing through triangular inter- 99m
Tc-stannous phytate and 99mTc-antimony were introduced in
muscular space reach the axilla, thus the node in the axilla may be a 1970s for lymphoscintigraphy.29
second node, with the SN in intermuscular space. The node in the The optimal particle size for SN detection is 100 to 200 nm
axilla may be a second node, with the SN in intermuscular space. In (Table 22.2). Larger particles (>200 nm) may have difficulty mov-
3.4% of posterior trunk melanoma, the lymphatic pathway is directly ing through the interstitial matrix to enter in the lymphatic capil-
anterior through the posterior abdominal or thoracic wall to paraver- laries. Most of the injected dose remains at the injection site. The
tebral, para-aortic or retroperitoneal nodes. In a few patients with mechanism of localization in the lymph node is more complex
melanoma of the periumbilical area, SNs are localized to internal than mechanical filtration. It is caused by the phagocytosis by
mammary chain with interval nodes localized along the costal margin. macrophages because of the delayed transit of these large tracers
For the lower and upper limb sites, popliteal fossa or epitroch- rather than particle’s trapping based on their size. 99mTc-human
lear nodes are occasionally observed in 3% to 5% of cases. Unex- serum albumin (HSA) colloid (albumin nanocolloid, Nanocoll, Sen-
pected lymphatic drainage from upper limb site includes direct tiscint) is currently used in Europe, 99mTc-sulfur colloid in North
drainage from the forearm or supraclavicular nodes. America, and 99mTc-antimony trisulfide colloid in Australia (1 to
In head and neck melanomas, lymphoscintigraphy showed dis- 30 nm diameter). The size range is 5 to 80 nm for Nanocoll, 100 to
cordant results compared to clinical predictions in a high propor- 600 nm for Senticint, and Nanocis has a median diameter of 100 nm.
tion of patients.
The drainage from the face is localized to preauricular and parotid
nodes and level I to III cervical nodes. The drainage across the midline
Tabl e 2 2 . 2
is observed in 15% of the patients. From the posterior scalp, the
drainage is particularly unpredictable and it tends to occur to post-
auricular, occipital, cervical (level I to V), and supraclavicular nodes.
Radiopharmaceutical Characteristics
Atypical drainage pathways are not unusual especially regard-
ing head and trunk regions. Particle Local Tissue Injection Volume
Radiocolloid Size (nm) Dose (mGy/MBq) (mL)
Radiopharmaceuticals 99m
Tc-nanocolloid 5–80 20–44 0.1–0.2
99m
Lymphoscintigraphy is in the acquisition of the imaging pathways Tc-antimony 1–30 27 0.1–0.2
sulfur colloid
of lymphatic flow and lymph nodes after the injection of an appro- 99m
Tc-sulfur colloid 100–220 20–46 0.1–0.2
priate radiopharmaceutical.

99m
Tc-sulfide colloid is filtered (0.22-mm filtration) or unfiltered superior to delayed static imaging only because the latter is more
form. The size of the radiocolloids influences the timing of image likely to fail in identifying SLNs.30 Delayed images should be per-
acquisition. formed in all node fields that could possibly receive lymphatic
The activity of injected radiocolloid varies from 5 to 120 MBq, drainage to identify unusual drainage pathway.
depending also on the surgical timing (1-day or 2-day protocol). If Single photon emission computed tomography (SPECT) or
2-day protocol is planned, the injected activity (adjusted for phys- combined SPECT/CT imaging improves lesion detectability and
ical decay) should exceed 10 MBq. Usually about 90% to 95% of the anatomic localization of nodes. In our opinion, SPECT/CT
the injected activity remains at the injection site. 99mTc-sulfur col- imaging, however, does not replace the conventional planar
loid has a prolonged injection site clearance half-life that can images. SPECT acquisition should be performed with a matrix size
impede identification of the SLNs close to the primary lesion. of 128 × 128, 180 degrees in the anterior L-mode rotation, and
step-and-shoot of 20 to 30 seconds at 3-degree intervals. CT
acquisition is usually performed as a low-dose CT (16 seconds for
Injection Technique and Image Acquisition each transaxial slice). SPECT/CT is particularly helpful in the head
Peritumoral intradermal injections of small (2 to 8) aliquots (0.1 to and neck region and also in the pelvis where planar images can-
0.2 mL each) of the radiocolloid should be administered by within not clearly identify lymph node locations. SPECT/CT identifies SNs
1 cm from the tumor or the excisional biopsy site of the mela- missed on planar images, including nodes invaded by metastases
noma. In patients with melanomas located in region with unpre- in 43% cases of primary melanoma located in the head and neck
dictable drainage (e.g., the head, neck, and trunk), radiotracer or trunk region.31
injections should be performed equatorially around the lesion. Interval nodes should be distinguished from dilatation of lym-
The injection should be performed using a 25- or 27-gauge needle phatic vessels. A lymphatic dilatation shows a rapid fade of radio-
inserted in a direction as tangent as possible to the skin surface. tracer and usually disappeared within 1 hour.
The injection site should be covered to prevent leakage of tracer Moreover, the patient’s body contour, useful to facilitate topo-
through the puncture site. Contamination of the skin can compli- graphic localization, may be defined by transmission imaging
cate image interpretation. The administration of radiocolloids has (e.g., 57Co flood source) or by manual tracing with an external
not been known to have interactions with drugs. Adverse effects source. The surface location of the SLNs should be marked on the
are rare. skin in the same position as for the surgical procedure.
Sequential or continuous imaging begins immediately after SLNs can be missed at scintigraphy and/or surgery where the
completion of injections and continues up to 1 hour or until the node is not visualized because it is obscured by another node or
SLN is identified. A large field-of-view camera head is preferable injection site or when the SLN contains only a small amount of
(Fig. 22.2). radioactivity. False-positive interpretation includes lymphangioma
The use of low-energy, high, or ultrahigh resolution collimators or lymphatic lakes, skin folds, and other tissues containing radio-
with parallel hole is recommended to reduce the septum penetra- activity or skin contamination from the injection.
tion from the injection site. The use of blue dye before surgery may be useful as a visual
A 10- to 30-minute dynamic image at 30 to 60 seconds per confirmation of the SN, especially when a melanoma is in proxim-
frame in a 128 × 128 matrix can help to determine the location of ity to its regional nodal basin. In this case, the injection site of the
the lymphatic collectors. Anterior and posterior static images (256 radiotracer causes a high background radioactivity that interferes
× 256 matrix, acquisition time 5 to 10 minutes) over the identified with the γ-probe localization. Blue dye (Isosulfan Blue or Patent
node region should be acquired to identify and localize the SLNs. Blue V) is injected intradermally (0.5 to 1 mL) 10 to 20 minutes
Lateral or oblique views are often helpful to correctly localize mul- prior to the surgical procedure around the site of primary tumor.
tiple nodes, especially in the head and neck, axilla, and groin
areas. Dynamic imaging combined with delayed static imaging is
g-Probe
Intraoperative SN detection is performed with the use of a γ-probe.
The first use of hand-held probe to identify SN intraoperatively
was reported by Alex et al. in 199332 in 10 malignant melanoma
patients. They reported a sensitivity equal to vital dye mapping,
showing that these techniques correctly permits SLN identification
and biopsy.
The hand-held probe, used to localize the SLNs, is a γ-radiation
Bilateral detector, either a crystal or a solid-state device. The collimation of
inguinal nodes the probe, resulting in a restricted field of view, is fundamental for
the correct locations of focal radioactive accumulation, avoiding
photons from sources that are not directly in front of the probe.
Removal of the collimator provides increased sensitivity but a loss
of spatial resolution. The unit connected to the probe provides a
count rate from measured γ-rays, usually by audible sound volume
variation and/or a visual display. A probe is sensitive in the range
650 to 900 cps/MBq for a 3-cm-deep node.
The number of SN removed depends on the anatomic location
Injection site of the primary tumor and the number of draining nodal basins
identified on preoperative lymphoscintigraphy.
Several probe criteria have been employed for identification of
the SN (e.g., count rate of the SN compared with other nodes
in vivo, ex vivo, or with background counts in vivo).
McMasters et al.33 suggested removal of all radioactive nodes
until the background counts of the undissected nodes decrease
Figure 22.2. Patient with anal melanoma. Anterior planar image of the pelvic region shows below 10% of those of the hottest node. Other investigators have
the presence of sentinel node in the bilateral inguinal region. suggested that removing the 3 hottest nodes and all blue-staining

nodes is sufficient to detect 100% of positive SLNs. In addition,

removing lymph nodes with less than 30% of the radioactivity of
that of the hottest node was found to be of no value.34
When a node occasionally is largely replaced by a tumor cell,
the radioactive tracer may be diverted to a secondary node, result-
ing in lower counts in the SN. Removing only the hottest node may
fail to remove the true SN in about 20% of patients. In fact, Martin
Injection site
et al.35 showed that the SLN with the highest counts is positive in
80% of patients with multiple SLN.
If preoperative lymphoscintigraphy identifies SNs that are not
identified intraoperatively, a lymph node dissection should be
performed.
Dosimetry
Cervical node
The estimated local radiation dose varies depending on the admin-
istered activity and retention time. Nevertheless, the absorbed
dose at the injection site (20 to 44 mGy/MBq) is below the thresh-

old for deterministic radiation effects. The different radiopharma-
ceuticals used are not associated with substantial differences in
terms of radiation exposure. The maximum effective dose has been
calculated as 0.0019 mSv/MBq. Obviously, SPECT/CT imaging
increases both the effective and local radiation dose. Figure 22.3. Lateral static image of the head in patient with left auricular melanoma. The
sentinel node is localized to the ipsilateral cervical node.
Operating room staff receive less than 6 μSv/h; the activity in
the removed SNs is usually less than 0.5 Bq/g.36 Necj et al.37 esti-
mated that the maximum dose is 1,900 times less than the current
1-year dose limit recommended by the International Commission metastases”) so the negative predictive value of SLNB is very high.
on Radiological Protection (ICRP). To determine the incidence of skip metastasis, investigators evalu-
ated patients with SLNB followed by complete lymphadenectomy.
Other studies based on the long-term recurrences in previously
Clinical Impact of Sentinel Lymph Node Biopsy mapped negative lymphatic basins suggested that the incidence of
The SLNB is a diagnostic tool designed to assess the status of false-negative SN studies may be higher, ranging from 4% to 16%.
regional lymph nodes providing critical prognostic information Many of these studies utilized either frozen sections, or incom-
and to determine further treatment. plete sampling of the node, or did not utilize IHC.
For thin melanomas (0.5 to 1 mm), the probability of a positive The SLN approach is particularly useful in head and neck mela-
SLN is 6%; for intermediate thickness melanomas (1.01 to 2 mm), the nomas, in which lymphatic drainage is variable (Fig. 22.3). How-
risk is 16%; for intermediate thickness tumors (2.01 and 4 mm), the ever, in 5% to 10% of patients, preoperative lymphoscintigraphy
risk is 34%; and for thick melanomas (4 mm), the risk is about 55%.38 fails to identify any SLNs in patients with head and neck melano-
The presence of a small size (<0.2 mm) nodal micrometastasis mas,47,48 making intraoperative localization of an SLN particularly
characterized only by IHC may not have an impact on prognosis.39 difficult. In a large prospective study, Pathak et al.49 showed that the
However, SLNB technique can identify these very early microme- lymphatic drainage is not predictable in around 10% of patients
tastases, raising the issue of the clinical relevance of these findings. with head and neck malignant melanoma. They correlated the ana-
In this scenario, some authors have advocated the “prognostic tomic distribution of pathologically involved lymph nodes with pri-
false-positivity” theory.40 Govindarajan et al.41 analyzed tumor mary melanoma sites and compared these findings with clinically
characteristics, SLN tumor burden, and the location of the metas- predicted patterns of metastatic spread. Furthermore, in 30% of
tasis in the SLN, to serve as additional prognostic factors compared patients the metastatic involvement affected more than one lymph
to non-SLN positive, disease-free survival, and overall survival. node basin.50
They found that submicrometastases (clusters of more than 10 The presence of a positive SLN is the most important prognos-
cells, but <0.1 mm) may not be considered as metastatic melanoma tic factor in patients with head and neck melanomas. In fact,
because the estimated 5-year distant metastasis-free survival in patients with negative lymph node involvement have a higher sur-
these patients was comparable to the overall survival rate for SN- vival rate than patients with positive SN biopsy.50 The presence of
negative patients. Consequently, these patients are highly unlikely recurrence in a previously node-negative basin by SLN, called false-
to benefit from lymph node dissection. negative rate, is approximately 3%.47 These false-negative results
In contrast, a study performed by Scheri et al.42 demonstrated were initially attributed to skip metastases. Later, Thompson51
that 5-year melanoma-specific survival rate was significantly less showed that 77% of node-negative SLN patients with recurrent
in the presence of micrometastases compared to negative SLNs nodal disease had undiagnosed micrometastases when the SLNs
(89% versus 94%). It has been proposed that SLN with a microme- were reexamined. Similar results were reported by Gershenwald
tastasis less than 0.2 mm should be regarded as node negative et al.52 estimating that with appropriate pathologic evaluation, the
[N0(i1)] and any positive lymph node with a greater than 0.2-mm nodal recurrence rate was 3%. Failure to identify and subse-
focus of tumor be classified as stage III disease.43,44 quently remove all the SLNs represents an inadequate nodal stag-
Thin melanomas treated by early detection and resection result ing procedure that may potentially place the patient at higher risk
in excellent long-term survival. However, approximately 15% of for nodal as well as visceral recurrences.
patients develop recurrence; regional node involvement in 5% of
cases and distant metastases in 3% to 4% of patients.45,46
SLNB could be effective in improving outcomes in selected
Future Perspectives
high-risk patients with thin melanoma <1 mm. The presence of Iron oxide nanoparticles (SPIONs), used as magnetic resonance
negative SLN, whereas another non-SN of the same basin con- imaging (MRI) contrast agents, may represent an interesting tracer
tains metastatic cells, occurs in less than 1% of the cases (“skip for SLN technique. These nanoparticles (diameter <10 nm) have

several properties including favorable superparamagnetic proper- In meta-analyses, the sensitivity, specificity, and accuracy of
ties and biodegradability as well as modifiable kinetics in vivo.53 18
F-FDG PET to detect recurrent melanoma ranged from 70% to
SPIONs labeled with 99mTc have been investigated in animals to 100%.58–60
develop a new multimodality SPECT/MRI contrast agent.54 After False-negative and false-positive rates of 18F-FDG PET can be
subcutaneous injection, the radiotracer showed high accumulation reduced through the use of PET/CT compared to PET alone.61,62 In
in SLN, preferably in the cortical and subcapsular sinuses. a study including 250 patients with melanoma (AJCC stages I to IV),
PET/CT was found to be significantly more accurate than PET alone
and CT alone for the staging of visceral and nonvisceral metastases.
Role of 18F-FDG PET PET/CT was particularly helpful for the detection of lung metasta-
ses that are often missed by PET alone. These data also showed an
Positron emission tomography (PET) with 18F-FDG has been incremental impact of PET/CT on treatment in the settings of
extensively investigated in patients with melanoma over the last two restaging and therapy control in patients with melanoma.63
18
decades, establishing an important role in the staging and a poten- F-FDG PET is not useful in the initial staging of primary cuta-
tial role in assessing response to therapy. The rationale for the use neous melanoma when there is no clinical evidence of local or
of 18FDG was demonstrated in a study performed by Wahl et al.55 distant metastatic lesions as detection of occult regional lymph
in 1991. Murine melanomas and human melanoma xenografts node metastases is limited (Fig. 22.4). The basis for the low sensi-
showed uptake of the radiotracer. Two years later, Gritters et al.56 tivity is likely in the small mean tumor volume of lymph node
found a sensitivity and specificity of 100% to detect visceral and metastases (<5 mm3) that is usually found in melanoma patients.64,65
lymph node metastases in 12 patients with melanoma. In early stage disease, the sensitivity of 18FDG PET/CT for detec-
More recently, a significant relationship between [18F]-FDG tion of tumor in regional nodes is unacceptably low, ranging from 0%
uptake and the expression of GLUT-1 and GLUT-3 in malignant to 22%. Consequently, for 18FDG PET/CT this imaging modality can-
melanoma was observed,57 whereas HK-2 and Ki-67 were not not replace the SLNB procedure.66,67 Whole-body MRI, with a sen-
related to 18FDG uptake of malignant melanoma. sitivity, specificity, PPV, NPV, and accuracy of 66%, 77%, 84%, 55%,
B C
A D E
Figure 22.4. 18F-FDG PET/CT (A: MIP image; B: PET/CT axial fused image; C: CT axial image; D: coronal PET/CT fused image; E: coronal CT image) in a patient
with surgically treated posterior cervical melanoma. PET scans confirm avid FDG uptake adenopathy. Ultrasound shows the presence of suspicious lymphadenopa-
thy in the right laterocervical region.

B C

A D E
Figure 22.5. 18F-FDG PET/CT (A: MIP image; B: PET/CT axial fused image; C: CT axial image; D: coronal PET/CT fused image; E: coronal CT image) in patient
with malignant melanoma of the right foot. The PET scan in (A) demonstrates cutaneous in-transit metastases and subcutaneous metastases in the right lumbar
region (arrow ).
and 67%, respectively, for the detection of lymph node metastases, melanoma and should be considered as part of preoperative
has been shown to be equal in accuracy to whole-body CT68 and workup.
inferior to 18F-FDG PET/CT.69 In a study performed by Steinert et al.,73 PET/CT correctly iden-
The utility of 18FDG PET in patients with known or suspected tified 37/40 metastases with a sensitivity of 92%, in mixed group of
local recurrence, satellite lesions, or in-transit metastases (Fig. 22.5) patients with known metastatic melanoma or high-risk primary
is not established because of the lack of a sufficient number of melanoma. In 18% of the cases, PET identified lesions not visual-
conclusive studies. Current estimate of the sensitivity ranges from ized with conventional staging modalities. Rinne et al.74 examined
50% to 93% and specificity from 50% to 100% to detect loco- patients with thick primary melanoma and clinical or CT findings
regional metastatic disease. suggesting metastatic disease. Sensitivity, specificity, and accuracy
Positive prognostic value of 18FDG PET/CT for the detection of were found to be 91.8%, 94.4%, and 92.1%, respectively, compared
recurrent metastases is stage dependent, yielding a higher PPV in with 57.6%, 45%, and 55.7% for conventional imaging modalities.
high-risk patients (80%) than in intermediate-risk patients (63%) The superiority of 18FDG PET was confirmed by Holder et al.75 in a
and low-risk patients (33%).70 group of patients with different stages of disease. 18FDG PET had an
Patients with suspected regional metastases based on physical overall sensitivity and specificity of 94.2% and 83.3% in the detec-
examination or other imaging modalities have a high prevalence of tion of liver, lymph nodes, and soft tissue lesions. CT showed overall
detectable metastases on PET (80% or greater). Blessing et al.71 sensitivity and specificity of 55.3% and 84.4%, respectively. The
found a sensitivity of 74% and a specificity of 93% for the evaluation accuracy of detection of lung metastases was found comparable,
of 20 clinically suspicious lymph node basins. Crippa et al.72 showed but other studies have not confirmed these data. 18FDG PET is supe-
an accuracy of 91% in the detection of metastases in 56 lymph node rior to conventional imaging to detect distant metastases, except in
basins and a negative predictive value of 89%. Sensitivity was found the lungs and brain, independent of the stage of the high-risk
to be very low for lymph nodes <5 mm but was 100% and 83% for patient.
nodes ≥10 mm and 6 to 10 mm, respectively. Three- and five-year overall survival is improved in patients
18
FDG PET is frequently used to evaluate patients with clinical, who undergo resection of pulmonary metastases in the absence
laboratory, or radiologic evidence of distant metastases (Fig. 22.6) of extrapulmonary lesions excluded by 18FDG PET before sur-
and in patients with previously treated distant metastases to gery. In a study performed by Gulec et al.,76 PET identified more
plan the management. Finally, 18FDG PET can detect unex- metastatic sites compared to CT and MRI, also visualizing metas-
pected metastases in patients with surgically treatable metastatic tases outside the field of view of these other imaging modalities.

B C
A D E
Figure 22.6. 18F-FDG PET/CT (A: MIP image; B: PET/CT axial fused image; C: CT axial image; D: coronal PET/CT fused image; E: coronal CT image) in patient
with surgically treated malignant melanoma of the trunk. A follow-up PET scan shows hypermetabolic nodes at hepatic hilum (white arrow ) and peripancreatic
pathological adenopathy (red arrow ).
Other PET Radiopharmaceuticals

18
FDG PET findings changed patient management in 50% of
cases.76
In conclusion, 18FDG PET is the most accurate imaging modal-
ity to identify metastases in patients at high risk for developing Several PET radiotracers have been developed in an attempt to
distant lesions. 18F-FDG PET displays false-negative findings identify melanoma metastases and to overcome problems associ-
caused by small skin metastases or primary small skin lesions of ated with 18FDG including accumulation in inflammatory lesions
melanoma.59,77 The cutaneous and subcutaneous lesions that were resulting in false-positive results, decreased uptake in hyperglyce-
missed by 18F-FDG PET had a diameter between 1 and 10 mm.59 mia, and lack of sensitivity to image brain metastases.
18
The use of 18FDG PET to evaluate response to therapy in F-thymidine is a pyrimidine analog phosphorylated by the
patients with melanoma is not well established. In a retrospective enzyme thymidine kinase 1 (TK1), leading to intracellular trapping.81
study performed by Strobel et al.,78 responders to chemotherapy During DNA synthesis, TK1 activity increases almost 10-fold and is,
identified by 18F-FDG PET/CT have a longer progression-free and therefore, an accurate reflection of cellular proliferation.82
18
overall survival than nonresponders. F-thymidine PET/CT has been reported to have a sensitivity of
Integrated PET/MRI can be useful in melanoma restaging (N- 88% for the detection of regional lymph node metastases and a
and M-staging) and response assessment in high-risk patients sensitivity of 60%. Brain metastases are readily detected with this
(AJCC stages III to IV) but clinical data are not available at pres- radiopharmaceutical as there is no physiologic uptake of 18F-FLT
ent. A hand-held 18F-FDG-sensitive intraoperative probe can be a in the brain.
11
valuable adjunct for the surgical localization of PET-positive C-methionine PET detects primary lesions greater than 1.5 cm
tumors.79 but fails to detect small pulmonary lesions in 50% of the cases.83
18
A pilot study performed by Essner et al.80 showed the utility of F-DOPA (3,4-dihydroxyphenylalanine) has demonstrated to
a hand-held 18F-FDG-sensitive intraoperative probe in metastatic play a role in selected 18FDG-negative melanoma metastases.84
18
or recurrent melanoma in these patients. The PET probe detected F-DOPA reflects the activity of L-DOPA decarboxylase that may
all 18F-FDG PET-positive lesions and the smallest detectable lesion be increased in malignant melanoma. Ishiwata et al.85 showed a
was 0.5 cm. In addition, the PET probe saw lesions that were not high uptake of 18F-DOPA in experimental studies using rats with
seen on the preoperative imaging study (retroperitoneal foci) or transplanted B18 melanoma cells. Van Langevelde et al.86 demon-
not immediately apparent at surgical exploration, particularly in a strated 11C-L-DOPA localization in a malignant melanoma. PET
previously explored field (neck, axilla, and abdomen). study obtained 40 to 80 minutes after injection of the [1-11C]

labelled DOPA confirmed that melanoma detection with D-DOPA melanoma.99 The melanin-binding decapeptide 4B4 was radiola-
was promising, producing better image than L-DOPA. D-DOPA beled with 177Lu, 188Ho, and 153Sm via a DO3A chelate.
showed a high uptake in tumor tissue, with relatively low uptake The melanocortin-1 receptor (MC1-R) is a family of G-protein
in bone, skin, and eye resulting in high tumor/nontumor ratio. linker receptors, which is primarily involved in the regulation of skin
Kubota et al.87 showed a preferential accumulation of 18F-DOPA pigmentation. α-MSH peptides bind the MC1-R selectively with
in cells of the S-phase in rats with transplanted B16 melanoma cells. nanomolar to subnanomolar affinities,100 made it attractive mole-
Further clinical trials are needed to clarify the role of 18F-DOPA in cule for the development of α-MSH peptide-based imaging and ther-
melanoma patients. apeutic agents because of the overexpression of MC1-R in malignant
melanoma. Numerous α-MSH analogs have been developed with
high affinities and specificities for α-MSH receptors.101 The preclini-
Primary Mucosal Melanoma cal studies demonstrate that α-MSH analogs, radiolabeled with
SPECT and PET radionuclides, are able to image primary and meta-
Primary mucosal melanomas represent a rare and aggressive static melanoma tumors in mouse animal models. The therapeutic
malignancy, accounting for 1.3% to 1.4% of all melanomas.88 efficacies of α-MSH analogs labeled with α- and β-emitting radionu-
The median age at presentation is the seventh decade. It origins clide have been demonstrated in mouse melanoma models.
from melanocytes in noncutaneous tissues, such as uvea, mucosa Receptor-mediated binding was only observed in tumor tissue,
of the gastrointestinal, respiratory, and genitourinary tracts, dif- resulting in the selective deposition of imaging and therapeutic radio-
nuclides in melanoma. The first radiolabeled peptide therapy study

fering from cutaneous melanoma in terms of risk factor and bio-
logical behavior.89 The most common site of presentation is the targeting the MC1-R was performed with 188Re-(Arg11)CCMSH and
head and neck region (50% of cases), followed by female genital the therapy studies were performed in C57 mice-bearing B16/F1
tract, anal/rectal, and urinary tract. The biological course is char- syngeneic murine melanoma tumors.102 188Re-(Arg11)CCMSH admin-
acterized by multiple local recurrences, development of distant istration resulted in tumor growth rate reduction, with no significant
metastases, and poor prognosis.90 Local excision does not usually increase in the mean survival times of the treatment group compared
change the 5-year overall survival which is only 25%. In loco- to the control mice group. The biodistribution and therapeutic effi-
regionally advanced disease, adjuvant RT may be useful if com- cacy of 177Lu-DOTA-Re(Arg11)CCMSH were examined in B16/F1
bined with surgical approach, especially in head and neck region tumor-bearing mice,102 showing encouraging results in terms of tox-
or genital tract. New biological therapies may play a role in the icity and efficacy. The therapeutic efficacy of 212Pb-DOTA-Re(Arg11)
management of this cancer.91,92 Uveal melanoma differs from CCMSH has been proven with moderate kidney damage.103
other mucosal melanomas in terms of etiopathogenesis, treat- Recently, the αvβ3 integrin avid peptide sequence Arg-Gly-Asp
ment, and prognosis and it should be considered as a different (RGD) was conjugated to the (Arg11)CCMSH α-MSH analog via a
biological entity. lysine spacer.104 The RGD peptide could induce cell apoptosis by
activating procaspase-3 directly upon entering the cell. 99mTc-RGD-
Lys-(Arg11)CCMSH exhibits rapid high melanoma uptake and pro-
Role of Nuclear Medicine in Mucosal Melanoma longed tumor retention in B16/F1 melanoma mouse model.
The diagnosis of mucosal melanomas is often delayed because of The major challenges to successful clinical translation of radio-
the absence of symptoms and anatomical localization. CT, mag- labeled MC1-R avid peptides for melanoma imaging and therapy
netic resonance, and 18FDG PET are fundamental diagnostic meth- are high nonspecific kidney uptake and low MC1-R receptor num-
ods to evaluate the extent of disease even though staging system ber. Radiolabeled benzamides are attractive candidates for tar-
has not been well established. 18FDG PET/CT detects the presence geted RT of metastatic melanoma as they bind melanin and exhibit
of loco-regional disease and distant metastases in patients with high tumor uptake and retention per tumor cell. The role of radio-
uveal melanoma with high sensitivity and specificity, improving the labeled benzamides for imaging melanoma was first realized in
staging when combined with conventional diagnostic methods.93,94 1986 when iodine-labeled compounds under investigation for
18
FDG PET has not been found to be superior to MRI for the detec- brain imaging were shown to localize to the pigmented eyes of
tion of small liver metastases. It may be useful, however, for the C57BL6 mice but not the unpigmented eyes of Wistar albino rats.105
evaluation of early response to treatment of hepatic lesions, based Subsequently, efforts have been focused on the development of
on the change of standardized uptake value (SUV). In general, liver melanin-localizing benzamides that exhibit rapid washout from
metastases from uveal melanoma show significantly lower nontarget tissues and prolonged tumor retention.
131
SUV(max) compared to liver metastases from cutaneous mela- I-MIP-1145 exhibited melanin-specific binding, rapid wash-
noma.95 Furthermore, 18FDG PET/CT in uveal melanoma is an out from nontarget tissues, and prolonged tumor retention, mak-
important tool after ophthalmic plaque radiation therapy to verify ing it an ideal candidate for systemic RT. 131I-MIP-1145 inhibits
the efficacy of the treatment. the SK-MEL-3 tumor growth, resulting in tumor regression and a
SPECT with N-isopropyl-p-[123I]iodoamphetamine (123I-IMP), a durable response with prolonged survival.
radiotracer to assess cerebral blood flow, is a sensitive and specific
technique for the diagnosis of uveal melanoma, especially in patients
in whom conventional diagnostic techniques are inconclusive.96,97 Conclusions
An accurate staging of patients with primary skin melanoma is
Radionuclide Therapy in fundamental to plan the treatment strategy. SN biopsy is the most
important tool to correctly identify loco-regional staging in stage I
Malignant Melanoma to II melanoma. US evaluation with FNA or clinical diagnosis of
lymph node involvement does not impact significantly on patient
Several years ago, the feasibility of targeting melanin, an intracel- outcome because of the failure to identify micrometastases. 18F-
lular melanocyte pigment, to deliver cytotoxic radiation to human FDG PET plays an important role in the evaluation of regional and
melanoma cells in vivo was demonstrated using a fungal melanin- distant metastases with higher sensitivity and specificity than
binding monoclonal antibody (mAb 6D2) with promising therapeu- other conventional diagnostic modalities. The role of other PET
tic results.98 radiotracers such as 18F-DOPA or 11C-methionine is to be estab-
A recent study showed that 188Rhenium-labeled melanin-binding lished. Radionuclide therapy in melanoma is still at its initial
deca- or heptapeptides is a promising therapy in experimental experimental stage and currently has no clinical application yet.

Acknowledgments 31. Even-Sapir E, Lerman H, Lievshitz G, et al. Lymphoscintigraphy for sentinel node
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Chapter 23
Neuroblastoma
Ettore Seregni • Alice Lorenzoni • Roberto Luksch • Cristina Nanni • Maria Rita Castellani • Emilio Bombardieri
Introduction Amplification of the proto-oncogene MYC is present in approx-

imately 25% of primary neuroblastomas and in 40% of advanced
Neuroblastoma (NB) is the most common solid extracranial malig- disease. It is associated with rapid tumor progression, and poor
nancy in childhood, accounting for 15% of cancer-related deaths. outcome. The myc oncogenes are important regulators of protein
The median age at presentation is 18 months and 90% of cases synthesis and cell cycle progression, stimulating the expression of
are diagnosed by the age of 6 years. The incidence of NB is 10.9 many genes that encode ribosomal proteins, translation factors,
per million children younger than 15 years.1 The tumor derives and enzymes, all of which play a part in the control of cell prolif-
from the neuronal crest sympathetic nervous system elements, eration. Supposed targets of myc include the cyclin-dependent
developing during fetal or postnatal life. The majority of the kinase, CDK4, and cyclin D2. Myc also represses genes involved in
tumors occur in the adrenal medulla. NB is an extremely hetero- the inhibition of proliferation (e.g., gadd45, p15Ink4b), preventing
geneous disease in terms of biologic behavior and clinical outgrowth arrest of transformed cells. Most neuroblastoma cell lines
come. The presence of some specific molecular features helps to have a near-diploid or hyperdiploid DNA content. Aggressive neu-
identify the therapeutic stratification. The 5-year survival rate is roblastomas are associated with near-diploid DNA content and
approximately 75% but in high-risk NB, long-term survival is only display generalized genomic instability, chromosomal rearrange-
40%.2 Patient age at the time of diagnosis represents an important ments, and translocation of genetic material within the cells. Less
prognostic factor. Some patients present as a result of paraneo- aggressive subtypes have a hyperdiploid DNA content and display
plastic phenomena (e.g., because of the production of vasoactive gain and loss of whole chromosomes secondary to abnormalities
intestinal peptides by NB cells, resulting in sweating, chronic in mitosis. Other potential markers reflecting the function of cel-
watery diarrhea, and hypertension). Opsoclonus-myoclonus lular programs for differentiation, proliferation, and apoptosis
(“dancing eye syndrome”) is characterized by ataxia and rapid, include: Deletion of chromosome 1p, gain of chromosome 17q,
abnormal movements of the eyes, and affects 2% to 4% of patients.3 expression of trk-A (gene for the receptor of the neurotrophin,
Other paraneoplastic phenomena include intractable secretory nerve growth factor), CD44 and multidrug resistance-associated
diarrhea (“Kerner–Morrison” syndrome) because of the secretion proteins (MRPs). Familial neuroblastoma occurs in 1% to 2% of
of vasoactive intestinal peptide. Furthermore, secretion of cate- cases and a gene conferring an inherited predisposition to devel-
cholamine metabolites may cause hypertension, flushing, sweat- oping familial neuroblastoma has not been localized, but chromo-
ing, and tachycardia. some 16p12-13 is suspected.
NB derives from progenitor cells of sympathetic nervous system The International NB Staging System (INSS), adopted in 1989,
which form the chromaffin cells of adrenal medulla and the paragan- classifies neuroblastoma into stages based on tumor resectability,
glia.4 Typically, NB is composed of small, uniform in size round cells. lymph node involvement, tumor location across the midline, and
The differentiation from other “small-blue-round-cell” tumors requires dissemination to distant organs (Table 23.1).
immunohistochemical evaluation.5 The International NB Pathology In 2009, The International NB Risk Group (INRG) introduced a
Classification (INPC) recognized four different morphologic groups: classification system based on clinical criteria and tumor imaging
NB (Schwannian stroma-poor), intermixed ganglioneuroblastoma, to establish a consensus approach for pretreatment risk stratifica-
nodular ganglioneuroblastoma, and ganglioneuroma, differing in tion. The INRG classification system includes seven factors that
prognosis.6,7 To identify the risk stratification and consequently the were highly statistically significant and also considered clinically
optimal treatment, multiple prognostic factors are used including age, relevant. They include the criteria INRG stage, age, histologic cate-
biologic features (i.e., MYC amplification), and histology. gory, grade of tumor differentiation, MYCN status, presence/absence
of 11q aberrations, and tumor cell ploidy. The extent of locoregional
disease is determined by the absence or presence of image-defined
risk factors (L1 and L2, respectively). Stage M is used for dissemi-
Table 23.1 nated disease and stage 4S tumors, metastases are limited to skin,
liver, and bone marrow without cortical bone involvement (Table
International Neuroblastoma Staging System 23.2). However, the definition of metastatic disease has been
expanded to include toddlers of age 12 to younger than 18 months
and large unresectable primary tumors.8 In the International NB
1 Localized tumor with complete excision, with or without microscopic
residual disease Risk Group Staging System (INRGSS), four stages have been pro-
2A Localized tumor with incomplete excision; ipsilateral nonadherent posed: Stage L1 is defined as a locoregional tumor without risk
lymph nodes negative
2B Localized tumor with or without complete excision, with ipsilateral
nonadherent lymph nodes positive. Enlarged contralateral lymph Ta b l e 2 3 . 2
nodes must be negative microscopically
3 Unresectable unilateral tumor infiltrating across the midline, with or International Neuroblastoma Risk Group
without regional lymph node involvement; or localized unilateral
Staging System
tumor with contralateral regional lymph node involvement; or
midline tumor with bilateral extension by infiltration (unresectable)
or by lymph node involvement L1 Localized tumor not involving vital structures as defined by the list of
4 Any primary tumor with dissemination to distant lymph nodes, bone, image-defined risk factors and confined to one body compartment
bone marrow, liver, skin, and/or other organs (except as defined L2 Locoregional tumor with the presence of one or more image-defined
for stage 4S) risk factors
4S Localized primary tumor (as defined for stage I, IIA, or IIB), with dis- M Distant metastatic disease (except stage MS)
semination limited to skin, live, and/or bone marrow (limited to MS Metastatic disease in children younger than 18 months with metas-
infants less than 1 year of age) tases confined to skin, liver, and/or bone marrow
324

Chapter 23 Neuroblastoma 325
factors identified on imaging; Stage L2 is defined as a locoregional preferred modality to monitor patients with low-risk abdominal or
tumor with at least one risk factor identified on imaging, such as pelvic neuroblastoma with no significant risk of epidural extension.
tumor encasement of blood vessels; Stage MS identifies metastatic
disease confined to the skin, liver, or bone marrow; and Stage M
identifies all other distant metastases.9
Computed Tomography
Three different risk categories may be recognized: Low-, interme- In most cases, however, more cross-sectional anatomic imaging,
diate-, and high-risk groups, based on stage, age, and MYC amplifica- that is, computed tomography (CT) or magnetic resonance imag-
tion. The probability of prolonged disease-free survival for patients in ing (MRI) are preferred to fully examine and stage the patient.13
each group is 95% to 100%, 85% to 90%, and less than 30%. Furthermore, CT and MRI have an important role in surgical plan-
Treatment options depend mainly on the initial stage. For ning, allowing assessment of invasion of adjacent structures, and
patients with stage I or II and favorable prognostic factors, surgery regional lymphadenopathy. CT has been the main initial anatomic
is curative in almost all cases. Chemotherapy is reserved for those investigation of masses in patients with suspected neuroblastoma
children with spinal cord compression or those with respiratory for many years, defining the site and extent of tumor, evidence of
compromise from massive hepatomegaly becaue of the hepatic regional invasion, vascular encasement, adenopathy, and calcifi-
infiltration in stage 4S tumors. Chemotherapy consists of carbopla- cation which are important issues regarding surgery and staging.
tin, cyclophosphamide, doxorubicin, and etoposide. Soft tissue calcifications are the characteristic findings of neuro-
In stage III, surgery and chemotherapy are the therapeutic blastomas and are present in 80% to 90% of cases. Calcifications
approaches used. In stage IV and patients with MYCN amplifica- in neuroblastomas are usually coarse, amorphous, and mottled in

tion, multimodal therapy is necessary, including high-dose therapy appearance as opposed to the discrete and punctate calcifications
with autologous hematopoietic stem cell rescue (ASCR). The high- observed in ganglioneuromas. On CT, neuroblastoma is usually
risk induction protocols vary not only in the use of chemotherapeu- characterized by an irregular shape, lobulations, and lack of cap-
tic drugs but also in the doses of these drugs. Following the sule. Furthermore, the mass tends to be inhomogeneous because
induction chemotherapy, surgical excision must aim to remove all of tumor necrosis and hemorrhage. CT has been the main method
the residual disease, though there are conflicting reports in the to differentiate between Wilms tumor and neuroblastoma, the two
literature regarding the extent of surgical resection in high-risk main malignant causes of an abdominal mass in childhood.
neuroblastoma.10,11 Involvement of the liver may occur in neuroblastoma and is part
Despite of all the advances in the management of high-risk of stage 4S disease. CT has a reported accuracy of about 80% in
neuroblastoma with many clinical trials conducted in several dif- tumor staging. Although uncommon, CT scans of the thorax should
ferent study groups, the outcome for this group has not dramati- be performed for pulmonary metastases and pleural involvement.
cally changed. The current therapies have led to only a modest Bone involvement may be detected on CT particularly involving
improvement in long-term survival rates for this group of patients, the skull and orbital regions. When CT is complemented with scin-
despite intensified therapeutic regimens. tigraphy or bone marrow aspiration, the accuracy of the com-
Tumor stage and biologic behavior of the disease should be bined examination has been reported to increase to 97%.
determined with imaging methods and biologic/molecular mark-
ers. The most common sites of involvement are the adrenal glands
(48%), retroperitoneum (25%), chest (16%) often encasing major
Magnetic Resonance Imaging
blood vessels.12 Unlike most solid cancers, NB usually presents MRI imaging has yielded high sensitivities (85% to 100%) also for
with substantial metastatic disease. About 60% of patients have the detection of abdominal disease. Primary neuroblastoma on
metastases in cortical bone, bone marrow, lymph nodes, and liver. MRI with gadolinium enhancement is typically heterogeneous.
Involvement of the lung or brain is rare despite hematogenous Calcification may not be detected on MRI but necrotic, cystic, and
dissemination. These clinical characteristics make assessment hemorrhagic areas are seen. MRI is the gold standard modality for
of disease status dependent on a multitude of studies: Conven- evaluating extension into the spinal canal and it is superior to CT
tional diagnostic imaging (ultrasound, computed tomography in assessing leptomeningeal or epidural extension, tumor invasion
[CT], or magnetic resonance imaging [MRI]), nuclear medicine of kidney and liver.14 Its advantages include lack of ionizing radia-
procedures, and histochemical examinations are fundamental to tion, excellent definition of the primary tumor with high intrinsic
evaluate the extent of disease. soft tissue contrast resolution, depiction of internal structure,
exact definition of intraspinal tumor extension, or diaphragmatic
involvement. Small lymph nodes (≤13 mm), however, are difficult
Conventional Imaging Modalities to define on MRI. False-positive studies on MRI for bone marrow
involvement after treatment have been described.15 Siegel et al.16
The initial imaging modalities most commonly used in patients who showed that MRI is more accurate than CT for detection of all
are eventually diagnosed with neuroblastoma include chest radio- stage IV disease (sensitivity 83% versus 43%) alone and in combi-
graphs for suspected pneumonia, ultrasonography to assess a pal- nation with bone scintigraphy. MRI is better than CT for posttreat-
pable abdominal mass, and spinal MRI for acute neurologic deficits. ment follow-up of midline or paraspinal neuroblastomas (neck,
chest, nonadrenal retroperitoneum), especially in patients with
low-risk or intermediate-risk disease whose management does
Direct Radiogram not routinely include radiotherapy. Either CT or MRI can be used
Chest radiographs reveal paravertebral masses in the posterior to monitor patients with high-risk disease whose treatment usu-
mediastinum, associated with calcifications or rib or vertebral ally includes local radiotherapy. Finally, the definition of response
body erosion. Skeletal radiographs also identify lytic lesions. to therapy requires three-dimensional measurements for determi-
nation of changes in tumor volume.
Ultrasonography
Ultrasound often is used initially to investigate an abdominal mass Nuclear Medicine in Neuroblastoma
or other soft tissue masses that are clinically evident, revealing a
retroperitoneal mass in a suprarenal or paravertebral location as Proper staging and monitoring of patients with neuroblastoma is
well as liver lesions. Infants with large livers or abdominal or pelvic dependent on scintigraphic studies. 123I-MIBG scintigraphy, 18F-
masses are readily examined by ultrasound. Ultrasonography is the FDG PET/CT, and in selected cases bone scintigraphy are important

Table 23.3 Radioactivity in the blood pool is caused by the MIBG labeling of
platelets, mediated by 5HT transporter. After intravenous injection,
Radionuclide Properties the majority of activity from injected radiotraces is excreted
through the urinary tract: 40% to 55% in 24 hours and 70% to 90%
Half- Photon in 96 hours. Most of this is in the form of intact l23I-MIBG whereas
Radionuclide life Decay Energy Pharmaceutical small fractions are excreted as l23I-4-hydroxy-3-iodobenzylguani-
dine (HIBG), metaiodohippuric acid and metaiodobenzoic acid. A
131
I 8.05 d γ, β 364 KeV MIBG small, but chemically uncharacterized portion of the activity, is
123
I 13 hour γ, Electron 159 KeV MIBG excreted into the gut.
capture High uptake is present also in normal sympathetically inner-
124
I 4.18 d Electron 511 KeVa MIBG vated tissue as salivary glands and heart. Normal adrenal glands
capture, β+ may also demonstrate MIBG uptake, especially after contralateral
18 a
F 110 min β+ 511 KeV MFBG, FIBG adrenalectomy. Minimal uptake may be seen in the lungs, and a
11
C 20 min β+ 511 KeVa HED physiologic uptake in brown adipose tissue can also occur, leading
a
to a difficult interpretation of the images in these regions.23,24 Cer-
Annihilation photon. ebellar visualization has been reported. Rare pathologic conditions
MIBG, meta-iodobenzylguanidine; FIBG, fluoro-iodobenzylguanidine; MFBG, metafluoro-
iodobenzylguanidine. such as myofibromatosis, pancreaticoblastomas, and neuroectoder-
mal tumors may also show MIBG uptake. Only 4% of nonsympatho-
medullary tumors (nonpheochromocytoma, nonneuroblastoma)
tools for optimal treatment planning. In 123I-MIBG-negative cases, showed MIBG uptake.25 The mechanism of localization in nonneu-
somatostatin receptor imaging with γ-emitters or PET tracers can roendocrine tumors is not clear. Postulated mechanisms include
be useful. For treatment monitoring, the imaging procedures dis- accumulation as a result of high tumor–dependent blood flow and
cussed above are also employed. 123I-MIBG scintigraphy is particu- nonspecific diffusional uptake. Bomanji et al.26 reported uptake of
123
larly important in this setting to differentiate between tumor tissue I-MIBG in a case of ectopic intracranial retinoblastoma.
and posttherapy changes in the early posttreatment phase. Radiation exposure to the thyroid gland from free radioiodide
as a result of in vivo deiodination of MIBG is blocked by the prior
administration of a saturated solution of potassium iodide (SSKI).27
Metaiodobenzylguanidine Scintigraphy The premedication should begin 1 day before the radiotracer
Metaiodobenzylguanidine (MIBG) is an analog of the false neu- administration and continue for 1 to 2 days. Recommended doses
rotransmitter guanethidine. It was developed as a tracer to image of potassium iodide range from 32 to 130 mg, depending on patient
the adrenal medulla in the 1970s. The role of iodine-labeled MIBG, age. In patients who are allergic to iodine, potassium perchlorate
tracing catecholamine metabolism, in clinical and research imaging is generally used on the day of the injection.
of neuroblastoma is well established.17,18 MIBG labeled with 131I was Adverse effects (tachycardia, pallor, abdominal pain) are related
initially used for neuroblastoma imaging, but the physical character- to pharmacologic effects of the solvent solution and they are very
istics (long half-life, high-energy photon, β-emission) are suboptimal rare if 123I-MIBG is injected slowly. If possible, injection into central
for diagnostic imaging. 123I-MIBG has a shorter physical half-life venous catheters should be avoided to prevent the visualization of
(13 hours), photon energy of 159 keV and lacks a β-particle.19 The radiotracer activity on the catheter during image acquisition. If a
use of I23I to label MIBG takes advantage of the better physical prop- central venous catheter is used, it should be flushed well after
erties of I23I for imaging, allows higher activities to be administered injection. Radiolabeled MIBG is usually a ready-for-use radiophar-
with favorable radiation dosimetry and greater photon flux resulting maceutical and no additional preparation is required.
in higher count, higher-quality planar images, and permits the per- The administered activity of 123I-MIBG (specific activity >300
formance of single photon emission computed tomography (SPECT). MBq/mg) should be calculated on a reference adult dose of 370
The dosimetry of l23I-MIBG is such that 10 mCi may be administered MBq scaled down for body weight (or body surface area), with a
with the same whole-body radiation absorbed dose as 0.5 mCi of minimum activity of 20 MBq.28,29 and maximum activity of 400
131
I-MIBG. The whole-body radiation absorbed dose for 123I-MIBG is MBq. To calculate the recommended activity administered, the
approximately 5% that of 131I-MIBG.20 The principal radionuclides Guidelines for Radioiodinated MIBG Scintigraphy in Children
that may be used to label MIBG and its analog and their properties should be consulted.30 Concerning 131I-MIBG, minimum and max-
are summarized in Table 23.3. imum recommended activities are 35 and 80 MBq, respectively.
123
I-MIBG was approved for clinical use in Europe in 1995 and The sensitivity of detection with MIBG increases with increased
in the United States by the Food and Drug Administration in 2008. It injected activity, as demonstrated for both 131I-MIBG and 123I-MIBG
is generally considered the tumor diagnostic agent of choice in neu- pretherapy diagnostic scans compared with immediate posttreat-
roblastoma. 123I-MIBG scintigraphy is routinely performed in patients ment 131I-MIBG scans. The biodistribution of 131I-MIBG is different
with NB and its importance is recognized in the guidelines of the with therapeutic doses compared to pretherapy doses. 131I-MIBG
International NB Risk Group Project. The use of this procedure has imaging following high therapeutic doses often reveals sites of
important prognostic implication during the follow-up of these occult metastatic disease that may be clinically relevant.
patients, to identify recurrent or refractory disease. Hickeson et al.31 investigated the biodistribution of therapeutic
131
I-MIBG in 18 patients with neuroblastoma to evaluate the sensi-
tivity of diagnostic versus therapeutic 131I-MIBG scans. In terms of
Radiochemistry of MIBG biodistribution, the posttherapeutic scan identified uptake in the
MIBG, an analog of guanidine in which the benzyl group is com- several regions not detected on the diagnostic scan: Nasal mucosa,
bined with the guanethidine group of guanethidine, is structurally cerebellum, central brain, adrenals, spleen, kidneys, thyroid, sali-
similar to norepinephrine. The radiotracer uptake into tumor cells vary glands, lower halves of the lungs, bladder, bowel, and an inci-
is mediated by the type I catecholamine reuptake system, which is sional scar. Posttherapeutic scans identified 210 lesions compared
physiologically utilized for noradrenaline accumulation. It is pri- to 151 on diagnostic scans, showing sites of disease not evident in
marily concentrated within the cytoplasm, rather than within nor- the diagnostic scan in 16 cases.
epinephrine storage granules in neuroblastoma.21,22 MIBG is not Furthermore, Parisi et al.32 showed that diagnostic MIBG scan-
metabolized by monoamine oxidase (MAO) and catecholamine-O- ning led to underestimation of the tumor burden by 50% compared
methyltransferase, which physiologically degrades catecolamine. with posttherapy scanning. This difference may be an important

Table 23. 4 for static images (or 250 Kcounts for the skull and the trunk and
100 Kcounts for the lower limbs) is a suitable compromise between
Mechanism of Reduced Mibg Uptake best image quality and limitation of scanning time. Concerning
whole-body scanning, a scan speed of 5 cm/min is appropriate
Medication Mechanism when available. A whole-body scan will require approximately
15 minutes in a 1 year old, 17 minutes in a 2 year old, 22 minutes
Sympathomimetics Depletion of storage vesicle contents in a 5 year old, 28 minutes in a 10 year old, and 34 minutes in a
Antihypertensive Depletion of storage vesicle contents 15 year old. In cases in which uncertainty exists as to the exact
Inhibition of catecholamine uptake site of MIBG activity, SPECT should be performed. The abdomen
Inhibition of vesicle active transport is the area in which this is most likely to occur, and less frequently,
Competition for transport into vesicles the chest. For the detection of lesions close to the liver, bladder, or
Atypical/tricyclic antidepressant Inhibition of catecholamine uptake any other area of physiologic uptake, SPECT may be an important
Antipsychotic tool. SPECT acquisition should be performed on a 128 × 128
matrix, 3-degree steps, with 30 to 35 seconds per step. To reduce
MIBG, meta-iodobenzylguanidine.
the time of acquisition, 3-degree steps or using a 64 × 64 matrix
with shorter times per frame can be used.
consideration in selecting therapeutic strategies for individual Gelfand et al.38 compared 35 SPECT and planar 123I-MIBG in 25
children with neural crest tumors and found no significant increase

patients.
In the high-risk neuroblastoma patient group, the radiation in the number of lesions detected by SPECT, although an improve-
hazard is far less than the risk resulting from false-negative or ment in certainty of interpretation was documented. Contrarily, in
false-positive scanning results.33 Indeed the need for high-quality a study performed by Ruffini et al.,39 SPECT detected a greater
images and the danger of under-staging patients because of inad- number of lesion compared to planar images, showing more accu-
equate counts from the study, outweigh the theoretical risks from rate depiction of extent of disease in 32% of abnormal scans.
a slightly higher dose of the radiotracer.34 Good hydration before SPECT allows better comparison with anatomic imaging data,
and after the injection will lower the radiation burden and reduce in particular when image fusion with CT or MR image is possible,
bladder activity, which could interfere with evaluation of the pelvis. or a combined SPECT–CT scanner is available.40 SPECT/CT
Several medications, including many antihypertensives, sym- improves uptake localization and lesion detection compared to
pathomimetics, tricyclic antidepressants, have the potential to SPECT alone. SPECT/CT increased the diagnostic certainty in 89%
interfere with MIBG uptake and storage. Accordingly, care should of discordant studies. Rozovsky et al.41 evaluated the contribution
be taken before prescribing medications around the time of MIBG of MIBG SPECT/CT to contrast-enhanced CT image analysis in the
scans (Table 23.4). follow-up of 11 patients with neuroblastoma. SPECT/CT provided
The most common agents that interfere with MIBG uptake and additional information in 53% of the cases and increased the diag-
retention in children are α- and β-adrenergic antagonists, such as nostic certainty in 89% of discordant studies. There is added value
pseudoephedrine and labetalol.35 Phenothiazines may interfere of SPECT/CT for correlation of MIBG scintigraphy and diagnostic
with MIBG uptake and should be avoided as sedatives before CT in neuroblastoma and pheochromocytoma. In cases of equivo-
imaging. Furthermore, venlafaxine and duloxetine can block nor- cal diagnostic CT or of suboptimal localization of MIBG-avid foci,
epinephrine reuptake.36 SPECT/CT helps to define the anatomic location of these foci and
to characterize the benign or malignant significance of uncertain
CT findings. Effective radiation dose for SPECT–CT ranges from
Image Acquisition 0.018 to 0.037 mSv/MBq. The image acquisition protocol is sum-
123
I-MIBG images are acquired 24 hours after the injection. marized in Table 23.4.
Selected delayed images (not greater than 48 hours) may be useful
in cases with equivocal findings, such as abdominal uptake that
Semiquantitative Score System
cannot be differentiated from the bowel or kidney. Rufini et al.37
showed that delayed 48-hour planar scanning may occasionally Semiquantitative scoring systems have been developed to evaluate
depict more lesions than 24-hour imaging but it may also miss the prognostic effect of tumor burden at diagnosis and to quantify
lesions with rapid washout. Furthermore, tumor uptake becomes response to treatment by MIBG scan. The introduction of a scoring
more distinct at later times compared with physiologic uptake; system improves the concordance between readers, and enables
early images after 4 to 6 hours are not routinely performed. Seda- one to differentiate a simple improvement from the disappearance
tion is usually not required for a technically satisfactory examina- of a lesion, or decreased intensity of lesions that can be subjective,
tion, except for children between 1 and 3 years, and others who from a significant response. The scoring systems are similar with
are unable to cooperate. minor variations, and take into account the frequent diffuse nature
As the principal energy of 123I is 159 keV, high-resolution col- of skeletal involvement.
limators should be used to acquire satisfactory images. However, The first method reported was developed at the Curie Institute
the presence of additional low-abundance high-energy photon in France42 designed for the comparative interpretation of MIBG
emission can degrade image quality. Thus, a medium energy col- scans in stage IV neuroblastoma, to predict response the final ther-
limator with higher acquisition times, to reduce scatter, can be apy during mid-course of induction chemotherapy. It divides the
used. A 256 × 256 matrix (preferred) or 128 × 128 matrix with skeleton into nine segments to view osteomedullary involvement,
zoom should be used. Images of the entire body, including the and adds a tenth sector that counts any soft tissue involvement.
skull (anterior, posterior, and lateral views), chest (anterior and The extension of bone metastases was separately quoted (score
posterior views), abdomen (anterior and posterior views), pelvis range: 0 to 3) as: 0, no sites per segment; 1, one site per segment;
(with empty bladder, anterior and posterior views), upper and 2, more than one site per segment; and 3, diffuse involvement
lower limbs (anterior and posterior views) should be acquired. (>50% of the segment). The intensity score is graded as: 0, for no
Alternatively, whole-body scan imaging with additional static uptake; 1, for doubtful uptake; 2, for definite uptake less than liver;
images including lateral views of the skull can be acquired. Lateral and 3, for intense uptake greater than that of liver. Thus, the max-
images are sometimes useful to discriminate between areas of imum score for either extension or intensity would be 30. The
overlapping uptake, for example, in the abdomen or pelvis, espe- intensity score is slightly more subjective but because of technical
cially if the bladder is not empty. Minimum 10 minutes per view factors, it showed lower concordance among readers. Relative

scores were calculated by dividing the absolute score at each time

by the corresponding pretreatment score. A relative score of 0.5 is
considered a partial response; a relative score of 0 is a complete
response. The score at mid-induction correctly predicted the over-
all response of metastases at the end of therapy. In a study per-
formed by Matthay et al.,43 the Curie score has been shown to have
an interobserver concordance 95% and to provide valuable prog-
nostic information for the overall response and event-free survival.
The Curie score is one of the most frequently used semiquantita-
tive scoring system by the Children’s Oncology Group and the New
Approaches to NB consortium. A study performed by Yanik et al.44
showed a significantly worse event-free survival (EFS) for patients
with scores >5 at the end of induction. Suc et al.45 proposed a mod-
ification of the Curie score in which the skeleton was divided into
seven segments. It showed good interobserver concordance but not
prognostic value for outcome. The Frappaz score uses seven seg-
ments of the skeleton, and initially did not include soft tissue in the
score.46 Messina et al.47 evaluated the Curie score systems and the
Frappaz score. Diagnostic MIBG scan pairs (n = 57) were collected
for patients who underwent 131I-MIBG therapy for relapsed neuro-
blastoma. The first method resulted in highest interobserver concor-
dance and correlated significantly with the overall response to
therapy, suggesting that any decrease in absolute score is indicative
of response in patients with scores below three to five at the com-
mencement of therapy but that the semiquantitative scoring system
is most useful in those with pretreatment score ≥3.
Despite a strong correlation with response by INRC, the second
method carried no significance in predicting PFS. Perel et al.48 pub-
lished a minor variation on the Curie score, in which the skeleton
was divided into 10 rather than 9 zones and soft tissue involvement
was not considered. Two-year EFS did not significantly differ for the
group of patients with initial MIBG score ≥10; however, for patients
older than 1 year, worse outcome was seen with MIBG score ≥10. In
a study performed by Katzenstein et al.,49 this method was shown to A B
have prognostic significance at the end of induction therapy, with a
better outcome for patients with score inferior to 3. Another major Figure 23.1. 123I-MIBG scan (A) anterior view, (B) posterior view in patient with newly diag-
variation of the Curie score was proposed by Lewington et al.50 in nosed neuroblastoma. Planar images show the presence of large mass in abdomen (black arrow )
and diffuse bone marrow involvement.
patients treated in the high-risk neuroblastoma SIOPEN study
(SIOPEN score). In the SIOPEN score, currently under prospective
evaluation in Europe, the skeletal distribution of MIBG was recorded
in 12 anatomic body segments (skull, thoracic cage, proximal right MIBG studies at the time of diagnosis have also an important
upper limb, distal right upper limb, proximal left upper limb, distal prognostic value, particularly in stage IV patients older than
left upper limb, spine, pelvis, proximal right lower limb, distal right 1 year. Whole-body evaluation is especially important in neuro-
lower limb, proximal left lower limb, and distal left lower limb). blastoma because of the potential for widespread metastatic dis-
The extent and pattern of skeletal MIBG involvement was ease (Fig. 23.1). Leung et al.25 evaluated the role of MIBG
scored using a 0 to 6 scale to discriminate between focal discrete scintigraphy in 100 patients with mass lesions and pathology
lesions and patterns of more diffuse infiltration. This method other than neuroblastoma to characterize the specificity of this
showed an interobserver concordance of 95% and it was slightly modality in sympathomedullary tumors. In this large retrospective
superior to the Frappaz score to measure of response. Curie score, study, MIBG uptake was observed in only four cases, two of which
however, has been tested more widely and over many years and is were of nonneural crest origin, confirming that, in children, MIBG-
less complex compared to SIOPEN score. Recently, Sano et al.51 avid lesions are almost certainly of sympathomedullary origin.
developed a new semiquantitative score based on 123I-MIBG reten- A prospective trial was conducted to confirm the diagnostic per-
tion ratio to assess the response to chemotherapy for advanced formance of 123I-MIBG scintigraphy in patients with known or sus-
neuroblastoma. 123I-MIBG retention ratio in tumors and normal pected neuroblastoma, showing sensitivity of 88% and a specificity
organs was compared to the Curie score. The difference in the of 83%.52 Most false-negative interpretations were in patients with
washout ratio of MIBG between the pathologic accumulation in minimal residual disease, whereas false-positive interpretations
neuroblastoma and the physiologic distribution in normal organs generally involved atypical adrenal or other physiologic uptake. To
was evaluated using early and delayed images. 123I-MIBG retention assess neuroblastoma lesions, Pfluger et al.53 showed that inte-
ratio was significantly higher in patients with stage M disease com- grated imaging with MRI showed an increase in both sensitivity
pared to stage I–II, demonstrating the utility for evaluation based and specificity. MIBG scintigraphy, MRI, and combined analysis
on the early response to chemotherapy. Furthermore, the retention showed a sensitivity of 69%, 86%, and 99% and a specificity of
ratio correlated with urine catecholamine metabolites before and 85%, 77%, and 95%, respectively. On MIBG scintigraphy, 10 false-
during chemotherapy. positive findings occurred in ganglioneuromas, benign liver
tumors, and physiologic uptake. On MRI, 15 false-positive findings
were recorded in posttherapeutic reactive changes, benign adrenal
Clinical Role of MIBG Scintigraphy
tumors, and enlarged lymph nodes.
The 123I-MIBG scan is currently the gold standard for initial stag- False-negative scans may be observed in approximately 10% of
ing of neuroblastoma with a specificity ranging from 85% to 96%. neuroblastomas that do not concentrate MIBG, because of low

expression of the cellular expression of the noradrenaline trans- observed. Patients with MIBG scores ≥3 following induction therapy
porter (NAT). In this setting, Carlin et al.54 demonstrated that tumors had significantly worse EFS than those with scores less than 3.
without MIBG uptake did not express detectable levels of the NAT Ongoing prospective studies of large numbers of uniformly treated
investigated with the real-time PCR. NB shows a great variability in patients in North America and Europe will further elucidate the
tracer uptake and it seems correlated with the level of urinary cat- prognostic significance of the initial MIBG score.
echolamine metabolites and tumor differentiation.52 Furthermore, NB shows a great variability in tracer uptake. It appears to be
tumor size reflects whether the uptake is uniform or irregular with correlated with the level of urinary catecholamine metabolites and
focal areas of reduced uptake, indicating central necrosis. In some tumor differentiation.52 Less than 10% of neuroblastomas demon-
of these tumors, the areas of reduced uptake may reflect areas of strate no radiotracer uptake and no relationship between MIBG-
dedifferentiation. negativity and biologic/prognostic features has been demonstrated.
Central nervous system (CNS) metastases are extremely rare at Biasotti et al.61 found negative MIBG scan at diagnosis in 16 patients
diagnosis, occurring later in the course of the disease. MIBG scans out of 196 neuroblastoma cases (8%). In patients with stage I or II
detect metastatic CNS lesions in only 43% of patients, probably disease, the MIBG scan was negative in 24% of the cases, contrarily
because MIBG does not cross the blood–brain barrier, or the tumor patients with stage III or IV demonstrated no MIBG uptake only in
has dedifferentiated. Matthay et al.55 evaluated 23 patients with 4% of cases. The negative MIBG scan at diagnosis was found to be
suspicious cerebral disease. The sites of recurrences were paren- associated with normal urinary vanillylmandelic acid (VMA) excre-
chymal in eight patients, parenchymal with meningeal involvement tion in almost 80% of cases and with pathologic excretion of
in seven patients, and meningeal involvement alone in the remain- homovanillic acids (HVAs) in 50% of cases.

ing eight patients. In patients with skull lesions, the detection of Histologic diagnosis of undifferentiated or poorly differentiated
CNS metastases may be difficult. In patients with only meningeal neuroblastoma was present in 43% of patient. Furthermore, in
disease, MIBG did not show good diagnostic accuracy. In five some patients with minimal residual disease after therapy, false-
patients with parenchymal lesion measuring >1 cm, MIBG did not negative MIBG scans may occur.62
detect the presence of disease. Indeed in some cases, the MIBG scan becomes positive at the time
The sensitivity of MIBG scintigraphy is limited in the detection of relapse caused by extreme tumor heterogeneity. After induction
of single bone and bone marrow metastases. Gordon et al.56 chemotherapy or before myeloablative therapy, positive scans may
reported negative findings on MIBG scintigraphy in 66 (29%) of 227 indicate a high likelihood of relapse, serving as a prognostic
skeletal lesions, whereas bone scintigraphy findings were positive. marker.63,64 The sensitivity of 88% to 94% and specificity of 83% to
In addition, small bone marrow tumors are often not detected, and 92% for64 MIBG scintigraphy indicate that an important tool to detect
therefore the MIBG scan must be supplemented with bone marrow unsuspected relapse of high-risk neuroblastoma, assessing relapse-
biopsy.57 free survival (RFS). Kushner et al.66 evaluated 113 patients with
Some studies demonstrated that MIBG score at diagnosis may asymptomatic/unsuspected relapse. The 123I-MIBG scan was the
be a prognostic indicator, to predict response to chemotherapy for most reliable study for detecting relapse with a detection rate of 82%.
metastatic neuroblastoma. Suc et al.45 have shown that a semi- 131
I-MIBG scan detected relapse in 64% of cases, proving to be sig-
quantitative score of >4 was associated with the failure to achieve nificantly superior to bone scan (36%) and bone marrow histology
complete remission after induction chemotherapy. Therefore, a (34%). These results suggest that periodic 123I-MIBG scans are essen-
high MIBG score at diagnosis is probably correlated with great tial for valid estimation of the duration of RFS. In 25% of patients,
overall tumor burden with a significant risk of harboring drug- however, the MIBG scan failed to detect bone marrow involvement.
resistant cells and thus with poor response to conventional che- Taggart et al.67 confirmed the important role of MIBG scintig-
motherapy. The hypothesis is supported by the mathematical raphy for response evaluation in relapsed neuroblastoma com-
model developed in 1970s by Goldie and Coldman,58 in which the pared to 18F-FDG PET/CT. The results showed that MIBG was
number of drug-resistant clones has been shown to be propor- more sensitive than 18F-FDG PET overall and for bone lesions
tional to the mutation rate. This was also suggested by Chan evaluated in 122 patients with both pre- and posttherapy imaging
et al.,59 who showed that these patients exhibited high levels of (sensitivity 94% versus 43%). The nonconcordance found with
pretreatment P-glycoprotein. P-glycoprotein was not detected in both 123I-MIBG-positive/18F-FDG PET-negative lesions and MIBG-
stage I–II neuroblastoma and in tumors associated with a good egative/FDG PET-positive lesions demonstrates that MIBG is more
prognosis that originated in the cervical, mediastinal, or pelvic sensitive, but both imaging modalities have the potential to identify
sympathetic ganglia but it was found in tumors associated with a lesions not visualized on the other scan, contributing unique infor-
poor prognosis that arose in the adrenal medulla and abdominal mation about disease sites.
sympathetic ganglia. Furthermore, the majority of metastatic Furthermore, MIBG scans allow functional assessment to differ-
lesions expressed higher levels of P-glycoprotein than the primary entiate residual tumor from posttherapy changes, being superior to
tumors. The use of the relative score after two or four cycles of conventional diagnostic imaging such as CT or MRI (Figs. 23.2,
induction therapy seems to be a more reliable predictor of EFS 23.3). Moreover, the study by de Cervens et al.68 demonstrated that
than the absolute score, although both measures significantly pre- in neuroblastoma patients younger than 1 year of age, normaliza-
dict response at the end of induction.60 The identification of poor tion of skeletal MIBG uptake correlates with response to chemo-
responders after two cycles of induction therapy will allow the therapy much earlier and with much more accuracy than the
routing of these patients into novel approaches. Most other stud- radiologic survey. Intermediate- and low-risk patients should have
ies, however, showed the initial MIBG score and clinical outcome MIBG scans at diagnosis, at the end of therapy and as surveillance
had no significance. at 6-month intervals until 1 year for low-risk stage II patients and
In a study performed by Perel et al.,48 the 2-year EFS did not for 2 years after therapy for intermediate-risk patients. Although
significantly differ for patients with initial MIBG or bone scintigra- low- and intermediate-risk neuroblastomas have an excellent over-
phy scores ≥10 compared to those with scores <10. However, for all survival, the event free survival is only approximately 80% for
patients older than 1 year, a trend associating worse outcome with stage II, stage III, stage IV and unfavorable biology 4S, suggesting
MIBG scores ≥10 at diagnosis was seen. Katzenstein et al.49 inves- that this modest surveillance schedule is reasonable to detect relaps-
tigated whether response to induction therapy, evaluated by MIBG ing patients.
and bone scintigraphy, correlates with EFS in 29 children with The addition of SPECT views may be critical in cases in which
high-risk NB. They found that the imaging scores calculated for the there is a question regarding physiologic uptake versus tumor
diagnostic MIBG and bone scans were not prognostic but an asso- uptake, or for precise localization of a tumor focus that is critical for
ciation between EFS and the postinduction MIBG score was patient management (e.g., distinguishing a vertebral lesion from

88% to 91%. Although additional information was gained in 65% of

cases regarding the precise anatomic location of uptake, Curie
scores would not have been substantially altered. However, Even-
Sapir et al.69 reported that SPECT/CT improved image interpreta-
tion by providing a better anatomic localization of SPECT-detected
lesions in 41% of the patients with known or suspected endocrine
tumor and detected unsuspected bone involvement in 15% of the
patients. Additional information of clinical value were found in 33%
of the cases.
Fukuoka et al.70 investigated lesion detectability of 123I-MIBG
scintigraphy and of high-dose 131I-MIBG and evaluated the incre-
mental role of SPECT/CT over planar image. SPECT/CT images pro-
vided additional diagnostic information over planar images in 25
studies (81%) of 12 patients (75%) in 123I-MIBG scintigraphy and in
9 studies (53%) of 9 patients (75%) in high-dose 131I-MIBG scintigra-
phy. The detection rate of the new lesions by SPECT/CT was higher
in 123I-MIBG scintigraphy than in high-dose 131I-MIBG scintigraphy.
It is thought that signal-to-noise ratio is high enough to be identified
in planar image when high dose is administered. There were no
apparent differences in the rate of alteration of anatomic location of
the lesions between diagnostic 123I-MIBG and high-dose 131I-MIBG
images.
99m
Tc-diphosphonate Bone Scintigraphy
in Neuroblastoma
Total-body bone scintigraphy (BS) using 99mTc-diphosphonate com-
A B pounds has been the main diagnostic investigative tool for detec-
tion of cortical skeletal metastases since the late 1970s. Bone
scintigraphy is a sensitive tool to evaluate the skeletal system in
Figure 23.2. 123I-MIBG scan for assessment of therapy response. A: Baseline scintigraphy children. The administered radiopharmaceutical dose is weight
shows multiple skeletal metastases. B: Posttherapy scan show marked reduction of disease.
based. Bone scans in children require careful attention to tech-
nique to obtain high-quality diagnostic images. The activity admin-
the adjacent pulmonary parenchyma). The addition of low-dose CT istered should be calculated on the basis of a reference dose for an
to SPECT (SPECT/CT) for both lesion localization and attenuation adult, scaled to body weight (with minimum of 20–40 MBq admin-
correction has promised in providing more precise determination istered activity).29 North American pediatric centers had variability
of the anatomic location of disease. In a study performed by Vik in the administered dose of the radiopharmaceutical 99mTc-methy-
et al.,52 SPECT views only marginally increased the sensitivity from lene diphosphate (MDP); minimum activities varied from 22.2 to
Figure 23.3. 123I-MIBG scintigraphy in patient with CT finding of abdominal lymphadenopathy

A (A) whole-body scan, (B) planar image of the abdomen confirms lymph node disease (arrow ).
The scan also reveals the presence of skeletal metastasis.

185 MBq, whereas the activity per kilogram varied from 7.4 to the same tumor. 111In-DTPA-octreotide scintigraphy yields impor-
13.3 MBq/kg and the maximum from 666 to 925 MBq.71 tant prognostic information and it may be useful in negative-MIBG
In 2011, the North American Consensus Guidelines established patient. Several studies have demonstrated that somatostatin
recommended radiopharmaceutical doses in children and adoles- receptor expression and/or positive 111In-Octreotide scan in these
cent72 to be 93 MBq/kg of 99mTc-MDP, with a minimum activity of patients is associated with a more favorable clinical outcome.77,80
37 MBq and maximum activity of 148 MBq. Whole-body imaging is Briganti et al.81 have shown that high levels of SST2 receptor
acquired after a delay of 2 to 3 hours postinjection of 99mTc-MDP. expression correlate with better survival, independent of N-Myc
SPECT is routinely used to further evaluate the area of suspected amplification. The 4-year survival probability is 95% in patient
abnormality or to further define an abnormality observed on planar with positive somatostatin receptor imaging compared to 62% in
imaging. negative patients. Juweid et al.82 compared In-111 pentetreotide
Combined functional and anatomic imaging using SPECT/CT scintigraphy and bone scan sensitivity and specificity in nine
imaging systems can improve diagnostic accuracy. 99mTc-MDP BS patients with neuroblastoma. 111In-octreotide scan showed a
has lower sensitivity with a high frequency of false-positive results greater number of bone lesions (30 versus 7) with a sensitivity of
for detection of skeletal metastases than MIBG scans. In general, 86%. Abnormalities detected on 111In-pentetreotide images are
BS do not provide additional information compared to MIBG scin- slightly different from those seen with MIBG, especially for bone
tigraphy.73 The metastatic pattern of neuroblastoma in bone is marrow. 111In-pentetreotide imaging of neuroblast-derived tumors
often symmetrical in the metaphyseal areas of the long bones, provided information different from and most likely complemen-
making detection on bone scan difficult because of the adjacent tary to that of MIBG. However, 111I-MIBG provides better images of

physiologic uptake in the physis. Symmetrical flaring and blurring the adrenal region (low kidney uptake) and, in many cases, of bone
of the growth plate with extension into the metaphysis should be marrow metastases.
considered abnormal and highly suggestive of metastatic dis-
ease.74
Minimal metastatic involvement within or adjacent to the
Other Radiotracers
growth plate may be missed. In about 60% of patients, the 99mTc- Several analogs of MIBG have been synthesized for investigation
MDP may also accumulate in the primary tumors because of the of the sympathetic innervation of the heart and for neuroendo-
characteristic calcifications, without particular prognostic signifi- crine tumor imaging and therapy.
cance.75 Focal abnormalities on bone scintigraphy involving the
orbits, skull, particularly parasagittal area, and multiple focal “hot” 123
I-amino Iodobenzylguanidine (AIBG)
and “cold” lesions in the spine are highly suggestive of skeletal
123
metastatic disease from neuroblastoma. Bone scans may identify I-amino iodobenzylguanidine (AIBG) has demonstrated selective
cortical lesion in patients with negative MIBG scan at diagnosis localization in organs rich with adrenergic innervation, such as the
which have worse prognosis compared to bone marrow metasta- adrenal medulla with the same mechanism as 123I-MIBG in animal
ses. Gordon et al.,56 in a review comparing bone with 123I-MIBG models. All areas of abnormal accumulation demonstrated on
123
scintigraphy, showed that 123I-MIBG may miss abnormalities sug- I-MIBG scintigraphy were identified by 123I-AIBG in three patients
gestive of metastatic disease. In 24 children, the 123I-MIBG scans with pheochromocytoma.83 However, 123I-AIBG had lower blood
revealed more extensive disease with 161 positive sites whereas clearance, greater background and in vivo deiodination greater than
123
the 99mTc-MDP scan showed only 100 positive sites; 34 of these I-MIBG.
sites were common to both studies.
99m
The superiority of MIBG scintigraphy was also demonstrated in Tc-sestamibi ( 99mTc-MIBI) Imaging
a study performed by Hadj-Djilani et al.76 in 27 patients with cortical
bone metastases. Thirty-five sites of cortical bone metastasis were The role of 99mTc-sestamibi (99mTc-MIBI) in predicting the therapeu-
shown in eight patients by both MIBG and DPD, twelve sites in seven tic response in patients with stage IV neuroblastoma has been stud-
patients by MIBG only, and seven sites in five patients by DPD only. ied by Burak et al.84 in nine patients. None of the primary lesions
In 14 patients, both MIBG and bone scan were negative. However, demonstrated significant 99mTc-MIBI accumulation. 99mTc-sestamibi
in a study performed by Shulkin et al.73 in 77 patients, 131I-MIBG was positive in 16 of 41 MIBG-avid metastatic lesions. Follow-up
showed complete concordance with bone scanning for the presence demonstrated that all lesions that were not 99mTc-MIBI avid at the
or absence of skeletal lesions. In 60% of patients, the 99mTc-MDP time of diagnosis remained negative. Clinical evaluation of patients
accumulated into the primary tumors but there is no prognostic with no 99mTc-MIBI uptake in primary and secondary sites of neuro-
significance to this finding. Rarely, other primary tumors in child- blastoma confirmed that they were resistant to multidrug chemo-
hood may accumulate the bone agent. therapy. 99mTc-MIBI, a substrate for P-glycoprotein–related multidrug
resistance, may provide prognostic information but it is not rou-
tinely used in clinical practice. Patients with negative scans have
Somatostatin Analog Scintigraphy poor prognosis and progressive disease regardless of MIBG uptake
with resistance to multidrug chemotherapy.
In-111 Pentetreotide/octreotide
99m
The role of In-111 pentetreotide/octreotide has been evaluated in Tc DMSA Imaging
the management of neuroblastoma because of the presence of Limouris et al.78 evaluated the clinical impact of 99mTc-(V)-DMSA
somatostatin receptors (SSTR) 1 and 2. The presence of function- in the management of neuronal crest tumor. In 7 patients with
ing SS receptors were demonstrated by studies in vitro77 and con- neuroblastoma, MIBG uptake was seen in 15 sites and 99mTc-(V)-
firmed in vivo by tumor imaging with either 123I-Tyr-octreotide or DMSA only in 3 sites, demonstrating the lack of a significant role
111
In-pentetreotide. for 99mTc-(V)-DMSA in evaluation of patients with neuroblastoma.
Several clinical studies have compared MIBG with 111In-DTPA-
octreotide scintigraphy to image neuroblastoma.78,79 The sensi-
tivity of 111In-DTPA-octreotide scintigraphy ranged from 55% to
Gallium-67 Imaging
70% compared with 88% to 94% for MIBG scintigraphy. Imaging Gallium-67 was shown to have a sensitivity of nearly 80% for
with somatostatin analogs is less sensitive than MIBG scans to detection of the primary tumor in 14 children with histopatho-
detect neuroblastoma, probably because SSTR expression is logically confirmed neuroblastoma. Ga-67 citrate, however, did
downregulated in more aggressive tumors and is variable within not visualize osseous metastases.85

Thallium-201 Imaging iffuse and homogeneous uptake in the thymus is common in

D
healthy children. Normal accumulation in bone marrow is gener-
Thallium-201 has been evaluated also in patients with neuroblas- ally homogeneous with more extensive distribution in children
toma. The radiopharmaceutical has been widely used as a tumor than in adults. Skeletally immature pediatric patients have physi-
imaging agent in adults with bone primary tumors such as lym- ologic linear uptake in physes and apophyses of bone structures.
phoma, brain tumors, thyroid carcinoma, and bone sarcomas. The use of combined PET/CT reveals many normal variants with
Howman-Giles et al.86 investigated the role of 201Tl scintigraphy in the precise localization of functional 18FDG PET data superimposed
six patients with neuroblastoma and positive MIBG findings. Only on conventional anatomic CT data. Administered activity in chil-
three patients showed 201Tl uptake, demonstrating no role of 201Tl dren and adolescent is 0.14 mCi/kg (approximately 5 MBq/kg)
scintigraphy in neuroblastoma. (equivalent to 10 mCi [370 MBq] in an adult). The effective dose
from this administered activity varies from 500 mrem (5 mSv) in a
Radioimmunoscintigraphy 1 year old to 860 mrem (8.6 mSv) in a 15 year old. The organ
receiving the highest absorbed radiation dose (target organ) is the
Radioimmunodetection of neuroblastoma was first demonstrated bladder.94
in the early 1980s with 131I-labeled UJ13, an IgG1 monoclonal anti- 18
FDG PET has potential in the staging, response assessment
body that recognizes the NCAM antigen on neuroectodermal tissue and detection of recurrence in neuroblastoma but it does not
including neuroblastoma. Subsequent radioimmunologic attempts replace standard imaging modalities in newly diagnosed patients.95
to enhance the detection of neuroblastoma in patients focused on Preclinical models have failed to verify any association between
the use of radiolabeled anti-GD2 monoclonal antibodies. In small 18
F-FDG and neuroblastoma proliferation.96 Higher spatial resolu-
studies, scintigraphy using the anti-GD2 IgG1 monoclonal antibody tion of PET imaging compared to single photon scintigraphy with
BW 575/9 labeled with 99mTc yielded mixed results: Good localiza- 123
I-MIBG identifies small lesions (e g., foci in lymph node or verte-
tion was noted in 2 of 3 patients,87 and, in a comparative analysis bral bodies) and localization the anatomic sites of disease. Kushner
involving 7 patients, 5 of 26 lesions were missed by 123I-MIBG, and et al.97 demonstrated that in high-risk NB patients, PET findings
8 lesions were undetected by immunoscintigraphy.88 correlated well with disease status determined by standard imag-
ing modalities, BM tests, urine VMA and HVA levels, and clinical
Iodine-131-3F8 history. In clinical practice, 18F-FDG activity is associated with
more aggressive disease and has been shown to predict worse
Iodine-131-3F8, a murine IgG3 monoclonal antibody specific for outcome.98
the ganglioside GD2 was evaluated in 42 patients with stage III 18
FDG PET/CT plays an important role in the management of the
unresectable stage IV neuroblastoma.89 Preclinical studies have small proportion of patients (less than 10%) who do not accumulate
shown that GD2 is present in high concentrations in human neuro- 123
I-MIBG.99 Indeed, in cases in which it is suspected that the extent
blastoma cells.90 In nude mice xenografted with human neuroblas- of disease exceeds that depicted with 123I-MIBG, 18FDG PET/CT is
toma, 131I or 125I-labeled 3F8 localized in the tumors with high useful. In general, 18F-FDG is less sensitive than 123I-MIBG for detec-
uptake at 24 hours of 131I-3F8 imaging revealed radiotracers tion of neuroblastoma, especially when evaluating high-risk patients
uptake suggestive of marrow involvement in 26 patients and or relapsed disease. In a retrospective study, Sharp et al.100 com-
detected more abnormal primary and metastatic sites than either pared the diagnostic utility of 18F-FDG and 123I-MIBG scintigraphy
123
I-MIBG or 99mTc-MDP bone scans. Two other monoclonal anti- in 60 patients underwent to a total of 113 paired scans. 18F-FDG
bodies against neuroblastoma have been used to define tumor was found to be superior to depict stage I and II neuroblastoma.
deposits. 131I-UJ 13A was found to localize in 15 sites of primary 18
F-FDG also gave important information prior to stem cell trans-
and metastatic lesions from nine patients with neuroblastoma. One plantation, depicting residual disease not seen with 123I-MIBG in
false-positive and two false-negative localizations were reported. some patients. 123I-MIBG scanning was superior to 18F-FDG PET in
In two of the 15 positive sites, tumor had not been demonstrated the evaluation of stage IV neuroblastoma, especially during initial
by other imaging techniques.91 This IgG1 antibody was also used chemotherapy, primarily because of the better detection of bone or
for target 131I therapy in four patients who failed other conven- marrow metastases.
tional treatments in a phase I study.92 Objective responses were By contrast, Kushner et al.98 found 18F-FDG PET equal or supe-
obtained in one of the four patients. IgG1 monoclonal antibody BW rior to 123I-MIBG scanning to identify neuroblastoma in soft tissue
575/9 showed good tumor localization in seven children with neu- and extracranial skeletal structures and to delineate the extent and
roblastoma. The majority of tumor sites were detected by BW localize sites of disease. In the study, 18F-FDG PET findings corre-
575/9 and 123I-MIBG. However, 5 of 26 lesions were undetectable lated with disease status determined by standard imaging modali-
by 123I-MIBG and 8 were not detected by immunoscintigraphy.93 ties, BM tests, urine VMA and HVA levels, and clinical history. The
Despite evidence of high sensitivity for detection of tumor sites, major drawback of 18FDG PET was the lack of visualization of
radioimmunoscintigraphy has remained investigational, at least lesions in the cranial vault because of the normally high physio-
in part because of greater ease of use and improved accuracy with logic brain activity. 18FDG PET/CT may detect localization to the
nonimmune scintigraphic modalities, primarily 123I-MIBG. liver where the intense accumulation of MIBG interferes with an
accurate diagnosis.
18
2-[fluorine-18]fluoro-2-deoxy-D-glucose F-FDG may exhibit accumulation in the activated bone mar-
row caused by previous therapies, reducing the accuracy to detect
(18FDG) PET Imaging disease,101 but it shows more osteomedullary abnormalities than
Positron emission tomography (PET) with 2-[fluorine-18]fluoro-2- bone scans. However, 18FDG PET and 123I-MIBG scans show similar
deoxy-D-glucose (18FDG) is increasingly being used in the evalua- patterns of diffusely abnormal skeletal findings in patients with
tion of pediatric oncology patients. The normal distribution and extensive bone marrow involvement, but neither imaging modality
physiologic variants of 18FDG uptake in children can differ from reliably detects minimal bone marrow disease. Taggart et al.67 com-
those in adults. It is important that these differences be recognized pared the role of 18F-FDG to 123I-MIBG scan in 21 patients who
so as to avoid misinterpretation. Although many of the normal underwent 131I-MIBG therapy. Complete response by FDG PET
variants in children are similar to those in adults, the normal dis- metabolic evaluation did not always correlate with complete response
tribution in children often differs in the visualization of lymphatic by MIBG uptake. MIBG was usually more sensitive for disease detec-
tissue in the Waldeyer ring, as well as in the ileocecal region, thy- tion, except in MIBG-negative patients and some soft tissue lesions.
mus, hematopoietic bone marrow, and skeletal growth centers. However, 18FDG-PET can identify disease in MIBG-negative lesions,


Figure 23.4. FDG PET (A) MIP image and
123
I-MIBG scintigraphy, (B) anterior view,
(C) posterior view carried out during therapy
in a little patient with a bony secondary lesion
in the right pelvis. FDG PET-CT was able to
early assess the response to therapy in com-
parison to 123I-MIBG scintigraphy (arrows
indicate persistent pathologic uptake). A B C
it serves as a complementary imaging modality in selected patients. AADC conversion. The enzyme AADC is strongly expressed in neuro-
Larger prospective studies of FDG PET at diagnosis, during, and endocrine cells. Like other tyrosine-based tracers, such as 11C-tyrosine,
18
after therapy correlated with survival would help to determine the F-ethyltyrosine, 123I-methyltyrosine, and other analogs, 18F-DOPA
relative utility of these modalities. enters cells through the amino acid transport systems for large neu-
18
F-FDG PET-CT has not had a significant clinical impact on the tral amino acids, which are present in nearly all cells. 18F-DOPA is
evaluation of therapy response in patients with low baseline uptake. metabolized by the AADC enzyme activity present in many tissues,
Conversely, in patients with moderate–high FDG accumulation this including the liver and especially the kidneys. Radiolabeled metab-
modality has a high accuracy for response assessment, also provid- olites include 3-O-methyl-18F-DOPA, 6-18F-fluorodopamine, l-3,4-
ing important prognostic information (Fig. 23.4).102 18F-FDG PET dihydroxy-6-18F-fluorophenylacetic acid, and 8-18F-fluorohomovanillic
has been shown to be inferior to 123I-MIBG in the evaluation of skull acid. The radiopharmaceutical identifies the increased activity of
lesions, except in case of considerable soft tissue component99 L-DOPA decarboxylase found in malignant neural crest tumors. The
because of the physiologic high FDG uptake in the brain. normal findings include high activity in the urinary excretion sys-
Papathanasiou et al.103 compared the diagnostic performance tems, including the collecting systems in the kidneys, ureters, and
of F-FDG PET/CT with 123I-MIBG imaging in 28 patients with
18
bladder. Intermediate and/or low activity levels are found in the stri-
refractory or relapsed high-risk neuroblastoma. 123I-MIBG imag- atum, myocardium, and liver. In general, low-level activity can be
ing is superior to 18F-FDG PET/CT for the assessment of disease observed in the small intestine and peripheral muscles. In children,
extent in high-risk neuroblastoma. However, 18F-FDG PET/CT has some uptake in the growth plates can be seen. Carbidopa is routinely
significant prognostic implications in these patients. MIBG remains used in 18F-DOPA imaging in neurology because it increases striatal
the first-line imaging agent for neuroblastoma, even though 18FDG uptake, mainly by increasing the concentration in plasma and
PET plays an important complementary role. In fact 18F-FDG PET decreasing renal excretion. After carbidopa premedications, liver
scan may be useful in the event of discrepant or inconclusive find- uptake increased slightly, and pancreatic uptake decreased consider-
ings on 123I-MIBG scintigraphy/SPECT and morphologic imaging. ably. Tumor uptake increased markedly, with standardized uptake
values (SUVs) increasing 10% to 30%. These effects clearly improved
18 the overall image quality and resulted in the detection of more lesions.
F-Fluoro-L-dihydroxyphenylalanine (DOPA) PET Carbidopa premedication in the pediatric population appears
18
F-Fluoro-L-dihydroxyphenylalanine (DOPA) PET is a promising feasible and seems to influence 18F-DOPA distribution in the liver
imaging modality for the diagnostic workup of patients with neuro- and pancreas in a manner similar to that reported in adults.104 Usu-
blastoma (Fig. 23.5), especially in advanced stages of disease. DOPA ally whole-body 18F-DOPA PET/CT is carried out 60 minutes after
is an amino acid that is internalized by the LAT2 amino acid trans- the injection of 210 to 370 MBq of tracer (4 MBq/kg). 18F-Fluoro-L-
porter. DOPA is an intermediate in the catecholamine synthesis path- DOPA PET/CT shows high overall accuracy and sensitivity, repre-
way produced after hydroxylation of the amino acid tyrosine, which senting an alternative approach to 123I-MIBG scan (Fig. 23.6).
enters the cell. DOPA may also be derived from phenylalanine, Piccardo et al.105 evaluated the role of 18F-DOPA PET/CT in stage
another essential amino acid. DOPA can be decarboxylated to dopa- III–IV neuroblastoma, comparing its diagnostic value with that of
123
mine by amino acid decarboxylase (AADC). It can also be converted I-MIBG scintigraphy. In a prospective study, they evaluated 28
by catechol-O-methyltransferase to 3,4-dihydroxyphenylacetic acid. paired 123I-MIBG and 18F-DOPA PET/CT scans in 19 patients: 4 at
The affinity of radioactive 18F-DOPA for catechol-O-methyltransferase the time of the NB diagnosis and 15 when NB relapse was sus-
metabolization appears to be low compared with the affinity for pected. No significant difference in terms of specificity was found.

B
A
D
C
Figure 23.5. 18F-DOPA PET-CT (A) CT axial cut, (B) PET axial cut, (C) fusion axial cut, (D) MIP image carried out to stage a little patient affected by neuroblastoma.
Arrows indicate the primary left paraspinal lesion highly accumulating 18F-DOPA. No metastasis were detected.
18
F-DOPA PET/CT showed a sensitivity and accuracy of 95% and able information on tumor cell receptor status when planning
96%, respectively, whereas 123I-MIBG scanning showed a sensitivity peptide receptor radionuclide therapy. Kroiss et al. evaluated the
and accuracy of 68% and 64%, respectively. role of 68Ga-DOTA-TOC in five patients, comparing the accuracy of
Lopci et al.106 have demonstrated that PET/CT with L-DOPA has 123
I-MIBG imaging with PET in the diagnosis and staging of meta-
higher sensitivity (100% versus 91%) and specificity (92% versus static neuroblastoma. In neuroblastoma patients, on a per-lesion
61%) compared to CT/MR in advanced stage neuroblastoma. In this basis, the sensitivity of 68Ga-DOTA-TOC was 97.2% and that of
study a total of 21 patients had 37 paired 18F-DOPA PET and CT/ 123
I-MIBG was 90.7%. Furthermore, 68Ga-DOTA-TOC PET identified
MR scans (4 at staging, 30 at restaging, and 3 during follow-up) with 257 lesions, anatomic imaging identified 216 lesions, and 123I-MIBG
a maximum elapsed time for the different imaging procedures less identified only 184 lesions. The relatively small number of patients
than 1 month. 8F-DOPA PET was false positive in one case at end- and the lack of follow-up imaging procedures make it difficult
treatment evaluation. There were no false-negative scans. Conven- to identify possible false-positive findings. Further studies are
tional imaging with CT/MR resulted in false-negative findings in two necessary to determine the effective role of SRS radiotracers in
cases and false positive in five cases. As for identification of the neuroblastoma.
primary tumor, the sensitivity of 18F-DOPA PET/CT and CT/MR were
identical. Conventional imaging showed higher sensitivity than
18
F-DOPA PET/CT for liver lesions (100% versus 63%). 18F-Fluoro- C-11 Hydroxyephedrine (11C-HED) PET
L-DOPA PET changed patient management in 32% of the cases. It In a preliminary study, Shulkin et al.107 evaluated the use of C-11
has an advantage in identifying locoregional soft tissue recurrence hydroxyephedrine (11C-HED) PET in seven patients with known or
compared to 123I-MIBG scan. However, no significant difference in subsequently confirmed neuroblastoma to stage disease. HED con-
the evaluation of bone marrow involvement has been found. tains an α-methyl group that prevents metabolism by monamine
oxidase and persists in the cytosol without vesicular storage.
68
Ga-(DOTA-D-Phe[1]-Tyr[3]-octreotide) Radiotracer retention is primarily because of the reuptake mecha-
nism, reflecting the functional integrity of the sympathetic neurons.
(DOTA-TOC) PET 11
C-HED imaging was obtained immediately after the injection of
68
Ga-(DOTA-D-Phe[1]-Tyr[3]-octreotide)(DOTA-TOC) PET has higher 185 MBq of radiopharmaceutical and continued for 30 minutes.
sensitivity than In-111 pentetreotide scintigraphy.107 It gives valu- PET scanning detected neuroblastoma lesion in all seven patients.


A B
C D
Figure 23.6. 18F-DOPA PET-CT (A) fusion axial cut, (B) MIP image, (C) fusion axial cut, (D) MIP image carried out before therapy (A,B) and after chemotherapy
(C,D) in a little patient affected by abdominal neuroblastoma (arrows ). It is important to notice that the primary lesion highly accumulated 18F-DOPA before therapy
but, despite a clear decrease in the uptake, a complete normalization was not obtained after therapy, indicating only a partial response.
124
Hepatic and renal uptake were prominent early but declined pro- I-MIBG Using PET
gressively. Tumors were clearly detected within minutes after 124
tracer injection. Tumor-to-liver accumulation is optimal 30 minutes I is an emerging radionuclide for PET imaging, presenting sev-
after injection principally because of hepatic clearance. Further eral advantages in terms of image quantification, secondary to the
124
studies are necessary to correctly determine the effective role of I half-life of 4.2 days which is closer to 8.02 days half-life of 131I
this radiopharmaceutical. than many other PET radiopharmaceuticals and whole-body PET
acquisition. 124I-MIBG PET/CT was evaluated in an animal model
to define the radiation dose estimation, as well as imaging tumors
4-18F-fluoro-3-iodobenzylguanidine prior to 131I-MIBG treatment of neuroblastoma. Lee et al.111 esti-
mated the human-equivalent internal radiation dose of 124I-MIBG
(18F-FIBG)
using PET/CT data in a murine xenograft model. They found that
18 124
F-fluorobenzylguanidine, an MIBG analog, was tested in preclinical I-MIBG PET is a useful tracer for pretherapy dosimetry, deliver-
studies.109 Localization in the heart and adrenals in vivo was demon- ing a significantly smaller radiation dose than 124I-NaI. However
124
strated, however, with significantly lower levels than observed with I-MIBG has not been systematically studied in human subjects.
MIBG. 4-18F-fluoro-3-iodobenzylguanidine (18F-FIBG) has shown 124
I-MIBG has been used for dosimetric purposes by Ott et al.112 in
similar uptake mechanism and tissue distribution pattern as MIBG in two NET patients (1 neuroblastoma, 1 pheochromocytoma) before
preclinical model with acceptable dosimetry for administration to receiving 131I-MIBG therapy. Two patients were injected with 22 and
patients.110 40 MBq of 124I-MIBG, respectively, and scanned at 24 and 48 hours

postinjection. The tomographic images produced were used to of two or three infusions, and three with a partial response (PR)
estimate the concentration of MlBG in normal and tumor tissue. after the first infusion and stable disease after the second. The main
This data permitted prediction of the radiation doses that would toxicity was myelosuppression, with 78% and 82% of patients
be achieved using therapeutic doses of 131I-MIBG. No other clinical requiring platelet transfusion support after the first and second
data has been reported. infusion. Several groups have evaluated this agent in combination
with other active agents for neuroblastoma. Mastrangelo et al.120
evaluated combination therapy with cisplatin and cyclophospha-
131
Radionuclide Therapy with I-MIBG mide with or without etoposide and vincristine in 16 patients with
relapsed or refractory neuroblastoma. The response rate with this
Radionuclide therapy with 131I-MIBG has been used for targeted combination therapy compares favorably with response rates of
radiotherapy since the mid-1980s. MIBG has a specific tissue <40% observed with 131I-MIBG monotherapy.
uptake and has prolonged intracellular retention compared with Gaze et al.121 evaluated 131I-MIBG together with the camptoth-
normal tissues. 131I-MIBG therapy remains controversial because ecin topotecan. Like cisplatin, topotecan is an active drug against
of a large variation in response rates in the published literature neuroblastoma with radiation sensitizing properties. This combi-
and the potential side effects. Response rates vary between 20% nation was well-tolerated and without unanticipated toxicities.
and 60% in newly diagnosed and relapsed or refractory patients. Response data were not provided from this pilot study. Hyperbaric
The application of 131I-MIBG therapy has been extensively reported oxygen has been used to enhance the radiation effect in children
in adults with pheochromocytoma and carcinoid tumors but in undergoing 131I-MIBG therapy. Voute et al.122 reported the cumula-
pediatric patients, it has been mainly used to treat neuroblastoma. tive probability of survival as 32% at 28 months for the group with
The most frequent application of 131I-MIBG in neuroblastoma is as hyperbaric oxygen and MIBG treatment.
single agent therapy in patients with metastatic neuroblastoma No further significant data have been reported to support this
who have failed to respond to conventional chemotherapy or have treatment method. 131I-MIBG in combination with myeloablative
recurrent relapsed disease after all other treatments have failed. regimens were investigated, demonstrating improved outcomes
Clinical trials conducted with high-dose 131I-MIBG used as for newly diagnosed patients with advanced neuroblastoma.
131
monotherapy or in combination with other agents for relapsed or I-MIBG has been added to myeloablative chemotherapy in com-
refractory high-risk neuroblastoma have demonstrated promising bination, or without radiotherapy. This is often supported by
response rates. Relatively few data describe the clearance of autologous bone marrow transplantation (ABMT) or peripheral
radiolabeled MIBG in children with neuroblastoma. In one study, stem cell infusion. Toxicity consisted mainly of expected myelo-
six children with neuroblastoma received 100 to 200 mCi of suppression and mucositis. The majority of patients had bone
131
I-MIBG and had urinary MIBG levels measured following the marrow recovery demonstrating the feasibility of incorporating
infusion.113 A median of 57% and 70% of the administered dose 131
I-MIBG into a myeloablative regimen.123 Several studies have
was excreted in the urine by 24 and 48 hours postinfusion, respec- incorporated this agent into the treatment of patients with newly
tively. Ehninger et al.114 confirmed that 70% of the administered diagnosed neuroblastoma, obtaining objective response rate in
dose is excreted in the urine by 48 hours postinfusion. The earliest 66% of the cases. Preoperative 131I-MIBG therapy in children with
studies of 131I-MIBG therapy for patients with neuroblastoma advanced or inoperable neuroblastoma has the objective of reduc-
focused mainly on the toxicity and feasibility of this approach. ing tumor volume, enabling better tumor resection.
Thrombocytopenia was the most prominent toxicity. De Kraker et al.124 treated 33 patients with untreated advanced
Three phase I dose escalation studies of 131I-MIBG monotherapy stage neuroblastoma. There was one complete response (CR), 18
in patients with neuroblastoma have been performed. In the first partial responses (PR), 11 had stable disease (SD), and 3 had pro-
study, 14 patients with relapsed or refractory neuroblastoma gressive disease (PD). After 131I-MIBG therapy and surgery, 12 of 33
received 131I-MIBG at doses escalating from 50 to 220 mCi115 with patients achieved a CR. Hoefnagel125 reported a higher objective
a minor response in 3 patients. Another phase I study in patients response (>70%) and less toxicity with this method compared with
with refractory stage III or IV neuroblastoma were performed by initial chemotherapy followed by 131I-MIBG therapy. Recent data
Ashford et al.,116 showing objective response rate in 33% of the has shown that combined 131I-MIBG and 90Y-DOTA-TOC can sig-
cases. In the third phase I study, 30 patients with relapsed or nificantly increase the delivered tumor dose over the dose of either
refractory neuroblastoma received 131I-MIBG at escalating doses agent alone.126 Low recurrent doses of 131I-MIBG have been evalu-
from 2.6 to 18.2 mCi/kg (90 to 819 mCi).117 Dose-limiting hemato- ated, limiting toxicity. Activities from 0.5 mCi (18.5MBq)/kg to a
logic toxicity was reached at 15 mCi/kg, at which level two of five maximum of 25 mCi (925 MBq) were administered every 4 to
assessable patients required bone marrow reinfusion. Responses 6 weeks and continued until efficacy was not seen, resulting in an
were seen in 37% of patients, with 1 complete response (CR), 10 excellent palliative effect.
partial response (PR), 3 mixed response, 10 stable disease, and 6 Dosimetry has been evaluated in therapeutic 131I-MIBG studies
progressive disease. The minimum dose of 131I-MIBG for 10 of the for several indications, such as to estimate tumor-specific radiation
11 responders was 12 mCi/kg. dose following 131I-MIBG therapy or to determine organ-specific
A phase II study performed in 164 patients treated with 131I-MIBG doses. Hematologic toxicity, most notably thrombocytopenia, has
at a dose of 18 mCi/kg showed overall response rate of 36% and been reported as the main toxicity in nearly all studies of 131I-MIBG
stable disease in 34% of the cases. A Dutch phase II study evaluated therapy. Primary hypothyroidism appears to develop in a signifi-
100 to 200 mCi of 131I-MIBG in 53 patients with relapsed or refrac- cant number of patients with neuroblastoma treated with 131I-MIBG
tory neuroblastoma118 showing an objective response rate of 56%, because of the uptake of free 131I by the thyroid gland. Second
including 7 complete responses. Only nine patients had progressive malignancies following 131I-MIBG therapy have been reported.
disease as their best response to therapy. Multiple treatments with
131
I-MIBG demonstrated that the majority of the clinical benefit with
131
I-MIBG therapy occurs after the first cycle of therapy, although
additional responses may be observed with subsequent cycles.
Patient Preparation Before
In this setting, Howard et al.119 determined the response rate MIBG Therapy
and hematologic toxicity of multiple infusions (two to four cycles) of
131
I-MIBG with activity of 3 to 19 mCi/kg per infusion in 28 patients. To avoid radioiodine uptake in the thyroid gland, high amounts of
Eleven patients (39%) had overall disease response to multiple ther- potassium iodide should be administered, starting 12 to 24 hours
apies, including eight patients with measurable responses to each before therapy and continuing for 2 to 4 weeks. Alternatively, or

in addition, perchlorate can be administered, starting 4 to 12 hours achieved in one patient and one withdrew. Phase II trials are
before 131I-MIBG administration, and continuing daily for 1 week. needed to establish the effective role of PRRT in patients with neu-
An increase of blood pressure after 131I-MIBG administration is not roblastoma.
as common as during treatment of pheochromocytomas or para-
gangliomas, nevertheless, antihypertensive medication should be
available, particularly α-blockers. Recommendations concerning Conclusion
the optimal therapeutic 131I-MIBG dosage differ widely; between
450 and 1850 MBq/kg (particularly if autologous stem-cell rescue NB, the most common solid extracranial malignancy in childhood,
is included in the therapeutic regimens) or standard activities of is a heterogeneous disease, consisting of neural crest-derived
7 GBq. Other institutions use 3.7 to 14.8 GBq/m2. tumors with remarkably different clinical behaviors ranging from
In case of existing bone marrow suppression or reduced renal spontaneous remission to rapid tumor progression. This clinical
function, a dose reduction should be considered. 131I-MIBG should diversity correlates with numerous clinical and biologic factors,
be infused over a period of at least 1 hour to avoid severe acute side including tumor stage, patient age, tumor histology, and genetic
effects of the 131I-MIBG itself, mainly blood pressure changes. Scin- abnormalities. However, the molecular basis underlying the vari-
tigraphy using the γ-energy of 131I is performed during subsequent ability in tumor growth, clinical behavior, and responsiveness
days for staging with high sensitivity, determination of 131I-MIBG- to therapy remains largely unknown. Thus, multidisciplinary
positive tumor sites, and dosimetry, if acquired quantitatively. approaches to diagnosis and therapy have been undertaken for all
Blood count controls are necessary during the first 6 weeks; patients to assess risk. Proper tumor staging is of fundamental

the time intervals dependent on the administered dose. Myelosup- importance for selection of optimal treatment. This includes bone
pression occurs within 2 to 4 weeks after therapy, the nadir is marrow aspirations and biopsies, CT, magnetic resonance imaging,
observed typically after 4 to 6 weeks. Rarer side effects are impair- radionuclide bone scan, and MIBG scintigraphy. Likewise, it is
ment of renal function and hypothyroidism, particularly in case of imperative to assess tumor response to therapy and detection of
insufficient thyroid blockade. Hepatic failure has to be considered recurrent disease to optimize treatment of residual disease and
also when higher doses are administered. improve patient survival. Nuclear medicine plays a pivotal role in
125
I-MIBG may be an even better treatment option for neuro- the management of children and adolescent with neuroblastoma,
blastomas with micrometastases or bone marrow infiltration and offering a wide spectrum of imaging modalities. The clinical role of
is being tested for the treatment of patients with expected survival iodine-labeled MIBG, tracing catecholamine metabolism, is well
of less than 15%. A recent study127 found that the overall treatment established for several decades. 123I-MIBG scan is the gold standard
response rate (46%) was high for all patients, older patient with for initial staging of neuroblastoma as well as for response evalua-
neuroblastoma had a significantly higher treatment response rate tion and during follow-up. PET/CT imaging with 18F-FDG is a useful
and exhibited a trend toward longer posttreatment overall sur- adjunct to conventional imaging in the initial staging and restaging
vival, indicating that 131I-MIBG might be an effective salvage agent of in selected patient with neuroblastoma. The current primary role
for neuroblastoma in this difficult to treat patient population. of 18FDG PET is the evaluation of known or suspected neuroblasto-
mas that do not demonstrate radioiodinated MIBG uptake, but the
published experience on neuroblastoma is limited. Other PET
Other Radionuclide Therapies radiotracers such as 18F-DOPA and 124I-MIBG are currently being
evaluated in these patients and show promising results. Further
in Neuroblastoma clinical trials are needed, however, to confirm the preliminary data.
Radiometabolic therapy with 131I-MIBG has proven to be effective
Various radiolabeled antibodies have been assessed for therapy. in advanced neuroblastoma. Despite a high variability in adminis-
These include the anti-GD2 antibody (131I-3F8) which shows excel- tered activities, therapeutic combinations, and outcome, several
lent targeting in neuroblastoma. In data from the Memorial Sloan studies have demonstrated that 131I-MIBG therapy is an effective and
Kettering128 using 131I-3F8, the overall survival at 18 months post- safe treatment modality. The combination of 131I-MIBG, high-dose
therapy was approximately 40%. The antibody localized in the chemotherapy, autologous hematopoietic stem cell transplantation
primary tumor and metastatic sites in lymph nodes, bone marrow, is a promising approach, associated with limited toxicity. Clinical
and bone in 42 patients. Severe side effects may be associated studies on potential improvement of the therapeutic effect of
with this therapy. Induction of HAMA response limits this therapy. 131
I-MIBG are under investigation. Further advances in understand-
Other antibodies (e.g., 131I-Ch14.18) are being assessed for radio- ing of the molecular biology of neuroblastoma, proper risk stratifica-
immunotherapy in neuroblastoma. Initial results are encouraging. tion and appropriate therapy based on risk assessment may improve
Severe myelosuppression frequently occurs and requires autologous the clinical outcome, in terms of event-free and tumor-free survival
bone marrow rescue or treatment with granulocyte macrophage which has not dramatically changed over the last years.
colony stimulating factor. The initial results have been sufficiently
promising that the addition of Ch14.18 antibody to standard ther-
apy is being tested in a prospective, randomized trial ANBL0032.
Benzylguanidine labeled with 211At, an α-particle emitter, has
Acknowledgments
also been proposed as a potential radiotherapeutic agent in neu- The authors would like to thank Dr. Massimino Maura, Dr. Podda
roblastoma.129 Meta-[211At]astatobenzylguanidine ([211At]MABG) is Marta (Department of Pediatrics, Fondazione IRCSS, Istituto Nazio-
an astatinated analog of MIBG has been tested in animal model, nale dei Tumori, Milan, Italy), and Professor Stefano Fanti (Nuclear
but no clinical applications has evolved. Medicine Department, Policlinico S. Orsola-Malpighi, Bologna, Italy)
NB expressing somatostatin receptors may be also targeted by for reviewing the manuscript and for their scientific contribution.
peptide receptor radionuclide therapy (PRRT). The radiopharma-
ceuticals most commonly used in PRRT are 90Y-DOTA-TOC and
177
Lu-DOTA0-Tyr3-Thre8-octreotide. In a phase I study, Menda References
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Chapter 24
Bone Tumors
Johannes Czernin • Ken Herrmann
Introduction it occurs at any age, its incidence peaks in the second and third
decades5 and ranges from 3.5 to 5.6 per year per million persons.6
This chapter discusses the role of radionuclide imaging and ther- The incidence of chondrosarcomas is around 3/106 people.
apy in the management of primary and metastatic bone tumors. They are most frequently located in the femur, pelvis, and humerus.
We are reviewing the epidemiology of primary and metastatic Eighty-five percent arise as primary lesions whereas the remain-
bone disease, its classification, and staging definitions. We then ing 15% develop in initially benign lesions such as enchondromas
address the role of radionuclide imaging in initial and subsequent or osteochondromas (secondary chondrosarcomas). They are
treatment strategy considerations. Throughout the chapter we will characterized by production of cartilaginous matrix.
emphasize the sometimes unique and at other times complimen- The incidence of Ewing sarcoma family of tumors (ESFTs) has
tary role of radionuclide approaches as an important component remained unchanged for 30 years at approximately 2/1,000,000
of the management of patients with primary or metastatic bone per year.8 It peaks at 9 to 10/1,000,000 in patients 10 to 19 years
cancer and are providing guidelines for the appropriate use and of age and occurs nine times more frequently in Caucasians than
applications of diagnostic radionuclide approaches for the assess- in African Americans.9 The most frequent primary sites are the
ment of bone diseases. We also present overviews of imaging pro- lower extremity (41%), pelvis (26%), chest wall (16%), and upper
tocols whereby we follow the guidelines of the Society of Nuclear extremity (9%). Extraosseous Ewing sarcoma occurs most fre-
Medicine and Molecular Imaging (whenever available). Finally, we quently in the trunk (32%), extremity (26%), head and neck (18%),
will discuss radionuclide-based treatment approaches for malig- and retroperitoneum (16%).10
nant bone diseases.
The chapter will first focus on primary bone tumors by high- Diagnosis of Primary Malignant Bone Tumors
lighting the three major types—osteosarcoma, chondrosarcoma,
and Ewing sarcoma. The role of imaging in multiple myeloma will Workup for the diagnosis of primary bone tumors is prompted by
be discussed separately. In the subsequent sections we will review symptoms such as painful swelling, limited limb motion, or bone
the role of radionuclide imaging in metastatic prostate, breast, fracture.11 However, patients may also present following trauma
and lung cancer in the context of other available diagnostic imag- which may obscure the diagnosis. A plain film x-ray is performed
ing approaches. The ability of hybrid imaging technologies to first that can frequently provide the diagnosis.12,13 Suspicious
achieve improved diagnostic accuracy will be emphasized. When x-ray findings lead invariably to a biopsy, frequently after an MRI
appropriate we will discuss the potential role of emerging PET
imaging probes for assessing bone malignancies. Finally, we are
reviewing the availability and effectiveness of radionuclide-based Tab l e 2 4 . 1
therapeutic approaches for malignant bone diseases.
World Health Organization Classification of
Malignant Bone Tumors
Primary Bone Tumors
Bone-forming tumors Conventional central osteosarcoma (OS)
Classification and Epidemiology Telangiectatic OS
Intraossesous well-differentiated OS
Primary malignant bone tumors occur at an incidence of about Round cell OS
8/106 persons and account for less than 0.5% of all cancers. They Parosteal (juxtacortical) OS
have been classified by the World Health Organization (WHO) Periosteal OS
based on histology and differentiation (Table 24.1).1 A total of High-grade surface OS
2,890 new cases of primary bone cancers (excluding myeloma) Cartilage-forming tumors Chondrosarcoma (CS)
were predicted in the United States and 1,410 patients were Periosteal CS
expected to die from primary bone cancer in 2012.2 Approximately Mesenchymal CS
55% of primary bone malignancies occur in males. Osteosarcomas, Dedifferentiated CS
chondrosarcomas, and Ewing sarcomas account for approximately Clear cell CS
35%, 30%, and 16% of primary bone malignancies, respectively.3,4 Malignant CS
Osteosarcoma and Ewing sarcoma occur mainly in children and Neuroectodermal origin Ewing sarcoma family of tumors
young adults whereas chondrosarcoma has a predilection for older
Marrow tumors Malignant lymphoma
patients.
Myeloma
Osteosarcoma arises most frequently from the metaphyses of
long bones, in particular the distal femur, proximal tibia, and Vascular tumors Angiosarcoma
proximal humerus5 and its incidence ranges from 3.5 to 5.6 per Malignant hemangiopericytoma
year per million persons.6 At 2.4%, osteosarcoma ranks eighth Other connective-tissue tumors Fibrosarcoma
among childhood cancers following leukemia (30%), brain and Malignant fibrous histiocytoma
other nervous system cancers (22.3%), neuroblastoma (7.3%), Liposarcoma
Wilms tumor (5.6%), non-Hodgkin lymphoma (4.5%), rhabdomyo- Malignant mesenchymoma
sarcoma (3.1%), and retinoblastoma (2.8%).6 Approximately 400 Leiomyosarcoma
individuals younger than 20 years are diagnosed with osteosar- Undifferentiated sarcoma
coma annually in the United States.7
Adapted with permission from Schajowicz F, Sissons H, Sobin L. The World Health Organization’s
Extraosseous osteosarcoma is a malignant mesenchymal neo- histologic classification of bone tumors. A commentary on the second edition. Cancer. 1995;
plasm without direct attachment to the skeletal system. Although 75:1208–1214.
340

Chapter 24 Bone Tumors 341
scan is performed. Biopsy usually provides the definitive diagnosis Tab l e 2 4 . 2

and identifies the histologic subtype.
Osteosarcomas must, by definition, produce osteoid.14 The American Joint Committee on Cancer (Ajcc) Staging
osteosarcoma subtypes are depicted in Table 24.1.1 The most System for Osteosarcoma
prevalent variant, conventional central osteosarcoma, features
areas of necrosis, atypical mitoses, and contains malignant oste- Stage Tumor Lymph Node Metastases Grade
oid. The other osteosarcoma subtypes are much less common,
each occurring at a frequency of less than 5%. IA T1 N0 M0 G1 or G2
Chondrosarcomas are characterized by the production of car- IB T2 N0 M0 G1 or G2
tilage tissue (Table 24.1). IIA T1 N0 M0 G3 or G4
Ewing sarcomas and Askin tumors (primitive neuroectodermal IIB T2 N0 M0 G3 or G4
tumors [PNETs] of the chest wall) belong to the group of PNETs. All III T3 N0 M0 Any G
are derived from the same bone marrow–derived mesenchymal IVA Any T N0 M1a Any G
stem cell.15 They belong to the group of “small, round, blue-cell” IVB Any T N1 Any M Any G
tumors.16 IVB Any T Any N M1b Any G
Tx, primary tumor cannot be assessed; T0, no evidence of primary tumor; T1, tumor 8 cm or
Prognosis of Primary Bone Tumors less in greatest dimension; T2, tumor >8 cm in greatest dimension; T3, discontinuous tumors

in the primary bone; Nx, regional lymph nodes not assessed; N0, no regional lymph node
The prognosis of osteosarcomas is determined by histologic metastases; N1, regional lymph node metastasis; Mx, distant metastasis cannot be assessed;
response to chemotherapy17 and is better in patients in whom clean M0, no distant metastasis; M1, distant metastasis; M1a, lung; M1b, other distant sites; Gx,
grade cannot be assessed; G1, well differentiated (low grade); G2, moderately differentiated (low
surgical margins are achieved.18 The 5-year survival rates range grade); G3, poorly differentiated (high grade); G4, undifferentiated (high grade).
from 60% to 70% but an average of only 10% to 30% for patients From Edge S, Byrd D, Compton C, et al. American Joint Committee on Cancer (AJCC) Cancer
with metastatic disease at the time of diagnosis. Patient age is Staging Handbook, 7th ed. New York, Heidelberg, London: Springer; 2010:333–344.
inversely correlated with higher survival6 rates in patients younger
than 30 years of age.19 Fifty percent of osteosarcomas in patients (maximal diameter >8 cm) have a poorer outcome than those with
older than 60 years are associated with pre-existing Paget disease. smaller tumors.41 Patients with primary tumors of the distal extrem-
The prognosis of such patients is significantly worse than that of ities have the best prognosis followed by those with proximal
patients with primary osteosarcoma.20 However, these data were extremity and pelvic primaries38,40,42,43 whereas tumors of the
not confirmed in more recent studies.21,22 sacrum carry the worst prognosis.44 Other prognostic parameters
In adolescents and young adults with osteosarcoma, age 18 to include age and gender, histopathologic treatment response,45 and
30 years is associated with a statistically significant poorer out- pretreatment serum Lactate dehydrogenase (LDH) levels.42 As
come because of an increased rate of relapse. This worse outcome expected, presence of metastatic disease at the time of diagnosis
is not explained by tumor location, histologic response, or meta- carries a poor prognosis.46
static disease at presentation.23 Other prognostic factors include
radiologic evidence of lung, bone, or distant metastases.
Staging of Primary Bone Malignancies
Metastases are found in approximately 20% of patients at diag-
nosis, with 85% to 90% presenting in the lungs. The second most In general all primary bone tumors are staged using the AJCC
common site of metastasis is a single additional or multiple TNM system4 (Table 24.2); however, tumor grade is also included
bones.24 The syndrome of multifocal osteosarcoma refers to a pre- in the staging system. T1, T2, and T3 denote tumors that are
sentation with multiple foci of osteosarcoma without a clear pri- <8 cm, >8 cm, or discontinuous, respectively, in the primarily
mary tumor, often with symmetrical metaphyseal involvement. affected bone. M1a signifies lung metastases whereas M1b indi-
These tumors carry an extremely poor prognosis.25 cates other distant disease sites. However, in osteosarcoma an
Chondrosarcomas are relatively indolent. In a series of 201 older staging system is frequently still used. This system, proposed
patients, survival was 92% and 84% at 5 and 10 years, respectively. by Enneking in 198047 classifies low-grade bone tumors as stage
Outcome was associated with histologic grade.26 Overall 5-year I, high-grade tumors as stage II, and metastatic tumors as stage
survival was better than 75% in a study of more than 200 patients III. T1 denotes intracompartmental tumors whereas extracom-
whereby patients with low-grade tumors had a significantly better partmental tumors are classified as T2.
outcome than those with high-grade disease.27 Survival of patients The original AJCC staging system48 included presence or absence
with high-grade variants ranges from 40% to 70%.28,29 However, of lymph node involvement and added grade 3 (poorly differenti-
dedifferentiated cancers carry 5-year survival rates of only 20%.30 ated) and grade 4 (undifferentiated) to further subclassify tumor
In another report outcome was only associated with tumor prolif- differentiation.
erative activity.31 Pelvic location of the primary tumor denotes a
less favorable prognosis. Local recurrence increases the risk for Management of Patients with Primary
distant metastasis and is associated with poor survival.28,32
In the ESFTs, the 5-year survival of localized disease is cur-
Bone Tumors
rently around 70% but it is lower for patients aged 15 to 19 than Complete tumor resection in conjunction with systemic combina-
for those younger than 15 years of age (76% versus 49%, respec- tion chemotherapy (with doxorubicin, ifosfamide, cisplatin, or
tively).33 The prognosis of early stage Ewing sarcoma patients high-dose methotrexate) is the first-line treatment of osteosar-
depends on tumor location whereby pelvic location denotes a less coma. Surgery alone results in 5-year survival rates of only 15% to
favorable outcome.34 Twenty-six percent to 28% of the patients 20%. In early randomized trials the addition of adjuvant chemo-
present with metastatic disease. Their 5-year survival is only therapy more than doubled49 or tripled 2-year disease-free sur-
around 40%.8,35–37 Among these, patients with lung involvement vival rates.50 With the addition of adjuvant chemotherapy 5-year
have better survival rates than those with bone metastases.38 survival now averages 61%.51 The role of neoadjuvant therapy is
Patient characteristics and outcomes differ among patients with not well established but tumor response to preoperative chemo-
extraosseous and those with skeletal Ewing sarcoma. The latter therapy appears to be an independent prognosticator.43 Nonresect-
have a slightly better prognosis and are likely older, female, non- able patients appear to benefit from radiation treatment.52
white, and more frequently have pelvic primary sites.39 Older age is Patients with chondrosarcoma have a relatively favorable prog-
a marker of poor prognosis.40 Moreover, patients with large tumors nosis.26 They are treated with surgery because these tumors are

chemotherapy and radiation therapy resistant which is explained

by their relatively low proliferative activity and poor vascularity.53
Wide en-bloc excision is necessary in intermediate- and high-grade
lesions whereas low-grade lesions are treated with curettage.54
Radiation treatment may be effective in treating positive resection
margins. Axial tumor sites (pelvis and spine) are difficult to treat
surgically and thus, these disease sites are associated with a less
favorable outcome.
Surgery is the treatment of choice in patients with Ewing sarcoma A B
with local disease whereas primary radiation therapy is most fre-
quently used in those with unresectable, nonmetastatic disease. Sys-
temic chemotherapy with or without radiation treatment and surgery
is used in patients with primary and metastatic disease. Chemother-
apy usually includes vincristine, doxorubicin, ifosfamide, and etopo-
side and is usually given for 6 to 12 months. In patients younger than
30 years of age who underwent surgery or radiation treatment for
local disease control the addition of ifosfamide and etoposide to a
standard combination chemotherapy regimen improved 5-year sur-
vival to 69 ± 3 months.40 Chemotherapy is the treatment modality of
choice in patients with metastatic disease; however, 5-year event-free
survival only ranges from 20% to 30%.46,55
Traditionally, the treatment of extraosseous Ewing sarcoma
has not included anthracyclines, a standard component of the
treatment for primary Ewing sarcoma of bone. A recent study sug-
gests, however, that a modified protocol including anthracyclines
significantly improved 5-year survival from 59% to 83%. The out-
come of patients with extraosseous Ewing sarcoma thus appears D
to be comparable to those with primary Ewing of the bone.56
Role of Imaging in Initial Treatment

Strategy Assessments of Primary C
Bone Tumors Figure 24.1. A 7-year-old patient with right forearm pain after injury. Radiograph revealed an
osteolytic lesion with cortical breakage in the distal radius (A). The lesion was hypervascular on
A plain film x-ray, prompted by patient symptoms can frequently dynamic flow phase (upper row, B) and showed increased blood pool activity (lower row, B).
provide the diagnosis.12,13 The initial assessment of tumor site and Whole-body bone scan confirmed a solitary lesion in the distal right radius (C). MRI showed an
aggressive enhancing tumor (gadolinium) on T1-weighted image (D). There was disruption of
tumor extent is used to define the best initial approach for local the anterior cortex of the radius with extension into the flexor compartment of the forearm.
control, that is, surgery versus radiation. Radiographic patterns of CT-guided biopsy confirmed the lesion as osteosarcoma. (Reprinted with permission from Wang
osteoblastic, osteolytic (occurring in <10% of all cases), and mixed K, Allen L, Fung E, et al. Bone scintigraphy in common tumors with osteolytic components.
tumors (the most prevalent radiographic finding) have no prognos- Clin Nucl Med. 2005;30:655–671.)
tic significance.13 As another limitation, plain film radiographs pro-
vide no insights into the whole-body distribution of the disease.
In general, initial staging should include bone scintigraphy, chest plain film x-rays of the primary tumor.59 Advanced imaging meth-
x-rays, and chest CT if abnormalities are noted on plain films.57 ods are applied to determine the extent of tumors, possible
18
F-FDG PET and MRI are increasingly used for staging because involvement of adjacent bones, joints and muscles, vascular struc-
local as well as distant sites of disease involvement can be charac- tures, and nerves. Figures 24.1–24.3 depict patients with osteo-
terized better. For instance, local disease may involve intra- and sarcoma, chondrosarcoma, and Ewing sarcoma, respectively,
extramedullary structures. The extent of intramedullary involve- imaged with plain film x-rays, conventional bone scans, and MRI.
ment including skip metastases determines the extent of surgery. Local staging is frequently considered to be best accomplished
Involvement of extramedullary structures such as joints determines by MRI using T1-weighted sequences (Fig. 24.4).58 In an early
the feasibility of limb-saving surgery.58 Presence of distant disease study of 56 patients with primary bone sarcomas (predominantly
involvement might alter the chemotherapeutic strategy. It should be osteosarcomas), MRI predicted bone disease extent with a signifi-
noted that MRI is limited in its ability to detect lung involvement. cantly higher accuracy than CT or bone scintigraphy. Moreover,
MRI was as accurate as CT in determining cortical bone and joint
involvement and was more accurate in determining muscle
Guidelines involvement.60 However, a subsequent larger multicenter trial in
The Children’s Oncology Group (COG) Bone Tumor Committee has 367 patients did not confirm these findings and reported a near
provided guidelines that specifically address imaging modalities at equal accuracy of both modalities.61
presentation prior to local control, at baseline after local control, Nevertheless, it could be argued that MRI should be the local
surveillance on and post chemotherapy.36 They were established staging modality of choice especially in the pediatric population to
by an expert panel consisting of pediatric oncologists, biologists, avoid the radiation exposure associated with CT. Advantages of CT
surgeons, radiologists, and radiation oncologists and apply to chil- imaging include the rapid image acquisition, more accurate
dren, adolescents, and young adults. They include recommenda- assessment of lung involvement, and the identification of subtle
tions for anatomical and functional imaging and can reasonably cortical lesions and new bone formation.62
be also applied to older adults. Assessment of metastatic disease is also necessary at initial
Imaging examinations at baseline are identical for osteosar- presentation because 20% of patients with osteosarcoma and 25%
coma, chondrosarcoma, and Ewing sarcoma and first rely on of those with Ewing sarcoma present with metastases to lungs or

Figure 24.2. Chondrosarcoma: A 65-year-

old female presented with painful left thigh
swelling. Radiograph showed an expansile,
lobulated osteolytic lesion with endosteal scal-
loping and spiculated periosteal reaction in the
proximal femur (arrow, A). Irregular matrix cal-
cification (arrowheads) was present. Bone
scan revealed a solitary lesion with increased
activity at its periphery compared to the center
(B). The pathologic diagnosis was chondro-
sarcoma. (Reproduced with permission from
Wang K, Allen L, Fung E, et al. Bone scintigra-
phy in common tumors with osteolytic compo- A B
nents. Clin Nucl Med. 2005;30:655–671.)
A B C
Figure 24.3. A 10-year-old boy presented with right forearm pain. Radiograph showed a permeative osteolytic lesion in the distal right ulna, with a spiculated
and onion skin type of periosteal reaction (A). Bone scan revealed intense tracer accumulation at the corresponding site and also showed a pulmonary metastasis
by demonstrating tracer accumulation in the right lung (arrows, B) which correlated to a lung mass on chest radiograph (not shown). Sagittal T1-weighted MRI
showed the hypointense tumor mass (C). Biopsy of the forearm lesion showed Ewing sarcoma. (Reprinted with permission from Wang K, Allen L, Fung E, et al. Bone
scintigraphy in common tumors with osteolytic components. Clin Nucl Med. 2005;30:655–671.)

A B C
Figure 24.4. A 13-year-old boy with distal femoral osteosarcoma. A: Lateral radiograph showing typical features of osteoblastic osteosarcoma. The relationship
of intraosseous tumor to the growth plate cannot be determined. The proximal tumor margin is not included on the radiograph. B: 99mTc-MDP bone scan indicates
that tumor extends to the level of the growth plate. C: Sagittal T1-weighted spin echo MR image clearly demonstrates that tumor stops at least 1 cm short of the
physis, permitting joint-sparing surgery. The proximal tumor margin is not included on the image. (Reprinted with permission from Saifuddin A. The accuracy of
imaging in the local staging of appendicular osteosarcoma. Skeletal Radiol. 2002;31:191–201.)
bones. Metastases are rare in the initial presentation of chondro- become an important component of the standard of care for osteo-
sarcoma. Noncontrast-enhanced CT is recommended for lung sarcoma staging. The considerable adoption of 18F-FDG PET/CT is,
evaluations63; however, the limitations of CT in differentiating at least in part, based on promising data from a prospective trial in
benign from malignant lung lesions are well established.64,65 Thus, 46 pediatric patients, 11 of which had osteosarcoma. In these
biopsies are frequently needed for verification of the CT findings. patients bone metastases were equally well detected with 18F-FDG
MRI is ill-suited for lung assessments. PET and conventional imaging including bone scans. Although lung
Bone imaging using 99mTc-labeled diphosphonates is recom- metastases were significantly better detected with CT than PET the
mended for the initial evaluation of primary bone tumors. Small emergence of PET/CT renders this an insignificant advantage.64
studies have suggested that 99mTc-MDP scans are more sensitive 18
F-FDG PET/CT has also been used to predict progression-free
than 18F-FDG for bone metastases in osteosarcoma but not in and overall survival in osteosarcoma patients.71,72 High baseline
Ewing sarcoma.64,66 However, this was not confirmed in a recent SUV was associated with poor outcomes.
study in patients with bone and soft tissue sarcomas67 in which 18F- Skeletal scintigraphy is of limited value in chondrosarcoma. In
FDG PET/CT and 99mTc-MDP performed equally well in Ewing and a retrospective analysis of 188 patients planar bone imaging failed
osteosarcoma. to add meaningful information to that obtained by MRI of the pri-
18
F-FDG PET imaging can play a significant role in characteriz- mary site.73 In fact, many additional sites of increased tracer activ-
ing lung lesions64 and its use prior to local control, although not ity were explained by degenerative joint disease, Paget disease,
required, is recommended.68 Moreover, with the emergence of PET/ and in one case a previously undiagnosed melanoma metastasis.
CT imaging anatomical and functional information about primary Thus, areas of focally increased uptake might result in a number
tumors and distant metastases can now be obtained in a single of “false-positive” results.
session.69 Patients with Ewing sarcoma need to undergo bone marrow
The pooled accuracy of 18F-FDG PET for diagnosing and stag- biopsies to rule out bone marrow involvement.11 The literature
ing of bone sarcomas is around 90%.70 Moreover, 18F-FDG not does not provide sufficient information about the utility of 18F-FDG
99m
Tc-MDP tumor-to-background ratios provided valuable prog- PET/(CT) for staging of chondrosarcoma.
nostic information in patients with osteosarcoma.71 Because the diagnosis of bone cancer is made by biopsy the
In contrast to the recent guidelines proposed by the COG,36 the major role of imaging in developing the initial treatment strategy is
guidelines of the European Society for Medical Oncology do not the appropriate staging of the disease. A recent meta-analysis
include 18F-FDG PET or PET/CT.14 This is inconsistent with the examined the accuracy of 18F-FDG PET/(CT) for staging (and restag-
practice of many institutions where 18F-FDG PET/CT imaging has ing) of Ewing sarcoma.74 Based on a priori established quality criteria

five studies that included a total of 279 patients were included. the end of cytotoxic treatment. In a mixed population of patients
Pooled sensitivity and specificity were 96% and 92%, respectively. with Ewing sarcoma and osteosarcoma decreases in tumor SUV by
Although 18F-FDG PET/(CT) was in general more accurate than ≥60% predicted histopathologic response to neoadjuvant chemo-
other imaging modalities, small lung metastases, as expected, therapy with a good accuracy (Fig. 24.5).75 Similar findings were
tended to be better detected with chest CT. reported recently by others.76–78
18
F-FDG PET was especially helpful in detecting bone metasta- However, the degree of changes in SUV that predicts histopath-
ses as confirmed in a prospective comparative trial of 18F-FDG and ologic response might differ between Ewing sarcoma and Osteo-
planar 99mTc-diphosphonate imaging.66 However, none of the major sarcoma.79 In fact, Ewing sarcoma responded to treatment with
professional organizations currently endorses the routine use of larger reductions in metabolic tumor volume (MTV) than osteosar-
18
F-FDG PET/(CT) for initial treatment strategy assessments in coma. A 50% reduction in MTV was associated with histopatho-
Ewing sarcoma. logic response in osteosarcoma but not in Ewing sarcoma for which
Subsequent treatment strategy assessments for primary bone a 90% decrease in MTV was required.79 Thus, different 18F-FDG
malignancies include restaging and monitoring of therapeutic PET response criteria might apply to these two types of primary
interventions. Restaging or posttreatment surveillance includes AP bone tumors.
and lateral x-rays of the primary site and the chest at 3-month In another study, 18F-FDG PET and MRI were performed prior
intervals for the first 2 years, then in 6-month intervals for 5 to 10 to and after completion of neoadjuvant chemotherapy (Fig. 24.6).80
years and subsequently at 6- to 12-month intervals.57 Chest CTs Reductions in tumor 18F-FDG uptake and absolute SUVmax at the
should be performed if plain film x-rays identify abnormalities end of treatment discriminated best among responders and nonre-

and an abdominal MRI should be done if further interventions are sponders in osteosarcoma. MRI parameters including tumor vol-
contemplated. Bone scanning is optional and 18F-FDG PET/(CT) or ume changes, contrast enhancement, and changes in soft tissue
MRI can be considered.57 component did not significantly discriminate responders from non-
The recommendations for treatment response assessments responders. 18F-FDG PET was superior to MRI parameters for
include plain films of the primary tumor, chest CT, bone scans, and response predictions in osteosarcoma but not in Ewing sarcoma
optional 18F-FDG PET/(CT).36 Contrast-enhanced MRI should be patients in whom both PET and MRI failed to provide reliable
considered if further interventions are contemplated. Plain films response assessments.
and CT should be done after 10 cycles of chemotherapy (approxi- Another study reported that a posttreatment tumor SUV of
mately half way through chemotherapy). <2.5 was associated with improved progression-free survival.81
Whole-body bone (unless negative at baseline) and 18F-FDG Taken together these 18F-FDG PET/CT data raise more questions
PET/(CT) scans (unless negative on baseline scan) are suggested at than providing answers. First, all but one study were retrospective.
Baseline Early follow-up Late follow-up

SUV 12.2 3.8 2
Size 22.1 23.1 21.8
Figure 24.5. FDG PET/CT at baseline, early follow-up,

and late follow-up—after completion of neoadjuvant
treatment in two patients with osteosarcoma. A histo-
pathologic responder (top) and a nonresponder (bottom)
are shown. Note the significant decrease in tumor 18F-
FDG uptake in the responder whereas uptake increased
in the nonresponder. (Reprinted with permission from Baseline Early follow-up Late follow-up
Benz M, Czernin J, Tap W, et al. FDG PET/CT imaging
predicts histopathologic treatment responses after neo- SUV 5.3 5.5 7
adjuvant therapy in adult primary bone sarcomas.
Sarcoma. 2010;2010:1–7.) Size 7.1 7.5 8.2

Figure 24.6. A 15-year-old girl with osteosarcoma of

the left femur visualized by MRI prior to neoadjuvant treat-
ment (top row): (left column, unenhanced T1-weighted;
second column, T2-weighted; third column, contrast-
enhanced fat-saturated T1-weighted) as well as FDG PET
(right column). After neoadjuvant chemotherapy (bot-
tom row), local MRI shows a stable tumor size (volume
reduction 9%) and unchanged soft tissue component; pat-
terns of T2 signal and contrast enhancement remained
similar to baseline. FDG PET reveals a partial response
with a reduction of 77%. Histopathologic evaluation
confirmed good response to neoadjuvant chemotherapy.
(Reprinted with permission from Denecke T, Hundsdörfer
P, Misch D, et al. Assessment of histologic response of
paediatric bone sarcomas using FDG PET in comparison
to morphological volume measurement and standardized
MRI parameters. Eur J Nuc Med Mol Imaging. 2010;37:
1842–1853.)
Second, the proportion of patients with Ewing sarcoma versus Osteo- bone destruction. As a consequence of bone marrow infiltration
sarcoma varied. Third, no prospective trials have attempted to apply and bone destruction patients develop anemia, thrombocytopenia,
a response threshold as suggested by PERCIST82 or EORTC.83 Finally, and leucopenia and are prone to infections. Bone pain and frac-
end of treatment evaluations of patients undergoing neoadjuvant tures occur as do hypercalcemia and renal insufficiency. Mono
therapy have a limited impact on patient management. Although clonal gammopathy (most frequently IgG or IgA) measurable in
no further PET-based management changes can be implemented serum or urine, fractures, and pain together with the typical lytic
at the end of neoadjuvant treatment PET responses may allow pre- lesion lead to the diagnosis.
dictions about the effectiveness of postsurgical chemotherapy.
Therefore, prospective studies in larger patient populations are
required to determine whether early monitoring of neoadjuvant
Staging of Multiple Myeloma
therapy, after one or two cycles (when changes in therapeutic Staging of multiple myeloma traditionally has followed the Durie–
approaches are still possible) might provide sufficiently accurate Salmon system.84 This classification considers serum hemoglobin
histopathologic response predictions to base management deci- and calcium levels, bone x-ray findings, and other parameters
sions on 18F-FDG PET/(CT). (Table 24.3). A recently revised system, the Durie–Salmon PLUS
In summary, radionuclide imaging approaches play an impor- staging system takes into account the number of bone lesions
tant role in the management of patients with primary bone tumors. identified with PET or MRI imaging. In addition, serum creatinine
18
F-FDG PET/CT is emerging as an important tool for staging and levels are included.85 Thus, the important role of 18F-FDG PET
restaging as well as for therapy response assessments in these imaging for refining prognostication is now acknowledged.
patients. Although its role is not yet firmly defined in guidelines An international staging system that considers serum albumin
provided by various professional organizations, it is anticipated and β2-microglobulin has been introduced more recently and pro-
that its use will significantly increase over the next few years. vides important prognostic information (Table 24.4).86 Although
mean survival for stage I disease is around 5 years, it averages only
2.5 years for patients with stage III disease.
Multiple Myeloma
In the United States, more than 21,000 new cases of myeloma will
Management of Multiple Myeloma
occur and more than 12,000 patients are expected to die from this Although overall survival durations have improved over the last
cancer in 2012.2 It is a disease of the elderly population with the decade multiple myeloma remains essentially noncurable.87 Treat-
highest incidence among patients older than 75 years of age. Bone ment with a variety of chemotherapeutic agents (vincristine, doxo-
pain associated with fractures is the most common symptom at rubicin, dexamethasone) has been used for many years; other
presentation. therapeutic approaches include ifosfamide or cyclophosphamide
Multiple myeloma is a clonal B-cell disease that initially arises combined with etoposide and epirubicin, or dexamethasone alone.
from the bone marrow but later results in predominantly lytic More recent strategies include bortezomib (a proteasome inhibitor)

Ta bl e 2 4 . 3
Durie–Salmon Staging System of Myeloma
Hb Serum Ca IgG IgA Urine M-protein

(g/dL) (mg/dL) X-ray (g/dL) (g/dL) (g/24 h)
Stage I >10 <12 Normal/solitary <5 <3 <4

Stage IIa — — — — — —
Stage III <8.5 >12 Advanced lytic >7 >5 >12
a
Stage II is neither stage I nor stage III.
From Durie B, Salmon S. A clinical staging system for multiple myeloma correlation of measured myeloma cell mass with presenting clinical
features, response to treatment, and survival. Cancer. 1975;36:842–854.
combined with cyclophosphamide or adriamycin and dexametha- high sensitivity for small osteolytic lesions, good specificity, and
sone. Thalidomide and lenalidomide have also been combined with fast whole-body assessments of soft tissues and bones.94 One the-

dexamethasone.88 Novel treatment approaches include targeted oretical disadvantage of CT is the involvement of ionizing radia-
small molecule inhibitors and others.88 Significant survival benefits tion. However, there are no data to support the notion that even
have been reported with autologous stem cell transplant but cure very frequent CT scans increase the risk for a secondary cancer in
has not been achieved. this population of mostly elderly patients with an underlying dis-
ease that carries a poor prognosis and is treated aggressively.
MRI is frequently used and recommended to assess myeloma
Role of Imaging in Multiple Myeloma patients. Its advantages include a high sensitivity for bone lesions
in the axial skeleton, its ability to distinguish between bone mar-
Conventional bone scanning does not play a role in initial or sub- row and bone and to determine nerve involvement. An additional
sequent treatment strategy assessments in multiple myeloma. In a advantage is its capability to distinguish among monoclonal gam-
comparison with plain film x-rays bone scintigraphy missed or mopathy of unknown significance (MGUS), asymptomatic myeloma,
underestimated disease in 27% of known disease sites among 51 and solitary plasmocytoma.94
patients with known myeloma. Moreover, scintigraphic findings The diagnostic performance of 18F-FDG PET/(CT) was system-
were not predictive of hematologic parameters of myeloma activity.89 atically compared to that of plain film x-ray surveys in a recent
Thirty-six percent of the positive scintigraphic findings were asso- analysis.96 This revealed superior diagnostic performance of PET
ciated with fractures whereas the remaining 64% of abnormal for all body regions except for the skull. As expected, 18F-FDG
findings were associated with bone destruction without fracture PET/CT was superior for treatment response assessments. Inte-
evidence. False-negative results are most likely explained by the grated PET/CT using 18F-FDG detects myeloma lesions with a high
relatively minimal or even absent osteoblastic response to bone accuracy.97 In a study of 66 patients who underwent 98 PET/CT
destruction in myeloma.90,91 The lytic nature of bone lesions also studies disease presence, remission, relapse, and activity were
explains why some myeloma lesions appear as “cold spots” on assessed with a high accuracy. MGUS was accurately distinguished
bone scintigraphy.92 However, skeletal scintigraphy might perform from active disease.98 In patients with suspected solitary plasmo-
better than plain film x-rays in some locations such as the lumbar cytoma, 18F-FDG PET detected additional disease involvement in
spine and ribs.93 8/23 patients.99
A recent consensus recommendation for the diagnostic workup In another study, PET-CT was superior to planar radiographs
of multiple myeloma includes standard serum and urine tests as in 46% of the patients including 19% with negative whole-body
well as imaging studies.94 Radiologic skeletal bone surveys (plain x-rays. However, MRI revealed an abnormal pattern of bone mar-
film radiographs) including spine, pelvis, skull, humerus, and row involvement in the spine in 30% of the patients in whom 18F-
femurs are mandatory. Disadvantages of plain film x-rays include FDG PET-CT was negative. When the information from MRI of the
a limited sensitivity and specificity, observer dependence, and spine and pelvis was combined with that from 18F-FDG PET-CT an
their inability to reliably assess therapeutic responses.94 As an accuracy of 92% for bone lesion detection was achieved.100
advantage, plain film x-rays are inexpensive. Taken together, these data suggest that the emergent hybrid
CT imaging detects more lesions and determines more accu- PET/MRI technology might become an important tool in the man-
rately fracture risk than plain film x-rays.95 Advantages include agement of myeloma patients.
The prognostic implications of 18F-FDG PET-CT and MRI in
Ta bl e 2 4.4 patients with newly diagnosed myeloma were determined in a recent
large prospective trial that included 239 patients by Bartel et al.101
International Staging System for Multiple Myeloma (Fig. 24.7). By multivariate analysis, the number of focal 18F-FDG
PET-CT lesions was correlated with gene expression profiles, focal
Stage Criteria Median Survival (months) lesions on MRI, and osteolytic tumor burden on plain films. Predic-
tors of event-free and overall survival (by multivariate analysis)
I Serum β2-microglobulin <3.5 mg/L 62 included >3 focal lesions on 18F-FDG PET, serum LDH levels >190 U/L,
Serum albumin ≥3.5 g/dL serum albumin <3.5 g/dL, and gene expression profiling. Moreover,
absence of 18F-FDG uptake prior to transplantation in initially posi-
II Not Stage I or III 44
tive lesions was associated with significantly longer survival both in
III Serum β2-microglobulin ≥5.5 mg/L 29 low- and high-risk groups as defined by serum and biopsy markers.
Among all imaging tests 18F-FDG PET was most highly correlated
There are two categories for stage II: Serum β2-microglobulin <3.5 mg/L but serum albumin
with patient prognosis. In fact, it identified 30% of patients who
<3.5 g/dL; or serum β2-microglobulin 3.5 to <5.5 mg/L irrespective of the serum albumin level.
From Greipp P, Miguel J, Durie B, et al. International Staging System for Multiple Myeloma. were at high risk that were otherwise classified as low risk by gene
J Clin Oncol. 2005;23:3412–3420. profiling.

Figure 24.7. Baseline imaging studies (top

row) showed no osteolysis on plain film x-rays
(top left), several foci on STIR-weighted MRI
images with the largest in the left ischium
(top middle), and 2 foci on FDG PET/CT imag-
ing (top right) with the largest again in the left
ischium with a maximum SUV of 4.1. The patient
was in near-complete remission 168 days
later, with a significant decrease in focal activity
in the left ischial lesion on PET (bottom right ).
(Reprinted with permission from Bartel T,
Haessler J, Brown T, et al. F18-fluorodeoxyglu-
cose positron emission tomography in the con-
text of other imaging techniques and prognostic
factors in multiple myeloma. Blood. 2009;114:
2068–2076.)
The National Oncology PET Registry (NOPR) group reported between invading tumor cells and osteoblast activity resulting in
that 18F-FDG PET/(CT) affected the management in more than sclerotic lesions (signifying abnormal bone formation) and osteo-
40% of 1,784 myeloma patients at initial staging102 or restag- clast activity that leads to osteolytic lesions.110 Osteolytic and
ing.103,104 Such comprehensive data are not available for any other osteoblastic activities frequently coexist resulting in mixed lesions.
imaging modality. Bone metastases from breast,111 lung, thyroid, and renal cell car-
Guidelines: Despite these promising data, 18F-FDG PET/CT is cinoma are predominantly osteolytic whereas those from prostate
mentioned but not recommended in the working group guide- cancer are predominantly osteoblastic.112 The accurate assess-
lines.94 It is listed as “optional” in the National Comprehensive ment of skeletal involvement in cancer is important because its
Cancer Network (NCCN) guidelines.105 It should be mentioned, treatment reduces the number of skeletal events113 as discussed
however, that the study by Bartel et al.101 had not yet been included later.
in the development of these guidelines.
In summary, although not yet firmly established in the diagnos-
tic guidelines it is anticipated that 18F-FDG PET/CT will emerge as
Prognosis of Metastatic Bone Disease
a critically important tool for optimizing initial and subsequent Prostate and breast cancer patients with bone metastases can
treatment strategies in myeloma patients.106 A specific role for achieve multi-year survival. Nevertheless, presence of bone metas-
PET/MRI imaging will have to be established by comparative tases signifies adverse long-term outcome when compared to
prospective studies. patients without metastases. Moreover, bone only disease carries
a better prognosis than visceral metastases with or without bone
involvement in breast cancer patients.107,114
Metastatic Bone Disease In metastatic lung cancer overall survival is measured in
months and bone involvement has little prognostic impact.
Epidemiology and Classification
Metastatic bone disease is a highly relevant health care problem.
The postmortem incidence of bone metastasis ranges from 20–25% Tab l e 2 4 . 5
for renal cell carcinoma to 65% to 75% for breast and prostate
cancer (Table 24.5).107 Complications of bone metastasis include Postmortem Incidence of Bone Metastases (%)
severe bone pain and spinal cord compression that can occur in
more than 5% of prostate cancer patients and less frequently in Cancer Postmortem incidence (%)
breast cancer and myeloma. Pathologic fractures occur in up to
40% of breast cancer patients. Palliative or preventative radiation Myeloma 70–95
is required in 20% to 30% of patients with breast and prostate Renal cell cancer 20–25
cancer.108 Bone metastatic involvement is a major health problem Melanoma 14–45
as it is associated with severe patient suffering and enormous Bladder 40
health care expenditures that amounted to $12.7 billion in 2007.109 Thyroid 60
Lung 30–40
Breast 65–75
Phenotypes of Bone Metastases Prostate 65–75
Bone metastases arise most frequently in the axial skeleton. Bone From Coleman R. Metastatic bone disease: Clinical features, pathophysiology and treatment
metastases and their phenotypes are driven by an interplay strategies. Cancer Treat Rev. 2001;27:165–176.

1.0
1.0
1.0
SUV >6.10 BSI >1.27 SUV >6.10 and
SUV ≤6.10 BSI <1.27 BSI >1.27
0.8
0.8
0.8
SUV ≤6.10 or
Surviving fraction
Surviving fraction
Surviving fraction
BSI <1.27
0.6
0.6
0.6
0.4
0.4
0.4
0.2
0.2
0.2
0.0
0.0
0.0
0 20 40 60 0 20 40 60 0 20 40 60
A Months B Months C Months
Figure 24.8. Kaplan–Meier survival curves: (A) FDG PET SUV—survival curves for 22 patients with low (≤6.1) and 21 patients with high (>6.1) SUVmax, p = 0.002.
B: Bone scan index (BSI)—survival curves for 22 patients with low (≤1.27) and 21 patients with high (>1.27) BSI, p = 0.004. C: Joint analysis of SUVmax and

BSI showing two patient groups with distinct prognosis. In the low SUV and low BSI group, median survival is 32.6 months; in the “high” SUV and BSI group, survival
was 14.4 months and there is a distinct difference between the curves ( p = 0.001). (Reprinted with permission from Meirelles G, Schöder H, Ravizzini G,
et al. Prognostic value of baseline [18f ] fluorodeoxyglucose positron emission tomography and 99mtc-MDP bone scan in progressing metastatic prostate cancer.
Clin Cancer Res. 2010;16:6093–6099.)
In prostate cancer, presence and extent of metastatic bone dis- SPECT imaging using 99mTc-diphosphonates can improve the
ease as detected by bone scintigraphy predict long-term sur- characterization of bone lesions as malignant or benign. In a
vival.115,116 However, in one report only lesion 18F-FDG SUV but study of more than 100 patients with a variety of primary cancers,
not extent of disease was an independent survival predictor by sensitivity, specificity, and accuracy of SPECT were 90.5%, 92.8%,
multivariate analysis117 (Fig. 24.8) suggesting that more aggres- and 92.4%, respectively. The accuracy for detecting spinal involve-
sive therapeutic interventions might be warranted in patients with ment in the subgroup of patients with breast cancer was 95.7%.119
high glycolytic activity of prostate cancer metastases. In another study of 174 patients, SPECT had a sensitivity of 87%,
a specificity of 91%, and an accuracy of 90% whereas planar
Diagnosis and Detection of Bone Metastases imaging had a lower sensitivity (74%), specificity (81%), and accu-
racy (79%) in diagnosing vertebral metastasis.120 Overall, SPECT
A variety of imaging methods can be used to detect bone metasta- appears to be more accurate than planar imaging for the assess-
ses the choice of which depends among others on test accuracy, ment of spinal involvement because disease localized to the facet
cost, and radiation considerations. These include radionuclide joints (most frequently benign) can be differentiated from involve-
imaging techniques, including planar whole-body and SPECT imag- ment of the pedicles (most frequently malignant).
ing, SPECT/CT, PET/CT, plain film x-rays, CT, and MRI. The utilization However, the accuracy of planar and SPECT imaging for detect-
of conventional bone imaging using 99mTc-diphosphonates intro- ing osteolytic bone lesions is limited. This is because osteoblastic
duced by Subramanian et al.118 in 1972 has decreased in recent responses to such lesions can be minimal. 18F-FDG PET therefore
years. This is in part explained by modifications of management plays an increasing role in the staging of lung and breast cancer
guidelines from various professional organizations but is also that most frequently exhibit osteolytic or mixed bone lesions.
caused by increased utilization of 18FDG PET/CT and MRI for bone In a retrospective comparative study of 257 patients with lung
metastasis detection. cancer, the accuracy of planar scintigraphy and 18F-FDG PET121
99m
Tc-labeled diphosphonates accumulate in regions of was 85% and 94% ( p < 0.05), respectively. The sensitivity of PET
increased osteoblastic activity such as for instance in regions of was also higher (91% versus 75%) whereas the specificity was
bone growth, trauma, and in response to benign neoplastic, near identical (95% and 96%), respectively. Thus, in lung cancer
inflammatory, infectious, or malignant processes. Thus, radionu- patients who undergo staging with 18F-FDG PET/(CT) the addition
clides targeting osteoblastic activity provide nonspecific informa- of bone scans appears to be redundant.
tion (Table 24.6). More specific information can be obtained by Similarly, 18F-FDG PET detects bone involvement in breast can-
using a variety of PET tracers targeting various phenotypes of cer patients with a high accuracy during staging,122–124 restag-
bone metastases as discussed later (Table 24.7). ing,125–127 and in inflammatory breast cancer.128
In general, the accuracy of 18F-FDG PET for detecting bone
Tab le 24. 6 involvement appears to be superior to that of conventional imaging.
The predominant phenotype of bone metastases affects their
Selected Reasons for False-Negative and detectability with radionuclide methods. In general, osteoblastic
False-Positive Bone Scan Findings lesions are well detected with planar or SPECT bone scintigraphy
and 18F-sodium fluoride (18F-NaF) PET/(CT) whereas osteolytic
False Positive False Negative lesions are well delineated with 18F-FDG PET/(CT). This is because
conventional bone scans probe osteoblastic activity whereas 18F-
Degenerative disease Osteolytic lesions FDG PET identifies viable tumor cells.
Trauma Small lesions Thyroid and renal cell cancer patients also develop predomi-
Benign bone tumors Renal failure nantly osteolytic metastases. In these malignancies planar imag-
Inflammation/infection Attenuation artifacts from metallic objects ing and SPECT have a limited sensitivity for detecting bone
Paget disease Instrumentation artifact involvement and 18F-FDG PET might play an important role for
Osteopoikilosis —
initial and subsequent management decisions.
Fibrous dysplasia —
A study in 23 patients with RCC revealed that 18F-FDG PET cor-
Hyperemia —
rectly identified 7/7 documented bone metastases.129 In another

Ta bl e 2 4 . 7
Pet Probes for Imaging Bone Metastases
Physical
Probe half-life (min) Target Process
18
F-FDG 110 Glut1,3; hexokinase Glycolytic activity Most cancers
11
C-choline 20 Choline kinase Phospholipid synthesis Prostate Cancer
18
F-choline 110 Choline kinase Phospholipid synthesis Prostate cancer
11
C-acetate 20 Fatty acid synthase Fatty acid synthesis Prostate cancer
11
C methionine 20 L-Amino acid Transport Amino acid metabolism Multiple myeloma
18
F-DOPA 110 L-Amino acid Transport Amino acid metabolism Neuoroendocrine tumors
18
F-fluorotyrosine 110 L-Amino acid Transport Amino acid metabolism ?
18
F-NaF 110 Hydroxyapatite Osteoblastic activity Osteoblastic
68
Ga-SSR ligands 68 SSR 2, 5 SSR expression Neuroendcorine tumors
18
F-estradiol 110 Estrogen receptor Receptor expression Breast cancer
18
F-FDHT 110 Androgen receptor Receptor expression Prostate cancer
124
I 4.2 d Sodium iodide symporter Iodine uptake Thyroid cancer
retrospective study of 66 patients who underwent 90 PET scans findings suggest that both metabolic and anatomic changes can
26/33 bone metastases were detected with 18F-FDG PET.130 In one provide important insights into treatment responses of bone
prospective study 18F-FDG PET was superior to CT imaging for metastases. The well-known flair phenomenon is also consistent
detecting distant metastases.131 with conversion of lytic into blastic lesions signifying healing of
The performance of 99mTc-diphosphonate imaging was com- osteolytic lesions.140,141
pared to 18F-FDG PET in 19 patients with 40 bone metastases. As Various tumor response criterion have been proposed for
expected (because of the lytic nature of bone metastases from renal instance in breast cancer patients but neither of those developed
cancer) 18F-FDG PET detected all 40 metastatic lesions whereas by the International Union against cancer (UICC)142 or Response
99
Tc-diphosphonate imaging identified only 31/40 lesions.132 Criteria in solid Tumors (RECIST) meet the clinical needs for
In thyroid cancer, 18F-FDG PET has also been used for detect- assessing therapeutic responses of bone metastases.111 However,
ing bone metastases. In one study of 19 patients with differenti- the revised, RECIST 1.1, now consider osteolytic or mixed (those
ated thyroid cancer 18F-FDG PET detected 5/6 documented bone with a soft tissue component), but not osteoblastic, sclerotic bone
metastases after TSH stimulation.133 This is in agreement with metastases as measurable disease.143,144 A measurable bone lesion
other studies that showed increased uptake in metastatic lesions is defined as one that can be accurately measured in at least one
after TSH stimulation.134,135 dimension and has a diameter of at least 10 mm by CT. Bone
131
I is sensitive for detecting well-differentiated thyroid cancer scans or plain film x-rays are not considered adequate to measure
metastases and lesion location is greatly improved by performing disease. Following treatment complete response (CR) and partial
SPECT/CT scans.136 However, especially in patients with negative response (PR) are defined as a complete disappearance and at
whole-body 131I scans 18F-FDG detects bone metastases with a high least 30% reduction in the sum of diameters of target lesions,
accuracy.137 The degree and number of 18F-FDG-avid bone meta- respectively. Progressive disease (PD) denotes an at least 20%
static lesions from thyroid cancer have prognostic implications as
demonstrated in a retrospective analysis of 400 patients. Age, ini-
tial stage, histology, serum thyroglobulin levels, radioiodine uptake,
and PET findings correlated with survival by univariate analysis 20 Osteolytic lesions
whereas only age and PET results predicted outcome by multi- Osteoblastic lesions (P1 = .20)
variate analysis.138 Mixed-pattern lessions (P2 = .013)
(P2 = .0007)
These findings in renal cell and thyroid cancer are important 15
CT-negative lesions (P1 = .003)
because such baseline information is a prerequisite for monitor- (P2 = .0002)
ing therapeutic interventions in patients with 18F-FDG-positive
SUVmax
bone metastases. 10
Monitoring Therapeutic Interventions

5
in Patients with Bone Metastases
Osteolytic bone metastases usually exhibit a high glycolytic activ-
ity and hence are intensely 18F-FDG avid. In contrast, osteoblastic,
sclerotic bone lesions show lower or no 18F-FDG uptake. In fact, in 0 10 20 30 40 50 60
a study of 25 patients with breast cancer only 60% of osteoblastic Lesion size (mm)
but 94% of osteolytic and more than 80% of mixed lesions showed
Figure 24.9. 18F-FDG uptake intensity of bone metastases. The FDG-avid lesions are grouped
increased 18F-FDG uptake.139 The degree of lesion uptake was size by radiographic appearances on computed tomography (CT).The FDG uptake intensity (maxi-
dependent (Fig. 24.9). mum standardized uptake value [SUVmax] on positron-emission tomography) and the size (the
Following treatment 80% of the 18F-FDG-positive osteolytic maximum long axis on CT) of 123 FDG-avid bone lesions are presented. p values indicate the
lesions converted into sclerotic, 18F-FDG-negative metastases. On SUVmax statistical differences between different groups of lesions. (Reprinted with permission
from Du Y, Cullum I, Illidge T, et al. Fusion of metabolic function and morphology: Sequential
the other hand, only around 50% of the 18F-FDG-positive sclerotic [18F]fluorodeoxyglucose positron-emission tomography/computed tomography studies yield
and the mixed lytic/sclerotic lesions converted into 18F-FDG- new insights into the natural history of bone metastases in breast cancer. J Clin Oncol. 2007;
negative sclerotic lesions following treatment (Fig. 24.10).139 These 25:3440–3447.)

A A

B B
C C
D D
Figure 24.10. Left, osteolytic bone metastases responding to hormonal therapy: (A) Baseline 18F-FDG PET/CT study shows two FDG-avid osteolytic metastatic
lesions in the third lumbar vertebra (arrows); (B) 3-month, (C) 7-month, and (D) 24-month follow-up studies show the gradual and long-lasting osteoblastic change.
Apart from multiple FDG-negative osteoblastic lesions, this patient is clinically well at 26-month follow-up. Right, progressive osteoblastic bone metastasis:
(A) Baseline 18F-FDG PET/CT study shows an FDG-avid osteoblastic lesion in the fifth lumbar vertebra (arrows) (B) 4-month, (C) 9-month, and (D) 18-month
follow-up studies show the CT radiographic and FDG metabolic changes of this progressive lesion. Iliac crest biopsy after the 18-month FDG PET/CT study confirmed
bone marrow metastasis. (Reprinted with permission from Du Y, Cullum I, Illidge T, et al. Fusion of metabolic function and morphology: Sequential [18F]fluorode-
oxyglucose positron-emission tomography/computed tomography studies yield new insights into the natural history of bone metastases in breast cancer. J Clin
Oncol. 2007;25:3440–3447.)
increase in the sum of diameters of all lesions or new lesions. lesion 18F-FDG uptake) were predictive of survival by univariate
Stable disease (SD) is characterized by neither sufficient shrinkage analysis. By multivariate analysis only the number of circulating
to qualify for PR or by insufficient increase to be classified as PD. tumor cells (< versus > than 5 cells/7.5 mL of blood) remained
The role of 18F-FDG PET is also addressed in the revised RECIST predictive. However, in a subset of patients the information derived
1.1 guidelines143,144 as follows: 18F-FDG-negative bone lesions that from PET and that from circulating tumor cells was discordant. In
convert to positive lesions after treatment are consistent with PD. PET nonresponders who had less than five circulating tumor cells
18
A positive posttreatment PET scan in patients without a baseline F-FDG PET provided important treatment response information.145
scan is consistent with PD if this lesion corresponds to a new lesion In another retrospective study of 102 patients with breast
on CT. If the lesion pre-existed on CT then this is consistent with cancer146 reductions in lesion 18F-FDG uptake by ≥8.5% predicted
stable disease. a favorable response with a good accuracy.
PET response criteria in solid tumors (PERCIST)82 does not spe- Thus, a variety of imaging modalities as well as imaging probes
cifically address bone metastatic responses to therapy. However, it (as discussed later) are available for the assessment of bone metas-
appears to be reasonable to apply PERCIST also to these lesions. A tases. However, current guidelines do not yet include advanced
complete metabolic response would be defined as a complete reso- imaging approaches.
lution of 18F-FDG uptake within a measurable lesion whereas a
partial metabolic response would require a ≥30% reduction in
lesion 18F-FDG uptake. Increases of lesion 18F-FDG uptake by more
Guidelines for Imaging
than 30% would be consistent with progressive metabolic disease The American College of Radiology has recently published their
whereas stable metabolic disease would be defined as absence of recommendations for the appropriate use of imaging of bone
complete or partial metabolic response or progression of disease.82 metastasis.147 In breast cancer, bone imaging with any modality is
Monitoring the effects of therapy on bone metastases can be unnecessary for stage I disease. In contrast, 99mTc-diphosphonate
accomplished with 18F-FDG PET/CT. In a retrospective study of 115 imaging is considered highly appropriate in patients with ≥stage II
patients with metastatic breast cancer the number of circulating disease who report hip and/or back pain. An equally strong recom-
tumor cells and the 18F-FDG PET response (>25% reduction in mendation was made for plain film x-rays of the spine and hips.

18
F-FDG PET imaging was considered to be of intermediate 24 hours. Binding to hydroxyapatite is reversible.154,155 The low
appropriateness. first-pass extraction fraction together with the slow renal clear-
In patients who are followed up (subsequent treatment strat- ance results in a low bone-to-background activity ratio at early
egy) a solitary “hot spot” in the spine should prompt an MRI if plain time points. Thus, imaging has to be performed 2 to 5 hours after
film x-rays are negative. In patients with three hot spots but no tracer injection when the target to background ratio is high.
back pain, x-rays, and if negative, MRI of the spine would be sug-
gested whereas 18F-FDG PET is of intermediate appropriateness.
An additional SPECT study of the spine could be added. Again, in
Dosimetry
this setting 18F-FDG PET was considered to be of intermediate The usual administered activity for adult patients is 740 to 1,110
appropriateness.147 MBq (20 to 30 mCi) injected intravenously. For markedly obese adult
Solitary rib lesions on bone scans are highly unlikely to represent patients, the administered activity may be increased to 11 to 13
metastases and should be further evaluated with plain film x-rays.148 MBq/kg (300 to 350 μCi/kg). For pediatric patients, the administered
Single hot spots in the sternum on follow-up should be further eval- activity is 9 to 11 MBq/kg (250 to 300 μCi/kg), with a minimum of
uated with a noncontrast CT or MRI. Based on a large retrospective 20 to 40 MBq (0.5 to 1 mCi). The maximum administered activity for
study such lesions are much more likely benign and represent pediatric patients should not exceed the administered activity for an
metastases in less than 10% of cases.149 Plain film x-rays, 18F-FDG adult.152
PET, and SPECT imaging are again of intermediate appropriateness.
When breast cancer patients present with a pathologic fracture
on plain film x-rays, whole-body bone scans should be done first
Guidelines
and, if results are negative, this might be followed by a whole- Procedure guidelines for 99mTc-diphosphonate planar, SPECT, and
body 18F-FDG PET scan. SPECT/CT bone imaging were provided by the Society of Nuclear
Initial imaging assessments of the skeleton are straightforward Medicine.156,157 Patient preparation includes hydration between
in patients with prostate cancer.147 Revised guidelines suggest injection and the time of image acquisition. Frequent urination
that imaging including bone scans is not necessary unless PSA is (before and after imaging) as well as continued fluid intake for at
≥20 ng/mL or the tumor is poorly differentiated. This is based in least 24 hours after injection is recommended to reduce radiation
part on an analysis of 23 studies that reported that metastases were doses to the urinary bladder.
detected in only around 2% and 5% of patients with serum PSA For tumor studies, delayed images are usually acquired from 2
levels of less than 10 and 10.1 to 19.9 ng/mL, respectively.150 Fur- to 5 hours after injection. Spot images or whole-body images may
thermore regular imaging follow-up is not recommended unless be acquired in anterior and posterior views using high-resolution
symptoms suggest bone involvement or serum PSA rises rapidly.151 collimators until 500,000 to 1 million counts are obtained. When
The recommendations by the National Comprehensive Cancer whole-body scanning is used >1.5 million counts are desirable.
Network are slightly different and suggest bone scans for patients SPECT imaging is helpful to better characterize the presence,
with a PSA level >10 ng/mL, a Gleason score ≥8, presence of symp- location, and extent of disease, especially when spinal involvement
toms consistent with bony metastases, or any clinical T3 or T4 is of concern. Additional views may be added as clinically indicated.
prostate cancer.151 Repeat imaging after voiding may be helpful to improve visualiza-
18
F-FDG PET/(CT) imaging is firmly entrenched in the initial tion of pelvic bones that can be obscured by bladder activity.
staging and bone evaluation of patients with non–small cell lung The Society of Nuclear Medicine SPECT/CT guidelines do not
cancer.147 A bone scan is not needed if a whole-body 18F-FDG PET/ provide specific indications for the use of SPECT/CT in skeletal
CT is done. evaluations.157 However, various considerations address the use of
In summary, conventional bone imaging using 99mTc-diphos- the CT component. Usually, SPECT/CT is performed when planar
phonates is firmly entrenched in the assessment of bone metasta- and SPECT imaging does not provide clear answers to the perti-
ses in prostate cancer. In lung cancer and breast cancer, because nent clinical questions.
of their predominantly osteolytic or mixed osteolytic/osteoblastic Patient preparation and precautions are identical for planar,
phenotypes, 18F-FDG PET(CT) is emerging as an important assess- SPECT, and SPECT/CT imaging. However, the addition of CT
ment tool. However, professional organizations have not yet fully increases the radiation dose to patients, and thus, the as low as
recognized its relevance and importance. Novel and previously reasonably achievable (ALARA) principle applies. Most frequently,
established PET probes that can provide important information on specific sections of the body are imaged. The CT can be done for
bone involvement in cancer will be discussed later. attenuation correction or lesion localization only. For these studies
a low-dose CT is sufficient. For a diagnostic CT scan, standard CT
settings are recommended.
Kinetics, Dosimetry, and Protocols
for Radionuclide Bone Imaging Image Interpretation
99m Abnormally increased tracer uptake can be focal or diffuse and
Tc-Labeled Diphosphonates denotes increased osteoblastic activity and/or increased blood flow.
The four radiopharmaceuticals that have been used for bone Focally reduced tracer might be explained by osteolytic lesions,
imaging are 99mTc-MDP (methylene disphosphonate), 99mTc-HMDP prior surgical interventions resulting in absent bone, and artifacts.
(hydroxyethylidene diphosphonate), 99mTc-HEDP (hydroxyethyli- The pattern of a superscan is characterized by poor or lack of visu-
dene diphosphonate), and 99mTc-PP (pyrophosphate).152 99mTc-MDP alization of the kidneys and intense uptake throughout the axial
is most frequently used in the United States. All are prepared by skeleton. This denotes widespread bone metastatic disease.
adding 99mTc-pertechnetate to stannous ions and either a diphos-
phonate or a pyrophosphate ligand.
After intravenous injection the tracer equilibrates with the PET Imaging Probes for the Assessment
extravascular fluid compartment in about 2 hours153 and 99mTc- of Bone Metastases
MDP is cleared to bone and excreted through the kidneys. Reten- 18
tion in bone tissue depends on osteoblastic activity, blood flow, and
F-FDG
renal function.154 Twenty-five percent of 99mTc-MDP binds initially 18
F-FDG is a probe of tumor glucose metabolism that is a major
to plasma protein, a fraction that increases to about 70% after source of energy for rapidly growing tissue.158 Glucose metabolism

also provides the carbon backbone for DNA and RNA syntheses.159 Bone SPECT is used with increasing frequency. A comparison
The targets of 18F-FDG are Glut1 and Glut3 as well as hexoki- between 18F-NaF PET, planar, and SPECT imaging was therefore
nase, all of which are upregulated to various degrees in cancer performed in 44 patients with high-risk prostate cancer.173 The
(Table 24.7). As discussed above, 18F-FDG PET/CT imaging accu- addition of SPECT to planar imaging resulted in a specificity of
rately detects osteolytic bone metastases whereas osteoblastic around 65% which was similar to that achieved with PET. How-
lesions might exhibit low or no FDG uptake. It is thus not surpris- ever, PET/CT imaging provided a sensitivity and specificity of 100%
ing that 18F-FDG PET/CT has frequently replaced conventional on a patient-based analysis.
bone scans for staging or restaging of cancers that most frequently
generate osteolytic or mixed lesions including (among others) lung Dosimetry
cancer and breast cancer.160 The dosimetry of 18F-NaF is favorable when compared with that
18
F-FDG PET and PET/CT imaging protocols as well as its of 99mTc-MDP. Its effective dose is 0.024 mSv/MBq in adults and
dosimetry are described elsewhere in this book. 0.086 mSv/MBq in children, or approximately 1/10th of the effec-
tive dose of 99mTc-MDP. The critical organ is the urinary bladder for
18 18
F-NaF and bone surfaces for 99mTc-MDP.174
F-NaF
18
F-NaF is delivered to bone via blood flow (the rate-limiting
step).161,162 Single pass extraction of 18F-NaF approaches 100%.163 Guidelines
Its first pass extraction by bone is higher than that of 99mTc-MDP. Guidelines for 18F-NaF PET/CT imaging were provided by the Soci-

Around one-third of the injected 18F-NaF is present in red ety of Nuclear Medicine.175 Tracer administration should be
blood cells. Because 18F-NaF is freely diffusible across mem- avoided in pregnancy “unless the potential benefits outweigh the
branes, this does not interfere with tracer delivery.164 radiation risk to the mother and fetus.” Hydration (two or more
The initial 18F-NaF distribution represents blood flow that varies 8-oz glasses of water within 1 hour before and after 18F injection)
among different bones.165 Because of rapid renal clearance only 10% is advised to reduce radiation to the urinary bladder. The urinary
of 18F-NaF remains in plasma 1 hour after injection. Before being bladder should be emptied immediately before imaging. Neither
deposited in bone 18F-ions “need to pass from plasma through the fasting nor discontinuation of any medication is required.
18
extracellular fluid space into the shell of bound water surrounding each F-NaF is injected intravenously at a dose of 185 to 370 MBq
crystal, onto the crystal surface and in the interior of the crystal.”161 18F (5 to 10 mCi) in adults. Pediatric activity should be weight-based
binds to hydroxyapatite by chemisorption and subsequently (2.22 MBq/kg [0.06 mCi/kg]), with a range of 18.5 to 185 MBq (0.5 to
exchanges rapidly for OH on the surface of the hydroxyapatite 5 mCi).
matrix (Ca10(PO4)6OH2) to slowly form fluoroapatite (Ca10(PO4)6F2).161,166 Patients may be imaged in the “arms-up” (to avoid CT beam
The area of the “exposed” bone surface is larger in various benign hardening artifacts) or “arms-down” position.
or malignant bone disorders resulting in abnormal uptake patterns. Noncontrast-enhanced CT is sufficient for evaluation of the skel-
The interplay between osteoblastic and osteoclastic activities deter- eton. CT data are used for attenuation correction but can also pro-
mines the incorporation of 18F-NaF into the bone matrix.167 Rapid vide critically important information for lesion detection and
blood and renal clearance168 as well as high bone uptake result in characterization. ALARA should be applied. The Society of Nuclear
high target-to-background ratios which enables whole-body imag- Medicine guidelines suggest that high-quality images can be
ing as early as 30 minutes after tracer injection. obtained with or without attenuation correction. However, the addi-
18
F-NaF imaging, largely abandoned in the 1970s when 99mTc- tion of CT improves the specificity for lesion characterization.169,176
labeled compounds became available,118 has gained renewed No specific guidelines for CT protocols were provided.175
interest. This is because of the availability of PET/CT, electronic PET image acquisition starts as early as 30 to 45 minutes after
generator networks, and the shortage of 99mTc generators. Few tracer administration. The Society of Nuclear Medicine suggests a
studies have systematically evaluated its performance for detect- longer tracer uptake (90 to 120 minutes) time to obtain high-quality
ing bone metastases. However, the superior spatial resolution and images of the extremities. Recent generation PET/CT systems only
the tomographic capabilities of PET should result in an exquisitely permit acquisition in the 3D mode, which in turn allows for short
high sensitivity of this approach. This advantage comes at the image acquisition times which range from 3 to 5 minutes per bed
potential cost of a reduced specificity. With the advent of hybrid position. The same iterative reconstruction protocols as used for
18
PET/CT imaging, however, the specificity can be significantly F-FDG PET imaging may be used for 18F-NaF.175
improved as shown in a study that compared 18F-NaF PET to
18
F-NaF PET/CT.169 In a population of 44 patients with a variety of Image Interpretation
18
malignancies the specificity of PET/CT was significantly higher F-NaF is faintly visible in the kidneys, ureters, and visible in the
than that of PET (97% versus 72%, p < 0.001). Advantages were urinary bladder (Fig. 24.11). Soft tissue activity reflects the amount
most pronounced for the thoracic cage and the spine. The overall of circulating 18F in the blood pool at the time of imaging. It may
sensitivity also significantly improved by PET/CT (85% versus be increased in patients with renal insufficiency resulting in
72%; p < 0.001). higher background activity. Hyperemia results in locally increased
The high sensitivity of the PET approach is also underscored tracer uptake. Skeletal tracer uptake is high and relatively uni-
by a study that compared planar bone scans to 18F-NaF PET in form. Increased uptake is seen in children and adolescents in the
patients with breast cancer.170 Despite the high prevalence of lytic growth plates (Fig. 24.12).
lesions in these patients the sensitivity and specificity of 18F-NaF Osteoblastic activity in new or reactive bone formation causes
PET by ROC analysis was high with an area under the curve of 1 increased uptake of 18F-NaF. This occurs in benign tumors, inflam-
for PET versus 0.82 for the planar bone scans (p < 0.05). A high matory, degenerative, traumatic, or infectious diseases as well as
detection rate of osteolytic lesions was also reported in another in malignant lesions. Focally increased tracer activity is therefore
study of breast cancer patients.171 not specific for malignancy (Table 24.6).
In a study of more than 120 patients with lung cancer 18F-FDG To avoid false-positive image interpretation for cancer, correla-
PET/CT and 18F-NaF PET detected bone metastases with a com- tions with plain film, CT or MRI frequently need to be performed.
parable accuracy and both PET approaches were superior to pla- However, the addition of CT in PET/CT frequently obviates the
nar bone scans.172 These results reflect our clinical experience and need for such further correlations. The number of false-positive
might explain the increasing number of 18F-FDG scans performed finding can likely be reduced by careful inspection of the CT
at the expense of bone scans in lung cancer patients.121 images (Fig. 24.13).

Figure 24.12. Maximum intensity projection

(MIP) 18F-NaF PET image of a 4-year-old boy being
evaluated for injuries as a result of trauma shows
Figure 24.11. Normal biodistribution of 18F-NaF; note the absence of bladder activity; kidneys typical body distribution of tracer with prominent
and ureters are faintly visualized. (Reprinted with permission from Drubach L, Connolly S, Palmer growth plate activity. Focally increased uptake in
E. Skeletal scintigraphy with 18F-NaF PET for the evaluation of bone pain in children. AJR Am thoracic spine (arrow) indicates compression frac-
J Roentgenol. 2011;197:713–719.) ture. (Reprinted with permission from Drubach L,
Connolly S, Palmer E. Skeletal scintigraphy with
18F-NaF PET for the evaluation of bone pain
in children. AJR Am J Roentgenol. 2011;197:
713–719.)
B C
D E
Figure 24.13. Maximum intensity projec-

tion PET image (A) and selected axial PET/CT
(B, D, F, H) and CT (C, E, G, I) images of 18F-
NaF PET/CT scan of a 63-year-old man with
prostate cancer. Increased 18F-NaF uptake can
be seen in benign changes of right cervical
F G facet joint (green arrow in A, B, and C), heal-
ing rib fracture ( yellow arrow in A, D, and E),
benign lumbar vertebral bone cyst (blue arrow
in A, F, and G), and osteoblastic metastasis in
sacrum (red arrow in A, H, and I). Additional
value of CT to characterize focally increased
tracer uptake is evident. (Reprinted with per-
mission from Czernin J, Satyamurthy N, Schi-
epers C. Molecular mechanisms of bone
A 18F-NaF deposition. J Nucl Med. 2010;51:
H I 1826–1829.)


Figure 24.14. Iodine-positive metastasis of the cervical spine. Identification is not possible Figure 24.15. Maximum intensity projection 18F-choline PET image shows uptake in the
with CT only (top), and identification but not localization is possible with PET only (center). prostate (arrowhead ), a right pelvic lymph node (curved arrow ), and two bone metastases
Combined PET/CT allows both detection and localization (bottom). (Reprinted with permission (straight arrows). (Reprinted with permission from Beheshti M, Imamovic L, Broinger G, et al.
from Freudenberg L, Jentzen W, Stahl A, et al. Clinical applications of 124I PET/CT in patients 18F choline PET/CT in the preoperative staging of prostate cancer in patients with intermediate
with differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2011;38:48–56.) or high risk of extracapsular disease: a prospective study of 130 patients. Radiology. 2010;
254:925–933.)
Emerging PET Probes for Imaging probes such as 11C- or 18F-choline (Fig. 24.15),187 11C-acetate, trac-
ers of amino acid transport and metabolism, probes of hormone
Bone Metastases
receptor expression and others (Table 24.7).18F-choline, 11C-choline,
124
I has a physical half-life of 4.2 days and decays by electron and 11C-acetate are metabolic imaging probes that provide insights
capture (74.4%) and positron emission (25.6%). 124I PET/CT into choline kinase and fatty acid synthase activity, respectively.
detected tumor lesions with a higher sensitivity than CT alone or Probe retention most likely reflects incorporation of the probes
131
I scintigraphy in 12 patients will well-differentiated thyroid car- into membrane lipid pools and the increased cell membrane turn-
cinoma (Fig. 24.14).177,178 124I was superior for detecting advanced over in cancer.188
thyroid cancer prior to treatment when compared to 131I179 and Recent studies provided preliminary information about the
detected 50% more lesions than 131I in a study of 25 patients with accuracy of 18F-choline PET for detecting bone metastases in pros-
advanced or metastatic well-differentiated thyroid cancer. Bone tate cancer. One prospective study included 130 presurgical
metastases were readily detected.180 patients who were at increased risk for extracapsular disease
These promising results suggest that 124I PET/CT imaging will involvement. A total of 43 metastatic bone lesions were detected
play an increasingly important role in the management of thyroid in 13/130 patients. It should be noted that these metastases were
cancer patients. However, larger prospective studies will have to also evident on CT in all but two patients.187
determine whether 124I PET/CT affects patient management and In another study of 40 patients with prostate cancer the perfor-
outcome of thyroid cancer patients. mance of 18F-choline PET was compared with that of 18F-NaF PET.189
Many other malignancies can give rise to bone metastases. Bone metastases were present in 22 patients. Sensitivity and accu-
These include neuroendocrine tumors such as neuroblastoma, car- racy were comparable for both tracers at around 90% and the spec-
cinoid, pheochromocytoma, and medullary thyroid carcinoma. ificity was similar for both probes (89% versus 83%; p = NS).
Imaging probes of amino acid transport (18F-DOPA),181,182 soma- In a small study of eight patients with prostate cancer all bone
tostatin receptors (68Ga-labeled somatostatin receptor ligands),183 metastases detected by 99mTc-MDP imaging were also detected
and norepinephrine transport and uptake (123I-MIBG)184,185 can be with 11C-acetate.190 However, 18F-FDG detected bone metastases
used to visualize bone metastases in these cancers. 18F-FDG PET with a higher sensitivity than 11C-acetate in another study.191 Both
appears to be most useful in dedifferentiated neuroendocrine the lesion uptake of 11C-acetate and 18F-FDG significantly corre-
tumors and in particular in patients with pheochromocytoma or lated with serum PSA levels.
paraganglioma with succinate dehydrogenase enzyme subunit B Taken together promising PET probes for imaging bone metas-
gene mutations.186 tases from prostate cancer are emerging. It is however unclear
A variety of PET imaging probes have become available that whether the different imaging phenotypes provide distinctive
depict various phenotypes of bone metastases. Among these are prognostic information. Larger prospective studies addressing

the prognostic value of these imaging probes are therefore needed. the study drug significantly increased bone-metastasis–free sur-
Moreover, their differential ability to monitor therapeutic responses vival by a median of 4.2 months. However, overall survival was
as well as their impact on patient management and outcome need not affected.199
to be defined. In another randomized trial that compared denosumab to the
biphosphonate zoledronic acid,200 denosumab delayed the time to
the first skeletal event by more than 3 months. However, the num-
Treatment of Metastatic Bone Disease ber of serious adverse events was higher in the denosumab group.
These reports underscore the need for early and accurate
Bone metastases from prostate and breast cancer account for detection of bone involvement in cancer because delays in symp-
more than 80% of all symptomatic bone involvement.192,193 Pain tomatic disease can be achieved. However, the symptomatic ben-
from metastatic bone disease has a detrimental impact on the efits come at considerable costs because biphosphonates and
quality of life of cancer patients. Other severe consequences of denosumab are expensive (>$30,000/year) and the drug costs
bone metastases include spinal cord compression, fractures, and exceed those of skeletal-related events substantially.201
the hypercalcemia syndrome of malignancies.107
The management of bone metastases is multidisciplinary194
including medical therapy (biphosphonates and RANK-ligand
Radionuclide Therapy
inhibitors, nonsteroidal anti-inflammatory drugs, steroids, narcot- A variety of radionuclides have become available but they are
ics), external radiation, chemotherapy, and surgery. Nevertheless, used infrequently because of inadequate information of treating
up to 45% of patients remain symptomatic even after these treat- physicians and poorly understood patient selection criteria.
ments have been applied.195 This is in part explained by dose lim- Patients with extensive bone metastatic disease might be candi-
iting side effects and inadequate bone pain assessments.195 dates for radionuclide therapy.
Combination treatments are frequently necessary to alleviate Table 24.8 depicts radiopharmaceuticals that have been intro-
bone pain. In addition to pain medication that includes nonsteroi- duced and used clinically.202 Strontium-89 (89Sr) and samarium-153
dal anti-inflammatory drugs, opiates and others, external beam (153Sm) are radioisotopes that are approved in the United States
radiation is the initial therapy of choice that results in some relief and Europe for the palliation of pain from metastatic bone cancer,
in 90% and complete and lasting pain relief in 54% of patients whereas rhenium-186 (186Re) is only approved in some European
with localized pain.196 countries and rhenium-188 (186Re) is investigational. The alpha-
However, external beam radiation is frequently not feasible in emitter 223Radium has been approved by the US Food and Drug
patients with widespread osseous involvement. Side effects of Administration (FDA) and European Medicines Agency (EMA).
32
whole- or hemibody radiation are frequently severe and hospital- Phosphorus was the first approved radiopharmaceutical.
ization is often required which adds to the cost of this strategy. Administered as sodium orthophosphate it decays by β-emission
Evidence-based standards for the management of metastatic with energy of 1.7 MeV. The ratio of 32P uptake in reactive bone
bone pain include screening for and rating of pain and functional surrounding metastatic lesion is three to five times higher than
impairment, single fraction radiation treatment of bone metasta- that in normal bone. The maximum particle range is around 8.5 mm
ses, corticosteroids for spinal cord compression, and rapid initia- and red marrow absorbs approximately 6.5 mGy/MBq.202 There-
tion of definitive treatments (surgery or radiation treatment) within fore, significant myelosuppression results in the need for blood
24 hours of evidence for spinal cord compression.197 Need for as transfusion in up to 30% of patients.203
well as type and dosage of pain medication should be recorded. Thrombocytopenia was the major side effect and occurred at
doses of <13 mCi. Complete blood counts usually returned to 80%
of the pretreatment levels within 8 weeks. Other side effects
Medical Therapy included fever, gastroenteritis, or minor hemorrhagic manifesta-
Whereas no survival benefit was demonstrated, treatment with tions. Myelosuppression developed in 24% and 47% of patients
the biphopshonate pamidronate reduced all skeletal events with metastatic breast and prostate carcinomas, respectively.203
32
(including fracture, need for radiation, spinal cord compression, P was largely abandoned in favor of 89Strontium chloride (89Sr)
and hypercalcemia) by around 40% in patients with breast cancer. that was approved for the management of cancer-related bone
More recently additional treatments such as denosumab, a mono- pain by the FDA in 1993.
89
clonal antibody against RANK-ligand198 that inhibits osteoclast- Strontium chloride has a half-life of 50.5 days and a β-energy
mediated bone destruction, have become available. In a study of of less than 1.5 MeV that limits bone marrow toxicity because of a
1,432 patients who were randomized to denosumab or placebo, β-range of less than 3 mm.204 Following intravenous injection about
Ta bl e 2 4 . 8
Physical Characteristics of Therapeutic Radionuclides for Bone Pain Palliation
Maximum Energy Mean Energy

Radionuclide Half-life (MeV) (MeV) Maximum Range γ-Emission (keV)
32
P 14.3 d 1.7 (β) 0.695 (β) 8.5 mm None
89
Sr 50.5 d 1.4 (β) 0.583 (β) 7 mm None
186
Re 3.7 d 1.07 (β) 0.362 (β) 5 mm 137
188
Re 16.9 h 2.1 (β) 0.764 (β) 10 mm 155
153
Sm 1.9 d 0.81 (β) 0.229 (β) 4 mm 103
117m
Sn 13.6 d 0.13/0.16 — <1 μm 159
conversion electrons
223
Ra 11.4 d 5.78 (α) average — <10 μm 154
Adapted with permission from Lewington V. Bone-seeking radionuclides for therapy. J Nucl Med. 2005;46:38S–47S.

50% of the injected dose is incorporated into the inorganic bone Reversible myelosuppression affects thrombocytes and leuco-
matrix and thus, accumulates in bone. Uptake and retention is 10 cytes with the nadir reached after 4 weeks.
times higher in metastatic lesions than in normal bone.205 Washout The degree of myelosuppression can be predicted from the
from normal bone (half-life of 14 days) is much faster than that bone scan index (BSI) normalized to body surface area.214 A flare-
from metastatic lesions. Ninety days after administration total body up of symptoms occurs in about 30% of patients.220 Efficacy
89
Sr retention varied from 11% to 88% dependent on the extent of appears to be comparable to that of 89Sr with symptomatic
scintigraphic bone involvement. Renal plasma clearance was sig- response rates ranging from 50% to 92%.217
nificantly lower than in healthy adult men likely because of Thus, 186Re has some potential advantages over 89Sr because of
increased renal reabsorption associated with imbalanced calcium its shorter half-life, rapid onset of palliative effects, lower bone
homoeostasis in patients with metastatic bone involvement. 89Sr marrow toxicity, and the ability to administer multiple doses. Its
retention in metastatic lesions peaked at 10 days after intravenous use has been approved in several European countries and is justi-
administration followed by a slow decline.204 fied in patients with the most severe bone pain (caused by its
In 1995 Robinson et al.206 summarized the clinical experience rapid onset of action) and limited life expectancy in whom rapid
with 89Sr therapy. They reported that pain relief was achieved in pain relief is necessary.
188
up to 80% of patients with metastases from breast or prostate Rhenium (188Re), a generator produced isotope that is a high-
cancer, an effect that lasted for several months. Pain relief was energy β-emitter, has a short half-life of 16.9 hours. Its maximum
associated with improved quality of life. Twenty percent of patients energy is 2.1 MeV resulting in a β-range of 10 mm. Because of this
became pain-free. Adverse effects included mild reversible bone long-range bone marrow toxicity is a concern. 188Re treatment

marrow toxicity in many patients.206 results in symptomatic improvement of 64% of patients with hor-
In a study of 137 patients with complete follow-up a dose of mone refractory prostate cancer.221 The same group subsequently
40 microCi/kg of 89Sr achieved response rates of as high as 80% conducted a randomized trial in hormone refractory prostate can-
and 89% in prostate and breast cancer, respectively.205 89Sr uptake cer to compare a single to repeated doses of 188Re.222 Repeated
remained high for more than 3 months in osteoblastic lesions yet dosing resulted in improved pain palliation and improved pro-
bone marrow toxicity remained mild and acceptable. Eleven per- gression-free and overall survival (by 5 months). Larger trials in a
cent of patients became completely pain-free. The need for pain variety of cancers will be needed to firmly establish the role of
188
medication decreased significantly within 3 weeks after start of Re for bone pain palliation.
153
therapy. These results were reproduced in a multicenter trial that Samarium (153Sm) was approved by the US FDA in the late
also showed that symptomatic improvement lasted for an average 1990s. It is a lanathanide and is chelated with ethylenediamine
of 6 months.207 tetramethylene phosphate (EDTMP). It has a half-life of 46.3 hours
In a randomized study of patients with metastatic prostate can- and decays by relatively low energy β-emission (0.81 MeV maxi-
cer, placebo and study drug achieved similar pain alleviation but a mum energy). Its target is hydroxyapatite and bone uptake is very
significant survival benefit was observed in the treatment group.208 rapid (5.5 minutes) and so is renal clearance (65 minutes).223
When patients were randomized to receive external beam radi- Overall skeletal uptake is high and correlates with tumor load.
ation with or without 89Sr, overall survival and symptomatic relieve Myelotoxicity occurs in 20% to 40% of patients but only at high
did not differ between groups. However, the need for pain medica- doses.224 Symptomatic improvement is achieved in up to 80% of
tion and repeat radiation treatment was significantly reduced in patients.225 153Sm application appears to be well tolerated and
the 89Sr group. Moreover, 89Sr treatment appeared to be associated pain flare is rare.
with delayed disease progression.209 Bone marrow toxicity, albeit A randomized placebo-controlled study of 118 patients who
manageable, occurred more frequently in the 89Sr group. received 1 mCi/kg of 153samarium showed significant pain reduc-
In a trial of patients with metastatic prostate cancer, 89Sr treated tions in up to 72% of patients. Complete relief was seen in 31%
patients required fewer radiotherapies to new disease sites.210 by week 4. Forty-three percent of patients improved symptom-
However, the effect on disease progression was not confirmed by atically after 16 weeks. Bone marrow suppression was mild, and
others possibly caused by lower treatment doses applied.211 no grade 4 toxicity was reported.226 153Sm but not placebo resulted
89
Sr has also been combined with chemotherapy. For instance, in pain relief and reduced need for opiates in another random-
89
Sr combined with low-dose cisplatinum achieved symptomatic ized trial.227
improvement in >90% of prostate cancer patients when compared Two different dose regimens (18.5 MBq/kg versus 37 MBq/kg)
to improvement in 63% of patients who were treated with 89Sr were assigned randomly to a mixed population of cancer patients.228
alone.212 The higher dose significantly improved pain levels and sleep pat-
Taken together these results demonstrate that 89Sr therapy terns. Survival benefits associated with the higher dose were seen
results in symptomatic improvements lasting for up to 6 months in breast but not in prostate cancer patients.228
in patients with metastatic bone disease and one randomized Other radiopharmaceuticals such as 117mSn and 223Ra are
trial suggested a survival benefit for patients undergoing 89Sr undergoing clinical evaluations. 223Ra (alpharadin) is of particu-
therapy. lar interest because it is the first radiopharmaceutical that
186
Rhenium ( 186Re) is a β-emitter with a maximal emission of appears to significantly prolong life in castrate-resistant prostate
1.07 MeV and a half-life of 89 hours. It also emits γ-emission of cancer patients with widespread metastatic disease. In a phase
137 keV which makes it suitable for γ-camera imaging. It strongly II study, patients with bone metastatic prostate cancer were
binds to hydroxyapatite and was first proposed as a therapeutic treated with external beam radiation and were randomized to
for metastatic bone pain in 1979.213 After chelating it with alpharadin or placebo. The study drug reduced bone pain, bone
hydroxyethylidene disphosphonate (HEDP) and after intravenous alkaline phosphatase, and PSA and tended to improve patient
injection its maximal uptake in the skeleton already occurs after survival.229 A subsequent phase III trial in castrate-resistant
3 hours214 whereby lesion-to-marrow dose ratios of 30:1215 or prostate cancer patients with bone metastases demonstrated
even higher216 have been reported. that “best” treatment combined with alpharadin resulted in a
Its relatively short half-life has potential advantages including survival benefit of 3 months.230 Bone marrow toxicity was mini-
higher dose rates, limited potential for repair of radiation-induced mal. Because of the survival benefit the trial was stopped and
damage, multiple dosing, and a more rapid palliation.217 Dose alpharadin was fast tracked by the FDA. Approval of this thera-
escalation studies revealed a maximum tolerated dose (MTD) of peutic is expected in the near future. This new approach marks
2,960 and 2,405 MBq in prostate and breast cancer, respec- the first therapeutic radiopharmaceutical that has an impact on
tively.218,219 patient survival.

Comparison Between Radiopharmaceuticals Future Considerations

for Bone Pain Palliation
In summary, a large body of evidence underscores the importance
Two randomized clinical trials compared the effectiveness of
of radionuclide bone imaging approaches in developing initial and
radiopharmaceuticals to alleviate bone pain in metastatic breast
subsequent therapy approaches in patients with malignant bone
and prostate cancer. Comparisons between 89Sr and 153Sm231 and
89 disease. Radionuclide techniques are an essential component of
Sr versus 186Re232 have been performed.
89 the management of patients with primary and metastatic bone
Sr and 153Sm achieved comparable palliation in 100 patients
cancers. Hybrid imaging techniques including SPECT/CT and PET/
that was however dependent on the phenotype of bone metasta-
CT have yielded improved accuracy for detecting bone involvement
ses; responses were attenuated in patients mixed osteoblastic/
and for assessing therapeutic responses. A variety of novel PET
osteolytic metastases. Complete pain responses tended to be more
imaging probes have become available that will provide insights
frequently observed with 153Sm (40% versus 29%).
into the metabolic phenotype of bone cancers. These include hor-
In a randomized trial of 50 breast cancer patients 186Re
mone receptor imaging approaches as well as probes of tumor
achieved earlier pain responses than 89Sr.232 Duration of responses
lipid metabolism such as labeled choline which might provide
was comparable and averaged more than 3 months in both
additional refinements in patient stratification and treatment
groups. Myelosuppression was similar in both groups but occurred
response assessments. These novel imaging probes will likely
earlier in patients treated with 186Re.
reshape therapeutic approaches by allowing for more individual-
Similar pain responses were reported for alpharadin.230
ized therapy approaches in patients with metastatic bone disease.
No randomized studies that compared pain responses to
Radionuclide therapy for metastatic bone disease is well-estab-
external beam radiation or medical treatment with biphopshon-
lished and its symptomatic benefits and impact on disease progres-
ates to those achieved by radionuclide approaches have been
sion have been documented. It appears very likely that radionuclide
reported.
therapy with 223Ra will be used extensively because of its favorable
In summary, a variety of palliative treatment options are avail-
safety profile and its beneficial effect on patient survival.
able for patients with bone metastases. These include medical
therapy, external beam radiation, and radionuclide therapy. The
recent study demonstrating a survival benefit of patients undergo-
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P a r t III
Special Topics In Nuclear Oncology
C h apt e r 2 5
Pediatric Tumors
Reza Vali • Martin Charron
PART III • Special Topics in Nuclear Oncology

Introduction every year.2,6 Notable increases are recorded for carcinomas, lym-
phomas, and germ cell tumors. However, the mortality rate has
Cancer is relatively rare in childhood with an overall incidence of decreased dramatically, probably caused by early detection and
approximately 130 per million children in the United States.1 improved treatment. The 5-year survival has increased from 58%
Because of the relatively low frequency of childhood malignancy, for children diagnosed between 1975 and 1977 to 83% for those
the incidence rate is quoted per million rather than per 100,000 diagnosed between 2001 and 2007.7
persons. The incidence of childhood cancers overall is about 140 Adult neoplasms are largely categorized according to the ana-
per million in Europe for young children (0 to 15 years old) and tomical site of the tumor. Childhood cancers, however, are more
approximately 157 per million for children and adolescents (0 to naturally classified based on both histology and anatomical site of the
19 years old).2 The total incidence of childhood malignancy varies cancer. The International Classification of Childhood Cancer (ICCC)
slightly between different regions of the world and in different divides these cancers into 12 main diagnostic groups, with further
ethnicities with a cumulative risk of 1 to 2.5 per thousand.3,4 subgroups and divisions.8 These 12 diagnostic groups are summa-
Approximately, 1 out of 500 to 600 children develops some forms rized in Table 25.1. The three most common cancers in children are
of cancer by 15 years of age.5 leukemia, central nervous system (CNS) tumors, and lymphoma,
Although cancer is rare in childhood, it is the second most accounting for approximately two-thirds of pediatric cancers.
common cause of death (after accidents) in children aged 1 to Each specific tumor type exhibits a different age-distribution pat-
14 years, accounting for 18% of all deaths in this age group. Over tern (Table 25.1). Overall, leukemia (30%) is the most common malig-
the last 30 years, the overall incidence has increased 0.5% to 1% nancy in children, and brain tumors (20%) are the most common
Ta b l e 2 5 . 1
AGE-Adjusted and Age-Specific Surveillance, Epidemiology, and end Results (SEER)

Cancer Incidence Rates, 2005–2009
No. Type Percentage (%) 0–14a 0–19a 5-Y Survivalb Peak Age (Y)
1 Leukemias 30 51.6 47.1 80.7 2–3
2 Brain and central nervous system 20 42.2 43.1 72.1 3c
tumors
3 Lymphomas 14 16.6 25.1 90 3–5 and 12–15
4 Soft tissue sarcomas 7 10.9 12.4 71 2–5
5 Sympathetic nervous system tumors 7 10.2 7.8 75.4 0–1
6 Renal tumors 6 7.8 6.3 88.8 1–3
7 Bone tumors 5 7.3 9.2 69 11–15
8 Carcinomas and melanomas 3 6.7 17.1 92.7 15–19
9 Germ cell tumors 3 5.7 11.9 91.2 0–2 and 12–15
10 Retinoblastomas 3 4.1 3.1 97.8 0–1
11 Hepatic tumors 1 2.5 2.2 68.2 0–2
12 Other and unspecified tumors 1 0.5 0.5 N/A N/A
a
Rates are per 1,000,000 and are age-adjusted to the 2000 U.S. standard population (19 age groups—Census P25-1130).
b
5-y relative survival (percent), 2002–2008 by International Classification of Childhood Cancer (ICCC) selected group and subgroup and sex and
age, excluding benign brain and myelodysplastic syndromes.
c
The age of diagnosis varied only slightly in pediatric central nervous system cancer.
From SEER Cancer Statistics Review 1975–2009. http://seer.cancer.gov/csr/1975_2009_pops09/results_merged/sect_29_childhood_cancer_iccc.pdf
363

364 Part III Special Topics in Nuclear Oncology
solid malignancy of childhood. Nonmalignant CNS tumors are also

categorized as CNS tumors because they have the same presenta-
Sedation
tion as the malignant CNS tumors and are generally treated in the Sedation should be performed only if necessary. Sedation is not a
same way. Lymphomas (14%) are the next most common malig- substitute for patient preparation or to decrease the time of acqui-
nancy in children followed by neuroblastoma (NB) (7%), soft tissue sition. Many strategies are available to avoid sedation including
sarcomas (7%), Wilms tumor (6%), bone tumors (5%), germ cell maximizing co-operation with the child, allowing the parents to be
tumors (3%), retinoblastoma (3%), carcinomas and melanoma (3%), with their child, using the child’s nap time and distracters (deco-
hepatic tumors, (1%) and other unspecified malignant tumors (1%). rating the room, reading a story, television, pacifier, bottle, or
The overall incidence rates are higher for boys than for girls in stuffed animal). Each center should follow their own institutional
all age groups; however, some tumors are more frequent in girls, guidelines for sedation. However, guidelines to monitor sedation
notably germ cell tumors in specific age groups, infant leukemia, of children were published by the American Academy of Pediatrics
renal cancer, melanomas, and thyroid carcinomas. The type of (AAP) and are helpful to develop the best strategy. The commonly
malignancy is slightly different among 15- to 19-year-old patients used medications for sedation are chloral hydrate, pentobarbital
in whom Hodgkin disease and germ cell tumors are more common sodium, and midazolam. APP recommends using oral chloral
and there is an increased incidence of non-Hodgkin lymphoma, hydrate (50 to 70 mg/kg; maximum 100 mg/kg) for infants and
osteosarcoma (OS), Ewing sarcoma, thyroid cancer, melanoma, young children (usually less than 15 kg) and a parental sedation
and soft tissue sarcoma other than rhabdomyosarcoma (RMS).1 like pentobarbital sodium (Nembutal) (2 to 6 mg/kg) for older chil-
Because of the relatively low frequency of childhood malig- dren and patients with mental deficiencies. Nembutal is contrain-
nancy, limited data are available about the etiology and risk fac- dicated in patients with porphyria and the dosage should be
tors of most childhood cancers. Overall, the risk factors can be adjusted for seizure patients. Midazolam (nasal: 0.2 mg/kg; oral:
categorized as genetic or environmental, though in many instances 0.5 to 0.75 mg/kg) is also suggested because of its amnestic effect
a more likely etiology is the result of exposure to an environmen- in children.
tal risk factor in a genetically susceptible individual.5 In adults, It should be kept in mind that recommended drugs and route of
except in some instances like hereditary nonpolyposis colorectal administration depend on the patient’s age, history of underlying
cancer (HNPCC) and multiple endocrine neoplasia (MEN), envi- illness (e.g., mental deficiency, cardiac or respiratory illness), expe-
ronmental factors have a greater role. rience and familiarity with certain drugs, institutional protocols,
To a greater degree than in adults, genetic factors may play a length of procedure, and availability of support (reversal drugs).
major role in childhood malignancy. A number of inherited genetic The nuclear medicine physician should always consult with the
syndromes are associated with childhood cancer. Down syndrome, anesthesiology department especially in patients with a history of
neurofibromatosis type 1, ataxia telangiectasia, Fanconi anemia, significant snoring, abnormal airway, congenital heart disease,
MEN 2B, Bloom syndrome, Gardner syndrome, Li–Fraumeni syn- reactive airways disease, and increased intracranial pressure.
drome, and Beckwith–Wiedemann syndrome are some examples.
Radiation, chemotherapeutic agents, diethylstilbestrol, dietary expo-
sure to N-nitroso compounds, atmospheric pollution, pesticides,
tobacco, alcohol, recreational drugs, and anemia during pregnancy Radiation Dose
are among the environmental factors that may induce cancer during
the prenatal period or childhood. The radiopharmaceutical dose to children is different from the
Early detection of childhood malignancy is essential for more adult dose for several reasons, especially the patient size. A child
effective treatment. Moreover, improving survival in childhood is not simply a small adult. Because the organs of children are
cancer requires an increasing need for long-term follow-up of late smaller and closer together, the absorbed dose to different organs
effects and complications. Diagnostic imaging has a pivotal role for differs from those of adults. Children are developing and growing.
diagnosis, staging, evaluation of the response to therapy, and Exposure to environmental harmful factors may result in more
surveillance of pediatric cancers. Imaging in children requires spe- profound damages than adults. Radiation is considered to be a
cial considerations and techniques. Interpretation of images often factor that may increase the risk of cancers and other diseases.
differs from the adult population. Epidemiologic and biologic research suggest that ionizing radiation
may increase the risk of malignant cell transformation.
The effect of low-dose radiation has been well described
recently by Hendee et al.10,11 Most of the epidemiologic informa-
Special Considerations in Pediatric tion about the radiation effect on humans are based on the Hiro-
Oncology Imaging shima and Nagasaki atomic bomb survivor studies as reported
by the Radiation Effects Research Foundation.12,13 Extrapolating
Success in obtaining high-quality studies in children is both chal- from this information to the low-dose consequences of radiation
lenging and rewarding. It is essential to know that in pediatric in humans may not be a true reflection of the effect of low-dose
nuclear medicine, the physician and technologists are working not radiation and may be an overestimate. Miller et al. found that the
only with a child who is anxious or frightened but also with anxious probability of malignant transformation from N particles hit on a
parents. With careful planning, good communication and a quiet cell is much greater than N times the probability of transformation
and friendly atmosphere create the right environment. The follow- to malignancy from a single hit.9,14 According to the epidemiologic
ing should be kept in mind when dealing with the pediatric patients. data, the lowest dose of x- or γ-radiation for which good evidence
exists of increased cancer risks in human is about 10 to 50 mSv
• Importance of communication appropriate for the child’s stage
for an acute exposure and approximately 50 to 100 mSv for a
of development
protracted exposure.15 The effective dose estimation for many
• Need for flexible scheduling
pediatric nuclear medicine procedures is less than 10 mSv. There
• Appropriate injection techniques
are even some theories about the protective effect of low-dose
• Imaging environment, including the use of immobilization
radiation on humans (hormesis).16,17
devices or safety restraints, distraction techniques, and the pos-
In light of these controversies, it is recommended to select a
sibility of sedation when necessary
more conservative approach for children. A study should be per-
Usually it takes about twice as long to complete a procedure on formed only if necessary and the radiation dose should be kept as
a pediatric patient as on an adult.9 low as possible without adversely affecting the quality of images.

Chapter 25 Pediatric Tumors 365
Table 25. 2
North American Consensus Guidelines for Administered Radiopharmaceutical Activities Generally used
in Nuclear Oncology in Children and Adolescents
Recommended Activity Minimum Maximum

Radiopharmaceutical (Based on Body Weight) Activity Activity Comments
123
I-MIBG 5.2 MBq/kg (0.14 mCi/kg) 37 MBq (1 mCi) 370 MBq (10 mCi) The EANM dosage card 2007 version administration
activity may be used in patients over 10 kg
99m
Tc-MDP 9.3 MBq/kg (0.25 mCi/kg) 37 MBq (1 mCi) The EANM dosage card 2007 version administered
activity may also be used.
18
F-FDG Body 37 MBq (1 mCi) The low end of the dose range should be considered
3.7–5.2 MBq/kg (0.1–0.14 mCi/kg) for smaller patients.
Brain Administered activity may take into account patient
3.7 MBq/kg (0.1 mCi/kg) mass and time available on the PET scanner. The
EANM dosage card 2007 version administered
activity may also be used
18
F-sodium fluoride 2.22 MBq/kg (0.06 mCi/kg) 18.5 MBq (0.5 mCi)

Conventionally the pediatric injected dose was calculated from the Standardized Uptake Value
adult dose with different formulas adjusting for weight ((body mass
(kg) × adult dose)/70 kg), body surface area (BSA (m2) × adult One of the parameters commonly used in oncology for quantifica-
dose)/1.73 m2), or age (Webster’s formula; age (years) + 7) × (adult tion of the intensity of FDG uptake is Standardized Uptake Value
dose)/(age (years) + 1)).18,19 However, in some cases, the adult dose (SUV). SUV is a semiquantitative value representing the ratio of
is based on the institutional experiences with a wide range of the radioactivity in a selected part of the body at a certain time
administered activities. With new technology and improved instru- point. Many factors influence the SUV including body composition
mentation, the optimum doses for the pediatric population can be and habitus, length of uptake period, blood glucose level, and par-
changed. New North American consensus guidelines were pub- tial volume effect.23,24 Consistency of SUV values is more challeng-
lished in 2010 to address this issue.20 Table 25.2 shows the recom- ing in the pediatric population because there are significant body
mended administered dose including the minimum and maximum changes during childhood. Fat has much lower FDG uptake than
doses of the commonly used radiopharmaceuticals in pediatric other tissues.23 The percentage of fat in the total body weight rises
oncology. from 11% in the newborn to approximately 26% during the fol-
Dosimetry associated with the CT on PET/CT and SPECT/CT lowing 5 months, and then decreases gradually until 12 months of
should also be considered. The effective radiation dose to children age.25 After that the amount of fat is variable and depends on
from the CT portion is usually the same or slightly higher than the many factors including diet, physical activity, and genetics. The
radiopharmaceutical dose. For the same CT acquisition parame- pediatric SUV normalized to body weight is not exactly the same
ters, the dose to a newborn is approximately twice that to a as that of adults. The clinical significance of SUV values in differ-
medium-sized adult. Therefore, CT acquisition parameters should ent pathologies and normal versus suspected malignancy refer-
be reduced for smaller patients.21 The radiation dose from the CT ence numbers in the pediatric population should be interpreted
portion depends on various CT acquisition parameters, including cautiously and not just based on adult reference values.
the tube voltage (kVp) and the tube current–time product (mAs).
The tube current could be adjusted based on the thickness of the Palatine and Lingual Tonsils
body. In thinner parts or in areas with less attenuating tissues
(e.g., the lungs) fewer x-rays can be emitted. Obtaining the CT The palatine and lingual tonsils are lymphatic tissues that are very
over a limited field of view (over the area of interest), or using a active during childhood. Therefore, it is not uncommon to see
higher pitch (faster bed speed) when using a helical CT will also increased 18F-FDG activity in these structures, even without appar-
decrease the radiation dose of CT part. ent inflammation (Fig. 25.1). Moreover, clinical or subclinical upper
respiratory infection is more common in children than in adults
especially in cold seasons. Lymphoma in the head and neck, post-
transplant lymphoproliferative disorder (PTLD), and secondary
Special Considerations in malignancy in the nasopharyngeal area and tonsils may mimic the
18
F-FDG PET/CT same pattern. The intensity of uptake and the symmetric/
asymmetric pattern of activity may be helpful to differentiate a
PET/CT has become a standard component of medical imaging in normal variant versus pathology. Symmetric pattern of uptake
oncology. The combination of the anatomic information from CT with similar shape is more likely to be physiologic uptake espe-
and the functional information from PET provides clinical infor- cially if there is no evidence of pathology on CT scan,26 whereas
mation not attainable from either study alone. However, the wide- asymmetric areas should be considered suspicious for the pres-
spread clinical application of PET/CT in pediatric oncology was ence of pathology. Comparison with the previous 18FDG PET study
slow for several reasons including the lack of availability of dedi- and correlation with the CT portion of PET/CT can be helpful for
cated PET/CT in pediatric centers, the radiation dose and the an accurate interpretation.
relative rarity of childhood malignancies. The usefulness of PET/
CT in the management of pediatric malignancies has been shown
Thymus
in several studies during the last decade. However, the physiologic
variation in FDG biodistribution and potential pitfalls in pediatric The thymus is a specialized organ of the immune system localized
population needs special attention.22 in the anterior superior mediastinum, in front of the heart and

Figure 25.1. Axial and coronal PET and fused PET/CT

images of a 20-month-old infant. Note the normal uptake
A B C in the area of the vocal cords (A), tonsils (arrows in B),
and thymus (C).
behind the sternum extends from the brachiocephalic vessels The average SUV for thymic carcinoma has been found to be
toward the right cardiophrenic angle. The thymus “educates” T much higher (7.2 ± 2.9) in a study by Sasaki et al.31 This value was
lymphocytes (T cells), which are critical cells of the adaptive significantly greater than the values found for invasive thymoma
immune system and becomes atrophic after puberty. The thymus (3.8 ± 1.3) and noninvasive thymoma (3 ± 1).29 By using an SUV
has a more quadrilateral shape during early childhood and a more of 5 as a cut-off, Ferdinand et al. achieved reasonable sensitivity
triangular shape during adolescence. The thickness and homoge- (84.6%), specificity (92.3%), and accuracy (88.5%) in differentiat-
neity of the gland is used to predict thymic disease on CT scan. ing thymic carcinoma from thymoma. In summary, heterogeneous
Thickness of the gland measured perpendicular to the length of a or focally increased activity, intense 18FDG uptake, or any changes
lobe should be less than 1.8 cm in patients under 20 years old and in the shape of the thymus should be correlated with CT findings
1.3 cm in older patients.27,28 In pediatric population, the thymus and needs further investigation.
often shows mild to moderate homogeneous increased FDG uptake
(Fig. 25.1) which decreases with age, notably at puberty, when the
thymus undergoes fatty infiltration and involution.29
Brown Fat
Thymus uptake can also increase in thymus hyperplasia. Thymic Brown fat is a type of adipose tissue with a thermoregulation func-
hyperplasia may be seen after chemotherapy, particularly in tion to control body temperature and energy expenditure. It is found
young patients treated for lymphoma or testicular cancer. This is in the neck region, shoulders, superior mediastinum, diaphragmatic
probably because of an immunologic rebound phenomenon char- hiatus, and perinephric area. The frequency of brown fat uptake in
acterized by infiltration of plasma cells after thymic aplasia in children is higher than in adults.32 Brown fat uptake is usually sym-
response to steroid-induced apoptosis and inhibition of lympho- metric (except for diaphragmatic hiatus) mild to moderate activity
cyte proliferation.30 which corresponds to hypodense regions on CT scan, similar to nor-
Differentiation of physiologic thymus uptake or thymus hyper- mal fat tissue (Fig. 25.2). There is a relationship between brown fat
plasia from malignancy is important. Correlative CT scan is useful uptake and cold temperature. Some medications (e.g., propranolol,
to evaluate the homogeneity and the size of the gland. On 18FDG diazepam) are suggested to decrease the brown fat uptake. The use
PET studies, the shape of the gland should be quadrangular or tri- of these medications is not recommended routinely in clinical prac-
angular with uniform uptake. Several investigators have studied the tice. Controlling the temperature of the injection room is the more
intensity of 18FDG uptake by means of SUV in normal thymus, thy- practical way to decrease the brown fat uptake. Knowledge of the
mic hyperplasia, and malignant infiltration of the gland. In a study physiologic distribution of brown fat and the use of fused PET/CT
by Brink et al.,30 the average SUV value of 2.7 (with a maximum of images help to differentiate brown fat uptake from pathologic
3.8) was reported for thymic hyperplasia. Ferdinand et al.29 sug- lesions. However, sometimes it is difficult to diagnose adjacent
gested that with an SUV value >4, further investigation should be pathology or small lymph nodes (especially in the neck and upper
performed before concluding that it is physiologic uptake. mediastinum) in the context of high uptake in brown fat.


Figure 25.2. Intense 18F-FDG activity in
brown fat tissues correlates with hypodense
regions on CT.
Other Issues
Bone marrow may be more active in children than adults, prob-
ably because of greater red marrow component. Following che-
motherapy or secondary to hematopoietic drug stimulators like
granulocyte colony-stimulating factor (G-CSF), bone marrow often
shows a diffuse intense 18FDG uptake (Fig. 25.3).33,34 Other condi-
tions, including β-thalasemia, severe anemia (hyperplasic mar-
row), and diffuse metastasis (less likely), or drugs (interferon),
have been reported to increase 18FDG uptake in bone marrow in
both pediatric patients and adults.35,36
Children usually move during the uptake interval post-injection
of tracer. Depending on the muscles involved, increased activity
may be noted in a muscle or a group of muscles which could be
symmetric or asymmetric. The pattern of uptake corresponding to
the muscle/s on CT scan is helpful to differentiate physiologic
uptake from pathology. However, especially in the head and neck
region, sometimes it is difficult to differentiate focal uptake
because of the physiologic activity in a small muscle and a patho-
logic lymph node, with a nondiagnostic CT scan or in cases of
misregistration of PET and CT. Patient movement may also inter-
fere with image acquisitions. Sedation during acquisition may be
needed for some patients.
Children may also talk or scream during radiotracer injection
or for a few minutes after during the uptake period. As a result, it
is not uncommon to see increased physiologic activity in the vocal
cords. The uptake is typically bilateral and symmetrical (Fig. 25.1) Figure 25.3. Maximum intensity projection image in a patient 3 days after G-CSF administra-
but it may be asymmetric. In cases of intense asymmetric vocal tion. Note increased 18F-FDG uptake in bone marrow.

cord uptake, correlation with CT scan is useful to exclude any pos- attracts to negatively charged mitochondria inside the cells. The
sible pathology or unilateral vocal cord palsy. Symmetric areas of accumulation of 99mTc-MIBI is inversely related to the P-glycopro-
mild FDG uptake may be seen in growth plates especially long tein (PGP) in the cell membrane. PGP is a cellular membrane pro-
bone physis which is more active in children. In girls of reproduc- tein which is responsible for pumping out cationic and lipophilic
tive age, foci of increased FDG uptake may be seen in the pelvic substances from the cells. Malignant tumors have increased
region because of the physiologic activity in the ovaries. expression of PGP because of the multidrug resistance gene (MDR-
1) which encodes for PGP. MDR-1 is responsible for resistance of
tumors to chemotherapy agents. The washout of 99mTc-MIBI may
Radiopharmaceuticals be an indicator of the degree of expression of PGP and a predictor
of chemotherapy resistance. The patient should be fast for 4 hours
Many different radiopharmaceuticals have been used in pediatric for both 201Tl and 99mTc-MIBI study. Imaging is usually performed
oncology for the detection of tumors, metastases, and evaluation 1 and 4 hours after the radiotracer injection with a low-energy
of response to therapy. high-resolution collimator. SPECT images over the lesion are also
recommended. Normal biodistribution of 201Tl is salivary glands,
thyroid, heart, liver, stomach, large bowel, kidneys, testes, muscles,
Gallium 67 eyes and slightly in choroid plexus of the lateral ventricles. The
Gallium scan has been used for staging, estimating prognosis, and kidney is the critical organ for 201Tl, receiving 0.03 cGy/37 MBq.
assessing the treatment response as well as the evaluation of resid- For 99mTc-MIBI, the normal biodistribution is heart, thyroid, liver,
ual disease in lymphoma and soft tissue tumors (RMS), and also for gallbladder, choroid plexus, lacrimal glands, lungs, salivary glands,
the evaluation of metastatic melanoma and hepatocellular carci- bowel, spleen, kidneys, and muscles. The large bowel and gallblad-
noma. 67Ga decays by electron capture and emits several γ-rays: der receive the highest dose. Increase uptake more than the back-
93 (41%), 185 (23%), 288 (18%), and 394 (4%) KeV. Imaging with ground activity is considered a positive finding. For brain lesion
a large-field-of-view multipeak γ-camera equipped with a medium- comparing with the contralateral region is suggested. A baseline
energy parallel hole collimator is preferred. The physical half-life study before treatment is helpful for comparison.
is 78 hours. The organ receiving the largest radiation dose is large
bowel (0.72 mGy/MBq). The effective dose equivalent for a 5-year-
old child is 0.4 mSv/MBq. The mechanism of 67Ga transport is
MIBG Scintigraphy
similar to iron, initially binding to transferrin (an iron transport Metaiodobenzylguanidine (MIBG) is a derivative of guanithidine,
protein) after intravenous injection. However, 67Ga has one valence structurally similar to norepinephrine that enters neuroendocrine
state (unlike Fe2+ or Fe3+) so the ultimate distribution is different. cells by an active type 1 uptake mechanism via the epinephrine
The mechanism of uptake in tumors may be caused by the leakage transporter and is stored in the neurosecretory granules. MIBG scin-
from the tumor vessels, intratumoral pH, or increased concentra- tigraphy with 131I or 123I has been used for the detection of neuro-
tion of transferrin in tumors (transferrin receptors are upregulated ectodermal tumors including pheochromocytoma and NB for the
in tumors with high proliferation ability). Because of the slow last 30 years. MIBG has been labeled with 131I, 123I, and recently 124I.
131
transfer of Ga-transferrin to the tumors and high background I MIBG is probably more commonly used in nuclear oncology
activity, imaging usually begins 48 hours after injection of 67Ga. because of its low cost and greater availability. Moreover, it may be
However, imaging as early as 24 hours may also reveal the tumor. preferred for dosimetric studies and treatment planning. 123I MIBG
Delayed images for up to 7 days may be needed to differentiate has the advantage of better physical characteristics, that is, shorter
bowel activity versus 67Ga-avid lesions in the abdomen. SPECT half-life (13 hours) and ideal energy of γ-rays (159 KeV), which
study is also suggested for the evaluation of chest and abdominal reduces the radiation dose to the patient and allows SPECT imaging.
region. The usual administered activity in children is 1.5 to Moreover, the study can be completed in a shorter period of time.37
2.6 MBq/kg (0.04 to 0.07 mCi/kg) with a minimum dose of 9 to 18 MBq Thus 123I MIBG is the preferred agent in pediatric population.
(0.25 to 0.5 mCi). Patient preparation is important for MIBG scintigraphy. Thyroid
Patients should be well hydrated and do not need to fast. Bowel blockade is necessary to reduce free iodine uptake by the thyroid
preparation prior to imaging is suggested to decrease bowel activ- gland. The pretreatment could be obtained by taking sodium or potas-
ity. Knowledge of the patient’s history of recent infection (false- sium perchlorate (300 to 600 mg/m2 BSA) daily (5 days before scan-
positive results for tumor), chemotherapy (will suppress 67Ga ning with 131I MIBG or 1 day with 123I MIBG) or Lugol iodine solution
uptake; should wait 4 weeks after chemotherapy), radiation, and (0.3 mL) three times a day (3 days before scanning with 131I MIBG or
recent blood transfusion and iron injection (altered 67Ga biodistri- 1 day with 123I MIBG). These medications should be continued for 1 to
bution) is essential before the examination. 67Ga is normally 2 days for 123I MIBG, or 2 to 3 days for 131I MIBG scanning.38
observed in the liver, spleen, bone marrow, lacrimal and salivary A number of drugs are known to interfere with MIBG uptake.
glands, breast tissues, thymus, nasopharynx, gastrointestinal activity These drugs include tricyclic antidepressants, certain antipsy-
(because of both the small bowel excretion and biliary excretion), chotics, CNS stimulants, calcium channel blockers, and α- and
and kidneys (during the first 24 hours). β-blocker labetalol. A list of interactive drugs and suggested time
of withdrawal are summarized in Table 25.3. These medications
201 99m should be discontinued with the supervision of the referring phy-
Tl and Tc-MIBI sician. It is also suggested that the patient is advised not to take
201 99m
Tl and Tc-methoxyisobutylisonitrile (MIBI) are taken up by a some foods containing vanillin and catecholamine-like compounds
number of tumors and is indicative of viability. Either 201Tl or (such as chocolate and blue-veined cheeses).38
99m
Tc-sestaMIBI is useful to assess treatment response in osteo- The administered dose should be calculated based on the adult
genic sarcoma, RMS, Ewing sarcoma, and brain tumors. 201Tl dose (40 to 80 MBq for 131I MIBG and 400 MBq for 123I MIBG) using
decays by electron capture with a γ-ray ranging from 69 to 83 KeV standard formulas. The recommended minimum and maximum
(94% abundance) and two less abundant γs: 167 KeV (10% abun- doses are 37 and 400 MBq for 123I-MIBG and 3.7 and 18.5 MBq
dance) and 135 KeV (3% abundance). The physical half-life is 73 for 131I MIBG, respectively.39 Slow infusion for at least 5 minutes is
hours. The mechanism of tumor uptake depends on tumor blood advised in a peripheral vein, followed by saline administration.
flow and sodium–potassium ATPase pumping system of the cell Rapid injection or injection from a central intravenous line
membrane. The mechanism of uptake of 99mTc-MIBI depends on its should be avoided because of the possibility of adverse reaction
lipophilic properties and passive diffusion into the cells. Then it (vomiting, tachycardia, pallor, abdominal pain).39 Patient should

Table 25. 3 the bladder and urinary tract show intense activity. Physiologic
activity is seen in the liver and to a lesser degree in spleen, lungs,
Drug Interactions with MIBG salivary glands, skeletal muscles, and sometimes nasal mucosa,
gallbladder, colon, uterus, muscles, and possibly brown fat tissues
Drug Group Examples (Recommended Withdrawal Time) in the upper chest. Sometimes gastrointestinal tract and thyroid
may be seen because of free iodine especially if the thyroid has
Antiarrhythmics for Amiodarone (not practical to withdraw), Combined α- not been blocked appropriately. Faint activity in the adrenal
ventricular arrhyth- and β-blocker, Labetalol (72 h), Adrenergic neurone glands may be seen approximately in up to 15% of cases with 131I
mias blockers, Brethylium (48 h), Guanethidine (48 h), MIBG and up to 75% when using 123I MIBG.
Reserpine (48 h) The sensitivity and specificity of MIBG are different in different
α-Blockers Phenoxybenzamine (IV doses only) (15 d) kinds of neuroectodermal tumors. The sensitivity of MIBG to
Calcium channel Amlodipine (48 h), Diltiazem (24 h), Felodipine (48 h), detect NB (primary tumor and metastases) is about 80% on a
blockers Isradipine (48 h), Lacidipine (48 h), Lercanidipine lesion-by-lesion basis and 90% to 95% in terms of staging. MIBG
(48 h), Nicardipine (48 h), Nifedipine (24 h), Nimodipine is highly specific (∼100%) for the detection of primary tumor and
(24 h), Nisoldipine (48 h), Verapamil (48 h)
metastases in NB.39,40
Inotropic sympathomi- Dobutamine (24 h), Dopamine (24 h), Dopexamine
metics (24 h)
Vasoconstrictor Ephedrine (24 h), Metaraminol (24 h), Norepinephrine
sympathomimetics (24 h), Phenylephrine (24 h) Sympathetic Nervous System Tumors

β-2 stimulants— Salbutamol (24 h), Terbutaline (24 h), Eformoterol (24 h),
sympathomimetics Bambuterol (24 h), Fenoterol (24 h), Salmeterol (24 h)
Other adrenoreceptor Orciprenaline (24 h), Pseudoephedrine (48 h), Phenyl-
Imaging
stimulants ephrine (48 h), Ephedrine (24 h), Xylometazoline Sympathetic nervous system (SNS) tumors account for about 7% of
(24 h), Oxymetazoline (24 h) all pediatric malignancies. NB, including ganglioneuroblastoma, is
Sympathomimetics for Brimonidine (48 h), Dipivefrine (48 h) the most common form of all SNS tumors in children (approxi-
glaucoma
mately 97%). NB is the most common extracranial solid tumor in
Antipsychotics Chlorpromazine (24 h), Benperidol (48 h), Flupentixol
childhood and the most frequently diagnosed malignancy during
(neuroleptics) (48 h or 1 mo for depot), Fluphenazine (24 h or 1 mo
for depot), Haloperidol (48 h or 1 mo for depot), infancy accounting for approximately a fifth (22%) of all cancers
Levomepromazine (72 h), Pericyazine (48 h), Per- diagnosed below the age of 1 especially during the first 3 months
phenazine (24 h), Pimozide (72 h), Pipotiazine (1 mo of infancy. The incidence of NB is rare after the age of 5. Almost
for depot 1), Prochlorperazine (24 h), Promazine (24 h), one-half (46%) of NBs develop in the adrenal gland followed by
Sulpiride (48 h), Thioridazine (24 h), Trifluoperazine retroperitoneal paraspinal and mediastinal tumors. Mediastinal
(48 h), Zuclopenthixol (48 h or 1 mo for depot), Amis- tumors are more frequent in infants than in older children.
ulpride (72 h), Clozapine (7 d), Olanzapine (7–10 d), The etiology of NB is not well understood. The higher incidence
Quetiapine (48 h), Risperidone (5 d or 1 mo for depot), during infancy is suggestive of a genetic susceptibility or environ-
Sertindole (15 d), Zotepine (5 d)
mental exposure during conception and gestation. Medication dur-
Antihistamines Promethazine (24 h)
Opioid analgesics Tramadol (24 h) ing pregnancy (amphetamines, diuretics, tranquilizers, phenytoin,
Tricyclic antidepres- Amitriptyline (48 h), Amoxapine (48 h), Clomipramine fertility drugs, etc.) has been reported to increase the incidence of
sants (24 h), Dosulepin (24 h), Doxepin (24 h), Imipramine NB.41,42 The effects of alcohol, smoking, and mothers’ occupational
(24 h), Lofepramine (48 h), Nortriptyline (24 h), exposures on the incidence of neuroblastoma are controversial.42–44
Trimipramine (48 h) Overall, long-term survival of the patients with NB is less than
Tricyclic-related anti- Maprotiline (48 h), Mianserin (48 h), Trazolone (48 h), 40%.45 A 5-year survival rate was improved from 35% during 1975
depressants Venlaflaxine (48 h), Mirtazepine (8 d), Reboxetine (3 d) to 1984 to 55% during 1985 to 1994 for children aged 1 to 4 years
Central nervous sys- Amphetamines, e.g., Dexamfetamine (48 h), Atomoxetine at diagnosis whereas it was essentially unchanged over these time
tem stimulants (5 d), Methylphenidate (48 h), Modafinil (72 h), intervals among infants (83%) and children 5 years or older (40%).46
Cocaine (24 h), Caffeine (24 h)
The diagnosis is usually based on histopathologic findings plus
From Giammarile F, Chiti A, Lassmann M, et al. EANM procedure guidelines for 131I-meta-iodo-
the high urinary levels of one of the catecholamines. In about 90%
benzylguanidine (131I-mIBG) therapy. Eur J Nucl Med Mol Imaging. 2008;35(5):1039–1047. of cases of NB, elevated levels of catecholamines or their metabo-
lites including dopamine, homovanillic acid (HVA), and/or vanil-
lylmandelic acid (VMA) can be detected in the urine or blood.47 On
be encouraged to drink water and fluids following injection and pathology, the tumor cells consist of neuroblasts, which are imma-
void frequently and before the imaging. ture, undifferentiated, small, round-shaped sympathetic cells, with
The administered dose is 0.52 MBq/kg (3.7 to18.5 MBq) for little cytoplasm, dark nuclei, and small indistinct nucleoli with
131
I-MIBG and 5.2 MBq/kg (37 to 400 MBq) for 123I-MIBG. Imaging pseudorosettes patterns (tumor cells around neutrophils).
is performed at 24, 48, and 72 to 96 hours with 131I-MIBG and at The clinical behavior of the tumor is variable in different patients
24 and 48 hours with 123I MIBG. SPECT views are usually obtained and different age groups. The tumor can regress spontaneously, or
with 123I MIBG scan. The effective radiation dose for 123I MIBG is can mature into a benign lesion even without treatment, or prog-
0.037 mSv/MBq and 0.017 mSv/MBq for 5- and 15-year-old chil- ress and metastasize rapidly with poor outcomes despite aggressive
dren, respectively. For 131I MIBG, it is 0.43 mSv/MBq and 0.19 mSv/ therapy. Prognosis for neuroblastomas is dependent on the age,
MBq for 5- and 15-yearold children, respectively.38 Liver receives stage of disease, the molecular biologic and cytogenetic character-
the highest radiation dose with both radiotracers (0.83 mGy/MBq istics of the tumor and other parameters such as tumor proto-
for 131I MIBG and 0.067 mGy/MBq for 123I MIBG). oncogenes, DNA content, and catecholamine synthesis.
Images should be obtained 24 hours after 123I MIBG injection Staging based on the International Neuroblastoma Staging Sys-
and 48 hours after 131I MIBG injection. SPECT study from chest, tem (INSS) is one of the variables that affect prognosis in patients
abdomen, and pelvis should be performed 24 hours after 123I with NB (Table 25.4). The classification evaluates the distribution of
MIBG administration. Delayed views may be obtained with equiv- the disease using radiographic and scintigraphic studies, surgical
ocal finding on first images with both radiotracers. operability, lymph node and bone marrow involvement. A new Inter-
After intravenous injection of MIBG, approximately 50% of the national Neuroblastoma Risk Group (INRG) classification system is
administered radioactivity appears in the urine by 24 hours. Thus, also proposed based on 13 potential prognostic factors. The patients

Table 25.4
International Neuroblastoma Staging System (INSS)
Stage Description
I Localized tumor with complete gross excision, with or without
microscopic residual disease; representative ipsilateral lymph
nodes negative for tumor microscopically.
IIA Localized tumor with incomplete gross excision; representative
ipsilateral nonadherent lymph nodes negative for tumor
microscopically
IIB Localized tumor with or without complete gross excision, with ipsilateral
nonadherent lymph nodes positive for tumor. Enlarged contralateral
lymph nodes must be negative microscopically.
III Unresectable unilateral tumor infiltrating across the midline with or
without regional lymph node involvement; or localized unilateral
tumor with contralateral regional lymph node involvement; or midline
tumor with bilateral extension by infiltration (unresectable) or by
lymph node involvement
IV Any primary tumor with dissemination to distant lymph nodes, bone,
bone marrow, liver, skin, and/or other organs (except as defined for
stage IVS)
IVS Localized primary tumor (as defined for stage I, IIA, or IIB), with
dissemination limited to skin, liver, and/or bone marrow (limited to
infants, 1 y of age)
Figure 25.4. Bone scan in a 6-month-old boy with adrenal tumor confirmed to be neuroblas-
toma after biopsy. Note 99mTc-MDP uptake in the tumor.
can be categorized into four groups (very low risk, low risk, interme-
diate risk, and high risk) with different 5-year event-free survival uptake in the skeleton. However, cold defects and asymmetric
rates (>85%, >75% to ≤85%, ≥50% to ≤75%, and <50%, respectively).48 metaphyseal increased activity may also reveal bone metastases. In
The clinical signs and symptoms depend on the size of the pri- children, detection of bone metastasis near the epiphysis is difficult.
mary tumor, effect of hormone production, and the location of dis- Even with a slightly blurring of the growth plate margins, bone
tant metastases. It may be found incidentally without any symptoms metastasis should be ruled out.51 Involvement of the skull and facial
or present with abdominal pain and mass, generalized bone pain, bone including periorbital regions may be also seen with more
anemia, malaise, fever, irritability, weight loss, encephalitic symp- advanced bone metastases. The sensitivity of MIBG to detect bone
toms and even blindness, and paraneoplastic syndrome. metastases is higher than bone scan (Fig. 25.4).52 Moreover, the
Because metastases are common at presentation, accurate specificity of the positive lesions in bone scan is lower than MIBG
staging depend on multimodality imaging. Initial imaging in chil- scintigraphy. However, there are some instances of positive bone
dren with NB is usually performed to confirm the diagnosis and scans with negative MIBG studies.53,54 Thus, bone scan is still needed
investigate the presenting symptoms. Chest x-ray, abdominal for accurate staging at diagnosis. Omitting bone scanning in the
radiographs, skeletal films, abdominal ultrasound or computer- diagnostic staging may lead to incorrect staging up to 10% of cases.55
ized tomography, spinal MRI (in cases of paraspinal NB), MIBG On the contrary, in a clinically responding patient, bone scan is not
scintigraphy, and probably bone scan are among the investiga- recommended in the routine follow-up studies unless MIBG scan is
tions depending on the clinical findings. not available, or with a negative MIBG scan and suspicious radio-
Ultrasonography (US) is the initial imaging modality for the graphic findings. Other incidental findings on bone scan are visual-
evaluation of abdominal mass in a child. It is useful for the diag- ization of the primary tumor caused by calcification in approximately
nosis of abdominal mass, and the evaluation of local extent of the 40% of cases (Fig. 25.4) and visualization of a displaced or hydrone-
primary tumor. On US, NBs are heterogeneous solid lesions, phrotic kidney.
mostly echogenic, with calcification and less commonly with cystic MIBG shows variable uptake in neuroectodermal tumors; some
anechoic areas. CT scan shows lobulated nonuniform masses with authors have found greater uptake in tumors with high catechol-
heterogeneous or little enhancement. Calcifications, pseudonecro- amine excretion, whereas others have reported more intense uptake
sis or hemorrhage may also be seen. Both CT and MRI are useful in more undifferentiated types of tumors. Thus, it is not possible to
for assessment of the location and the size of the primary tumor, differentiate the different types of neuroectodermal tumors based on
vascular encasement, tumor respectability, and retrocrural and the positivity and intensity of MIBG uptake (40). MIBG scan has a
paravertebral extension.49 high sensitivity (80% to 90%) and excellent specificity (∼100%) for
MRI is superior to CT to assess bone marrow infiltration and the detection of primary tumor and metastases in NB.39,40
intraspinal extension of tumor. Moreover, the lack of ionizing radi- MIBG scintigraphy is a sensitive modality for the detection of
ation and the absent necessity of using oral contrast are other bone marrow involvement in NB patients. It is as sensitive as MRI
advantages of MRI.49 On MRI, the tumor is typically heterogeneous and bone marrow aspirate. The sensitivity of MIBG may be even
with a variable enhancement pattern, prolonged T1 and T2 relax- better than bone marrow because it has the advantage of evalua-
ation times with low signal intensity on T1W and high signal tion of the whole skeleton (Fig. 25.5).56 MIBG is more specific than
intensity on T2W images. Epidural invasion of NB and leptomen- MRI to assess response to treatment. However, still MIBG-negative
ingeal involvement should be assessed with MRI on any patient NB tumors is a concern, which is usually seen in stage I and II
with paraspinal NB.40,50 tumors.53 If the tumor is MIBG avid at diagnosis, follow-up MIBG
Bone metastasis is relatively common in NB. Detection of bone study is recommended to evaluate response to therapy and when-
metastasis is important for staging (stage IV). Whole-body bone scan ever the treatment regimen changes.
with 99mTc-MDP has been widely used in NB to evaluate bone metas- MIBG scan has also a prognostic value. Several scoring systems
tasis. Bone metastases are usually present with focal increased have been suggested to predict the response to therapy based on

the number of MIBG uptake in different organs at diagnosis or shown to be superior to 111In-octreotide planar scintigraphy and
during midcycle of therapy.57–60 In addition, a negative MIBG scan SPECT imaging in neuroendocrine tumors (NETs).63,67 Kroiss et
after therapy in a patient with previous positive study indicates a al. showed that 68Ga-DOTA-TOC PET has a high sensitivity
good prognosis and longer disease survival.61 Evidence of residual (97.2%) compared to MIBG (90.7%) in a pilot study.68 Further
disease and persistent positivity during and after induction sug- studies with a larger number of subjects are needed to validate
gest a poor prognosis.50 In summary, MIBG scan is indicated for the findings and the exact role of somatostatin receptor scintig-
the evaluation of NB at diagnosis, for staging, after completion of raphy in NB.
18
therapy, and whenever any changes in the therapeutic regimen is F-FDG PET has been also used in patients with NB. 18F-FDG
needed especially before decision about MIBG therapy. can accumulate in primary neoplasm and metastases even in the
NB tumors also exhibit somatostatin receptors. Thus cases of MIBG-negative tumors. Sharp et al.69 compared the diag-
111
In-DTPA-D-Phe1-octreotide (111In-octreotide; Octreoscan) or nostic utility of 123I MIBG and 18F-FDG PET in NB in 60 patients.
other somatostatin receptor radiotracers are potentially useful They concluded that 18F-FDG PET was superior for stage I and II
for the detection of NB tumors and metastases.62 Many investi- neuroblastomas, but 123I MIBG might be needed to exclude higher-
gators compared the sensitivity of octreotide with MIBG in NB. stage disease. 18F-FDG PET also provided important information
The sensitivity of Octreoscan was 50% to 70% compared to 83% for patients with weakly positive MIBG scan and at major decision
to 94% for MIBG.63 However, in most of those studies, only pla- points during therapy (i.e., before stem cell transplantation or
nar images were obtained for octreotide scintigraphy. With before surgery). They also concluded that 18F-FDG PET may be
SPECT/CT, the sensitivity of Octreoscan will increase. They also better for the detection of lesions in the chest, abdomen, and pel-

suggested that a positive Octreoscan indicates a favorable prog- vis. In addition, the study can be completed in 2 hours. Because of
nosis.64–66 New PET tracers for somatostatin receptors the ability of MIBG to identify bone and bone marrow metastases,
(68Ga-DOTA-Tyr3-octreotide), (68Ga-DOTA-TOC), (68Ga-DOTA- 123
I MIBG was overall superior for stage IV NB, especially during
NOC), and (68Ga-DOTA-TATE) may have a higher sensitivity for initial chemotherapy. 18F-FDG PET may be of limited value for the
the detection of NB lesions. 68Ga-DOTA-TOC PET has been detection of bone marrow and bone metastasis. Moreover, it is not
A B C
D E F
Figure 25.5. Bone scan in a 4-year-old boy with NB showed an abnormal activity in the skull (A) with no significant abnormal uptake in the vertebrae, pelvis, and
femurs (B and C). 123I-MIBG scan (D–F) revealed multiple bone metastases. (continued )

G H
Figure 25.5. (Continued ) 123I-MIBG scans 5 months

J after treatment (G–I) and 4 years later on follow-up
studies (J) were normal.
a specific radiotracer and can be positive in other neoplastic and 123I-MIBG scintigraphy detected the lesions correctly in 16
lesions or inflammatory processes. (94%) and 11 (65%), respectively. On scan-based analysis, the sen-
Kushner et al.70 proposed that 18F-FDG PET scan with bone sitivity of 18F-DOPA PET/CT and 123I-MIBG were 95% and 68%,
marrow study may be sufficient for monitoring NB after resection respectively, with similar specificity. In 9 of 28 paired scans (32%)
18
of the primary tumor. However, in another comparative study by F-DOPA PET/CT results influenced the patient management.74
Taggart et al.,71 in 21 patients with relapsed NB, MIBG scintigraphy
was significantly more sensitive for individual lesion detection
than 18F-FDG PET, though 18F-FDG PET could sometimes play a
Treatment
complementary role, particularly in soft tissue lesions. The exact The treatment of NB depends on the stage of disease and the age
role of 18F-FDG PET should be clarified with further studies. of patient. In stage I and II surgical excision of the tumor is the
Other radiotracers have also been used in NB. Shulkin et al.72 first-line treatment. For stages III and IV, the treatment is usually
used C11-hydroxyephedrine (HED) and 123I MIBG in seven patients a combination of surgery and chemotherapy and sometimes bone
with NB and found similar results in both studies. In two patients, marrow transplantation with high-dose chemotherapy. However,
detection of lesions was better visualized in the abdomen with despite an initial good response to therapy, 50% to 60% of patients
MIBG scintigraphy because of the relatively less hepatic accu- with high-risk neuroblastoma have a relapse, probably because of
mulation of MIBG than HED. Piccardo et al.73 showed that 3,4- drug resistance.48
dihydroxy-6-F-18-fluoro-l-phenylalanine (18F-DOPA) PET/CT has 131
I-MIBG has been used for the treatment of NB cells since
a higher sensitivity than 123I-MIBG scintigraphy to detect NB 1984.75 As 131I-MIBG has a high specificity in NB cells and because
lesions. They prospectively evaluated 28 paired 123I-MIBG and of a prolonged intracellular retention at tumor sites and in contrast
18
F-DOPA PET/CT scans in 19 patients with stage III and IV NBs. NB to normal tissues, 131I-MIBG is a good radiotracer for the treatment
lesions were confirmed in 17 of 19 patients. 18F-DOPA PET/CT of NB.

Usually, 131I-MIBG is used as a single agent in progressive or The clinical presentation is variable from asymptomatic cases to
recurrent neuroblastoma after conventional therapy. In 1991, Hoef- symptoms caused by increased serum catecholamine level (hyper-
nagel et al.76 published a study in 49 children with high-risk progres- tension, palpitations, headaches, pallor, and tremors). Elevated levels
sive or relapsed NB patients after conventional therapy. They used a of plasma and urinary catecholamines are diagnostic. Localization
fixed dose of 100 to 200 mCi of 131I-MIBG for the treatment of NB. studies should be performed after a conclusive biochemical diagnosis
Seven patients showed complete responses and 23 showed partial has been made. However, in patients with a hereditary predisposi-
responses. Similar results were shown by other investigators.77,78 tion for pheochromocytoma, even with lower or normal levels of cat-
131
I-MIBG has also been used in combination with myeloablative echolamines further diagnostic imaging may be needed because of a
therapy before autologous bone marrow transplantation (ABMT). higher chance of developing paraganglioma or malignant disease.84
Voute et al.79 combined 131I-MIBG therapy with hyperbaric oxygen in MRI has an excellent sensitivity (90% to 100%) for the detection
recurrent stage IV NB. They concluded that the survival rate at of pheochromocytoma. However, additional imaging with a higher
28 months has increased compared to 131I-MIBG treatment alone. specificity like 123I-MIBG is needed to confirm the diagnosis and
Other investigators have combined 131I-MIBG therapy with che- evaluate extra-adrenal metastatic involvement.85 18F-FDG PET/CT
motherapeutic agents.80,81 By adding chemotherapeutic agents to is also another modality which is useful to detect the lesion and its
MIBG therapy, the hematologic toxicity will increase. Thus, in metastases. Pheochromocytomas are generally slow-growing tumors.
some of these studies, they followed the treatment by stem cell Surgery is the mainstay of therapy with excellent response if the
rescue or autologous bone marrow transplantation. 131I-MIBG tumor is resected before becoming metastatic. However, in cases of
therapy can also be used preoperatively, at diagnosis, for inoper- metastatic disease, the treatment options are very limited and the
disease can be eventually fatal.63,86

able stage III and IV diseases for shrinkage of the tumor.
The protocol and indications for 131I-MIBG therapy is different
in different centers. Intravenous infusion of fixed doses of 100 to
300 mCi 131I-MIBG in 1 to 4 hours is the most common approach. Central Nervous System Tumors
Patients should have MIBG-positive lesions in whole-body MIBG
scintigraphy. Premedication with thyroid-blocking agent before and CNS neoplasms account for approximately 16% to 20% of all
during the therapy is essential. The thyroid-blocking agents (sodium malignancies during childhood and adolescence. CNS cancer is
or potassium perchlorate or Lugol iodine solution) should be started the most common solid tumor in children and the second most
3 to 5 days before the therapy and continued for 10 days after the common pediatric malignancy. Brain tumors are the leading cause
therapy. The interactive medication with MIBG uptake should also of cancer deaths in pediatric oncology patients. Primary brain
be discontinued (Table 25.3). It is suggested to discontinue these tumors in children are generally classified based on the cell type
medications 1 or 2 weeks before the therapy. Pregnancy and and location of origin in the brain. Brain cells arise in early devel-
breast-feeding, life expectancy less than 1 month, evidence of opment from primitive neuroectodermal tissue. Although there
myelosuppression (Hb < 90 g, total white cell count <4 × 109, plate- are some other cells in the brain, neurons and glial cells are two
lets <100 × 109), and rapidly deteriorating renal function main cell types in the brain. Thus the majority of brain tumors are
(GFR < 30 mL/min) are contraindications for the MIBG therapy. from neuroepithelial cells. Table 25.5 shows the WHO classification
Hematologic toxicity is one of the main concerns after MIBG
therapy. Thrombocytopenia is a common side effect probably
caused by radiation to the bone marrow (possibly megakaryo- Tab l e 2 5 . 5
cytes) or uptake of MIBG by thrombocytes.82 The absorbed dose to
bone marrow which is the critical organ should not exceed 2 to World Health Organization Histopathologic
2.5 Gy. The hematologic toxicity will increase when there is bone Classification of Central Nervous System Tumors
marrow involvement at the time of MIBG therapy. Other side
effects are, decrease in erythrocytes and leukocytes (particularly Tumor Origin Tumor Cell Type (Tumor Examples)
with high-dose MIBG therapy), deterioration of renal function
(in the cases of using chemotherapeutic agents affecting renal Tumors of Astrocytic tumors (Astrocytoma, Anaplastic Astrocytoma,
function, simultaneously), and hypothyroidism (in the cases of neuroepithelial Pilocytic Astrocytoma, Pleomorphic Xanthroastrocytoma,
inadequate suppression before and during the therapy). tissue Subependymal Giant Cell Astrocytoma)
Oligodendroglial tumors (Oligodendroglioma, Anaplastic
Isolation of patients is important for radiation safety. By invit-
Oligodendroglioma)
ing parents to be involved, explaining the procedure, increase the Ependymal tumors (Ependymoma, Anaplastic Ependymoma,
distance and decrease the time of exposure, and encouraging Myxopapillary Ependymoma)
them to wear disposable gown, gloves and mask, isolation will be Choroid plexus tumors (Choroid Plexus Papilloma, Choroid
practical and safe. In addition, the external radiation dose to par- Plexus Carcinoma)
ents can be measured by a pocket dosimeter and probably urine Neuronal tumors (Gangliocytoma, Ganglioma, Desmoplastic
sample if internal contamination is suspected. Infantile Neuroepithelioma, Dysembryoplastic Neuroepithelial
Tumor)
Pineal tumors (Pineocytoma, Pineoblastoma)
Pheochromocytoma Embryonal tumors Primary neuroectodermal tumors (PNETs) (Medulloblastoma,
Neuroblastoma, Ependymoblastoma)
Pheochromocytomas are rare in children and are seen primarily Other embryonal cells (Medulloepithelioma, Neuroblastoma,
Ependymoblastoma)
in adolescence or young adulthood. The average age of presenta-
tion is 11 years. These tumors arise from chromaffin cells of adre- Germ cell tumors Germinoma
nal medullary or extra-adrenal paraganglionic tissue. The majority Embryonal carcinoma
of cases arise from adrenal medulla (85%), with the remainder Endodermal sinus tumor
Choriocarcinoma
occurring in extra-adrenal sites, like organ of Zuckerkandl and
Teratoma
sympathetic ganglia surrounding the kidney. In children, approxi- Mixed germ cell tumors
mately 40% of pheochromocytomas are associated with genetic Ependymoblastoma
mutations.83 Pheochromocytoma is seen in several familial syn-
Tumors of the Pituitary adenoma
dromes: MENs (MENIIA and IIB), von Hippel–Landau syndrome,
sellar region Craniopharyngioma
neurofibromatosis (NF-1), and familial paraganglioma syndromes.

based on the histopathologic origin. In general, astrocytomas rep- MIBI has the advantages of better image quality and no significant
resent for approximately 52% of CNS malignancies, PNET accounts brain uptake. The sensitivity of 99mTc-MIBI has been reported to be
for 21%, other gliomas 15%, and ependymomas for 9%.87 In the similar to 201Tl, but the specificity is slightly higher. Brain tissue
posterior fossa (infratentorial), medulloblastoma, cerebellar astro- does not show any 99mTc-MIBI activity, however, mild physiologic
cytoma, ependymoma, and brain stem gliomas (BSGs) are most activity may be seen in the choroids plexus. Both 201Tl and 99mTc-
common. Hypothalamic gliomas, craniopharyngiomas, and germ MIBI are lipophilic radiotracers and their uptake does not rely on
cell tumors are more common in the third ventricle. Astrocytomas alteration of blood brain barrier. Other radiotracers like 99mTc-
(many of them low grade) are the most common neoplasms in the labeled glucoheptonate (GHA), and 99mTc HMPAO/201Tl have also
supratentorial region. been used for the assessment of brain tumor recurrence.
Unlike adults and older children, the frequency of cerebellar Many studies have been reported the use of 18F-FDG PET in
and the brainstem malignancy is relatively higher in young chil- brain tumors for diagnosis, preoperative assessment, and to deter-
dren. The frequency of brain tumors has slightly increased during mine postoperative/radiation changes versus viable/recurrence
the last two decades probably because of the improvement in tumor (Fig. 25.6).90 Increased activity in the tumor relative to back-
diagnosis or changes in the environmental factors. In general the ground uptake is considered positive for tumoral involvement.
prognosis of brain cancer is not good. The prognosis is even worse However, because of the relatively high uptake in the brain tissue,
in infants with ependymoma or PNET. detection of tumors with less metabolic activity is difficult espe-
MRI and CT are the principal imaging modalities used in staging cially with small tumoral foci. High-grade tumors usually show
and surveillance of children with brain tumors. Their main limita- higher FDG uptake.91,92 However, the higher activity in 18F-FDG is
tion is the inability to differentiate between viable residual tumor or not always correlate well with magnetic resonance spectroscopic
recurrence and postsurgical or postradiation changes. Functional imaging (MRSI). In a study by Hipp et al.93 in 37 pediatric patients
imaging with 201Tl or 99mTc-MIBI has unique ability to determine with brain tumor, the agreement between the intensity of activity
viable residual tumor or recurrence. The sensitivity and specificity in 18F-FDG PET and tumor metabolism based on the maximum
of 201Tl for the detection of childhood recurrence brain tumor are choline:N-acetyl-asparate (Cho:NAA) on MRSI was low. Active
approximately 80% and 90%, respectively.88,89 However, evaluation tumor metabolism was observed more frequently using MRSI com-
of small residual tissues or tumors with a central necrosis and a rim pared to 18F-FDG PET. The results indicated that 18F-FDG PET and
of viable tissue may be difficult. The ratio of 201Tl uptake in the MRSI detected similar but not identical regions of tumor activity.
region of tumor versus contralateral brain tissue may be also help- Increased activity in a low-grade tumor with low FDG uptake
ful to determine a viable tumor versus postradiation changes. 99mTc- may indicate progression to a higher-grade tumor.72 The higher
Figure 25.6. 18F-FDG PET scan in a patient

with PNET reveals multiple hypermetabolic
lesions in the brain, spinal cord, and liver, as
well as a bone lesion in the anterior superior
iliac crest.

FDG uptake in the tumors may indicate a worse prognosis with a Tab l e 2 5 . 6
lower survival rate.74 Zukotynski et al.94 evaluated the associations
between 18F-FDG uptake and progression-free survival (PFS), Hodgkin Disease Staging
overall survival (OS), and MRI indices (tumor volume on fluid-
attenuated inversion recovery, baseline intratumoral enhance- Stage Description
ment, diffusion and perfusion values) in 40 children with a newly
diagnosed diffuse intrinsic BSG. Increased FDG uptake in at least I Involvement of a single lymph node group or localized involvement of
half of the tumor associated with poorer survival than those with an extralymphatic organ
uptake in less than 50% of the tumor. Intense tracer uptake in the II Involvement of more than one lymph node group; or localized
tumors, compared to gray matter, was also associated with involvement of an extralymphatic organ on the same side of the
decreased survival. Higher 18F-FDG uptake was seen in tumors diaphragm
with enhancement on MR images. Further studies are needed to III Involvement of more than one lymph node group on both sides of the
confirm these findings. 18F-FDG PET may be also helpful to dif- diaphragm with or without localized involvement of an extralymphatic
organ
ferentiate between post operation/radiation changes and viable
IV Diffuse involvement of one or more extralymphatic organs with or
tumor.95 However, increased FDG activity may be also seen after without lymph node involvement
intensive radiation66 or shortly after radiation therapy.67
(11C) l-methionine [11C-MET] has also been used for pediatric
brain tumors. The uptake of 11C-MET is minimal in the normal
brain tissue thus allows a better tumor to background activity.96 sentation. Sometimes mediastinal adenopathy can cause a cough

11
C-MET was useful for initial tumor assessment,97 for differentia- or shortness of breath. B symptoms (fever, anorexia, weight loss,
tion of recurrence/viable residual tumor versus scar,98 to predict and night sweats), tiredness, pruritus, neurologic symptoms, ane-
prognosis99 and in combination with MRI for surgical plan in mia, and bone pain are other symptoms. The diagnosis will con-
neurosurgery.97 firm with histopathology. Initial examinations usually include
laboratory examination, chest x-ray, chest, abdominal, and pelvic
CT scans, and 18FDG PET study. Bone marrow aspiration may be
Lymphoma done when there are B symptoms, in stage III or IV and when there
is evidence of bone marrow involvement like thrombocytopenia,
Lymphoma accounts for approximately 15% of pediatric cancers. anemia, and leukopenia.
67
It is the third most common type of cancer in children after leuke- Ga citrate scan has been used as the most useful functional
mia and brain tumors with the peak age at 15 to 19 years. The imaging modality for the evaluation of lymphoma (for staging and
percentage of lymphoma to the childhood malignancy is only 3% response to therapy) for decades. The sensitivity of 67Ga scintigra-
for children younger than 5 years of age to 24% for 15 to 19 years. phy in detection of lymphoma depends on the grading and type of
Lymphoma can be simply categorized into Hodgkin disease and lymphoma (Tables 25.6 and 25.7). 67Ga scan is more positive in
the non-Hodgkin lymphomas (NHL). For younger children NHL is high-grade, B-cell or Burkitt lymphoma.101 The sensitivity and
more common than Hodgkin disease, whereas the reverse is true specificity of 67Ga scan to detect lymphoma and its metastases is
for adolescents. The 5-year survival rate is approximately 91% for approximately 80% to 90%, respectively.102 A baseline 67Ga scan is
Hodgkin disease for the patients younger than 20 years, com- essential to evaluate the uptake of the tumor and to have a base-
pared to 72% for NHL. The 5-year survival rate for patients less line for assessing response to therapy (Fig. 25.7). There are some
than 20 years of age with NHL increased from 56% in 1975 to reports on the use of gallium study for the evaluation of early
1984 to 72% in 1985 to 1994.100 response to therapy and restaging of lymphoma.103 Gallium study
HL is less common than NHL and accounts for 6% of childhood is especially useful for the evaluation of residual viable tumor after
malignancy. There are two peak ages for HL; 15 to 30 year old and therapy versus nonviable scar tissue. MRI and CT scan have a
>55 year old. The etiology of HL is not well understood. A genetic limited role to differentiate viable residual/recurrence versus
predisposition and prior viral infection have been proposed as the posttherapeutic fibrosis. 67Ga scan has also prognostic value after
possible causes. According to the Revised European American therapy; a positive scan may indicate a worse prognosis whereas
Lymphoma Update of the WHO classification, HL is divided into a negative study (after treatment of a positive tumor) is suggestive
two main categories: (1) Classical HL and (2) nodular lymphocyte of a good prognosis. Thyums rebound, reactive bilateral hilar
predominant Hodgkin lymphoma (NLPHL). Classical HL is further uptake and activity in the parotid or salivary gland may be inter-
divided into four histologic subtypes: (1) Nodular sclerosis (most preted as a positive gallium scan.104,105 SPECT study and correla-
common; approximately 70% of cases, with good prognosis), tion with anatomical modality is helpful to diagnose these potential
(2) mixed cellularity (intermediate prognosis), (3) lymphocyte rich
(good prognosis), (4) lymphocyte depleted (worst prognosis; rare
in children; more common in HIV patient and positive EBV). Tab l e 2 5 . 7
NLPHL has an excellent prognosis.
The incidence of NHL varies much less by age than Hodgkin Non-Hodgkin Lymphoma Staging
disease. NHL incidence increases up until age 4 where it reaches a
plateau and maintains until the second decade of life when rates
Stage Description
increase again. Congenital immunodeficiency disorders (CIDs) and
HIV are associated with an increased risk of NHL. The NHLs of I A single tumor or lymph node group (not involving the mediastinum or
children are a heterogeneous group of tumors which can be clas- abdomen)
sified histopathologically into many subgroups. The major sub- II Either a single tumor with regional nodal involvement, two or more
groups are: (1) Burkitt and Burkitt-like lymphomas (more common nodal groups on the same side of the diaphragm, or a primary
in 5 to 14 years old; often occur in the abdomen), (2) lymphoblastic gastrointestinal tumor (irrespective of regional nodal involvement)
lymphoma precursor T (usually mediastinal), (3) anaplastic large which is completely resected
cell lymphoma, and (4) diffuse large B-cell lymphoma (DLBCL; III Either involvement of nodal groups on both sides of the diaphragm, any
most common subtype among 15 to 19 year old). primary intrathoracic tumor, extensive intra-abdominal disease,
paraspinal disease, or epidural disease
In general, the patients with lymphoma present with only minor
IV Bone marrow or central nervous system involvement
symptoms. Peripheral lymphadenopathy is the most common pre-

Figure 25.7. 67Ga scan in a 12-year-old

boy with Hodgkin disease revealed Ga-avid
tumor in the neck and mediastinum (A). After
two cycles of chemotherapy (B), the lesions
A B were not metabolically active indicative of a
good response to therapy.
false-positive findings. Although 67Ga scan was used for a long Bone involvement is relatively rare in primary lymphoma.
time in lymphoma, 18F-FDG PET scan is now the preferred modality. However, it may be seen in up to 30% of disseminated HL. Whole-
With 18F-FDG PET study, the time of imaging is shorter, the radia- body bone scan with 99mTc-MDP can be useful for the detection of
tion dose is less, and the image quality is much better. bone metastasis. Bone scan may show focal or diffuse uptake or
201
Tl scintigraphy has also been used in combination with the areas of decreased activity. The sensitivity of bone scan for the
67
Ga scan. 67Ga scan may be positive in inflammatory/infectious detection of bone metastasis is more than radiography for HL. The
process and thymic rebound. A negative 201Tl scan is helpful in usefulness of bone scan for NHL is controversial.107 67Ga, 18F-FDG
these cases. However, it should be kept in mind that some lympho- PET, CT scan, and MRI are usually better for the detection of bone
mas are not 201Tl avid. A negative or low-level uptake in 201Tl scan involvement in lymphoma (Fig. 25.8). 67Ga is better than bone
in a previously positive 201Tl study is a reliable finding to differen- scan for the evaluation of response to therapy.108
tiate tumor versus other inflammatory/infectious process. 201Tl 18
F-FDG PET has replaced 67Ga for the evaluation of lymphoma
shows more uptakes in low-grade lymphoma than 67Ga study, in recent years. It is especially useful in children because of the
whereas 67Ga has a more uptake in high-grade lymphoma.106 less radiation than 67Ga. Moreover, better image quality and the
Thus, 201Tl may have a role in 67Ga-negative tumors. shorter time needed to complete the study are other advantages
A B C
Figure 25.8. A 15-year-old girl with primary bone lymphoma. (A) Bone scan and (B) 67Ga scan showed increased activity in the proximal right tibia and left
ischium. Abnormal increased activity in the proximal right tibia has markedly decreased on the follow-up 67Ga scan (c) after treatment with normalization of the
lesion in the left ischium.


A B
Figure 25.9. 18F-FDG PET/CT in a 7-year-old patient revealed multiple hypermetabolic lesions in the neck, mediastinum, and hilar regions (A) before treatment
and resolution of the lesions after two cycles of chemotherapy (B) indicative of a good response to therapy.
of 18F-FDG PET. The uptake of 18F-FDG also depends on the grad- Based on RRCML, a routine 18F-FDG PET during therapy is not
ing and type of lymphoma. 18F-FDG PET can be used at diagnosis recommended. However, a routine restaging after completing the
for staging of lymphoma. According to the Revised Response Cri- chemotherapy and/or radiotherapy is recommended especially for
teria for Malignant Lymphoma (RRCML), 18F-FDG PET is recom- Hl and DLBCL. Because posttherapeutic inflammatory process
mended (although is not mandatory yet) at diagnosis, for routine may also show increased uptake on 18F-FDG PET, the study should
evaluation of FDG-avid lymphomas which are curable.109 18F-FDG be done at least 3 weeks after chemotherapy. In the cases of radio-
PET shows increased uptake in most common types of lympho- therapy PET study should be performed at least 2 to 3 months
mas (e.g., diffuse large B-cell NHL, follicular NHL, mantle cell later. 11C-MET PET has also been used in NHL with superior tumor
NHL, HL) with a sensitivity of more than 80% and a specificity of to background contrast. 18F-FDG PET was superior to 11C-MET
about 90% which is superior to CT scan.110,111 In many studies the PET in differentiation between low-grade and high-grade tumors.
use of 18F-FDG PET at diagnosis has led to change in disease stage Further studies with a higher number of patients are needed to
and change of management approximately in 10% to 20% of confirm these findings.120 In summary, 18F-FDG PET is recom-
cases.112–114 The other purpose of initial study is to have a baseline mended for staging of lymphoma at diagnosis and evaluation of
for the evaluation of response to therapy (Fig. 25.9). However, treatment response after completion of therapy. PET will probably
18
F-FDG PET/CT at initial evaluation may be of interest not only play more role in future for the evaluation of therapy response
for disease staging or posttherapy evaluation but also to guide the during the treatment (between cycles 1 and 4), for monitoring the
therapeutic strategy and sometimes to guide biopsy.115,116 18F-FDG patients, radiation field planning, planning for biopsy, and evalu-
PET at diagnosis may also have a prognostic value. In a study by ation of complications.
Okada et al.117 in adult population, patients with recurrence had a Other radiotracers have also been used in lymphoma. Soma-
higher FDG uptake pretherapy at diagnosis. tostatin receptors have been found in HL. 111In-DTPA-D-Phe-Octreo-
18
F-FDG PET has a validated role in response assessment fol- tide had a sensitivity of 94% in a study by Lugtenburg et al.121
lowing therapy in lymphoma. CT scan is a reliable method for Eighteen percent of stage I and II HL were upstaged after the
staging and restaging of lymphoma. However, it has a low specific- Octreoscan results. Probably because of the introduction of 18F-FDG
ity to assess the response to therapy especially in patients with in recent years, somatostatin receptor scintigraphy has not found
bulky disease before treatment in whom there is usually a residual general acceptance. 99mTc LL2 monoclonal antibody to the CD22
mass after treatment.110 The residual tissue may be viable or it receptor on B lymphocytes has also been introduced with similar
may be necrotic. 18F-FDG PET has a high sensitivity to detect via- result compared with 67Ga study.122 However, it is not generally
ble residual tissue posttherapy. High negative predictive value of accepted too. Lymphoma tumors can show 99mTc-sestaMIBI uptake.
18
F-FDG PET after treatment makes it a reliable method to rule In a study by Kapucu et al.123 the uptake of 99mTc-MIBI was associ-
out any viable residual tumor or recurrence.118 However, there are ated with the future response to therapy. However, the exact sensi-
some reports that 18F-FDG PET did not detect the microscopic tivity and specificity of 99mTc-MIBI in lymphoma are not well
viable tumors.117 The sensitivity of PET for the detection of resid- established.
ual tissue is approximately 90% to 100%. However, the specificity
is only 57% to 75%. False-positive results were reported in 16% to
18% of the cases.119 The reasons for false-positive results were Bone Tumors
fibrosis, abdominal wall hernia, inflammatory process like appen-
dicitis, thymus, and HIV-associated lymphadenopathy. Malignant bone tumors accounted for approximately 6% of child-
18
F-FDG PET has been used during the therapy for the early hood cancers reported by Surveillance, Epidemiology, and End
assessment of the treatment and prediction of the future response. Results (SEER) program of National Cancer Institute (NCI) areas

Table 25.8 The tumor is not radiosensitive, thus radiotherapy is reserved for
inoperable tumors. Staging usually depends on grading of the
Surgical Staging for Osteosarcoma tumor (>15% risk of metastatic disease with a high-grade OS) and
whether the tumor is contained within an anatomical compart-
Stage Description ment (Table 25.8). Most OSs are high grade and intracompart-
mental. If there are distant metastasis, compartment status is less
IA Low grade, intracompartmental important.
IB Low grade, extracompartmental The most common presentation is pain and swelling around a
IIA High grade, intracompartmental joint. The first investigation is usually a plain x-ray followed by
IIB High grade, extracompartmental further evaluation with CT scan, MRI, chest x-ray, chest CT scan,
III Metastases bone scan, and probably FDG PET scan. The most common
involved area is the metaphyseal portion of long bones. Nearly
half of the cases occur around knees. Plain radiography usually
from 1975 to 1995. OS and Ewing sarcoma are the most common shows a moth-eaten appearance of bone destruction with endos-
types of malignant primary bone tumors in children. The inci- teal and periosteal sclerosis (resulting from malignant new bone
dence of OS is almost double that of the Ewing sarcoma. The formation). There is also extensive periosteal reaction with an
incidence of bone cancers increases gradually between age 5 and adjacent soft tissue swelling. CT scan is useful for the evaluation
age 10 and then a steeper rise is seen after age 11 until age 18 of intramedullary extension, and to detect skip metastases in the
(peak age). Survival rates for OS were higher than those for bone. Chest CT scan is useful to detect pulmonary metastases. MRI
Ewing sarcoma especially in the earlier time period. The 5-year is the best modality for the evaluation of marrow extension and
relative survival for children with bone cancer improved from adjacent soft tissue extension.
49% in the period 1975 to 1984 to 63% in the period 1985 to On the bone scan, the tumor is usually positive on flow and
1994. blood pool images (hyperemia) as well as an intense increased
uptake on delayed views. Multifocal bone lesions or skip metas-
tases may be detected by bone scan. However, the main indi-
Osteosarcoma cation for bone scan is to detect distant bone metastases
OS is the most common primary bone tumor of childhood. OS (Fig. 25.10). Other findings that may be detected on bone scan
originates from primitive bone-forming mesenchymal stem cells include bone tracer uptake in pulmonary metastatic sites, the
and most commonly involves the metaphyseal portion of the long pattern of hypertrophic osteoarthropathy (with pulmonary
bones. The peak age for OS in children is 11 to 18 years. The etiol- metastasis), and postsurgical changes after amputation or surgi-
ogy is unknown. However, an association has been proposed with cal implants. Bone scan may be positive for a long time after
direct ionizing radiation, pre-existing benign disease (Paget dis- radiation therapy. Other radiotracers like 201Tl or 18F-FDG may
ease) and genetic susceptibility (Li–Fraumeni, bilateral retinoblas- be more useful in this context.
201
toma, and Ruthmond–Thompson syndromes). The 5-year survival Tl usually accumulates in OS and can be used as a marker
rate for children with OS is currently 70% to 80%. With the new for the detection of viable tumor.124,125 Decrease 201Tl uptake after
advances in chemotherapy combined with surgery the survival treatment is indicative of a good response to therapy. Rosen et al.
rate has markedly improved. Advances in surgical techniques described how serial 201Tl studies could be helpful to monitor the
have led to better functional outcomes with limb salvage surgery. tumor response. In their study, 201Tl scan could differentiate
Figure 25.10. Bone scan in a 12-year-old

girl with osteosarcoma of the distal right
A B femur (A) without distant bone metastases.
(B) Follow-up bone scan after surgery.

responders versus nonresponders to chemotherapy and guided bone scans) are also needed during the first 2 years because of the
the oncologist for earlier amputation or limb salvage therapy.123 high risk of bone metastases which were not detected initially.
Although there are not many large studies with 99mTc-sestaMIBI, Detection of bone metastases on follow-up bone scan have been
the result seems to be similar to 201Tl scintigraphy.126 reported in 33% to 45% of patients who were free of metastasis at
The early result with 18F-FDG PET was promising. In a pro- presentation.130,131 Decreased uptake at the site of tumor after
spective multicenter study by Volker et al.127 on 46 pediatric treatment is indicative of a good response to therapy; however,
patients (Ewing sarcoma family tumors = 23; OS = 11; RMS = 12) increased or persistent activity may be suggestive of recurrence or
to evaluate the usefulness of 18F-FDG PET for initial staging and superimposed complications (fractures, infection, etc). In a study
therapy planning, PET was as accurate as the combination of all by Erlemann et al.,132 the accuracy of bone scan for the assess-
conventional imaging modalities (CIMs) (including ultrasound, CT ment of therapeutic success was less than MRI (50% to 85%).
scan, MRI, and bone scintigraphy). 18F-FDG PET was superior to Thus, further evaluation (with MRI or other methods) is indicated
CIMs for the assessment of lymph node involvement (sensitivity, for equivocal bone scan findings.
67
95% versus 25%) and bone manifestations (sensitivity, 90% versus Ga uptake has been reported in EWS. 67Ga may also show soft
57%), whereas CT was more accurate than 18F-FDG PET for lung tissue involvement (adjacent to the tumor or distant metastasis).
metastases (sensitivity, 100% versus 25%). A combination of 18F- 67
Ga scintigraphy may be useful for evaluation of the response to
FDG PET with diagnostic CT from the chest may be the best option therapy and appearance of recurrences.133 However, it is generally
for the evaluation of these patients. 18F-FDG PET may be also use- not used routinely in clinical practice. EWS may also show 201Tl
ful to assess or predict the response to therapy.128 However, the uptake. However, the degree of 201Tl uptake in EWS is less than
usefulness of 18F-FDG PET for the evaluation of treatment response OS. Because the findings on 67Ga scintigraphy as well as bone scan

was not confirmed in a study by Huang et al.129 on 10 patients are not specific, 201Tl scan may be more accurate to assess the
with OS. In their study, the average tumor necrosis rate deter- response to therapy and for follow-up. The accuracy of 201Tl scan
mined by 18F-FDG PET was 22%, whereas it was 54.5% on histo- to differentiate recurrence versus posttherapeutic changes in EWS
pathology. The use of 18F-FDG PET is still not recommended was approximately 96% in a study by Kostakoglu et al.134 18F-FDG
routinely for the evaluation of treatment response. PET/CT may be useful for the evaluation of local extension and
distant metastases at diagnosis and restaging after therapy
(Fig. 25.12).127 18F-FDG PET/CT may be also helpful for differen-
Ewing Sarcoma tiation of recurrence versus posttherapy changes.135 Further
The term Ewing sarcoma (EWS) describes a spectrum of small investigations are needed to assess the exact accuracy of 18F-FDG
round cell tumors including Ewing sarcoma of bone, extraosseous PET in these scenarios.
Ewing sarcoma, and peripheral primitive neuroectodermal tumors
(PNETs). EWS of bone is the second most common primary bone
tumor in children (3% of all childhood malignancies). The EWS Rhabdomyosarcoma
most likely originates from neural crest tissue and can involve
both the extremities and the central axial skeleton. The etiology is RMS accounts for approximately 4% to 8% of all malignant dis-
unknown. In black children, the incidence is much less than in eases in children less than 15 years old. The peak age of occur-
caucasian children. The overall 5-year survival is approximately rence is 2 to 5 years; a second peak occurs at 15 to 19 years.
70%. The survival is better in younger children than in older chil- RMS is the third most common extracranial solid tumor in child-
dren or adults. The prognosis depends on the size and surgical hood, after neuroblastoma and Wilms tumor. The overall survival
resectability of the tumor, the presence of metastases, and the rate is approximately 70%, which has increased from about 20%
response to chemotherapy. Almost 25% of patients have detect- in the 1960s. The etiology is not well understood. The majority
able metastases at diagnosis. Treatment involves intensive chemo- of cases are sporadic, however, a higher incidence has been
therapy and surgical resection of tumor with or without radiation reported in some congenital/genetic abnormalities (neurofibro-
to the tumor site. matosis type 1, Beckwith–Wiedemann syndrome, Gorlin syn-
Patients may have variable symptoms depending on the site of drome, hereditary retinoblastoma syndrome, Costello syndrome,
origin of the disease. Generally, they present with local pain and Rubinstein–Taybi syndrome). Maternal or paternal use of mari-
swelling similar to osteomyelitis or OS. A plain film is usually the juana and cocaine has also reported to increase the risk of RMS
first diagnostic procedure. The plain film shows ill-defined, per- in their child. RMS can occur anywhere but it is more common
meative bone destruction or lytic lesion of flat bone or diaphysis in the head and neck (35% of cases; especially in the orbit and
or metadiaphysis of tubular bone with periosteal reaction (“onion- paranasal sinuses), genitourinary tract (about 20%), and extrem-
skin” type pattern). Periosteal reaction may have a spiculated pat- ities (about 20%). The presentation depends on the location of
tern. The CT scan shows the extent of cortical disruption and aids the tumor and is usually a mass or bulging with no history of
in surgical biopsy planning. The CT scan is not sensitive for the trauma. Generally, a multimodality approach is needed for the
evaluation of intramedullary tumor extension. MRI is the most treatment of RMS including surgery, radiation, and chemother-
useful technique for the evaluation of intramedullary and soft tis- apy. The prognosis depends on many factors including the loca-
sue extent of disease including the relationship to surrounding tion, histology, and staging (Table 25.9). Unfavorable sites include
normal structures such as the neurovascular bundle. MRI may parameningeal site, bladder/prostate, trunk, retroperitoneum,
also show skip metastases (bone metastases involving bone mar- and extremities. Adverse prognostic factors include unfavorable
row in the same bone). Pulmonary metastasis can be assessed sites, alveolar type, undifferentiated histology, distant metastases
with a chest CT scan. including bone or regional lymph node involvement, tumor size
A radionuclide bone scan usually shows intense increased >5 cm, and older age.
activity, although the lesion may also show no activity or only little For the evaluation of bone metastasis, a radionuclide bone
uptake (probably more aggressive tumors) especially in the pelvic scan is indicated. The sensitivity of the bone scan to detect bone
region (Fig. 25.11). Compared to OS, the uptake is more homoge- metastasis in RMS is more than 95%.136 A soft tissue tumor may
neous and the location is more diaphyseal or metadiaphyseal be seen on the bone scan, especially in early flow and blood pool
(rather than nonhomogeneous uptake in the metaphyseal region images. 67Ga scintigraphy is also useful for the evaluation of RMS.
which is commonly seen in OS). Bone scintigraphy is indicated at In a study by Cogswell et al., 67Ga uptake was observed in 86% of
diagnosis because asymptomatic metastases may be detected by the primary tumor. Although the sensitivity of bone scan was higher
the radionuclide bone scan. Follow-up studies (including serial than 67Ga scintigraphy, the 67Ga study had a higher sensitivity

Figure 25.11. Bone scan in anterior (A) and

posterior (B) projection in a 13-year-old boy
with pelvic Ewing sarcoma. Corresponding MRI
B C axial images (C) revealed a big mass with
invasion to the sacrum.
for the detection of soft tissue metastases. If a tumor is 67Ga-avid, 18

F-FDG PET for staging and restaging of RMS by reporting a com-
follow-up 67Ga scan is useful for the evaluation of recurrence in parative study on 35 children using 18F-FDG and conventional
patients in whom recurrence is suspected. The incidence of late imaging modalities (CT scan, MRI, and radionuclide bone scan).
recurrence is low in RMS; thus a routine bone scan or 67Ga study Using 18F-FDG PET/CT, the M stage was correctly assessed in 89%,
is not indicated. MRI may be better for the follow-up evaluation. whereas the accuracy of CIM to assess the M stage was 63%. TNM
201
Tl scintigraphy has been also used for follow-up studies. How- stage was correctly evaluated with 18F-FDG PET/CT in 86% and
ever, lower sensitivity has been reported for 201Tl compared with with CIM in 54% of the patients. Similar results were reported by
67
Ga scan. Both 201Tl and 67Ga scan are usually negative in pulmo- other investigators.127,143,144 18F-FDG PET findings altered the ther-
nary metastases. The CT scan is a better modality to detect pulmo- apy of patients mostly by detecting nodal disease and bone
nary metastases. Sentinel lymph node study is also useful for the involvement.
evaluation of regional lymph node involvement especially for RMS The 18F-FDG PET scan is also useful to detect recurrent disease
of the extremities or paratesticular region.137–139 and to assess response to therapy. Arush et al.135 reported that
18
Rhabdomyosarcoma and other soft tissue sarcomas have been F-FDG PET detected local relapse and distant metastases of sar-
shown to be 18F-FDG avid.140 There is a wide range of SUVmax in coma more accurately than CT/MRI/bone scan. However, the sen-
RMS (Fig. 25.13). The 18F-FDG uptake is higher in high-grade RMS sitivity of 18F-FDG PET is relatively low for pulmonary metastases.127
tumors. The majority of high-grade RMS tumors have an SUVmax Evaluation with a diagnostic CT scan is recommended when pul-
of more than 1.6.141 Tateishi et al.142 showed the usefulness of monary metastasis is suspected.


A C
Figure 25.12. Bone scan (A) in a 14-year-old girl

with Ewing sarcoma of the proximal right tibia with
multiple bone metastases. 18F-FDG PET images (B)
obtained 3 days later revealed numerous areas with
abnormal FDG uptake in bones. Follow-up 18F-FDG
PET/CT 6 months later (C) showed progressed dis- B
ease with multiple bone and lung metastases.

Table 25.9 leukemia (ALL) and acute myeloid leukemia (AML) are the most
common forms, approximately 75% and 15% to 20%, respectively.
TNM Staging of Rhabdomyosarcoma The peak age is 2 to 4 years for ALL and neonate and teen ages
for AML. The incidence of leukemia is substantially higher for
Stage Description white children than for black children. Survival of those diagnosed
with ALL (80% to 90%) is higher than for those diagnosed with
I T1 or T2 (a or b), N0/1/x and M0 and in favorable site such as head AML. ALL was a fatal disease in 1970s but survival for children
and neck (excluding parameningeal), orbit, genitourinary (nonbladder/ with ALL has markedly improved during the last three decades
nonprostate), biliary tract because of improvements in treatment. Survival for children with
II T1 or T2a (not b), N0 or Nx (not N1) and M0 and in bladder/prostate, ALL is very dependent upon age at diagnosis, and the most favor-
extremity, cranial parameningeal, other areas including trunk, able outcome is seen for patients between 1 to 10 years old. The
retroperitoneum, etc. most important risk factors for ALL are prenatal exposure to radia-
III T1 or T2a, N1, M0 in bladder/prostate or tion (x-rays) and specific genetic syndromes (e.g., Down syndrome).
T1 or T2b, N0 or N1 or Nx, M0 in extremity, cranial parameningeal and
For AML, however, many risk factors have been proposed
others including trunk, retroperitoneum, etc., except biliary tract
IV M1, irrespective of T and N and the site of tumor including Genetic syndromes (Down syndrome, neurofibromato-
sis type 1, etc.), immunodeficiency syndromes, ionizing radiation,
T1, confined to anatomic site of origin (a ≤5 cm in diameter in size; b >5 cm in diameter in size); chemotherapy agents (nitrogen mustard, cyclophosphamide, ifos-
T2, extension and/or invasion to surrounding tissue (a ≤5 cm in diameter in size; b >5 cm in famide, chlorambucil, melphalan, etoposide), and benzene.
diameter in size); N0, regional nodes not clinically involved; N1, regional nodes clinically involved Skeletal involvement is common in leukemia; however, a rou-
by neoplasm; Nx, clinical status of regional nodes unknown (especially sites where lymph node
evaluation is not possible; M0, no distant metastasis, M1, distant metastasis present. tine bone scan is not indicated as it usually does not change the
management. A bone scan may be indicated when there is skeletal
pain especially with equivocal radiographic findings. The lesions
Leukemia could be seen on bone scan as focal or diffuse increased uptake.
However, photopenic lesions may also be seen because of aggres-
Leukemias are the most common form of pediatric cancer account- sive tumoral growth, bone necrosis or after methotrexate therapy,
ing for more than one-quarter of childhood cancers. Acute lymphoid or radiation.145
Figure 25.13. 18
F-FDG PET/CT in a
20-month-old baby with rhabdomyosar-
coma of the left thigh showed moderate
FDG uptake in the lesion. The study was
negative for regional lymph node involve-
ment or distant metastases.

Table 25. 10 combination of radical surgery, chemotherapy, and sometimes

radiotherapy. The 5-year survival rate for children with hepato-
Staging System used for Wilms Tumor blastoma is approximately 60%. Survival rates are lower for chil-
dren with hepatocellular carcinoma. The etiology of hepatoblastoma
Stage Description is not well understood.
In general, conventional imaging techniques (US, CT, and MRI)
I Tumor limited to kidney and completely excised are the initial modalities for diagnosis and staging of hepatoblas-
II Tumor extends beyond the kidney but is completely removed toma. Liver and spleen scan with sulfur colloid or hepatobiliary
III >1 of the following criteria must be met: scan with BrIDA may be useful to differentiate follicular nodular
1. Unresectable primary tumor hyperplasia versus other tumors. 99mTc-labeled RBC scinitigraphy
2. Lymph node metastasis is useful to rule out liver hemangioma. 18F-FDG PET has a limited
3. Positive surgical margins role in the initial diagnosis and staging of hepatic tumors. How-
4. Tumor spillage involving peritoneal surfaces either before or during ever, it may have a role for restaging and detection of recurrence.
surgery, or transected tumor thrombus
Tumor markers, including α-fetoprotein (AFP) and conventional
IV Hematogenous metastases
imaging modalities are generally used for follow-up and detection
V Bilateral renal involvement at diagnosis
of recurrence. In a study by Wong et al.,146 the 18F-FDG PET scan
along with AFP measurement were useful to detect recurrence. In
a study by Mody et al.147 on seven children with hepatic cancers
for staging (one patient) or restaging (six patients), 18F-FDG PET

Wilms Tumor was probably most useful to assess response to therapy, in follow-
ing AFP-negative cases and to detect metastatic disease. However,
Wilms tumor (nephroblastoma) is the fourth most common form large prospective studies are needed to confirm the result. 18F-
of childhood cancer and the most common primary renal tumor FDG PET may also provide prognostic information. High 18F-FDG
in children (6% of all childhood cancer). Wilms tumor is by far the uptake in a tumor is suggestive of a less-differentiated tumor and,
most common form of renal cancer in children (approximately thus has poor prognosis.
95% of renal cancers). Other types of renal cancers are much less
common (renal carcinomas, the most common form of renal can-
cer in adults, accounts for only 2.6% of renal cancers in children). Thyroid Cancer
The peak age for Wilms tumor is 3 to 4 years. The etiology is
unknown. However, in 5% of cases, Wilms tumor is associated Thyroid cancer, the most common type of endocrine cancer, affected
with a number of genetic disorders (Beckwith–Wiedemann, Denys– almost 60,000 people in the United States in 2013.148 Of these
Drash, and Perlman syndromes). In the majority of cases, Wilms cases, only 5% occur in children and adolescents, representing
tumor arises from a focal area in the kidney, but it may be multifo- about 1% to 1.5% of all pediatric malignancies.149 Thyroid cancer is
cal within the same kidney (10%). In 5% of cases, it involves both very rare in early childhood; the incidence is higher in the 15- to
kidneys. Invasion to the regional lymph nodes is not uncommon. 19-year-old group. The majority of thyroid cancers are of differenti-
The lung and the liver are the most common sites of metastases ated type, mainly papillary (85%) and to a lesser extent follicular
(Table 25.10). The overall 5-year survival for children with Wilms cancer (10%).150 The anaplastic (undifferentiated) thyroid cancer
tumor is approximately 90%. and medullary cell carcinoma have poorer prognoses than other
Ninety percent of patients present with an asymptomatic types. There is no documented single cause for thyroid cancer.
abdominal mass. In others, symptoms include abdominal pain, However, there are many risk factors that are considered to increase
hypertension, fever, hematuria, anemia, and weight loss. Ultra- the risk of thyroid cancer including ionizing radiation (from both
sound usually shows a fairly homogeneous area with overall echo- environmental and therapeutic sources), family history of thyroid
genicity similar to liver, sometimes with increased or decreased cancer, female gender, and sex hormones. The incidence is higher
echogenic foci caused by hemorrhage or necrosis. Ultrasound is in females; however, the prognosis is slightly worse in males.
useful to identify extension of tumor to adjacent vessels and to Long-term prognosis of differentiated thyroid carcinoma (DTC)
evaluate bilateral disease and liver metastases. CT scan shows a is usually favorable, with overall survival rates of 80% to 95% at
heterogeneously enhancing mass, with foci of low attenuation 10 years for middle-aged adults and about 95% for children. Local
caused by hemorrhage or tumor necrosis. Presence of high atten- recurrence and distant metastases are not infrequent, particularly
uation foci caused by calcification is very rare. CT scan is espe- during the early years of follow-up, but may occur years later as
cially useful for the assessment of local extension into the adjacent well. Survival rates decrease to 40% with distant metastases.151,152
tissues, evaluation of enlarged regional lymph nodes, intravascu- Unlike adults, children with thyroid cancer may present with
lar extension, contralateral kidney for bilateral disease, and finally more advanced disease and have a higher rate of local recurrence
lung and liver for metastases. Because of the renal excretion of and distant metastases.153 The frequency of regional lymph nodes’
18
F-FDG, the usefulness of 18F-FDG PET/CT in diagnosis and eval- involvement at presentation is higher in children than adults. The
uation of local extension of tumor is limited. It may have a role, risk of pulmonary metastases is also higher in children. In our
however, for the evaluation of recurrence versus scars and assess- experience, 18% of our patients with DTC had pulmonary metas-
ment of distant metastases. tases either at presentation or during follow-up. In children,
because the response to treatment is better, the long-term surveil-
lance of DTC recurrences and metastases is crucial throughout the
Hepatoblastoma patient’s life.154
The DTC patients can be categorized into low-, intermediate-,
Primary liver malignancies are rare in children, accounting for and high-risk groups based on the revised American Thyroid
approximately 1% of neoplasms. Two histologic subtypes of pri- Association (ATA) management guidelines.155 Briefly, low-risk
mary liver cancers are most common: Hepatoblastoma (more patients include those with: (i) no local or distant metastases,
than two-thirds of the cases) and hepatocellular carcinoma (most (ii) all macroscopic tumors resected, (iii) without aggressive histology
of the remaining cases). Hepatoblastoma occurs primarily in chil- or vascular invasion, and (iv) no evidence of any abnormal radioio-
dren younger than 5 years of age whereas hepatocellular carci- dine uptake outside the thyroid bed on the first posttherapeutic whole-
noma is more common after the age of 10 years. Treatment is a body scan (RxWBS). Patients are put into the intermediate-risk

group when there is evidence of (i) microscopic invasion of tumor maximum administered dose depends on the radiation absorbed
into the perithyroidal soft tissues at initial surgery; (ii) cervical dose for the bone marrow and lungs (in the case of pulmonary
lymph node metastases or 131I uptake outside the thyroid bed on metastases). The effective absorbed dose to bone marrow should
the RxWBS done after thyroid remnant ablation; or (iii) tumor not exceed 200 cGy and the cumulative exposure of the lungs
with aggressive histology or vascular invasion. Finally, patients should be less than 80 mCi (3,000 MBq) retained activity at
are categorized as high risk when they have (i) macroscopic tumor 24 hours. In our center, low-risk patients are usually treated with
invasion, (ii) incomplete tumor resection, (iv) distant metastases, 370 MBq 131I adjusted for their weight. Higher dosage may be used
and possibly (v) elevated serum thyroglobulin (Tg) levels out of if the patient is high risk or if there are pulmonary or bone metasta-
proportion to what is seen on the posttreatment scan. ses. The patient should stop interfering medications (4 weeks
prior to treatment for levothyroxine and 2 weeks for liothyronine)
and have a low iodine diet for a week before the treatment. History
Imaging of recent diagnostic imaging with contrast materials or any other
The incidence of thyroid cancer in single nodules is relatively high iodine-containing medications should also be obtained. If thyroid
in children. Evaluation with thyroid ultrasound is indicated in every hormones have been withdrawn, the patient should be hypothyroid
patient with a thyroid nodule.155 The use of thyroid scintigraphy for before the iodine administration (TSH > 30 to 40 IU/mL). As an
the evaluation of thyroid nodule is controversial. Thyroid scintigra- alternative, recombinant TSH injections have been used with
phy with 99mTc or 123I can be helpful to determine the functional similar results.163
status of the nodule. As in the adult population, the risk of thyroid Surgery is the main treatment for medullary thyroid cancer.
cancer is higher in cold nodules. However, unlike adults, the risk of Postsurgical ablation therapy with 131I has no role. If the tumor is
thyroid cancer is not very low in hot nodules is children. Thus, fine MIBG avid, 131I-MIBG therapy may be useful for the treatment of
needle aspiration is indicated for every child with a solitary thyroid metastases. Radioimmunotherapy with anticarcinoembryonic
nodule, regardless of the radionuclide imaging findings. antigen (CEA) antibodies have also been used in advanced disease
Conventionally, measurement of serum Tg level and diagnostic with promising results.164
whole-body iodine scanning (DxWBS) are used to detect thyroid
tissue remnant and recurrence in the follow-up of patients with
DTC.156 RxWBS are usually obtained usually 7 to 10 days after the Future Considerations
therapeutic dose of 131I, taking the advantage of high radioiodine
activity that improves the sensitivity of scintigraphy.157,158 The sen- The usefulness of 18F-FDG PET in the diagnosis, evaluation of
sitivity of diagnostic whole-body iodine for the detection of recur- treatment response, and surveillance of childhood cancers has
rence or distant metastases is approximately 70% and the been discussed in many studies with encouraging findings. How-
specificity is more than 95%. Measurement of serum Tg level ever, the information remains very limited in pediatric malignan-
alone, although is very useful, may be misleading. Park et al.159 cies. Further multicenter studies with a larger number of patients
reported a 6.3% of false-negative Tg measurements using RxWBS are needed to define the exact role of PET/CT in pediatric nuclear
as a reference standard. In 15% to 25% of cases, anti-Tg antibody oncology. In addition to the well-established clinical data about
may be high in DTC patients which may result in inaccurate Tg the utility of 18F-FDG PET/CT in lymphoma, soft tissue tumors,
levels, falsely increased or decreased values. Some authors sug- neuroblastoma, etc, initial studies in other rare cancers were
gest following up low-risk DTC patients with ultrasound and Tg promising.
measurement. The sensitivity of ultrasound to detect regional In a recent study, Cheuk et al.165 evaluated the usefulness of
lymph node involvement is greater than 90% but it is not a very 18
F-FDG PET/CT for the evaluation of nasopharyngeal carcinoma
specific modality, especially in children with a higher frequency of (NPC) in pediatric patients. They compared 18F-FDG PET/CT and
enlarged lymph nodes caused by inflammation. On the contrary, MRI for restaging of disease in 18 patients with NPC. They found
the whole-body iodine scan is useful to detect distant metastases out that 18F-FDG PET/CT may underestimate tumor extent and
(lung and bone) as well as regional lymph node involvement and regional lymphadenopathy compared with MRI at the time of
is an essential component of the treatment plan. diagnosis, but it helps to detect metastases and to clarify equivocal
In case of a positive Tg level (Tg > 1.5 ng/mL) and negative findings. 18F-FDG PET/CT was sensitive and specific for follow-up
whole-body scan, further evaluation with 201Tl, 99mTc-sestaMIBI, or and enabled earlier determination of disease remission. They con-
18
F-FDG PET is recommended. Sometimes, the lesions are only cluded that 18F-FDG PET/CT is a useful modality to evaluate and
visible on imaging after whole-body iodine therapy (when the monitor NPC in children.
administered dose of radioiodine was high and background activ- The use of 18F-FDG for the diagnosis and assessment of treat-
ity is low after 7 to 10 days). ment in PTLD has been confirmed in adults. PTLDs are a hetero-
The incidence of medullary thyroid cancer is very rare in chil- geneous group of diseases that occur after transplantation ranging
dren (approximately 2% of thyroid cancers). Thus the information from EBV-driven polyclonal proliferation similar to infectious
about the diagnosis and treatment of medullary thyroid cancer in mononucleosis to monomorphic proliferations that may be indistin-
children is very limited and is based on adult data. In general, guishable from aggressive types of lymphomas. It is very common in
laboratory examination (serum calcitonin level, CEA measure- pediatric oncology especially during the first year following trans-
ment, etc.), ultrasound, CT scan, 201Tl scan, 111In-octreotide scin- plantation and occurs most frequently in multiorgan transplant
tigraphy, 123I-MIBG scan, 99mTc(pentavalent)-DMSA study, 18F-FDG recipients, followed by bowel, heart–lung, and lung recipients.136
PET/CT, and 18F-DOPA PET/CT have been used to detect and It may involve any of the organ systems. The current classification
follow up lesions.160–162 system includes four subtypes that have different prognoses
requiring different treatment strategies. PTLD is usually associ-
ated with EBV virus infection; however, it may occur in EBV sero-
Treatment negative patients. Tissue sampling is necessary for diagnosis and
The main treatment of DTC consists of total or near-total thyroid- further subcategorization. The initial studies with 18F-FDG PET/
ectomy, with resection of involved regional lymph nodes and dis- CT were promising and showed that 18F-FDG PET/CT is a very
section of the central compartment followed by ablation of thyroid useful method for diagnosis, assessment of the extent of disease,
remnants and possible metastases using radioactive iodine and guide for biopsy, and evaluation of treatment response.166 Larger
TSH suppression medication. The administered dose of radioio- studies are needed to fully assess the exact role of 18F-FDG PET in
dine varies in different institutes from 1,110 to 7,400 MBq. The pediatric PTLD.

Congenital hyperinsulinism is a relatively rare disease, which brain MRI to evaluate the extent of disease. Initial experience with
18
is mostly seen in newborn and infants and if it is not treated may F-FDG PET/CT showed that the information provided by PET/CT
lead to severe hypoglycemia and permanent brain damage. Glucose was clinically useful to evaluate disease activity and response to
infusion and surgery should be done before any complications. therapy. This information was not provided by bone scan and
However, exact detection and localization of the hyperfunctioning radiography.170 In another study, Phillips et al.171 showed that
18
foci in the pancreas is of pivotal importance to decrease the chance F-FDG PET is useful for locating active or reparative LCH dis-
of relapse or diabetes after surgery. Selective percutaneous pan- ease as well as response to therapy. In their study, changing in the
creatic vein catheterization and measurement of the insulin level intensity of FDG uptake (in terms of SUVmax) was a good tool to
may detect the foci of hyperfunctioning pancreas in half of the detect the activity of disease earlier than radiography or bone
patients. 18F-DOPA PET has been reported to have a high sensitiv- scan. PET was superior to detect all lesions except in the verte-
ity and specificity for the detection of foci of hyperinsulinemia.167,168 brae where MRI was superior.
18
F-DOTA TATE may be also useful in these cases. With the introduction of modern imaging techniques like PET/
18
F-FDG PET/CT has been used in adult germ cell tumors for MRI or diffusion MRI, the application and indication of PET/CT
detection and management of disease.169 However, limited data may change in future. New radiotracers [e.g., 68Ga-DOTA TATE,
18
are available in pediatric populations. It seems that PET/CT is F-DOPA, 18F azomycin-arabinoside (18F-FAZA), 18F-flourothimi-
useful in these cases based on extrapolating the adult’s findings. dine (18F-FLT) (Fig. 25.14)] are more specific and will probably
Further evaluation will clarify the role of PET/CT in malignant change the management of cancers in children. Tumor receptor
germ cell tumors in children. imaging will be probably more sensitive and specific for the eval-

Although Langerhans cell histiocytosis (LCH) is no longer con- uation of cancers and may open a new horizon in diagnostic imag-
sidered a malignancy, oncologists usually manage the patients. ing. Tumor receptor imaging techniques (tumor antigens, tumor
LCH is a disease of immune system previously named as histiocy- cell surface receptors, and specific surface receptors of the endo-
tosis X and is characterized by overproliferation of the Langer- thelial cells of the tumor vessels) have the potential to significantly
hans cell. These cells may accumulate in every organ in the body increase the sensitivity and specificity of imaging techniques by
and present with a spectrum of disease from a local bone lesion improving tumor detection and characterization. These new
to widespread visceral involvement. Radiography shows a typical applied molecular imaging techniques are expected to develop our
lytic bone lesion. After confirming the diagnosis by biopsy, further knowledge of the biology of pediatric cancers, and improve the
evaluation includes bone scan, abdominal and chest CT scan, and diagnoses and therapies.172
Figure 25.14. 18F-FLT PET/CT in a 6-year-

old patient with Hodgkin disease (upper
row) showed foci of increased proliferation in
the mediastinum (arrow). The SUVmax of the
lesions was borderlined on 18F-FDG PET/CT
(lower row) 2 days prior to the 18F-FLT PET.
Note the difference in biodistribution of FLT
(intense bone marrow and liver uptake with
no cardiac or brain activity).

Acknowledgment 34. Tang B, Patel MM, Wong RH, et al. Revisiting the marrow metabolic changes
after chemotherapy in lymphoma: A step towards personalized care. Int J Mol
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thy and splenomegaly following interferon-alfa-2b adjuvant therapy for mela-
the PET/CT images. noma. Clin Nucl Med. 2007;32(10):793–796.
36. Aflalo-Hazan V, Gutman F, Kerrou K, et al. Increased FDG uptake by bone
marrow in major beta-thalassemia. Clin Nucl Med. 2005;30(11):754–755.
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C h apt e r 2 6
Cancer of Unknown Primary

Zohar Keidar • Gad Abikhzer • Ron Epelbaum
Introduction markers, enzymes, structural and cell-specific components, hor-

mones and hormone receptor, and oncofetal antigens. The goal is to
Cancer of unknown primary (CUP) is defined as a metastatic determine the broad tumor type, whether carcinoma, lymphoma,
malignant disease whose primary site cannot be identified after a melanoma, or sarcoma. For carcinoma, the major CUP histologic
standard diagnostic workup. CUP accounts for 2% to 8% of all diagnosis, the second step is to detect whether it is one of the five
malignant tumors, with an estimated 31,000 people diagnosed in major histologic subtypes of CUP which include well- or moderate-
the United States in 2012. It is the seventh to eighth most common differentiated adenocarcinoma (60%), poorly or undifferentiated
malignancy and the fourth most frequent cause of cancer death.1,2 adenocarcinoma (30%), squamous cell carcinoma (SCC) (5%), poorly
However, the actual number of CUP patients might be greater, or undifferentiated carcinoma (5%) and neuroendocrine tumors
because some of them are classified and treated under known (NETs) of unknown primary (1%), or one of several other solid can-
primary categories, after a primary site is suspected based on cers, such as germ cell, renal cell, or thyroid tumors.1,3,9,10
clinical and pathologic features, but still remains uncertain. On the Based on clinical and pathologic characteristics, CUP has been

other hand, improving diagnostic technologies might decrease the categorized into two major prognostic groups. The group of cancers
number of CUP patients in the future as more of them are diag- that has a favorable prognosis includes9–11 the following:
nosed.3 It is important to note that even after autopsy studies, 20% • Poorly differentiated carcinoma with midline distribution, mainly
to 50% of patients will not have an identifiable primary tumor.4,5 affecting young men. It involves mediastinal and retroperitoneal
Although rare, some primary cancers may have undergone spon- lymph nodes and occasionally peripheral nodes and lung paren-
taneous regression after the seeding of metastases.6 chyma. It resembles extragonadal germ-cell tumor. Serum β-HCG
The pathophysiology of CUP is poorly understood. Although and AFP are elevated in approximately 20% of cases.
representing a group of metastatic tumors with unidentified pri- • Serous papillary adenocarcinoma of the peritoneal cavity in
maries, the association of clinically undetectable small dormant women, with a clinical picture that resembles advanced-stage
primary tumor with a propensity for early dissemination with an ovarian cancer. The disease predominantly involves the peritoneal,
unpredictable metastatic pattern might define CUP as a biologically mesenteric, and omental surfaces. IHC expression is also similar
distinct entity but no pivotal aberration characterizing this entity to ovarian cancer.
has been found thus far in the search for a CUP molecular signa- • Isolated axillary nodal adenocarcinoma in women. The clinical
ture. Frequent expression of oncoproteins, lack of activating epi- picture resembles that of stage II breast cancer. Mean age of
dermal growth factor receptor/c-Kit mutations or amplification, diagnosis is about 50 years and most patients are postmeno-
uncommon presence of tumor- or metastasis-suppressor gene pausal. Occult breast carcinoma can be identified in 72% of
mutations, and highly active angiogenesis have been reported but patients following mastectomy.
these findings are similar to the molecular signature of known pri- • SCC with mostly unilateral involvement of cervical lymph nodes,
mary cancers.5,7 Specific risk factors for CUP are difficult to identify which usually occurs in elderly male patients.
in such a diverse group. However, it has been shown that smoking • Isolated SCC in inguinal lymph nodes, probably originated in
increases the likelihood of identifying primary tumors in autopsy genitalia or anal regions.
studies of CUP, particularly pancreatic and lung cancer. More than • NET, either low-grade malignancies with an indolent course or
half of the patients with CUP have a history of smoking. Other com- high-grade tumors with an aggressive behavior.
mon risk factors for some gastrointestinal tumors eventually found • Osteoblastic bone metastases and elevated serum prostate-spe-
to be the primary tumors of CUP include older age, diet, alcohol, cific antigen (PSA) in men. Histology is adenocarcinoma with
and obesity. Exposure to sunlight may be a risk factor for mela- positive immunohistochemistry staining for PSA.
noma, another source of CUP.8 • Single small, potentially resectable tumor in various sites, with
Patients with CUP have a wide and heterogeneous clinical pre- different histopathologies.
sentation, natural history, and response to therapy. Most have • Adenocarcinoma with a colon cancer profile—metastatic ade-
a short period of symptoms and signs associated with the metastatic nocarcinoma or poorly differentiated adenocarcinoma in liver,
sites, such as a lump, pain or cough, or nonspecific symptoms of peritoneum, or other sites.
anorexia, weight loss, and fatigue. Most common sites of meta-
static involvement in CUP are the liver, lungs, lymph nodes, and The group that has an unfavorable prognosis includes9–11 the
bones. Prognosis for these patients is poor, as they have an aggres- following:
sive clinical course, refractory to systemic therapy. The median
• Multiple adenocarcinoma metastases to liver, lymph nodes,
survival is about 6 to 9 months and 1-year survival ranges from
lungs, bones, and brain.
15% to 35%. About 20% of CUP patients have a better prognosis.
• Malignant ascites of nonpapillary serous adenocarcinoma with
The favorable subset of patients are more responsive to chemo-
diffuse carcinomatosis of the peritoneal surface, usually of gas-
therapy and have longer survivals.3 Patients with CUP should
trointestinal tract origin.
undergo a systematic diagnostic evaluation to identify the primary
• Multiple cerebral adenocarcinoma or SCC metastases.
in a subset of patients who might respond to therapy. The minimal
• Multiple lung or pleural adenocarcinoma metastases.
standard clinical workup includes a thorough medical history and
• Adenocarcinoma with multiple bone lesions.
physical examination, blood indices and biochemistry survey, uri-
nalysis, fecal occult blood test and CT scan of thorax, abdomen and Patients with CUP require specific workup with additional pro-
pelvis, or the head and neck in patients presenting with cervical cedures to identify the primary tumor according to these clinico-
adenopathy. pathologic subsets. For example, women with axillary adenopathy
The standard pathologic evaluation includes light microscopy proceed to mammography or breast MRI and measurement of
examination and immunohistochemical (IHC) staining using a series blood CA 15-3. Other tumor markers should be measured in some
of monoclonal and polyclonal antibodies directed against cellular cases, that is, α-fetoprotein and β-human chorionic gonadotropin
389

in males with midline metastatic poorly differentiated carcinoma, often define the extent of disease and more importantly may reveal
PSA in males with metastatic adenocarcinoma to the bone, and the primary site. These findings will subsequently dictate treatment
CA-125 in women with serous peritoneal adenocarcinoma. Endos- and provide information regarding the expected outcome and over-
copies are performed based on the presence of relevant symptoms all prognosis. Cases in which imaging studies have assisted in the
or signs, or according to site-specific (IHC) profile. Panels of cyto- clinical evaluation and defined the primary site are managed
keratins and other IHC markers, such as CK-7, CK-20, CDX2, and according to their defined tumor type. A body CT study can detect
TTF1 create phenotypic expressions that correlate with specific 32% to 46% of sites of unknown primary tumors in patients with
tumor sites and can therefore predict or identify the primary site CUP14,15 and CT of the neck detects 25% of primary lesions in cases
of the adenocarcinoma. Altogether, these techniques can accurately presenting with metastatic cervical lymphadenopathy.16
predict the primary site in 30% to 40% of CUP patients.10,12 Whole-body (WB) turbo short tau inversion recovery (STIR) MRI
A further increase in the detection rate of tissues of origin is has been shown to have a high accuracy in a small group of
the result of gene expression profiling. Several gene expressing pro- patients with CUP.17 More recently, WB diffusion-weighted MRI
file assays have been developed using real-time quantitative reverse with fat suppression by STIR detected 83% of primary tumors in
transcription–polymerase chain reaction (qRT–PCR) (10- and 92- 29 CUP patients.18 Breast MRI has a definite role in the evaluation
gene assays) or microarray approach (1,500 and 1,900 genes). of patients with metastatic axillary lymph nodes. Breast MRI has a
Another form of molecular profiling is miRview®, based on the pres- high sensitivity to detect primary breast cancer in patients with
ence of 48 microRNAs (miRNAs). Retrospective studies correlated the negative mammograms, although false-positive results have been
molecular assays with the clinical and pathologic findings and found a reported.19,20
correct prediction of the primary tumor site in 61% to 95% of cases.3,10 Prior to the advent of 18F-fluorodeoxyglucose (FDG) positron
Treatment of patients with CUP should be tailored according to emission tomography (PET), very few studies looked at the role
their clinicopathologic subset. Patients belonging to the favorable of nuclear medicine in the workup of CUP. One study compared
group have specific treatable clinical syndromes, even if the pri- Thallium-201 (Tl-201) single photon emission tomography (SPECT)
mary site is not identified. Patients with poorly differentiated carci- and CT/MRI in the detection of CUP of the head and neck. The
noma with midline distribution are treated with cisplatin-based authors reported similar diagnostic accuracy in 32 patients who
chemotherapy, similar to germ-cell tumor regimens, with a response underwent Tl-201 SPECT and 29 patients examined with CT or
rate of about 50%, and almost 20% enjoy long-term disease-free MRI, 69% and 72% respectively.21 Gallium-67 has also been used to
survival. Women with peritoneal carcinomatosis are treated, simi- evaluate patients with CUP. Only modest results were reported in a
lar to advanced stage ovarian cancer, with surgical cytoreduction single study performed specifically to search for a primary tumor.22
followed by taxane and platinum chemotherapy, with a response These tracers are rarely used currently for oncologic imaging and
rate of 80% and a median survival of 3 years. The recommended have been replaced by FDG PET/CT (where available).
approach in women with axillary lymph node metastases is similar
to early stage breast carcinoma, including mastectomy or breast
irradiation, axillary lymph node dissection, and adjuvant treatment. FDG PET/CT for Assessment of CUP
Prognosis is similar to stage II to III breast cancer. The approach in FDG uptake reflects glucose metabolic rate which is increased in
patients with SCC involving cervical lymph nodes should be similar metabolically active cells and is therefore useful to detect increased
to locally advanced squamous carcinoma of the head and neck, glycolytic rates in malignancies. Integrated PET/CT provides both
with neck dissection and/or combined chemoradiotherapy achiev- functional and anatomical information. Metabolic imaging with the
ing long-term disease control in 50% to 60% of cases. Isolated SCC PET component can evaluate the biologic characteristics of a tumor
involving inguinal lymph nodes is treated as primary tumor of the with high lesion-to-background ratio. The high-resolution CT com-
anorectal or genital areas. Inguinal dissection approach, with or ponent can be used to determine tumor localization and the extent
without radiation or chemotherapy, results in a 5-year survival of of metastatic spread. 18FDG PET/CT is now widely used for diagno-
15% to 20%. Treatment of NETs is related to their aggressiveness, sis, staging, determining prognosis, and assessing response to
being mainly platinum-based chemotherapy in poorly differenti- therapy in a large variety of malignancies.23,24 18FDG PET/CT is
ated tumors and somatostatin or radiolabeled somatostatin ana- included in the National Comprehensive Cancer Network (Category
loges for the low-grade malignancies. Men with elevated serum PSA 2B recommendation) list of procedures for the initial evaluation of
or PSA tumor staining and osteoblastic bone metastases are treated CUP.9 The overall aim of performing 18FDG PET/CT in patients with
as having metastatic prostate cancer. Patients with only one small CUP is to
metastatic site receive local therapy including resection with or
without radiation therapy and may enjoy a prolonged disease-free • search for the occult primary tumor.
survival. Patients with a colon cancer profile respond very well to • guide biopsy to evaluate the extent of disease prior to multimo-
standard colon cancer therapy with a median survival of 20 to 24 dality therapy.
months. The median survival of patients in all favorable CUP sub- • confirm solitary site of disease when surgical resection or radi-
groups was found to exceed 24 months.1,11 In patients with CUP in ation therapy is considered.
the unfavorable subsets, empiric chemotherapy of various types has • assess response to therapy.25
been administered along the years, with median survival of 6 to 13
months, and a 2-year survival of less than 20%. Although there is 18
FDG PET/CT Imaging Protocol
currently no standard chemotherapy for these patients, administra-
tion of platinum-based therapies has been associated with improved
in Patients with CUP
response rates and survival.1,13 A standard departmental protocol for 18FDG PET/CT imaging
should be also used in patients with CUP. Based on the known
Imaging in Assessment of Carcinoma origin of most CUP in the head and neck, lungs, and solid abdomi-
nal organs, it is reasonable not to include the lower extremities in
of Unknown Primary the routine protocol for 18FDG PET/CT imaging of CUP. An example
of an exception to this statement is metastatic melanoma. More
Imaging studies are of crucial importance in the standard workup specific protocols should be considered on a case-by-case basis.
of patients with CUP. Patients are classified as CUP when a primary For patients with cervical adenopathy, a dedicated separate acqui-
tumor is not identified after undergoing standard imaging proce- sition of the region of the head and neck can be performed. A
dures such as a chest x-ray and CT. These imaging procedures prospective study aimed at detection of an unknown primary in the

Chapter 26 Cancer of Unknown Primary 391
Ta b l e 2 6 . 1
The Use of FDG PET or PET/CT in the Assessment of CUP Outside the Head
and Neck Region
Number Primary Tumor Change in

of Detection Patient
Authors Year Patients Technology Rate FP FN Management
1 Kole et al.a 1998 29 PET 7 (24%) 0 3 (14%) 3 (10%)

2 Lassen et al. 1999 20 PET 9 (45%) 4 (20%) 2 (10%) N/A
3 Lonneux et al. 2000 24 PET 13 (54%) 5 (21%) 0 10 (42%)
4 Rades et al. 2001 42 PET 18 (43%) N/A N/A 12 (29%)
5 Mantaka et al. 2003 25 PET 12 (48%) 5 (20%) 0 11 (44%)
6 Alberini et al. 2003 41 PET 26 (63%) N/A 2 (5%) 11 (27%)
7 Joshi et al. 2004 62 PET 16 (26%) 4 (7%) 33 (53%) 17 (27%)
8 Gutzeit et al.a 2005 45 PET/CT 15 (33%) 3 (7%) 2 (4%) N/A
9 Nanni et al. 2005 21 PET/CT 12 (57%) 1 (5%) 0 N/A
10 Pelosi et al. 2006 68 PET/CT 24 (35%) 5 (7%) 5 (7%) 33 (49%)

11 Ambrosini et al. 2006 38 PET/CT 20 (53%) 1 (3%) N/A N/A
12 Fencl et al. 2007 82 PET/CT 18 (22%) 13 (16%) 15 (18%) N/A
13 Yapar et al. 2010 94 PET/CT 32 (34%) 7 (7%) 6 (6%) N/A
a
Mixed population of head and neck and non–head and neck cancer of unknown primary.
FP, false-positive findings on PET or PET/CT; FN, false-positive findings on PET or PET/CT; N/A, not Available.
head and neck performed two separate PET/CT acquisitions. A injection-to-imaging time of 45 minutes was shorter than current
first study acquired images in the region from the thoracic inlet to standards of 60 to 90 minutes, with longer uptake times having
the upper thighs, for 4 minutes per field of view (FOV) in patients been shown to increase tumor uptake.43,44
weighing between 127 and 150 kg, and 3 minutes per FOV in During 18FDG PET/CT interpretation, special attention needs to
patients weighing less than127 kg. This study was followed by a be placed toward the most common sites of primary tumors based
dedicated acquisition of the neck with 5 to 6 minutes per FOV. A on the known histologic subtype and location of the metastases in
low-dose CT for attenuation correction and localization was then the individual. Interpretation of studies in patients presenting with
performed, followed by a contrast-enhanced diagnostic CT scan of metastatic melanoma should focus both on the skin as well as addi-
the neck and chest.26 The added value of PET/CT compared to PET tional common sites of primary tumor location, such as the vulva or
alone in patients with CUP is now clearly established.27–29 the eyes. Patients with left supraclavicular lymph node metastases
The use of intravenous (IV) contrast-enhanced PET/CT to (Virchow’s node) should be interpreted with particular attention
increase the diagnostic accuracy is performed routinely in many toward a potential primary gastrointestinal tract or pelvic tumor.45
facilities, with excellent results for the detection of occult primary The definition of false-negative cases varies. Although some
head and neck tumors.27 The added value of contrast-enhanced studies include patients in whom the primary tumor was not identi-
PET/CT for extracervical CUP is less evident. In a study investigat- fied by any modality or follow-up,46 most reports defined false-
ing the prognostic and diagnostic accuracy of 18FDG PET/CT in negative cases only when the primary was detected by other
190 patients with CUP, mainly in extracervical sites, a contrast- modalities. It is important to realize that even a perfect imaging
enhanced CT component was performed in about half of the study modality may not detect all occult primary tumors as even autopsy
population. There was no statistically significant difference in the
detection of the primary tumor site between the group with con-
trast- and noncontrast-enhanced 18FDG PET/CT.30
Performance of 18FDG PET/CT in Assessment

of Non–Head and Neck CUP
The detection rate of 18FDG imaging in CUP studies that did
not exclusively include head and neck patients is 22% to 63%
(Table 26.1).28–40 The location of the most common primary lesions
is presented in Figure 26.1 for patients with non-head and neck
CUP. A primary lung cancer represented the origin of the majority
of CUP, which were diagnosed by 18FDG imaging even in patients
with CT scans of the chest that were considered normal or incon-
clusive.41 The most recent meta-analysis reported an overall diag-
nostic accuracy, sensitivity, and specificity of 37%, 84%, and 84%,
respectively.42 There are many explanations for the variability of
primary tumor detection rate between the studies. With respect to
the study design, different trials have used different definitions for
CUP. In addition, the workup prior to performance of 18FDG imag-
ing varies greatly among studies. There is a wide variability in
Figure 26.1. Distribution of primary sites in 216 patients with non–head and neck cancer of
imaging-related parameters among studies, with early studies unknown primary presented in Table 26.1. “Others” category includes patients diagnosed with
performed with PET only instruments, often without attenuation the primary tumor in the following sites: Anus, mediastinum, urethra, thymus, esophagus, and
correction. Results have improved with PET/CT.29,38 The initial vagina.

Figure 26.2. Distribution of 18 reported false-negative sites on FDG imaging in patients with
head and neck cancer of unknown primary presented in Table 26.2. “Others” category includes
a single case in each of the following sites: scalp (melanoma), esophagus, salivary gland, and
nasopharynx.
Figure 26.3. Distribution of 40 reported false-negative sites on PET or PET/CT in patients with
47 non–head and neck cancer of unknown primary presented in Table 26.1. “Others” category
studies identify the primary in up to 55% of cases. Therefore, the includes a single case in each of the following sites: Neuroectodermal, testis, prostate, bowel,
reported results for 18FDG PET/CT are comparable to autopsy stud- thymoma, esophagus, cutaneous epidermoid carcinoma, myeloma, larynx, pancreas, adrenal,
ies. False-negative studies occur when a primary tumor may be and cholangiocarcinoma.
located in sites such as the oropharynx, breast, and lungs (Figs. 26.2
and 26.3). The histology of the suspected specific malignancy
known to be less 18FDG avid needs also to be considered when Performance of 18FDG PET/CT in Assessment
searching for a primary tumor. 18FDG imaging has limited sensitiv-
ity for detection of certain histologic subtypes of breast cancer such
of Head and Neck CUP
as ductal carcinoma in situ, tubular carcinoma, and invasive lobu- The detection rate of 18FDG imaging in patients presenting with cer-
lar carcinoma,48 as well as for mucinous adenocarcinoma and pros- vical metastases and CUP varies from 28% to 63% depending on the
tate adenocarcinoma which can show minimal or no 18FDG inclusion criteria (Table 26.2).26,46,53–63 For patients with SCC metas-
uptake.49 False-negative 18FDG PET/CT results may also be related tases in cervical lymph nodes, particular attention should be directed
to small size of the primary tumor, below the resolution of the imag- to the tonsils and base of tongue, as these are the sites of most com-
ing device, or to the merging of 18FDG uptake in primary and meta- mon head and neck unknown primaries (Figs. 26.4 and 26.5). In
static lesions in close proximity. Physiologic tracer uptake in various addition to demonstrating the value of 18FDG PET/CT in SCC-type
organs may limit the ability of 18FDG imaging to detect and charac- cervical adenopathy CUP which represent the majority of cases,
18
terize primary tumors in these sites. Urinary excretion of the radio- FDG PET/CT has been assessed in patients with cervical metasta-
tracer may obscure visualization of primary renal tumors or those ses of nonsquamous histology; 50% of primary tumors are detected.59
located in the ureter and bladder. Focal uptake in the colon is often The WB 18FDG PET/CT can detect unsuspected synchronous pri-
indicative of a malignant or premalignant lesion but is also a fre- mary tumors that are frequent in this population.64,65 In patients
quent site of false-positive uptake,50 with uptake in the colon presenting with SCC cervical node metastases and CUP, panendos-
accounting for 58% of false-positive 18FDG PET studies in patients copy is usually performed and in the absence of suspicious findings,
with CUP according to one meta-analysis.51 The use of dual time blind biopsies are taken from the nasopharynx, the base of tongue
point imaging of focal sites of colon uptake has been suggested to and the tonsils. The yield of these blind invasive procedures is low.
reduce false-positive interpretations as 47% of focal sites of uptake Several studies have looked at the change in yield of directed pan-
will no longer be present or change in location on delayed images.52 endoscopy guided by 18FDG imaging results. Additional studies have
Ta b l e 2 6 . 2
The Use of FDG PET or PET/CT in the Assessment of Head and Neck CUP
Number Primary Tumor Change in

of Detection Patient
Authors Year Patients Technology Rate FP FN Management
1 Braams et al. 1997 13 PET 4 (30%) 0 1 (8%) N/A

2 Aassar et al. 1999 17 PET 9 (53%) 3 (18%) 0 N/A
3 Bohulaviski et al.a 2000 53 PET 27 (63%) 6 (11%) 4 (8%) N/A
4 Regelnik et al. 2002 50 PET 16 (32%) 2 (4%) 0 10 (20%)
5 Stoeckli et al. 2003 18 PET 5 (28%) 1 (56%) 3 (17%) N/A
6 Freudenberg et al. 2005 21 PET/CT 12 (57%) 0 2 (10%) N/A
7 Nassenstein et al. 2007 39 PET/CT 10 (26%) 4 (10%) 0 N/A
8 Paul et al. 2007 14 PET/CT 7 (50%) 1 (7%) 2 (14%) N/A
9 Wartski et al. 2007 38 PET/CT 13 (34%) 0 1 (3%) 23 (60%)
10 Johansen et al. 2008 60 Mixed 18 (30%) 13 (22%) 3 (5%) 30 (25%)
11 Miller et al. 2008 31 PET 9 (29%) 1 (3%) 5 (16%) N/A
12 Yabuki et al. 2010 24 PET 9 (38%) 3 (13%) 1 (4%) N/A
13 Rudmik et al. 2011 20 PET/CT 11 (55%) N/A 1 (5%) 4 (20%)
a
44/53 patients in this study had head and neck cancer of unknown primary.
FP, false-positive findings on PET or PET/CT; FN, false-positive findings on PET or PET/CT; N/A, not available.

Figure 26.4. A 49-year-old male present-

ing with metastatic squamous cell cervical
lymphadenopathy of unknown primary. FDG
PET/CT (transaxial PET slice left; fused image
right) demonstrates a tracer-avid primary
lesion in the left lingual tonsil (arrow ), in addi-
tion to intense uptake in left cervical lymph-
adenopathy (level IIA, arrowhead ).
assessed whether negative 18FDG PET/CT studies can predict a neg- The value of 18FDG PET/CT in patients with cervical lymph node
ative endoscopy. In a study of 13 patients with metastatic cervical metastases and CUP is not limited to the detection of the primary
lymph nodes and unknown primary after physical examination, CT tumor in the head and neck region. Cervical lymph node metastases
and/or MRI of the neck, both WB 18FDG imaging and panendoscopy can also arise from lung cancer, one of the most common sites of
were performed.54 18FDG studies correctly identified the primary unknown primary tumors, and supraclavicular lymph node metasta-
tumor site in 3/13 patients in the region of the head and neck and 1 ses may also originate from the gastrointestinal tract. Furthermore,
lung cancer. The initial panendoscopy was negative in the three patients with cervical lymph node metastases from unknown pri-
patients, with primary head and neck cancer, and only a repeat mary head and neck tumor often present with advanced disease. WB
procedure guided by the 18FDG results was able to identify the pri- 18
FDG imaging detects unsuspected metastases in mediastinal lymph
mary tumor site. Endoscopy identified a base of tongue cancer that nodes, lungs, and bones in approximately 20% of patients with CUP
was not seen on 18FDG imaging.54 An additional study in patients in the head and neck.27 These patients can be spared curative-intent
with SCC cervical lymph nodes with unknown primary found that extended field radiotherapy with its associated morbidity. It appears
18
FDG PET/CT identified 55% of primary tumor sites whereas pan- reasonable that 18FDG PET/CT should be performed prior to invasive
endoscopy identified 25%.26 These results were further confirmed in panendoscopy in patients presenting with metastatic cervical SCC.
another series showing that 18FDG imaging identified tumors not Panendoscopy should be directed to suspicious head and neck
seen by CT, MRI, or endoscopy.55 Several studies present conflicting sites found on 18FDG PET/CT. Panendoscopy can probably be
results suggesting that a negative 18FDG study does not preclude omitted in patients whose primary tumor is identified outside the
negative panendoscopy and the invasive diagnostic procedure head and neck region as well as in those who are diagnosed with
should still be performed.27,61 Stoeckli et al.56 found that panendos- distant metastatic disease in spite of not identifying the site of the
copy identified additional sites of primary tumors that were not primary tumor.
identified by 18FDG imaging, whereas 18FDG PET did not detect any False-positive studies can be the result of prominent lymphoid
tumors not identified by panendoscopy. tissue uptake in Waldeyer’s ring that can be asymmetric, espe-
cially in the presence of an infectious or inflammatory process.
Asymmetric physiologic uptake can also mimic malignancy.66 With
the introduction of PET/CT technology for clinical use and the
gradual replacement of the older PET cameras, PET/CT scanners
equipped with 4, 16, or 64 slice CT scans have become the stan-
dard. The additional images provided by the CT component of the
PET/CT reduce false positives.28,57 Physiologic sites of uptake or
normal variants are localized better and recognized as nonmalig-
nant findings. Inflammatory and infectious causes of 18FDG uptake
such as pneumonia, hypermetabolic atheromas, and degenerative
changes are recognized, avoiding misinterpretation of these sites
as possible sites of primary tumors. The location of the most com-
mon sites of false positives is presented in Figures 26.6 and 26.7
for patients with both cervical and extracervical CUP.
Impact of 18FDG PET/CT on Clinical Management

Figure 26.5. Distribution of primary sites in 145 patients with head and neck cancer of and Prognosis of Patients with CUP
unknown primary presented in Table 26.2. “Others” category includes up to two patients diag- 18
nosed with the primary tumor in the following sites: Epiglottis, esophagus, maxillary sinus, FDG PET or PET/CT has been reported to affect patient manage-
prostate, axilla, bone, rectum, sarcoma of neck, skin (melanoma). ment in 10% to 60% of patients with cervical CUP and in 10% to 49%

Figure 26.6. Distribution of 30 reported false positive PET or PET/CT sites in patients with
head and neck cancer of unknown primary presented in Table 26.2. “Others” category includes
a single finding in each of the following sites: Maxillary sinus, esophagus, floor of mouth, salivary
glands, larynx, rectum, retromolar, mediastinum, and hypopharynx.
Figure 26.7. Distribution of 34 reported false-positive PET or PET/CT sites in patients with
of patients in studies with metastatic sites, the head and neck as well non–head and neck cancer of unknown primary presented in Table 26.1. “Others” category
as other regions of the body (Tables 26.1, 26.2). includes a single finding in each of the following sites: Cardiac, renal, uterus, esophagus, and
The role of 18FDG imaging in CUP is not limited to the detection nasopharynx.
of the primary tumor site; it often detects additional metastatic
lesions and thus, the extent of disease (Fig. 26.8). 18FDG PET/CT modality to detect additional metastases, 1-year survival was 47%.
spares unnecessary surgery in patients previously considered to Even if 18FDG PET/CT failed to detect the primary tumor site and
be candidates for curative therapy. In patients with localized dis- demonstrated only local disease, 1-year survival improved to
ease, 18FDG imaging confirms the absence of widespread dissem- 73%.35 Curative local therapy may be possible in up to 28% of
ination and thus can guide therapy with curative intent (Fig. 26.9). patients with CUP, following WB staging with 18FDG PET/CT which
18
FDG imaging studies are also of prognostic significance in demonstrated the presence of isolated disease.30,35 An additional
patients with CUP. In patients with bilateral cervical lymph node study showed that a positive 18FDG PET/CT showing 18FDG uptake
metastases and an unknown primary, the 5-year survival rate is in either the primary malignancy or the metastasis was associ-
17% to 28%.46 In contrast, in SCC of the head and neck presenting ated with poorer survival. Fencl et al.30 studied 190 patients with
18
with bilateral lymph node metastases, 5-year survival rates of 55% FDG PET/CT performed for the workup of CUP. Of these 190
are reported,67 highlighting the importance of detecting occult pri- patients, 82 had histologically proven metastatic disease and 108
maries in the head and neck. In patients with localized disease in had clinical suspicion of malignancy that only partially meets the
whom 18FDG PET/CT detected the primary tumor site followed by definition of CUP. The presence of a positive 18FDG PET/CT study
an appropriate change in management, 1-year survival was reported in both patient populations was associated with a statistically sig-
at 100%. In cases where 18FDG imaging was the only diagnostic nificant lower overall survival after a mean follow-up of 5 months
Figure 26.8. A 50-year-old male, presenting with liver metastases from

adenocarcinoma of unknown origin. FDG PET/CT transaxial slices (upper left,
PET; lower left, fused image) demonstrates focal uptake in the pancreatic tail,
the primary tumor site (arrows). Multiple, previously unsuspected bone metas-
tases are also demonstrated (right, selected sagittal fused image).

Figure 26.9. A 50-year-old female, post oophorectomy, with histology demonstrating metastatic adenocarcinoma (Krukenberg tumor). FDG PET/CT (left, trans-
axial slices, fused image left; center, PET; right, CT) demonstrates intense focal uptake (arrow) in a thickened midesophagus (arrowhead) representing the primary
tumor. PET/CT indicated that the primary esophageal cancer was the only site of disease once the ovarian metastasis had been resected and the patient was referred
for therapy with curative intent.
(range: 1 to 23 months) than in patients with negative 18FDG PET/ who underwent a variety of 410 diagnostic tests, revealing only
CT studies.30 Based on these study results, 18FDG PET/CT has a four primary sites, with the majority not surviving for more than

prognostic role in CUP. Follow-up 18FDG PET/CT has been also 1 year, was $17,973 per patient. Identification of the primary sites
used to monitor the response to therapy in patients with CUP. did not result in a change of therapy with curative intent.68
Three of seven patients had a complete response and four had The use of 18FDG PET/CT as an initial diagnostic test may reduce
either stable or progressive disease, resulting in a change in che- the number of investigations performed in search of the unknown
motherapy regimen (Fig. 26.10).40 The change in management that primary with an overall cost savings. In a group of 42 patients with
results after 18FDG PET/CT allows more appropriate and targeted CUP, a median of seven invasive and noninvasive diagnostic proce-
therapy for patients. Alternatively, inappropriate and unnecessary dures (range: 3 to 11) were performed prior to 18FDG imaging.
surgery, as well as expensive chemotherapy or radiation therapy Despite the extensive workup, 18FDG imaging detected 62% of
can be avoided when 18FDG PET/CT detects additional sites of unsuspected primary sites. Furthermore, follow-up studies were
unsuspected metastatic disease.62 The detection of false-positive unable to detect the primary tumor site in all patients with negative
sites of increased 18FDG uptake can lead to additional investiga- 18
FDG studies.35 A study by AAssar et al.53 showed the superiority of
18
tions and procedures and their additional costs need to be taken FDG imaging which detected 47% of primary tumors in patients
into consideration in a cost-effectiveness evaluation. with metastatic head and neck cancer, compared to 33% with CT or
MRI. A primary tumor was not identified in all 18FDG negative
Cost Effectiveness of 18
FDG PET/CT patients with a mean follow-up of 29 months. These results suggest
that 18FDG PET should be used as an initial diagnostic procedure in
in Patients with CUP patients with CUP and that further investigation with other diagnos-
The multiple diagnostic procedures obtained in patients with met- tic modalities is of little yield, with cost savings because of the
astatic disease and an unknown primary site can be costly. The reduction in the number of diagnostic procedures performed in the
average cost of the diagnostic evaluation in a group of 56 patients search for an unknown primary.33
Figure 26.10. A 49-year-old male, presented with malignant ascites. Peritoneal tap
showed adenocarcinoma. Maximal intensity projection (MIP) images (left) of initial FDG
PET/CT do not reveal the primary site of tumor but demonstrate extensive peritoneal
disease and abdominal lymphadenopathy. Repeat FDG PET/CT study after chemo-
therapy (right, MIP image) demonstrates complete response to therapy.

Figure 26.11. An 84-year-old male, pre-

sented with recurrent hypoglycemia and mul-
tiple liver metastases. Liver biopsy revealed
metastatic neuroendocrine tumor. Ga-68-
DOTA-NOC PET/CT (left, maximal intensity
projection, transaxial slices; upper right,
PET; lower right, fused image) demonstrates
multiple liver metastases (arrowhead ) and
focal, intense uptake in the pancreatic tail
representing the primary malignancy (arrow).
Final diagnosis was metastatic insulinoma.
Metastatic Neuroendocrine Tumor the specificity of FDG PET, with more precise assessment of the
of Unknown Primary head, neck, breast, and abdominal organs. Review of the MR com-
ponent of a PET/MR examination may allow the detection of non–
Metastatic NET disease from unknown primary is also frequent. 18
FDG-avid tumors where CT is of limited value, such as prostate
18
FDG PET/CT has a limited role in the evaluation of NET, espe- cancer or certain ovarian cancers. However, based on current avail-
cially in the well-differentiated subtypes.69 In-111 octreotide (pen- able evidence, it does not seem that the fusion of these two modali-
tetreotide) has traditionally been the tracer used to image NET, ties will replace PET/CT in patients with CUP, mainly because of the
with excellent results.70 More recently, Ga-68-DOTA-NOC has pro- high frequency of occult lung primaries. Some of the current limita-
vided images that are superior to In-111 octreotide71 and it is also tions of MRI may affect patients with CUP, including the use of
more cost effective.72 In-111 octreotide was found to detect 35% sequences with high sensitivity at the cost of low specificity78 and
of occult primary NET73 whereas Ga-68-DOTA-NOC detected 59% the low sensitivity for detection of peripheral skin and lung lesions.79
of occult primary tumor in a group of 59 patients with NET. CT In a study population of 98 oncology patients, 18FDG PET/CT was
had a detection rate of only 20%. Where available, it now appears superior to WB MRI in a subgroup of 12 patients with CUP and 13
that Ga-68-DOTA-NOC PET/CT is the tracer of choice to image with head and neck tumors.80 Extensive studies will be necessary to
patients with NET (Fig. 26.11).74 A study comparing Ga-68-DOTA- assess the potential clinical added value with PET/MR in the search
NOC PET/CT and WB MRI to stage NET found comparable overall for CUP when compared to PET/CT.
detection rates for metastatic disease but PET/CT was superior for Detection of very small occult primary breast tumors may sig-
lymph node and pulmonary disease and WB MRI for liver and nificantly alter therapy, offering the possibility of breast conserv-
bone metastases. Hybrid PET/MR, an emerging technology, may ing surgery.81 The combination of positron emission mammography
become the comprehensive examination of the future.75 (PEM) and MRI has been shown to provide the highest sensitivity
for detection of malignant lesions, while improving on the low
specificity of MRI.82 Dedicated breast PET/MRI devices are techni-
Future Directions for cally feasible and integration of the strengths of both modalities
Assessment of CUP can theoretically be of added value.83
Current PET/CT devices have improved reconstruction, scatter

and attenuation correction algorithms, which, together with the Conclusions
implementation of time of flight (TOF), produce low-noise PET
images.76 These devices have a spatial resolution of 4 to 6 mm and CUP presents with various signs, symptoms, locations, and histolo-
are also equipped with helical 64-slice CT with a resolution of gies. The PET/CT detection rate of the primary tumor varies greatly
0.5 mm.77 These devices have the potential to increase the detec- and ranges from 22% to 63%. It is increasingly accepted that 18FDG
tion rate of small primary tumors which has been the basis of imaging should be a part of the standard workup of this spectrum
many false negatives in patients with CUP. of malignancies especially when other modalities failed to reveal
MRI provides excellent soft tissue contrast and high spatial reso- the origin of the metastatic disease. It should be taken into consid-
lution without ionizing radiation.77 The recent development of WB eration that false-positive and false-negative rates are not negligi-
hybrid PET/MR systems combines the high sensitivity of MRI with ble and can contribute significantly to inaccurate 18FDG PET/CT

reports when assessing patients with CUP. Improved molecular 32. Lassen U, Daugaard G, Eigtved A, et al. 18F-FDG whole body positron emission
tomography (PET) in patients with unknown primary tumours (UPT). Eur J
imaging technologies are expected to improve the assessment of Cancer. 1999;35:1076–1082.
patients presenting with metastatic CUP. 33. Lonneux M, Reffad A. Metastases from unknown primary tumor. PET-FDG as
initial diagnostic procedure? Clin Positron Imaging. 2000;3:137–141.
34. Mantaka P, Baum RP, Hertel A, et al. PET with 2-[F-18]-fluoro-2-deoxy-d-glu-
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C h apt e r 2 7
Assessment of Lymph Nodes in Oncology

Ansje S. Fortuin • Thomas C. Kwee • Sandip Basu • Drew A. Torigian • Babak Saboury •
Willem M. Deserno • Jelle O. Barentsz • Abass Alavi
Introduction medullary sinuses (Fig. 27.4). Lymph from all lobules drains into
efferent lymphatic vessels that exit the node at the hilum (Fig. 27.4).
Humans have around 450 lymph nodes.1 Knowledge about lymph The blood supply enters the lymph node by one or more arterioles
node involvement in cancer is of great importance for cancer stag- at the hilum, where they branch to the capsule, and then further
ing, treatment planning, and determination of prognosis. Lymph divide into the medulla, dividing further into capillary networks in
node excision, followed by histopathologic examination, is regarded the cortex and paracortex. Note that single arterioles reach the
as the gold standard for the assessment of lymph nodes.2 However, capsule through trabecular structures at many sites and anasto-
surgical removal of lymph nodes is a costly and invasive procedure mose with branches coming from the hilum. Capillaries empty into
with associated potential complications.3–5 Another limitation of high endothelial venules that condense repeatedly in the interfol-
surgical lymph node mapping in general is that only lymph nodes licular cortex and in the periphery of the deep cortical unit (DCU).
Then they change into medullary venules at the corticomedullary

inside the surgical area are assessed and therefore, there is no
information about lymph nodes outside this field. junction. Merging medullary venules return centripetally to the
Imaging modalities, including ultrasound (US), computed tomog- hilar vein (Figs. 27.2 and 27.3).1,2,6,7 Although it has been reported
raphy (CT), magnetic resonance imaging (MRI), positron emission that superficial (inguinal) lymph nodes are generally supplied by a
tomography (PET), and lymphoscintigraphy, provide a noninvasive single artery that penetrates the hilum, deep (mesenteric) lymph
approach to evaluate lymph nodes in the entire body. These proce- nodes are invariably supplied by several separate arteries that pen-
dures may reduce the number of invasive procedures needed etrate the capsule, enter the trabeculae, and run centripetally.8 The
for lymph node assessment or modify surgical lymph node assess- lymphatic and vascular systems communicate at certain points in
ment.6 the lymph node. First, part of the lymph fluid enters the conduit
system inside the lymphoid compartment and leaves the lymph via
the blood circulation at the high endothelial venules, which are also
the main site of entry of lymphocytes to the lymph node.1,2,6,7 Sec-
Basic Anatomy of Normal ond, blood could possibly enter into the lymph sinuses through the
Lymph Nodes lymphatic venous communications between the veins and sinuses
in the node.9
Lymph Circulation
High hydrostatic pressures in arterial capillaries force protein- Lymph Node Metastasis
aceous fluid into the interstitium. Lymph is derived from this inter-
stitial fluid and originates in the interstitial spaces of most tissues. Arrival and Spread of Tumor in the Lymph Node
A vast system of converging lymphatic vessels, containing one-way Tumors generally lack a lymphatic network.10 Therefore communi-
valves, funnels lymph to the thorax. In the thorax it is returned to cation of tumor cells with lymphatic channels occurs only at the
the venous circulation via the thoracic and right lymphatic ducts tumor periphery and not within the tumor mass. In addition,
(Fig. 27.1). At sites where lymphatic vessels converge, lymph flows tumor cells do not have to penetrate a basement membrane to
through lymph nodes. Lymph nodes are ovoid, round, or bean- enter the lymphatic system, as lymphatic vessels lack basement
shaped nodular formations composed of dense accumulations of membranes.11 Most tumor cells reach the (sentinel) lymph node in
lymphoid tissue. They vary in size from 2 to 20 mm, average 15 mm the afferent lymph as emboli, in the form of either single cells or
in longitudinal diameter, and contain large numbers of lymphocytes, clumps. Within 10 to 60 minutes after initial arrest in the subcap-
macrophages, and antigen-presenting cells.1,2,6,7 sular sinus of the lymph node, a significant fraction of the tumor
cells detach and enter efferent lymphatic vessels. These tumor cells
Global Organization of Normal Lymph Nodes eventually end up in the regional or systemic venous drainage
because of the existence of numerous lymphaticovenous communi-
The lymphoid lobule is the basic anatomical and functional unit of cations.12 Malignant cells first lodge in the subcapsular sinus and
the lymph node. The smallest lymph nodes may contain only a few the cortex of the lymph node near the afferent lymphatic vessel,
lobules or even just one, whereas large lymph nodes may contain where neoplastic tumor growth usually starts. Subsequently, the
a great number.1 Lobules are anchored in the hilum by their vas- metastatic tumor gradually spreads from peripheral sinuses to the
cular roots but are otherwise separated from the capsule by the medulla, replaces the entire lymph node, and extends into adjacent
subcapsular sinus. The apex forms part of the nodal cortex (i.e., extra nodal tissue.13,14 As the lymph node is replaced by tumor, the
superficial cortex, which mainly contains B-cells that are arranged afferent lymph will be directed into collateral vessels to fresh
as follicles) and paracortex (i.e., deep cortex, which mainly contains nodes. With increasing lymphatic obstruction, the lymph flow may
T-cells), and the base forms part of the nodal medulla (Figs. 27.2 be reversed (Figs. 27.5 and 27.6), with retrograde spread of tumor
and 27.3).1,2,6,7 to distant and sometimes anomalous locations.12 Detection of
lymph node metastasis with modern functional imaging techniques
Lymphatics and Blood Supply of Normal further increases our knowledge about distribution of lymph node
metastasis in primary and recurrent diseases.15–17
Lymph Nodes
Afferent lymphatic vessels deliver a constant stream of lymph to
the subcapsular sinus over each lobule. Lymph spreads through
Role of Neoangiogenesis
the subcapsular sinus over the lobule’s apex, flows down the sides It is still unclear whether the growth of metastatic tumor deposits in
of the lobule through transverse sinuses, and then flows into the lymph nodes is dependent on neoangiogenesis. It has been reported
399

Deep cervical
Scalenus anticus muscle
Right lymphatic duct
Thoracic duct
Mediastinal nodes
and vessels
Intercostal nodes
and vessels
Common
Receptaculum intestinal trunk
chyli
Preaortic nodes
and vessels
Lumbar
Common
intestinal trunk
Internal iliac
Sacral
External iliac
Figure 27.1. Schematic drawing of deep lymph nodes and vessels of the thorax and abdomen, including the thoracic and right lymphatic ducts. Afferent
vessels are represented by continuous lines, and efferent and internodular vessels by dotted lines.

Chapter 27 Assessment of Lymph Nodes in Oncology 401
Figure 27.2. Lymphoid lobule: The simplest possible lymph node

containing a single lymphoid lobule is depicted in this illustration.
The lobule has a bulbous apex and a base of slender medullary
cords. It projects into and fills the lumen of a dilated lymphatic sac
and is anchored by its blood vessels in the hilum. The lumen of the
encapsulated lymphatic sac is divided into a system of sinuses that
surround the lobule. Lymph from the afferent lymphatic vessel

spreads over the lobule’s apical surface in the subcapsular sinus,
moves down its sides through lateral transverse sinuses, and then
flows through medullary sinuses surrounding the medullary cords
and exits via the efferent lymphatic vessel in the hilum. The sinuses
are spanned by a delicate reticular meshwork, indicated here by a
lacy background texturing. The lobule contains a denser reticular
meshwork, shown here by a darker, more condensed background
texturing. The reticular meshwork provides a three-dimensional
scaffold with spaces for lymphocytes, antigen-presenting cells, and
macrophages to interact. B-lymphocytes home to follicles in the
superficial cortex where they interact with follicular dendritic cells.
Three follicles are depicted by small spheres. Follicles are sur-
rounded and separated by interfollicular cortex. In the paracortex
(deep cortex), T-lymphocytes home to the deep cortical unit (DCU),
depicted here as a large sphere, where they interact with dendritic
cells. The DCU has a center and a periphery. The peripheral DCU
and the interfollicular cortex are transit corridors that convey arte-
rioles, high endothelial venules, and paracortical sinuses. These
structures are suspended in the reticular meshwork and can be
seen more clearly in Figure 27.3 where the meshwork has been
omitted. The follicles and central DCU do not contain these struc-
tures and their capillary beds ( purple ) and reticular meshwork are
less dense than in the transit corridors. (From Willard-Mack CL.
Normal structure, function, and histology of lymph nodes. Toxicol
Pathol. 2006;34(5):409–424; copyright © 2006; reprinted with
permission of SAGE Publications.)
Figure 27.3. Lymph node: An idealized midsagittal section of a

small lymph node containing three lymphoid lobules. Each lobule is
centered under its own afferent lymphatic vessel. Taken together,
the follicles and interfollicular cortex of these lobules constitute the
superficial cortex of the lymph node, their deep cortical units (DCUs)
constitute the paracortex (deep cortex), and their medullary cords
and medullary sinuses constitute the medulla. Left lobule: Arterioles
(red ) and venules (blue) are conveyed in the medullary cords. Arte-
rioles arborize in the paracortical cords of the peripheral DCU and
interfollicular cortex and give rise to capillary beds (purple). Capil-
laries are present in the follicles and central DCU, but are less
dense than in the other areas. They are omitted from the medullary
cords for clarity. Capillaries empty into high endothelial venules,
which condense repeatedly in the interfollicular cortex and periph-
eral DCU and then transition to medullary venules at the corticomedul-
lary junction. Center lobule: This lobule, with the reticular meshwork
superimposed on the vasculature, is shown in Figure 27.2.
Note the paracortical sinuses. The center lobule is separated from
the left lobule by a transverse sinus. Right lobule: A micrograph
from a rat mesenteric lymph node shows a lobule as it appears in
histologic section. Densely packed basophilic lymphocytes fill the
lobular reticular meshwork. Five cortical follicles give the superficial
cortex a lumpy appearance. Small empty paracortical sinuses are
visible in the peripheral DCU. The medullary sinuses contain mac-
rophages, lymphocytes, and erythrocytes. (From Willard-Mack CL.
Normal structure, function, and histology of lymph nodes. Toxicol
Pathol. 2006;34(5):409–424; copyright © 2006; reprinted with
permission of SAGE Publications.)

A B C
Figure 27.4. The hilum of three different nodes on thin-slab maximum intensity projections (MIPs) over 2 mm of a three-dimensional T1W MR image (180-μm
isotropic resolution). Solid white arrows: Afferent lymphatic vessels. Open white arrows: Efferent lymph vessels. Thin black arrow: B-cell follicle. A: An area of low
signal intensity (black arrow ) is visible in the lymph node capsule. This corresponds to a B-cell follicle at pathologic examination. B and C: The MIP is oriented in
such a way as to depict all efferent vessels and as many afferent vessels as possible. Not all afferent vessels can be seen in one view. (Reprinted with permission
from Korteweg MA, Zwanenburg JJ, van Diest PJ, et al. Characterization of ex vivo healthy human axillary lymph nodes with high resolution 7 Tesla MRI. Eur Radiol.
2011;21(2):310–317; Springer Science + Business Media.)
Normal cell
Cancer cell
Lymph node
Arterial blood flow

Venous blood flow
Normal lymph flow
Reversed lymph flow
A B Obstruction of lymph flow
C D
Figure 27.5. Schematic drawings showing blood supply and lymphatics of lymph nodes in normal (healthy) and different pathologic situations, and problems
that may arise when using radiotracers/contrast agents that reach the lymph nodes through the interstitium. An example of a normal (healthy) situation with
two sentinel lymph nodes, second echelon nodes, arterial and venous blood flow to and from the lymph nodes, interstitium and flow of lymph from the inter-
stitium to the sentinel lymph nodes and second echelon nodes (A). The same situation as in (A), but with cancer cells in the tissue. There are no lymph node
metastases, and flow of blood and lymph to the lymph nodes is not impeded (B). The same situation as in (B), but with metastatic cancer cells in the corre-
sponding sentinel lymph node (C). Although the metastatic cancer cells occupy a part of this sentinel lymph node, lymph flow to this node is not impeded. In
addition, blood flow to this node is not impaired either. The same situation as in (C), but with progressive sentinel lymph node metastasis (D). The sentinel
lymph node is entirely replaced by tumor cells, as a result of which flow of lymph to this node is obstructed and reversed to the next (sentinel) lymph node.
Radiotracers and contrast agents that reach the lymph nodes through the interstitium will fail to depict this metastatic sentinel lymph node. On the other
hand, vascular supply of this metastatic sentinel lymph node is not impeded, as a result of which systemically administered compounds can still reach and
depict this involved node. (Reprinted with permission from Kwee TC, Basu S, Torigian DA, et al. Defining the role of modern imaging techniques in assess-
ing lymph nodes for metastasis in cancer: Evolving contribution of PET in this setting. Eur J Nucl Med Mol Imaging. 2011;38(7):1353–1366; Springer
Science + Business Media.)

A B

C D
Figure 27.6. Conventional planar lymphoscintigraphy and SPECT/CT lymphoscintigraphy in a 71-year-old patient with penile carcinoma with palpable left groin
lymph nodes and clinically negative right groin lymph nodes. Early (A) and delayed (B) conventional anterior scintigraphic images 2 hours after peritumoral injection
of 99mTc-nanocolloid show no lymphatic drainage to the left groin. Two-dimensional axial (C) and three-dimensional volume-rendered (D) fused SPECT/CT images
obtained immediately after conventional images show that this blockage is caused by enlarged lymph node in left groin (solid arrows). Two sentinel nodes with
uptake of radioactivity are seen in right groin (dashed arrows). (Reprinted with permission from Leijte JA, van der Ploeg IM, Valdés Olmos RA, et al. Visualization of
tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J Nucl Med. 2009;50:364–367.)
that additional blood vessels may not be essential for the growth of it has been reported that up to 70% of lymph node metastases
metastatic tumor because of the rich vascularity of the lymph node. can be found in normal-sized lymph nodes.17,20 Consequently,
Furthermore, early in the process of lymph node metastasis, the conventional MRI and CT with size measurements achieve poor
tumor cells occupy and grow within lymph sinuses where there is sensitivity and specificity for the detection of lymph node
no restraint on availability of nutrients. After leaving the sinuses, the metastasis (Table 27.1).21–25 Adding morphologic criteria to
rich vascularity of the lymph node can provide the required nutri- MRI evaluation might improve discrimination of lymph node
ents for tumor growth.18 Other researchers have speculated, how- metastases but their value may be limited, especially in smaller
ever, that the degree of angiogenesis-dependent and independent nodes.26
growth of lymph node metastases may be determined by their growth
pattern.19
Tabl e 2 7 . 1
Meta-Analysis of Pooled Sensitivity and Pooled

Conventional Imaging Specificity in Staging Pelvic Lymph Nodes in
Patients with Prostate Cancer
In routine practice, size measurements using conventional MRI
and CT are still the most frequently used methods to differentiate
malignant from nonmalignant lymph nodes. Lymph nodes with a Pooled Sensitivity (%) Pooled Specificity (%)
short-axis diameter larger than 10 mm are generally considered
to be malignant (although variable cutoff values have been sug- CT 0.42 0.82
gested for different anatomic areas). Imaging with size criteria is MRI 0.39 0.82
limited because lymph nodes can enlarge as a result of benign Modified from Hövels AM, Heesakkers RA, Adang EM, et al. The diagnostic accuracy of CT and
inflammatory or infectious processes, and normal-sized lymph nodes MRI in the staging of pelvic lymph nodes in patients with prostate cancer: A meta-analysis. Clin
may contain (micro-) metastasis. In prostate cancer, for example, Radiol. 2008;63(4):387–395.

There is also a role for US in conventional lymph node imag- extra cranial oncologic applications have recently become subject
ing. With US, both the size of a node can be determined as well as of active investigation.6 Lymph nodes have a relatively long T2
additional morphologic characteristics (such as round shape, relaxation time43,44 and an impeded diffusivity caused by their high
irregular border, loss of fatty hilum) and (hypo) echogenicity can cellularity.2 Therefore, lymph nodes can generally easily be identi-
be taken into account.27 However, these characteristics also lack fied as high signal intensity structures at DW-MRI, irrespective of
sufficient accuracy to differentiate malignant from benign nodes their histologic composition. Furthermore, assessment of signal
and, therefore, fine needle aspiration cytology (FNAC) is frequently intensity at DW-MRI or quantification of diffusivity in lymph nodes
employed to improve sensitivity and specificity. In the head and by means of apparent diffusion coefficient (ADC) measurements
neck, US combined with FNAC results in values of 63% to 97% and may aid in the histologic characterization of lymph nodes, because
69% to 100%, respectively.28–30 A major limitation of US is that it different pathologic processes may lead to differences in diffusivity
has limited utility for the evaluation of deep lymph nodes and because of differences in cellularity, intracellular architecture,
lymph nodes located behind bone or gas-containing structures. US necrosis, and perfusion (Fig. 27.7).42 Several studies, for example,
can be helpful, however, for targeted image-guided FNAC of a (US in patients with head and neck, lung, esophageal, colorectal, cervi-
accessible) lymph node that has been identified with another cal and uterine, and prostate cancers,45–52 found a significant dif-
imaging modality. ference in ADCs between metastatic and nonmetastatic lymph
nodes, independent of size criteria. In all but one study,48 ADCs of
metastatic lymph nodes were significantly lower than those of non-
Functional Imaging metastatic lymph nodes. This is because malignant tissue generally
exhibits hypercellularity, increased nucleus-to-cytoplasm ratios,
Sentinel Lymph Node Mapping and an increased amount of macromolecular proteins,2 resulting in
The rationale for sentinel lymph node mapping and biopsy is that decreased diffusivity in the extra- and intracellular compartments.42
the sentinel lymph nodes accurately reflect the status of the lym- On the other hand, there are other studies that report ADCs of met-
phatic basin draining a primary tumor.6 This assumption has been astatic and nonmetastatic lymph nodes that were not significantly
proven for malignant melanoma,31 early-stage breast cancer,32 and different, for example, in cervical and uterine cancer.53,54 This may
penile carcinoma.33 Sentinel lymph node mapping is usually per- be because of different cell density of different tumors. The sensi-
formed with radiocolloids (e.g., 99mTc-sulfur colloid, 99mTc-antimony tivities and specificities from the studies with reported significant
trisulfide colloid, or 99mTc-nanocolloid) and vital blue dyes. After differences varied between 69% and 94% and 56% and 100%
injection the radioactive particles and vital blue dye become effi- respectively (Table 27.2).45–52 Another issue is the reproducibility of
ciently trapped in sentinel lymph nodes. Subsequently, the sentinel ADC measurements of lymph nodes. Normal-sized lymph nodes
lymph nodes can be identified by preoperative lymphoscintigraphy, may be less reliably assessed because of the combination of image
an intraoperative γ-detecting probe, and/or by the intraoperative distortions (especially adjacent to air-containing organs), insuffi-
visualization of blue-stained lymph nodes.34 Patients with a positive cient spatial resolution, and partial volume effects.55 It can be
sentinel lymph node biopsy may benefit from early regional lymph argued that the use of improved echo planar imaging technology,
node dissection, whereas patients without metastasis in the senti- dedicated coils, and dedicated sequence optimization may improve
nel lymph node are spared such dissection.6 Although this method spatial resolution and reduce susceptibility and motion artifacts,
may reduce the number of unnecessary regional lymph node dis- such that the reliability and reproducibility of ADC measurements
sections in patients with melanoma, early-stage breast cancer, and may improve.6 Another important issue is that although tissue dif-
penile carcinoma, it is still an invasive and costly procedure with fusivity may differ between metastatic and nonmetastatic lymph
associated complications.4,5,35,36 Another drawback is the fact that nodes, there is a considerable overlap.45–54 The ADC threshold is
only lymph nodes in the vicinity of the primary tumor are assessed.6 therefore influencing the considerable variation of sensitivity and
Furthermore, the false-negative rate of this procedure (i.e., the frac- specificity reported (Table 27.2). Various nonmalignant conditions
tion of patients with metastatic lymph nodes that are missed by the such as ischemia and inflammation also reduce ADC, potentially
procedure and become evident later on when the metastatic lymph resulting in false positives. In addition, false-negative ADC mea-
nodes become clinically detectable) is not negligible.6 In a study that surements may occur in case of a low intranodal metastatic vol-
prospectively included 1,313 consecutive patients with melanoma ume, because this is less likely to form sufficient tissue boundaries
who had a median follow-up of 4.5 years, the false-negative rate of to impede water molecule diffusion.6 Therefore, the clinical utility
sentinel lymph node mapping and biopsy was reported to be of ADC measurements in the assessment of lymph nodes is still
14.4%.37 In yet another study including 323 patients with penile questionable.
carcinoma who had a median follow-up of 17.9 months, the false-
negative rate was 7%.38 There are several explanations for the Ultrasmall Superparamagnetic Iron
false-negative results of sentinel lymph node mapping and biopsy. Oxide–Enhanced MRI
First, tumor cells may only be present in afferent lymph node ves-
sels at the time of the sentinel lymph node biopsy. Second, tumor Ultrasmall superparamagnetic iron oxide (USPIO)–enhanced MRI
cells may simply bypass the sentinel lymph node and travel to and was introduced in the beginning of the 1990s as a new method for
lodge in the next lymph node. Third, increasing tumor growth in the nodal staging, independent of size criteria.56 After intravenous
sentinel lymph node may obstruct its afferent lymphatic vessels.6,12 administration, USPIO particles reach lymph nodes by two path-
Consequently, the flow of lymph containing the injected radiotrac- ways. The first pathway is via direct transcapillary passage through
ers and blue dyes may be diverted to neighboring unaffected lymph the high endothelial venules within individual lymph nodes. The
nodes (Figs. 27.5 and 27.6).12,39–41 In this respect, clinically suspi- second pathway is via nonselective endothelial transcytosis across
cious nodes should be removed even if there are minimal radioac- permeable capillaries throughout the body into the interstitium.
tive counts or no blue staining.34 It may also be of value to perform USPIO particles are subsequently taken up from the interstitium by
preoperative US-guided FNAC.38 afferent lymphatic vessels and transported to regional lymph nodes.
Macrophages within both normal and hyperplastic lymph nodes
phagocytize mainly the USPIO particles that arrive by this second
Diffusion-Weighted MRI pathway. The intracellular iron particles cause changes in mag-
Diffusion-weighted MRI (DW-MRI) provides information on a netic properties.57 The result is that benign lymph nodes will lose
molecular level. It allows noninvasive visualization and quantifica- signal on T1-weighted gradient echo, T2-weighted, and T2*-weighted
tion of the random (brownian) motion of water molecules.42 Its images.57,58 On the other hand, metastatic deposits in lymph nodes

A B

C D
Figure 27.7. Diffusion-weighted MRI (DW-MRI) in a 67-year-old female with grade I follicular lymphoma and cervical lymph node involvement. Coronal T1-weighted
(A), T2-weighted short-inversion time inversion recovery (B), DW-MRI (acquired using a b-value of 1,000 s/mm2) (C), and apparent diffusion coefficient (ADC) map
(created using b-values of 0 and 1,000 s/mm2) (D) show an enlarged cervical lymph node (arrows). A region of interest (ROI) was placed in the lymph node on the
DW-MRI in (C) and copied and pasted onto the corresponding ADC map. The ADC of the lymph node was relatively low ([0.62 ± 0.21] × 10−3 mm2/s), which may
suggest lymphomatous involvement. The size of the lymph node decreased after chemotherapy. (Reprinted with permission from Kwee TC, Basu S, Torigian DA, et al.
Defining the role of modern imaging techniques in assessing lymph nodes for metastasis in cancer: Evolving contribution of PET in this setting. Eur J Nucl Med Mol
Imaging; Springer Science + Business Media. 2011;38(7):1353–1366.)
Table 27. 2
Characteristics and Reported Sensitivity and Specificity in Diffusion-Weighted MRI
Origin of B-Values in Threshold ADC Malignant Sensitivity Specificity Field

Author/Year Cancer s/mm2 in mm2/s Compared to Benign Significance (%) (%) Strength in T
De Bondt et al., Head and neck 0 and 1,000 1,000 Lower Yes 92 84 1.5
2009a
Vandecaveye Head and neck 0 and 1,000 940 Lower Yes 84 94 1.5
et al., 2009b
Sakurada Esophagus 0 and 1,000 — Higher Yes — — 1.5
et al., 2009c
Yasui et al., 2009 Colorectal 0 and 800 1,440 Lower Yes 75 76 1.5
Kim et al., 2008 Uterine cervical 0 and 1,000 862 Lower Yes 87 80 1.5
Park et al., 2009d Uterine cervical 0 and 1,000 790 Lower Yes 79 93 1.5
Eiber et al., 2010 Prostate 50, 300, and 1,300 Lower Yes 86 85 1.5
1,000
Nakai et al., 2008e Gynecologic 0 and 800 — Higher No — — 1.5
Lin et al., 2008 Uterine cervical 0 and 1,000 780 Higher No 89 88 3
Nakayama Lung 50 and 1,000 1,540 Lower Yes 83 85 1.5
et al., 2010f
a
With a lower threshold of 900 mm2/s, sensitivity dropped to 69% with a rise in specificity to 92%.
b
On per-neck-level base with the same threshold sensitivity and specificity were 94% and 97%, respectively.
c
Mean ADCs of metastatic and nonmetastatic lymph nodes were 1.46 ± 0.35 and 1.15 ± 0.25 × 10−3 mm2/s. No threshold and sensitivity and specificity based on ADC measurements were given.
d
With the rADC criteria of 0.423, the sensitivity and specificity for differentiating metastatic from nonmetastatic lymph nodes were 86% (95% CI, 68%–96%) and 93% (95% CI, 88%–96%), respec-
tively. rADC was calculated by ADClesion/ADCreference site.
e
The ADC values of total, metastatic, and nonmetastatic nodes on DW images were as follows in mm2/s: Total nodes, 1,300 ± 250; metastatic nodes, 1,400 ± 400; and nonmetastatic nodes, 1,300 ±
240. The ADC values were not statistically significant between nonmetastatic and metastatic nodes (p = 0.28).
f
When corrected for ADC of the primary tumor, the sensitivity and specificity were 87% and 100%, respectively. Quantitative analyses of DW-MR images on a per patient basis including lymph nodes
that were not detected resulted in sensitivity and specificity of 56% and 100%, respectively.

Efferent
lymphatics
Metastasis
Intravenous
injection
Iron particles
Interstitial space
Afferent
lymphatics
Lymph
node
Metastasis
Blood Macrophage Lymph

vessel vessel
Medullary
Metastasis sinus
Figure 27.8. Uptake scheme for ultrasmall
superparamagnetic iron oxide (USPIO) parti-
cles. USPIO particles are intravenously injected.
They are transported to the interstitial space
Lymphocytes and via lymph vessels into the lymph nodes.
There is accumulation of USPIO particles in
macrophages in normal nodal tissue but not
Macrophage
in metastases. Therefore, normal nodal tissue
will have a low signal intensity 24 to 36 hours
after contrast injection, whereas metastases
will have unchanged or slightly higher signal
intensity. Thus normal and metastatic nodes
can be differentiated. (Reprinted with permis-
sion from Deserno W.M.L.L.G, Harisinghani
After approximately MG, Taupitz M, et al. Urinary bladder cancer:
24 hours preoperative nodal Staging with ferumoxtran-
10-enhanced MR imaging. Radiology. 2004;
233:449–456.)
do not change signal intensity since they fail to take up the USPIO Tabl e 2 7 . 3
particles (Figs. 27.8 and 27.9). Failure of metastatic lymph nodes to
take up USPIO particles can be explained by obstruction of afferent Meta-Analysis of Pooled Sensitivity and
lymphatic vessels (Fig. 27.5), replacement and displacement of Specificity for Ultrasmall Superparamagnetic
intranodal macrophages by metastatic tumor deposits that do not Iron Oxide (USPIO)-Enhanced MRIa
phagocytize the contrast agent (Fig. 27.8), and tumor-induced
changes in lymph node physiology causing macrophages to fail to Pooled Sensitivity Pooled Specificity
phagocytize the contrast agent.57 A noniron sensitive sequence is (%) (%)
useful to identify the fatty hilum of a lymph node and therefore to
discriminate the hilar fat from nodal metastases. This sequence is USPIO-enhanced on a 90 96
useful also for initial anatomic localization and node detection node-by-node basis
(Fig. 27.9). Optimal uptake in the lymph nodes is reached after 24 to USPIO-enhanced on a 89 89
36 hours.59 A meta-analysis of 34 studies investigated the diagnostic patient-by-patient basis
performance of USPIO-enhanced MRI for nodal staging in various Nonenhanced MRI 39 90
tumors, and reported that overall (node-by-node base) sensitivity and a
specificity of USPIO-enhanced MRI (90% and 96%, respectively) were On a node-by-node basis and patient-by-patient basis as well as the pooled sensitivity and
specificity on nonenhanced MRI for these studies.
higher than those of unenhanced MRI (39% and 90%, respectively) Modified from Wu L, Cao Y, Liao C, et al. Diagnostic performance of USPIO-enhanced MRI for lymph-
(Table 27.3).60 node metastases in different body regions: A meta-analysis. Eur J Radiol. 2011;80(2):582–589.

A B C

Figure 27.9. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI in a 62-year-old patient with prostate cancer and pelvic lymph node metastases.
The MRI examination was performed because of rising prostate-specific antigen levels after prostatectomy. Coronal T1-weighted (A), T2*-weighted (B), and diffusion-
weighted (acquired using a b-value of 600 s/mm2) (C) images of the pelvis 24 hours after the administration of USPIO particles show that several right-sided
metastatic lymph nodes appear “white” (i.e., hypersignal intensity) (solid arrows) whereas a left-sided nonmetastatic lymph node appears “black” (i.e., hyposignal
intensity) (dashed arrows). Note that diffusion-weighted imaging suppresses vascular structures (C), which may facilitate image interpretation. Reprinted with per-
mission from Kwee TC, Basu S, Torigian DA, et al. Defining the role of modern imaging techniques in assessing lymph nodes for metastasis in cancer: Evolving
contribution of PET in this setting. Eur J Nucl Med Mol Imaging; Springer Science + Business Media. 2011;38:1353–1366.)
A notable development in USPIO-enhanced MRI is the addition of particular CT, allows precise localization of foci with increased
postcontrast DW-MRI.61 As mentioned previously, DW-MRI is a very PET radiotracer uptake and provides information on structural
effective method to highlight lymph nodes, irrespective of their histo- lymph node abnormalities, thereby increasing the diagnostic yield
pathologic composition. Furthermore, DW-MRI (acquired using echo of PET alone. Another important issue is that PET radiotracer,
planar imaging) is very susceptible to magnetic field in homogeneities which is systemically administered, arrives in the lymph node
that are caused by the USPIO particles. Thus, theoretically, in USPIO- through its arterial blood supply. Therefore, lymphatic obstruction
enhanced DW-MRI, only malignant lymph nodes are highlighted; the and the subsequent reversal of lymph flow will not affect the per-
high metastatic lymph node-to-background contrast will reduce formance of PET in diagnosing metastatic lymph nodes (in con-
image interpretation time and may increase sensitivity for the detec- trast to sentinel lymph node mapping [Fig. 27.5]).
tion of small metastatic lymph nodes (Fig. 27.9).6 The feasibility of this The glucose analog 18F-fluoro-2-deoxy-D-glucose (FDG) is cur-
new concept has recently been demonstrated in a study involving 28 rently the most frequently used PET radiotracer in clinical prac-
patients with urinary bladder and prostate cancer.61 In this study, tice.6 The rationale for the use of FDG for PET imaging in oncology
patient-based and pelvis side-based diagnostic accuracies for the is that the vast majority of malignant cancer phenotypes exhibit
detection of lymph node metastasis were comparable between USPIO- an increased glucose metabolism (i.e., the Warburg effect).63
18
enhanced DW-MRI and conventional USPIO-enhanced MRI (both FDG-PET plays a pivotal role in the evaluation of many malig-
90%), but interpretation time of the former (median: 13 minutes; nancies.63,64 Overall, diagnostic performance of 18FDG-PET in
range: 5 to 90 minutes) was significantly shorter (p < 0.0001) than nodal staging is suboptimal. 18FDG-PET is reported to have a
that of the latter (median, 80 minutes; range, 45 to 180 minutes).61 pooled sensitivity of 79% (and a pooled specificity of 86%) in
Although a potentially useful method for nodal staging, USPIO- patients with head and neck squamous cell carcinoma.65 Further-
enhanced MRI has disadvantages and drawbacks. First, USPIO more, in patients with a clinically negative neck, pooled sensitiv-
acts as a negative contrast agent. That is, the absence of contrast ity and specificity were only 50% and 87%, respectively. Further
agent uptake is used as evidence for neoplastic involvement. The meta-analysis investigated the diagnostic performance of 18FDG-
specificity of this method may be suboptimal because the uptake of PET in assessing axillary lymph node status in breast cancer66
USPIO particles is also impaired in nonneoplastic disease pro- and in detecting para-aortic lymph node metastasis in patients
cesses such as reactive hyperplasia.62 A second disadvantage of the with cervical cancer.67 18FDG-PET cannot yet reliably replace sur-
current generation of USPIO particles is that they need to be gical biopsy of the axillary lymph nodes in patients with breast
injected 24 hours before scanning, which places an additional bur- cancer. 18FDG-PET performs acceptably only in populations with
den on the patient and on financial and logistical resources.6 Third, a relatively high probability of para-aortic lymph node metastasis
metastatic deposits in lymph nodes may be missed when the in the case of cervical cancer. In another meta-analysis in patients
applied dose of USPIO particles is too high (i.e., oversaturation).6 with nonsmall cell lung cancer (NSCLC),68 it was reported that the
Fourth, the iron sensitive sequence has to be compared to a non- presence or absence of lymph node enlargement at CT influenced
iron sensitive sequence (or a precontrast sequence). Consequently, the diagnostic performance of 18FDG-PET in mediastinal lymph
image interpretation is complicated and time consuming. Adding node staging. 18FDG-PET is more likely to yield both true-negative
DW-MRI, as described above, might reduce this disadvantage.6 and false-negative findings in patients without lymph node
USPIO contrast agents have not yet been approved for human enlargement because of its limitations in detecting small hyper-
use, neither by the Food and Drug Administration (FDA) nor by metabolic lesions of any origin (note that current commercially
the European Medicines Agency (EMA). available PET systems have a spatial resolution of about 4 to
7 mm for whole-body imaging). However, in patients with
enlarged lymph nodes, 18FDG-PET is more likely to reveal both
PET and PET/CT true-positive findings that are caused by metastasis and false-
Important advantages of PET are its high tumor-to-background positive findings that are caused by hyperplasia, infection, inflam-
contrast. The combination of PET with anatomical imaging, in mation, or granulomatous disease.68,69

B C
Figure 27.10. CT, early FDG-PET imaging (60 minutes after radiotracer injection), and delayed FDG-PET imaging (3 hours after radiotracer injection) in a
patient with lung adenocarcinoma and mediastinal lymph node metastasis (lymph node 7) in the subcarinal area. CT images (A) show a nodule in the right lung
(arrows) without any significant mediastinal lymph node enlargement. Early FDG-PET imaging (B) shows strong accumulation in the lung nodule (solid arrow ) but
only faint accumulation in lymph node 7 (dashed arrow ). Delayed FDG-PET imaging (C) shows increased uptake in both the lung nodule (early standardized
uptake value [SUV] of 6.85, delayed SUV of 10.01) (solid arrow ) and in lymph node 7 (early SUV of 3.49, delayed SUV of 5.08) (dashed arrow ), while background
SUVs decrease. (Reprinted with permission from Uesaka D, Demura Y, Ishizaki T, et al. Evaluation of dual-time-point 18F-FDG PET for staging in patients with lung
cancer. J Nucl Med. 2008;49(10):1606–1612.)
Future advances in PET technology that provide a higher signal- est malignant lesion-to-background contrast, and, consequently, the
to-noise ratio and a higher spatial resolution are likely to increase the potentially highest diagnostic yield can be achieved when performing
diagnostic performance of FDG-PET in nodal staging. Additional PET imaging at approximately 3 or 4 hours after 18FDG administra-
improvements in the diagnostic yield of 18FDG-PET for nodal staging tion rather than at 60 minutes as is the case with most studies.6
may be achieved with delayed PET imaging (i.e., 3 or 4 hours after Several studies (e.g., in lung, esophageal, and cervical cancer74–80)
18
FDG administration). The rationale for delayed imaging is based on have shown that delayed or dual-time-point 18FDG-PET imaging
the fact that several tumors exhibit a maximum 18FDG uptake well may be beneficial for lymph node staging compared to early, single-
beyond 60 minutes after 18FDG administration whereas surrounding time-point 18FDG-PET imaging alone (i.e., 50 to 60 minutes after
normal tissues and benign pathologies show a decline in 18FDG 18
FDG administration). However, other studies (e.g., in lung and
uptake with time.70–73 This phenomenon occurs because malignant nasopharyngeal cancer81–83) did not show any advantage of this
cells have substantially enhanced glucose transporters on their sur- method.6 These discrepant findings may be explained by heteroge-
face and express high levels of hexokinase and low levels of glucose- neity in the expression of glucose transporters, hexokinase, and
6-phosphatase, which leads to an accumulation of 18FDG in these glucose-6-phosphatase in different cancers. More research is war-
cells. By contrast, inflammatory cells have higher levels of glucose-6- ranted to elucidate in which cancers delayed or dual-time-point
18
phosphatase than malignant cells, and therefore a lower ratio of hexo- FDG-PET imaging is beneficial for nodal staging.6
kinase to glucose-6-phosphatase. Consequently, 18FDG-6-phosphate The limitations of 18FDG-PET are apparent in slow-growing
is rapidly dephosphorylated and cleared from the cell, leading to tumors such as prostate carcinomas because of their lack of an
decreasing concentration of this metabolic product over time.70–73 increased glucose metabolism. Many primary prostate cancers
Therefore, malignant lymph node-to-background contrast can con- show either relatively low 18FDG uptake84 or no visible uptake.
siderably be increased at delayed PET imaging (Fig. 27.10).70–73 Fig- Furthermore, 18FDG is less useful in the pelvic area as 18FDG accu-
ure 27.11 shows the summarized time activity curves of SUVmax in mulates in the bladder and thus obscures parailiac and pelvic
malignant lesions and in normal organs of three patients with non- structures. An alternative PET radiotracer is 11C-choline. Tumor
small cell lung cancer who had undergone FDG-PET at several time cells are characterized by their ability to actively incorporate cho-
points, beginning at 5 minutes and extending up to 8 hours after line to produce phosphatidylcholine (a membrane constituent) to
18
FDG administration.6 These figures well demonstrate that the high- facilitate tumor cell duplication. 11C-choline is incorporated into

16
14
12
Lung neoplasm
10
SUVmax
Mediastinal lesion 1
Mediastinal lesion 2
8 Adrenal
Right iliac
6
2
0 100 200 300 400 500
A Min

Figure 27.11. Summarized time activity curves of SUVmax in 4
malignant lesions (A) and normal organs (B) of three patients Heart
with nonsmall cell lung cancer who had undergone FDG-PET at Lung
3
SUVmax
several time points, beginning at 5 minutes and extending up to

8 hours after FDG administration. These figures well demonstrate Large bowel
that the highest ratio of SUVmax of malignant lesions to that of Small bowel
normal organs can potentially be achieved when performing PET 2
Liver
imaging at approximately 3 or 4 hours after FDG administration
Kidney
rather than at 60 minutes as is the case with most studies.
1
(Reprinted with permission from Basu S, Kung J, Houseni M, et al.
Temporal profile of fluorodeoxyglucose uptake in malignant
lesions and normal organs over extended time periods in patients 0
with lung carcinoma: Implications for its utilization in assessing
malignant lesions. Q J Nucl Med Mol Imaging, Edizioni Minerva
0 100 200 300 400 500
B Min
Medica. 2009;53(1):9–19.)
tumor cells by conversion into 11C-phosphorylcholine, which is Other PET radiotracers have been tested for evaluating lymph
trapped inside the cell. Upregulation of the enzyme choline kinase node metastases. The PET radiotracer 3′-deoxy-3′-(18F) fluorothymi-
and the rapid biosynthesis of cell membranes in tumor cells lead dine (18F-FLT) can image tumor cell proliferation and it may provide
to increased uptake of choline and upregulation of the enzyme biologic tumor information in enlarged lymph nodes. However, in
choline kinase. Several authors compared 11C-choline to 18FDG for recent literature, the value of 18F-FLT PET is limited to determining
diagnosis and staging of prostate carcinoma lymph node metasta- the lymph node status, for example, in head and neck squamous
ses. Whereas FDG accumulates in the bladder, 11C-choline has cell carcinoma or rectal carcinoma.89,90
minimal urinary excretion and activity in the bladder. These
advantages underlie reports on 11C-choline PET/CT (choline PET/
CT) as accurate and sensitive in preoperative staging of pelvic Conclusion
lymph nodes.85–87 As 11C-choline has a rapid clearance from the
blood pool and rapid uptake in prostate cancer tissue (primary Lymph node status in patients with cancer has important implica-
tumor and metastases), optimal tumor-to-background contrast is tions with regard to treatment planning and prognosis. Knowledge
reached within 5 to 7 minutes. Just like FDG-PET, 11C-choline about the dissemination of lymph node metastasis is increasing
PET is also limited in spatial resolution. A recent study underlined and may improve both diagnostic and therapeutic strategies. Exci-
this limitation in comparison to better spatial resolution (and there- sion followed by histopathologic examination is still the gold stan-
fore better detection of small lymph node metastases) in USPIO dard for the assessment of lymph nodes, but this is invasive, costly,
MRI.17 and only provides information about lymph node status in the sur-
An important limitation of 11C-choline is that it is limited to PET gical area. There is, therefore, an important role for noninvasive
centers that have onsite cyclotrons because of its short half-life imaging techniques in lymph node staging.
(approximately 20 minutes). This drawback prompted the devel- Conventional imaging techniques that are frequently used in
opment of 18F-flurocholine, a radiotracer with a half-life of 110 min- routine clinical practice for lymph node assessment include CT,
utes, to image prostate cancer and associated lymph node MRI, and US. However, these conventional imaging techniques
involvement.88 18F-flurocholine can be produced commercially and rely on size criteria, which is insensitive and nonspecific. To
is potentially readily available in clinical PET centers. It provides overcome this disadvantage, functional imaging techniques,
higher resolution images as a result of its shorter positron length which go beyond structural assessment and allow in vivo visual-
path. 18F-flurocholine, like FDG, has greater urinary excretion than ization and quantification of physiologic and biochemical pro-
11
C-choline, but routinely performed dynamic pelvic acquisition cesses, have been developed. There are a multitude of functional
overcomes this drawback as pathologic uptake begins 1-minute post imaging techniques that can be used for lymph node metastasis
injection, before urinary excretion and bladder filling. It is likely that assessment. Sentinel lymph node mapping and biopsy, DW-MRI,
18
F-flurocholine PET/CT will even be more useful as an accurate and USPIO-enhanced MRI, and PET (most frequently with FDG) are
noninvasive staging tool, at least in selected groups of patients with functional imaging techniques that are currently in or approaching
high suspicion of metastatic lymph node disease. clinical use.

Sentinel lymph node mapping with biopsy has shown its value with a biochemical recurrence after radical prostatectomy. Int J Radiat Oncol
Biol Phys. 2012;82:1405–1410.
in determining the status of the lymphatic basin drainage in malig- 17. Fortuin AS, Deserno WM, Meijer HJ, et al. Value of PET/CT and MR lymphogra-
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879–892. cancer. Radiother Oncol. 2011;98:357–359.

Chapter 28
Sentinel Lymph Node Detection and Imaging in Oncology

Gang Cheng • Drew A. Torigian • Abass Alavi
Introduction As a multidisciplinary procedure, SLNB requires close coopera-

tion between nuclear medicine physicians (for lymphatic map-
ping), surgeons (for identification and biopsy of the SLN), and
In any specific region of the skin or subcutaneous tissues, there is a pathologists (for histologic evaluation of the biopsied SLN). Gener-
preferred lymphatic drainage to which afferent lymphatic vessels ally, 99mTc-sulfur colloid is injected intradermally at the site near
drain first. That is, there is one preferred lymph node (the sentinel the primary tumor, with or without local anesthesia. This is often
lymph node [SLN]) that will be the first to receive lymphatic drain- performed in the nuclear medicine department a few hours before
age from a given regional lymph node basin. This also applies to surgery. Serial lymphoscintigraphy is obtained in the next few
lymphatic drainage of malignant tumor cells that spread in a step- hours by the nuclear medicine physician, who may also mark the
wise manner from the primary site to the regional lymph nodes. The location(s) of detected SLN on the skin. Figure 28.2 shows lym-
underlying rationale of sentinel lymph node biopsy (SLNB) is that phatic drainage in the first 20 minutes after the injection of 99mTc-
when lymph node metastases occur, metastatic tumor cells drain via sulfur colloid. Surgery can be performed on the same day or on the
afferent lymphatics to a limited number of SLNs that are at highest following day. During surgery, a surgeon uses a hand-held γ-probe
risk for nodal metastasis because these lymph nodes represent the moving over the regional nodal basin (with the help of lymphoscin-
first nodal sites along the path of regional lymph drainage from the tigraphic findings and skin marking) to detect a “hot spot” of SLN.
tumor (Fig. 28.1). Accordingly, examination of the tumor status of A surgeon may also intradermally inject a vital dye at the begin-
the SLN reflects the tumor status of the entire lymphatic drainage ning of surgery, at the site of the primary tumor, often after the
basin: A negative finding of SLN typically indicates no other nodal induction of anesthesia. The injected dye will migrate in a manner
metastasis in the same drainage basin with a high degree of confi- similar to the injected radiotracer, concentrate at sites of SLN, and
dence whereas a positive finding of SLN indicates the likely involve- is identified visually during surgery. After intradermal injection of
ment of other nonsentinel lymph nodes (nonSLNs) as well. Because vital dye at the primary site at the beginning of surgery, incisions
only a limited number of SLNs are biopsied and examined, this pro- are made over the regional nodal basin to follow the migration of
cedure allows more focused and more intensive pathologic assess- the dye and thus the lymphatic drainage channels, to identify blue-
ment including more sections and immunohistochemistry (IHC) stained SLN. The major drawback of vital blue dye is that it is
evaluation of the regional tumor-draining nodes. dependent on visual identification. Thus meticulous dissection of
Morton et al.1,2 reported their pioneering development of intra- subcutaneous tissues is required to follow dye migration to find SLN.
operative lymphatic mapping in the early 1990s. Their work began The use of a radiolabeled agent makes it easier to identify SLN,
in 1985 and relied solely on vital dyes to identify the SLN. The because a hand-held γ-probe is often able to pinpoint the location of
initial description of SLNB by Morton et al. was rejected by several a “hot” node, eliminates the need for meticulous dissection of subcu-
major medical journals before eventually being published in the taneous flaps, and can identify additional SLN at the same time.
Archives of Surgery. Since then, their work has become one of the Local excision of the primary tumor is performed after excision of
most frequently cited in surgical oncology. Their technique gained the SLN. Rescanning of relevant nodal basins with the hand-held
widespread acceptance in the early 1990s followed by continuous γ-probe is performed again to ensure removal of all SLNs, especially
modifications and improvements. In the early 1990s, a radioactive ectopic lymph nodes. All SLNs excised are evaluated by pathologists
tracer was incorporated into the intraoperative procedure as a sec- for the presence of metastases, first by frozen sectioning and H&E
ond mapping agent so that an SLN can be identified by blue stain- staining during surgery which will generate the first diagnosis, and
ing and/or by increased radioactivity. The addition of a hand-held later by permanent sectioning and H&E staining, also with IHC
γ-probe3 made it more convenient to identify SLNs containing staining using appropriate antibodies, to generate a final diagnosis.
radioactivity. For patients with negative SLNB, no further surgery for regional
Figure 28.1. Model of lymphatic mapping. Schematic of afferent lymphatic

channels draining from the primary tumor to sentinel nodes in the regional nodal
basin. A: A sentinel lymph node (SLN) without metastatic cells identified by the
injected blue dye or 99mTc-colloid. B: An SLN with metastatic cells identified by
the injected blue dye or 99mTc-colloid. C: An SLN with overloaded metastatic cells
is not identified, because of blockage of afferent lymphatic flow or depleted nodal
space. D: An in-transit node with metastatic cells identified by the injected blue
dye or 99mTc-colloid. Please note that second-tier nonSLNs may be occasionally
identified by pass through of the injected blue dye or radiolabeled colloid.
412

Chapter 28 Sentinel Lymph Node Detection and Imaging in Oncology 413

Figure 28.2. Serial lymphoscintigraphy for a 56-year-old female with right breast cancer. This patient received periareolar subdermal injection of filtered 99mTc-
sulfur colloids, and serial planar images are shown at 1-minute interval (from 6 to 20 minutes). Lymphatic drainage pathway to the axillary basin is visualized clearly
in the first few minutes and is then cleared, whereas activity in a hot spot of a right axillary sentinel lymph node persists.
nodal basins is needed. SLNB procedure guidelines are available interstitium into venous capillaries. Particles that are too large will
for breast cancer4 and melanoma.5 migrate too slowly through the lymphatic channels, preventing suf-
SLNB allows focused assessment of regional lymph node involve- ficient accumulation in lymph nodes before imaging. Numerous
ment by removal and examination of only a few SLNs receiving radiolabeled agents have been used to detect SLNs.6 In the United
lymph drainage from the site of the primary malignancy. It allows States, 99mTc-sulfur colloid is the most commonly used radiolabeled
more precise nodal staging than clinical evaluation, without morbid- agent for lymphoscintigraphic SLN detection. The particles of
99m
ity and tissue damage associated with complete lymphadenectomy Tc-sulfur colloid vary significantly in size (from 15 to 5,000 nm,
as previously performed. SLNB is cost effective and offers an improve- depending on preparation methods), with an average size range of
ment in health outcomes. Currently, it has become the standard of 305 to 340 nm. In practice, 99mTc-sulfur colloid is filtered through
care in patients with melanoma and breast cancer. The procedure a 0.22-μm filter to produce particles between 100 and 220 nm in
applied to other solid cancers is under investigation. Over the past size. In Europe, 99mTc-nanocolloidal albumin (Nanocoll, GE Health-
two decades, SLNB has gained widespread acceptance as a model care) is the preferred agent with a particle size of 5 to 100 nm.
99m
procedure of minimally invasive oncologic surgery. A great deal of Tc-antimony trisulfide is the most commonly used agent in
experience with SLNB has accumulated. SLNB has undergone con- Canada and Australia with a particle size of 3 to 30 nm.
tinuous fine-tuning with improved performance. There is no consen- All of these agents are able to detect SLN effectively and reliably,
sus, however, regarding how the procedure should be performed. and the selection of a radiolabeled agent is often based more on
Controversies exist with regard to the selection of agents (vital dyes local availability rather than on differences in performance. Although
or radiolabeled agents), the size of labeled particles, the optimal site the success rate in the identification of SLN is not significantly
of injection, and the value of preoperative lymphoscintigraphy. affected by the particle size, knowledge of the effect of particle size
on the detection of SLN is useful, because drainage and clearance by
the lymphatic system varies with particle size. Small particles are
Technical Considerations of Sentinel drained and cleared first, whereas large particles are drained slowly
and may have long retention at the injection site.6 Smaller particles
Lymph Node Biopsy have the advantage of rapid (in minutes) visualization of SLN,
whereas larger particles have the advantages of longer retention in
Radiolabeled Agents SLN to permit intraoperative detection the following day. Thus, the
timing of preoperative lymphoscintigraphy and intraoperative detec-
An ideal radiolabeled agent to identify SLN should permit good
tion of SLN should be adjusted accordingly. It is believed that radio-
visualization of the lymphatic channels leading from the primary
colloids with 100 to 200 nm particles represent the best compromise
tumor site to the corresponding regional lymph nodes. The radiola-
between an efficient lymphatic drainage and early scintigraphic
beled agent should clear fast enough from the injection site to allow
visualization versus the need for satisfactory retention in SLN for
scintigraphic visualization of SLN in minutes to hours, but is
intraoperative detection.6
retained in the SLN long enough to allow intraoperative identifica-
tion via a hand-held γ-probe. The clearance of colloidal radiolabeled
agents through lymphatic channels and lymph nodes is dependent
on the particle size.
Vital Dyes
Radiolabeled particles must be small enough to enter the A vital blue dye was the first marker used to identify SLN in mela-
lymphatic channels, yet not so small that they diffuse out of the noma.1 It was later used in patients with breast cancer and other

malignancies.7 Different vital dyes are currently used, and the com- Indocyanine green absorbs light in the near-infrared range and
mon ones include patent blue V, isosulfan blue, and methylene blue. emits maximum fluorescence at a wavelength of 840 nm. Motomura
Multiple studies have confirmed vital dyes as valid markers for SLN et al.20 at the Osaka University Medical Center first reported the
identification with high detection rates, close to those achieved by use of indocyanine green as a tracer for SLN mapping in breast
radiolabeled agents.8 In most cases, the same SLNs are detected by cancer patients in 1999, and later the combined use of 99mTc-sulfur
both blue dyes and by radiolabeled agents.9 colloid and indocyanine green. Use of indocyanine green for lymph
It should be recognized that the use of vital dyes is associated node mapping was subsequently extended to melanoma and other
with a low but definite risk. Most reactions are mild and are noted cancers. Important advantages in the use of indocyanine green are
in 1% to 2% of cases, including urticaria, hives, generalized rash, or high safety, and the ability to allow for simultaneous localization of
pruritus.10 Hypotensive reactions or anaphylaxis (bronchospasm green staining and fluorescent marking of lymphatic tissues using
and respiratory compromise) are unusual after the injection of a an infrared imaging device combined with a charge-coupled device
blue dye. If it occurs, most patients can be treated with short-term (CCD) and a light-emitting diode (LED). A major limitation to the
vasopressor support.11 However, death, although extremely rare, widespread use of indocyanine green is the need for portable,
has been reported.12 Use of methylene blue as an alternative to intraoperative imaging systems to allow for visualization of fluo-
other vital dyes may help to decrease these adverse reactions. Pre- rescent structures. Although very promising, indocyanine green is
operative prophylaxis with corticosteroids and antihistamines was still under investigational use. More in-depth studies are needed to
tested to reduce these side effects but showed no significant differ- fully evaluate its potential and limitations.21
ence and may lead to increased wound infection and dehiscence.13
The advantages of vital dyes are the convenience of use (with- Injection Techniques
out radiation safety issues and imaging facility requirements), as
well as visual identification of positive nodes. The disadvantages For cutaneous melanoma, intradermal or subdermal radiolabeled
are that they are less efficient in identifying distant and deep-lying agent injection is recommended using a 25- or 27-gauge needle.
nodes, and lead to more exploratory dissections and tissue dam- The number of radiocolloid aliquots and the sites of injection vary,
age. For example, blue dyes have very limited value in identifying depending on the size and location of the primary tumor and
extra-axillary nodes (internal mammary or supraclavicular nodes) whether there is a wide excision scar. Total injected activity ranges
in patients with breast cancer.14 Another disadvantage is that blue from 0.2 to 1 mCi (7.4 to 37 MBq), often divided into 3 to 4 aliquots,
dyes may interfere with pulse oximetry readings. Use in certain and the injection volume should be small (0.1 to 0.2 mL). The injec-
patients, therefore, should be performed with caution.15 Finally, tion sites are often 0.5 to 1 cm from the scar or tumor margin.
blue dyes are not recommended for use in pregnant women.16 Research has demonstrated that intradermally injected radiocol-
loid surrounding a biopsy excision site at distances of 1.5 or 0.5 cm
showed similar detection rates for SLN.22 In general, injections
Combined Agents should not be made into inflamed, infected, or scarred areas, and
SLN identification with isosulfan blue dye or patent blue dye is contamination of the patient’s skin and clothing should be avoided.
enhanced by the addition of radiolabeled sulfur colloid and intra- For breast cancer, peritumoral injection was the original
operative use of the hand-held γ-probe. Use of radiolabeled agents method used for SLNB and was very successful.3 Later, multiple
results in higher SLN identification rate compared to blue dyes injection methods have been recommended for breast cancer
alone, regardless of the injection methods.8,17 SLN identification SLNB, including deep subcutaneous or parenchymal (peritumoral,
rates in patients with cutaneous melanoma improved from 84% to subtumoral, intratumoral) injections and superficial (intradermal
87% (blue dye alone) to 99% to 99.5% (blue dye plus sulfur colloid) or subdermal) periareolar or subareolar injections.17
( p < 0.0001) with the combined technique at all anatomic sites Multiple studies demonstrate that all of these injection methods
examined. It is generally accepted that radiocolloids and blue dyes are similarly successful for the identification of SLNs. The underlying
are complementary to each other for SLNB. The advantages of reason is likely that for most of the breast tissue and overlying skin,
adding radiolabeled agents also include the ability to identify deep- there seems to be a preferred drainage to the same few axillary
lying and more distant nodes, “real time” efficiency in guiding the SLNs, such that the identification of these few nodes is not affected
γ-probe to SLN, with reduced exploratory dissections and tissue by injection location.23,24 Still, some researchers believe that the
damage, thus decreasing the morbidity associated with conven- superficial methods have the highest detection rate for SLN.
tional nodal dissection. The addition of vital blue dyes to radiola- In addition to the success rate of SLN detection, other factors
beled agents during lymphatic mapping may be helpful in the should be considered when choosing an injection technique.
absence of “hot spots” on lymphoscintigraphy or where only weak Superficial injection is easy to perform, results in less interference
hot spots are detected at lymphoscintigraphy. with scintigraphic imaging, and is more painful (addition of pH-
balanced 1% lidocaine improves patient comfort without compro-
mising SLN identification).25 Deep injection is more difficult to
Other Tracers Used for Sentinel Lymph
perform if the tumor is nonpalpable, such that ultrasound guid-
Node Mapping ance may be needed. It may interfere with detection of SLN on
The disadvantages of 99mTc-sulfur colloid have been recognized, preoperative scintigraphy. An important advantage of deep injec-
including a mixed particle size of 50 to 1,000 nm that cannot be tion is the improved detection of extra-axillary nodes, especially for
maintained as a homogeneous suspension (and which is therefore detection of internal mammary nodes (IMNs).26 It is likely best to
not a true colloid), a relatively high level of free pertechnetate which use a combination of a radiolabeled agent and a blue dye with both
can freely “leak” into lymphatic channels and cause high back- superficial and deep injections to further improve detection of
ground activity, and relatively low extraction by SLN (thus with SLN.8,26
easy travel to second-tier nodes).18 Lymphoseek was developed by
Neoprobe (Dublin, Ohio) to address these problems. Lymphoseek is Scintigraphic Imaging and Intraoperative
composed of a dextran backbone attached to diethylene triamine
penta-acetic acid (DTPA) and 99mTc. It has more uniform binding to
g-Probe Detection
the surface of reticuloendothelial cells compared to filtered 99mTc- The combination of preoperative scintigraphic mapping with intra-
sulfur colloid. Lymphoseek has faster clearance from the injection operative γ-probe detection proves to be highly efficient to identify
site and a lower mean number of SLN detected per study,19 and has SLN. The original method described by Morton et al. depended on
been recently approved by FDA. the surgeon’s experience. Two of the three surgeons in the study

A B C

D E F
Figure 28.3. Lymphoscintigraphy for an 82-year-old male with right breast cancer. This patient received intradermal injection of filtered 99mTc-sulfur colloids, and
planar anterior view (A, B, D, E ) and right lateral view (C, F ) scintigraphic images are shown at 5 minutes (A–C) and at 20 minutes (D–F ) post injection. Addition
of 57Co transmission imaging (B, E) provided information of body outline for the patient, indicating the lower neck and superior axillary regions were not well included
on the early images (A–C), but were properly included after position adjustment (D, E).
who had performed over 30 procedures were able to locate SLN in Generally, after the injection of 99mTc-sulfur colloid, scintigraphic
the regional node field in only 75% of the time of the third surgeon.2 images of selected regions of the body are obtained to evaluate
In current practice, the application of preoperative lymphoscintigra- drainage of the radiocolloid and to detect SLN (Figs. 28.2–28.4).
phy and an intraoperative hand-held γ-probe allows the surgeon to Transmission images of the patient body outline, using either a
pinpoint to the location of SLN with identification rates close to Cobalt-57 (57Co) flood source or a Gadolinium-153 (153Gd) line
100%. source, are often obtained at the same time to provide orientation
and better localization of the SLN nodes (Figs. 28.3 and 28.4).27 A
mark is often made on the skin overlying each detected radioactive
focus to indicate the location of possible SLN. Preoperative lympho-
scintigraphy can conveniently scan a large area of the body and
facilitate surgical planning because SLNs may be located in unex-
pected distant regions or in multiple nodal basins, which is particu-
larly true for melanomas of the trunk and head/neck. Preoperative
scintigraphic imaging also helps in intraoperative searches for all
radio-positive SLNs and may lead to more nodal removal.28 It is
especially helpful if a node of interest is located close to an injection
site, or if SLNs are located in deep tissues (e.g., to evaluate the status
of IMN in breast cancer patients) or at a distance from the injection
A B site (e.g., to evaluate the status of triangular intermuscular nodes in
patients with back melanoma).
The timing of preoperative lymphoscintigraphy should be
adjusted according to particle size, because the rate of migration
along lymphatic channels is inversely related to particle size. For
commonly used 99mTc-radiocolloids, SLNs are frequently seen
within a few minutes, and the vast majority of SLNs are identified
by 90 minutes. Babiera et al.29 demonstrated that the location and
number of SLNs detected scintigraphically after injection of 99mTc-
sulfur colloid were essentially the same whether the scintigraphic
images were obtained early (15 minutes to 4 hours) or delayed (18
C D to 24 hours) after injection. In fact, 99mTc-sulfur colloid injection
can be performed the day before surgery for SLN detection. Gray
Figure 28.4. Lymphoscintigraphy for a 61-year-old male with posterior right shoulder mela- et al.30 found that the success of SLN mapping in breast cancer
noma. This patient received intradermal injection of filtered 99mTc-sulfur colloids, and planar patients was very similar regardless of whether the lymphoscin-
scintigraphic images are shown 20 minutes post injection. Multiple sentinel lymph nodes (SLNs)
are visualized in the right axilla. A, C: Anterior views. B, D: Right lateral views. A 57Co transmis- tigraphy was performed on the same day or on the following day
sion imaging was used to provide body outline for orientation of the SLNs (C, D). after injection, although the mean number of SLNs was statistically

A B
Posterior Anterior Right Left
C D E
Figure 28.5. Lymphoscintigraphy for a 67-year-old female with left breast cancer. This patient received 37 MBq (1 mCi) of filtered 99mTc-sulfur colloids (in four
divided doses). Planar images at 30 minutes post tracer injection ([A, B]; [B] is the same image of [A] but with higher contrast) revealed no overt evidence of positive
sentinel lymph nodes (SLNs). Single photon emission computed tomography (SPECT) images were subsequently obtained (C–E) and revealed two positive left axillary
SLNs. C: Anterior view of a maximum projection SPECT image. D: A sagittal view of SPECT images showing one of the two positive SLNs. E: A coronal view of SPECT
images showing both positive SLNs.
significantly greater among those injected the day prior to surgery It is difficult to determine the exact locations of head and neck
(2.71) than among those injected on the day of surgery (2.33). SLN on planar lymphoscintigraphy because a standard planar scin-
The use of a hand-held γ-probe was first described by Krag tigraphic imaging provides limited anatomic and spatial resolution
et al.3 in the identification of SLN in melanoma patients, and then and does not show relationships between SLN and important ana-
in breast cancer patients. The hand-held γ-probe usually detects tomic structures of the head and the neck. This is partly because of
more SLN than preoperative scintigraphy,31 and helps to localize the complex three-dimensional anatomy of the head and neck. A
SLN located outside of the formal nodal basin. Even if preoperative “hot” spot on a planar imaging may represent a deep or superficial
lymphoscintigraphy is negative, SLN can still be identified intraop- SLN and there is no information of the position relative to other
eratively by a hand-held γ-probe. Intraoperative SLN detection cervical structures such as muscles and vasculature. In addition,
with a hand-held γ-probe can be performed successfully up to 16 SLN may be missed on planar images because the SLN may be
to 18 hours after injection with radiocolloids of 200 to 1,000 nm.4 obscured by the high activity at the injection site if SLN is close to
If the particle size of radiocolloids is small, thus favoring rapid the primary tumor site and because the pattern of SLN drainage is
clearance, reinjection of extra radiocolloids may be needed just often unpredictable in the head and the neck.33 These factors lead
before surgery. to considerably lower success rates of SLNB in the head and neck
as compared to SLNB in the trunk and extremities.
The additional value of SPECT/CT to detect and localize SLN in
Value of Single Photon Emission the head and neck has been demonstrated in patients with oral/
oropharyngeal squamous cell carcinoma (OSCC),33,34 melanoma,35
Computed Tomography and other skin malignancies. SPECT/CT helps in surgical planning
Single photon emission computed tomography (SPECT)/computed and facilitates surgical exploration in these patients.36 For example,
tomography (CT) is a more sensitive technique than conventional Vermeeren et al.35 reported that SPECT/CT depicts an additional
planar scintigraphy for detection of SLN because it provides higher SLN in 16% of patients with melanoma, leading to modification of
resolution tomographic images with anatomic correlation (Fig. 28.5). the surgical approach in 55% of patients. Bilde et al.34 reported that,
van der Ploeg et al. reported that SPECT/CT visualized more SLN, compared with planar lymphoscintigraphy, SPECT/CT imaging
identified additional SLN in patients with nonvisualized SLN based demonstrates additional SLNs in 47% of patients and provides
on planar scintigraphy, and decreased false-positive SLN based on additional anatomical and spatial information about their locations.
planar images (related to skin contamination artifact) in patients Similarly, SPECT/CT is helpful in patients with complex lymphatic
with breast cancer. Based on the SPECT/CT findings, a more precise drainage such as those with scapular melanoma, breast cancer
incision was made in 36% of patients, an extra incision was made patients who have had prior surgery or who have extra-axillary
in 4% of patients, and an incision was avoided in 1.5% of patients.32 SLN, in patients with tumors draining to deep (pelvic) nodes,37 and
The clinical value of SPECT/CT remains under investigation but is in patients with prostate cancer.38 SPECT/CT is also indicated in
appealing in certain situations. any patient with nonvisualized SLN.39 However, if SPECT/CT is

planned, it is performed in conjunction with conventional planar

imaging, where sequential planar images should be obtained first
Sentinel Lymph Node Biopsy
because they remain critical to distinguish SLN from secondary Application in Breast Cancer
nodes.
Breast cancer is the most common malignancy diagnosed in
women, with an estimated 230,480 new cases and 39,520 deaths
How Many Lymph Nodes Should Be
in 2011 in the United States.47 The status of the axillary lymph
Removed During SLNB? nodes is the most important prognostic factor in patients with early
Theoretically, an SLN is the first lymph node in the lymphatic chain stage breast cancer. Axillary lymph node dissection (ALND) has tra-
that receives lymph drainage from a tumor basin. In SLNB, the SLN ditionally been a routine procedure in the management of early
detected or removed could be any lymph node that has increased breast cancer. Before the introduction of SLNB in the 1990s, ALND
radioactivity or vital dye staining. It has been recognized that was often the preferred method of treatment for removal of all of
removal of just one or two nodes may miss potential metastases in the axillary lymph nodes to reduce axillary recurrence. Although
regional lymph nodes,40 whereas indiscriminate removal of multiple reliably identifying nodal metastases and maintaining regional con-
nodes may cause soft tissue damage, increasing the morbidity of trol, ALND is associated with an indisputable high incidence of
SLNB. postsurgical complications including lymphedema and shoulder
Efforts have been focused on determining a reasonable upper dysfunction, nerve injury, and a compromise in the quality of life.48
threshold for the number of SLNs that should be removed. Goyal SLNB was first introduced in the early 1990s as an option to

et al.41 evaluated 803 patients with breast cancer, and found that the accurately stage axillary nodal involvement in breast cancer,3 and
false-negative rate (FNR) was 10% if only one SLN was collected, has since proved to be a great success and widely accepted as the
versus 1% if three or more nodes were harvested. At the same time, standard of care in patients with early stage breast cancer without
99.6% of positive nodal metastasis was detected within the first four clinical evidence of nodal metastasis. SLNB is simple, accurate, and
SLNs removed,41 consistent with other reports.42 Similar findings effective in the identification of potential nodal metastases in these
were reported in patients with cutaneous melanoma. Abou-Nukta patients and spares the majority of patients from the potentially
and Ariyan43 reported that excision of the three hottest nodes and devastating side effects of ALND, reduces the costs of hospital
all blue nodes detected 100% of nodal metastases. At the same time, stays, and maintains the curative effects of surgery.49,50 With appro-
removing nodes with radioactivity of less than 30% of the hottest priate training, this technique leads to successful identification of
nodes may be unnecessary, because most (98%) of the positive SLN in >95% of patients with breast cancer. Approximately 20% to
lymph nodes had radioactivity counts greater than 30% of the hot- 35% of these patients with early breast cancer are expected to
test node.43 Overall, it is believed that removal of three to four SLNs have positive tumor involvement in SLN16 and will be treated with
will significantly reduce the FNR and will identify 98% to 99% of elective lymph node dissection (ELND). Use of SLNB spares approx-
patients with nodal metastases, whereas removal of more than five imately 70% of early stage breast cancer patients from ALND and
SLNs has limited value and is not necessary. associated complications and morbidity, while providing similar
staging accuracy and survival benefit. Kell et al. reported a meta-
analysis involving a total of 9,608 breast cancer patients with no
Pregnancy clinically palpable nodes to systematically appraise the outcome of
Pregnancy itself is not regarded as a contraindication for radioactive SLNB when compared to ALND. It was found that SLNB is at least
scintigraphic SLN detection.4 Multiple studies have shown that the equivalent to ALND in detecting metastatic axillary nodes (the
procedure of SLN detection is safe and successful in pregnant overall rate of axillary lymph node positivity was 27.6% for SLNB
women with minimal risk to the embryo/fetus.44 To evaluate the risk and 28.8% for ALND), but with significantly less risk of postopera-
to the embryo/fetus associated with SLNB and lymphoscintigraphy tive morbid effects (including infection, seromas, arm swelling, and
in pregnant patients, Keleher et al. calculated the absorbed dose to numbness) relative to ALND.51
the embryo/fetus after injection of 92.5 MBq (2.5 mCi) of filtered These findings were confirmed by other randomized research
99m
Tc-sulfur colloid in two nonpregnant women with breast cancer. projects. The National Surgical Adjuvant Breast and Bowel Project
In the worst case scenario, one can assume that the entire injected trial B-32 (NSABP B-32) was a randomized controlled phase 3 trial
radioactivity is instantaneously transported to the urinary bladder, performed at 80 centers in Canada and USA between 1999 and
where it remains and is eliminated only by physical decay. Under this 2004, with 5,611 women with invasive breast cancer randomly
assumption, this leads to a maximum absorbed dose (4.3 mGy) to the assigned to either SLNB + ALND (group 1) or to SLNB alone with
embryo/fetus (given the proximity of the urinary bladder to the ALND only if the SLNs were positive (group 2). With a follow-up of
uterus), but is still well below the 50 mGy level that is believed to be 95.6 months (range: 70.1 to 126.7), this study demonstrated that
the threshold absorbed dose for adverse effects. The absorbed dose the overall survival and disease-free survival were statistically
to the embryo/fetus will be 50-fold lower (0.0774 mGy) assuming equivalent between the two groups: The overall survival was 91.8%
that all of the injected radioactivity remains in the breast and is elim- in group 1 and 90.3% in group 2; the disease-free survival was
inated only by physical decay, and will be 12-fold lower (0.342 mGy) 82.4% in group 1 and 81.5% in group 2. Also, there was no statis-
assuming that the injected radioactivity behaves as though it were tical difference in regional node recurrences in these two groups
administered intravenously (with predominant biodistribution in (p = 0.22).52 Similar findings were reported in other randomized
the liver, spleen, and bone marrow), as Keleher et al. reported.45 controlled studies.53 The equivalent overall survival, disease-free
More direct measurement of radiation exposure in pregnant women survival, and regional recurrence in negative SLN patients with or
and the embryo/fetus found that the uterine exposure to radioactiv- without ALND indicate that SLNB alone with no further ALND is an
ity from radiocolloids associated with SLNB and lymphoscintigraphy appropriate, safe, and effective therapy for breast cancer patients
is much lower than Keleher et al. assumed (similar or less than the with clinically negative lymph nodes.
average daily background radiation), without significantly increased The adoption of SLNB leads to replacement of ALND as the stan-
risk of prenatal death or developmental abnormalities.46 Overall, the dard node staging procedure for patients with breast cancer. ALND
patient is more likely to be adversely affected by the procedure of is spared in approximately 70% of patients when the diagnosis of
surgery or anesthesia rather than by the radiation exposure itself. negative SLNB is established. Accumulating evidence supports that
Please note that the safety of vital blue dyes has not been tested SLNB is safe for these patients, because long-term follow-up studies
for pregnancy, and thus these dyes should not be used in pregnant in SLN-negative women treated without ALND reveal low rates
patients.16 of axillary recurrence. Recently, Andersson et al. reported their

findings in a large-scale, prospective multicenter study of SLNB as biopsy results are negative.56 A formal ALND or axillary irradia-
a single axillary staging procedure for breast cancer. From a total tion should be performed if SLNs cannot be identified or are pos-
of 2,195 SLN-negative patients with 2,216 breast tumors and with itive for metastasis.
median follow-up of 65 months, 23 patients (1%) had isolated axil-
lary recurrence. There was no difference in recurrence rates
between different centers. The overall 5-year survival rate was
Reoperative Sentinel Lymph Node Biopsy
93.1% and the event-free 5-year survival rate was 88.8%.54 The low with Prior Breast or Axillary Surgery
axillary recurrence in these patients demonstrated that SLNB can It is relatively common that patients with prior history of SLNB,
safely replace ALND in SLN-negative patients, and that false-negative ALND, or breast surgery develop ipsilateral breast cancer recur-
findings of SLNB are not a major concern. rence or a second primary breast cancer. Port et al.61 reported that
In current practice, SLNB is the standard of care for staging 5% to 10% of patients with breast conservation therapy, with or
the axillary nodes in patients with clinically node-negative breast without ALND, have local recurrence. Previous breast surgery or
cancer.55,56 At the same time, ALND remains the standard approach axillary biopsy had been considered as a relative contraindication
for patients with positive axillary nodes confirmed by fine-needle to SLNB, because the pattern of lymphatic drainage may have been
aspiration (FNA) or SLNB. altered or interrupted. In current practice, however, it is convinc-
SLNB has undergone significant and continuous modifications ingly demonstrated that reoperative SLNB is technically feasible
and refinements since its introduction, however, and the details of and very effective after previous SLNB, ALND, or breast surgery.
SLNB procedure have not been standardized. There are technical The successful detection rate of a reoperative SLNB in patients
variables that are mainly selected by personal preference including with prior breast surgeries ranges from 55% to 97% and has been
the materials injected (radioactive colloid alone, blue dye alone, or successfully reported in patients with previous breast-conserving
a combination), the timing, location, and method of injection, and surgery,61,62 previous aesthetic breast surgery (either breast aug-
use of scintigraphic imaging as described above. There are also mentation or reduction),63 and previous mastectomy.64 The suc-
continuing discussions including indications for SLNB and the cessful detection rate of a second SLNB has been reported as high
significance of positive findings on SLNB. as 95% to 99% in patients who underwent prior SLNB65 or prior
diagnostic excisional biopsy of breast cancer, comparable to pri-
Patients with Palpable Axillary Nodes mary SLNB. Port et al. reported that in breast cancer patients with
local recurrence after breast conservation therapy with either
SLNB should not be performed in breast cancer patients who have SLNB or ALND more than 6 months prior, reoperative SLNB was
evidence of axillary node metastases. Based on this, clinically pal- successful in 55% of patients, and identified positive reoperative
pable axillary nodes were also considered as a contraindication to SLN in 16% of successful cases. These patients had no local or
SLNB,40,57 assuming that the palpable nodes indicate metastatic axillary recurrences at a mean follow-up of 2.2 years (although
disease. However, controversies exist in this regard because clini- systemic recurrence was noted). The success rate of reoperative
cal axillary examination in breast cancer is subject to high false- SLNB was inversely related to the number of nodes removed pre-
positive results and because palpable axillary nodes do not always viously. It is more likely to succeed when less than 10 nodes were
harbor metastases.58 Specht et al. reported a study designed to removed during the prior procedure and were more likely to be
evaluate the accuracy of clinical examination of the axillary nodes successful after a previous SLNB (rather than a previous ALND) as
in breast cancer patients with palpable axillary nodes. Clinical the lymph drainage is less interrupted.61 Preoperative lymphos-
examinations of the axilla in 2,027 consecutive breast cancer cintigraphy is especially helpful in these patients, because nonax-
patients with SLNB were classified as either moderately or highly illary drainage was significantly more common in reoperative
suspicious for metastasis, and then correlated with pathologic find- SLNB than in primary SLNB.61,66 Taback et al.66 reported that in
ings on SLNB. It was found that clinical examination was inaccu- 73% of patients undergoing reoperative SLNB, migration to
rate in 41% of patients overall, and was falsely positive in 53% of regional nodal drainage basins was noted in ipsilateral axillary,
patients with moderately suspicious nodes and in 23% of patients supraclavicular, internal mammary, interpectoral, and contralat-
with highly suspicious nodes. It was concluded that clinical axillary eral axillary nodes after prior breast-conservation surgery with
examination in breast cancer is subject to false-positive results, SLNB and/or ALND.
and that palpable axillary nodes alone does not provide sufficient
justification for ALND.59 Lanng et al. performed another study
involving 301 consecutive breast cancer patients undergoing either
Postneoadjuvant Chemotherapy
ALND or SLNB prospectively to evaluate the reliability of clinical More patients with breast cancer now receive neoadjuvant che-
axillary lymph node assessment by experts and to assess whether motherapy (NAC). NAC is used to treat not only patients with
inaccuracy can be related to lymph node size. They also demon- advanced inoperative breast cancer but also those with initially
strated inaccurate findings on clinical assessment of axillary lymph operable breast cancer. The timing and accuracy of SLNB in
nodes. The risk of having axillary nodal metastasis was 40.4% if patients receiving NAC for breast cancer are controversial because
the preoperative clinical assessment was “nonpalpable,” 61.5% if there are concerns that the preoperative lymph drainage may not
the preoperative clinical assessment was “palpable but benign,” represent lymph drainage in the tumor basin before chemother-
and 84.4% if there were “suspicious lymph nodes.” Furthermore, apy, therefore leading to false-negative results. The NCCN guide-
there was no significant association between lymph node size and lines recommend prechemotherapy SLNB as the preferred option
palpability or nodal metastasis.60 for surgical axillary staging in patients with clinically negative
The American Society of Clinical Oncology (ASCO) Guidelines ipsilateral axillary nodes, because it provides additional informa-
do not recommend SLNB in the case of palpable axillary nodes in tion to guide local and systemic treatment decisions. If the SLN is
breast cancer patients, whereas ALND is recommended in the histologically positive, level I and II axillary dissection is indicated
case of a failed or technically unsatisfactory SLNB procedure and at definitive surgical therapy.56
in the case of detection of additional clinically suspicious axillary However, available data show that SLNB after NAC in breast
nodes after the removal of all SLNs.55 Another reasonable option cancer patients is feasible and accurate, with no significant differ-
for patients with palpable or other clinically suspicious axillary ences in the success rate of SLNB according to clinical tumor size
lymph nodes would be, as recommended recently by the National or clinical nodal status, and accurately selects patients who required
Comprehensive Cancer Network (NCCN) guidelines, to perform complete level I and II axillary dissection.67,68 In a systematic review
either a core biopsy or FNA of these nodes, followed by SLNB if of 27 clinical trials of SLNB in 2,148 patients with invasive breast

cancer who underwent SLNB after NAC followed by an ALND, van 25 (1.1%) patients. In addition to exploration of the IMC, the axilla
Deurzen et al.69 reported a pooled SLN identification rate of 90.9%, was explored for radioactive and/or blue-containing SLN, which
an FNR of 10.5%, and a negative predictive value (NPV) and accuracy led to three positive cases in the IMC and four positive cases on
of 89% and 94.4%, respectively. The data demonstrate the clinical additional axillary exploration in these 25 patients.77
value of SLNB after NAC, and the potential to reduce the morbidity It has been reported that IMN mapping leads to stage migra-
associated with ALND for breast cancer patients after NAC. tion and modification of postoperative treatment planning with
respect to radiotherapy and systemic therapy in up to one-third of
breast cancer cases.75,79 However, the significance of internal
Multifocal and Multicentric Breast Cancer mammary SLNB is still under debate. Considering that there was
Multifocal breast cancer indicates breast cancer with separate foci no survival benefit from extended mastectomy compared with
of ductal carcinoma of more than 2 cm apart but within the same radical or modified radical mastectomy, the lack of data regarding
quadrant of the breast, whereas multicentric breast cancer indi- a survival benefit from sentinel IMN biopsy, and the availability of
cates cancer with separate foci of carcinoma in different quad- systemic therapy, most centers do not perform IMN biopsy/dissection
rants of the breast.70,71 SLNB had been regarded as contraindicated because of concerns about risk of added morbidity and lack of
in patients with multicentric and multifocal breast cancers, because established survival benefit.80 Recent NCCN guidelines recom-
of the concern that it might be difficult to localize the true SLN, and mend that IMN excision is considered as optional if SLNs are visu-
that negative findings might not accurately represent the true alized in the IMC.56
nodal status.57

It has been recognized that the majority of the breast essen- Micrometastasis or Isolated
tially has a single unit of functional lymphatic anatomy with lymph
drainage to only a few designated lymph nodes in the axilla,23,24
Tumor Cells
which provides the scientific basis for successful SLNB in patients Micrometastasis indicates a deposit of metastatic tumor >0.2 mm
with multifocal or multicentric breast cancer. Multiple studies but ≤2 mm, whereas isolated tumor cells indicate a lesion of
have demonstrated equal efficacy of SLNB for patients with multi- ≤0.2 mm. Small metastases at this size range cannot be reliably
focal or multicentric breast cancer as in patients with unicentric detected by any imaging studies, and are often missed by routine
breast cancer, although there are no randomized trials in this sectioning and H&E staining of lymph nodes. However, as SLNB
regard. Gentilini et al.72 reported that for patients with multicentric allows focused histopathologic examination on only a few lymph
breast cancer, SLN identification rate was 100% whereas the axil- nodes, more detailed analysis with multiple sectioning becomes
lary recurrence rate was 2.2% after a median follow-up of 5 years possible. In addition, IHC, reverse transcription polymerase chain
(range: 17 to 134 months). A recently performed meta-analysis reaction (RT-PCR), and flow cytometry also improve sensitivity,
revealed that for “multiple breast cancer” (combining a total of leading to more frequent diagnosis of micrometastasis or isolated
996 multicentric and multifocal cases), the overall success rate of tumor cells in clinical practice.81 However, it remains unclear if the
SLN identification was 92% to 100%, the SLN positivity rate was presence of SLN micrometastases indicates increased risk of non-
12% to 63%, the FNR was 0% to 25%, and the accuracy was 82% SLN metastases. Some clinicopathologic variables have been
to 100%.73 The presence of nodal metastasis was significantly found to be associated with increased likelihood (odds ratio >2) of
higher in SLN as well as in nonSLN in patients with multicentric nonSLN metastases when the SLN is positive, including SLN
breast cancer; however, the sensitivity, FNR, and overall accuracy metastases >2 mm in size, extracapsular extension in the SLN, >1
of SLNB was similar to those in unicentric breast cancer positive SLN, ≤1 negative SLN, ratio of positive sentinel nodes
patients.70,71 >50%, tumor size >2 cm, and lymphovascular invasion in the pri-
mary tumor.82
Available data have confirmed the prognostic importance of
Internal Mammary Nodes identifying SLN micrometastases,83 and the ASCO guidelines in
The status of the internal mammary nodes (IMNs) is an important 200555 and the NCCN guidelines in 200956 both recommend that
prognostic factor in patients with breast cancer but is hard to eval- a completion ALND should be performed for patients in whom
uate because of the difficulty of access. There was great variation SLN micrometastases are identified, regardless of the method of
in the frequency of IMN visualization on SLNB procedure in early detection. However, the management of the axilla in patients with
studies. Later, it was recognized that mapping of IMN requires micrometastases or isolated tumor cells in SLNs without simulta-
deep injection of radiolabeled agents, either peritumoral or intra- neous macrometastases remains a topic of great debate. Multiple
tumoral.26,74 IMN is also more commonly identified in patients with studies have demonstrated that detection of micrometastatic car-
medially located primary tumors.74,75 Radiolabeled agents must be cinoma in SLNs of invasive breast cancer patients is a major indi-
used so that preoperative scintigraphic imaging can be performed cator of worse survival,84,85 and others have observed no significant
to guide intraoperative detection. Injection with blue dyes does not difference in the risk of distant disease,86 in regional axillary
help in identifying IMN because the medial chest wall is not rou- recurrence,87 or no statistically significant differences in overall or
tinely explored during the breast surgery. disease-free survival88 in patients with micrometastases com-
Sentinel IMNs are much less commonly detected and harvested pared to those with negative SLN. An analysis of 97,314 patients
in breast cancer patients as compared with those for axillary with breast cancer from the National Cancer Data Base (1998 to
nodes. IMNs are detected in approximately 20% to 34% of patients 2005) found an insignificant trend toward better outcomes (axil-
with breast cancer,75–77 of which about 63% to 92.5% can be har- lary recurrence and overall survival) for ALND (versus SLNB
vested during surgery,74,76,78 and of which 11% to 28% harbor alone) in patients with macroscopic nodal metastases (n = 20,075),
metastases.77–79 A prospective study on SLNB enrolled a total of although there were no significant differences in axillary recur-
1,008 consecutive patients with clinically node-negative operable rence or survival between SLNB alone and complete ALND in
primary breast cancer. 20% of patients had IMN visualized on lym- patients with microscopic nodal metastases.89,90 It is likely that the
phoscintigraphy. Sampling of the internal mammary basin was incidence of nonSLN involvement is low in patients with micro-
successful in 71% of patients, where metastases were found in 22% metastatic SLN, especially in patients with a single SLN microme-
of cases (29% of which had only positive nodes in the internal tastasis among four or more SLNs harvested.91 In addition, the
mammary chain [IMC]).76 Retrospective analysis of 2,203 breast postsurgery systemic therapy has an effective salvage effect. As
cancer patients revealed that 426 (19%) patients had lymphatic the recent American College of Surgeons Oncology Group
drainage to the IMC, whereas exclusive IMC drainage was seen in (ACOSOG) randomized trial Z0011 demonstrated that SLNB alone

was similarly effective as SLNB followed by ALND in patients with Scintigraphic Nonvisualization of Sentinel
breast cancer with positive SLN,92,93 the significance of microme- Lymph Nodes
tastases in SLN is likely not clinically critical.
Preoperative scintigraphy visualizes SLNs in approximately 90% of
cases of breast cancer patients. In the majority of patients with
Ductal Carcinoma In Situ lymphoscintigraphic nonvisualization, SLNs will be identified
In the United States, the incidence of ductal carcinoma in situ intraoperatively either by γ-probe alone (detection rate of 84.6%)
(DCIS) rose significantly in the last 30 years, partly because of or by γ-probe combined with blue dye (detection rate of 88.4%).99
increased use of mammography. DCIS is defined as a proliferation However, negative lymphoscintigraphy is associated with a lower
of malignant epithelial cells within breast ducts without invasion intraoperative identification rate and fewer detected SLNs in breast
through the basement membrane. Theoretically, DCIS indicates cancer patients.99 SLN cannot be detected intraoperatively in
stage 0 noninvasive breast carcinoma with no metastatic lesions, approximately 1% to 2% patients, which is associated with old age,
and thus ALND is not indicated in these patients. However, some obesity, and tumor location in locations other than in the upper
patients with DCIS develop regional or distant disease. This is outer quadrant.99 Additional radiolabeled agent injection following
likely as a result of sampling error upon pathologic examination, an initial failure may increase the SLN detection rate scintigraphi-
and many cases with the initial diagnosis of DCIS are actually cally without compromising accuracy. SPECT/CT is also advocated
invasive carcinomas with axillary metastases found postsurgically. to detect “hidden” SLN in patients with nonvisualization on planar
Thus an accurate diagnosis (including assessment of DCIS size lymphoscintigraphy,37,39 and is receiving more interest in recent
and grade) is critical to make a sound treatment plan, whether years.
excision alone, excision plus radiation, or mastectomy. Some studies suggest that preoperative scintigraphic nonvisual-
About 15% of patients with DCIS initially diagnosed on core ization of SLN indicates an increased risk for positive axillary node
needle biopsy prove to have invasive breast cancer upon excision involvement. Brenot-Rossi et al.100 reported that metastases were
or mastectomy. Risk factors related to DCIS recurrence include found in 28.5% of cases with presurgically visualized SLN, com-
younger age, positive surgical margins, palpability, tumor size and pared to 63.3% of cases with lymphoscintigraphically nonvisualized
grade, comedo morphology, and necrosis.94 5.4% to 12% of high- SLN. Also, multiple nodal metastases are associated with more fre-
risk DCIS patients with invasive ductal carcinoma at final diagnosis quent scintigraphic nonvisualization of SLN.100,101 Rousseau et al.99
had positive SLN, the majority of which had micrometastases reported that these negative lymphoscintigraphy SLNs had fewer
only.94 Ansari et al.95 performed a meta-analysis of 22 published micrometastases and more macrometastases, and had larger size.
studies and reached an estimate of 7.4% for the incidence of SLN It is likely that gross tumor involvement of a lymph node may inter-
metastases in patients with a preoperative diagnosis of DCIS, in fere with the uptake of both radiocolloid and blue dye and deviate
contrast to 3.7% in patients with a definitive (postoperative) diag- lymph flow to a node other than the true SLN, causing a false-
nosis of DCIS. SLNB is recommended for patients diagnosed with negative finding. In addition, retention of a radioactivity in the SLN
DCIS by needle biopsy when they have a high risk for harboring is dependent on the phagocytic activity of macrophages. As the
invasive ductal cancer.94 Because the rate of SLN metastasis is amount of metastatic tumor in a lymph node increases, macro-
very low in pure DCIS, SLNB is not indicated in these patients.94 phages are replaced by tumor, leading to reduced or lack of macro-
phage function, and hence false-negative imaging findings. It is
safer to perform ALND in these patients if no SLNs are identified
Prophylactic Mastectomy during surgery.
Prophylactic mastectomy is performed in high-risk patients to
decrease the risk of breast cancer. There is no clear evidence of ben- False-Negative Sentinel Lymph
eficial effect of SLNB at the time of prophylactic mastectomy. A recent
meta-analysis (including six studies and a total of 1,251 patients who
Node Biopsy
underwent 1,343 prophylactic mastectomies) indicated that the The FNR of SLNB refers to the frequency of negative SLNB in
pooled rate of positive SLN was very low (1.9%, 95% CI 1.2% to 2.6%). patients with positive nodal metastases (i.e., the number of false-
As a result of SLNB findings at the time of prophylactic mastectomy, negative cases on SLNB/total positive cases on either SLNB or
a significant change in surgical management was recorded in 2.8% ALND), and varies widely,17 with an average 7.3% based on a
of cases (95% CI 2% to 3.8%), about half because of negative SLN with meta-analysis of 69 trials before 2003.102 FNR is independent of
invasive cancer (avoiding ALND) and half with positive SLN without experience and injection technique103 but appears more common
invasive cancer (needing a subsequent ALND).96 with vital dye injection,102 with previous excisional biopsy,28 and
when too few sentinel nodes are removed.40,104 In practice, the FNR
cannot be determined if SLNB is adopted, because the majority of
Male Breast Cancer patients will not have ALND. It remains to be determined if a false-
Breast cancer in men accounts for approximately 1% of all breast negative SLNB will compromise the therapeutic efficacy in breast
cancer cases.97,98 SLNB is equally successful and accurate in male cancer. However, the very low axillary recurrence rate in all breast
patients with breast cancer as it is in female patients, with a suc- cancer patients with negative SLN54 indicates that SLNB is a reli-
cess rate of SLN detection ranging from 97% to 100%.97,98 Com- able procedure.
pared to breast cancer in women, breast cancer in men tended to False-negative SLNB results compromise patient outcome by
be larger and was more likely to be associated with positive missing positive nodes and understaging disease, which might
SLN,97,98 likely because of a higher stage of cancer at the time of lead to regional recurrence and/or distant metastases, and under-
diagnosis. A review of 7,315 SLNB procedures from September treatment with systemic therapy. The FNR should be reduced to as
1996 to July 2005 at the Memorial Sloan-Kettering Cancer Center low as possible, and may be decreased by use of combined radio-
(78 of which were in men) indicated that SLNB was successfully labeled agents and a blue dye for SLN, use of preoperative lympho-
performed in 97% of male patients. Positive SLNs were found in scintigraphy (and SPECT/CT in difficult cases), biopsy of multiple
49% of patients, the majority of whom underwent immediate SLN, application of multilevel sectioning and IHC in pathologic
ALND based on node positivity determined intraoperatively, assessment of SLN, and assurance of adequate experience of sur-
whereas patients with negative SLNs did not undergo ALND. There geons who perform SLNB. The criteria used to define a “hot” SLN
were no axillary recurrences at a median follow-up of 28 months also affect the performance of SLNB. Song et al. performed a study
(range: 5 to 96 months).98 to evaluate three different definitions of a “hot” SLN in patients

with early stage breast cancer: (1) the node with the highest higher rate of estrogen/progesterone receptor positivity,109,110 often
radioactivity, (2) any node with an in vivo hot spot-to-background with micrometastases rather than macrometastases,109–111 and
activity ratio of ≥3 or an ex vivo SLN-to-nonSLN ratio of ≥10, and (3) more frequent use of adjuvant systemic therapy or radiation therapy.114
all radioactive hot nodes. These three different definitions led to an It is likely that ALND could be avoided in most patients with an
FNR of 21.1%, 7.9%, and 2.6%, respectively, and an accuracy of intraoperative false-negative SLNB, if axillary radiotherapy or
90.1%, 96.3%, and 98.8%, respectively (p < 0.05). Removing the first adjuvant systemic therapy is added.114
one, the first two, the first three, and the first four hottest SLNs iden-
tified 81.1%, 89.2%, 94.6%, and 97.4% of the positive-SLN patients, Is Axillary Lymph Node Dissection
respectively.104 Really Indicated with Positive Sentinel
Another way to decrease FNR is to not miss suspicious non-
SLNs. After excising the blue-stained or radioactive nodes, intra-
Lymph Node Biopsy?
operative palpation should be performed in the axillary node Some studies have questioned the value of ALND in breast cancer
basin and all suspicious palpable SLNs that are not either blue- patients with SLN metastasis because SLNs are frequently the only
stained or radioactive should be excised.105 Choi et al.106 reported involved nodes after an axillary dissection, indicating that SLNB
that biopsy of a suspicious palpable SLN should be done as part may also provide a therapeutic benefit in controlling regional dis-
of SLNB in breast cancer patients and helps to reduce the number ease.115 Recently, the ACOSOG Z0011 trial demonstrated that SLNB
of false-negative findings of SLNB, because positive axillary nodal alone had equivalent survival benefit compared to SLNB followed
involvement was identified solely by biopsy of suspicious palpable by ALND in selected patients with breast cancer and positive

nodes in 6.5% of patients with SLN metastases. SLN.92,93
The Z0011 trial examined the outcome of patients who do not
undergo ALND for positive SLN. In this prospective randomized
Intraoperative Pathologic Analysis trial, all patients (with T1/T2 breast cancer, but N0, M0) received
After the intraoperative identification and biopsy of SLNs, ALND lumpectomy, SLNB, adjuvant systemic therapy, and tangential-field
is preferably performed as a synchronous procedure in patients whole breast radiation therapy. Patients with positive SLN metas-
with positive nodes (to avoid subsequent reoperation) if frozen tasis were randomized to SLND alone (446 patients) or SLNB +
section analysis of SLNs can be performed promptly. An important ALND (445 patients). Patients with SLNB + ALND had more (median
issue here is the accuracy of the intraoperative pathologic evalua- of 17) axillary nodes removed compared with patients with SLNB
tion of SLNs in predicting nodal metastases. alone (median of 2). In the SLNB + ALND group, 27.3% of patients
It is generally believed that frozen section analysis is less accu- had additional metastasis in lymph nodes removed by ALND. How-
rate compared to permanent section analysis, and is associated ever, there were no statistically significant differences in local
with high false-negative findings. Intraoperative FNR is the pro- recurrence or regional recurrence between these two groups. Local
portion of patients undergoing SLNB with negative intraoperative recurrence at a median follow-up of 6.3 years was only 1.8% in the
pathologic findings among the total number of patients with posi- SLND alone group versus 3.6% in the SLND + ALND group; local
tive nodes (i.e., the number of intraoperative SLN false-negative recurrences at 5 years were 1.6% and 3.1% in the SLND only and
cases/total positive node cases). Most studies demonstrate that the SLND + ALND groups, respectively (p = 0.11). Regional recurrences
sensitivity of intraoperative analysis for SLN metastases in breast in the ipsilateral axilla were 0.9% in the SLND alone group and
cancer patients varies in the range of 60% to 75%.107 This variation 0.5% in the SLND + ALND group.92 In addition, this study revealed
is partially because of the different histopathologic techniques no significant difference in overall survival or disease-free survival
used, as imprint or smear cytology analysis is associated with in these patients with T1/T2 breast cancer and positive SLN who
higher false-negative findings compared to frozen sections.108 were treated with lumpectomy, adjuvant systemic therapy, and
However, the specificity of intraoperative SLN evaluation is very tangential-field whole breast radiation therapy. The 5-year overall
high (close to 100%), allowing for synchronous ALND in those survival was 91.8% (95% CI, 89.1% to 94.5%) for the SLNB + ALND
patients with positive SLN.107,109 group and 92.5% (95% CI, 90% to 95.1%) for the SLND alone group,
It is important to note that the intraoperative FNR is associated and the 5-year disease-free survival was 82.2% (95% CI, 78.3% to
with tumor stage and the size of metastatic tumor cells in the 86.3%) for the SLNB + ALND group and 83.9% (95% CI, 80.2% to
SLN.109,110 Pugliese et al.109 found that the sensitivity of intraopera- 87.9%) for the SLND group.93 The findings indicate that SLNB alone
tive SLN evaluation for lymph node metastasis is 5% for N1mi can offer excellent regional control and may be a proper manage-
disease and 63% for N1a-3a disease, although the specificity was ment option for selected patients with early stage breast cancer
99.7%. Liu et al. performed a meta-analysis of 47 studies including treated with breast-conserving therapy and adjuvant systemic
13,062 patients to determine the accuracy of intraoperative frozen therapy.
section of SLN during breast cancer surgery. They found that intra- It is important to note that ALND removed additional positive
operative frozen section had a mean sensitivity of 73% and a mean nonSLN in 27% of patients, and that regional recurrence with SLNB
specificity of 100%. Importantly, the mean sensitivity was 94% for alone was <1%. This indicated that the majority of the metastases in
the macrometastasis group and only 40% for the micrometastasis/ undissected axillary nodes (after SLNB but without ALND) did not
isolated tumor cell group.111 develop into clinically detectable disease, or that adjuvant systemic
A clinically important question is whether patients with a false- therapy is effective as a second-line treatment. It is possible that use
negative intraoperative SLN assessment need additional surgery of systemic therapy was effective to treat occult metastases in these
with ALND. The ACOSOG trials Z0010 and Z0011112 and other patients. As a result, removal of additional involved nodes with
studies113 demonstrated that delayed ALND is equally effective in ALND did not result in fewer locoregional recurrences than did
patients with false-negative SLNB as ALND at the time of initial SLND alone.
surgery. However, multiple studies have reported that axillary Findings from the Z0011 trial indicate that in patients with clin-
recurrence rates were low in patients who had SLN metastases, ical T1/T2 tumors undergoing lumpectomy and radiation therapy
regardless of whether delayed ALND is performed.89,90 Also, there followed by systemic therapy, a positive SLN is not an indication for
was similar recurrence-free survival of patients with negative addition of ALND, because these patients do not benefit from ALND
SLNB and of patients with intraoperative false-negative SLNB in terms of local control, disease-free survival, or overall survival.
without ALND (with a median follow-up period of 58.1 months).114 However, the Z0011 trial did not evaluate the value of ALND in
It is likely that the intraoperative SLNB FNR is more often observed other breast cancer patients such as those undergoing other surgi-
in patients with early stage disease, less nodal involvement, and a cal procedures such as mastectomy, those receiving neoadjuvant

therapy, or those not receiving chemotherapy or radiotherapy. 80% have no nodal involvement (and who therefore do not need
Future studies are needed to redefine the role of ALND and improve nodal dissection).1
clinical outcomes in breast cancer patients to minimize the compli- Morton et al.2 pioneered vital blue dye detection of the status of
cations associated with ALND and to improve quality of life while SLN intraoperatively in patients with melanoma, and demon-
maintaining survival. strated that the pathologic findings of the SLN accurately reflected
the status of the lymphatic basin. The addition of injection of radio-
labeled agents with scintigraphic imaging and the addition of
Sentinel Lymph Node Biopsy intraoperative hand-held γ-detector probes led to increased effi-
Application in Melanoma ciency and enhanced identification rates of SLN. In the following
20 years, much knowledge and experience have been accumulated
regarding the techniques, diagnostic performance, complications
Melanoma is a relatively common malignancy with increased inci-
and morbidity, prognostic value, and appropriate patient candidate
dence every year and a suspected doubling of the incidence every 10
selection for SLN detection. In an analysis of over 2,000 patients
to 20 years. Based on the data from the American Cancer Society in
with early stage melanoma, Morton et al.119 reported an overall
2011, melanoma is the fifth most common cancer in males and the
SLN identification rate of over 95%. It is well established that SLNB
seventh most common cancer in females, with 70,230 new cases
can accurately stage regional lymph node basins in stage I and II
and 8,790 deaths from melanoma predicted in 2011.47 On the basis
melanoma patients with minimal morbidity, and is widely accepted
of data from 2005 to 2007, the lifetime risk of developing melanoma
as the standard procedure when melanomas are 1 mm or thicker.
is 2.73% (1 in 37) for men and 1.82% (1 in 55) for women.47 Although
SLNB may also be appropriate for patients with thin melanomas if
melanoma represents only 10% of all skin cancers, it accounts for at
the tumor depth is at least 0.76 mm or if there are other high-risk
least 65% of deaths related to skin cancers.116
factors such as ulceration or high mitotic rates.
The prognosis for melanoma patients is determined by multi-
ple factors related to the primary tumor such as the depth of
tumor invasion, ulceration of the overlying skin, mitosis of tumor Accuracy of Sentinel Lymph Node Biopsy
cells, and by the presence of regional and distant metastases.
Melanoma thickness is a major factor in determining the T cate-
for Nodal Staging in Melanoma
gory and overall staging of cutaneous melanoma (Table 28.1). SLNB is a minimally invasive procedure that accurately detects nodal
Nodal metastasis is a common initial manifestation of melanoma metastasis with high NPV in early stage melanoma patients.120,121
and is the most important prognostic factor for recurrence.117 The As with breast cancer, SLNB allows more focused pathologic exami-
5-year survival rate was 72.3% among patients with tumor-posi- nations of limited SLN and can detect subclinical metastatic deposits.
tive SLN versus 90.2% among those with tumor-negative SLN (p < A negative SLNB spares a melanoma patient from further complete
0.001).118 Accurate determination of nodal status is therefore lymph node dissection (CLND). If the SLNB is positive, CLND can be
important for staging, surgical/(adjuvant) therapeutic planning, performed immediately, before the development of clinically evident
and prognosis assessment. ELND had been a routine procedure in metastatic disease.122 The incidence of complications is low and the
the surgical management of early melanoma patients with clini- procedure is generally well tolerated.
cally normal regional lymph nodes. However, prospective ran- SLNB in melanoma patients is usually performed with intrader-
domized trials did not show an overall survival benefit for ELND mal injection of 99mTc-sulfur colloid and vital blue dyes. Preopera-
versus observation for patients receiving wide local excision tive scintigraphic imaging is also employed. Although lymphatic
(WLE) of the primary malignancy.1 The limited beneficial effect of drainage in breast cancer is more predictable, lymphatic drainage
ELND was probably because of the observation that for early in melanoma is much more variable because melanoma may occur
stage melanoma patients, only 20% have occult nodal disease anywhere in the body. After intradermal injection of radiocolloid,
(who might therefore benefit from ELND) whereas the remaining lymphatic flow rates vary according to the location of the primary
Ta bl e 2 8 . 1
Simplified Staging of Cutaneous Melanoma
Melanoma Primary Tumor T Classification

Tumor Thickness Regional Distant
T Classification (mm) — Nodes (N) Metastasis (M) TNM Staging
Tis No tumor invasion — 0

a: No ulceration & —
mitosis < 1/mm2 IA
b: with ulceration or —
T1 < = 1.0 mm mitosis ≥ 1/mm2 IB
a: with no ulceration — IB
T2 1.01–2.0 mm b: with ulceration — IIA
a: with no ulceration — IIA
T3 2.01–4.0 mm b: with ulceration — IIB
a: with no ulceration — IIB
T4 > 4.0 mm b: with ulceration — IIC
any T > = N1 M0 III
any T any N M1 IV
Modified from Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol.
2009;27(36):6199–6206.

tumor. Lymph drainage is fastest from melanoma sites in the distal who underwent SLNB, compared to 23.2% in those who underwent
limbs, particularly in the lower limbs, and is slowest from the head SLNB + CLND.131 One important contributing factor is that 70% to
and neck region and the proximal limbs.123 Multiple variations of 80% of patients will have negative SLN and require no further lymph
lymphatic drainage pathways have been described. Radiocolloid node dissection. The reduced complications and morbidity associ-
injection at the site of cutaneous melanoma of the back may drain ated with SLNB is among the major factors that have driven its wide
to SLN in the bilateral triangular intermuscular spaces, superior acceptance in current practice. However, CLND remains indicated
and lateral to the scapulae.124 There is direct lymphatic drainage after identification of a metastatic lymph node by SLNB.
through the posterior body wall to SLN in the retroperitoneal and
paravertebral regions,125 and it is not infrequent to visualize drain-
age to interval nodes that lay outside standard nodal fields.126 Survival Benefit of Sentinel Lymph Node Biopsy
These findings indicate that in previous (pre-SLNB) trials, elective It is well established that the status of SLN is an important predic-
dissection of draining lymph nodes in melanoma patients could be tor for survival in melanoma patients, that SLNB is highly accu-
performed in the wrong field in up to 30% of patients.127 rate for nodal staging, and that SLNB significantly decreases
The incidence of lymph node metastasis is related to Breslow morbidity and surgical complications compared with CLND. How-
thickness of melanoma (7.3%, 19.7%, 33.2%, and 39.7% for primary ever, SLNB is recommended not because of a survival advantage
lesions ≤1 mm, 1.01 to 2 mm, 2.01 to 4 mm, and >4 mm, respec- (compared with WLE of the primary melanoma without SLNB) but
tively).122 In SLN-positive melanoma patients, approximately 20% of because of its minimally invasive nature with little morbidity.
them have additional nonSLN involvement in the CLND specimen. Multiple retrospective studies have reported conflicting findings,

ELND is performed if positive SLNs are detected, either immediately some reporting promising survival benefit for SLNB120,122 and oth-
following SLNB or during a separate procedure, depending on ers reporting limited or nonsignificant value.132 Morton et al.
whether intraoperative pathologic analysis is performed. ALND for reported that patients who underwent immediate (after lymph node
melanoma should include all level I to III nodes.128 However, the mapping and sentinel lymphadenectomy) dissection of nodal
management of inguinal lymph node metastases is controversial metastases had 5-, 10-, and 15-year survival rates of 73%, 69%, and
because patients with involved superficial inguinal nodes often have 69%, respectively, in contrast to 51%, 37%, and 32%, respectively
involved pelvic nodes. A superficial inguinal lymph node dissection (p ≤ 0.001), for patients who underwent delayed (after observation)
should be considered in the presence of a single positive superficial dissection of nodal metastases.122 A more recent analysis of 673
inguinal or femoral triangle node either on SLNB or clinically. A consecutive melanoma patients with or without SLNB and a median
pelvic lymph node dissection should be considered if there is evi- follow-up of 64 months showed a significantly better recurrence-
dence of more than one positive inguinal and/or femoral triangle free survival, distant metastasis-free survival, and overall survival
node, either on clinical examination, CT, ultrasonography (US), or for patients of the SLNB group than for nonSLNB group.121
SLNB (including presence of micrometastases). A pelvic lymph node The only randomized trial to evaluate the potential survival ben-
dissection is also indicated for microscopic or macroscopic involve- efit of SLNB was reported by Morton et al., who demonstrated the
ment of Cloquet node,128 because its tumor status may serve as an contribution of SLNB (with immediate nodal dissection when posi-
indicator of the tumor status of the iliac lymph nodes. SLNB + ELND tive SLNB was identified) to improved survival outcomes. The study
in patients with positive SLN prolongs disease-free survival. How- analyzed 1,269 patients with intermediate-thickness (1.2 to 3.5 mm),
ever, there is no convincing evidence of overall survival advantage newly diagnosed primary melanoma. These patients were ran-
for patients undergoing SLNB.118 domly assigned to wide excision plus postoperative observation
There is clearly a learning period for surgeons performing this (with lymphadenectomy if nodal relapse subsequently developed),
procedure. Morton et al. reported in the Multicenter Selective or wide excision plus SLNB (with immediate CLND if nodal micro-
Lymphadenectomy Trial (MSLT-I) that even after a 30-case learning metastases were detected on SLNB). Five-year melanoma-specific
phase and 25 additional cases of SLNB, the accuracy of SLNB con- survival rates were similar between the observation group and
tinued to improve with surgeon experience. The FNR was 10.3% for SLNB group. However, among patients with nodal metastases, the
the first 25 cases versus 5.2% after 25 cases.119 5-year survival rate was higher in the SLNB group (who underwent
immediate lymphadenectomy) than in the observation group (who
Fewer Surgical Complications and Morbidity had lymphadenectomy when clinical nodal recurrence later
with Sentinel Lymph Node Biopsy occurred) (72.3% versus 52.4%, respectively; p = 0.004). This was
likely because of disease progression during the observation period,
CLND used to be a common procedure in the treatment of mela- because there were more nodal metastases in the observation
noma, and delays nodal recurrence and prolongs disease-free sur- group than in the SLNB group (the mean number of tumor-involved
vival for melanoma patients. However, as with breast cancer, CLND nodes was 1.4 in the SLNB group versus 3.3 in the observation
is associated with considerable and sometimes severe morbidity, group; p < 0.001).118 Pasquali et al.133 recently performed a meta-
without benefit of overall melanoma-specific survival. SLNB in mela- analysis that showed that although no significant survival differ-
noma patients is a minimally invasive procedure associated with ence was observed between early (SLNB-guided) and delayed
many fewer complications, compared to CLND, as observed in lymphadenectomy in melanoma patients, the pooled data from
breast cancer patients. Comparison of morbidity in 315 patients multiple retrospective studies did suggest that SLNB-guided nodal
with SLNB versus CLND revealed that complication rates after SLNB dissection is associated with a significantly better outcome com-
were low, and that most complications of SLNB were minor and pared with CLND for clinically evident lymph node disease.
short-lived (with 13.8% overall incidence of at least one complica-
tion, a 11.3% short-term complication rate, and a 4.1% long-term
complication rate), whereas complications after CLND were much False-Negative Findings and
more frequent and more often severe (with 65.5% overall incidence
of at least one complication, a 50% short-term complication rate,
Regional Recurrence
and a 50% long-term complication rate).129 In fact, complications The FNR of SLNB is approximately 5% in melanoma patients,
from groin dissection were more severe than those from axillary determined by concomitant CLND at the time of SLNB,134 and false-
dissection, mandating additional surgery in 25.6% in groin dissec- negative results were reported in up to 25% cases with long-term
tion versus 8.5% in axillary dissection.130 Evaluation of 2,120 mela- follow-up.135 However, the true FNR is difficult to determine and
noma patients with a median follow-up of 16 months revealed an could be because of deficiencies in nuclear medicine, surgery, or
overall 4.6% incidence of major or minor complications in patients pathology.

A prospective multi-institutional study with the largest patient Sentinel Lymph Node Micrometastases
population (2,451 patients with melanoma of thickness >1 mm who
underwent SLNB with median follow-up of 61 months) demon- As the evaluation of the SLN is not well standardized, the detection
strated an FNR of 10.8%. The true-positive (TP) and true-negative of micrometastases varies and depends on the techniques employed
(TN) SLN results were found in 19.8% and 77.8% of patients, respec- (how many sections are examined, and if IHC is employed, etc.).
tively. The overall 5-year survival rate was significantly higher in the Micrometastases are more common in melanoma than in breast
TN group (86.7%) compared with the TP (62.3%) and FN (51.3%) cancer. Morton et al.118 reported an incidence of 16% of SLN micro-
groups (p < 0.0001), although the overall survival rate was not sig- metastases in a prospective study. However, the significance of
nificantly different between the TP and FN groups (p = 0.32).136 positive findings of micrometastases in SLN remains unclear.
False-negative SLNB is associated with poor outcome in patients Although some studies indicate that patients with minimal tumor
with melanoma, likely because of a delay in treatment.137 False- burden (<0.1 mm) of SLN micrometastases have an overall 5-year
negative SLNB may occur if SLNs are close to the primary lesion survival rate similar to that of SLN-negative patients,145 other stud-
(with high radioactivity) and is more likely to occur when only ies indicate that the prognosis is worse in patients with SLN micro-
a single SLN is harvested. False-negative SLNB is more common metastases, even in those with lesions of less than 0.1 mm and
for melanoma of the head and neck site and increased tumor invasion depth of ≤0.3 mm.146 According to the current 2009
thickness.138 Quantitative RT-PCR significantly increases positive American Joint Committee on Cancer (AJCC) staging system, all
findings in SLNB and may help to reduce FNR.122,135 As with breast patients with microscopic nodal metastases, regardless of the extent
cancer, there is a learning phase for SLNB in melanoma, and the of tumor burden (including nodal micrometastases at a microscopic
percentage of false-negative sentinel node procedures in melanoma level consisting of aggregates of only a few cells detected by IHC),
patients decreases as experience increases.139 In patients with neg- are considered positive nodal metastases and classified as at least
ative SLNB, ulceration was a predictive factor for false-negative stage III.147
SLNB, and closer follow-up is recommended for these patients.134 It remains unclear if early removal of micrometastases by radi-
cal lymph node dissection has any survival benefit. The currently
ongoing prospective randomized study of Multicenter Selective
Lymphadenectomy Trial II (MSLT-II) may provide a direct answer
Micromorphometric Parameters of Sentinel for this question. The International Sentinel Node Society 2008
Lymph Nodes guideline148 and the 2010 European Dermatology Forum guide-
In general, CLND is performed in patients with evidence of metas- line149 recommend that the presence of micrometastasis in SLN is
tases in SLN. However, the majority of these patients do not have an indication for CLND in patients with melanoma, even when
additional nodal metastases in other nonSLNs, because addi- node involvement is limited to micrometastasis in a single SLN. In
tional nodal metastasis is observed in approximately 20% patients current practice, it is prudent to treat patients with micrometasta-
with positive SLNB. Thus, it would be very helpful if one could ses as other positive SLN before more convincing evidence is avail-
determine which patients with positive SLNs are unlikely to har- able regarding the effect on long-term prognosis.
bor additional nodal metastases in the nonSLNs so that CLND can
be avoided, and which patients are likely to harbor additional
nodal metastases in the nonSLNs so that CLND and adjuvant
In-Transit Lymph Node Metastases
treatment can be planned. As experience with lymphoscintigraphy increased, it was gradually
To avoid unnecessary surgery in these patients, multiple stud- recognized that regional lymph node drainage is not well ordered
ies have tried to explore the predictive values of SLN micromor- and not confined to defined pathways, because some patients were
phometric features in a patient with positive SLN for identifying found to have unexpected or aberrant drainage patterns.124,125,150
the risk of positive nonSLN and in determining the likelihood of Isolated lymphatic nodes are often found in the area between the
developing regional recurrence within the nodal basin. It has primary melanoma and a recognized regional basin, and could be
been reported that 5-year overall survival rates are significantly anywhere along the pathway of a lymphatic channel. These nodes
correlated with SLN tumor burden (100%, 63%, and 35% for the are called “in-transit nodes” or “interval nodes,” likely embryonic
patients with SLN tumor burden of <0.1 mm, 0.1 to 1 mm, and residuals of lymphatic tissue lying outside of an expected nodal
>1 mm, respectively), and that there is no additional nonSLN basin. These “in-transit nodes” are very likely the first nodes
positivity for patients with <0.1 mm SLN micrometastases.140 receiving lymph drainage from the primary tumor/injection site
Frankel et al. found that CLND was more likely to find additional and are therefore, by definition, true SLNs (Fig. 28.1). They are
nodal metastases in patients with primary melanoma on the head more common in patients with melanomas of the trunk than in
and neck or lower extremity ( p = 0.01), Breslow thickness >4 mm those with melanoma of the lower limbs, and may be the only
( p = 0.001), presence of angiolymphatic invasion ( p < 0.0001), lymph nodes that contain metastatic disease. Nuclear medicine
satellitosis ( p = 0.004), extranodal extension ( p = 0.0002), multi- physicians should be able to recognize different lymphatic drain-
ple positive SLN ( p = 0.02), and tumor burden within SLN >1% of age patterns, and in-transit nodes should be suspected when a hot
the surface area ( p = 0.004). In contrast, finding an additional spot of increased radioactivity is seen along a lymphatic channel.
positive nonSLN had no association with gender, age, ulceration, An evaluation of 2,045 patients with cutaneous melanoma with
Clark level, histologic subtype, regression, or location (capsular, SLNB showed that the incidence of in-transit nodes was 7.2%.
subcapsular, or parenchymal) of metastases within a node.141 Mul- Micrometastasis was found in 14% of interval nodes that under-
tiple studies found that invasion depth of melanoma in sentinel went biopsy, similar to that found in SLNs located in recognized
node metastases and diameter of metastasis correlate best with nodal fields.126 Evaluation of 911 patients with a clinically localized
the presence of additional nodal disease.142,143 Bogenrieder et al.144 primary cutaneous head and neck or truncal melanoma and a min-
demonstrated that a combination of <2-mm Breslow thickness and imum of 10-year follow-up after SLNB and surgery revealed that
low SLN tumor load (Breslow thickness <2 mm and SLN tumor visualization (but without removal) of in-transit nodes was associ-
load <0.2 mm2 or tumor deposit <500 μm or tumor penetrative ated with a significantly higher risk of recurrence than in patients
depth <600 μm) predicts the absence of nonSLN metastases in without in-transit nodes.151 The melanoma patients with in-transit
melanoma patients with positive SLN. However, no feature can nodes tended to have slightly thicker primary tumors and slightly
reliably predict additional nodal involvement in nonSLN, and no more frequent ulceration (although not statistically significant), and
long-term follow-up data are available in this regard. Thus, the significantly more regular regional SLNs visualized at scintigraphy
biologic significance of these findings remains to be determined. compared with the other patients with only regional nodes.

It was suggested that performance of an SLNB procedure in difficult to predict. SLN identification rate is generally lower for
patients with cutaneous melanoma increases the incidence of in- the head and neck region as compared with other superficial
transit metastasis (ITM),152 but this argument was not supported by lymph node basins. From the analysis of 2,001 patients with early
the results of subsequent studies.153,154 Evaluation of 2,018 mela- stage melanoma, Morton et al.119 reported an overall SLN identifi-
noma patients who were treated with WLE only, WLE + SLNB, and cation rate of 95.3% (99.3% for the groin, 95.3% for the axilla, and
WLE + ELND revealed that there was no significant difference 84.5% for the neck basins). Preoperative lymphoscintigraphy is
between these groups with regard to the total incidence of ITM or important for surgical planning and complete removal of all
ITM as a first site of recurrent disease.153 An increased risk of devel- SLNs.164,165 Multiple studies have demonstrated that SPECT/CT
oping ITM as a first recurrence after SLNB is associated with SLN has additional value for detection and localization of SLN in
status (but not the procedure itself), Breslow thickness, and extrem- patients with a melanoma of the head and neck and is therefore
ity location of the primary melanoma (p = 0.005).154 It is more likely recommended in these patients. Vermeeren et al.35 reported that
that the nature of the patient’s underlying melanoma, rather than SPECT/CT depicted additional SLNs in 16% of patients with better
the SLNB procedure itself, determines the likelihood of ITM. anatomic location correlation in all patients, leading to an adjusted
surgical approach in 55% of cases. Although head and neck mela-
noma is associated with an increased number of positive SLNs,
Patients with Previous Local Excision
there is no association between number of SLNs removed and
of Primary Melanoma overall survival or recurrence-free survival in all patients or in
It is known that previous surgical procedures can alter lymphatic patients with negative SLNs.166

drainage pathways, for both breast cancer and melanoma patients.
However, SLNB can still be successfully performed and accurately Intraoperative Frozen Section Analysis
reflects the status of the regional lymph node basin in selected mela-
noma patients with a previous WLE of the primary lesion. There was Controversies exist regarding the value of intraoperative analysis
no significant difference in relapse-free survival and in overall sur- of SLNB to detect nodal metastases in patients with primary cuta-
vival whether SLNB is performed in patients with previous WLE or neous melanoma. The advantage of intraoperative examination is
SLNB is performed concurrently with WLE.155 However, these that if evidence of metastases is found, regional lymph node dis-
patients may have unusual drainage pathways leading to more com- section can be performed at the same time of SLNB so that the
mon visualization of SLN in unexpected locations.156 For these patient can avoid separate surgery and the related risks and addi-
patients, inclusion of radiolabeled agents and preoperative scinti- tional costs. The disadvantage is that intraoperative examination
graphic imaging is critical, as vital blue dye injection may have only is not as accurate as a permanent section examination.
limited value. Intraoperative pathologic evaluation can be performed either by
frozen section analysis or more simply by imprint touch cytology
(ITC) analysis. Both methods have consistently high specificity
Thin Melanomas (100% positive predictive value [PPV]) in detecting lymph node
The majority (65%) of newly diagnosed melanomas are ≤1 mm in metastases. That is, patients with a positive finding on frozen sec-
thickness.157 Most patients with thin melanomas ≤1-mm Breslow tion or ITC will also have positive findings on permanent section
depth have a very good prognosis after WLE alone, with recurrent analysis, so that these patients will benefit from a synchronous pro-
disease observed in a small percentage of patients (4.3% with cedure of lymph node dissection. The problem is that neither frozen
regional nodal recurrence and 3.9% with distant metastatic recur- section nor ITC has satisfactory sensitivity in detecting lymph node
rence) as reported by Karakousis et al.158 in a study of 882 patients metastases. ITC has a sensitivity of 33% to 47%, whereas frozen
with a median follow-up of 16.4 years. In addition, the SLN status section analysis has a sensitivity of 59% to 75%, and the combina-
is significantly linked to overall survival in patients with thin mela- tion of frozen section and ITC has a sensitivity of 80%.167 These
noma, with a mean 10-year disease-free survival rate of 96% for findings suggest that intraoperative frozen section analysis or ITC
patients with tumor-negative SLN versus 54% for patients with can be beneficial to some patients with cutaneous melanoma
tumor-positive SLN (p < 0.001), at a median follow-up of 57 months because there is no risk of over-treatment from false-positive
for 631 patients.159 results, and all patients with negative intraoperative frozen section
Efforts have been made to identify “higher-risk” patients with thin or ITC should have permanent section analysis. However, data is
melanoma for regional nodal metastases. The incidence of positive limited and more research is indicated in this regard.
SLNB in thin melanoma patients was 6.4%, in contrast to a 23.8%
overall incidence of positive SLNB.160 However, all nodal metastases
Role of Ultrasonography
in thin melanoma were found in the group with a Breslow thickness
of 0.76 to 1 mm, resulting in 12.8% of positive SLNB in this sub- Controversies exist regarding to the role of US in the evaluation of
group.160 Kesmodel et al.161 found that patients with a mitotic rate of SLNs in melanoma patients. US using high-frequency probes pro-
>0 and a tumor thickness ≥0.76 mm had a 12.3% incidence of SLN vides detailed visualization of subcutaneous lymph nodes includ-
metastases, in contrast to 5% of incidence of positive SLN in all thin ing their internal structure. The appearance of a normal hilum
melanoma patients, consistent with other studies.158,161–163 and subcapsular sinus as well as a smooth surface outline and
In addition to Breslow thickness and mitotic rate, many other fac- shape often indicate a normal lymph node. However, deep lymph
tors are related to positive nodal metastases from thin melanoma, nodes (e.g., iliac and obturator nodes, and SLN in the retroperito-
including ulceration,158,162,163 angiolymphatic invasion,162,163 micro- neal, paravertebral, and para-aortic regions) can be difficult to
satellitosis,162 vertical growth pattern,158 patient age,162 and male visualize. The axilla is also a difficult region to examine with US.
gender.158 Although some conflicting data exist, these findings indi- More importantly, melanoma metastasis at presentation is fre-
cate that SLNB should be performed in thin melanoma patients with quently microscopic and below the detection resolution limit of
a Breslow thickness ≥0.76 mm (but not in patients with a Breslow US. The benefit of nodal US in combination with fine-needle aspi-
thickness <0.76 mm) and in patients with other high-risk factors. ration cytology (FNAC) in identifying nodal involvement in mela-
noma patients remains to be determined.
The utility of US with FNAC to detect SLN metastases is cur-
Melanoma in the Head and Neck Region rently being investigated but has a limited role at present, as the
SLNB in the head and neck region is a technically demanding sensitivity of currently available US technologies is insufficient for
procedure, and the number and location of SLNs are variable and detection of micrometastases (<2 mm in diameter), even though

micrometastases are common in most melanoma patients with squamous cell carcinoma of the oral cavity regardless of their tumor
positive SLN.168 depth and thickness.175
Data are conflicting regarding the sensitivity and specificity of SLNB with lymphoscintigraphy may provide more accurate
US combined with FNAC in the analysis of SLN in melanoma staging than current elective neck dissection protocols, and may
patients. Rossi et al.169 reported that high-resolution US combined serve as an alternative to elective cervical node dissection for the
with FNAC in the analysis of SLN in melanoma patients during management of OSCC. Many centers with adequate experience
preoperative staging had a sensitivity and specificity of 39% and have abandoned routine elective neck dissection and offer SLNB in
100%, respectively, with an FNR of 61%, mainly caused by tumor observational trials to appropriate patients with nodal negative T1
deposits <2 mm in diameter. Another study revealed that the sen- and T2 OSCC for accurate staging of the neck.176,177 Although not yet
sitivity of targeted US in the detection of positive SLN was very low widely applied, available data demonstrate that SLNB has the abil-
(only 24.3%), although the specificity was as high as 96.8%.170 In ity to select patients with occult lymphatic disease for elective neck
an analysis of 127 patients with melanoma (median Breslow depth dissection with a reported SLN detection rate of more than 95% and
of 2.1 mm) who underwent SLNB as well as RT-PCR of SLN an NPV of 95%,176,178 and to eliminate the costs and morbidity asso-
aspirates obtained by ultrasound-guided fine-needle aspiration ciated with nodal dissection in patients with negative SLN.
cytology (US-FNAC), US-FNAC had a sensitivity of 82% and a spec- According to the “Joint Practice Guidelines for Radionuclide
ificity of 72% in predicting nodal involvement, and may eliminate Lymphoscintigraphy for Sentinel Node Localization in Oral/Oro-
the need for SLNB in 16% of all SLNB patients.171 More recently, pharyngeal Squamous Cell Carcinoma,” the most important clini-
Voit et al.172 reported that US-FNAC before SLNB had a sensitivity cal indication for SLNB in patients with OSCC was a cN0 neck by
of 82% and PPV of 52%, and identified up to 65% of all SLN physical examination and imaging studies.179 SLNB is more likely
metastases. to be successful in patients with cN0 necks, and is most commonly
It is likely that a positive finding by US-FNAC may eliminate the performed to stage the ipsilateral cN0 neck in patients with a uni-
need for therapeutic lymph node dissection, although negative US lateral primary tumor, but can also be performed to evaluate bilat-
(with or without FNA) of regional nodes is not a reliable substitute eral cN0 necks in primary tumors close to, or crossing, the midline.
for SLNB. Also, the routine use of US-FNAC before SLNB is unlikely In general, SLNB is contraindicated if there is positive cervical
to be cost effective.148 At this time, there is no evidence to recom- node involvement, because gross lymphatic involvement can lead
mend US-FNAC as a standard procedure in melanoma patients. to distortion of the normal architecture, leading to aberrant drain-
age patterns and biopsy of false SLN.180 However, the Guidelines
also recommend the use of SLNB to assess the contralateral cN0
neck in primary tumors close to the midline with an ipsilateral
Sentinel Lymph Node Biopsy clinical node-positive (cN+) neck, to determine whether these
Application in Other Malignancies patients need bilateral neck dissections or ipsilateral neck dissec-
tion alone.179 Patients who have received prior radiation therapy
The success of SLNB in melanoma and breast cancer has created or surgical treatment to the neck may have distortion of the nor-
great interest in the use of SLNB in the management of other solid mal lymphatic pathways, which can give rise to unexpected pat-
cancers such as head and neck cancers, gynecologic cancers, thyroid terns of metastasis,181 and are thus not candidates for SLNB.179
cancers, gastric cancer, colon cancer, and prostate cancer, and has SLNB is easier to perform for tumors located in the oral cavity
had variable success. For example, in the setting of gastric cancer, and accessible subsites of the oropharynx. However, for tumors
SLNB has an overall sensitivity of 85.4%, which is low, although located in other locations such as the hypopharynx and supraglot-
the specificity (98.2%) and NPV (90.7%) are good,173 and in the tic larynx, poor access to these sites (via endoscopic guidance for
setting of colorectal cancer, SLNB has a low sensitivity (76%) as radiolabeled agent injection) and close proximity of the primary
well.174 As such, for most other tumor applications, SLNB is still a tumor to the first-echelon lymph nodes (potentially obscuring the
subject of research investigation. The value of SLNB in the man- true location of SLN) make it difficult to perform the procedure
agement of thyroid carcinomas will be discussed in a separate and effectively detect SLNs on preoperative lymphoscintigraphy.
chapter. In addition, the detection of SLNs may be less successful for floor-
of-mouth tumors. Alkureishi et al. analyzed a total of 227 SLNB
procedures in patients with early head and neck squamous cell
Oral/Oropharyngeal Squamous Cell Cancer carcinoma with a success rate of 93%, with upstaging in 34% of
As with melanoma and breast cancer, the status of lymph node cases. The detection of SLN for floor-of-mouth tumors was 88%
involvement is the single most important adverse prognostic factor versus 96% for nonfloor-of-mouth tumors. The sensitivity and NPV
for patients with OSCC. The current standard of care for a clinically were also lower for patients with floor-of-mouth tumors compared
node-negative (cN0) OSCC patient is to offer elective lymphadenec- with other sites. The overall sensitivity of SLNB was 91% based on
tomy (or elective neck dissection). However, the risk of occult metas- a minimum follow-up of 5 years.182 Although SLNB can be used as
tasis for most head and neck sites is approximately only 25% to the sole staging tool for the majority of patients with OSCC, its
30%, which means that the majority of patients who have nonselec- value remains to be determined for patients with floor-of-mouth
tive cervical node dissection do not harbor occult metastases, yet tumors. Additional imaging with SPECT/CT may help to improve
are exposed to additional costs and morbidity. Traditionally, the SLN detection and localization in patients with head and neck
depth of tumor invasion has become widely regarded as a prognos- cancers.33,34
tic parameter of nodal metastases for patients with OSCC, and was
used as a criterion in selecting low-risk patients for “watchful wait-
ing” (where patients would be observed after removal of the pri- Gynecologic Malignancies
mary tumor, with neck dissection being performed only if there was
Squamous Cell Vulvar Carcinoma
clinical evidence of developing metastases). However, evaluation of
patients with oral cancer who underwent SLNB found that tumor Squamous cell cancer of the vulva is a rare disease in which
depth and tumor thickness could not predict occult metastases in unrecognized positive inguinofemoral lymph nodes are often fatal.
the context of SLNB. In contrast, poorly differentiated carcinomas, Radical excision of the tumor with inguinofemoral lymphadenec-
carcinomas with lymphovascular invasion, and carcinomas with tomy is the current standard surgical procedure in patients with
invasive growth patterns had a high probability of positive SLNB, early stage disease with tumors that have an invasion depth of
indicating that SLNB should be performed in patients with early ≥1 mm. Similar to breast cancer, there is morbidity associated with

lymphadenectomy without proven benefit for the majority of patients, SLNB is not a standard procedure for cervical cancer patients
because two-thirds of patients do not have nodal involvement.183 in current practice, however, because uncertainties remain regard-
A modified superficial inguinal lymphadenectomy (instead of a ing the false-positive rate (FPR), the significance of parametrial
complete inguinofemoral dissection) has been proposed to reduce nodes, and other relevant topics of interest. Large-scale, prospec-
surgical complications but was later abandoned because of high tive randomized studies are needed to confirm the safety of omit-
regional recurrence rates. Application of SLNB in the manage- ting CLND in patients with negative SLN, before pelvic
ment of patients with squamous cell cancer of the vulva, however, lymphadenectomy is replaced with SLNB as a standard of care in
has produced very encouraging results. the surgical management of early stage cervical cancer.
The vulvar region drains into the inguinofemoral lymph nodes
and then to the pelvic lymphatic nodes via external iliac pathway.
The absence of inguinofemoral lymph node involvement is a reliable
Endometrial Cancer
indicator of negative pelvic lymph node metastases. The SLNB pro- Endometrial cancer is the most common gynecologic malignancy
cedure in vulvar cancer is highly accurate to identify lymph node and the second most lethal gynecologic malignancy. In the major-
metastases with a sensitivity of above 90% and an NPV approaching ity of cases, the disease is confined to the uterus at the time of
100%.184 Van der Zee et al. reported a multicenter study of SLNB diagnosis with a relatively favorable prognosis. The surgical treat-
using a radiolabeled agent and blue dye, performed in 623 groins of ment of early stage endometrial cancer includes total hysterec-
403 patients with T1/T2 (<4 cm) squamous cell cancer of the vulva. tomy and bilateral salpingo-oophorectomy with or without pelvic
Two-hundred-and-fifty-nine patients with unifocal vulvar disease and para-aortic lymphadenectomy.

and a negative SLN received no inguinofemoral lymphadenectomy, SLN mapping for endometrial cancer is technically more chal-
and had 2.3% of inguinal recurrence and 97% of 3-year survival lenging because the lymphatic drainage of the uterine corpus is
upon median follow-up of 35 months. In addition, these patients had located bilaterally with multiple lymphatic pathways. The lower
significantly less short-term and long-term morbidities.183 uterine segment drains into the pelvic lymph nodes whereas the
It appears that SLNB is a safe and feasible alternative to CLND upper segment of the uterine corpus drains into the para-aortic
in early stage vulvar cancer patients. Although patient survival is lymph nodes.188 Several injection strategies have been described for
excellent and treatment-related morbidity is minimal, there has endometrial cancer SLNB, including injection into the cervix, the
been no large-scale randomized controlled trial to confirm these endometrium during hysteroscopy, or the uterine subserosa during
findings. In addition, there is a learning curve associated with the laparoscopy/laparotomy.189 Cervical injection is the most conve-
SLNB procedure, and an exposure of at least 5 to 10 SLNB proce- nient route for both blue dye and radiolabeled agents, and is cor-
dures per year is recommended,183 although this is hard to achieve related with an increased detection rate in the range of 80% to
for a rare tumor such as vulvar cancer except for those surgeons 100%.190 Ballester et al. recently reported a prospective, multicenter
practicing in a major oncology center. cohort study including 125 patients with early stage endometrial
cancer. SLNB was performed via cervical combined injection, and
SLNs were serial sectioned and examined by IHC. The SLN detec-
Cervical Cancer tion rate was 88.8%, with pelvic lymph node metastases in 17% of
The lymph node status is the most important prognostic factor for cases and para-aortic node metastases in 5% of cases. SLNB
patients with cervical cancer, and the presence of node metastasis upstaged 10% of low-risk patients and 15% of intermediate-risk
is associated with significantly reduced 5-year overall survival patients with endometrial cancer. SLNB had a sensitivity of 84%
rates. Regional pelvic and/or para-aortic lymphadenectomy remains and an NPV of 97%.191
the gold standard in the treatment of early stage cervical cancer as The role of SLNB remains investigational in endometrial cancer.
an integral part of radical hysterectomy and/or radical cervicec- In general, SLN detection rate remains low for patients with endo-
tomy, but is associated with unnecessary and significant morbidity, metrial cancer compared to melanoma or breast cancer patients. A
because more than 70% of patients with early stage disease have recent meta-analysis of the detection rate and/or sensitivity of
no lymph node metastases. SLNB is used in cervical cancer to SLNB in endometrial cancer (including 26 eligible studies and
reduce the morbidity of lymph node dissection while ensuring that 1,101 SLN procedures) revealed an overall SLN detection rate of
lymph node metastases are accurately detected. 78% (95% CI, 73% to 84%) and an overall sensitivity of 93% (95%
Radiolabeled agent injection for cervical cancer is more techni- CI, 87% to 100%).190 The current literature does not provide suffi-
cally challenging. Generally, the injection of both 99mTc-radiolabeled cient evidence to establish the value of SLNB in endometrial cancer
agent and blue dye is given directly in divided doses to the area of because of very small sample sizes in the majority of available stud-
the normal cervix–tumor interface (or to the bed of the cone in ies, and the lack of prospective randomized controlled trial design.
patients who have undergone a prior cone biopsy). As the cervix
has a midline position and the cervical lymphatics drain bilaterally,
lymphatic mapping should be performed accordingly. Using the Conclusion
combination of lymphoscintigraphy and blue dye injection followed
by laparoscopic lymph node mapping, SLN removal, and lymph Regional node status is the most important prognostic indicator for
node dissection, Lecuru et al. reported that lymph node mapping in patients with invasive breast cancer or melanoma. Since its first
early stage cervical carcinoma was feasible with high SLN detection description in early 1990s, SLNB has become the standard for
rate (97%) and with high sensitivity (92%) and NPV (98.2%) for accurate staging of regional lymph node involvement in multiple
metastasis detection, without false-negative results. Bilateral nega- malignancies, most commonly breast cancer and melanoma. SLNB
tive SLNB accurately excluded lymph node metastasis in early cer- has revolutionized the management of patients with breast cancer
vical cancer.185 Positive SLNs are frequently located at the external and melanoma by providing accurate lymph node staging, with the
iliac, internal iliac, and obturator regions. Para-aortic metastasis majority of patients being spared from a comprehensive lymphad-
without pelvic node involvement is rare. It is likely that bilateral enectomy and its associated morbidity. SLNB is routinely per-
pelvic CLND could be avoided in 75% of patients with early stage formed using a combination of blue dyes and radiolabeled agents,
cervical cancer if SLNB is applied.186 In addition, SLNB allows for and preoperative scintigraphic imaging is commonly performed to
identification of lymph node metastases in atypical regions. SPECT/ assist in the intraoperative search for SLN, which is especially
CT is helpful to delineate different lymph node groups in cervical valuable in the setting of melanoma, for detecting IMN SLN in
cancer, especially external iliac versus internal iliac nodes, and patients with breast cancer, and for detecting SLN in any patients
parametrial nodal uptake.187 who have undergone prior biopsy or surgery. SPECT/CT can also

Table 28.2 intraoperative portable γ-probes have been applied in clinical and
experimental settings in the last 10 years192 and have been very
Indications for Sentinel Lymph Node Biopsy promising for the detection of occult SLNs. These devices, dedicated
in Cutaneous Melanoma to accurate and real-time intraoperative imaging and direct visual
guidance, are able to provide visualization of the size, shape, and
Tumor location of target “hot” spots in real time, and help to find additional
Thickness SLNs in multiple malignancies including breast cancer,193 mela-
(mm) Risk of Metastases Indicated? noma,193 gynecologic malignancies,193 urologic malignancies,194 head
and neck melanoma, and oral cavity carcinoma.195
>4 Nodal metastases about 40%; Indicated Another very promising potential improvement in SLNB tech-
also high risk of distant niques is intraoperative pathologic evaluation by RT-PCR. The
metastases pathologic evaluation is ideally performed immediately to deter-
1–4 Nodal metastases 8–30% Indicated mine if there is evidence of metastasis in the SLN to provide guid-
0.76–1 Nodal metastases about 5% Indicated for high-risk patients ance for the subsequent surgery. However, intraoperative frozen
(ulceration, mitotic rate section analysis of SLN has a high FNR, which cannot be improved
≥1 per mm2; Clark level IV–V) significantly. RT-PCR is a highly sensitive method to identify spe-
≤0.75 Low risk for metastasis Not indicated
cific mRNA markers of malignancy. Multiple targets of one or more
tumor-associated antigens for a malignancy can be used for simul-
taneous RT-PCR analysis to increase both sensitivity and specificity.
be employed in difficult clinical situations. When performed appro- Addition of RT-PCR analysis significantly decreases the FNR of
priately, the SLN identification rate is >95% in patients with breast SLNB. For example, in cutaneous melanoma, the FNR was 3.6%
cancer or melanoma. with RT-PCR versus 17.9% without RT-PCR, when all lymph nodes
SLNB is indicated for the majority of patients with breast cancer were examined.196 In recent years, rapid highly automated real-
without nodal or distant metastases. Only a small fraction of breast time RT-PCR–based platforms have been developed which allow
cancer patients should not have SLNB, including: (1) patients in very for incorporation of lymph node staging into the ongoing surgical
early stage breast cancer (low grade DCIS); (2) patients with histo- procedure and avoid a separate delayed lymph node dissection in
logically confirmed positive axillary or extra-axillary lymph nodes or patients with breast cancer197 or head and neck cancer.198 Impor-
distant metastases; (3) patients with inflammatory breast cancer; tantly, the assay can be performed in a little more than half an
(4) patients who cannot tolerate the procedure; and (5) patients who hour. Because the technique of RT-PCR is much easier to improve,
are allergic to vital dyes or radiolabeled agents. Pregnancy, pal- and multiple options exist for targeting different genes, more
pable axillary nodes, multifocal or multicentric tumor, and prior promising developments will likely be realized in this field in the
breast or axillary surgery are not contraindications for SLNB in near future.
breast cancer patients. The significance of micrometastatic nodes
remains to be clarified, but there is a trend toward more conservative
treatment.
SLNB should be offered to patients with clinical stage T1b to References
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Chapter 29
PET/CT Hybrid Imaging in Radiotherapy Planning

Egesta Lopci • Mink S. Schinkelshoek • Filippo Alongi • Lidija Antunovic • Stefano Arcangeli • Anna Maria Ascolese •
Valentino Bettinardi • Francesca Lobefalo • Pietro Mancosu • Giovanna Pepe • Giacomo Reggiori • Marcello Rodari •
Pietro Rossi • Giovanni Tosi • Angelo Tozzi • Marta Scorsetti • Arturo Chiti
Target Identification and Tumor RT planning. Most modalities do not provide functional information,
so that a distinction between actively dividing, for example, hypoxic
Delineation tumor tissue and healthy tissue is difficult although tissue densities
are similar. Furthermore, patients can gain or lose weight in the
Radiotherapy (RT) is an important means of treatment in current interval between treatment planning and actual RT. During that
oncology practice. In recent decades, a growing interest has period, tissues borders could change significantly, because of tumor
emerged in the planning of RT. To target the tumor tissue and leave growth or other factors.4 The potential to circumvent these practical
the healthy tissue out of the radiation beam, specific tumor identi- problems is growing, especially by correcting for different computer
fication and delineation are needed. In the early years of RT use in programs. At this time, a margin around the tumor tissue is still
management of cancer patients, few tools were available to readily necessary.
identify the total extent of the tumor and the growth of tumor cells
into adjacent healthy tissues. By means of planar x-rays, oncologists
estimated the tumor size and location in a two-dimensional (2D) Imaging Modalities
view. Evaluating growth in the third dimension was not possible, so
margins were vast to correct for this lack of information. Moreover, The most frequently used technique for RT planning is computed
dose calculations were done by hand based only on visual informa- tomography (CT) and the role of other modalities, such as magnetic
tion, so that the possibility of specifying tumor dose distribution resonance (MR) and positron emission tomography (PET), is increas-
was limited. ing. In many tumor types, co-registration of two or more modalities
With the new imaging tools that became available in recent is used, because the combination may improve tumor staging, iden-
years, the possibilities to distinguish between tumor tissue and adja- tification and delineation, and RT planning. An improvement in the
cent healthy tissue broadened. More recently, the addition of a third accuracy of tumor identification and delineation may in turn lead to
dimension to imaging modalities eliminated the problem of irregu- a decrease in inter- and intraobserver variability. This section des
lar growth and consequently reduced dose administration to healthy cribes the several modalities used for RT planning as well as their
tissue. Along with the improvement in imaging equipment, software advantages and disadvantages for tumor detection, staging, and delin-
was introduced to calculate the radiation dose distribution based on eation of the tumor.
the imaging. This proved to be a valuable tool to further reduce the
damage to healthy tissue adjacent to the tumor and beyond. Imaging
plays an increasing role in the planning stage of RT treatment of
Computed Tomography
patients. Several modalities are used to identify and delineate the The role of CT in RT planning is historically very important. In many
tumor volume for RT. The actual process of delineating the tumor tumors, a CT scan is used as the basis to delineate the tumor. The
involves the assessment of three different volumes. First, based on reasons for this pivotal role of CT are the excellent image resolution
the image the gross tumor volume (GTV) is depicted. This volume of this modality and the tissue attenuation information that can be
contains the location and extent of the tumor as far as it is visible or used for RT planning. Other advantages of this modality are the
palpable. Second, the clinical target volume (CTV) is composed. This wide availability and the low costs compared with the other modal-
volume contains the GTV and the microscopic tumor outgrowth that ities discussed here. Nevertheless, there are certain problems that
is not incorporated in the GTV, but should be eliminated as well. impair the image quality and accuracy of target-volume delineation
Third, the planning target volume (PTV) is a construct which takes in RT planning.
into account that RT is not as precise as targeting the CTV only, Planning is often carried out manually, which is still one of the
because of several patient-related as well as procedure-related fac- major courses of inaccuracy of tumor delineation, even if the
tors. Examples of these factors are movement of the patient during delineation is done by experienced clinicians. Many studies show
the procedure, motion of the organs of the patient between the plan- that inter-observer variation is a serious problem in delineating
ning and the actual therapy or during therapy itself, and differences tumor tissue for RT.5,6 Another problem arises because it is diffi-
between placement of the patient between the planning procedure cult to distinguish tumor tissue from healthy tissue if the densities
and the RT procedure.1,2 of both tissues are similar. This might result in failure to identify
Based on the PTV, a computer program calculates the dose and some tumors. Contrast media enhance the ability of CT to distin-
placement of the beams for the RT procedure. This leads to the guish tissues from each other.7 Furthermore, the ionizing radia-
treatment that administers high doses of radiation to tumor cells tion delivered by CT is a burden to the patient. Whereas RT should
while sparing healthy tissue close to the tumor. In this way, it is deliver the dose exclusively to the tumor, CT radiates the whole
possible to establish a steep radiation gradient at the edges of the body, so that there is radiation exposure of uninvolved tissues
PTV, leading to a reduction of side effects of the RT. Intensity- that may impose additional theoretical risks, especially in younger
modulated radiation therapy (IMRT) is an example of a further patients.8
refinement of dose administration. In this technique, implemented
in clinical practice approximately 10 years ago, it is possible to
vary the radiation flux in one single beam, so that spatial distribu-
Magnetic Resonance Imaging
tion of the radiation dose is more flexible than before. This allows Even though MR imaging renders excellent soft tissue contrast and
for further sparing of the tissues surrounding the tumor, while circumvents the problem encountered in the CT of artifacts associ-
being able to increase the dose administered to the cancer cells.3 ated with dental fillings and metal prostheses, there are some
Even though tumor identification and delineation are a result of features of this modality that limit its use as a single means of RT
the newer technologies, there are remaining problems that impact planning. MR does not give radiation attenuation information
432

Chapter 29 PET/CT Hybrid Imaging in Radiotherapy Planning 433
needed for dose distribution calculations in RT planning. Moreover, alone but as an addition to conventional RT planning, it increased
geometric distortions are important sources of position errors of MR. the GTV by adding undetected tumor tissue to the conventional GTV.
These distortions are caused by inhomogeneities of the main It is still uncertain if this information has any value for treatment
magnetic field and nonlinearity in the applied magnetic field gra- decisions or disease outcome. Brændengen et al. concluded that
dients. At the edges of the field of view (FOV), the distortions are until the difference 18F-FDG PET-CT makes is found to have an effect
mostly greatest. on clinical choices or outcome, the use of 18F-FDG PET-CT should
With increasing use of CT–MR fusion in RT planning of different not be advised.
tumors, the question arises whether it is possible to base RT on MR By comparing CTVs acquired by either CT or 18F-FDG PET-CT in
alone. Jonsson et al.9 have assessed this idea to lower costs and patients with several tumor types, Marta et al.16 tried to answer the
decrease patient dose. The main limitations to this approach appear question if 18F-FDG PET-CT really is of additional value when com-
to be the geometrical distortions and lack of tissue attenuation pared with CT alone. They could only detect a significant difference
information in MR. Attenuation density information is needed for in CTV in patients with lymphoma, lung or head and neck tumors.
RT dose calculations. Jonsson et al.9 investigated if the accuracy of This led to the conclusion that more research is needed on this
dose calculation differs from the dose calculation achieved by CT- topic to provide firm evidence for the additional value of adding
18
derived attenuation information. If the differences are negligible, F-FDG PET-CT to conventional RT planning with CT in these
MR without CT for RT planning would be possible. These differ- tumors.
ences were assessed in different tissues and tumor types. Jonsson Muijs et al.17 conducted a systematic review on the role of 18F-
et al.9 concluded that dose calculation accuracy is not a limiting FDG PET-CT on RT planning in patients with esophageal cancer.

factor to the sole use of MR as a means of RT planning. CT is no They focused on tumor detection, delineation, and treatment out-
longer absolutely necessary in RT planning of cancer. come of the patients after RT planned on the basis of 18F-FDG PET-
Beavis et al.10 address the same problem in their study on the CT. The use of FDG PET in tumor detection seems to be justified,
possibility of using MR alone as the modality for RT planning in because both sensitivity and specificity are sufficiently high to detect
brain tumors. In RT planning, the better soft tissue delineation and most tumors. Tumor delineation is significantly different in 18F-FDG
definition of organs at risk are advantages. However, the disadvan- PET-CT compared to conventional planning CT, but evidence is lim-
tages of a lack of tissue attenuation information and geometric ited, so that definite conclusions are hard to draw. When Muijs et al.
distortions stood in the way of using only MR for RT planning. did their review, there was no evidence yet about the increased
Therefore, conventional practice is CT–MR fusion, because adding survival or other outcome measures following RT planning with
18
CT to the procedure diminishes the disadvantages of MR alone. In F-FDG PET-CT. They concluded that it is not yet justified to put
18
this study, Beavis et al. took electron density as being homogeneous F-FDG PET-CT into everyday practice of esophageal cancer treat-
throughout the brain. They assumed that this lack of tissue attenu- ment, because evidence is lacking. More research on the use of this
ation information would not significantly change dose distribution modality in RT planning of patients with esophageal cancer is
to the tumor. They reached the conclusion that the uncertainty needed.
caused by the lack of information was acceptable and did not out- These studies show that the role of FDG PET in RT planning is
weigh the advantages of eliminating CT in RT planning. the object of research in many different cancer types. This specific
Stanescu et al.11 also tried to establish a way to use MR only in radiopharmaceutical can be broadly used because its accumula-
the RT planning of intracranial lesions. They used bulk density tion is based on enhanced glycolysis, a property of many different
assignment, as Jonsson did, and atlas-based software to diminish tumors. Because of the slightly different structure compared to glu-
the problem of lack of attenuation density information and by using cose, this compound could not be degraded in nor exported out of
software to correct for geometrical distortion. After these adjust- the cell, leading to its entrapment in the tumor cell.18
ments, they compared the planning volumes of CT–MR with those Another radiopharmaceutical used is 11C-CHO, a tracer of lipid
acquired by MR only. They were comparable in shape and showed metabolism. The compound enters the cell via the choline trans-
an acceptable difference in location and size. This means that MR port system and is processed in the cell to eventually become a
alone can be used in RT planning in patients with brain tumors. phospholipid for cell membrane construction. This step is very
The superior soft tissue contrast is thought to add valuable important in tumor cells, because for proliferation new cell mem-
information to the information acquired by CT, so that tumor tissue branes should be synthesized. 18F-fluoroethylcholine (FEC) and
18
could be delineated more accurately, thereby sparing the adjacent F-fluoromethylcholine (FMC) are similar radiopharmaceuticals.
healthy tissue. Even though the increased soft tissue contrast could These markers seem to have some value in RT planning in patients
be a valuable addition in delineating every tumor type, the use of with prostate cancer, as the following studies conclude.
MR in RT planning has been more intensively studied in only cer- It is assumed that 11C-CHO PET-CT is a modality in the field of
tain tumor types. This depends on the importance of adjacent nuclear medicine that could be particularly valuable in detecting
healthy tissues, such as the reproductive system in prostate, cervi- and defining the borders of prostate tumor cells. Souvatzoglou
cal, and rectal cancer and the spinal cord and the brain in head et al.19 evaluated the role of 11C-CHO PET-CT in RT planning in
and neck and brain tumors or because the conventional planning patients with recurrent prostate cancer. They measured the inci-
CT is evidentially suboptimal.12–14 dence of 11C-CHO PET-CT positive findings in these patients and
compared the differences in PTV between conventional planning CT
and 11C-CHO PET-CT. This research question is of specific interest
Positron Emission Tomography because neither CT nor MR nor bone scintigraphy seemed to be able
In RT planning, a role for PET in adding functional information to to detect low-volume metastases as a marker for recurrent disease.
the anatomical information of CT and MR leads to a better definition Because of the functional information that 11C-CHO PET-CT gives, it
of tumor volume and detection of physiologically distinct areas in was hypothesized that this modality would improve the definition of
the tumor. Brændengen et al.15 conducted a study in which they tumor tissue in patients with recurrent prostate cancer. 11C-CHO PET-
assessed the influence of 18F-FDG PET-CT on GTV size, shape, and CT showed an increase in PTV in 13% of the cases. The conclusion
localization compared to the conventional way of defining GTV in drawn from this result is that 11C-CHO PET-CT can be used to indi-
rectal cancer with MR and CT. The advantage of using 18F-FDG PET- vidualize treatment in these patients, but that its use should be fur-
CT was thought to be that functional information would now be ther investigated before it can be used in conventional clinical
added to the delineation process. Brændengen et al. wanted to mea- practice.
sure the advantage that this new modality might offer. Their results In another study on prostate cancer, Würschmidt et al.20 evalu-
showed that 18F-FDG PET-CT rendered a smaller GTV when used ate the use of 18F-FEC PET-CT in staging and RT planning in primary

and recurrent prostate cancer. Like Souvatzoglou et al.,19 PET-CT and PET-MR in Radiotherapy Planning
Würschmidt et al. hypothesized that the additional functional infor-
mation supplied by FEC PET-CT would lead to a more accurate Most commonly PET-CT imaging is performed in the whole-body
definition of tumor volume and the possibility of dose escalation to mode with the CT and complementary PET scan covering a coaxial
tumor sites while sparing adjacent healthy tissues. They focused on scan range from the head/neck to the upper thighs.
clinical outcome by monitoring the (disease free) survival of patients With a patient displacement error still negligible (<0.5 mm), PET-
participating in this study. Their results showed a possibility to CT offers anatomical and functional images that can guide radiation
escalate doses administered to the tumor though avoiding radiation therapy planning. A flat radiation therapy pallet is mounted on the
damage to normal tissues. Even a significant part of the patients top of the PET-CT patient pallet and allows patient positioning as
with tumor invasion of lymph nodes, detected during RT planning in the actual radiation treatment of the patient. Last but not the least,
by FEC PET-CT, was still disease free at the end of the study. This the new PET-CT scanners have an increased bore diameter that
underlines the value of FEC PET-CT in RT planning and on the allows reproducible patient positioning with standard RT-positioning
outcome of treatment. aids during the diagnostic, pretreatment PET-CT scan. The choice of
Amino acids are other possible compounds for RT planning. a reconstruction algorithm with its parameters is a compromise that
Tumor cells proliferate rapidly, so they need relatively large amounts can affect the presence of artifacts, the SNR, the resolution, the quan-
of amino acids to synthesize proteins for new cells. tification accuracy, and the reconstruction time (i.e., quantification is
l-[methyl-11C] methionine (11C-MET), O-(2-[18F]fluoroethyl)-L- crucial in standardized uptake value (SUV) evaluation, high resolution
tyrosine (18F-FET) and 18F-FDOPA are some examples of this type of is necessary for accurate target delineation for RT). A trade-off
radiopharmaceuticals. These markers measure amino acid uptake between high resolution and high SNR has to be done for heterogene-
which is high in tumor cells compared to healthy cells. Currently, ity assessment and dose painting; in any case, a low-quality data also
these amino acids are mainly used for brain tumor RT planning, even dramatically influences the best reconstruction protocol. Moreover, in
though other applications are under evaluation. Astner et al.21 con- modern PET-CT scanners, gated acquisitions minimize motion blur.
ducted a study on the use of MET PET in meningiomas. Currently, anatomical image data guide radiation treatment plan-
The use of 11C-MET PET for RT planning in skull base menin- ning. Nevertheless, functional imaging supplies complementary
giomas is thought to visualize tumor cells, because the uptake of information to anatomical imaging in certain situation in which the
this particular amino acid is much higher in metabolically active latter ones are inadequate such as, for example, in the distinction
cells like meningioma cells, compared with the gray and white mat- between necrotic and viable tumor volume. In these situations, PET-
ter adjacent to those tumor cells. Astner et al.21 assess the effect of CT can help in the delineation of biological target volume (BTV) or
adding MET PET to the conventional combined CT–MR RT plan- GTV. The reason for integrating functional imaging in the GTV defi-
ning in skull base meningiomas. Therefore, they measured GTV in nition is its higher sensitivity and specificity for malignant tissues.
both CT–MR and MET PET. These images were co-registered and The GTV can be delineated on the RT treatment planning environ-
GTVs were compared. Their results showed that MET PET can both ment or on the nuclear medicine workstation; in the first case, the
increase and decrease GTV, depending on the site of the tumor. anatomical and biologic imaging datasets are transferred as DICOM
Either way addition of MET PET led to a more accurate and precise datasets. In the second case, data are transferred to the treatment
delineation of the tumor volume. planning system as a set of regions of interest (ROI) forming a
Although all radiopharmaceuticals discussed above are only volume of interest (VOI) together with the DICOM image objects. The
based on the distinction between tumor and nontumor cells, there data transfer between the nuclear medicine imaging workstation
is a growing interest in radiopharmaceuticals that describe the and RT planning modalities can also be done through a hospital
tumor cells they target. One example of this approach is the hypoxia PACS. There are several modes (manual or automatic) for target
markers, such as 18F-FMISO, 18F-FAZA, and 64Cu-ATSM. They volume contouring on PET images. A threshold-based method is
become trapped in hypoxic cells in many different ways, but seem supported by most systems, where the actual VOIs can be defined
to reflect the O2 status of tumor cells quite accurately. Many more of with respect to the maximum specific uptake value or maximum
these kinds of markers based on a specific feature of a tumor cell activity in a predefined VOI-mask.
(like also 68Ga-DOTATOC) are currently developed. The following PET/MR gives the opportunity to cover a wide range of imaging
two studies illustrate the place of a hypoxia marker and 68Ga-DOT- from morphology (MR) to physiology (MR + PET) and biochemistry
ATOC in RT planning of different tumors. With the development of (PET), and comprises a PET scanner and an MR scanner; both
new and more specific markers, it becomes possible to individualize machines have a 3-T magnetic field. The attenuation correction for
cancer treatment. PET is directly based on MR images. Simultaneous imaging has a
great improvement on the spatial correlation; it seems to be very
helpful for radiation treatment planning. At the moment, these
Multimodality Imaging scanners are few in number around the world, so their use is still
Because none of the modalities described above shows a perfect in the research stage.
resolution, contrast, and electron density, their combination in RT
planning is increasing. Many of the studies presented above
PET Imaging in Stereotactic Body Radiotherapy
already make use of RT planning with different modalities.
The use of multiple modalities has the benefit of using the Stereotactic body radiotherapy (SBRT) is an emerging technology
advantages of each modality while compensating for each draw- that allows precise delivery of high doses of radiation with a sharp
back. However, there are some disadvantages related to the use dose gradient in selected patients. It is defined by prescription and
of more than one modality. To be able to have a single image for precise delivery of a limited number of fractions (typically less than
inspection co-registration of separate images is needed. This asks 5) to treat small treatment volumes with high doses of radiation.
for identical patient placement in both modalities of RT planning Originally, stereotaxy as applied to radiation was pioneered by
scans and in RT itself. Differences in positioning the patient lead Leksel et al.22 to treat intracranial tumors using a framed position-
to further inaccuracy of the final image. PET-CT has the advan- ing system for the Gamma Knife Radiosurgical System (Elekta
tage that both scans can be executed in the same session, without Instruments AB, Stockholm, Sweden). More recent technologies
moving the patient.7 Another problem arises because computer have adapted linear accelerators to similarly allow precise radia-
programs fuse the images acquired by different scans. These pro- tion delivery to extracranial sites using a frameless system. SBRT
grams insert another error-prone procedure to the total process requires a high degree of precision in all aspects of treatment plan-
of RT planning.3 ning and delivery to minimize toxicity to adjacent structures.23

However, many questions still remain regarding the utilization prerequisite. PET can frequently differentiate radiation necrosis
of PET-CT in conjunction with SBRT. Ongoing research tries to shed from tumor recurrence and identify smaller tumor deposits when
light on the utility of PET and/or PET-CT in treatment planning, the compared with CT, which may significantly modify treatment plans.
appropriate interval to image patients after treatment, and the rela- In most studies, pretreatment PET was not well correlated with
tionship between PET-CT and clinical outcomes, among other top- survival or other outcome measures. However, in follow-up, PET
ics. In this section, we provide an overview of SBRT, explore the may offer important prognostic information. Further research in the
relationship between PET and SBRT in a variety of sites, and sum- field and larger study samples are needed to more accurately define
marize the evidence on these topics. the role of PET in SBRT.
In the conventional fractionated treatment, PET has demon-
strated numerous uses. Studies have assessed its potential for more
precise target delineation and its role in treatment follow-up to Other Modalities and Future
detect recurrence.24,25 In addition, PET has the potential to assess
response and serve as an early surrogate of treatment failure. This
Perspectives
may be particularly important in operable patients receiving SBRT
Even though PET is extensively discussed here, MR spectroscopy
in whom PET enables earlier detection of failure and, thus, could
and single photon emission computed tomography (SPECT) are also
decrease the doctor’s delay for surgical salvage therapy.26
modalities that have the ability to depict the biologic characteristics
However, SBRT differs in many respects from conventional
of tumor cells. The research done on the role of these two modalities
fractionated RT and this may present both novel applications and
is very limited and it is improbable that those will overtake the lead-

challenges for PET imaging. SBRT delivers large doses of radiation
ing role PET has in adding functional information to RT planning.
during each fraction, making precise target delineation essential.
The role of CT in RT planning is still most important, but the
The ability of PET to distinguish malignant from atelectatic or
addition of MR and PET have the potential to increase the accuracy,
normal tissue may be used to decrease treatment volumes and
precision of tumor-volume definition (TVD), and the possibility to
reduce adverse effects. Furthermore, the radiobiology of cell death
show the diversity in tumor types. Even though first studies show
in SBRT with high doses per fraction may differ from conventional
promising results, a lack of randomized clinical trials and large
fractionated RT, possibly affecting PET uptake in irradiated tissue.
numbers of patients included in these trials still keeps these modal-
Referring to the literature on conventional fractionated radiation
ities from establishing a place in conventional clinical practice.
therapy, a few salient issues regarding the utility of PET for treat-
Another problem is the absence of measurements of effects on clin-
ment planning for SBRT applications emerge. These include the
ical outcome. Nonetheless, there is a strong rationale for the suc-
differences in tumor edge determination with PET and CT-based
cessful use of these techniques in radiation oncology.
treatment plans and the effect of respiration on image quality and
The new PET markers that are developed provide the possibil-
fusion for PET-CT. These issues will be briefly discussed here.
ity to further individualize RT by visualizing the biologic diversity
One potential source of error in using the two imaging modali-
of tumor cells in the tumor. With this information, an approach
ties lies within the technique and fusion of the two types of images.
with increased dose administration to relatively therapy resistant
Unlike the rapidly acquired CT image, PET images may take sev-
tumor parts comes into sight. The same need for extensive pro-
eral minutes during which the patient is breathing. This may result
spective studies counts for these PET markers before they could be
in image blurring, degraded contrast, and an overestimation of
implemented in conventional clinical practice.
volume, thereby potentially interfering with the accurate detection
of tumor edges required for SBRT.27,28 In light of the precise tumor
definition required for SBRT applications, single-gantry PET-CT
imaging using gating or breath-holding techniques may be critical Current Radiation Therapy Systems
for increasing the accuracy of tumor edges for SBRT application.29
Studies have also assessed the accuracy and correlation of PET- The basic principle of external beam RT is to deliver one or several
based gross tumor volume (GTV; GTV-PET) with CT-based GTV (GTV- beams of high-energy x-rays or electrons to a patient’s tumor.
CT) planning in conventional fractionated radiation therapy. Work at Beams are generated outside the patient by means of a linear accel-
Emory in head and neck patients receiving IMRT revealed GTV-PET erator and then targeted at the tumor site. Though the working
was smaller than GTV-CT in most cases (75%), but the GTV-PET was principle of the linear accelerator has not changed since the begin-
not necessarily encompassed by the GTV-CT. This resulted in insuf- ning, the evolution of RT in the last 10 years has seen the advent of
ficient dose delivery in portions of the GTV-PET in 25% of cases.30 several systems with different geometrical principles (e.g., isocentric,
Another area of concern with PET-CT and SBRT is the appropri- nonisocentric, etc.) that have greatly extended the potentialities of
ate management when SUV is low or intermediate. In this situation, this technique.
the clinician is faced with the decision to either treat or pursue Today, there is a wide variety of image-guidance systems available
diagnostics. Given the high doses and conformal nature of SBRT, we that can give different information about the patient anatomy and
believe that histologic evaluation of areas with intermediate SUV positioning according to the different treatment devices considered.
should be executed whenever possible prior to treatment. Specifically, point-based imaging systems, such as the ones based on
Certainly, using PET for treatment planning for SBRT requires detecting locations of implanted electromagnetic transponders or
a degree of precision that exceeds the requirement for conven- photon emission seeds, provide location of a single point within the
tional fractionated radiation therapy. Incremental advances to patient. Also, x-ray planar imaging, including floor-mounted or gan-
facilitate improved co-registration of images, minimize respiratory try-mounted kilovoltage (kV) images, operated in radiographic or
artifacts, and determine optimal PET SUV thresholds will certainly fluoroscopic mode or megavoltage (MV) images obtained via elec-
be of tremendous value to those looking forward to PET-CT–based tronic portal imaging devices, generates a 2D intensity array. More
treatment planning for SBRT. recently, in-room volumetric imaging systems, such as MV CT, kV, and
In summary, SBRT is a new radiation treatment paradigm that MV cone-beam CT, have provided superior volumetric images of
enables precise delivery of high-dose radiation in a hypofractionated patient geometry.
schedule. A number of treatment platforms are available and
although studies have not compared outcomes between platforms,
our experience has demonstrated outcomes to be platform indepen-
Linac and Cobalt
dent. SBRT requires accurate tumor detection and delineation, and Medical linear accelerators (linacs) and cobalt RT units are used
in many sites PET appears to be quite useful in accomplishing this in external-beam radiation therapy to treat cancer. Though the

technique used to produce γ-ray photons is different, linacs can be oncology requires the use of dedicated equipment for scanners
considered the evolution of cobalt RT units. The reason is that and their rooms. Therefore a new procedure, called hot setup, has
linacs operate with an isocentric technique just as cobalt units; the been introduced as an addition to the traditional procedure. There
main differences are the higher photon energies achievable with are some important differences between both the procedures: The
linacs and the absence of a radioactive source with all the related cold setup procedure is a series of actions aimed at preparing con-
radiation protection and dosimetric complications. Cobalt units taining systems and the acquisition of a target volume and its coor-
and low-energy linacs are used primarily to treat bone cancer and dinates (x, y, and z), whereas hot setup focuses on patient centering
tumors of the head, neck, and breast. High-energy linacs are used and the acquisition of images to determine the BTV. The hot setup
to treat deep-seated neoplasms and tumors of the pelvis and tho- procedure takes an average 20 to 25 minutes which is more or
rax. Nowadays cobalt RT units are almost entirely being substi- less the same as the duration of a session of RT.
tuted by linacs in modern centers but are still used, especially in As mentioned before, the room where the PET scanner is
developing countries because of the lower costs and the simpler placed is equipped with devices specifically used for setup proce-
utilization and maintenance. dures. There are basic devices without which it would not be pos-
Most of the linear accelerators currently produced are con- sible to execute hot setup procedures; they are dependent on the
structed so that the radiation source can rotate around a horizon- room user; the laser tracking system fixed to floor, walls, or ceil-
tal axis. As the gantry rotates, the collimator axis (supposed ing; and a patient bedtop cover as part of the scanner.
coincident with the central axis of the beam) moves in a vertical To further ensure the comfort of the patient, it is very important
plane. The point of intersection of the collimator axis and the axis to lay down the patient in an easily achievable and natural position
of rotation of the gantry is known as the isocenter. These units are (compatible with the position required by the treatment) and to
suitable for isocentric treatment techniques in which beams are make sure that the masks or thermoplastic sheets are shaped per-
directed from different directions but intersect at the same point, fectly over the surface of the skin.
the isocenter, placed inside the patient. Imaging can be performed PET scanning consists of three steps: Radiopharmaceutical
by either exploiting the treatment beam with appropriate detec- administration, uptake, and image acquisition. The time these steps
tors (MV-imaging) or supplying the RT unit with an x-ray tube and take depends on the radiopharmaceutical used.
a dedicated detector that moves jointly with the gantry (kV-imaging).
The modern linacs usually use both these techniques together to
increase the treatment accuracy. Radiation therapists can use 2D Movement Correction
digital radiographies to verify or correct pretreatment setup by
using anatomy match or marker match functions. Soft tissue- During the PET-CT procedure, breathholding is not feasible,
based image-guided radiotherapy (IGRT) is currently replacing 2D because of the long acquisition time needed to complete a whole-
verification and frame-based intra- and extracranial stereotaxy. body PET study (1 to 3 min/FOV × 6 to 8 FOV). Therefore, the
study must be performed in a free-breathing condition. During the
scan, the patient advances through many full breathing cycles
CyberKnife and, consequently, the reconstructed PET images are somewhat
The CyberKnife stereotactic radiosurgery system was developed blurred, because of the internal motion induced by breathing,
by Accuray Inc. (Sunnyvale, CA, USA) and is a device designed for especially in the case of thorax and upper abdomen organs.
robotic image-guided stereotactic radiosurgery and RT through- Whereas cardiac motion has important local effects on the heart
out the whole body. Typical CyberKnife applications are the treat- itself and on areas proximal to the heart, respiratory motion
ment of intracranial lesions close to critical structures that require affects the imaging for the majority of the body extent, from the
small margins (≤2 mm). thorax to the abdomen (including heart, lungs, liver, pancreas,
and kidneys). It has been reported that organ displacements 5, 5,
and 30 mm, or even more, may occur in anterior–posterior, left–
Tomotherapy right, and superior–inferior directions, respectively during normal
The equipment is designed to be a purpose-built IGRT system, to breathing.
deliver IMRT while also being able to verify the setup of the patient Motion produces two distinct challenges for PET/CT. First, it
and, in the future, the dose delivered during treatment. The helical blurs PET emission data. In addition, the fast acquisition of modern
tomotherapy machine can be described as a combination of a multi-slice CT produces images that represent a specific moment
helical CT scanner and a linear accelerator. The radiation unit is within the respiratory cycle, whereas the much slower acquisition
a linac that combines fan beam delivery in a continuously rotating time of PET produces an image that represents the average of many
gantry, with binary multileaf collimators that allow IMRT. respiratory cycles. This mismatch in phases can produce artifacts
as shown in Figures 29.1–29.3, for CT on mobile phantom, PET on
mobile phantom, and PET on patients, respectively.
Brachytherapy These movements lead to the spread of activity distribution—
The American Brachytherapy Society (ABS) endorses the use of in particular, for the focal lesions—resulting in inaccurate radio-
brachytherapy as an integral component of the definitive treatment of activity concentration quantification (i.e., SUV), and in an
locally advanced cervical cancer (LACC). Several studies have shown erroneous estimation of the lesion shape and volume. Therefore,
decreased recurrence rates and increased survival when brachyther- it is self-evident that limitations in PET image quality and quanti-
apy is a component of treatment.31,32 Patients selected for brachyther- tative accuracy caused by motion explain the growing interest in
apy may have any stage of cervical cancer. In particular, brachytherapy studying the effects of breathing and in developing methods to
is indicated after external beam for all cases of locally advanced dis- control and compensate for patient motion. The existing proposed
ease (stages IB2eIVA); brachytherapy alone may be used as a primary methodologies for respiratory motion compensation involve the
treatment for those with early stage disease (stage IAeIB1). use of respiratory synchronized or respiratory gated acquisitions.
A large number of studies have been devoted to the development
of respiratory gating protocols for PET and CT imaging.
Patient Setup Researchers have investigated a large number of different respi-
ration monitoring systems, including a transducer and an impedance
Patient setup has always been a very important part of RT and ECG monitor measuring changes in abdominal or thoracic cir-
essential for the success of treatment. The use of PET in radiation cumference, a thermistor measuring the temperature of circulating


Figure 29.1. CT scans (64-slice) of a moving sphere over an ellipsoid path (motion of 5/10/30 mm in anterior–posterior, left–right, and cranial–caudal directions,
respectively, over a breathing cycle of 2.5 seconds). The scans were acquired consecutively using standard helical parameters without considering the phantom
motion. The same coordinates are used for the three images, revealing motion artifacts. Data courtesy of Hospital Sao Rafael, Salvador de Bahia, Brazil.
air during patient respiration, a spirometer measuring respiratory volume is depicted in a single respiratory phase, corresponding to a
flow, or systems tracking the displacement of infrared reflective specific moment of the breathing cycle, without information on the
markers in the patient chest. With the exception of the spirometer whole respiratory motion of the organ/lesion under examination.
and the thermistor, the majority of these systems provide a respira- Prospective 4D-CT protocols are commonly used, independently
tory signal through the measurement of the displacement of the from the association with PET or 4D-PET, for RTx applications per-
thoracic cage. The majority of them lead to an accurate and repro- formed in gated mode over the same phase (e.g., end-expiration or
ducible respiratory signal. end-inspiration).
Respiratory gated four-dimensional (4D) PET/CT acquisition tech- The retrospective 4D-CT technique requires the acquisition of
niques have been proposed to reduce the unwanted blurring on PET data at each table position (over the same anatomical region) for
images and to improve the spatial matching between PET and CT the duration of at least one complete patient’s breathing cycle. Once
images. Briefly, a 4D-PET/CT acquisition protocol consists of a 4D-CT reconstructed, the 4D-CT images are sorted in a number of phases
and a 4D-PET acquisition synchronized to the patient’s breathing (e.g., 10 to 20), each representative of the anatomical volume in a
cycle. After the acquisition, both 4D-CT and 4D-PET data are sorted, specific moment of the patient’s breathing cycle. Contrary to the
divided, and processed to generate new sets of images (phases), each prospective technique, the retrospective 4D-CT technique, by pro-
of which is representative of a specific moment of the patient’s respi- ducing a set of images representative of the whole breathing cycle,
ratory cycle. Therefore, the aim of 4D-PET/CT techniques is, in fact, allows the detection of the complete organ/lesion motion during
to produce “motion free” and well-matched PET and CT images cor- respiration. 4D-CT acquired using a retrospective protocol, despite
responding to specific phases of the patient’s respiratory cycle. the higher radiation dose, is preferable as it allows detection of the
There are two techniques to acquire motion-free CT images: Pro- complete organ/lesion motion and the attenuation correction of
spective and retrospective 4D-CT methods. In the prospective 4D-CT PET images with CT phase-matched images. Once generated, the
technique, data are selectively acquired during a time window 4D-CT phases can be used for TVD. The contour of the target in
within the breathing cycle, corresponding to a specific respiratory each of the 4D-CT phases represents the GTV in different moments
phase. When using the prospective 4D-CT technique, the anatomical of the patient’s breathing cycle. The combination of the GTVs gives
Figure 29.2. PET/CT images of a sphere phantom. Left: The sphere was not moved in both CT and PET acquisitions. Center and right: The phantom was
moved over cranial–caudal direction (15 mm) over a period of 6 seconds, inducing mismatch between PET and free-breathing CTs.

mediastinum). Finally, both MIP and AVE images may be used only
for lung studies.
4D-PET Data Acquisition

Counts collected during a 4D-PET scan are subdivided among the
image phases representative of a respiratory cycle. The number of
phases has to be sufficiently high to produce motion-free or almost
motion-free images. A main limitation in 4D-PET is thus repre-
sented by the statistical noise in the individual phases. As a result,
the total acquisition time of the 4D-PET scan has to be longer than
that of the conventional (non-4D) scans to collect enough counts to
balance statistical noise and motion compensation in each image
phase. 4D-PET studies should be performed in three-dimensional
(3D) list mode, to take full advantage of the higher sensitivity of the
3D acquisition mode as well as of the retrospective data postpro-
cessing protocols flexibility. The suggested number of phases is six,
as this represents a good compromise between statistical noise and
motion compensation.
The acquisition time for an RG 4D-PET (per single FOV) can be
Figure 29.3. Whole-body PET images demonstrating artifacts at the level of the diaphragm
as a result of respiratory motion using CT transmission maps used for attenuation correction. estimated as the product of the time per bed position, in a conven-
Left: CT acquired at end inspiration breath-hold. Right: CT acquired at end expiration breath- tional PET scan, and the established number of phases. In a 4D
hold. Data courtesy of Visvikis D, Lamare F, Bruyant P, et al. Respiratory motion in positron PET/CT study, the number of 4D-CT and 4D-PET phases has to
emission tomography for oncology applications: Problems and solutions. Nucl Instrum Meth A. be the same. Noise control in 4D-PET is also important to allow
2006;569:453–457.
quantitative or semiquantitative (SUV) assessment of radioactivity
concentration.
the internal target volume (ITV) representing the volume of space

encompassing the motion of the tumor because of the patient’s res-
Clinical Examples
piration. Figure 29.4 shows difference in volumes for target defini-
tion, considering the standard approach based on free-breathing
Head and Neck Cancer
CT or the 4D-CT acquisition technique. Head and neck cancer (HNC) is a general description that is used for
Further data processing of 4D-CT images, to be used for TVD of a number of different types of malignant tumors that occur in the
lung cancer, consist of the generation of maximum intensity projec- mouth, throat, sinuses, nasal spaces, the larynx, salivary glands, and
tions (MIP) or an averaged (AVE) set of CT images. Briefly, in an MIP the cervical lymph nodes. Tumors of the brain or thyroid are usually
image each voxel reflects the greatest density values throughout all not considered to be a part of this general category of tumors. HNCs
the 4D-CT phases, whereas in an AVE image each voxel is obtained may spread to lymph nodes in the neck, and to other parts of the
as the arithmetic mean among the 4D-CT phases. Because of this body.
effect, the contouring of AVE images may underestimate the volume The cure of HNC, especially in advanced disease, still remains
of space encompassing the tumor motion. Furthermore, MIP and poor.33 Because of this poor outcome, there have been efforts to
AVE images have to be carefully evaluated in all the regions where improve outcome through the use of targeted agents, new radiation
the background and the tumor present similar Hounsfield numbers techniques as well as new types of diagnostic imaging.34–36 Because
(e.g., tumors located closed to the diaphragm, nodal volumes in the of the highly conformal dose distribution and steep dose gradients
70
+14%
VOL3D
60 VOL4D
+5%
50
+35%
Volume (cc)
40
+17%
+27%
30
+17%
+42%
+28%
+20%
+113%
20
+56%
+66%
+27%
Figure 29.4. Bar graph showing mean three-dimen-

+63%
–13%
+34%
+14%
10
+135%
+32%
+9%
–8%
sional volume and mean four-dimensional volume of lung

lesions acquired with standard spiral CT (for 3D case) and
4D-CT techniques. The percentage difference between them
0 is specified on top of the bars for each lesion. Data courtesy
of Aristophanous M, Berbeco RI, Killoran JH, et al. Clinical
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
utility of 4D FDG-PET/CT scans in radiation treatment plan-
Lesion ning. Int J Radiat Oncol Biol Phys. 2012;82:e99–e105.

used in IMRT, knowledge about the localization and boundaries of et al.43 reported 18FDG PET improved both T and N and M in head
the primary tumor and of the cervical lymph node metastases is of and neck tumors and altered the management of 13.7% of patients
increasing importance. taking part in their study. Another study by Kyzas, et al.,44 assessed
the role of 18FDGPET in general staging, but also in patients with
distant metastases and no cervical lymph node involvement. 18FDG
Delineation of Radiation Therapy Target Volume PET showed high specificity and sensitivity in detecting the primary
in Head and Neck Squamous Cell Carcinoma tumor, but failed to visualize the distant metastases in 50% of the
patients.38
In head and neck squamous cell carcinoma (HNSCC), constituting
A multi-center study on 233 HNC patients prospectively com-
90% of all head and neck tumors, delineation is usually executed
pared therapeutic decisions based on conventional work-up (CT and
with planning CT. Additional value of MR has yet not been shown
MR) with those additionally performing a whole-body 18FDG PET
in clinical studies.37 CT and MR both seem to be suboptimal in
scan. Functional imaging resulted in up- or downstaging of the
delineating tumor volume. That is why there is a growing interest
lymph node status in 10% of patients (upstage in 16 patients and
in the role of PET in delineating the tumor. Potential advantages
downstage in 7 patients). However, the detection on metastatic or
are the reduction of inter-observer variability and GTV size, while
additional disease had a greater impact on patient management.43
providing additional information about involved lymph nodes and
The value of 18FDG PET for the identification of lymph node
tumor-resistant areas in the tumor. The low spatial resolution and
metastases in nasopharyngeal is controversial. Chang et al.42
the lack of a gold standard in signal segmentation are disadvan-
performed a retrospective analysis on 95 nasopharyngeal cancer
tages of this modality.38 Multiple studies have assessed these

patients and found little discrepancy between MR and FDG PET for
hypotheses. Gardner et al.39 hypothesized that 18F-FDG PET-CT
neck node staging. In patients with advanced nodal disease, FDG
could detect those lymph nodes thereby ameliorating tumor-
PET may reveal distant metastases missed by all other conventional
volume definition for RT. They compared organs at risk and GTV
imaging modalities.
and evaluated later on if 18F-FDG PET-CT had really changed the
In summary, there is not a solid evidence to support the routine
planning volumes. They concluded that each modality added com-
clinical application of FDG PET in the pretreatment evaluation of
plementary information and improves treatment volume accuracy,
the lymph node status in patients with head and neck tumor, includ-
but adding MR or 18F-FDG PET-CT to conventional CT is not ben-
ing patients with clinically negative neck. Other imaging methods
eficial if the tumor did not extend intracranially or if the patient
appear to have similarly limited or even worse diagnostic perfor-
had no contraindication for CT. The problem in many studies is
mance in these patients. There is insufficient evidence to support
that at the time of the study outcome measures are not yet avail-
the routine clinical application of FDG PET in the pretreatment
able, so that changes in tumor volumes observed between different
identification of lymph node metastases. Thus, ultrasound-guided
modalities could not be interpreted. Daisne et al.40 analyzed the
fine needle aspiration cytology still remains the gold standard.
surgical specimen of the tumor (pharyngolaryngeal squamous cell
carcinoma [PLSCC]) visualized with CT, MR, and 18F-FDG PET-CT.
Part of the patient population underwent total laryngectomy so Dose Escalation and Adaptive Radiotherapy
that their surgical specimens could be examined as a control mea-
sure for the imaging modalities. The goal of the study was to comin Head and Neck Squamous Cell Carcinoma
pare the delineation of GTV in treatment planning of PLSCC Arens et al.45 and Moule et al.46 investigated if the adaptive threshold
between the three modalities. The GTVs acquired using 18F-FDG method they used was beneficial for tumor delineation with a pos-
PET-CT were smaller than those acquired using the other two sibility for dose escalation and adaptive RT using FDG PET. Pretreat-
modalities, although the GTVs of all three modalities did not over- ment tumor delineation seemed to be justified allowing higher doses
lap completely. All three modalities overestimated the GTV com- to tumor volume without higher healthy tissue dose. However, the
pared to the surgical specimen. An interesting finding was that software used was not able to distinguish tumor tissue from adja-
none of the modalities managed to visualize superficial tumor cent healthy tissue during treatment so that adaptive RT was not
extensions. Overall, 18F-FDG PET-CT was the modality that approx- possible. Geets et al.47 concluded in their study that FDG PET had a
imated the GTV of the surgical specimen the closest. significant impact on dose distribution in pharyngolaryngeal tumors
There are several ways in which 18F-FDG PET-CT can alter RT and could, therefore, prove useful in dose escalation strategies. In
planning: The target is only visible on PET, not on CT only; the another study, Geets et al.37 assessed the impact of FDG PET on dose
tumor volume found by PET-CT is bigger than that found by CT distribution and the impact of MR–CT during treatment on target-
only; specific hypermetabolic regions found by PET are apparent in volume delineation and dose distribution. PTVs, GTVs, and CTVs
the CT delineated tumor volume. All of these differences impact the were all smaller when executing FDG PET pretreatment and MR–CT
RT planning and could thus alter clinical outcome. Scarfone et al.41 during treatment leading to new avenues for dose escalation without
investigated the influence and accuracy of 18F-FDG PET-CT com- exposing healthy tissue to higher doses.
pared to conventional planning CT in head and neck tumors. Their Duprez et al.48 were the first to escalate doses based on adap-
results showed that PET could be helpful in identifying metaboli- tive methods of FDG PET imaging during radiotherapy. Their
cally hyperactive sites for dose intensification. There was a differ- results showed that they could expose the shrinking target volume
ence in tumor volumes between both procedures, but it was not to higher doses without inducing adjacent tissue toxicity or increased
clear to what extent these alterations could be attributed to imper- side effects. The results of this study should be validated in larger
fections in the process of co-registration in 18F-FDG PET-CT. Even prospective trials before it can be used in conventional clinical
though these outcomes are promising, histologic validation and practice.
clinical studies are necessary before 18FDG PET-CT can find a place
in conventional RT planning in HNSCC.38
Hypoxia in Head and Neck Squamous
Cell Carcinoma
Primary Tumor and Metastases in Cervical Nodes
One of the reasons for treatment failure in RT is the presence of low
in Head and Neck Squamous Cell Carcinoma oxygen levels in the tumor tissue. First postulated by Thomlinson
Chang et al.42 evaluated the value of 18FDG PET in staging nasopha- and Gray,49 the concept of hypoxia correlation with a worse outcome
ryngeal carcinoma (NPC). They concluded that 18FDG PET stages N in solid tumors is nowadays a well-known fact, taken in serious con-
and M status more accurately than the usual CT and MR. Lonneux sideration when planning the most appropriate therapeutic regimen

in oncology. The underlying condition explaining tumor-resistance vitro and in vivo tumor models.60 64Cu-ATSM presented a threefold
in the presence of hypoxia is in part explained by the fact that higher retention in cells with hypoxia as compared to normally oxy-
hypoxic tumors have a more aggressive phenotype, selected geneti- genated cells. Some definite advantages of the copper compounds
cally throughout unstable cells within the hypoxic environment. over the commonly used 18F-FMISO for imaging oxygenation status
Secondarily, the presence of hypoxia activates specific molecular are (1) higher uptake (Cu-ATSM demonstrated up to 90% better
pathways, responsible for new gene-expression and more indepen- uptake in certain cell lines than FMISO); (2) better hypoxia-selectivity
dent cell survival mechanisms. The aggressiveness is then expressed of Cu-ATSM, as FMISO indicates hypoxia at lower pO2 values than
either by increased incidence of distant metastases or with reduced Cu-ATSM, meaning that good FMISO retention occurs only in areas
response to current treatments, including radiation therapy.50,51 with pO2 < 2 to 3 mm Hg, whereas Cu-ATSM is taken up also by
Moreover, hypoxic tissues are known to require up to three times the cells with pO2 > 3 mm Hg; (3) more rapid washout from normally
radiation dose usually applied in normo-oxygenated cells.52 oxygenated tissues. A small study enrolling 12 advanced HNC
There is growing interest in diagnosing hypoxic HNSCC before patients investigated the prognostic effect of 60Cu-ATSM and its role
therapy in the hope of applying novel treatment strategies that may in treatment guidance.61,62 They showed that patients with tumor to
overcome resistance to conventional chemoradiation.53 Several muscle ratio (T/M) larger than 4 after 60Cu-ATSM uptake had poorer
tracers are developed to identify hypoxic tumor cells, so that they prognosis compared to those with smaller T/M. There is a need for
can be targeted for dose escalation. Some examples of these hypoxia larger trials to confirm the advantage of copper ligands in func-
markers are 18F-FMISO and 18F-FAZA. It is not yet clear to what tional imaging over the already established radiotracers.63
extent these markers will differ in their clinical performance. Even
more, the clinical value of characterizing the biologic features of
tumor cells is still to be assessed. The potential utility of these and
Prostate Cancer
other tracers for targeting areas for dose painting could be evalu- External beam radiation therapy (EBRT) can be offered to patients
ated in clinical studies and a growing interest is emerging on exe- with localized disease as radical treatment, alternative to radical
cuting these kind of studies.54 Lee et al.55 examined the utility of prostatectomy, or after surgery as adjuvant or salvage therapy.64–74
18
F-FMISO PET–CT-guided IMRT. Their goal was to escalate doses The clinical implementation of three-dimensional conformal
to a maximum in hypoxic areas, visualized by the hypoxia marker. radiotherapy (3DCRT), IMRT, and IGRT techniques has allowed
They showed that they were able to escalate doses to hypoxic areas clinicians to perform a dose escalation with better positioning
without exceeding the normal tissue tolerance. Doses above normal control and reduced toxicity.75,76
tissue tolerance were successful in half of the patients. Thorwarth In prostate cancer patients, the volumes of treatment are related
et al.56 investigated the effect of dose painting by numbers based on to the intent. In the radical setting, prostate gland, and seminal
hypoxia information acquired by 18F-FMISO PET. They concluded vesicles when indicated, is defined as CTV. In the postoperative
that this method of dose escalation was more effective than boost- setting, the prostatic bed represents the CTV, encompassing ana-
ing the tumor area an additional time. FMISO PET showed an abil- tomic regions at high risk of local relapse, according to the per-
ity to adequately quantify hypoxia in the tumor area so that dose formed prostatectomy.77,78 Recent trials suggested the role of
painting by numbers is achievable leading to increased tumor con- precautional pelvic lymphatic irradiation in prostate cancer patient
trol. FMISO is not the only hypoxia marker used. Grosu et al.57 candidate to EBRT.79 However, the irradiation of draining pelvic
evaluated the effect of the use of another hypoxia marker, 18F-fluo- lymph nodes remains an object of debate and it is prescribed only
roazomycinarabinoside (FAZA), in FAZA PET-CT in RT planning of when the risk of extraprostatic disease is significantly high.
patients with HNC. It was hypothesized by Grosu et al. that adding The installation of CT scan as simulator in daily practice of
FAZA PET to conventional planning CT could add information radiation oncology departments has modified the way to identify
about tumor diversity to RT planning. That information could be target volumes, from 2D to 3D customized targets. CT accuracy of
used in dose escalation in hypoxic areas of the tumor. The results pelvic lymph node metastases, based on lymph node enlargement,
showed that FAZA PET can indeed add the before-mentioned infor- is, however, low; nodal size and metastatic involvement are poorly
mation to conventional CT imaging, both in primary tumor and in correlated.80,81 Thus, CT simulation images are not useful for com-
lymph node metastases, thereby visualizing tumor diversity and plete staging of pelvic extension of disease.
making way for accurate dose escalation. On the basis of these Molecular imaging has become fundamental for tumor stag-
promising studies, further prospective studies are needed for better ing, for biologic definition, and for delineation of target volumes
understanding the effect of hypoxia on dose escalation. Potential in radiation oncology. PET and hybrid PET-CT modalities thus
tumor hypoxia imaging agents include 18F-FMISO and 60Cu(II)- are also of increasing interest for radiation oncologists in pros-
diacetyl-bis(N4-methylthiosemicarbazone). 18F-FMISO is reduced tate cancer. In prostate cancer, however, 18F-FDG PET has shown
and bound to cell constituents under hypoxic conditions with the to be of limited value (Fig. 29.5), because of the reduced rate of
level of hypoxia depicted by 18F-FMISO before treatment, correlating glycolysis present in prostate cancer cells and the relatively slow
with locoregional failure and the absence of hypoxia associated with growing characteristics.82 Another reason is related to the
a low risk of locoregional failure. Treating patients with hypoxic pri- increased renal excretion and 18F-FDG accumulation in the blad-
mary tumors with additional cytotoxin resulted in significantly fewer der, which determines a reduced visibility of the pelvic structures,
local failures than treating patients with chemotherapy alone, thus especially lymph nodes.83,84 Moreover, the tracer is not exclu-
showing that hypoxia identification by using biologic imaging can be sively tumor specific, but also has an increased uptake in benign
crucial for prognostication.58 conditions, such as prostatic hyperplasia or postirradiation
In addition to fluorine-based compounds, the last decade of inflammation.85–87
functional imaging has encountered copper-based agents, because The issues mentioned above have driven the efforts to identify
of their well-suited biophysical properties for PET in terms of half- new tracers capable to properly investigate prostate cancer. The
life, emission characteristics, and cell membrane permeability. most widely utilized radiopharmaceutical, applied in clinical setting,
Although the first Cu isotope examined for tumor hypoxia was is radiolabeled choline (11C-CHO, 18F-fluorocholine).88–91
62
Cu,59 currently the two most commonly investigated copper-based Another tracer more recently employed in prostate cancer imag-
radiotracers are 60Cu-ATSM (t1/2 = 23.7 minutes) and 64Cu-ATSM ing is 11C-acetate.92 This tracer is known to be involved in cell metab-
(t1/2 = 12.7 hours) (diacetyl-2,3 bis(N(4)-methyl-3-thiosemicarba- olism and lipid synthesis, and since several studies have demonstrated
zonato) ligand). With high cell membrane permeability and low increased fatty acid synthesis in prostate cancer,93,94 acetate-PET is
redox potential which confers stability in normal tissue, Cu-ligands establishing a role in the detection of this tumor. Compared to choline
have proven to exhibit high selectivity for hypoxic cells in both in derivatives, radiolabeled acetate has shown similar diagnostic


11C-Cho
18F-FDG
Figure 29.5. In this multipanel image are represented the staging FDG PET (left) and Choline PET (right) of the same high-risk prostate cancer patient (PSA,
150 ng/mL). Note the different tracer uptake between the two examinations at the level of primary tumor and lymph node metastases.
performance, with a potential use in the evaluation of early meta- cancer, is an insufficient tool to distinguish between isolated local
bolic changes after anti-androgen therapy.95 In RT planning, recurrence and occult distant metastases. In the detection of positive
11
C-Acetate has recently been utilized for the definition of malignant lymph node metastases of prostate cancer by choline PET, a sensitiv-
intraprostatic lesions (IPLs) in prostate cancer for simultaneous inte- ity of 80%, a specificity of 96%, and an accuracy of 93% have been
grated boost IMRT (SIBIMRT) capable to give increased doses in high reported, whereas morphologic imaging such as CT and MR cor-
metabolic areas, without increasing treatment toxicity.96 rectly detected lymph node metastases in only 7/15 patients (47%
sensitivity with a specificity of 98%).86 High PSA levels and advanced
11
C-CHO and 18F-CHO for Radiotherapy pathologic stage are significantly associated with an increased rate
of positive 11C-CHO PET-CT findings, and PET could have the poten-
with Salvage Intent in Prostate Cancer tial to detect an isolated nodal recurrence.99,100,103
Recurrent disease in clinically organ-confined prostate cancer sub- Accurate staging is critical in postoperative setting as it greatly
mitted to radical prostatectomy occurs in 30% to 50% of patients.97,98 influences further therapeutic considerations. Schilling et al. per-
In the presence of detectable PSA after surgery or evidence of local formed a histologic verification of 11C-CHO PET-CT nodes in a small
recurrence, RTx is to be considered a salvage approach. The use of population study of 10 patients with biochemical failure after treat-
choline PET scan seems to be promising as restaging procedure for ment for localized prostate cancer.104 The positive predictive value
patients who underwent surgery with a rising PSA and appears was 70% and this limited value should lead to a critical interpreta-
superior to FDG PET and complementary to conventional imag- tion of the results.
ing.99 One of the principal limits of this technique is a low sensitivity Pelvic nodal recurrence occurring after primary therapy is a neg-
when PSA is lower than 1 ng/mL, that is, when the cancer burden ative prognostic factor in prostate cancer patients and it could change
is lowest but most amenable to local therapies, reducing the useful- the treatment planning from salvage to palliative, enabling appropri-
ness of this technique dramatically in studying these kind of ate selection of patients for salvage local therapy in prostatic bed.
patients.100,101 In the light of the suboptimal sensitivity and specific- Soyka et al. evaluated the clinical impact of 18F-CHO PET-CT in
ity provided by current imaging modalities, the perfect timing for patients with recurrent prostate cancer.105 In 75 of 156 patients
salvage radiation treatment after biochemical relapse still remains (48%) analyzed and submitted to the diagnostic procedure, the treat-
a matter of debate. Nevertheless, salvage RT, with postsurgical PSA ment plan of RT was changed because of the PET-CT findings. PET-
values >1 ng/mL is recognized to result in poor outcome and this CT with 18F-CHO has shown to have an important impact on the
constitutes a problem, because of the low sensitivity of choline therapeutic strategy in patients with recurrent prostate cancer,
PET.101 Nevertheless, in controversial cases, it is necessary to per- increasing the possibility of determining an appropriate treatment.
form a biopsy of the prostatic bed or a biopsy of the prostate to In a mixed population of 38 patients, composed of primary recur-
confirm definitively the presence of a local recurrence under MR or rence and metastatic prostate cancer sites, Jereczek-Fossa et al.106
TRUS guidance.102 reported on CyberKnife-based stereotactic RT for 19 isolated lymph
The correct site of recurrence is crucial for the choice of treat- node metastases, showing an excellent in-field tumor control and a
ment influencing on individual therapy. Choline PET can be useful low toxicity profile. The median follow-up period was 16.9 months and
both in detecting metastatic disease and in localizing isolated lymph 13 out of 16 patients treated for lymph node metastases (81%) were
node relapse. A significant PSA rise, after local therapy for prostate free of late toxicities; no in-field progression or distant recurrence was

documented. In this subset of prostate cancer patients, the optimal Tab l e 2 9 . 1

combination with androgen deprivation remains a crucial point, with-
out a clear consensus between researchers. FDG PET in the Evaluation of Indeterminate
Lung Lesions
11 18
C-CHO and F-CHO for Radical Treatment
Author and Year Sensitivity (%) Specificity (%)
Recently, several studies on the use of choline PET as a guiding
modality for radical radiation treatment in prostate cancer patients Ung (2007) 79 90
became available.104,107 In comparison with the conventional whole- Fischer (2001) 96 78
prostate dose escalation, an integrated boost to the macroscopic Hellwig (2001) 96 80
malignant lesion has been proposed.108 Using IMRT modalities, Gould (2001) 91 78
treatment planning with 18F-CHO PET-CT has allowed clinicians to Wahidi (2007) 87 83
perform dose escalation to a macroscopic intraprostatic lesion with-
out significantly increasing toxicity.108 Focusing the dose escalation Modified from: Hellwig D, Baum RP, Kirsch C. FDG-PET, PET/CT and conventional nuclear
medicine procedures in the evaluation of lung cancer: A systematic review. Nuklearmedizin.
on the actual tumor is a way to increase tumor control without 2009;48(2):59–69.
increasing toxicity. Further clinical results are needed to support the
effectiveness of the concept.109 Nevertheless, Choline PET-CT is still
not suggested for use in primary prostate cancer because of an nodes appears to be fundamental in FDG PET-CT scanning. Finally,
important limitation of relatively poor values of sensitivity and spec- as PET-CT is a total-body imaging technique, it allows for the detec-
ificity for localizing tumor disease in the prostate gland (71.6% and tion of distant metastases with a mean sensitivity of 93% and a
42.6%, respectively).110 Cost-effectiveness analyses are also needed mean specificity of 96% as reported by the National Institute for
to evaluate PET choline-tailored treatments.111 Clinical Excellence (NICE),130 data confirmed also by Ung et al.120
Local recurrence is detected with a reported sensitivity of 99% and
specificity of 89%.113,122,128
Lung Cancer PET-CT improves the RT performance and, therefore, its clini-
The introduction of PET and PET-CT in the routine protocols for cal outcome concerning the selection of patients and allowing a
the diagnosis and staging of lung cancer has been proved having more suited treatment for patients eligible for RT. If available,
a high impact on the management of patients.112–114 There are PET-CT should always be used to contribute to definitive RT plan-
many studies assessing the sensitivity of PET in lung cancer, par- ning of NSCLC.
ticularly in non–small-cell lung cancer (NSCLC).115
Surgery is still the treatment of choice for eligible patients, but
RT is a key element in the treatment strategy. Its role in the patient’s
Small-Cell Lung Cancer
work-up is well established in NSCLC and is of improving impor- Small-cell lung cancer (SCLC) is responsive to the treatment with
tance in SCLC. A more tailored therapy planning relies on advanced both chemotherapy and RT. These treatment modalities can more
diagnostic procedures and 18F-FDG PET-CT is widely recognized as effectively prolong survival than local treatment like surgery
high performing imaging for lung cancer.116 With regard to RT because the disease is more likely to spread with metastasis than
planning, we can summarize PET-CT applications as follows. to develop a local invasion pattern. If the tumor is confined to the
hemithorax of origin, the mediastinum, or the supraclavicular
• Evaluation of indeterminate lung lesions
lymph nodes, patients are designated as having limited-stage dis-
• Staging either for nodal involvement or for distant metastasis
ease (LD). Patients with tumors that have spread beyond the supra-
• Detection of recurrent/relapsed disease
clavicular areas are said to have extensive-stage disease (ED) and a
We here intend to catch a glimpse of PET-CT applications in lung worse prognosis. Patients with distant metastases are always con-
cancer and give a close look at the state of the art usage of PET-CT sidered to have ED.131,132
in RT planning for lung cancer, pointing out its clinical role. Data Schumacher et al.24,133 confirmed that PET-CT clinical role over-
for both NSCLC and SCLC have been evaluated separately into two whelms its mere diagnostic importance as the differentiation
sections. between LD and ED is fundamental not only for staging purposes
but also for choosing therapy strategies. Sensitivity and specificity
reported for the distinction of LD and ED range between 89% to
Non–Small-Cell Lung Cancer 100% and 78% to 100%, respectively (Table 29.3).133,134 FDG PET-
Clinical and pathologic features contribute to staging the tumor CT appears to be more accurate than conventional imaging with
which plays a critical role in the management of the patients with CT in depicting the extrathoracic nodal metastasis and initial bone
NSCLC. Surgery is the best option when applicable, although RT and
chemotherapy might be proposed for patient with no surgery eligi-
bility or with the aim of palliation in advanced-stage diseases.117–119 Tab l e 2 9 . 2
18
F-FDG PET and PET-CT specificity and sensitivity have been
investigated in several studies, particularly in the evaluation of FDG PET in Mediastinal Lymph Node Staging
indeterminate lung lesions where a high sensitivity is reported, of Non–Small-Cell Lung Cancer
ranging from 79%120 to 96%.121 Specificity has been reported rang-
ing from 40% to 80%, the specificity being lower than the sensitivity Author and Year Sensitivity (%) Specificity (%)
because of the possible false-positive results caused by inflamma-
tory changes (Table 29.1).122–124 Gould (2003) 85 90
Nodal involvement and distant metastasis are crucial to deter- Toloza (2003) 84 89
mine whether a patient needs to undergo RT or not, identifying Birim (2003) 83 92
those who can benefit from radical RT and excluding incurable Hellwig (2006) 83 89
Silvestri (2007) 74 85
patients that will need different palliative cures. Sensitivity (74% to
85%) and specificity (85% to 92%) for detecting nodal involvement Modified from: Hellwig D, Baum RP, Kirsch C. FDG-PET, PET/CT and conventional nuclear med-
were analyzed in various studies (Table 29.2).125–129 Moreover, the icine procedures in the evaluation of lung cancer: A systematic review. Nuklearmedizin. 2009;
high negative predictive value (90%) in the detection of mediastinal 48(2):59–69.

Table 29. 3 in contrast to the observations by Akhurst et al.143 who found that
preoperative chemotherapy reduces the activity of the glycolytic
Diagnostic Performance of FDG PET in enzyme hexokinase which resulted in a reduction in sensitivity of
Small-Cell Lung Cancer standard FDG PET for colorectal metastasis. In any case, FDG PET
holds promise when considering irradiating liver metastasis up to
Author and Year Sensitivity (%) Specificity (%) a high dose, but warrants further research.
Ung (2007) 89–100 78–95 Esophageal Tumors

Brink (2004) 100 Not reported
Fischer (2006) 93 83–100 In the treatment of esophageal cancer, RT is commonly used in
combination with chemotherapy as neoadjuvant treatment prior to
surgery or as definitive approach in patients not fitted for extensive
marrow involvement.133,134 Trials with chemotherapy and RT have surgery. Currently, modern RT includes TVD based on planning CT
shown increased survival in patients with LD. PET-CT can be used scan. The value of FDG PET to determine the regional extent of the
in SCLC patients mainly to upstage from LD to ED or vice versa and disease has been investigated in a few studies. Shimizu et al.144
possibly to extend the tumor target volume for RT to additionally investigated FDG PET-CT and EUS in 20 patients who received
detected nodes,135 but there is still a limited experience when radical surgery for SCC of the esophagus. They found that the
compared to NSCLC. detection rate of subclinical lymph node metastasis did not improve

with the addition of PET.
RT Planning in Lung Carcinoma

Pancreatic Carcinomas
Integrating PET-CT in RT planning needs rigorous procedures and 18
a chain of quality controls to ensure the correct patient position- F-FDG PET/CT shows a sensitivity of 94% and a specificity of
ing, thereby avoiding discrepancies between the “imaging posi- 90% for primary cancer, superior to that of CT (84% and 75%,
tion” and the “treatment position.” This is made possible; thanks respectively),145,146 but has a suboptimal performance for locore-
to the positioning tools like immobilization devices fixed on a firm gional lymph nodes (49% to 76%).147,148 The sensitivity, however,
flat couch top and laser beams. A dedicated PET-CT is required increases significantly (up to 95%) when looking for distant metas-
when only a diagnostic PET-CT is available.136 tases, such as hepatic or bony lesions.149 Despite these good pre-
The definition of the target volume can be visually or semiau- rogatives, FDG PET has been employed only in a few cases for RT
tomatically assessed. The GTV definition can benefit from SUV- planning.150–153
based contouring and threshold techniques to distinguish the Other tracers have been investigated. 18F-fluorothymidine (FLT) is
lesion from the background.137–139 an example of an amino acid tracer that is now assessed by several
groups. In the first pilot study,154 FLT focal uptake was detected only
in malignant lesions, suggesting that FLT PET might have an addi-
Gastrointestinal Tumors tional value over FDG PET for differentiating cancer from benign
pancreatic lesions. More recently, in a pool of 46 patients with pan-
Liver Tumors creatic tumors staged and evaluated before surgical resection, FDG
In recent years, the potential for SBRT to target small tumor vol- PET showed a higher sensitivity, but lower specificity than FLT
umes in this setting has become a topic of active investigation. PET.155 Moreover, mean SUVmax for FDG PET was significantly
Current experience supports the curative potential for tumors higher than that of FLT PET (3 versus 7.9, respectively; p < 0.001). At
under 5 to 6 cm.140 Few studies have evaluated the relationship of the moment, the role of FLT PET in pancreatic cancer seems to be
PET imaging with SBRT in the liver. A study by Casamassima insufficiently assessed and still limited, when compared to FDG.150
et al.141 included 48 patients (15 primary, 33 metastases) treated for
69 liver lesions with SBRT. PET images were available in 22
Rectal Cancers
patients prior to treatment. Response was evaluated 60 days after
treatment by CT, carcinoembryonic antigen (CEA) levels (for those Preoperative chemoradiation is the standard treatment for locally
with colonic metastases) and PET (n = 9). At median follow-up of advanced rectal cancer.156 The CTV includes the primary tumor,
8.2 months (range: 2 to 24), 28 patients were still alive, 7 died from regional lymph nodes, and pelvic areas at risk for subclinical
progressive disease in liver, 7 from progressive disease outside the disease.157 Accurate dose delivery and the possibility of modulating
liver and 6 died of other causes. In the nine patients with PET the dose prescription with IMRT pave the way for the use of molecu-
imaging, one demonstrated resolution of uptake, in six there was lar imaging as a promising tool for selecting specific areas in a tumor
visually apparent decrease in uptake (SUV unavailable) and for the that may be more radiation resistant. The usefulness of PET with
18
remaining two, SUV was 4.5 and 8. Although tumor response was F-FDG has been investigated for the initial staging of colorectal
difficult to evaluate by CT because the irradiated area appeared cancer.158–160 All of those studies suggested that preoperative PET is
hypodense, the authors argued that both CT and blood tumor useful for the diagnosis of the primary tumor but is of limited value
markers may be more reliable than PET in the evaluation of tumor for detecting metastases to the regional lymph nodes (Fig. 29.6).
response owing to the uptake of reactive tissue. So far one study One study has evaluated the accuracy of TVD based on the PET
retrospectively reviewed the value of FDG PET-CT for RT planning data from an integrated PET-CT system with 2-[(18)F]fluoro-2-
in 19 patients with colorectal liver metastasis treated with HDR deoxy-D-glucose (FDG) for standardized target-volume delineation.
brachytherapy for 38 lesions in 25 sessions.142 Adding the informa- Buijsen et al.161 have investigated 42 patients undergoing FDG PET
tion from FDG PET to the planning CT resulted in a change in the before RT planning. When using an automatic contouring, authors
CTV in 84% of all sessions. An increase was observed in 15 ses- detected an increased inter-observer agreement on tumor delinea-
sions, although in 6 sessions the CTV decreased. The median PET-CT tion, associated with an additional improvement in GVT definition.
CTV was significantly larger than the CT CTV with a median increase In fact, up to 29% of the cases, PET images determined an exten-
of 24.5% (p = 0.022). The authors observed a significantly larger rate sion of CTV outside CT/MR treatment planning. However, these
of early local progression in those patients with incomplete PET-CT findings must be interpreted with great caution. The limited accu-
CTV coverage. They, therefore, concluded that PET is particularly racy of FDG PET in detecting microscopic lymph node invasion
informative for pretreated lesions, when CT is inconclusive. This is makes it unsuitable for the automatic definition of a CTV or PTV.162

A B
C D
Figure 29.6. FDG PET for radiotherapy planning of a patient with colorectal cancer. (A)] Local recurrence in the pelvic structures involving also sacral bone.
(B and C): Loco-regional lymph node metastases, omolateral (C) and contralateral (B) to the relapse. (D): Distant liver metastasis.
Reducing the inter-observer variability by means of functional First, FDG PET helps in proper staging of the disease (up to 23%
image-guided radiation treatment planning still remains a felt and change in tumor stage), and second, it determines a better delinea-
debated concern in the radiation oncology community. This issue tion of the target volumes.166,167 Moreover, Mai et al.165 have investi-
has been addressed by Patel et al.163 who compared the nodal and gated the impact of FDG PET findings on treatment decisions and
primary tumor GTV contour for a hypothetical boost volume on discovered that the reduction of the irradiation dose to PET-negative
conventional CT alone and on FDG PET-CT and FLT PET-CT in six inguinal lymph nodes does not affect disease failure.
rectal cancer patients. They found that the boost volumes based on
combined PET-CT resulted in a lower inter-observer variability
compared with CT alone, particularly for nodal disease. In conclu-
Cervical Cancers
sion, even if PET can provide additional functional information, CT and MR provide an accurate evaluation of the primary tumor
which can be worthwhile in the delineation of the GTV in rectal size, depth of stromal invasion, stage of disease, and detection of
cancer, its usefulness in the treatment of rectal cancer is still ques- lymph nodes or distant metastasis. However, they are not suffi-
tionable and needs to be evaluated in prospective trials. Further- ciently accurate for the adequate evaluation of nodal spread.168
more, an accurate definition of the margins around the CTV is PET-CT with 18F-FDG seems to have an important role in staging
mandatory when delivering high doses onto a highly deformable and restaging of gynecologic malignancies, especially regarding
and mobile organ such as the rectum. lymph node involvement or recurrent tumor because of the simul-
taneous functional and anatomical information.169,170 There is also
a large field of PET-CT application in response monitoring and RT
Anal Cancers planning. 18F-FDG PET-CT can be used for “dose painting,” with the
Despite the fact that there is still limited evidence of the role of FDG intent to deliver higher dose toward the more sensitive tumor
PET in RT planning of anal cancer,150,164–166 data so far available dem- areas.171 Although there are several studies that evaluate the role of
onstrate a relevant impact of the method on delineation volumes. FDG PET in primary tumor staging, neither PET nor CT are useful


Figure 29.7. Evidence of FDG-positive lymph
node in common iliac region.
methods for detecting parametrial disease and both are limited in Concomitant chemo-radiotherapy (CT/RT) represents the stan-
detecting the primary tumor, especially in early stage disease.172 dard treatment in patients with LACC based on the results of five
The presence of lymph node involvement is one of the strongest randomized phase III studies that demonstrated an advantage in
prognostic factors in patients affected by cervical cancer (Fig. 29.7). terms of disease-free survival (DFS) and overall survival (OS) for CT/
When para-aortic lymph node metastases are detected, patients RT compared to exclusive RT.178,179 Details of the EBRT fields used
benefit from pelvic RT combined with chemotherapy protocols.173 in the management of cervical cancer are well described by other
The evaluation of lymph node metastasis with MR and CT is based authors.173,178–190 In the setting of pelvic nodal or parametrial disease,
on lymph node dimensions and usually could detect abnormali- additional dose may be delivered by anterior posterior:posterior
ties greater than 1 cm. anterior (AP:PA) fields using a midline block, 3DCRT or IMRT. The
The accuracy of FDG PET-CT in the evaluation of pelvic lymph cumulative dose delivered by EBRT and brachytherapy must be care-
node status in early stage cervical cancer patients is demonstrated fully integrated during treatment planning to avoid significant over-
to be low and to be unfit for replacing surgical exploration.174 exposure to midline structures, particularly the ureters and rectum.
In patients with advanced disease and negative conventional 3DCRT or IMRT may also be used for a nodal boost in the para-
imaging, PET-CT specificity and accuracy for detecting para-aortic aortic region to minimize the dose to small bowel.191,192 Normal-
lymph node metastasis were particularly high (84% and 75%) and tissue constraints and dose reporting for the small bowel and
there was a treatment modification in 25% of patients based on PET kidneys are described in the Quantitative Analyses of Normal-
results.175 In a recent prospective cohort study that included 560 Tissue Effects in the Clinic review.193,194 Although IMRT is becoming
patients with newly diagnosed cervical cancer, the extent of lymph more widely available, the use of IMRT in the definitive treatment
node involvement on PET seems to stratify patients into distinct of cervical cancer has not yet been validated, given the concerns
outcome groups, suggesting that lymph node staging with FDG PET about target definition, inter- and intrafraction motion, and tumor
influences the prognosis of patients. The frequency and the pattern regression during treatment.195,196
of cervical cancer lymph node metastasis on FDG PET are correlated Narayan et al.197 assessed whether PET or MR could avoid sur-
to the FIGO stage and parallels historical surgical data.176 gical staging in 27 patients with locally advanced cervical carci-
The FDG PET-CT detection of supraclavicular lymph node metas- noma planned for RT. The authors concluded that PET had
tasis is a predictor of a very poor patient’s prognosis and can obviate superior sensitivity to MR but still missed small-volume disease
unnecessary treatments since even if aggressive therapy can be use- and they recommended para-aortic lymph node dissection in all
ful to control pelvic disease all patients tend to develop distant patients with positive pelvic lymph nodes on PET. Conversely, the
metastasis in time. Tran et al.177 reported that the frequency of PET- 98% positive predictive value of PET-CT was high enough to avoid
detected supraclavicular metastasis was around 15% for patients pathologic confirmation and led to extended field RT.
with clinical stage IIIb disease and about 40% for those with abnor- PET-CT with FDG represents a useful tool to better select can-
mal FDG uptake in para-aortic nodes, so FDG PET-CT seemed to be didates for concomitant chemoradiation. Loft et al.198 prospectively
an appropriate method for evaluating the supraclavicular lymph assessed the diagnostic value of PET-CT in 120 patients with cervi-
nodes in patients with invasive cervical carcinoma.177 cal cancer stage P1B. Sensitivity and specificity of PET-CT for pelvic

Figure 29.8. Evidence of residual tumor

with faint FDG uptake after brachytherapy.
node diagnosis were 75% and 96%, respectively. Regarding para- Further studies are necessary to strengthen the evidence of PET-
aortal nodal disease, sensitivity and specificity were 100% and CT impact on patient life quality improvement and overall survival.
94%, respectively. This confirms that the use of whole-body FDG
PET-CT scanning for newly diagnosed cervical cancer with FIGO Brain Tumors
stage P1B2 has a high sensitivity and specificity and allows a more
adapted therapeutic strategy. According to the current World Health Organization (WHO) clas-
A few studies have assessed the use of PET for 3D brachyther- sification of brain tumors, gliomas are assigned grades I to IV, as
apy. Malyapa et al.199 compared 2D treatment planning orthogonal shown in Table 29.4. These tumors are usually surrounded by
radiography-based brachytherapy with a 3D treatment planning extensive edema and, in 5% to 10% of glioblastomas, the disease
based on 18F-FDG PET in 11 patients with cervical cancer. The is already multifocal at the time of diagnosis.200 Consequently,
patients underwent two PET scans: First one to visualize the tumor gliomas cannot be totally removed by any form of local treatment,
and second one with the FDG placed inside the tandem and ovoid surgery included (Table 29.5). Cytotoxic therapy may fail too,
applicators to visualize the author’s treatment source positions for because migrating cells are less likely than non-migrating cells to
3D treatment planning. They concluded that this technique was be in the chemosensitive cell-division phase.
feasible and accurate relative to 2D treatment planning (Fig. 29.8). The treatment of gliomas is highly individualized at present,
based on the histologic diagnosis and other factors, and will be
Tab le 29.4
Tab l e 2 9 . 5
The Incidence of Brain Tumorsa
Primary Treatment of Different Types
Percentage Incidence of Gliomaa
WHO of All Brain (Per
Tumor Type Grade Tumorsb 100,000/Yr) Pilocytic astrocytoma (WHO grade I) Surgical resection (level III
evidence)
Neuroepithelial tumors I–IV 34.3 6.46 Astrocytoma (WHO grade II) Surgical resection, or biopsy and
Glioblastoma IV 17.1 3.17 wait-and-see, or radiotherapy
Anaplastic astrocytoma III 2.1 0.4 (level III evidence)b
Pilocytic astrocytoma I 1.7 0.33 Anaplastic astrocytoma, oligodendroglioma/ Surgical resection (or biopsy) and
Oligodendroglioma II 1.4 0.27 oligoastrocytoma (WHO grade III) chemotherapy (or radiotherapy)
Ependymoma II/III 1.4 0.26 (level 1b evidence)
Mixed glioma II/III 1 0.19 Glioblastoma (WHO grade IV) Surgical resection (or biopsy) and
Anaplastic oligodendroglioma III 0.7 0.12 radiotherapy and chemotherapy
Diffuse astrocytoma II 0.5 0.09 (temo-zolomide) (level Ib evidence)
a a
Central Brain Tumor Registry of the United States (CBTRUS; www.cbtrus.org/). From the treatment recommendations of the Neuroonkologische Arbeitsgemeinscjhaft (NOA).
b b
Not all brain tumors are gliomas. The available evidence from the clinical trials does not permit any definite recommendation.

Table 29. 6 of an oligodendroglial component. As much of the tumor as pos-

sible should be removed by open, microsurgical resection, if the
Function and Significance of the Main Molecular location of the tumor permits.205 After resection, a combination of
Markers of Glioma chemotherapy and RT has no advantage over either of these
modalities alone with respect to overall survival,211 nor is there
Molecular Marker Function and Significance any difference between chemotherapy alone and RT alone (multi-
center trial of the Neuro-Oncology Working Group of the German
MGMT (methylguanine MGMT is a repair enzyme that protects cells from Cancer Society, NOA-04 Study).205 The median overall survival
methyltransferase) damage by ionizing radiation or alkylating agents. time in the NOA-04 Study was 72.1 months after RT and 82.6
promoter methylationa, b Glioblastoma patients with a methylated (and months after chemotherapy; the difference was not statistically
therefore functionally impaired) MGMT promoter significant.
have better overall survival and better responses The RT of glioblastoma involves the delivery of an overall dose
to radio- and chemotherapy than glioblastoma of 60 Gray (in fractions of 1.8 to 2 Gy each) focused on the tumor
patients with an unmethylated MGMT promoter .
target volume, with a marked dose fall-off in the surrounding brain
40% to 50% of glioblastomas have a methylated
MGMT promoter.185 MGMT status is currently the tissue. IMRT is a recent advance in technique that allows modifica-
most important molecular parameter in the treat- tion of linear accelerator output, which improves target coverage
ment of glioblastoma.186,187 and allows for reduction of radiation dose to radiation-sensitive
Isocitrate dehydrogenase Heterozygous mutations (mainly of the IDH-1 structures. Use of abbreviated course of radiation (total: 40 to 50 Gy)
in older patients has been shown to be efficacious.212

(IDH)-1 and -2a, b enzyme) are seen in over 80% of all low-grade
gliomas and secondary glioblastomas. 12% of
glioblastomas have IDH-1 mutations.188 IDH-1
and -2 mutations are associated with a better
prognosis; in patients with glioblastoma, they are Impact of PET Imaging in Radiation Therapy
associated with longer progression-free survival Planning in Brain Tumors
and longer overall survival.186
Loss of allele on chromo- Loss of allele on chromosome 1p and 19q is seen Radiation therapy is so far a milestone in brain tumor treatment,
some 1p/19qa in 60–80% of anaplastic oligodendrogliomas either at first presentation or after relapse and surgical removal.
(WHO grade III) and predicts chemosensitivity in Especially in a postoperative setting, RT is known to increase overall
oligodendroglioma.189,190 Patients with 1p/19q survival in high-grade gliomas, namely glioblastoma multiforme
allele loss have longer progression-free survival (GBM) and anaplastic astrocytoma.213–216 As for other districts, RT
and better overall survival after radiotherapy or planning requires a proper definition of treatment volumes, includ-
chemotherapy. ing GTV, which defines gross tumor mass extension. However,
BRAF fusion gene This gene can be found in more than 60% of because of the major functional relevance of brain structures, the
pilocytic astrocytomas, but only rarely in diffuse
definition of these volumes for RT planning necessitates additional
astrocytomas191
attention and a high accuracy of imaging techniques.
a
Current therapeutic trials must be stratified according to these markers in view of their major Up to now, definition of GTV is mainly based on CT and MR.
clinical importance. Both these imaging modalities accurately show primary tumor and
b
These markers are suitable for routine clinical use. surrounding areas, thanks to the contrast enhancement and hyper-
intensity on T2- or flair-MR,217 but these findings are not always
even more so in the future. It is now well established that the tumor specific. CT and MR in fact can give outstanding information
prognosis of a patient with glioma depends, in general, on the his- on tumor localization and dimension but cannot differentiate
tologic classification of the tumor, the tumor grade, the patient’s residual tumor from fibrotic tissue and posttreatment alterations.
Karnofsky performance score, and neurologic deficits as well as the The reason stands on the direct dependence of CT and MR imaging
patient’s age. New molecular markers, such as loss of heterozygos- on the discontinuity of blood–brain barrier (BBB) to characterize
ity (LOH) of chromosome 1p/19q, methylation of the methylguanine pathologic tissue. But these same findings can be present also in
methyltransferase (MGMT) promoter, and mutations of isocitrate edema, postradiation injuries, regenerative tissue, etc.213,218–220 For
dehydrogenase-1 (IDH-1), now enable more accurate prognosis this reason, functional imaging with PET has gained an increas-
(Table 29.6).201–207 ing role in radiation therapy planning also for brain tumors
No advantage in terms of overall survival has been found for (Fig. 29.9).
immediate postoperative RT of grade II gliomas as compared to The first PET radiopharmaceutical utilized for imaging of brain
follow-up observation after resection, despite the demonstrated tumors was 18F-FDG.221 The tracer is the principal oncologic com-
advantage with respect to the time to tumor progression.208 Thus, pound worldwide and has also been investigated in central ner-
once the diagnosis of grade II glioma has been histologically con- vous system malignancies.222,223 18F-FDG uptake is generally high
firmed, it is best to adopt a wait-and-see strategy. This is particularly in high-grade tumors and brain metastasis, demonstrating an
true for patients under age 40, whose prognosis is better than that of important prognostic value in attrition.224 However, recent studies
others by virtue of their age.209 have demonstrated some diagnostic limitations of 18F-FDG PET.
On the other hand, the standard treatment for tumor progres- Because of the high rate of physiologic glucose metabolism in nor-
sion after initial resection of low-grade gliomas (LGGs) is fraction- mal brain tissue, the detectability of tumors with only modest
ated low-dose RT to 45 or 50.4 Gy, possibly preceded by resection increase in glucose metabolism, such as low-grade tumors and in
of the recurrent tumor.210 No benefit has yet been documented for some cases of recurrent high-grade tumors, is difficult. 18F-FDG
chemotherapy instead of, or in addition to, RT in the treatment of uptake in low-grade tumors is usually similar to that in normal
diffuse grade II astrocytoma. white matter, and uptake in high-grade tumors can be less than or
Newly diagnosed gliomas of WHO grade III include anaplastic similar to that in normal gray matter, thus decreasing the sensitivity
astrocytoma, oligoastrocytoma, and oligodendroglioma. Oligo- of lesion detection.225
dendroglial tumors also often have areas of calcification and mild The number of radiolabeled compounds available for PET
perifocal edema. There is no substitute for histologic confirmation imaging is relatively high (Table 29.7)52,221,230–236 and principally
of the diagnosis, because grade III tumors cannot be securely dif- includes amino acids (i.e., 11C-MET, 18F-FET, etc.), which remain
ferentiated from grade II tumors on radiologic grounds alone, nor the tracers more widely employed and investigated in brain
can imaging studies conclusively show the presence or absence tumors (Fig. 29.10).217,230,231

GTV-MR GTV-MR GTV-MR
+ + +
PET PET PET
100% overlap 50% overlap 0% overlap

PET PET PET
Figure 29.9. Herein are represented the
possible clinical target volumes (CTV) accord-
CTV CTV ing to the percentage of overlap between
CTV gross tumor volumes (GTV) based on MR and
PET imaging.
11
C-MET is undoubtedly the principal PET tracer for brain neo- The main limitation, however, of 11C-MET is the short half-life
plasms,237 concerning either initial diagnosis and image-guided of the radionuclide carbon-11 (t1/2 ∼ 20 minutes), thus the absolute
biopsy,238–240 staging and restaging tumor recurrence,241–245 necessity of an on-site cyclotron for its production. For this rea-
prognosis246 or RT planning.217,247 Overall, the method has demon- son, another amino acid tracer is also being employed in imaging
strated a good performance in diagnosing brain tumors (sensitivity brain tumors, this is the case of fluoroethyltyrosine (FET), labeled
and specificity of 87% to 100% and 75% to 100%, respectively),237–240 with fluoride-18 (t1/2 ∼ 110 minutes). The diagnostic accuracy of
as well as in differentiating recurrence from radiation necrosis or this other tracer has so far resulted equal to that of 11C-MET, with
other postoperative alterations (sensitivity and specificity of 78% to a high sensitivity and specificity up to 80% to 90% (Figs. 29.11,
100% and 60% to 100%, respectively).237,243–245 29.12).230,248
Tab le 29.7
Principal PET Tracers Utilized for Imaging Primary and Secondary Brain Tumors
Radiopharmaceutical
Tracer Compound Function Biomarker Activity Application in Brain Imaging
11
C-MET208,209 Carbon-11 methionine Amino acid Amino acid metabolism and protein Low-grade and high-grade gliomas
synthesis Meningiomas
Brain metastasis
18
F-FET208 Fluoride-18 fluoroethyltyrosine Amino acid/tyrosine analog Amino acid metabolism and protein Low-grade and high-grade gliomas
synthesis
18 203
F-FDG Fluoride-18 fluorodeoxyglucose Glucose analog Glycolytic metabolism High-grade gliomas
Brain metastasis
18
F-MISO210 Fluoride-18 fluoromisonidazole Nitromidazole derivative/ Hypoxia/oxygen depletion High-grade gliomas
nitroreductase enzyme substrate
18 211
F-DOPA Fluoride-18 fluorodihydroxyphe- Amino acid/phenylalanine analog Protein metabolism and catechol- Low-grade and high-grade gliomas
nylalanine amine pathway
11
C-CHO226 Carbon-11 choline Natural amine (Vitamin J)/ Cell membrane turnover Low-grade and high-grade gliomas
phospholipid precursor
18
F-FLT227 Fluoride-18 fluorothymidine Pyrimidine base/thymidine analog TK1/proliferative activity High-grade gliomas
18
F-RGD228 Fluoride-18 arginine-glycine- Cell adherence receptor αvβ3- Angiogenesis High-grade gliomas
aspartic acid peptides integrin antagonists
68
Ga-DOTATOC229 Gallium-68 DOTA-Tyr- Somatostatin analog Somatostatin receptor expression Meningiomas
Octreotide (mainly sstr2 and sstr5)


Figure 29.10. Axial images of fused FDG
PET-CT (upper panel), MET PET-CT (middle
panel) and corresponding low-dose CT (lower
panel) of the same patient. Note the different
patterns of uptake in between a glucomimetic
tracer, such as 18F-fluorodeoxyglucose (dashed
arrow ), and an amino acidic tracer, such as
11
C-Methionine (straight arrow ). Both scans
demonstrated increased uptake in the same
region, although MET PET had a higher and
more distinguishable uptake than FDG PET. The
lesion, surrounded by a vast hypointense area
in the left peritrigonal region, is also well visual-
ized on LD CT (arrowhead ).
Amino Acid Tracers with 18F-fluoromisonidazole (FMISO),255–257 a nitromidazole deriv-

ative.255,258 In the presence of oxygen depletion, nitromidazoles
One of the first evidences of implemented value of 11C-MET in are metabolized by the enzyme nitroreductase, thus can be cova-
brain tumors was reported on brachytherapy in gliomas.249 Out of lently bound to intracellular macromolecules and be entrapped
the 46 patients investigated, disease extent with MET PET resulted within the cells. This is the mechanism used in the case of FMISO,
superior in 67% of the cases, compared to that determined by CT/ which is collected in the tumor cells proportionate to the amount
MR, concluding that the method could improve tumor delineation of hypoxia.253,258
and provide additional information on therapeutic effects.86,249 In glioma, the binding potential of FMISO has demonstrated a fair
Findings were subsequently confirmed by Nuutinen et al.250 in correlation with tumor grade,259 with glioblastoma showing a high
LGGs, where MET PET improved GTV delineation in 63% of the tracer uptake in all cases and LGGs having no FMISO uptake.259,260
patients: 27% of cases in outlining MR-GTV and 46% in giving Moreover, according to recent findings,257,260 viable hypoxic
complementary information. tissue assessed by FMISO PET seems to occupy regions straddling
Also in postoperatively imaged high-grade gliomas, Grosu et al.251 the outer edge of the T1-weighted Gd-enhanced areas on MR, sug-
report that 11C-MET uptake and MR contrast enhancement could gesting as underlying cause the driving of peripheral infiltration by
correspond in only 13% of patients (n = 39), with a mean volume of tumor hypoxia.256 On a molecular level, the explanation for this
13 mL (33%) of the tumor showing no contrast enhancement on MR. characteristic appears to be related to the expression level of HIF-
The same authors had previously demonstrated that in 79% of the 1, a transcriptional factor playing a crucial role in promoting cell
patient, the region of MET uptake was larger than that of contrast survival, tumor invasiveness, and aggressiveness.260,261 More spe-
enhancement on MR (up to 45 mm beyond), whereas in 74% the cifically, some studies have demonstrated that HIF-1α localizes in
MR-contrasted area extended beyond the MET.252 cells around necrosis and tumor cells infiltrating the surrounding
Also in a pool of 16 patients with malignant glioma, candidates brain close to tumor margins.259,262
for Carbon Ion radiotherapy, Mahasittiwat et al.213 could detect a When comparing MET PET and FMISO PET, it seems likely that
mean extended volume (EV) of MET PET over MR CTV of 0.6 and the two tracers give complementary information, helping in a more
2.2 mL, which significantly correlated with patient survival: Greater efficient tumor delineation and better RT planning. These findings
survival rate (p = 0.0069), regional control (p = 0.0047), and distant appear to open the way to the possibility of dose-painting treat-
control time (p = 0.0267) for those having a negative EV, compared ment planning, based on the hypoxic target volumes derived from
to those with a positive EV. FMISO PET. This is the reason why various clinical trials are being
conducted on hypoxia imaging of brain tumors (Table 29.8). Further
Hypoxia Agents data and dedicated investigation are, however, necessary to prop-
erly define the role of hypoxia imaging in RT planning of brain
One of the reasons for treatment failure in RT is the presence of tumors.
low oxygen levels in the tumor tissue. The brain tumor known for
hypoxic areas is glioblastoma. This type of tumor presents with a
Other PET Tracers
variable pattern of tissue neovascularization, associated with oxy-
gen depletion and promotion of new aberrant tumor cell prolif- Imaging gliomas are not only a prerogative of 11C-MET or 18F-FET,
eration.52,253,254 This is the reason why new PET tracers have been because other radiopharmaceuticals, usually employed for other
applied for the characterization of tumor oxygenation, starting malignancies or body districts, have been applied in brain tumors

Figure 29.11. In this multipanel image are shown MET PET

and RM of a patient with recurrent pilocytic astrocytoma of the
right thalamus: (A) axial PET images for radiotherapy planning; B
(B) corresponding T1-w contrast enhanced MR images.
(Table 29.7). The tracer showing more uptake similarities to the diagnosed gliomas (sensibility and specificity of 85% and 89%,
abovementioned amino acid tracers is 18F-fluorodihydroxyphenyl- respectively).232,267 The tracer uptake was reported to correlate to
alanine (18F-DOPA). First developed for PET imaging of neurode- histologic findings and tumor grade, giving additional prognostic
generative and movement disorders,263 the radiopharmaceutical is information, compared to the other amino acid tracers.232
nowadays largely employed for imaging neuroendocrine tumors Also 11C-CHO has been investigated in imaging brain tumors.233
(NET).264 As an analog of the amino acid phenylalanine, 18F-DOPA As an essential amine, it enters several metabolic pathways, but the
is actively taken up via the large amino acid transporter (LAT) and most relevant one for cancer imaging is its incorporation into cell
subsequently decarboxylated within the cell into dopamine, thanks membranes as phosphatidylcholine.268 The increase of choline levels
to the aromatic acid decarboxylase (AADC).265 This mechanism is in brain tumors is a well-known process on which relies MR spec-
increased also in tumors other than NET, including primary brain troscopy269 and more recently, also PET imaging. Available data233,270–272
tumors,266 and has resulted helpful in detecting or defining newly show a good diagnostic accuracy for 11C-CHO in different gliomas,


A
Figure 29.12. Same patient as in Figure 29.11, but herein are

shown the radiotherapy planning (A) and the corresponding MET
B
PET, green line, and CT contouring, red line (B).
Table 29. 8
Ongoing Trials on FMISO PET Imaging in Radiotherapy Planning in Brain Tumors
Start
Study Name/Title Neoplasia Study Type Institution/Site Date Status
Assessment of primary and metastatic brain (1) Newly diagnosed primary malignant brain Observational University of Utah 2011 Recruiting
tumor hypoxia with fluoromisonidazole, FDG tumors WHO grade III–IV Case control
and water (2) Newly diagnosed brain metastasis (>1 cm Prospective
in diameter) who will be receiving
radiotherapy
Evaluation of [18F]-FMISO for Non Operated Glioblastoma proposed for a radical treatment Interventional University Hospital, 2009 Recruiting
Glioblastoma (MISOGLIO) consisting in conformational Phase II Bordeaux
radiotherapy and/or chemotherapy Open label
HYPONCO—Hypoxia in brain tumors Anaplastic glioma Interventional University Hospital, 2010 Recruiting
Phase II Caen
Open label
PET scan using 18F-fluoromisonidazole and MRI Newly diagnosed WHO grade IV glioma (GBM) Interventional National Cancer 2009 Recruiting
in assessing tumor hypoxia in patients with Phase II Institute (NCI)
newly diagnosed glioblastoma multiforme Open label
http://clinicaltrials.gov.

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C h apt e r 3 0
Bone Mineral Densitometry in Oncology

William D. Leslie
Introduction treatment decision-making (see Fracture Risk Assessment).13 In

the absence of a defining fracture, the diagnosis of osteoporosis is
Osteoporosis is defined by the World Health Organization (WHO) as based on the measurement of BMD by DXA (Table 30.1). The WHO
“a systemic skeletal disease characterized by low bone mass and has provided an operational definition of osteoporosis given as a
microarchitectural deterioration of bone tissue, with a consequent BMD that lies 2.5 standard deviations (SDs) or more below the
increase in bone fragility and susceptibility to fracture.”1 The pres- average mean value for young healthy women (T-score ≤−2.5 SD)
ence of osteoporosis is a major risk factor for the development of based upon a standardized reference site (the femoral neck) and a
fractures of the hip, proximal humerus, vertebra, and forearm but standard reference range for both men and women (the NHANES
most other skeletal sites are also at increased risk of fracture.2 III data for women aged 20 to 29 years).1,14,15 Microarchitectural
Worldwide, the number of fracture sufferers in 2000 was estimated deterioration also has an important effect on bone strength. Typical
at 56 million with approximately 9 million new osteoporotic frac- changes in trabecular bone include reduction in trabecular thick-
tures each year.3 Older age and female sex are primary risk factors ness and number, and perforation of trabeculae by deep resorption

for osteoporosis, with the global burden of osteoporosis is projected pits. This results in loss of trabecular connectivity and is currently
to increase markedly over the next few decades as the number of believed to be irreversible. These microarchitectural changes may
elderly individuals increases.4 Cancer is the second leading cause of not be reflected by reductions in bone density but still contribute
death in the United States and is expected to surpass heart disease to skeletal fragility and fracture susceptibility.
over the next few years.5 Cancer in industrialized nations is a dis- The consequences of fracture include increased mortality, mor-
ease of aging, with a median age of 67 at diagnosis. Improvements bidity, institutionalization, and economic costs.16,17 An individual with
in outcome imply that more elderly cancer patients will survive and a hip fracture has a markedly increased risk of death within the first
be at risk for osteoporosis, a consequence of some of the treatment 6 months that is partly attributable to the fracture itself. Both hip and
regimens (e.g., aromatase inhibitors (AIs) for breast cancer, andro- vertebral fractures are associated with an excess risk of death beyond
gen deprivation therapy for prostate cancer, and TSH suppression the first year,18–20 and this is largely attributed to underlying comor-
for differentiated thyroid cancer). bidity.21,22 Moreover, all osteoporosis-related fractures can lead to
Bone mass is the primary determinant of bone strength, as significant long-term disability and decreased quality of life.23,24
studies of excised bone have demonstrated that approximately The economic impact of fractures is also noteworthy. Studies
80% of bone strength is determined by the amount of bone. Bone have consistently shown hip fractures to be associated with the
mineral density (BMD) is an integral element in fracture risk highest costs, typically exceeding $25,000 US in the first year.16,25–27
assessment and in the diagnosis of osteoporosis.6,7 Dual-energy Spine fractures show costs up to $14,977 US in the first year post
x-ray absorptiometry (DXA) provides an objective and quantifiable fracture.25,27 Fractures other than hip and spine showed costs in the
index of skeletal strength that is widely used in clinical practice first year post fracture are still quite significant ($9,183 US for age
guidelines and recommendations from expert bodies,8–12 notwith- 50 to 64 years, $6,106 US for age 65 years and older).27 Because of
standing increasing recognition of the importance and indepen- their high prevalence, the total first-year costs of nonhip nonspine
dent contribution of clinical risk factor (CRF) evaluation as part of fractures are greater for those age 50 to 64 years than for hip and
spine fractures combined.27,28
Table 30. 1
Diagnostic Classification of Bone Density

Pathophysiology of Osteoporosis
Results
Bone is a dynamic living tissue consisting of cellular, organic, and
inorganic components with a complex internal structure that
Age Category Criteriaa undergoes continuous remodeling throughout life. The mature
skeleton consists of a mixture of cortical bone (85%) and trabecular
Menopausal women Severe (established) T-score ≤–2.5 with bone (15%), the relative amounts of which vary widely between
Men ≥50 y osteoporosis fragility fracture different anatomic sites (Fig. 30.1).
Osteoporosis T-score ≤–2.5
Low bone mass Bone reacts to stress and injury through a well-orchestrated
T-score between
Normal -1 and -2.5 sequence for removing old bone and building new tissue. Bone
T-score ≥–1 remodeling is carried out by the basic multicellular unit (BMU),
which consists of both osteoclasts and osteoblasts. The BMU typi-
Premenopausal women Below the expected range Z-score ≤–2
Men <50 y
cally takes 3 to 6 months to complete a cycle (Fig. 30.2). Bone
for age Z-score >–2
Within the expected range remodeling affects 3% to 5% of cortical bone per year, but up to
for age 25% of trabecular bone due in part to its greater relative surface
area. The osteoclast, a multinucleated cell of monocyte origin,
a
This classification is applied to the lowest value for lumbar spine (minimum two vertebral lev- resorbs bone through the release of acid and enzymes such as
els), total hip, and femoral neck. If either the lumbar spine or hip is invalid, then the forearm cathepsin K from its ruffled border. Osteoblasts, derived from mes-
should be scanned and the distal 1/3 region reported. The T-score is the number of standard
deviations that bone mineral density (BMD) is above or below the mean normal peak BMD
enchymal cells, enter the resorption pit and lay down organic
(NHANES III for hip measurements). The Z-score is the number of standard deviations that BMD matrix (osteoid). The osteoblast then dies or enters a dormant
is above or below the mean normal BMD for sex, age, and (if reference data are available avail- stage and is known as an osteocyte (if trapped within calcified tis-
able) race/ethnicity. Osteoporosis cannot be diagnosed by BMD alone in premenopausal women sue) or a lining cell (if found on the surface of calcified tissue). The
or men below the age of 50 years.
From Leslie WD, Adler RA, El-Hajj FG, et al. Application of the 1994 WHO classification to popu-
osteoid is subsequently mineralized over a period lasting several
lations other than postmenopausal Caucasian women: The 2005 ISCD Official Positions. J Clin months. There is close coupling in osteoclast and osteoblast activi-
Densitom. 2006;9(1):22–30. ties, although the intercellular signaling involved is incompletely
457

Skeletal mass accumulates rapidly during childhood, espe-

cially during the years of most rapid growth in early adolescence,
Total body 15% with peak bone mass achieved by 25 years. Determinants of peak
bone mass included genetics, physical activity, and diet (espe-
cially calcium intake). The major genes that influence peak bone
mass have yet to be elucidated, but twin studies suggest that 60%
to 90% of the variation in peak bone mass and the majority of
variation in bone loss is determined by genetic factors.30,31 Ethnic-
ity is also important. Blacks have higher average bone mass than
Vertebra 66%
Caucasians who in turn have higher average bone mass than
Radial shaft <5% Asians.14,32
Femoral neck 25% Distal radius 25% After early adulthood, both men and women experience a slow,
Trochanter 50% progressive decline in bone mass that continues until death. Bone
turnover accelerates in women at the time of menopause, espe-
cially in trabecular bone, and often results in the loss of 5% to 15%
of bone mass over the first 5 years after menopause. After early
menopause, age-related bone loss continues at a rate of 0.5% to 1%
per year and may actually accelerate again in later life.33 The
pathogenesis of age-related bone loss is unclear, but may be related
in part to changes in calcium absorption and vitamin D availability.
Calcaneus 90% Technical Aspects of Bone

Densitometry
Figure 30.1. Percent of trabecular bone in skeletal sites commonly assessed with bone
densitometry. (Reproduced with permission from Leslie WD, Roe BE. Bone densitometry. In: Dual Energy X-Ray Absorptiometry
Leslie WD, Greenberg D, eds. Nuclear Medicine. Austin: Landes Bioscience; 2003:93–120.)
DXA is the most widely used technique for measuring BMD in clin-
ical practice. DXA has a well-established role in the evaluation of
understood. It is clear, however, that processes which stimulate (or individuals at risk of osteoporosis, and in helping clinicians advise
suppress) one cell type result in stimulation (or suppression) of the patients about the appropriate use of antifracture treatment. DXA
other. For example, after menopause, osteoblast activity increases in examinations have three major roles: The diagnosis of osteoporo-
an attempt to compensate for increased osteoclastic resorption. On sis, the assessment of a patient’s risk of fracture, and for monitoring
the other hand, antiresorptive treatments targeted at suppressing response to treatment. DXA evolved from dual-photon absorpti-
osteoclast activity are only able to achieve a slight gain in bone mass ometry (DPA) which used gadolinium-153 as the photon source,
as there is a parallel reduction in osteoblast activity. The bone and suffered from the need for radionuclide source changes, poor
remodeling cycle is regulated by a myriad of growth factors and image resolution and reproducibility, and has been largely replaced
cytokines. A recently recognized system has recently been discov- by DXA.
ered and shown to be the primary regulator of osteoclastogenesis DXA uses an x-ray tube to generate two different x-ray ener-
activity. Three molecules, the receptor activator of NF-κ B (RANK), gies. Bone blocks (or attenuates) x-rays to a greater degree than
its ligand RANK-L, and the decoy receptor of RANK-L, osteoprote- soft tissue, and lower x-ray energies are attenuated more than
gerin (OPG), play a pivotal role as central regulators of osteoclast higher energies. An x-ray detector records the amount of attenua-
function.29 RANK/RANK-L signaling is required for osteoclast devel- tion for the two energies and can calculate both the amount of soft
opment, whereas OPG inhibits RANK/RANK-L signaling and osteo- tissue (using an estimated soft tissue attenuation value from the
clast activity. nonbone pixels) and the amount of bone calcium (using hydroxy-
Bone cell activity can be evaluated through the measurement apatite as the reference material) in the path of the beam. The
of biochemical markers. Osteoblasts produce type I collagen (the x-ray tube and detector scan over the area of interest, building up
primary collagen of bone tissue), noncollagenous proteins (such as an image of bone mineral content (BMC) expressed in grams of
osteocalcin), and enzymes (such as alkaline phosphatase). Many of calcium. The densitometer’s software identifies the projected bone
these are measured in the serum as indices of bone formation. area using an edge-detection algorithm. Dividing BMC (grams of
Collagen is a triple-helical molecule that undergoes extensive post- calcium) by the bone area (cm2) yields BMD as g/cm2. DXA has the
translational modifications including hydroxylation, glycosylation, advantage of being rapid (particularly with newer scanners that
and covalent cross-linking. The degradation products of cross- use higher output x-ray tubes and a fan-beam configuration) and
linked type I collagen, which include C-telopeptide, N-telopeptide, is able to scan the structures of greatest clinical interest such as the
and deoxypyridinoline, can be measured in the urine or serum as spine, hip (Fig. 30.3), forearm, and total body. The effective radia-
an index of osteoclast activity. tion dose from a lumbar spine scan is much less than 10 μSv
A D
B C Figure 30.2. Bone remodeling cycle. Proceeding from

left to right the sequence is (A) osteoclast resorption,
(B) osteoblast proliferation, (C) osteoid matrix deposition,
and (D) mineralization. (Reproduced with permission from
Leslie WD, Roe BE. Bone densitometry. In: Leslie WD,
Greenberg D, eds. Nuclear Medicine. Austin: Landes
Bioscience; 2003:93–120.)

Chapter 30 Bone Mineral Densitometry in Oncology 459
Upper

Lower
Figure 30.3. Lumbar spine and left hip dual-energy

x-ray absorptiometry scans in a 76-year-old white
female with papillary thyroid cancer. Based on total hip
T-score of −1.6 she would be designated as having low
bone mass (not osteopenia). BMC, bone mineral content;
BMD, bone mineral density; YA, young adult.
(1 mRem), a value similar to one day’s normal background radia- ment errors in the BMD results.34,35 Figure 30.4 shows the error that
tion and of negligible risk. Effective doses from scans of the hip, can be introduced in the calculation of BMD when an incorrect soft
forearm, and total body are even lower. tissue attenuation value is generated by the inclusion of a staghorn
calculus in the soft tissue region, even when bone edge detection is
unaffected. Assessment of bone and soft tissue typing is an essential
Limitations and Errors in Dual Energy component of DXA quality control.
Because most bone density techniques give an area measure-
X-Ray Absorptiometry ment based upon a two-dimensional projection of bone (in g/cm2),
Measurement errors in DXA of the spine and hip are typically on larger bones will have a higher apparent bone density than smaller
the order of 5% to 7%, but in individual cases may be much bones because of the increased depth (Fig. 30.5). Many of the
larger.34,35 The principal source of error relates to the inherent reported area BMD differences related to sex, ethnicity, childhood/
assumption that the body is composed of two tissue types: Bone and adolescence, and conditions associated with short stature (e.g.,
soft tissue. In reality, soft tissue can be decomposed into lean and dwarfism, Turner syndrome) relate to the effect of bone size on areal
fat components, with the former have significantly greater density bone density measurements.36–44 The confounding effect of skeletal
than the latter. If the composition of the soft tissue overlying the size has also been seen among a relatively homogeneous population
bone region of interest (ROI) is not known, or is not correctly esti- of 16,205 White women aged 50 years and older, in whom total hip
mated from the nonbone pixels, then this will cause an error in the areal BMD categorized a substantially higher fraction of women
BMD measurement. Because of the large thickness of tissue in the with smaller bone area as being osteoporotic despite similar inci-
abdomen, the areal soft tissue mass for a spine DXA scan is consid- dent fractures and paradoxically lower prevalent fractures.45
erably greater than that of bone mineral (range: 15 to 25 g/cm2 Although techniques have been developed to try to address this
compared with a typical BMD value of 1 g/cm2), and therefore even (such as estimations of skeletal volume to provide a “volumetric”
small differences in x-ray attenuation between lean and adipose bone mineral apparent density [BMAD] reported in g/cm3),46 only
tissue discussed above can generate clinically significant measure- quantitative CT (QCT) provides a true volumetric measurement.

Figure 30.4. A large left renal staghorn calculus is seen (left). If this is not excluded from the soft tissue map (middle), then the lumbar spine bone mineral
density (BMD) measurement is 0.756 g/cm2. After correct exclusion from the soft tissue map (right), the lumbar spine BMD measurement is 0.834 g/cm2 (9.1%
difference).
Apparent discrepancies between hip and spine BMD measure- measurements are less susceptible to degenerative changes, but
ments are common and emphasize the complexity of skeletal thickening of the medial cortex of the femoral neck (“buttressing”)
metabolism. As a “systemic skeletal disorder,” osteoporosis affects will be reflected in bone density measurements (Fig. 30.8). The
all bones but the degree is modified by local determinants of bone trochanteric region appears to be relatively unaffected by these
metabolism that include bone composition (trabecular bone under- changes. Overlying artifact, previous fracture, surgery, or Paget’s
goes more rapid turnover and loss), mechanical loading (weight disease (see Fig. 30.8) can affect hip results and the contralateral
bearing enhances osteoblast activity), and age-related artifacts hip should be measured under such circumstances.
(usually elevating spine BMD). Together these factors help to
explain why differences between spine and hip BMD measure-
ments are so common. Vertebral Fracture Assessment
Attention to correct patient positioning is paramount in ensur-
The majority of spine fractures are not clinically diagnosed, but
ing reliable BMD measurements (Fig. 30.6). Bone density may be
may still have health consequences and economic implications.47
overestimated in anteroposterior measurements of the lumbar
Significant vertebral fractures (usually showing >25% height loss
spine because of the presence of degenerative sclerosis or osteo-
and end-plate interruption) unrelated to trauma are associated
phytes, acquired conditions (e.g., ankylosing spondylitis, Paget’s
with a fivefold increased risk for recurrent vertebral fractures;
diseases, compression fractures, metastases), superimposed vas-
mild spinal deformities (<25% height loss without definite end-
cular calcification, or other dense materials (e.g., barium, iodinated
plate fracture) are not strong predictors of future osteoporotic
contrast or undissolved calcium tablets) (Fig. 30.7). Discrepancies
fractures or low bone density.48 Vertebral Fracture Assessment
between spine measurements and other skeletal sites are more
(VFA) is a scanning and software option on modern DXA instru-
typically seen in older subjects (more than 60 years of age) and
ments which use a fan-beam scanning technology and can detect
those with known spine disease. Hip measurements are affected by
fracture (Fig. 30.9) and nonfracture abnormalities in the thoraco-
patient positioning and the degree of hip rotation which make it
lumbar spine (Fig. 30.10). It can be easily performed at the time
critical for technologists to adopt a standardized technique. Hip
of BMD measurement, allowing integration of BMD and vertebral
fracture information in the clinical care of patients evaluated
for osteoporosis. VFA is associated with low radiation exposure
(2–50 μSv versus 600 μSv for lateral spine radiographs). When
Genant’s SQ approach for vertebral fracture grading is used
(Fig. 30.11), caution should be exercised when diagnosing Grade 1
Mass 8 g
Projected area 4 cm2 deformities as fractures, particularly when such deformities are
Areal density 2 g/cm2 observed in the thoracic spine as Grade 1 fractures are less pre-
2 cm dictive of future fractures, and are more difficult to detect on
VFA.49 Therefore, only Grade 2 and 3 deformities should generally
be considered as clear fractures. Like radiographic fractures, ver-
tebral fracture identified on VFA predict future osteoporotic and
hip fractures independently of age, weight, and BMD.48,50 A pro-
posed set of indications for VFA are listed in Table 30.2.51
Mass 1 g An additional benefit of VFA is the detection of abdominal aor-
Projected area 1 cm2 tic calcification (AAC) (see Fig. 30.10), an important marker of
1 cm Areal density 1 g/cm2 subclinical CVD.52 AAC from VFA has been shown to predict sub-
sequent vascular events independent of the Framingham risk
score.53 Among 408 women (aged >75 years) who sustained an MI
Figure 30.5. Bone volume strongly affects measured bone density using areal techniques
such as dual-energy x-ray absorptiometry (DXA). Assume that two cubes are constructed from
or stroke during a median 4-year follow-up period and randomly
hydroxyapatite (1 g/cm3). The larger cube will have twice the areal density of the smaller cube selected 408 controls, the odds ratio (OR) of incident MI or stroke
because of its greater depth because this is not measured in DXA. for those in the top tertile compared with the bottom tertile of AAC


Figure 30.6. Incorrect (left) and correct
(right) positioning in dual-energy x-ray
absorptiometry. The lumbar spine should be
aligned with the table center line. The femur
should be internally rotated and the shaft
aligned with the table center line.
Table 30. 2
Indications for Vertebral Fracture Assessmenta
Postmenopausal women with low bone mass (osteopenia) according to BMD criteria, Men with low bone mass (osteopenia) by bone mineral density (BMD) criteria, plus:
plus: Any one of the following:
Any one of the following: • Age 80 y or older.
• Age greater than or equal to 70 y. • Historical height loss greater than 6 cm (2.4 in).
• Historical height loss greater than 4 cm (1.6 in). • Prospective height loss greater than 3 cm (1.2 in).
• Prospective height loss greater than 2 cm (0.8 in) • Self-reported vertebral fracture (not previously documented).
• Self-reported vertebral fracture (not previously documented). Or two or more of the following:
Or two or more of the following: • Age 70–79 y.
• Age 60–69 y. • Self-reported prior nonvertebral fracture.
• Self-reported prior nonvertebral fracture. • Historical height loss of 3–6 cm.
• Historical height loss of 2–4 cm. • On pharmacologic androgen deprivation therapy or following orchiectomy.
• Chronic systemic diseases associated with increased risk of vertebral • Chronic systemic diseases associated with increased risk of vertebral fractures.
fractures. Women or men on chronic glucocorticoid therapy (equivalent to 5 mg or more of predni-
sone daily for 3 mos or longer).
Postmenopausal women or men with osteoporosis according to BMD criteria, if docu-
mentation of one or more vertebral fractures will alter clinical management.
a
Consider vertebral fracture assessment when the results may influence clinical management.
From Lewiecki EM, Gordon CM, Baim S, et al. International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions. Bone. 2008;43(6):1115–1121.

A B
Figure 30.7. Spine dual-energy x-ray

absorptiometry artifacts. A: Severe degenera-
tive disk disease (L1–L4 T-score −0.8, total
hip T-score −4 for the same patient). B: Anky-
losing spondylitis (L1–L4 T-score +4.5).
C: Paget’s disease affecting L1 (L1 T-score
+2.1 versus L2–L3 −0.8). D: Metastastic pros-
C D tate cancer involving T12, L1, and L3 (T-scores
L1 +5.7, L2 +1, L3 +6.5, L4 +1.4).
score were 1.74 (95% confidence interval (CI): 1.19 to 2.56) for a ultrasound (QUS). One is the speed of sound (SOS), a measure of the
24-point scale and 1.77 (95% CI: 1.22 to 2.55) for an 8-point scale, speed with which sound travels from one transducer to the other
adjusted for age, high-density lipoprotein and low-density lipopro- through the bone (m/s). The other is broad beam ultrasound attenu-
tein cholesterol, triglycerides, blood pressure, smoking, renal ation (BUA) which is the slope of the relationship between attenua-
function, health status, and baseline diagnoses of diabetes melli- tion and frequency (dB/kHz). Because of the ultrasound’s difficulty in
tus, hypertension, angina, and prior stroke. penetrating deep structures, most devices measure the more acces-
sible bones such as the calcaneus, phalanges, and tibia. Although
x-ray–based techniques are calibrated against calcium content,
Other Bone Measurement Technologies there is considerable controversy over the physical properties mea-
Conventional DXA (also known as central DXA) is able to measure sured by bone ultrasound. Whether QUS measures bone quality
all skeletal structures, including those in the thicker body regions independent of bone density is currently an area of controversy.
such as lumbar spine and hip. Unfortunately, conventional DXA CT scanners are capable of measuring spine and hip bone density
equipment is relatively expensive and heavy. Therefore, a variety by using a calibrated phantom and specialized software. Such mea-
of compact, portable devices have been developed for measuring surements are known as QCT and give bone density in terms of vol-
bone density in the extremities such as the forearm and calcaneus. ume (mg/cm3). Although QCT is expensive and has a relatively high
Single photon absorptiometry (SPA) used a radionuclide source radiation dose (1500–3000 μSv for multidetector CT), it has the
(iodine-125) but required periodic source replacements and advantage of providing a true volumetric measure of bone density
immersion of the body part in water. Peripheral DXA (pDXA) (rather than areal as with DXA). This can be advantageous when
devices avoid these limitations and impart an exceedingly small skeletal size deviates markedly from average or when there are
radiation dose of less than 0.1 μSv (0.01 mRem). dense artifacts (such as heavily calcified aorta or osteophytosis of the
Ultrasound has emerged as another tool for characterizing bone lumbar spine) that preclude accurate DXA measurements. Smaller
strength and has the advantages of being radiation-free and using CT devices have been developed for studying the distal radius and
relatively inexpensive, portable devices. Ultrasound penetrates bone distal tibia, known as peripheral QCT (pQCT). High-resolution devices
poorly, and higher frequencies are attenuated more than lower fre- (HR-pQCT) are capable of imaging the structure of bone and provide
quencies. Two measures are typically derived from quantitative insights into alterations in cortical and trabecular microarchitecture.


B
Figure 30.8. Hip dual-energy x-ray absorp-

tiometry artifacts. A: Advanced hip osteoarthri-
tis produced “buttressing” with overestimation
in femoral neck bone mineral density (right hip
T-scores femoral neck +1.5, trochanter –3.2;
left hip T-scores femoral neck –1, trochanter
–3.2). B: Credit card artifact (T-score +0.9
before, –2.2 after removal). C: Previous left hip
pinning with pin removed (left total hip T-score C
0, right total hip T-score –2.7).
Although conventional x-rays are not quantitative, they are still est in plain radiographs of the hands as an accessible and low-
an important component in the assessment of osteoporosis cost alternative to the methods previously listed.
because the presence of fragility fractures (such as vertebral com-
pression fractures) indicates osteoporosis. Plain radiographs of
the hand can also be used to measure cortical width in the fingers,
Accuracy and Precision
but this is a relatively insensitive technique. With the introduction Bone density measurement has a primary clinical role in the initial
of aluminum calibration wedges, however, there is renewed inter- diagnostic and fracture risk assessment of osteoporosis,7,54 and is

Figure 30.9. Vertebral fracture assessment in three different patients. Normal (left), moderate T12 fracture (arrow; middle) (same case as Figure 28.3), and
multiple severe fractures (right).
Figure 30.10. Nonfracture vertebral fracture assessment abnormalities. Ankylosing spondylitis (left), metastasis from breast cancer (arrow; middle), and aortic
calcification (right).

Normal
(grade 0)
Wedge Biconcavity Compression
Mild fracture
(grade 1)
Figure 30.11. Genant’s semiquantitative classification

of vertebral fractures based upon severity and shape. Mild
(Grade 1) refers to 20% to 25% height reduction, moder-
ate (Grade 2) 26% to 40% height reduction, and severe
(Grade 3) >40% height reduction. Vertebral fracture is Moderate fracture
diagnosed when reduction of height in anterior, middle, or (grade 2)
posterior dimensions of vertebral body exceeds 20%. The

approximate degree of height reduction determines
assignment of grade to vertebra. Fractures are classified
as wedge, biconcave, or crush, depending on whether
anterior, middle, or posterior portion of vertebral body is
most diminished in height. (Reproduced with permission
from Genant HK, Wu CY, van KC, et al. Vertebral fracture Severe fracture
assessment using a semiquantitative technique. J Bone (grade 3)
Miner Res. 1993;8(9):1137–1148.)
also widely used for serial monitoring of patients with suspected or ash-weight of bone samples. DXA is the predominant technology
confirmed osteoporosis.55 A formal quality assurance program is used for evaluating bone density, and has a measurement error of
an essential component of a bone density program. In the case of 5% to 7%. This error is small relative to the range of values in the
DXA, this should minimally consist of a daily calibration check population, enabling its use as a tool to diagnose osteoporosis and
(usually with an anthropomorphic spine phantom) which is com- assess fracture risk.
pared with predefined tolerance limits. The cumulative data must Precision (also referred to as reproducibility) is the ability of a
be inspected regularly to look for subtle changes or drifts in per- system to obtain the same results in repeated measurements of
formance signaling the need for corrective action (Fig. 30.12). the same individual. A technique must have good precision if
Accuracy refers to how closely a measured result approximates serial measurements are to be used in following an individual.
the “true” value and is of critical importance when comparing an Greater precision makes it possible to detect smaller changes in a
individual patient to a reference population. The accuracy of bone subject. Current methodologies typically demonstrate precision
mineral measurements is determined by comparison with dry- or errors that are larger than annual changes in bone density. Thus,
1.03
1.02 + 2% limit
1.01 + 1% limit
1 Mean
0.99 – 1% limit
0.98 – 2% limit
0.97
1.03
1.02 + 2% limit
1.01 + 1% limit
1 Mean
0.99 – 1% limit
0.98 – 2% limit
0.97
Figure 30.12. Quality assurance plots from three hypotheti-
cal systems with mean 1, standard deviation 0.005 (coefficient 1.03
of variation 0.5%). The upper plot indicates a stable machine, 1.02 + 2% limit
the middle plot indicates an abrupt shift in baseline (regression
lines plotted to the data prior to and after the shift), and the 1.01 + 1% limit
lower plot indicates a continuous drift in baseline (regression Mean
1
line plotted to all time points). The latter is particularly insidious
and would be difficult to identify by visual inspection of the data 0.99 – 1% limit
alone. (Reproduced with permission from Leslie WD, Roe BE.
Bone densitometry. In: Leslie WD, Greenberg D, eds. Nuclear
0.98 – 2% limit
Medicine. Austin: Landes Bioscience, 2003:93–120.) 0.97

Figure 30.13. Effect of a large soft tissue

fold (pannus) on hip dual-energy x-ray absorpti-
ometry assessment is illustrated in this 64-year-
old Caucasian woman (height 162.56 cm [64
in], weight 118 kg [261 lb], body mass index 45
kg/m2). The upper images show the scan before
displacement of the pannus (arrowheads) and
the lower images after displacement of the pan-
nus (bone display on the left, tissue display on
the right). The total hip measured bone min-
eral density decreased from 0.867 to 0.779 g/
cm2 (8.5% difference).
in an individual patient, it may be difficult to determine whether a m

small change in the bone mass measurement reflects precision SD = ∑ d /2m 2
j
error or true change. DXA reproducibility is influenced by instru- j =1
ment-, operator- and subject-dependent factors. These last two

tend to be much more important than the instrument itself, and where m subjects have paired measurements with dj the differ-
patient positioning is the single most important determinant (see ence in the first and second measurements. (Slightly different for-
Fig. 30.6). Although DXA instruments are ultimately calibrated mulae are used for 15 individuals with three scans or where
against excised bone samples, methodologic differences in how subjects have unequal numbers of scans.56)
this is performed have led to large discrepancies in patient mea- Subjects’ scans are commonly performed after simple reposi-
surements when performed on instruments from different vendors. tioning (arising from the scanner table between the repeat mea-
Calibration differences between otherwise identical machines also surements), though this is known to underestimate day-to-day
occur. Such differences are usually small (1% to 2%) but on occasion measurement error,60,61 and can lead to a significant rate of over
can be clinically significant (exceeding instrument reproducibility). categorization of change (up to 19.3% for the lumbar spine and up
Therefore, measurements from different machines are very difficult to 18.3% for the total hip).61 Other factors shown to have an
to compare, and whenever possible follow-up examinations should adverse effect on BMD precision are obesity,62 an abdominal pan-
be performed on the same machine. nus overlying the hip63 (Fig. 30.13), and the presence of focal
Assessment of precision errors in BMD testing is a prerequisite structural defects with the lumbar spine necessitating vertebral
for characterizing longitudinal changes (see Monitoring with Bone exclusions.64,65
Densitometry).56,57 The International Society for Clinical Densi- Precision can be stated as either SD or percent coefficient of
tometry (ISCD) has proposed a standardized methodology for such variation (%CV, defined as 100 • √SD/mean). Although precision
precision studies.58,59 The ISCD procedure states that precision error is commonly stated as a %CV, error is independent of bone
error (SD) should be obtained from an assessment with 30 degrees mass and will therefore be underestimated in the lower (osteopo-
of freedom (e.g., 30 individuals with two scans) drawn from the rotic) range.66 It is therefore preferable to express precision error
patient referral population and using the root mean square (RMS) as the absolute SD (g/cm2), and to use this as the basis for deter-
approach: mining whether change in BMD is significant or simply because of

1200 have merits and are complementary. An age-adjusted measure-

ment indicates whether the individual is average for their age and,
1100 if not, how markedly they deviate from the expected value. On the
other hand, bone strength depends upon bone mass and not the
sBMD (mg/cm2)
1000
age of the subject, therefore predictions in terms of fracture risk
900 are best based upon comparison with an absolute standard (young
T = –2.5 adult).
800
T = –2.5 Z = –2.5 In 1994, the WHO formulated diagnostic ranges for osteoporo-
700 sis based upon T-score which have been refined more recently.1,14,15
Z = –0.5 Fracture risk is continuous – there is no “fracture threshold”68 –
600 and these ranges were originally intended to be used to provide a
framework for collection of epidemiologic data. The classification
500
20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 was based upon data derived almost exclusively from postmeno-
Age pausal Caucasian women, but in recent years have been extended
to all menopausal women and also men after the age of 50 (Table
Figure 30.14. An 80-year-old woman’s bone mineral density (BMD) of the hip that is average 30.1). The operational definition of osteoporosis is a BMD T-score
for her age (648 mg/cm2) will have a Z-score of –0.5 but a T-score of –2.5. A 30-year-old that lies 2.5 SDs or more below the average mean value for young
woman with exactly the same bone density measurement would have a T-score and Z-score
that are both –2.5. WHO, World Health Organization. (Reproduced with permission from Leslie healthy women (T-score ≤−2.5 SD) based upon a standardized ref-

WD, Roe BE. Bone densitometry. In: Leslie WD, Greenberg D, eds. Nuclear Medicine. Austin: erence site (the femoral neck) and a standard reference range for
Landes Bioscience, 2003:93–120.) both men and women (the NHANES III data for women aged 20
to 29 years). Classification of T-scores between −1 and −2.5 is
more controversial.69 In the past this was referred to as “osteope-
the measurement error.66 The smallest change that must be pres- nia,” terminology that created problems as a word commonly used
ent before one can conclude (with 95% confidence) that the change by radiologists to describe the radiographic appearance of bones,
in BMD is not related to measurement error is 2.77 • SD,56,57 and and confused with “osteoporosis” by patients and physicians as an
a value known as the least significant change (LSC). Vendors fre- equally serious medical disorder requiring treatment. For these
quently cite in vivo precision as ~1% for DXA instruments, but this reasons, the term “osteopenia” is best avoided, and the descriptive
significantly underestimates the error seen in nonresearch, clini- term “low bone mass” or “low bone density” is now preferred for
cal populations. The minimum acceptable precision is: Lumbar people with T-scores between −1 and −2.5.
spine: 1.9% (LSC = 5.3%), total hip: 1.8% (LSC = 5%), femoral neck: The occurrence of fragility fractures, especially minimal trauma
2.5% (LSC = 6.9%).67 Reproducibility is optimized through a sys- vertebral compression fractures, is sufficient for a clinical diagno-
temic process that includes careful quality control of the instru- sis of osteoporosis in any group providing that other pathologic
ment, scanning technique, and analysis. Reproducibility is further causes (such as neoplasm) have been excluded. The criteria for
compromised when examining smaller regions of interest. Femo- diagnosing osteoporosis from bone density alone are more contro-
ral neck precision is much worse than the total hip region, and versial when applied to groups other than postmenopausal Cauca-
Ward’s region (a subregion within the femoral neck that contains sian women. For example, men have higher average bone density
little trabecular bone) is so variable that it is of no clinical value. than women but also have a lower fracture rate. The absolute like-
lihood of fracture in men seems to show the same relationship to
T-Scores and Z-Scores absolute bone density as in women.70,71 This has led to uncertainty
over whether the osteoporosis threshold in men should be based
Absolute measurements of bone density are of limited value. They upon a male or female reference group.72 Similar concerns arise
are influenced by the site chosen for measurement, calibration over comparison to non-Caucasian groups.69 Black subjects have
used by the equipment manufacturer, and even the particular significantly higher bone density and lower fracture rates than
instrument. Because bone density follows a bell-shaped (Gaussian) Caucasians, suggesting a similar relationship between absolute
distribution, measurements are conventionally described in terms bone density and absolute fracture risk. In contrast, Asians have
of the number of SDs that a value deviates from the population lower hip bone density than Caucasians but paradoxically have a
mean (Fig. 30.14). Age-related changes in bone density, described much lower fracture likelihood. The reasons for this are still
earlier, must be taken into account. debated but include shorter stature, likelihood of falling, and pos-
The Z-score refers to the number of SD above or below the sibly shorter femoral neck (resulting in shorter hip axis length).
mean for an age- and sex-matched population (if reference data Finally, osteoporosis should not be diagnosed by BMD alone in
are available then race/ethnicity should also be considered): premenopausal women, men younger than the age of 50, or chil-
dren.69 The recommendation to use Z-scores in young adults is, in
(patient’s measured BMD part, intended to prevent misapplication of WHO criteria, which
– mean BMD of age – matched population) are based upon the T-score, and to avoid inappropriate treatment.
Z-score =
(SD of BMD of young normal population) The WHO criteria were developed for postmenopausal females,
and extrapolation to other groups may not identify people at equiv-
The T-score refers to the number of SD above or below the
alent levels of fracture risk. Age is a strong predictor of fracture
mean for a young adult population (age 20 to 30 years):
risk that is independent of BMD. Because healthy young adults
(patient’s measured BMD have low short-term fracture risk across the BMD spectrum an
− mean BMD of young normal population) arbitrary T-score (or Z-score) diagnostic cutoff does not have the
T -score =
(SD of BMD of young normal population) same significance in a 30-year-old as in a 70-year-old. BMD mea-
surement in healthy premenopausal women and men younger
In interpreting an individual patient’s test results, the following than the age of 50 cannot be used to assess short-term fracture
question is confronted: Should you compare the patient with risk and is only recommended to assess the skeletal impact of spe-
someone of the same age or with a young adult? The former cific conditions. Conceptually, the Z-score is best suited to this pur-
masks the increasing prevalence of osteoporosis with advancing pose and avoids incorrectly labeling patients according to WHO
age, while judging a 90-year-old against the same standard used criteria. Figure 30.15 shows DXA results for a 28-year-old healthy
in a 30-year-old seems unreasonable. In reality, both approaches male who had unnecessary BMD testing. He was concerned to be

Neck
1.4
1.2 DXA results summary:

1.0
Region BMD T - score Z - score
BMD
0.8 (g/cm2)
Neck 0.703 –1.7 –1.6
0.6
Total 0.879 –1.0 –1.0
0.4
Total BMD CV 1.0%
0.2
20 25 30 35 40 45 50 55 60 65 70 75 80 85
WHO classification: Osteopenia
Fracture risk: Increased
125 × 149 Age
NECK: 49 × 15
T-score versus white male; Z-score versus white male.
Source:BMDCS/NHANES
L1–L4
1.6
1.4
Region BMD T - score Z - score
1.2 (g/cm2)
1.0 L1–L4 0.807 –2.6 –2.6
BMD
0.8
Total BMD CV 1.0%
0.6 WHO classification: Osteoporosis
0.4 Fracture risk: High
0.2 Figure 30.15. Dual-energy x-ray absorptiometry
20 25 30 35 40 45 50 55 60 65 70 75 80 85 (DXA) results for a 28-year-old healthy male who had
116 × 139 Age unnecessary bone mineral density (BMD) testing.
told that he had osteoporosis and high fracture risk based upon the Pediatric Bone Densitometry
lumbar spine T-score of −2.6, highlighting the harm that can be
done by inappropriate testing and reporting. A more accurate It is inappropriate to generate T-scores or apply WHO diagnostic
interpretation would be that his spine BMD is “below the expected criteria to children because they have not yet achieved peak bone
range for age” (hip BMD is “within the expected range for age”) mass. The interpretation of BMD in children is challenging as
and his fracture risk is currently low. Reduced BMD in healthy BMD is expected to increase (not remain stable as in adults), and
young people does not predict high fracture risk (young age is a BMD measurements by DXA are strongly affected by height status.
stronger BMD-independent protective factor).73 Reduced BMD in Delayed skeletal growth and maturation interferes with the use of
healthy young people usually reflects reduced attainment of peak age-matched reference data. Erroneous interpretation can arise
bone mass, not BMD loss or high bone turnover (which are char- when appropriate adjustments are not made for children with
acteristic features of postmenopausal and age-related osteoporo- growth or maturational delay. Many methods to adjust BMC/BMD
sis). Drug therapy is usually not warranted, though optimization of Z-scores for height give biased results, though the height-age
diet, exercise, and lifestyle would be reasonable, in addition to lim- Z-score (HAZ) method show the least biased relative to HAZ and
ited investigation to exclude an undiagnosed medical condition. age and can be used to evaluate the effect of short or tall stature
The reduced BMD in this case was attributed to being very slim on BMC/BMD Z-scores.74,75
with small skeletal size that did not provide an accurate measure- Figure 30.16 shows the DXA assessment in a young female
ment of his true volumetric BMD (see Limitations and Errors in with steroid-dependent lupus scanned initially at the age of 10.5
Dual Energy X-ray Absorptiometry). and again at the age of 16.6. BMD measurements were virtually
Figure 30.16. Total-body dual-energy x-ray

absorptiometry assessment in a young female
scanned initially at age 10.5 and again at age
16.6 (see text). BMC, bone mineral content;
BMD, bone mineral density.

Figure 30.17. Body composition analysis

for a 50-year-old woman being assessed
prior to bariatric surgery. The body mass
index (BMI) is in the obese range, with a total-
body fat mass 53.8 kg and a total-body lean
tissue mass 47.6 kg.
identical (0.884 g/cm2 and 0.896 g/cm2) but because of the chang- as the trunk, can be extracted from these scans. Regional fat tissue
ing age-specific reference data the Z-scores were very different composition can be measured from spine and hip DXA, and esti-
(initial −0.2 was within the expected range for age, final −2.9 was mates total-body composition more accurately than with BMI.91
below the expected range for age). Height at the time of the final DXA-derived abdominal fat measurement has been shown to pre-
scan was 147.2 cm (58 in) which is well below the average age dict risk for subsequent diabetes diagnosis in 30,252 nondiabetic
(HAZ −2.4). When BMD is HAZ-adjusted, the Z-score improves to women aged 40 years and older referred for baseline osteoporosis
−1.7 which is now within the expected range for age (though still assessment.92 During mean 5.2 years of observation, 1,252 (4.1%)
slightly below average), indicating the importance of considering women met the case definition for diabetes. Greater proportion of
and adjusting for impaired skeletal growth. For a detailed review abdominal fat from spine DXA was strongly related to subsequent
of pediatric bone densitometry the reader is encouraged to read diabetes diagnosis in models adjusted for age, BMI, and other
the reviews and Official Positions from the 2007 International comorbidities. Those in the highest quintile had 3.56 (95% CI: 2.67
Society for Clinical Densitometry Pediatric Position Development to 4.75) times the risk for subsequent diabetes diagnosis compared
Conference.76–79 with those in the lowest quintile.
DXA-derived body composition is still largely a clinical research
tool, but may assume increasing clinical relevance for cancer survi-
Body Composition vors. AIs used as adjuvant therapy in postmenopausal breast can-
Overweight and obesity are reaching epidemic proportions in cer induce a reduction in bioavailable estrogens with alterations in
countries around the world, predicted to result in a high popula- body composition.93 In a subanalysis of a 2-year randomized clini-
tion burden of diabetes, cardiovascular and cerebrovascular cal trial of 82 women with nonmetastatic breast cancer, newly
diseases.80,81 Body mass index (BMI) is most frequently used to menopausal following chemotherapy, women on AIs gained a sig-
assess overweight and obesity, but may erroneously categorize nificant amount of lean body mass compared to baseline as well as
some individuals.82 For example, it does not distinguish increased to non-AI users. Women not on an AI gained total body fat com-
weight related to muscle mass in athletes from adiposity. It also pared to baseline and AI users. There are epidemiologic data link-
does not account for the distribution of excess weight, and may ing overweight, diabetes, and postmenopausal breast cancer.94 The
not accurately reflect intra-abdominal fat83,84 which is more closely RR for postmenopausal breast cancer is around 1.5 for overweight
linked to metabolic syndrome and its complications than other fat women and >2 for obese women; diabetes is associated with post-
depots.85,86 The greater importance of abdominal fat is highlighted menopausal breast cancer with summary RRs from meta-analyses
in data from 2,739 US women who participated in the Heart and of 1.15 to 1.20. A systematic review and meta-analysis concluded
Estrogen/progestin Replacement Study which found that larger that women with breast cancer and pre-existing diabetes have a
waist circumference was associated with increased mortality greater risk of death, tend to present at more advanced stages and
whereas higher BMI (adjusted for waist circumference) was associ- receive altered treatment regimens.95 Changes in body composition
ated with decreased risk of total mortality, independent of cardiac are also relevant to men with prostate cancer undergoing androgen
risk factors.87 deprivation therapy (ADT). A systematic review and meta-analysis
DXA can estimate soft tissue composition by decomposing the found that ADT for prostate cancer is associated with increased fat
amount of attenuation from the two x-ray energies in bone-free and decreased lean mass96 which likely contributes to the reported
pixels to calculate the amount of lean tissue and fat tissue in the increased risk for diabetes and cardiovascular disease in men with
path of the beam. DXA is most widely used for assessment of osteo- prostate cancer receiving ADT.97 Pooling data from 16 studies
porosis but is also a well-validated technique for body composition showed that ADT increased percent body fat by on average 7.7%
analysis (Fig. 30.17).88 DXA measures account for 80% of the varia- (95% CI: 4.3, 11.2, from seven studies, p < 0.0001) and decreased
tion in intra-abdominal fat as measured by CT.89 Data indicate that percent lean body mass by on average −2.8% (95% CI: −3.6, −2,
DXA-derived body composition can in turn be used to predict over- from six studies, p < 0.0001), with increased body weight (2.1%,
all mortality and cardiovascular-related deaths.90 Whole-body fat p < 0.0001 from nine studies) and BMI (2.2%, p < 0.0001,
mass and lean mass can be measured and specific subregions, such from eight studies).96

1200 except for measurements at hip and spine, which have better pre-
dictive ability for fractures in hip (RR per SD 2.6) and spine (RR per
1100
SD 2.3), respectively. Figure 30.19 illustrates why a larger gradient
1000 of risk improves fracture risk stratification.
sBMD (mg/cm2)
900
Z = 0: RR = 1 Absolute Fracture Risk Assessment Tools
800
Z = –1: RR 2.6 The ability to accurately determine fracture risk is critical in identi-
700
fying cost-effective thresholds for intervention.13,98 Recently, there
600 Z = –2: RR 2.6 × 2.6 = 6.8 has been a shift from risk assessment based upon T-score categories
500 to absolute fracture risk based on 10-year absolute fracture proba-
Z = –3: RR 2.6 × 2.6 × 2.6 = 17.6
bility.13 Although reduced bone mass is an important and easily
400 quantifiable measurement, studies have shown that most fractures
20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
occur in individuals with a BMD T-score above the operational
Age
threshold for osteoporosis.2,99 The use of new fracture risk predic-
Figure 30.18. A 60-year-old woman has bone density measurements of the hip with a tion systems that integrate multiple CRFs has been shown to
T-score of –2 and a Z-score of –3. The relative risk (RR) of hip fracture (compared with an enhance the performance of BMD in the prediction of hip and other
average 60-year-old woman) increases with an RR of 2.6 for each standard deviation below major osteoporotic fractures.100 This has initiated a paradigm shift
average. Therefore, the RR of hip fracture is increased 18-fold (2.63), placing the woman at mark-
edly increased risk. (Reproduced with permission from Leslie WD, Roe BE. Bone densitometry. In: in the field of osteoporosis. One such example, the fracture risk
Leslie WD, Greenberg D, eds. Nuclear Medicine. Austin: Landes Bioscience, 2003:93–120.) assessment tool (FRAX, http://www.shef.ac.uk/FRAX), was devel-
oped by the WHO Collaborating Centre for Metabolic Bone Diseases
for estimation of individual 10-year osteoporotic and hip fracture
Fracture Risk Assessment probability (Fig. 30.20).101 The output of FRAX is the 10-year prob-
ability of a major fracture (hip, clinical spine, humerus, or wrist
Predicting Fractures from Bone Density fracture) and the 10-year probability of hip fracture. In addition to a
prior fragility fracture, age, sex, BMI, and additional risk factors for
Measurements fractures were identified including the prior use of glucocorticoids,
The mechanical strength of excised bone is strongly related to the secondary osteoporosis, rheumatoid arthritis, a parental history of
amount of bone mineral. Although bone density is on average sig- hip fracture, current cigarette smoking, and alcohol intake of three
nificantly lower in fracture patients than in nonfracture patients, or more units daily (Table 30.3).102 Femoral neck BMD can be option-
there is considerable overlap between the two groups. Risk of ally entered to enhance fracture risk prediction. Unlike other algo-
fracture shows a continuous gradient relationship with bone den- rithms,103–105 fracture probability is computed taking both the risk of
sity: There is no “fracture threshold.” Bone density measurement fracture and the risk of death into account. This is important because
provides a relative gradient of risk (usually expressed as a rate ratio some of the risk factors affect the risk of death as well as the fracture
[RR] per SD) that is as good as other commonly used risk stratifica- risk. Examples include increasing age, low BMI, low BMD, glucocorti-
tion measures such as blood pressure for stroke and serum choles- coids, and smoking. Population-specific FRAX tools are customized to
terol for cardiovascular disease.68 The increase in fracture risk with the fracture and mortality epidemiology in a specific region.101 Table
decreasing bone density is exponential (not simply additive). The 30.4 shows the marked variation in fracture probabilities that occur
effect of a progressive reduction in hip BMD on hip fracture risk is by using a different FRAX calculation tool. The highest and lowest
shown in Figure 30.18, where a reduction by 3 SDs translates into calculated probabilities differ by more than an order in magnitude,
a 17.6-fold increase in fracture risk. Prospective studies show that consistent with the large global variation in fracture rates, and high-
all studies measuring bone density at any site had similar predictive lighting the importance of using the appropriate FRAX tool. At present
ability for a decrease of 1 SD in bone density (RR per SD ∼1.5), more than 50 FRAX models are available, and others are being
45
40
RR = 2.50
35
30
Fracture risk
RR = 2.25
25
20
RR = 2.20
15
10 RR = 1.75
RR = 1.50
5
RR = 1.25
0 Figure 30.19. Relative fracture risk according to bone
–4 –3 –2 –1 0
mineral density T-score and gradient of risk (relative risk
T-score [RR] per standard deviation reduction).


Figure 30.20. Screen page for input of data and format of
results for a US Caucasian model using the fracture risk
assessment tool known as FRAX. Results are for a hypo-
thetical 65-year-old Caucasian woman who smokes ciga-
rettes and has a femoral neck T-score of −2.3 which is above
the osteoporotic threshold. Under the National Osteoporosis
Foundation (NOF) and American Association of Clinical Endo-
crinologists (AACE) guidelines, she would qualify for treat-
ment based upon a 10-year hip fracture probability exceeding
3%. (US FRAX tool version 3.4, http://www.shef.ac.uk/FRAX.)
developed. The FRAX system has been endorsed and integrated into with femoral neck BMD based upon the strength of the association
CPGs by several national bodies.106–114Despite the wide acceptance of with subsequent fractures (particularly hip fractures) in the FRAX
FRAX, it should not be uncritically used in the management of derivation cohorts and the availability of a standardized young
patients without an appreciation of its limitations as well as its adult reference database (NHANES III white female) for calculation
strengths. Some of these limitations were highlighted in a recent set of T-scores. Lumbar spine BMD is also strongly associated with
of reports from joint IOF–ISCD Task Forces.115 For example, mea- future fracture risk, especially spine fractures.68 Therefore, FRAX
surements other than BMD or T-score at the femoral neck by DXA may underestimate or overestimate major osteoporotic fracture
cannot be used in FRAX. The FRAX algorithm was calibrated for use risk when lumbar spine T-score is much lower or higher (>1 SD
discrepancy) than femoral neck T-score. It is not uncommon to find
Table 30. 3 situations where T-scores in the lumbar spine and femoral neck
show “discordance,” given the modest correlation in BMD between
Clinical Risk Factors in the World Health Organization these two sites (typically R = 0.6 to 0.7).116,117 One report found that
Fracture Risk Assessment (FRAX) Algorithm approximately one in eight women had discordance exceeding 2 SD
based upon lumbar spine, femoral neck, total hip, and trochanter.118
It may seem intuitively obvious to practicing clinicians that when
• Age
• Sex two individuals differ in their spine measurements (e.g., Patient 1
• Body mass index with lumbar spine T-score = −1.5 versus Patient 2 with lumbar
• Previous fragility fracture, particularly of the hip, wrist, and spine spine T-score = −3.5) but who are identical in all other respects
• Parental history of hip fracture (Patient 1 and Patient 2 both have femoral neck T-score = −1.5), the
• Glucocorticoid treatment (>5 mg prednisone daily for 3 mos or more) individual with the lower lumbar spine measurement (Patient 2)
• Current smoking would be at higher fracture risk. These two individuals would gen-
• Alcohol intake 3 or more units daily erate identical fracture probabilities under FRAX, though available
• Rheumatoid arthritis data suggest that Patient 2 in the scenario above does indeed have
• Other secondary causes of osteoporosis
higher fracture risk than Patient 1.119 Observed fracture rates
• Untreated hypogonadism in men and women, for example, premature menopause,
bilateral oophorectomy or orchidectomy, anorexia nervosa, aromatase inhibitors for exceeded those predicted by FRAX when the lumbar spine T-score
breast cancer, androgen deprivation for prostate cancer, hypopituitarism was much lower than the femoral neck T-score (>1 SD discrepancy),
• Inflammatory bowel disease, for example, Crohn’s disease and ulcerative colitis and conversely, fracture rates were lower than predicted when the
• Prolonged immobility, for example, spinal cord injury, Parkinson’s disease, lumbar spine T-score was much higher than the femoral neck
stroke, muscular dystrophy, ankylosing spondylitis T-score.120
• Organ transplantation A simple procedure for adjusting the FRAX estimation of major
• Type 1 diabetes osteoporotic fracture probability based upon the T-score difference
• Thyroid disorders, for example, untreated hyperthyroidism, overtreated (offset) between the lumbar spine and femoral neck has been
hypothyroidism
endorsed with the ISCD–IOF Task Force.120 For every offset SD dif-
• Chronic obstructive pulmonary disease
ference there was an approximately 10% change in fracture risk
Modified from Kanis JA, McCloskey EV, Johansson H, et al. How to decide who to treat. Best that was higher when the lumbar spine T-score was less than the
Pract Res Clin Rheumatol. 2009;23(6):711–726. femoral neck T-score and lower when the lumbar spine T-score was

Ta b l e 3 0 . 4
Variation in FRAX 10-Year Fracture Probabilities (%) According to Country

(Highest to Lowest) for an Individual Aged 65 Years with a Prior Fragility
Fracture with Femoral Neck T-Score −2.5
Major Fracture Hip Fracture

Female Male Female Male
Denmark 28 23 Denmark 8.9 11
Sweden 24 21 Sweden 8 9.9
Switzerland 23 18 Taiwan 6.8 8
United States (Caucasian) 22 18 Austria 6.7 7.7
United Kingdom 20 16 Malta 6.5 7.6
Austria 20 17 Belgium 5.8 6.8
Taiwan 19 16 Singapore (Chinese) 5.8 7.1
Canada 19 16 Switzerland 5.7 6.8
Malta 18 16 Singapore (Malay) 5.6 6.7
Belgium 18 15 South Korea 5.3 5.5
Singapore (Malay) 17 14 Singapore (Indian) 5.2 6.5
Japan 17 14 Italy 5.1 6
Singapore (Chinese) 16 14 Argentina 4.9 5.3
Italy 16 13 Czech Republic 4.9 6.9
South Korea 15 12 United Kingdom 4.9 5.8
Singapore (Indian) 15 13 Hungary 4.8 4.8
Hungary 15 11 United States (Caucasian) 4.8 5.8
Czech Republic 15 15 Germany 4.6 5.2
Argentina 15 12 Finland 4.4 5
Germany 14 12 Canada 4.2 5.2
Finland 14 11 Romania 4.1 4.4
United States (Hispanic) 13 11 Mexico 4 4.7
Turkey 13 10 Netherlands 3.9 4.8
Mexico 13 11 Turkey 3.7 4.3
United States (Asian) 12 10 France 3.6 4.2
Romania 12 9.4 New Zealand 3.5 4.1
Netherlands 12 11 Poland 3.5 3.8
Poland 11 8.2 Japan 3.4 4.1
New Zealand 11 9.2 Jordan 3.3 3.4
France 11 9.5 Australia 3 3.8
United States (Black) 10 7.5 Colombia 2.9 3.4
Jordan 10 7.5 Spain 2.9 3.4
Spain 9.3 7.7 United States (Asian) 2.7 3.4
Colombia 9 7.4 United States (Hispanic) 2.7 3.4
Australia 9 8 Lebanon 2.5 2.6
Lebanon 8.4 6.3 China 2.2 2.4
Hong Kong 7.1 5.6 Hong Kong 2.2 2.4
China 7.1 5.6 Philipines 2.1 2.1
Philipines 7 5 United States (Black) 2.1 2.4
Tunisia 2.5 2 Tunisia 0.8 0.9
From version 3.4 FRAX, www.sheffield.ac.uk/FRAX.

greater than the femoral neck T-score. The offset adjustment was Pharmacologic Therapy
found to reclassify fracture probability in a relatively small propor-
tion overall (less than 10%) but reclassified a larger number of indi- There are expanding evidence-based options for osteoporosis ther-
viduals with moderate risk and an offset greater than 1 SD (one in apy.124 Estrogen replacement has largely been replaced by bisphos-
four). The rule that was developed was, “Increase/decrease FRAX phonates, nasal calcitonin, selective estrogen receptor modulators
estimate for a major fracture by one-tenth for each rounded T-score (SERMs), and denosumab. These agents act primarily through inhi-
difference between the lumbar spine and femoral neck.” An exam- bition of osteoclast number and activity. In contrast, there is only
ple of the rule application follows: “Consider an individual with one group of approved anabolic agents that act by stimulating osteo-
femoral neck T-score −1.7 and major osteoporotic FRAX probability blast activity. For vertebral fracture prevention, the following agents
18%. If the lumbar spine T-score is −3.5 then this indicates an offset have good evidence to support their use for individuals at high risk
of −1.8 (3.5 minus −1.7). This is rounded to the nearest whole num- of fracture: Alendronate, risedronate, ibandronate, zoledronic acid,
ber (−2). One-tenth of the FRAX estimate based upon the femoral teriparatide, raloxifene, denosumab, and estrogen.124 There is fair
neck is 1.8%, which is multiplied by the rounded offset value (giving evidence for the use of calcitonin in vertebral fracture prevention.
3.6%). This is then added (because lumbar spine T-score is lower For hip fracture prevention, the following therapies have good evi-
than femoral neck T-score) to the original FRAX estimate (18%) giv- dence: Alendronate, risedronate, zoledronic acid, denosumab, and
ing a final (rounded) probability of 22% (= 18% + 3.6%). estrogen. For nonvertebral fracture prevention, there is good evi-
dence for alendronate, zoledronic acid, risedronate, teriparatide,
denosumab, and estrogen.124 Therapeutic benefit is reduced or elim-
inated if there is suboptimal adherence to the regimen, including

General Approach to Osteoporosis frequently missed doses, failing to take the medication correctly to
in Oncology optimize absorption and action, or discontinuation of therapy.125–127
Compliance rates at 1 year in the range 25% to 50% with oral anti-
Although primary osteoporosis is most commonly seen in post- osteoporosis agents are commonly reported, and are only margin-
menopausal women and the elderly, a number of secondary causes ally better with less frequent dosing regimens.125,127
of bone loss should be considered in the evaluation of an individual
with low bone mass (Table 30.3). These factors may exist in isola- Bisphosphonates
tion, or accelerate bone loss in primary osteoporosis. The clinical
assessment should be directed toward elucidating these potential This class of drugs inhibits osteoclast number and activity, have few
causes and any fracture history. Assessment of the risk factors for extra-skeletal effects and have become the first-line treatment for
falls is an important adjunct to measuring bone density. Labora- osteoporosis. Alendronate is a potent aminobisphosphonate that is
tory testing can be limited to the measurement of serum calcium, capable of increasing bone density at the lumbar spine by 8% over
alkaline phosphatase, creatinine, and a complete blood count. In 3 years. More importantly, a meta-analysis of 11 studies representing
individuals with postmenopausal or age-related osteoporosis, all of 12,068 women receiving at least 1 year of alendronate for postmeno-
these indices should be within the normal range. These investiga- pausal osteoporosis128 was associated with significant reductions in
tions may be further expanded to include serum TSH, parathyroid vertebral fractures (RR: 0.55; 95% CI: 0.43 to 0.69) and for the sec-
hormone (PTH), serum 25-hydroxyvitamin D, protein electropho- ondary prevention of nonvertebral fractures (RR: 0.77; 95% CI: 0.64
resis, and 24-hour urinary calcium determination, as guided by to 0.92), wrist fractures (RR: 0.50; 95% CI: 0.34 to 0.73), and hip
clinical judgment. Although not routinely required, imaging of the fractures (RR: 0.47; 95% CI: 0.26 to 0.85).128 Similarly, a meta-anal-
thoracolumbar spine helps to determine the number and type of ysis assessing the efficacy of risedronate in the prevention of osteo-
pre-existing vertebral fractures, and their presence indicates high porotic fracture in postmenopausal women found a 37% (CI: 0.51 to
risk for further fractures. Biochemical markers of bone metabolism 0.77) reduction for vertebral fractures, a 20% reduction for nonver-
provide an indirect method to evaluate the rate of bone turnover.121 tebral fractures (RR: 0.80; 95% CI: 0.72 to 0.90), and a 26% reduction
Osteocalcin, bone-specific alkaline phosphatase, and procollagen I (RR: 0.74; 95% CI: 0.59 to 0.94) for hip fractures.129 In two trials with
peptide can assess the level of bone formation whereas urinary or zoledronic acid there was evidence of vertebral (RR: 0.33; CI: 0.274
serum measurements of type 1 collagen cross-links (such as deoxy- to 0.4), nonvertebral (RR: 0.75; CI: 0.66 to 0.85), and hip fracture
pyridinoline, N-telopeptide, and C-telopeptide) reflect the level of (RR: 0.62; CI: 0.47 to 0.83) reduction.130
bone resorption. These markers have not been useful for diagnos-
ing osteoporosis or for predicting bone loss, but some studies sug- Estrogen
gest that they independently predict fracture risk.122
Hormone replacement therapy (HRT) is effective at preventing bone
loss in postmenopausal women and is associated with a bone den-
Nonpharmacologic Therapy sity increase of 4% to 6% in the first 2 years of therapy. HRT reduces
General measures to reduce the risk of fractures should include overall fractures by about 30%, with benefit seen for vertebral frac-
assessment of hazards in the home environment, sedative use, tures (RR: 0.67; CI: 0.48 to 0.93), nonvertebral fractures (RR: 0.73,
muscle weakness, postural hypotension, and uncorrected visual CI: 0.64 to 0.81), and hip fractures (RR: 0.60; CI: 0.42 to 0.93).130
deficits. Exercise should also be encouraged in an attempt to pre- HRT is also associated with increased risk of breast cancer, cardio-
serve bone mass and to maintain or improve muscular condition- vascular events, and thromboembolism. Therefore, HRT is no longer
ing. Calcium supplementation is often necessary in postmenopausal seen as a first-line treatment for osteoporosis, but can be beneficial
and elderly women to reach recommended targets (1,200 mg/day). in women with moderate-to-severe vasomotor symptoms.
Calcium carbonate is the most commonly used supplement and is
recommended for those who do not have achlorhydria (common
in the very elderly and those on acid suppressing medication).
Selective Estrogen Receptor Modulators
Vitamin D supplementation (minimum recommended 600 to 800 New agents have been developed that retain estrogen’s positive
IU daily, maximum 4,000 IU daily) is also advised, even in those effects on bone, while attempting to minimize the associated risks
on antiresorptive therapy.123 The importance of calcium and vita- and side effects. This class of drugs is termed SERMs and includes
min D supplementation is even greater in the elderly as calcium raloxifene and tamoxifen. Raloxifene reduces the risk of vertebral
absorption is impaired and sunlight exposure is reduced, espe- fractures by approximately 40% (RR: 0.64; CI: 0.54 to 0.78), and
cially in winter months. produces increase in bone density of approximately 3% at the spine

in its first 3 years, but has not been shown to protect against nonver- associated with bisphosphonate therapy for osteoporosis appears to
tebral fractures.131 It also lowers total and LDL cholesterol, does not be much smaller than the number of vertebral, hip, and other frac-
stimulate the endometrium, and reduces the risk of breast cancer. tures that are prevented by bisphosphonates.
Calcitonin Who to Treat?

Salmon calcitonin has been used subcutaneously for many years. The
Fracture rates are known to vary by more than an order of magni-
intranasal form is more acceptable for long-term use. Despite modest
tude worldwide, therefore a single approach cannot be universally
effects on bone density, vertebral fracture risk is reduced by approx-
applied to all countries. National considerations must reflect the
imately 35% (RR: 0.65; CI: 0.48 to 0.88) though there is no effect for
burden of osteoporosis, available resources, the disease costs to the
nonvertebral fractures.130 Intranasal calcitonin has been shown to
individual and society, and how these relate to competing health and
reduce pain associated with acute vertebral fractures. A possible
other societal priorities. Recent developments in terms of diagnosis,
association between calcitonin use and cancer has recently led to a
fracture risk prediction, and therapeutic options have prompted
call for discontinuing its use in long-term osteoporosis treatment.132
many countries to review and update their clinical practice guide-
lines for the prevention and management of osteoporosis intended
Denosumab for use in primary care in the general adult population. A recent
Denosumab is a human monoclonal antibody to the RANK-L that review examined updated guidelines from the following countries:
blocks its binding to RANK, inhibiting the development and activa- Australia, Belgium, Canada, Germany, the United Kingdom, and the
tion of osteoclasts. In an RCT of 7,868 women, denosumab given United States.138
twice yearly reduced the risk of hip fracture by 40% compared to The American Association of Clinical Endocrinologists (AACE)
placebo (hazard ratio: 0.60; 95% CI: 0.37 to 0.97; ARR 0.5%) and updated US guidelines for prevention of and treatment of osteopo-
also reduced the risk of nonvertebral fracture by 20% (hazard rosis and related fractures in 2010.139 The scope of the guideline
ratio:, 0.80; 95% CI: 0.67 to 0.95; ARR: 1.5%).133 was limited to postmenopausal women. Bone densitometry was
recommended for all women aged 65 and older, and for postmeno-
Anabolic Agents pausal women younger than the age of 65 with one or more addi-
tional risk factors for fracture. The diagnosis of osteoporosis by
Strategies which directly stimulate osteoblast activity have the poten-
BMD criteria was limited to BMD at the lumbar spine, total hip,
tial to produce larger increases in bone density and potentially larger
femoral neck, and one-third radius site. Recommendations are also
effects on fracture prevention. One such strategy is the use of inter-
given for work-up of individuals with osteoporosis by bone density
mittent PTH therapy which has been demonstrated to produce large
criteria or fragility fractures for causes of secondary osteoporosis,
increases in BMD. Teriparatide, a recombinant form of PTH (amino
indications for lateral spine imaging to detect prevalent vertebral
acid sequence 1 through 34), is approved for the treatment of osteo-
fractures, for calcium and vitamin D intakes, and for lifestyle inter-
porosis in men and postmenopausal women who are at high risk for
ventions to reduce risk of fractures.
fracture. A meta-analysis concluded that both vertebral fractures
The AACE endorsed the U.S. National Osteoporosis Foundation
(RR: 0.36; CI: 0.23 to 0.57) and nonvertebral fractures (RR: 0.49; CI:
2008 guidelines, and on these aspects the two guidelines are iden-
0.27 to 0.87) were reduced by teriparatide.130 However, this agent is
tical. Pharmacotherapy (with an oral or IV bisphosphonate, calci-
contraindicated in those diagnosed with cancer because of an asso-
tonin, denosumab, raloxifene, or teriparatide) is recommended for
ciation between the drug and osteosarcomas in laboratory rats.
those who have had a hip or vertebral fracture (radiographic or
clinical), T-score ≤−2.5 at femoral neck, total hip, or lumbar spine,
Adverse Events or T-score −1 to −2.5 with hip or major osteoporotic 10-year frac-
Although generally well tolerated, there are a number of uncommon ture risks, respectively, of ≥3% or ≥20%. This guideline recom-
or rare adverse effects that have been associated with approved mends pharmacologic therapy for a substantially wider proportions
treatments, though a causal link has not always been clear.134,135 An of the population than other guidelines; for example, 91% of non-
infrequent adverse effect of oral aminobisphosphonate use is ero- Hispanic white women aged 80 and older with T-scores between
sive esophagitis, especially in patients with prior esophageal dis- −1 and −2.5 would be offered drug therapy using this guideline.140
ease, gastroesophageal reflux, or when directions are not carefully Because of their proven hip fracture reduction efficacy, alendro-
followed.134 Osteonecrosis of the jaw (ONJ) was initially described in nate, risedronate, zoledronic acid, and denosumab are recom-
2001 in oncology patients receiving high-dose intravenous bisphos- mended as the first-line agents. Simultaneous use of two or more
phonate therapy. Large epidemiologic studies have described an agents is not recommended. However, sequential therapy is stated
incidence of ONJ ranging from 2% to 11%; concomitant use of glu- to be appropriate at times, especially use of antiresorptive agents
cocorticoids, several chemotherapies, and recent dental extractions after a treatment course of teriparatide. The duration of drug ther-
appears to enhance the risk of ONJ. Among osteoporosis patients the apy considered to be safe is explicated in the guideline. Drug hol-
risk is much less clear, with an incidence between one in 10,000 and idays after many years of bisphosphonate therapy are thought to
one in 100,000.134,135 Severe bone pain, esophageal cancer, and be reasonable so long as BMD is followed and treatment reiniti-
atrial fibrillation have been described among bisphosphonate users, ated if bone loss occurs.
but their relationship is questionable. Of great concern are emerging Glucocorticoids are often used in the management of oncologic
reports of atypical subtrochanteric or diaphyseal femoral fractures and inflammatory conditions, but are associated with increased
in osteoporosis patients that have received long-term bisphospho- risk for osteoporosis, with resultant fractures.141 A rapid decline in
nate therapy.136 Major features include a transverse or short oblique BMD begins within the first 3 months of glucocorticoid initiation
orientation, minimal or no associated trauma, a medial spike when and peaks at 6 months, followed by a slower steady loss with
the fracture is complete, and absence of comminution; minor fea- continued use. An increased risk of both vertebral and nonverte-
tures include cortical thickening, a periosteal reaction of the lateral bral fractures occurs with dosages of prednisone or equivalent as
cortex, prodromal pain, bilaterality, delayed healing, comorbid con- low as 2.5 to 7.5 mg daily. In 2010, the American College of Rheu-
ditions, and concomitant drug exposures, including bisphospho- matology (ACR) published recommendations for the prevention
nates, other antiresorptive agents, glucocorticoids, and proton pump and treatment of glucocorticoid-induced osteoporosis.141 Updated
inhibitors. Recent observations suggest that the risk rises with approaches to identify patients at highest risk for fracture using
increasing duration of exposure.137 It is important to keep these the 10-year absolute probability of fracture calculated by the FRAX
reports in perspective: The incidence of atypical femoral fractures tool are incorporated into these guidelines.

Monitoring with Bone Densitometry Specific Applications in Oncology

Monitoring BMD in patients not receiving active treatment can
help in the identification of individuals with rapid bone loss (“fast Breast Cancer
losers”). Repeat testing may also be useful in confirming a positive Breast cancer is the most common cancer of women in both the
treatment response, although some evidence suggests that much of developing and developed world.146 Breast cancer survivors are at
the antifracture effect of current antiresorptive therapies is medi- increased risk for osteoporosis147 and fractures.148 This has been
ated through mechanisms other than increasing bone mass.142 attributed to the effects of chemotherapy, ovarian failure, early
Stable BMD is consistent with successful treatment. Therefore, the menopause, and more recently AIs. In postmenopausal women,
major objective of repeat testing in treated patients is to identify the use of AIs increases bone turnover and induces bone loss at
individuals with continued BMD loss, despite appropriate osteopo- sites rich in trabecular bone at an average rate of 1% to 3% per
rosis treatment. Measurement error must be considered when year leading to an increase in fracture incidence compared to that
interpreting serial BMD assessments to determine whether the seen during tamoxifen use.149 The bone loss is much more marked
change is real and not simply random fluctuation or artifact. Con- in young women with treatment-induced ovarian suppression fol-
tinued BMD loss exceeding the LSC may reflect poor adherence to lowed by AI therapy (average: 7% to 8% per annum). Pretreatment
therapy, failure to respond to therapy, or previously unrecognized with tamoxifen for 2 to 5 years may reduce the clinical signifi-
secondary causes of osteoporosis (e.g., vitamin D insufficiency). cance of the adverse bone effects associated with AIs, particularly
Patient-related factors also need to be considered at the time of if this leads to a shortening in the duration of exposure to an AI.
repeat testing, including the average rate of expected bone loss and

The rate of bone loss in women who experience a premature
the maximum rate of loss that is likely to be encountered. The latter menopause before the age of 45 or are receiving ovarian suppres-
is critical because follow-up bone mass measurements should ide- sion therapy is accelerated by the concomitant use of AIs. The
ally identify patients who are failing treatment before substantial Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial
bone loss develops or fractures occur. Average rates of bone loss are included a BMD substudy; 108 patients treated with monotherapy
greater in untreated early postmenopausal women (approximately AI or tamoxifen were included in the primary analysis.150 Among
2% per year) than in older women (less than 1% per year). The site anastrozole-treated patients, there was a decrease in median
of most rapid bone loss also changes with age. Loss of trabecular BMD from baseline to 5 years in lumbar spine (−6.08%) and total
bone from the spine exceeds that of the hip in early postmeno- hip (−7.24%) compared with the tamoxifen group (lumbar spine,
pausal women. Similarly, increase in skeletal mass from antiresorp- +2.77%; total hip, +0.74%). Importantly, no patients with normal
tive treatment is usually most evident in the spine because of the BMD at baseline became osteoporotic at 5 years.
relatively faster turnover of trabecular bone. For untreated older Studies in breast cancer patients receiving adjuvant AIs versus
subjects the decline in the hip generally exceeds that of the spine tamoxifen have documented an increased risk of fracture (increase
because of the development of age-related degenerative artifacts in 15% to 113%).149,151–155 It is notable that placebo arms were not
the spine. It should be emphasized that measurement imprecision included so that the effect of AIs alone is less clear, as tamoxifen
makes it difficult to accurately assess loss rates in individuals. These has a favorable effect on BMD in postmenopausal women156 and
have been stated to exceed 5% per year in some cases but the fre- this appears to translate into a reduced incidence of osteoporotic
quency of such rapid loss in the absence of major medical factors fracture.157 There has been no large adjuvant study of AIs versus
(such as high-dose steroid therapy) is low. It is likely that active placebo except for NCIC MA17.158 After 30 months of letrozole
treatment induces a “shift to the right” of the bone loss distribution, there was no difference in the incidence of fractures but because
decreasing the number of cases in which rapid loss occurs. of the prior exposure to tamoxifen in all the patients in this study,
No randomized trials have directly assessed the value of repeat it remains unclear what the effect the AI would be on the inci-
BMD testing on persistence with medication or fracture reduction. dence of fracture compared to untreated patients. Support for the
Notwithstanding the lack of conclusive data, many patients and possibility that some of the differences in fracture risk between
clinicians find value in an objective measurement that documents tamoxifen and AIs occur through a protective effect of tamoxifen
the effect of treatment.143 With careful attention to factors that can comes from population-based study of 2,748 older breast cancer
affect comparisons (Table 30.5), serial BMD testing can be a help- patients (mean age 73 years, 28.2% AI users, 27.8% tamoxifen
ful clinical tool.144 Depending on the clinical situation, BMD scans users, the remainder not using hormone therapy).159
are usually repeated every 1 to 3 years, with a decrease in testing Several randomized trials have confirmed that antiresorptive
once therapy is shown to be effective. In those at low risk without treatments can preserve BMD in women with primary breast can-
additional risk factors for rapid BMD loss, a longer testing interval cer under AI treatment, however reduction in fractures remains to
(5 to 10 years) may be sufficient.33,145 If BMD is stable then less be established (see review by Theriault160). For example, zole-
frequent monitoring can be considered. dronic acid and risedronate have been demonstrated to reduce
AI-associated BMD loss. Zoledronic acid prevents bone loss in
postmenopausal women with osteoporosis or low bone mass
Table 30 . 5 starting letrozole.161 Up-front zoledronic acid prevented AI-associ-
ated BMD loss with early breast cancer more effectively than
Checklist for Ensuring a Valid Bone Density delaying therapy until BMD loss or fracture occurs.162 As well, the
Comparison addition of zoledronic acid to adjuvant endocrine therapy improves
disease-free survival in premenopausal patients with estrogen-
Verify: responsive early breast cancer.163 For patients taking adjuvant
1. Same vendor and instrument anastrozole for early breast cancer, risedronate resulted in sig-
2. Machine quality control satisfactory (especially if recent servicing). nificant increase in lumbar spine and total hip BMD.164 A small
3. Consistent patient positioning. trial has also shown that the RANK ligand inhibitor, denosumab,
4. No dramatic change in weight. increased lumbar spine BMD by 5.5% and 7.6% at 12 and 24
5. Any bone mineral density change is reflected in an equivalent bone mineral months versus placebo (p < 0.0001 at both time points); increases
content change (not just different area). were also observed at the total hip, total body, femoral neck, and
6. Changes are consistent between sites (considering site-responsiveness and the one-third radius whereas bone turnover markers decreased.165
precision).
Serum estrogen is a risk factor for breast cancer166 and serum
7. Changes are consistent with therapeutic regimen.
estrogen is expected to confer a reduced risk for osteoporotic

Upper
Lower
Figure 30.21. Baseline dual-energy x-ray absorpti-

ometry scans for a 60-year-old Caucasian woman with
breast cancer starting aromatase inhibitor therapy (anas-
trozole). She had natural menopause at age 53, body
mass index 23.4 kg/m2, and no additional risk factors for
fracture. Her 10-year major osteoporotic fracture proba-
bility is 14% and hip fracture probability 4%. BMC, bone
mineral content; BMD, bone mineral density. (US FRAX
tool version 3.4, http://www.shef.ac.uk/FRAX.)
fracture because of its effect on BMD.167 Interestingly, there are Figures 30.21 and 30.22 show two representative cases
data showing that BMD measurements are associated with of women undergoing AI therapy for breast cancer. The case in
increased risk of overall and ER-positive breast cancer, and this Figure 30.21 shows a woman starting anastrozole who is osteo-
risk is independent of the Gail score.168–170 porotic on her baseline BMD test with 10-year major osteoporotic
The National Comprehensive Cancer Network (NCCN) guideline fracture probability 14% and hip fracture probability 4%. Under
on breast cancer (version 2.2011) recommends BMD monitoring at the National Osteoporosis Foundation (NOF) and AACE guidelines,
baseline and periodically in AI recipients. The optimal testing inter- she would qualify for osteoporosis treatment (in addition to opti-
val is unclear; a UK expert group suggested that postmenopausal mizing calcium and vitamin D) even in the absence of AI therapy
women with normal BMD at baseline do not require monitoring based upon her osteoporotic BMD and hip fracture probability
beyond the usual recommendation for healthy postmenopausal exceeding 3%. The case in Figure 30.22 indicates BMD loss in a
women.150 Women who experience premature menopause are at woman who has completed 3 years of anastrozole. Despite a 9.2%
greater risk for rapid BMD loss, and periodic monitoring is war- decrease in spine BMD and a 10.7% decrease in hip BMD, mea-
ranted in those receiving AIs even when baseline BMD is normal.150 surements remain average to above average for age and her
The NCCN also suggests that women treated with a bisphosphonate 10-year fracture risk is low. Continued monitoring and nonphar-
should undergo a dental examination with preventive dentistry macologic management without drug treatment for osteoporosis
prior to the initiation of therapy, and should take supplemental cal- would be appropriate.
cium and vitamin D. A UK expert group concluded that bisphospho-
nates, along with a healthy lifestyle and adequate intake of calcium
and vitamin D are the treatments of choice to prevent bone loss.149
Prostate Cancer
Because of the rate of bone loss associated with breast cancer treat- ADT, achieved by bilateral orchiectomy or administration of lutein-
ments, and uncertainties about the interaction between AI use and izing hormone-releasing hormone (LHRH) agonists, is the mainstay
BMD for fracture risk, the threshold for intervention was set at a of treatment for advanced prostate cancer. Serum testosterone and
higher level than that generally recommended for postmenopausal estrogen fall to subnormal levels, and these hormones are impor-
osteoporosis. tant for maintaining bone mass because they exert antiapoptotic

Upper

Lower
Figure 30.22. Repeat (US FRAX tool version 3.4,

http://www.shef.ac.uk/FRAX.) scans for a 62-year-old
Caucasian woman with breast cancer after 3 years of
aromatase inhibitor therapy (anastrozole). She had natu-
ral menopause at age 53, BMI 34.9 kg/m2 and current
smoking as an additional risk factor. Her 10-year major
osteoporotic fracture probability is 5.2% and hip fracture
probability 0.1%, which is low despite a significant
decrease in spine BMD (0.103 g/cm2, 9.2%) and total hip
BMD (0.120 g/cm2, 10.7%). BMC, bone mineral content;
BMD, bone mineral density. (US FRAX tool version 3.4,
http://www.shef.ac.uk/FRAX.)
effects on osteoblasts and osteocytes and proapoptotic effects on fragility fracture with current ADT were 1.71 (95% CI: 1.13 to
osteoclasts. Use of ADT can improve survival in men with locally 2.58)175 and 1.65 (95% CI: 1.53 to 1.77).176 Independent predictors
advanced prostate cancer but its prolonged use can lead to sig- of fragility and any fracture were increasing age, prior bone thin-
nificant bone loss that may affect health-related quality of life in ning medications, chronic kidney disease, prior dementia, prior
these men. More than 70% of men with prostate cancer are older fragility fracture, and prior osteoporosis diagnosis or treatment.175
than 65 and already at risk for osteoporosis or fragility fracture.171 A number of studies have investigated the effectiveness of anti-
Studies on bone health in men with prostate cancer receiving ADT osteoporosis therapies in men with nonmetastatic prostate cancer
and the current evidence regarding bone-health monitoring and receiving ADT. A systematic review and meta-analysis of bisphos-
management have been reviewed.172 phonates in the treatment of osteoporosis in patients with prostate
Bone loss in men who are receiving ADT is not a trivial issue. adenocarcinoma under ADT identified 15 published, randomized,
Men with nonmetastatic prostate cancer receiving continuous or placebo-controlled trials (2,634 participants). Treatment with
intermittent ADT can have significant BMD loss as early as the first bisphosphonates showed a substantial effect in preventing frac-
6 to 12 months after starting ADT, with annual BMD decrements of tures (RR, 0.80; p = 0.005) and BMD-defined osteoporosis (RR:
–1.4% to –4.6% at the lumbar spine, –0.6% to –3.3% at the total 0.39; p < 0.00001). Zoledronic acid showed the lowest number
hip, and –0.7% to –3.9% at the femoral neck.173 Several cohort needed to treat (NNT), compared with placebo, in relation to frac-
studies have shown that men who receive ADT for prostate cancer tures and osteoporosis (NNT = 14.9 and NNT = 2.68, respectively).
are also at much higher risk for fracture.172,173 In a linked database The between-group difference (bisphosphonates versus placebo) in
of the Surveillance, Epidemiology, and End Results (SEER) pro- lumbar spine and femoral neck BMD were 5.2% and 2.4%. Deno-
gram and Medicare, significantly more fractures occur in the sumab has been evaluated for men receiving ADT in a double-
50,613 men with prostate cancer surviving at least 5 years after blind, randomized trial.177 At 24 months, lumbar spine BMD had
diagnosis in 1992 to 1997 who received ADT with LHRH agonists increased by 5.6% in the denosumab group (loss of 1% in the pla-
(19.4%) than in those who did not (12.5%, p < 0.001).174 In more cebo group, p < 0.001) and had also significantly increased at the
recent population-based studies, adjusted odds ratios (ORs) for total hip, femoral neck, and distal third of the radius. Patients who

received denosumab had a decreased incidence of new vertebral 359 (16.4%) had subclinical hypothyroidism and 142 (6.5%) had
fractures at 36 months (1.5%, versus 3.9% with placebo, RR: 0.38; subclinical hyperthyroidism; no clear association between subclin-
95% CI: 0.19 to 0.78; p = 0.006). There are insufficient fracture ical thyroid dysfunction and hip fracture was observed. In contrast,
data in studies with SERMs and salmon calcitonin. 18 of 184 men with subclinical hypothyroidism sustained a hip
A cost-effectiveness study concluded that universal alendronate fracture (multivariable-adjusted hazard ratio: 2.31; 95% CI: 1.25 to
use without a BMD test was not justifiable in a hypothetical cohort 4.27) compared with 4 of 29 men with subclinical hyperthyroidism
of men 70 years of age receiving a 2-year course of ADT for locally (adjusted hazard ratio: 3.27, 95% CI: 0.99 to 11.30).
advanced or high-risk localized prostate cancer.178 The comparison The largest study to date used population record-linkage tech-
looked at three patient groups: No BMD test and no alendronate nology to identify patients over 18 years old with subclinical
therapy; a BMD test before ADT with selective alendronate therapy hyperthyroidism (identified from biochemistry, prescription, admis-
for 5 years in patients with osteoporosis; and universal alendro- sion, and radioactive iodine treatment records) and five matched
nate therapy for 5 years without a baseline BMD test. Universal comparators from the general population.185 There were a total of
alendronate use was justifiable in men 80 years of age and older 2,004 patients (77.4% female, mean age 66 years) with subclinical
with a previous low-trauma fracture or with low BMD at baseline hyperthyroidism (1,491 had serum TSH from 0.1 to 0.4 mU/L, 414
(femoral neck T-score −1.8 SDs or lower) and that alendronate can had TSH concentrations <0.1 mU/L). During the total follow-up
be considered for men in whom BMD test finds osteoporosis. period of 76,124 years (median, 5.6 years), subclinical hyperthy-
Under the NCCN guideline for prostate cancer (version 4.2011), roidism was associated with a slightly increased risk of osteoporotic
screening and treatment for osteoporosis are advised according to fracture (HR: 1.25; 95% CI: 1.04 to 1.50), but this was no longer
guidelines for the general population from the NOF (www.nof.org). significant when patients who developed overt hyperthyroidism
This includes recommendations for supplemental calcium (1,200 mg during follow-up were excluded (though there was increased risk of
daily) and vitamin D3 (800 to 1,000 IU daily) for all men over the cardiovascular morbidity [HR = 1.36 (1.19 to 1.57)], dysrhythmia
age of 50 years, and additional treatment for men when the 10-year [HR = 1.39 (1.02 to 1.90)], and dementia [HR = 1.79 (1.28 to 2.51)]).
probability of hip fracture is 3% or the 10-year probability of a The NCCN guidelines (version 2.2012) recognize the potential tox-
major osteoporosis-related fracture is 20% according to the WHO– icities associated with TSH-suppressive doses of levothyroxine—
FRAX system. A baseline BMD study should be considered for men including bone demineralization (particularly in postmenopausal
with surgical or medical ADT. When men with prostate cancer are women)— and that patients whose TSH levels are chronically sup-
diagnosed with low BMD or osteoporosis, their management should pressed should be counseled to ensure adequate daily intake of cal-
follow the guidelines set out for men with osteoporosis. cium (1,200 mg/day) and vitamin D (1,000 U/day). There are no
specific recommendations regarding BMD testing and monitoring
though this would appear to be prudent in selected cases (e.g.,
Thyroid Cancer women aged 65 years or older, and younger postmenopausal women
Most guidelines recommend the use of levothyroxine to maintain or with additional risk factors, especially when serum TSH suppres-
low TSH levels in treatment of patients with papillary, follicular, or sion <0.1 mU/L is required). An individualized approach to TSH man-
Hürthle cell thyroid carcinoma.179 Thyroid hormone is known to agement should consider the benefits and potential for adverse
stimulate the bone remodeling cycle, and biochemical markers of effects induced by iatrogenic subclinical hyperthyroidism.186 More
bone turnover are elevated in women with excess thyroid hor- aggressive TSH suppression is indicated in patients with high-risk
mone.180 This has created the concern that excess thyroid hormone disease or recurrent tumor, whereas less aggressive TSH suppression
as used for TSH suppression may be associated with detrimental is reasonable in low-risk patients. Normalization of serum TSH is
effects on bone, even in asymptomatic persons. appropriate for long-term treatment of disease-free elderly patients
Clinically diagnosed hyperthyroidism has been associated with with differentiated thyroid cancer and significant comorbidities.
reduced BMD and increased hip fracture risk in older women,181 Figure 30.3 illustrates these principles applied to a 76-year-old
but not premenopausal women.182 Whether subclinical hyperthy- woman with papillary thyroid cancer who requires aggressive
roidism is a major risk factor for osteoporosis and/or fractures is TSH suppression for presumed residual disease based upon a
less clear. The Study of Osteoporotic Fractures (SOF) prospectively markedly elevated serum thyroglobulin (>500 ug/L) that could not
measured serum TSH and serial BMD measurements in a sub- be localized on extensive imaging including FDG PET/CT and was
group of 487 women (including 198 thyroid hormone users) older resistant to empirical radioiodine. Her fracture risk is relatively
than 65 years of age.180 Bone turnover markers (serum osteocalcin low based upon BMD measurements (10-year major osteoporotic
and bone-specific ALP) were elevated in women with low TSH, sug- fracture probability 10% and hip fracture probability 1.9% from
gesting accelerated bone remodeling, but there was no consistent the US FRAX tool version 3.4). However, VFA done at the time of
evidence that low TSH was associated with low baseline BMD or BMD testing showed a moderate asymptomatic T12 vertebral
accelerated bone loss in older ambulatory women. A separate compression fracture (Fig. 30.9 [middle]), not reported on the
report from the SOF cohort assessed serum TSH in a nested case- prior CT scan but confirmed on review with benign features.
control subgroup of women older than 65 years of age (148 women Under the NOF and AACE guidelines, she would qualify for osteo-
with new hip fractures, 149 women with new vertebral fractures, porosis treatment (in addition to optimizing calcium and vitamin
and 398 randomly selected women).183 Women with a low TSH D) based upon the vertebral fracture.
level (<0.1 mU/L) had increased risk for hip fracture (adjusted
relative hazard: 3.6; [95% CI: 1 to 12.9]) and vertebral fracture
(adjusted odds ratio: 4.5 [CI: 1.3 to 15.6]) compared with women Summary
who had normal TSH levels. Unfortunately, serum thyroxine or tri-
idothyronine levels were not measured and it was not possible to More cancer patients are surviving into old age and are at risk for
determine the independent effect of subclinical versus overt hyper- osteoporosis. Osteoporosis is also a consequence of some cancer
thyroidism. Use of thyroid hormone itself was not associated with treatments (e.g., AI for breast cancer, ADT for prostate cancer, and
increased risk for fracture if TSH levels were normal. The Cardio- TSH suppression for differentiated thyroid cancer). Bisphospho-
vascular Health Study (CHS) is a prospective community-based nates, along with a healthy lifestyle and adequate intake of cal-
cohort study of community-dwelling men and women aged 65 cium and vitamin D, are currently the treatments of choice to
years and older of whom 3,567 had biochemically defined sub- prevent bone loss. Randomized clinical trials for some of these
clinical thyroid dysfunction or euthyroidism with 39,952 person- conditions show that targeted treatment can prevent the BMD loss
years of follow-up (median, 13 years).184 Among the 2,195 women, and the accelerated bone turnover associated with oncologic

therapy. Treatment initiation is based on an assessment of frac- 30. Duncan EL, Brown MA. Clinical review 2: Genetic determinants of bone den-
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154. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane 183. Bauer DC, Ettinger B, Nevitt MC, et al. Risk for fracture in women with low
versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane serum levels of thyroid-stimulating hormone. Ann Intern Med. 2001;
Study): A randomised controlled trial. Lancet. 2007;369(9561):559–570. 134(7):561–568.
155. Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with 184. Lee JS, Buzkova P, Fink HA, et al. Subclinical thyroid dysfunction and incident
endocrine-responsive early breast cancer to anastrozole after 2 years’ adju- hip fracture in older adults. Arch Intern Med. 2010;170(21):1876–1883.
vant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 185. Vadiveloo T, Donnan PT, Cochrane L, et al. The Thyroid Epidemiology, Audit,
2005;366(9484):455–462. and Research Study (TEARS): Morbidity in patients with endogenous subclini-
156. Ding H, Field TS. Bone health in postmenopausal women with early breast cal hyperthyroidism. J Clin Endocrinol Metab. 2011;96(5):1344–1351.
cancer: How protective is tamoxifen? Cancer Treat Rev. 2007;33(6):506–513. 186. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of
157. Cooke AL, Metge C, Lix L, et al. Tamoxifen use and osteoporotic fracture risk: adverse effects in differentiated thyroid cancer. Thyroid. 2010;20(2):135–
A population-based analysis. J Clin Oncol. 2008;26(32):5227–5232. 146.

Chapter 31
Non-FDG PET/CT Imaging in Oncology

Cristina Nanni • Valentina Ambrosini • Lucia Zanoni • Monica Celli • Paolo Castellucci • Stefano Fanti
Introduction The uptake mechanism of 11C-METH within malignant cells is

still uncertain but the best corroborated theories combine passive
Because its introduction in the clinical practice, PET/CT has been diffusion throughout the damaged brain–blood barrier (BBB) and
associated with the use of fluorodeoxyglucose (FDG). FDG, a glucose active tumor uptake mediated by a membrane-specific carrier,
analog, that is vigorously accumulated in more than 90% of malig- overexpressed as a response to the increased protein synthesis
nant tumor cells. FDG PET/CT is clinically very useful for staging, (related to the active proliferation).1
restaging, assessing therapy response, and during the follow-up of One of the great advantages of using 11C-METH for the diagno-
most malignancies. Furthermore, FDG can be employed to identify sis of brain tumors is the very low background that is found in
several types of dementia, in advance of a clinical diagnosis, and for healthy brain. Normal brain tissue, in fact, recognizes glucose as
the evaluation of cardiac viability. the sole metabolic substrate and, therefore, does not accumulate
11
Despite the spectrum of applications, FDG is relatively insensi- C-METH to a significant degree. On the other hand, brain tumors
tive for the detection of some malignant well-differentiated tumors have increased protein synthesis and tracer uptake. Therefore, the
(such as prostate cancer, neuroendocrine tumors [NETs], hepatic tumor-to-background ratio is favorable, making the 11C-METH
tumors, and others), that are not characterized by an overexpres- PET images relatively easy to read and interpret.
sion of the glycolytic pathway generally because of a relatively From a practical point of view, a 11C-METH PET/CT is easy and
slow growth. Furthermore, FDG is not useful to evaluate malig- fast to perform. Usually 370 to 740 MBq of tracer are injected
nant masses located in tissues (such as the central nervous system intravenously. Because of the short half-life of 11C-labeled tracers
[CNS]) with high glucose utilization. Finally, a high incidence of (20 minutes), the uptake time is only 20 to 30 minutes. At that
false-positive (FP) results occurs in case of inflammation, compli- time, a segmental static image acquisition is performed on brain
cating the differential diagnosis between benign and malignant for 10 to 15 minutes. No fasting is required and no collateral
processes. effects have ever been described.
In addition to FDG, other positron emission tomography (PET) The role of 11C-METH PET/CT in clinical practice is limited to
tracers have been introduced into the diagnostic routine to cover those patients with brain tumors and inconclusive MRI (or CT)
the niches where FDG is noninformative. The most important after radical treatment. It is well known, in fact, that after surgery,
tracers are choline and acetate (labeled either with 18fluoride or chemotherapy or radiotherapy paraphysiologic phenomena such
11
carbon), 11C-methionine (11C-METH) and 18F-fluoroethyltyrosine as fibrosis, necrosis, or edema may occur as a response to ther-
(18F-FET) (and the family of labeled amino acids), 18F-DOPA, apy. Those phenomena may present with morphologic imaging
68
Ga-DOTA-NOC (and other somatostatine analogs), 18F-FLT, and characteristics resembling a disease relapse, rendering the inter-
18
F-fluoride (Tables 31.1 and 31.2). In this chapter, the most pretation of conventional imaging equivocal. However, the early
important (in terms of clinical impact on patient management) identification of disease relapse is important in the clinical course
non-FDG tracers used in oncology will be described. of these patients, because second-line therapy can improve their
survival (Fig. 31.1).2
Because fibrosis, necrosis, and edema are acellular processes,
11
C-Methionine PET/CT and Other they do not present any significant increase in the tracer uptake. A
differential diagnosis between disease relapse (positive 11C-METH
Labeled Amino Acids PET) and benign response to therapy (negative 11C-METH PET) can
be proposed with very good accuracy.
11
C-METH is an amino acid PET tracer whose main use involves This accuracy is a consequence of the fact that no tracer uptake
CNS tumors. Methionine is, in fact, one of the five essential is detectable in necrosis; tracer distribution is not influenced by
amino acids involved in metabolic pathways at a cellular level. corticosteroid therapy (usually administrated as an antiedema ther-
The main destiny of this molecule is the protein synthesis apy), its uptake is proportional to the grade of the disease (even
within ribosomes, but it can also enter the citric acid cycle (to low-grade brain tumos are positive) and FP results (quite rare) are
produce energy) and serves as a cofactor to transfer monocar- caused by very well recognizable clinical events (very recent biopsy,
bon units. acute inflammations, hematoma, acute stroke with reperfusion).3
Ta b l e 3 1 . 1
Tracer Characteristics
Tracer Half-Life (min) Dose (MBq) Uptake Time (min) Indication

11
C-METH 20 370–740 20–30 CNS tumors
68
Ga-DOTA-PEPT 68 75–250 45–90 NET
18
F-DOPA 110 5–6/kg 60–90 NET
18
F-FLT 110 3–5/kg 40–60 Breast, esophageal, lymphoma,
colorectal, ENC, gastric
18
F-FLUORIDE 110 185–370 45 BONE METS
11
C-CHOL 20 370–740 3–5 PROSTATE CA
18
F-CHOL 110 250 10–60 PROSTATE CA
482

Chapter 31 Non-FDG PET/CT Imaging in Oncology 483
Ta b l e 3 1 . 2
Uptake Mechanism of PET Tracers
Tracer Uptake Mechanism Marker of

11
C-METH AA transporter, passive diffusion Protein metabolism
68
Ga-DOTA-PEPT SSTR Receptorial expression
18
F-DOPA APUD system Neuroendocrine differentiation
18
F-FLT Na+-dependent carrier-mediated; substrate by TK1 Cell proliferation
18
F-FLUORIDE Replaces a hydroxyl group in hydroxyapatite crys- Osteoblastic remodeling
tals to form fluoroapatite
11
C-CHOL Substrate for the synthesis of phosphatidylcholine Membrane synthesis
18
F-CHOL Substrate for the synthesis of phosphatidylcholine Membrane synthesis
The main limitations of this technique are the spatial resolu- Besides brain tumors, other minor applications of 11C-METH
tion (approximately 5 mm) and the limited availability of the PET/CT have been reported. A possible role of this tracer was

tracer. In fact, the short half-life of 11C prevents it from being dis- found in the diagnosis of hyperparathyroidism. The principle of
11
tributed. A cyclotron-based PET center with experience synthesiz- C-METH uptake in hyperfunctioning parathyroids relies on the
ing 11C-based molecules is required. fact that this tracer is an amino acid that can be incorporated into
Despite the main clinical application of 11C-METH PET/CT to parathyroid hormone, which is produced in these glands. The
identify disease relapse of low- and high-grade tumors, this exam- advantages over MIBI-SPECT are, of course, the lower radiation
ination has been used also for other purposes. 11C-METH PET/CT dose delivered to the patient, the much higher anatomical detail
can be successfully used to guide tumor biopsy by indicating the provided by the computed tomography (CT) (which is important
most active area inside the mass4 and can be used as a prognostic for localization prior to surgical removal), the higher spatial reso-
index, because its uptake is proportional to the malignancy of the lution compared to conventional scintigraphy and the much
tumor and its cellular proliferative index. In fact, the proportional- shorter time needed to complete the entire procedure. It has been
ity between tracer uptake and tumor grade may be used to show a demonstrated that 11C-METH PET/CT is accurate both for primary
change in tumor grade early without any invasive procedure. This and secondary hyperparathyroidism, with a true-positive rate of
is not always possible with magnetic resonance imaging (MRI) as approximately 85%.8 Further studies are needed.
many high-grade tumors do not have any significant enhance- Besides 11C-METH, labeled amino acids are available for PET
ment.5 The tumor grade serves as a prognostic index, and there- studies of CNS malignancies. 18F-FET (fluoro-ethyl-tyrosine) dem-
fore a correlation between 11C-METH uptake and survival was onstrated results comparable to 11C-METH in identifying primary
found. Patients with hypermetabolic tumors in terms of protein brain tumors. The uptake mechanism is similar to 11C-METH but
synthesis have a significantly worse prognosis, whereas patients the half-life of the tracer is much longer (110 minutes). While a
with hypo- or isometabolic tumors have a better life expectancy.6 disadvantage in terms of dose delivered to the patients, produc-
Furthermore, 11C-METH PET/CT may also be used to detect a tion and distribution of the compound allows potentially wider
response to both chemotherapy and radiation therapy.7 Although use.9
other PET tracers have been used to evaluate brain tumors (18F- The same considerations are applicable to 18F-DOPA ([18F]-l-
FLT, 18F-FDG, 11C-choline), 11C-METH is the most accurate and dihydroxyphenylalanine), whose diagnostic potential is high for
therefore it is recognized as the PET tracer of choice. NETs as well as primary and metastatic malignant brain lesions.10
A B C
Figure 31.1. Patient operated for astrocytoma. Diagnostic CT (A) showing postsurgical changes (red cross). 11C-Methionine PET/CT (B: PET; C: fused images)
showing a disease relapse (red cross, hot area).

68
Ga-DOTA-Peptides and 18F-DOPA (labeled with 68Ga) and subsequent treatment (when labeled with
177
lutetium or 90yttrium).
PET/CT Imaging From a technical point of view, 68Ga-peptides present several
advantages for PET/CT imaging of NET. The synthesis and label-
68
Ga-DOTA-peptides and 18F-DOPA are most frequently used to ing process is quite easy and economic: Gallium-68 can be easily
study NETs. NETs are heterogeneous group of slow-growing eluted from a commercially available Ge-68/Ga-68 generator, not
tumors characterized by their endocrine metabolism and histol- requiring an on-site cyclotron. 68Ga (t1/2 = 68 minutes) has an 89%
ogy pattern, occurring in 1 to 4/100,000 people per year.11 NETs positron emission and negligible γ-emission (1,077 keV) of 3.2%.
derive from neuroendocrine cells which are widely dispersed in The long half-life of the parent radionuclide 68Ge (270.8 days)
the human body (bronchopulmonary endocrine cells, thyroid C makes it possible to use the generator for approximately 9 to
cells, paraganglia, gastro-entero-pancreatic neuroendocrine cells, 12 months depending upon the requirement, rendering the whole
adrenal medulla, glial cells, leptomeninx, anterior pituitary gland, procedure relatively economic.21 Moreover directly binding to
Merkel skin cells, and neuroendocrine cells in miscellaneous sites SSR, 68Ga-peptides provide an indirect measure of tumor cell dif-
including ovary, endometrium, breast, kidney, larynx). The most ferentiation, offering data not only on disease extension but also
common sites of NET occurrence are the gastro-entero-pancreatic on tumor cell receptor expression status, particularly relevant
tract followed by the bronchus and lungs. Less frequent sites of before initiating targeted nuclide therapy. Finally, compared to
localization include the skin, adrenal glands, thyroid, and genital SRS, PET/CT is a single-day examination.
tract.11,12 Indications to perform 68Ga-DOTA-peptide PET/CT imaging
For decades, somatostatin receptor scintigraphy (SRS) has of NET patients include disease staging/restaging, follow-up,
represented the imaging method of choice to study NET. Several detection of unknown primary tumor sites, and evaluation
studies reported on the utility of SRS was the diagnosis of soma- before and after therapy. Clinical literature supports the superi-
tostatin receptor (SSR) positive tumors13,14 with an overall detec- ority of 68Ga-DOTA-peptide PET/CT imaging over SRS for
tion rate of 80% to 100%. The radiopharmaceuticals used by SRS both the detection of primary and secondary lesions (Fig. 31.2).
allow tumor visualization as well as confirm the presence of SSR One of the largest studies (84 patients)22 demonstrated that
receptors which allows selection of patients for treatment with 18
Ga-DOTA-TOC PET/CT accuracy (96%) was significantly higher
either hot or cold somatostatin analogs. Currently, the most fre- than that of CT (75%) and In-111 SRS-SPECT (58%). The sites in
quently used compound for SRS imaging is 111-Indium DTPA- which PET/CT was superior to CT alone or SPECT were lymph
octreotide, commercially available as Octreoscan (Covidien, nodes, liver, and bone. Overall, PET/CT-derived data changed
Petten, Netherlands). Octreoscan specifically binds to SSR which clinical management in 14% of the cases compared to SPECT
are over-expressed on NET cells, with particular affinity to sub- and in 21% compared to CT.
types 2 and 5. However, SRS has some limitations including 68
Ga-DOTA-peptides influenced the clinical management of
imaging organs with higher physiologic uptake (e.g., liver), lim- NET patients.23 In a population of 90 cases with biopsy-proven
ited detection of small lesions (because of suboptimal physical NET, 68Ga-DOTA-NOC PET/CT findings affected either stage clas-
resolution of 111Indium SPECT imaging),15,16 the relatively higher sification or therapy modifications in half the patients. Moreover,
costs (as compared to PET imaging), and the longer image acqui- PET/CT with 68Ga-DOTA-NOC provided prognostic information.24
sition time. In fact, 68Ga-DOTA-peptide positive lesions have a higher differen-
New positron-emitting radiopharmaceuticals have been intro- tiation grade, are associated with a better prognosis, and are
duced in clinical practice with PET/CT used for the diagnostic more likely to positively respond to treatment with either hot or
assessment of NET. PET/CT has several advantages over SRS cold somatostatin analogs. Semiquantitative and visual interpreta-
including better spatial resolution equipment that is superior to tion of the uptake of 68Ga-DOTA-peptides measured by PET/CT is
the γ-camera, the possibility to integrate PET functional data on used to guide the quantity of radiation and the timing of targeted
CT anatomical information, and the opportunity to better charac- radionuclide therapy, using 177Lu- or 90Y-DOTA-TOC. In this set-
terize the disease by using both metabolic (18F-DOPA) and receptor- ting, 68Ga-DOTA-peptide PET/CT represents an indispensable pro-
based tracers (68Ga-DOTA-peptides). In fact neuroendocrine cells cedure to plan targeted treatment.
present peculiar biologic characteristics that have been exploited Another clinical setting in which PET/CT has been increas-
to design specific PET tracers; neuroendocrine cells contain secre- ingly used to detect primary tumor site (Cancer of unknown pri-
tory granules, produce biogenic amines and polypeptides, have mary, CUP) in patients with biopsy-proven secondary lesions
the ability to take up and decarboxylate amine precursors and and negative physical examination, laboratory tests, and con-
express in high quantities several different peptide receptors on ventional imaging procedures (including chest x-ray, abdominal
cell surface. and pelvic CT, mammography in women, etc.). Conventional
imaging, in fact, fails to identify the primary lesion in approxi-
68 mately 20% to 27% of cases. From a clinical perspective, the
Ga-DOTA-Peptides and PET/CT Imaging identification of the primary tumor is of crucial importance to
Somatostatin receptors (SSR), over-expressed on NET cell sur- choose the most appropriate intervention. The single published
faces, serve as the target of a novel group of PET radiopharmaceu- study addressing this issue reports high accuracy of 68Ga-DOTA-
ticals named 68Ga-DOTA-peptides. Of the five different SSR, most NOC to identify the primary tumor site.25
NET express SSR2 predominantly with lower percentages of SSR1 There are only a few studies directly comparing 68Ga-DOTA-
and SSR5.17 The 68Ga-DOTA-peptides (DOTA-TOC, DOTA-NOC, peptides and 18F-DOPA imaging. 68Ga-DOTA-peptides are superior
DOTA-TATE) all bind SSR with different affinity; although all bind in well-differentiated NET for detection of both the primary tumor
SSR2 and SSR5, only 68Ga-DOTA-NOC has high affinity for SSR3.17–19 and metastatic sites.26,27 68Ga-DOTA-peptides are easy to prepare
The first compound used for NET PET imaging was DOTA-TOC, and are economical.28,29 They provide the possibility to study SSR
however both DOTA-NOC and DOTA-TATE have been used more expression prior to treatment. Hence, they are more frequently
often in the past few years at specialized centers in Europe. At used than the 18F-DOPA in well-differentiated NET. By contrast,
18
present, there is insufficient evidence to support the preferential F-DOPA has advantages for the detection of tumors with a low
use of one analog over the other.20 Factors supporting the use of or absent expression of SSR (such as medullar thyroid carcinoma,
DOTA-NOC include the wider spectrum of SSR affinity and lower neuroblastoma, and undifferentiated NET) and to study diseases
dosimetry, whereas on the other side both DOTA-TOC and DOTA- at sites of known physiologic 68Ga-DOTA-peptide uptake (e.g.,
TATE have the advantage that they can be used for diagnosis adrenals).


Figure 31.2. Patient affected by metastatic neuroen-
docrine tumor. 68Ga-DOTA-NOC PET/CT shows increased
uptake also in small lymph node metastatic lesions
(A: PET MIP; B: CT axial; C: fused images). The arrow A C
indicates a laterocervical lymph nodal metastasis.
68
PET/CT Imaging Using Ga-DOTA-Peptides: Pitfalls in image interpretation include the presence of acces-
Technical Aspects sory spleens, inflammation (because of the presence of SSR on
activated lymphocytes), and the presence of increased tracer
Recently the European Association of Nuclear Medicine (EANM) uptake at the head of the pancreas. In fact, increased 68Ga-DOTA-
published guidelines for 68Ga-DOTA-peptide PET/CT image peptide uptake in the exocrine pancreas (head) has been reported
acquisition.20 68Ga may be eluted from a commercially available to be a relatively frequent finding (Gabriel et al.: DOTA-TOC,
68
Ge/68Ga generator and the labeling of the DOTA-peptide with 67.8%; Castellucci et al.: DOTA-NOC, 31%) not necessarily associ-
68
Ga is performed following standard procedures using semiau- ated with the presence of disease.22,35 Small lesion dimension
tomated or fully automated systems. Prepurification and con- (<5 mm) and variable or absent expression of SSR account for
centration of the generator eluate using an anion-exchange28,29 false-negative (FN) reporting.
or cation-exchange technique,30,31 can be used as just a fraction
of the generator eluate directly for radiolabeling.32,33 Radiola- 18
beling is performed with a suitable buffer at an elevated
F-DOPA PET/CT Imaging
temperature followed by chromatographic purification of the NET cells belong to the APUD (amine precuros and decarboxy
radiolabeling solution using a C-18 cartridge and an appropri- lation) cell system and are avid of 18F-DOPA, an aromatic amino-
ate aseptic formulation. The method employed ensures the level acid labeled with 18fluorine. At the central and peripheral
of 68Ge in the final preparation is less than 0.001% of the 68Ga nervous system level, 18F-DOPA is transformed by the catechol-
radioactivity. Quality control protocols include tests for radionu- O-methyl-transferase (COMT) in 3-O-methyl-fluoro-l-DOPA
clide purity, radiochemical purity (HPLC, TLC), chemical purity (3-OMFD) and by aromatic amino acid decarboxylase (AAAD) in
(buffer, solvents), and sterility and endotoxin testing using vali- 6-fluorodopamine (FDA) which, in turn, is stored in secretory
dated methods.20 granules. Accordingly, 18F-DOPA can be used as a marker of NET
PET/CT imaging is performed following the intravenous metabolism.
administration of approximately 100 MBq (75 to 250 MBq) of the Clinical indications to perform PET/CT with 18F-DOPA in NET
radiolabeled peptide (68Ga-DOTA-NOC, DOTA-TOC, DOTA-TATE). include staging/restaging, assessment of tumor response to treat-
Images are generally acquired after an uptake time of 60 minutes ment, and detection of the unknown primary tumor. Several stud-
(45 to 90 minutes). ies report that 18F-DOPA was useful to assess NETs and performed
68
Ga-DOTA-peptides have physiologic uptake in the pituitary better than conventional morphologic procedures (US, CT, MRI)
gland, spleen, liver, adrenal glands, the head of the pancreas, and SRS, with reported sensitivities ranging from 65% to 100%.36,37
thyroid (very mild), and the urinary tract (kidneys and urinary Moreover, 18F-DOPA PET was reported to influence the clinical
bladder). No fasting or discontinuation of somatostatin management in a limited population of biopsy-proven NET38
analog treatment are required before imaging.20,34 Patients are patients with an unclear clinical presentation or with inconclusive
encouraged to void before image acquisition to reduce the findings on other imaging modalities (US, CT, SRS, MRI).
background noise as well as the radiation dose to kidneys and The difficulties in 18F-DOPA synthesis process and the relatively
bladder. high costs have limited its widespread clinical use. Conditions in

which 18F-DOPA may still offer clear advantages over 68Ga-DOTA- to obtain. Furthermore, excision biopsy presents various grades
peptides include cases with NET showing a low or variable SSR of risk, particularly in mediastinal, abdominal, or radio-treated
expression (e.g., medullary thyroid carcinoma, neuroblastoma). In lesions.
18
fact, the 2009 American Thyroid Association MTC management FLT has already been successfully used to study solid malig-
guidelines39 suggest that 18F-DOPA PET/CT should be performed nancies, and preliminary results confirmed its capability to dis-
in addition to cervical ultrasonography in any patient with a post- criminate cancer from inflammation. Excellent correlations were
surgical basal calcitonin level of ≥150 pg/mL. The clinical utility of obtained between 18FLT standardized uptake value (SUV) and
18
F-DOPA over 18F-FDG in medullary thyroid carcinoma is still cancer proliferative activity measured by Ki-67 or PCNA immu-
somewhat controversial although most studies show clear superi- nostaining. The more recent literature on 18FLT is focused on
ority of 18F-DOPA PET/CT over 18F-FDG PET/CT.40,41 It is assumed monitoring tumor treatment response and exploring the effects of
that the combination of the two tracers would probably provide new anticancer agents on tumor cells.46
the highest diagnostic sensitivity and specificity.42 18F-DOPA has
been reported to be superior to 68Ga-DOTA-peptides to detect
recurrent medullary thyroid carcinoma lesions in patients with
Radiosynthesis
elevated serum calcitonin levels.43 18
FLT was originally developed as an antiviral compound for the
Successful 18F-DOPA PET/CT utilization is reported in neuro- treatment of patients with HIV and was subsequently labeled with
blastoma,44 another condition with variable expression of SSR.45 18
F. A reliable radiosynthesis is based on [18F] fluoride displace-
In a recent report in a small patient population with stage 3 and ment of a protected nosylate precursor. A fully automated method
4 neuroblastoma, 18F-DOPA PET/CT showed higher sensitivity and has been developed with a yield of 50% radiochemical yield
accuracy (95% and 96%) than 123I-metaiodobenzylguanidine by modifying a commercial FDG synthesizer and its disposable
(MIBG) scintigraphy (68% and 64%, respectively). fluid pathway, however FLT preparation is still in the process of
Finally, to assess the response to treatment, 18F-DOPA PET/CT optimization.
may be more useful than 68Ga-DOTA-peptides. In fact, although
the detection of a lower posttreatment 18F-DOPA uptake directly
indicates efficacy, a reduced 68Ga-DOTA-peptide uptake merely
Pharmacokinetics
reflects a lower receptor expression that may be explained also by After intravenous administration, capillary transport of fluori-
the presence of less differentiated cells. nated pyrimidine analogs occurs rapidly by passive diffusion in
most tissue and organs (the brain being an exception). Cell trans-
18 port is related to rapid, equilibrate, facilitated diffusion by an Na+-
PET/CT Imaging Using F-DOPA: dependent carrier-mediated mechanism. Once inside the cell,
Technical Aspects 18
FLT is accepted as a substrate by TK1, phosphorylated and
PET/CT image acquisition starts 60 to 90 minutes after the intra- thereafter trapped. 18FLT-monophosphate (MP) is further phos-
venous injection of 5 to 6 MBq/kg of 18F-DOPA. Oral premedication phorylated to diphosphate and triphosphate which is not signifi-
with carbidopa, a peripheral aromatic amino acid decarboxylase cantly incorporated into DNA and persists in the cytosol (unlike
11
inhibitor, has been reported to enhance sensitivity by increasing C-thymidine and some other analogs). One major advantage of
18
the tumor-to-background ratio of tracer uptake. Carbidopa admin- FLT over thymidine is that it is resistant to degradation by
istration may therefore be particularly useful for the evaluation of thymidine-phosphorylase (TP). The placement of fluorine in
lesions at sites of increased 18F-DOPA physiologic uptake such as deoxy-ribose sugar at the 3′ position in 18FLT, stabilizes the glyco-
the pancreas. Physiologic 18F-DOPA uptake has been seen because solic bond and prevents degradation. However, glucuronidation of
18
of its excretion in the bile ducts, gallbladder, and digestive and FLT can still occur. This characteristic results in higher levels of
urinary tracts. Additionally mild, nonfocal uptake in the striatum FLT circulating blood concentration after injection. In addition
18
and pancreas has been reported. FLT is not a substrate for thymidine-kinase 2 (TK2), implied
in mitochondrial DNA replication and repair, resulting in an
exclusive linkage to the thymidine salvage pathway in relation to
18
F-Fluoro-3-Deoxy-3-l-Fluorothymidine nuclear DNA synthesis.
The limiting step of 18FLT accumulation in proliferating cells is
Because activated macrophages and other inflammatory cells TK1 phosphorylation but not direct incorporation into DNA,
present increased glucose metabolism as well as cancer cells, excluding 18FLT from the list of true tracer of proliferation. How-
18
FDG uptake is not tumor specific and it has been reported in ever, TK1 is selectively upgraded before and during S-phase and
aseptic inflammations (healing, burns) or septic bacterial, viral, virtually absent in quiescent cell. It has been demonstrated that
or mycosis infection providing relatively frequent FP results. TK1 activity is three to four times higher in malignant cells than
18
F-fluoro-3-deoxy-3-l-fluorothymidine has been developed as in benign cells and 18FLT uptake, as a measurement of TK-1 activ-
a PET proliferation tracer. As a key component of tumor devel- ity, correlates strongly with markers of cellular proliferation as
opment and growth, cell proliferation is an attractive biologic PCNA and Ki-67 score.
target in cancer imaging. 18FLT uptake is independent from glu-
cose metabolism. Thymidine is a native nucleoside that is uti-
lized by proliferating cells for DNA replication during the
Biodistribution
S-phase of the cell cycle. 18FLT is handled by cytosol thymidine 18
FLT provides high contrast images of proliferating tissues but
kinase 1 (TK1), the salvage pathway key enzyme, whose activ- research studies have shown interspecies differences of biodistribu-
ity is cell cycle dependent and three to four times higher in tion. Human studies revealed high bone marrow uptake, and sig-
malignant cells than in benign cells. Indeed, in numerous tumor nificant liver and urinary tract distribution (kidneys and bladder).
cell lines, excellent correlations have been demonstrated Unlike 18FDG, 18FLT is not taken up by normal brain cortex, which is
between FLT uptake and the proportion of cells in S-phase, TK1 clearly an advantage in assessing brain lesions and presumably
over-expression, or Ki-67 rates. At present cellular prolifera- reflects the known lack of nucleoside transportation across the blood
tion can be assessed only by a number of in vitro assays that brain barrier (BBB). All the studies comparing 18FLT to 18FDG uptake
require tissue from biopsies. However, biopsy results may not revealed that 18FDG SUV was almost twice than that of 18FLT. Despite
be representative of the proliferating activity of the whole this limitation, 18FLT uptake in the surrounding tissue was proven to
tumor because of tumor heterogeneity and they may be difficult be low; therefore tumor/normal tissue ratios of 18FLT are similar

18 18
to that of FDG, and result in good visualization of FLT-positive tumor proliferation status in clinical practice. However, it was not
lesions. expected to have the same sensitivity as 18FDG because of a lower
overall uptake in tumors and a higher background activity in liver
and bone marrow, resulting in more FN findings and therefore, it
Clearance is not regarded as a staging tool for cancer. However, the specific-
In all species, physiologic accumulation was found in kidneys and ity of 18FLT was expected to be significantly higher than that of
18
bladder, related to the clearance of FLT, primarily undegraded, in FDG PET, giving fewer FP findings because of negligible accumu-
the urine. lation in granulocytes.49
Though most of initial reports were optimistic, new adverse
Safety data are emerging. Zhang et al.,50 validating FLT as a proliferation
tracer in the preclinical setting in a panel of proliferating xeno-
In terms of radiation exposure, 18F-FLT has similar whole-body grafts, concluded that FLT avidity failed to reflect the tumor
and bladder wall absorbed radiation doses as 18FDG. In fact, brain growth rate across different tumor types, despite the high expres-
and heart receive lower whereas liver and bone marrow receive sions of Ki-67 and TK1.
higher doses compared to 18FDG. Unlike 18FDG, no dietary restric- The human oncologic setting has been largely explored but
tion or fasting is required before 18FLT imaging. This is an advan- the clinical relevance of these studies is limited, in part, because
tage in diabetic patients. Also, 18FDG biodistribution is not of the small cohort of patients and the methodologic heteroge-
influenced by movement during the interval between injection and neity.51,52
imaging.47

In several clinical studies FLT PET has been directly compared
with 18FDG PET. In many series, 18FLT SUV has been shown to
Tumor Proliferation Imaging (Differential have good correlation with Ki-67 (breast cancer, hepatocarcinoma
[HCC], thoracic tumors, ovarian cancer, lymphoma, brain cancer,
Diagnosis of Tumor and Inflammation) colorectal cancer, sarcoma of the extremities).
Preclinical 18F-FLT studies with tumor cell line studies and animal In lymphoma patients, a clear dichotomy between aggressive
studies have included pancreatic cancer cell lines in vitro, human and indolent forms was noted (Fig. 31.3); conversely, considering
lung adenocarcinoma cells in vitro, B-cell lymphoma (both murine the high normal bone marrow uptake, FLT presented several lim-
model and human disease), murine model bearing the radiation- itations for staging.
induced fibrosarcoma 1 tumor (treated with 5-fluorouracil [5-FU]), Unlike 18FDG, 18FLT has shown a very low background uptake
rodent model with both tumor and sterile muscular inflammation, in the brain related both to the low proliferation in normal brain
and dogs with spontaneous non-Hodgkin lymphoma (NHL) and and to the low ability of the tracer to cross the BBB. 18FLT is only
soft tissue sarcoma.48 retained in lesions where either the BBB is disrupted or signifi-
18
FLT has shown strong correlation with Ki-67 immunohisto- cantly impaired or in high-grade gliomas, whereas a variable sen-
chemical marker expression which is the gold standard to assess sitivity of 79% to 82% suggests the possibility of FN results in case
B F
C G
A D E H
Figure 31.3. Suspected bronchial NHL relapse detected by 18F-FDG PET/CT and confirmed by 18F-FLT. A 66-year-old underwent surveillance imaging for a
marginal splenic non-Hodgkin’s lymphoma treated with splenectomy. 18F-FDG PET/CT (left: A, MIP; B, transaxial CT; C, transaxial PET; D, transaxial fused images)
presented intense uptake of the glycomimetic tracer in the right inferior bronchus (arrow, SUVmax = 8.6) and in the sternum (SUVmax = 3.8). 18F-FLT PET/CT
(right: E, MIP; F, transaxial CT; G, transaxial PET; H, transaxial fused images) showed intense uptake of the proliferative tracer in the same bronchus (arrow,
SUVmax = 5.8). It was not possible to assess the sternum because of the high physiologic FLT uptake in the bone marrow. Finally, both lung disease and bone
marrow involvement were biopsy proven. In addition, PET helped depict a histologic transformation into a more aggressive diffuse large B-cell lymphoma.

of low-grade gliomas. At the same time nontumorous lesions dis- center. FP results with FLT have been further detected in nonspe-
rupting the BBB may represent FP results, in particular subacute cific interstitial pneumonia, squalene-induced lipoid pneumonia,
infarction, multiple sclerosis, and focus of radiation necrosis which and groin lymph nodes. In addition, increased perfusion and vas-
have already been depicted; furthermore, FLT PET may represent cular permeability, aside from the proliferation of inflammatory
a potential outstanding indicator of prognosis. cells, results in nonspecific 18FLT uptake in benign lesions.
With regard to colorectal cancer, 18FLT would be useful to eval-
uate treatment response to induction chemo–radiotherapy but it
has no role for staging because of high-background activity in the
Monitoring of Tumor Response to Therapy
liver. Measuring tumor proliferative activity by 18FLT PET offers great
Finally, few benign FP findings should be mentioned in patients potential for assessing the viability of tumor cells during or early
with sarcoma of the extremities. Indeed, 18FLT was able to differ- after treatment. Most of the studies in a wide range of cancers
entiate between low- and high-grade lesions but not between low- registered significant early changes between baseline and post-
grade and benign lesions. treatment scan. To date, there has been little consistency in the
A number of studies report a lack of correlation between 18FLT clinical studies (scans performed 1 day to 2 weeks from the initia-
uptake and Ki-67 expression, in particular as follows: tion of treatment administration). However, the early assessment
of FLT uptake suppression occurs long before treatment-induced
• Breast cancer: The tumor-to-background contrast of 18FLT is
change in tumor size became measurable.
equivalent to 18FDG, in clinical practice, assessing the response
For example, 18FLT is a useful probe to monitor the efficacy of:
to therapy in locally advanced breast cancer treated with neo-
adjuvant chemotherapy. 18FLT has been helpful to assess nodal • the cytostatic drug cisplatin.
involvement of both breast cancer and melanoma patients. The • docetaxel, an anticancer agent that induces G2/M block, in
sentinel node procedure remains superior because of the lim- breast cancer; a recent study identified 18FLT as a sensitive
ited spatial resolution of PET cameras. negative predictor of lesion response.
• Esophageal cancer: Despite negative results, assessing regional • combined 5-FU-epirubicin, cyclophosphamide, in breast cancer,
lymph node in esophageal squamous cell carcinoma shows during the first week.
fewer FP results with 18FLT than with standard 18FDG. • R-CHOP/CHOP in non-Hodgkin lymphoma within 1 week after
• Aggressive NHL (treated with R-CHOP). the first cycle; interestingly there was no reduction after Ritux-
• Locally advanced gastric cancer (treated with cisplatin– imab alone indicating no early antiproliferative effect of immu-
leucovorin–5FU). notherapy.
• Thoracic tumors. • chemoradiotherapy in head and neck squamous cell carcino-
• Metastatic germ cell tumors (treated with cisplatin). mas during radiotherapy (4 weeks after initiation) FLT uptake
• Colorectal cancer. decreased more significantly than 18FDG; higher specificity and
• Head and neck cancer: 18FLT has been valid to assess primary overall accuracy was registered in particular for primary
tumors but not for lymph nodes because of the high prolifera- lesions.
tion rate of B-lymphocytes in the germinal center of reactive
These changes in 18FLT avidity do not always predict clinical
nodes with abundant Ki-67 scores that cause a high rate of FP
response and improvement in survival rates. Highly effective and
findings and very low specificity, 16.7%53; eventually there can
potentially curative treatments usually inhibit 18FLT uptake in
be an advantage of 18FLT over 18FDG in differentiating postra-
most tumors but a complete response is achieved in only a subset
diotherapy changes from recurrent or residual tumor.
of patients.
A systematic review and meta-analysis of 27 different studies Moreover, 18FLT does not always reflect cellular proliferation
(from 1998 to 2011) with a total of 509 patients have been recently and the use of 18FLT in the evaluation of chemotherapy is compli-
performed by the London group of Chalkidou and coworkers. It cated by the fact that many antitumor drugs interfere with cellular
showed that, given an appropriate study design, the FLT/Ki-67 nucleotide metabolism. It should be recalled that some chemo-
correlation is significant and independent of cancer type with therapeutic agents such as 5-FU and methotrexate cause the cell
either the use of Ki-67 average measurements regardless of nature arrest in S phase and an inhibition of the de novo synthesis of
of sample, or whole surgical samples when measuring Ki-67 max- nucleotides leading to a compensatory up-regulation of the sal-
imum expression. In particular, there is already sufficient data vage pathway DNA synthesis and thus a transient induction of
to support a strong correlation for brain, lung, and breast TK1 activity with a consequent increase in 18FLT uptake, whereas
cancer.54 tumor cell proliferation remains impaired. Similar results were
The study by Brockenbrough et al. evaluating the relationship reported in an in vitro model involving the alkylating agent ACNU.
between preoperative FLT static lung and dynamic uptake mea- The mechanism behind underpinning this 18FLT “flare effect”
sured by PET and TK1 protein expression and enzymatic activity seems related in part to the redistribution of the human equilibra-
in a series of 25 lung lesions, documented the absence of observ- tive nucleoside transporter type 1 (hENT1) to the outer cell mem-
able correlation of the imaging parameters with TK1 activity. Pos- brane. In addition complex relation between Ki-67 index and
sible explanation are because of either sampling errors in the pKi-67 mRNA have been observed in colorectal cancer, whereas
highly heterogeneous group of non–small cell lung cancer (NSCLC) in lung adenocarcinoma cells, functional p53 signaling is needed
or in vitro TK1 assay conditions which did not reflect the full com- to maintain TK1 activity and S-phase percentage following radia-
plexity of the in vivo relationship.55 tion treatment. How this relationship is affected by cytostatic
As stated above, many groups aimed to directly compare 18FLT treatments remains to be fully understood.
with the standard tracer 18FDG. For example, in detecting primary Drugs inhibiting the de novo pathway of DNA are thus expected
lung cancer the sensitivity of 18FLT compared to FDG was 79% to to induce an 18FLT “flare response” which has been documented,
100% and 89% to 100%, and the specificity was 86% to 100% and for example, at 1 hour after administration of capecitabine in
57% to 73%, respectively. human breast cancer and 24 hours after cytotoxic drugs (5-FU,
Despite the encouraging literature available, it is important to methotrexate, and gemcitabine) in esophageal squamous cell
recognize that 18FLT may accumulate in lesions with a higher carcinoma.
turnover and brisk proliferation of inflammatory cells. High tracer Apparently in the interpretation of images, a paradoxical
uptake in nonmetastatic lymph nodes has been proven to be increase of cellular 18FLT uptake after treatment must be consid-
related to reactive B-lymphocyte proliferation in the germinative ered. Therefore, it may be important to examine the mechanism

of action of antitumor drugs and to select an appropriate time tent PET protocol, a fixed small region of interest 1 cm3 in volume
point for 18FLT PET imaging after treatment (the optimal time in the most active region metabolically active tumors to minimize
might differ for different drugs).56 statistical variability, assessing tumor size, treating SUV measure-
It was concluded that 18FLT uptake and retention within the ments in the 1 up to 5 most metabolically active tumor focus as a
tumor cells is directed by a variety of undetermined factors. To continuous variable, requiring a 30% decline in SUV for response,
review, the most probable factors that influence 18FLT uptake are and deferring to RECIST 1.1 criteria in nonavid or technically
as follows: unsuitable cases.
The recommended timing and duration is considered optimal
• Loss of cell cycle–specific regulation of TK1.
for lung and high-grade brain tumors but may be slightly different
• Cell ATP levels.
for other tumor types.57
• Contribution of the de novo and salvage pathways to DNA syn-
thesis.
• Diversity of tumor entities in a specific cohort. Other Thymidine Analogs
• Difference in the phosphorylation rate between FLT and thymi- 18
F-FLT has undergone the most widespread testing and is consid-
dine.
ered to be an attractive tracer.
• p53 regulation of TK1 activity: p53 function may be compro-
Thymidine is the only nucleoside that is DNA specific, incorpo-
mised in 50% of all human cancers inducing a state of differen-
rated in DNA but not in RNA.
tial cell cycle control in which TK1 activity is uncoupled from
The halogen substitution in the in the 3′position of 18F-FLT
tumor proliferation and more closely associated with tumor

results in a decreased affinity for the pyrimidine transporter com-
DNA repair.
pared with thymidine. Moreover, 18FLT affinity for TK1 is reported
• Cell cycle–dependent rearrangement of hENT1.
to be 30% lower than the affinity of thymidine (explaining low
• A multitude of transport mechanism.
uptake in tumor cells).
• “Flare” 18FLT uptake enhancement.
In mice and rats, the tracer 11C-Thymidine shows prolonged
• Indirect linkage with proliferation rate because FLT is not
retention in rapid proliferating tissue such as thymus, spleen, and
incorporated into DNA.
duodenum, whereas in dogs and humans, it is converted to a
18
Hence, additional data are needed to validate the use of FLT spectrum of blood metabolites thus hampering PET image inter-
PET to assess treatment. pretation. In addition to this rapid catabolism, the short half-life
of 11C and the need for an on-site cyclotron make it less suitable
Recommended Scan Acquisition and for clinical practice.
Other pyrimidine analogs such as 2′-fluoro-5-methyl-1-β-d-
Interpretation Methods arabinofuranosyluracil (FMAU) and 2′-deoxy-2′-fluoro-5-bromo-
18
FLT uptake tends to be modest to low. Tumor localization should 1-β-d-arabinofuranosyluracil (FBAU) offer the potential advantage
be based or confirmed with coregistered anatomic and 18F-FDG over FLT with retention in DNA, reflecting DNA synthesis directly.
scans. Pitfalls may come from the following aspects: However, being also substrates for TK1, some of the same limita-
tions as 18FLT should be encountered.
• Region of interest definition (manual or automatic). 18
F-FMAU rapid liver uptake appears to decrease clearance into
• Location and number of core biopsies used for correlation with
kidneys and bladder, allowing improved imaging in the pelvis com-
proliferation markers.
pared to 18FLT and 18FDG. Therefore, it can be used to image pri-
• SUV analysis at later time points (beyond 1 hour) not fully
mary tumors within the prostate. Moreover, less retention is seen
accounting for contribution of labeled metabolites.
in the bone marrow leading to the ability to detect bone metastases
• SUV analysis, to evaluate the effects of novel drugs, affected by
(BMs). It is a better substrate for TK2, and it is therefore more
blood flow underestimating 18FLT metabolic flux because of
relevant to measure oxidative stress rather than proliferation.58
reduced tracer delivery to the tumor.
Different methods have already been proposed for a better
18
standardization. F-Fluoride PET/CT in the Assessment
• Method 1: dynamic PET at 0 to 90 minutes with a four-parameter of Bone Metastases from Solid
model. The arterial input function can be estimated during the
first several minutes from PET images of the heart or aorta and
Primary Tumors
thereafter from a modest number of peripheral venous sam-
Bone metastases (BMs) represent the most common bone malig-
ples; the 18F-FLT component of the time–total activity curve for
nancy as they affect 30% to 70% of the whole oncologic population.
blood can be estimated with a chromatographic analysis of one
In women, the leading cause for BMs is breast cancer whereas in
sample taken near the end of the scanning sequence. This
men, it is prostate cancer, followed by lung neoplasms in both sexes.
method is proposed in initial studies for a specific type of cancer
When confined exclusively to bone, metastases often translate
or to determine the effect of novel therapies on tumor cell pro-
into a prolonged clinical course compared to visceral involvement.
liferation.
However, if untreated, BMs may eventually give rise to dreadful
• Method 2: dynamic PET at 0 to 60 minutes with a three-parameter
complications, known as “skeletal-related events” (SREs), includ-
model. In both methods 1 and 2, voxel-by-voxel modeling can
ing severe refractory pain, pathologic fractures, cord compression,
produce parametric images of the 18FLT ﬂux (i.e., K 18FLT).
and hypercalcemia impairing patient’s quality of life and survival
• Method 3: static PET at 40 to 60 minutes, with the tumor activ-
and creating considerable health care costs.
ity concentration expressed in terms of SUV.
Early detection of BMs and accurate assessment of their true
To assess treatment responses, changes in tumor SUV more extent is pivotal to guide the most appropriate therapy and for
than 20% are considered significant. Recently a novel approach prognostic stratification. For decades whole-body assessment of
was elaborated by the Society of Nuclear Medicine for 18FDG PET bone metastatic spread has been provided by 99mTc-diphosphonate
and the same approach could be used for 18FLT: PET Response scintigraphy (BS) as a consequence of its high sensitivity, wide
Criteria in Solid Tumours (PERCIST). The principal components of availability, and low cost, although burdened by a relatively low
these criteria include assessing normal reference tissue values in specificity, high incidence of equivocal findings, and lack of mor-
a 3-cm diameter region of interest (liver for FDG) using a consis- phologic correlation which may eventually delay diagnosis.59

18
Complementary single photon emission tomography (SPET) and F-Fluoride uptake in BMs is fast and it is 3- to 10-fold higher
hybrid single photon emission tomography/computed tomogra- than that of normal bone resulting in optimal disease to normal
phy (SPET/CT) acquisitions may obviate these drawbacks and bone ratios with short uptake time (approximately 45 minutes).
improve BS diagnostic accuracy, especially in the spine. This Blastic and mixed lesions appear diffusely 18F-Fluoride avid,
approach, however, may not be routinely feasible.60,61 Moreover, whereas osteolytic metastases may appear as relatively “cold”
published studies comparing the diagnostic accuracy of 99mTc- lesions with a “hot” rim, representing the reparative osteoblastic
diphosphonate bone imaging and tumor-specific PET radiophar- reaction. Lytic lesions are the most common expression of bone
maceuticals which directly visualize tumor cells (e.g. 18FDG), have metastatic growth (60%). Purely lytic metastases are quite uncom-
highlighted the superiority of the latter to detect early bone mar- mon as the majority of metastases prompt some degree of osteo-
row–based and osteolytic lesions as well as providing extra- blastic reaction, albeit not detectable on CT. Some tumor histologies
osseous disease assessment and a tool for therapy monitoring. In such as thyroid cancer, multiple myeloma, neuroblastoma may
such a composite scenario, encouraged by the recent worldwide present with purely lytic metastases and 18F-Fluoride PET, like
99
Mo/99mTc supply shortage, 18F-fluoride has emerged as an 99m
Tc-diphosphonate, but with higher contrast, would identify them
extremely sensitive bone-specific PET agent, able to image areas as photopenic lesions compared to normal bone background. The
of abnormal osteogenic activity in a shorter time than BS and with high resolution of PET images with morphologic and anatomical
high accuracy for both lytic and sclerotic lesions, leading to the correlation of low-dose CT in modern hybrid PET/CT systems
suggestion that 18F-fluoride might be a complementary study to allows for detection of even small metastatic foci.
18
tumor-specific PET imaging. F-Fluoride is not tumor-specific. Semiquantitative analysis of its
uptake by means of SUVmax does not discriminate between malig-
nancy and benign causes for bone remodeling (i.e., trauma, degen-
Physiopathology of Bone Metastases erative changes, benign tumors). However, uptake pattern and
Bone architecture consists of a structural compartment (cortex morphologic correlation with low-dose CT of hybrid PET/CT systems
and trabeculae) that houses the bone marrow. Structural bone is permit easy discrimination between benign and malignant findings.
a dynamic tissue consisting of osteoblasts that deposit osteoid
matrix and promote its mineralization with hydroxyapatite crys-
tals (bone formation) and osteoclasts that are bone-resorbing
Synthesis and Safety
cells. When injured, the structural bone reacts by increasing its A cyclotron-derived radioisotope, 18F-Fluoride results from direct
bone mineral turnover in the attempt to self-repair. 11 MeV proton irradiation of 18O-enriched water. 18F-Fluoride is
The role of red bone marrow is hematopoiesis and its micro- then separated by adsorption on anion exchange resins and eluted
environment is characterized by a rich blood supply (e.g., Batson with sterile isotonic saline yielding 18F-Fluoride in physiologic
vertebral venous plexus) and an abundance of growth factors that solution (Na18F).67 18F-Fluoride synthesis is simple and with high
generally make it the first and most suitable “soil” for hematoge- yields that make it relatively inexpensive and, although cyclotron
nous metastatic “seeds” from any osteophilic solid tumors. produced, its half-life (t1/2 = 109.8 minutes) allows for distribution
Once in the red bone marrow, metastatic cells may remain dor- to peripheral PET facilities.
18
mant for a variable time but eventually activate, establishing com- F-Fluoride has an established monograph in the U.S. Phar-
plex, bidirectional biochemical interactions with the surrounding macopoeia68 and an FDA-approved NDA for skeletal PET. In the
microenvironment leading to neoangiogenesis, metastatic growth, E.U., 18F-Fluoride quality controls such as standards for produc-
and local uncoupling of bone deposition and resorption, generally tion, radioisotopic and radiochemical purity are described in the
in favor of the latter. European Pharmacopoeia (Ph. Eur., 7th ed., 2011).69 Its clinical
More aggressive tumor histologies are generally thought to be use, however, is also subject to variable national regulatory
responsible for predominantly lytic BMs, whereas predominantly authorities and it is not extensively accepted. All U.S. and E.U.
sclerotic lesions represent a slow tumor growth rate, as sclerosis suppliers must comply with national directives and GMP
is caused by the reparative reaction of surrounding bone. guidelines. To date, no safety issues concerning clinical use of
18
F-Fluoride have been reported.
18
F-Fluoride
18
F-Fluoride PET/CT
Pharmacokinetics
Acquisition Protocol
18
F-Fluoride is a short-lived β+ emitter isotope (β+ decay = 97%; Eβ+
= 0.635 MeV; t1/2: 109.8 minutes) and a hydroxyl ion analog which No specific preparation is required for patients undergoing a
18
is highly sensitive to detect areas of abnormally increased osteo- F-Fluoride PET/CT except good hydration on the day of exami-
genic activity. First introduced by Blau et al.62 in 1962 and despite nation (possibly two glasses of water before 18F-Fluoride adminis-
its ideal bone pharmacokinetics, 18F-Fluoride was soon abandoned tration and two more glasses during the uptake time). Patients can
in favor of 99mTc-diphosphonate as the high-energy photons were eat normally and take their usual medications. It should be noted
unsuitable for the thin crystals used for low-energy γ-imaging. Nev- that the impact of ongoing treatments such as bisphosphonates,
ertheless, the advent of PET imaging in the clinical practice has antihormonal therapy, chemotherapy, and radiotherapy on
revived interest in 18F-fluoride as the ideal bone-seeking PET agent. 18
F-Fluoride uptake has not been determined. History of recent
Similar to the 99mTc-diphosphonate compounds, 18F-Fluoride traumas, orthopedic surgery, and bone metabolic disorders should
accumulates as a consequence of both local blood flow and osteo- be obtained.
blastic activity. Soon after intravenous injection, 18F-Fluoride first- Recommended 18F-Fluoride activities for adults range from
pass distribution depicts blood supply that varies among different 185 to 370 MBq. Higher doses (444 MBq) are reserved for obese
bones.63 18F-Fluoride rapidly clears from plasma (two-fold faster patients. Pediatric activity is weight based (2.1 MBq/kg), ranging
than 99mTc-diphosphonate) being freely diffusible across mem- from 19 to 148 MBq. For intravenous administration an indwelling
branes and not binding to plasmatic proteins.64 Once diffused catheter should be used to avoid accidental tracer extravasation.
through bone capillaries virtually all 18F-Fluoride ions reach the Images can be acquired 45 minutes after 18F-Fluoride administra-
extracellular fluid and are chemisorbed onto actively remodeling tion in patients with normal renal function. Patients should be
bone surfaces by replacing a hydroxyl group in hydroxyapatite invited to void before scanning and even after the study has been
crystals to form fluoroapatite.65,66 completed to reduce the effective dose to the bladder and pelvic

organs. 3D-mode PET acquisition is preferable to limit the scan- radiologic evidence of bone relapse. If BMs are known, 99mTc-MDP
ning time of a large area. A total-body scan (from vertex of skull BS clinical indication should imply a possible change in clinical
to toes) is generally preferable, however whole-body studies from management. Recently PET imaging has also demonstrated high
vertex to mid-tibiae have also been suggested for cancers that diagnostic accuracy in assessing skeletal disease in similar diag-
predominantly metastasize via venous retrograde flow (e.g., pros- nostic scenarios by means of several tumor-specific tracers (i.e.,
18
tate and breast cancers) and with no clinical suspicion of periph- FDG, 18F-choline, 68Ga-DOTA-TOC) which directly image tumor
eral involvement. This would reduce effective dose and acquisition tissue.
time. Conversely, neoplasms likely to spread via arterial emboliza- Comparative studies have demonstrated the superiority of
tion (e.g., lung and kidney carcinomas) as well as clinical suspi- oncotropic PET/CT compared to BS in detecting predominantly
cion of peripheral skeletal involvement prompt a total-body scan.70 lytic and bone marrow–based BMs. In spite of this superiority,
18
FDG PET may still fail to image sclerotic BMs with scarce, slow-
proliferating cellularity, not prone to hypoxia and non–18FDG-avid
Radiation Dosimetry BMs.73–75 A highly sensitive bone-seeking PET agent, 18F-Fluoride
The effective dose for an adult receiving 370 MBq of 18F-Fluoride can detect early and accurately BMs regardless of their prevalent
is 8.9 mSv (effective dose equivalent = 0.024 mSv/MBq). If a radiologic appearance (lytic, blastic, and mixed) proposing as a
whole-body low-dose CT is performed (hybrid PET/CT systems), complementary study to tumor-specific PET/CT imaging in staging
additional 7 mSv should be considered so that the cumulative and restaging contexts (Fig. 31.4).
dose for an 18F-Fluoride PET/CT is approximately 16 mSv 15.9 Comparative studies have highlighted the superior diagnostic
mSv. Compared to a typical 99mTc-methylene diphosphonate [MDP] accuracy of 18F-Fluoride PET compared to 99mTc-MDP BS and

BS (740 MBq, Effective dose = 4.2 mSv), 18F-Fluoride PET/CT radi- SPET in a wide range of solid malignancies. 18F-Fluoride PET has
ation dose to patients is approximately 3- to 4-fold higher. proven significantly more accurate in detecting both blastic and
The highest absorbed doses extrapolated to patients are in lytic lesions, regardless of their anatomical localization and easily
bone surface, bone red marrow, and bladder walls for both differentiates benign from malignant lesions.76–79 The use of
modalities.71,72 low-dose CT (hybrid PET/CT systems) improves specificity by
reducing the number of equivocal findings and helps lesion local-
ization.80–82 Although 18F-Fluoride PET approximately changed
Clinical Applications clinical management in approximately 10% of selected popula-
99m
Tc-MDP BS is still the most widely used whole-body imaging tions, its cost-effectiveness compared to 99mTc-MDP BS and SPET
technique to assess bone metastatic disease, its use being tradi- has not been proved yet. When compared to tumor-specific PET,
18
tionally advocated in staging high-risk patients and in restaging F-Fluoride PET confirms its highest diagnostic accuracy in
symptomatic patients and/or patients with biochemical failure or detecting both lytic and blastic lesions but may fail to detect early
Figure 31.4. Staging [18F-]fluoride PET/CT in lung adenocarcinoma. A: There are three [18F-]fluoride avid lesions: One small, sclerotic lesion
at the left posterior aspect of T10; second lesion at the same level, right-sided, shows very mild and diffuse sclerosis and it is hardly detectable
on CT. Third lesion is sclerotic and involves the seventh left rib. B: median lytic lesion in L2 vertebral body, posteriorly. Patchy [18F-]fluoride uptake
observed along a very thin sclerotic rim.

bone marrow–based metastases which have not evoked bone Clinical Applications
remodeling.83,84 11
In prostate cancer, 18F-Fluoride PET/CT could play a complemen- C or 18F-Choline PET/CT imaging has been proposed to detect
tary role to conventional radiology and tumor-specific 18F-choline primary prostate cancer, to stage the tumor, to identify nodal
PET imaging to stage high-risk patients (i.e., PSA > 10 ng/mL, T3 involvement, and finally for the detection of tumor recurrence in
or T4, Gleason score (Gs) > 7) or symptomatic patients and/or case of biochemical relapse. In a recent publication, Soyka et al.89
patients with equivocal findings (e.g., non–18F-choline-avid scle- showed that the use of choline PET/CT in 156 patients resulted in
rotic lesions). 18F-Fluoride PET could be equally advocated for major changes in clinical management in 31%. In 21%, the
restaging patients with bony pain and/or biochemical failure (i.e., approach changed from palliative to curative and in 10% from
PSA > 10 ng/mL, PSA doubling time < 6 months) or evidence of curative to palliative.
skeletal recurrence on conventional imaging (XR, CT, MRI) if
whole-body assessment is thought to potentially influence thera-
peutic management.
Staging
Assessing response to hormonal/systemic treatments by means Accurate staging should exactly define the extent of local disease
of 18F-Fluoride PET could be insidious. Indeed an effective (T stage) and assess the presence of locoregional nodal and dis-
response to treatment can foster bone healing at BM-involved tant metastasis (stage N and M). In case of localized disease radi-
sites, resulting in a “flare” pattern on 18F-Fluoride PET.84 cal prostatectomy (RP), with or without pelvic lymphadenectomy
In breast cancer BMs are predominantly lytic (60%) and are (PLND), or radiation therapy (RT) are currently the only therapeu-
found in up to 70% of patients in advanced stages. Skeleton is the tic options. In case of distant metastasis a less invasive approach
first site of relapse in approximately 25% of patients. Risk factors is suggested (RT and/or systemic therapy).
for metastatic involvement include primary tumor size (T2 or
more), lymph nodal involvement (>3 metastatic nodes), and a T staging
positive estrogen receptor status. In patients with a locally At the present time, PET/CT with choline has limited value in
advanced breast tumor 18F-Fluoride PET/CT could be useful to assessing T status, and it has probably no role in assessing extra-
complete the staging work-up, when conventional imaging is capsular extension of the disease.
negative but concerns remain about skeletal disease. During
follow-up 18F-Fluoride PET/CT can also be indicated if patients N staging
become symptomatic or there is a rise in tumor or bone markers Metastatic lymph nodal spread is relatively low; it occurs in about
(i.e., CA 15.3, alkaline phosphatase [ALP]). 20% to 35% of patients with high-risk histology according to
In small cell lung cancer (SCLC) and locally advanced NSCLC nomograms,90 based on PSA levels, age, Gs, T status. The 5-year
total-body 18F-Fluoride PET/CT may assist 18FDG imaging in pre- disease-free survival rate decreases from 85% for pN0 patients to
operative staging if no BMs have been detected but the risk of 50% for pN1 patients.91 European guidelines on prostate can-
skeletal spread is deemed high. cers92 do not suggest any imaging method to stage the disease
because of the lack of accuracy to date that either CT or MRI have
shown in the detection of lymph nodal metastasis 93 In low-risk
Choline PET/CT for Prostate Cancer: patients (because the probability to have lymph nodal metastasis
is lower than 10%), European Guidelines do not suggest any
Main Clinical Applications imaging procedure, whereas in high-risk patients the only recom-
mended procedure is the extended pelvic lymph node dissection
The most widely used radiopharmaceutical used in functional (ePLND).
imaging of prostate cancer is choline, labeled with 11C or 18F. The three largest studies of PET/CT either labeled with 18F or
11
C-choline for nodal staging, gave similar results that PET/CT
has a high specificity and a low sensitivity. In 2008, Schiavina
Radiopharmaceutical et al.94 studied 11C-choline PET/CT in 57 patients with intermedi-
Choline is a substrate for the synthesis of phosphatidylcholine that ate- and high-risk PC using histology as reference after ePLND.
is the major phospholipids in the cell membrane.85 Choline kinase On a patient basis, sensitivity, specificity, PPV, NPV, and accuracy
activity is substantially upregulated in tumor cells.86 A recent in were 60%, 97%, 90%, 87%, and 87% respectively; on a lymph
vitro study by Müller et al.87 showed that the uptake of choline is node basis these values were 41%, 99%, 94%, 97%, and 97%
mediated by a selective choline transporter. respectively. Beheshti et al.95 evaluated 18F-choline PET/CT in 111
patients, who subsequently underwent RP with ePLND. On a
patient basis, PET/CT showed a sensitivity, specificity, PPV, and
Technical Aspects NPV of 66%, 96%, 82%, and 92%, respectively; on a lymph-node
Images of good diagnostic quality are usually obtained 3 to basis PET/CT showed a sensitivity, specificity, PPV and NPV of
5 minutes after tracer injection with 11C-choline and with dual 45%, 96%, 82%, and 83%, respectively. Moreover, early BM were
image acquisition (after 10 and 60 minutes from injection) with detected in two patients exclusively by PET/CT. Overall PET/CT
18
F-Choline. The physiologic uptake of 11C-choline includes sali- led to a change in therapy in 15% of all patients and 20% of high-
vary glands, liver, kidneys parenchyma, and pancreas and faint risk patients.
uptake in spleen, bone marrow, and muscles. Bowel and bladder Poulsen et al.96 confirmed these data in a study performed on
activity can occasionally be observed. 11C has a half-life of 210 patients with intermediate- and high-risk prostate cancer. A
20 minutes, so it must be used rapidly after production. This is sensitivity of 73% and 56% was observed on a patient, and a
the main drawback of 11C agents which require the presence of lymph node basis respectively with a specificity of 87% and 94%.
an on-site cyclotron. Consequently their distribution to distant The main drawback of this study is that “only” 1,093 lymph nodes
PET centers is not possible. To overcome the drawback of short were removed in the 210 patients (a mean of 5 lymph nodes per
half-life of 11C, an 18F-labeled choline tracer (18F-fluorocholine or patient) and only 73/1,093 were positives.
FCH) was developed as an alternative. The main difference In summary, the use of choline-PET/CT, labeled with either 11C
between 11C-choline and 18F-choline is the earlier urinary or 18F, for preoperative lymph nodal staging showed good specific-
appearance of the 18F probably because of incomplete tubular ity and poor sensitivity. This could lead to the use of PET/CT with
reabsorption.88 choline as a whole-body staging procedure in patients who are

et al.101 found that on multivariate analysis, PSA levels as well as

advanced pathologic stage, previous biochemical failure, and
older age (>65 years) were significantly (p < 0.05) associated with
an increased the likelihood of positive 11C-choline PET/CT find-
ings.
Castellucci et al.102 investigated the relationship between
11
C-choline PET/CT detection rate and PSA kinetics (PSA velocity
B and PSA doubling time). They enrolled a total of 190 patients after
RP who showed an increase in PSA (mean: 4.2 ng/mL; median:
2.1 ng/mL; range: 0.2 to 25.4 ng/mL). Authors found that PSAdt
and PSAvel values were statistically different between patients
with PET-positive and PET-negative findings. Authors concluded
that PSA kinetics should always be taken into consideration before
performing 11C-choline PET/CT in patients with biochemical fail-
C ure because it is the most relevant factor for a positive result.
Another study in which the influence of PSA kinetics has been
proved,103 evaluated 102 patients previously treated by RP who
presented only a mild increase of PSA serum levels <1.5 ng/mL
(mean: 0.86 ± 0.40 ng/mL). Overall, 11C-choline PET/CT showed

positive findings in 29/102 patients (28%). Using a retrospective
cutoff value for PSAdt of 7.25 months, there were only 2/56
D (only 3%) positive 11C-choline PET/CT in patients with a PSAdt
slower than the cutoff, whereas there were 27/46 (58%) positive
11
C-choline PET/CT in patients with a faster PSAdt value (p < 0.001).
In summary, choline PET/CT could represent an important
imaging modality in the detection of lymph nodal and distant
recurrence in PC patients with biochemical recurrence. In particu-
A lar, it could play a crucial role as the first diagnostic procedure in
E
patients who demonstrate a fast PSA kinetics and low PSA values.
Figure 31.5. A 63-year-old patient with prostate cancer staged wit 11C-choline PET/CT before In patients with slow PSA kinetics, the sensitivity of 11C-choline
primary treatment. PSA 23 ng/mL; Gs 4+4; T3a. A: MIP projection; B: left subclavicle positive PET/CT is limited.
lymph node; C and D: para-aortic and right common iliac positive lymph nodes; E: primary
prostate cancer.
Preclinical Applications
high risk for lymph nodal positive status (according to nomo-
grams), to reduce the number of negative or inconclusive choline Molecular imaging includes a range of techniques meant to visual-
PET/CT performed (Fig. 31.5). More prospective studies are ize molecular events at the cellular level in living organisms in a
needed to determine cost-effectiveness and the real impact of cho- noninvasive way. In the preclinical setting, the most interesting
line PET/CT. molecular imaging techniques are PET104 and MRI with molecular
contrast agents that allow in vivo accurate quantitation or semi-
quantitation of many molecular phenomena. Another important
Restaging technique is the CT with or without vascular or liver contrast
Monitoring PSA serum level is the best way to detect early recur- agents. CT does not provide “molecular” information, but is very
rence of the disease after primary treatment. In the event of bio- useful for observing the morphology of tissues and lesions (e.g., to
chemical relapse (PSA > 0.2 ng/mL), the role of imaging is to find accurately measure a tumoral mass over time) because it is very
the site of recurrence to establish the most appropriate therapy fast and complements the data obtained by PET and MRI.
(“salvage” radiotherapy in the prostatic fossa; “palliative” treat- It is now possible to utilize small animal PET, MRI, and CT
ment with hormonal deprivation; chemotherapy, etc.). The prob- scanners and the future likely includes hybrid scanners. At pres-
ability of the site of recurrence, local versus distal, is often guided ent, small animal PET/CT scanners are already available, whereas
by the PSA value and by its kinetics (rate of increase).97 As for PET/MRI scanners are still emerging.
staging, there are no precise guidelines about the role of imaging PET is used to provide information about tumoral metabolic
in the restaging of PC patients after biochemical relapse. The activity105,106 and allows for the exploration of different metabolic
European Guidelines on prostate cancer92 do not suggest any pathways in physiologic and pathologic tissues. The main advan-
imaging procedure if PSA is lower than 20 ng/mL, because the tage of small animal PET and MRI, over the standard methods of
accuracy of TRUS, CT, MRI, and BS is limited,98 particularly in preclinical experimentation requiring ex vivo examination, is the
patients with low PSA values. possibility to analyze the same animal more than once over time,
The first large prospective study of 11C-choline was performed allowing one to observe, for example, the response of a disease
by Picchio et al.99 comparing 11C-choline PET to 18F-FDG PET condition to a new therapeutic agent or the development of
results in 100 PC patients with biochemical recurrence (mean PSA disease, thereby significantly reducing the number of animals
value: 6.57 ng/mL). 11C-choline PET detected areas of abnormal employed and increasing the reliability of the results.
uptake in 47% of patients, 27% with 18F-FDG PET. None of FDG Furthermore, the use of small animal PET technology allows
PET-positive patients were choline PET-negative. for the detection of very low (picomolar) concentrations of radio-
Krause et al.100 evaluated 63 PC patients with biochemical tracers with great sensitivity to detect very small variations in
relapse (mean PSA: 5.9 ng/mL) after primary treatment by uptake.104 MRI, although less sensitive than PET, produces very
11
C-choline PET/CT. They demonstrated a significant and strict high resolution imaging.
correlation between PET/CT detection rate and PSA serum levels Another very interesting characteristic of preclinical molecular
and showed an overall detection rate of 59% for 11C-choline PET/ imaging is summarized by the word “translational.” By employing
CT. In 358 PC patients (mean PSA: 3.7 ng/mL), Giovacchini the same technology (PET, MRI, or CT) in the experimental setting

and in clinical practice, the step between preclinical science and all proposed compounds for oncologic studies from the past
clinical applications in human patients is shortened, reducing the decade.
overall time required to effectively verify the clinical utility of a Small animal CT can be used as a supporting modality for
new approach. One significant example in this field is the in vivo small animal PET for several reasons. First, it allows, as in the
testing of new radiolabeled compounds designed to increase the clinical setting, the correct anatomical localization of PET findings.
specificity of PET imaging for a specific disease. The creation of This is of particular importance in the field of small animal imag-
animal models of human disease for in vivo testing of new coming. Second, the CT image can be used as an attenuation correc-
pounds avoids evaluating compounds that are neither sensitive tion map for PET images, as in the clinical setting for humans.
nor specific for the disease process of interest. Actually this is of less importance because the animal body is
The translational applicability of these techniques, the possi- small and the highly energetic photons are subjected to negligible
bility for accurate quantitation106 and the high spatial resolution tissue attenuation, although it can be important to achieve accu-
(1 mm for PET and <1 mm for MRI and CT) are all very impor- rate quantitation of PET radiotracer uptake when one is studying
tant to study small animals like rodents in vivo. The high sensi- larger animals such as primates. Third, CT images are useful to
tivity and the possibility to use targeted probes to increase integrate the metabolic results obtained by the PET. CT images
specificity of disease characterization are features that make can be used, for example, to exactly measure the size or volume
these procedures very desirable in the preclinical scenario, of organs or tumors and these measurements can be noninva-
despite their relatively high cost compared with that of standard sively monitored over time. CT also provides an attenuation map
ex vivo studies. which can be useful to detect the onset of lesional necrosis, small
hepatic lesions, ascites, and so on. Small animal CT is especially
useful for the evaluation of the osseous structures and the lungs,
Applications of Small Animal PET in Oncology even in the absence of intravenous contrast material.109
The vast majority of studies employing small animal PET scanners Recently, a technologic development has enabled CT images
are not based on the comparison between PET results and other with cardiac gating and/or respiratory gating. Although respira-
preclinical imaging procedures but instead take into consideration tory gating is used to improve the spatial resolution predomi-
histochemical analyses or autoradiography to verify imaging nantly at the lung bases by compensating for respiratory motion
results. This is mainly because of the high costs of the scanners, artifacts, cardiac gating has much more scientific utility in the
which makes it very difficult to access multimodality technology. study of cardiac performance such as ejection fraction. Most of the
In the future, it is likely that this approach will change, and more published studies regarding the small animal PET/CT imaging are
and more complementary imaging techniques will be employed performed using two separate scanners with a multimodality gan-
for evaluation of the same animal models. try bed that is shifted from one scanner to the other. In this way,
Small animal PET allows one to noninvasively measure a range the change in the position of the experimental animal is kept to a
of tumor-relevant parameters at both the cellular and the molecu- minimum, and the image sets (usually in DICOM format) can be
lar level, which can be observed longitudinally over time. Studies coregistered.
to evaluate tumor response to a therapeutic intervention can
achieve statistical significance using smaller groups of animals, as
tumor cell physiology and tumor burden can be accurately deter- Conclusions
mined before and after therapeutic intervention.
The most widely employed PET imaging probe is [18F]-2-fluoro- Labeled amino acids to image brain malignancies is now a reality,
2-deoxy-d-glucose, which achieves tumor-specific accumulation even though only a few patients have benefited to date. 68Ga-DOTA-
because tumor cells have a higher rate of glucose uptake and metab- peptides and 18F-DOPA are principally useful to evaluate patients
olism (glycolysis) than normal tissues. FDG is generally used in with NET. Both 68Ga-DOTA-peptides and 18F-DOPA are valuable trac-
oncology to predict cancer cell engraftment107 and to measure the ers. A consistent literature demonstrates their accuracy compared to
response to therapy. [18F]-3′-fluoro-3′-deoxy-l-thymidine (FLT) and conventional imaging (CT, MRI) and SRS. 68Ga-DOTA-peptides
its analogs (e.g., [18F]-1-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl) are likely to become the tracers of choice to study patients with
thymine are another family of compounds that are widely used in well-differentiated NET. At present, however, their use is limited to
preclinical PET because they demonstrate the proliferative index of specialized centers in Europe. The advantages of these tracers
tumor masses with high accuracy, which is far higher for animal include not only to a better overall accuracy but also the possibility
models of cancer than for human patients.108 to obtain data regarding SSR expression on target lesions. These
Many other PET probes have either been developed or are data noninvasively identify patients eligible for therapy with either
under development to obtain tumor specificity via a variety of hot or cold somatostatin analogs. From a technical point of view, it
tumor-specific mechanisms. The development of targeted radiola- is also worth mentioning that the relatively easy and economic
beled ligands has further enabled PET to image many aspects of synthesis process of these tracers renders them suitable for use
in vivo tumor biology. Radiolabeled annexin-V, arginine-glycine- even in small centers without an on-site cyclotron. In view of both
aspartic acid (RGD) peptide, vascular endothelial growth factor the relatively difficult and expensive synthesis process and the
(VEGF), and αvβ3 integrin, for example, have successfully been documented lower accuracy, 18F-DOPA role may be more relevant
tested in tumor models as well as in models of cardiac infarction. in the clinical settings in which 68Ga-DOTA-peptides show subopti-
The pharmacokinetics and pharmacodynamics of radiolabeled mal performance. For example, 18F-DOPA PET/CT is a valuable to
anticancer therapeutics can, in principle, also be monitored by image NET cases with variable or absent SSR expression (e.g.,
these methods, leading to rapid improvements in drug dose medullary thyroid carcinoma, neuroblastoma) or to assess the
scheduling or design. response to treatment. Finally, two issues still need to be addressed.
Finally, the effects of receptor therapies (e.g., inhibitors of First of all, considering the wide spread clinical use of SRS, it is
androgen receptors, estrogen receptors, and of epithelial growth worth mentioning that SRS is still a valuable technique to study
factor receptor [EGFR]) can theoretically be predicted thanks to well-differentiated NET. Of course, as stated above, the use of
the in vivo demonstration of the receptor after injection of a par- PET/CT with 68Ga-DOTA-peptides, when available, offers several
ticular radiolabeled ligand.106 advantages. The employment of a more sensitive imaging proce-
The literature includes a wide number of PET radiolabeled dure, however, may not always have a direct impact on clinical
compounds for preclinical evaluation of specific molecular management. In fact, in most cases the detection of a higher num-
events, and it would be very difficult to provide a complete list of ber of metastatic lesions by PET/CT compared to morphologic

imaging or SRS, is not followed by a change in the therapeutic ally complementary to tumor-specific PET, and reserved to specific
approach. On the contrary, therapeutic management may be influ- patient subsets. Undoubtedly 18F-fluoride PET studies would be of
enced by the detection of unsuspected metastatic spread or local great value in assessing those primaries which cannot be effec-
relapse, by the identification of the site of the occult primary tumor tively investigated by any oncotropic PET agent.
or by the confirmation or exclusion of SSR expression on tumor The role of functional imaging in the evaluation of prostate
cells. Therefore, the choice between performing PET/CT or SRS cancer patients is not well established. The use of choline PET/CT
should be mainly driven by the local availability of the procedure for staging is recommended only in patients with high-risk pros-
itself. If SRS is performed, PET/CT should be recommended only in tate. The main clinical application of choline PET/CT is the restag-
cases in which the detection of a more extensive disease would ing of the disease in cases of biochemical relapse to detect LN and
change the therapeutic approach (e.g., SRS-negative cases, cases distant recurrence.
in which SRS showed only the primary, equivocal SRS findings).
Another relevant issue to be discussed is the potential role of 18F-
FDG compared to 18F-DOPA and 68Ga-DOTA-peptides in NET lesion Future Considerations
detection. Although a detailed analysis of the role of 18F-FDG is
beyond the scope of this chapter, it is worth mentioning that it may It is likely that there will be wider use of amino acid tracers in the
provide valuable information in NET forms characterized by lower future as the means of production and distribution improves. Con-
differentiation grade. In fact, although it is well known that 18F- sidering the polymorphic nature of neuroendocrine cells (the wide
FDG has a limited role in the assessment of well-differentiated range of both surface receptors and hormone products), further

NET, because of their slow glucose metabolic rate, it should also be studies are needed to ascertain whether the use of alternative
reminded that NET may show variable degrees of differentiation radiolabeled compounds or the definition of criteria for the com-
both between patients and in different lesions within the same bined use of available radiotracers may provide additional value
patient. From a prognostic point of view, the detection of FDG-avid for NET patient management.
lesions is associated with a worse prognosis, reflecting the pres- Larger, prospective studies are warranted to better validate
18
ence of lesions with a lower differentiation grade. F-FLT. These should include:
18
FLT is more tumor specific than 18FDG but its tumor uptake
• use of PET-guided biopsy particularly for highly heterogeneous
is lower resulting in lower sensitivity. It is not useful for tumors
tissues.
within the liver, bone, or pelvic region because of high accumula-
• use of mean and maximum measurement both for the SUV and
tion of the radiotracer. Although cellular proliferation is a hall-
Ki-67 scoring, and the use of SUVpeak (1 mL volume containing
mark of malignancy, cell division can also occur in benign
the highest SUV).
processes, including certain forms of infection and inflammation.
• development of guidelines with detailed report of methodology
Therefore, proliferation markers cannot replace 18FDG but rather
and execution of both FLT PET/CT and histopathology measure-
should be used as complementary tools to provide additional diag-
ments.
nostic specificity and biologic information for therapy planning
and monitoring. 18FLT PET could serve as a noninvasive tool to The added value of 18F-fluoride PET/CT to assess BM should
establish tumor grade, to visualize heterogeneity within the lesion, imply a significant change in patients’ therapeutic management
to help defining the optimum biopsy site, and to select patients compared to well-established diagnostic techniques. With this
who might benefit from adjuvant treatment. regard well-controlled trials are supported by Medicare and Med-
Imaging BM often results in a complex and multimodality strat- icaid Services (CMS) with the aim of providing evidence on the
egy that is primarily influenced by a patient’s underlying primary real cost-effectiveness of 18F-fluoride PET/CT, especially in assist-
tumor, clinical situation, and expected change in clinical manage- ing the primary therapeutic strategy by the detection and quanti-
ment. Nonetheless when a whole-body skeletal assessment is fication of bone lesions in patients in whom metastases are
needed, 99mTc-DP BS is the modality of choice in a variety of solid strongly suspected, based on clinical symptoms or results of other
primaries. Despite preliminary well-controlled reports of higher diagnostic studies.
diagnostic accuracy compared to 99mTc-diphosphonate planar and Better understanding of both malignant and benign causes for
tomographic imaging, [18F-]fluoride PET has found it hard to enter 18
F-fluoride uptake may result from the introduction of hybrid
clinical practice. This could be ascribed to the parallel increasing PET/MRI systems in clinical settings. Indeed not only will tumor-
availability of tumor-specific PET and PET/CT in staging and specific and bone-specific PET imaging be implemented with
restaging scenarios which has partially obviated the need for high-detailed morphostructural information but further functional
bone-seeking radionuclide imaging. Indeed 18PET has been proven data will help better understand BM pathophysiology.
effective in assessing not only primary tumors and their visceral Also, 18F-fluoride shares a similar mechanism of uptake with
metastases but also early bone marrow–based and lytic disease 223
Ra-chloride, an α-emitter recently introduced for systemic
with better accuracy than 99mTc-DPD BS. Similar results have treatment of multimetastatic patients. Exploiting this similarity, a
been described for other metabolic and receptorial tumor- recent pilot study111 has proposed semiquantitative 18F-fluoride
specific radiopharmaceuticals (i.e., 11C-choline in prostate can- PET as a method to monitor BM treatment response at clinically
cer, 68Ga-DOTA-TOC in NETs84,110). Moreover, impaired diagnostic relevant intervals.
accuracy of tumor-specific PET in osteoblastic lesions could be Future efforts should aim to study the role of 11C-choline PET/
partially obviated by low-dose CT from modern hybrid PET/CT CT imaging as the initial diagnostic imaging procedure in patients
systems. Although 18F-fluoride PET has been proven clearly to be with prostate carcinoma with fast PSA kinetics.
more accurate than 99mTc-diphosponate imaging in detecting blas-
tic, mixed, and lytic lesions even with poor and/or undetectable
osteoblastic reaction on CT, its costs and relatively lower avail- References
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Chapter 32
Assessment of Response to Antitumor Treatment

Masahiro Yanagawa • Noriyuki Tomiyama • Tadashi Watabe • Kayako Isohashi • Jun Hatazawa
Introduction PET, with the glucose analog 18F-fluorodeoxyglucose (FDG), has

been widely used as a technique to evaluate metabolic activity in
In recent years, cancer mortality rates have continued to increase tumors. This metric is more informative for the evaluation of treat-
so that it is expected that in the future, cancer will be the most comment response after chemotherapy than simply reduction of tumor
mon cause of death worldwide. Anticancer drugs, surgery, and volume.13 Recently, Wahl et al.14 proposed the PET Response Criteria
radiation therapy are the major cancer treatment modalities. The in Solid Tumors (PERCIST) as a new standardized method for
goals for anticancer drug administration can be described as quantitative assessment of metabolic tumor response. PERCIST data
follows: Reduce or eliminate cancer tissue, prolong life, and relieve are expected to provide improved information for a therapeutic
symptoms. Many patients undergo neoadjuvant therapy before strategy for cancer patients.
resection, others receive adjuvant therapy after resection, and still
others receive continued palliative chemotherapy. Assessment of Therapeutic Response
Currently, various treatment options for cancer are available,
including use of novel agents that target specific molecules (such
of Various Tumors
as Avastin [bevacizumab], Tarceva [erlotinib], and Iressa [gefitinib]).
Selection of an effective treatment and appropriate evaluation of
Brain Tumors
treatment response are important to accomplish prolonged sur- For brain tumor patients, treatment response is usually evaluated
vival and to preserve quality of life. by gadolinium (Gd)-enhanced MRI. However, one of the major prob-
Selection of appropriate methods to evaluate therapeutic effi- lems encountered is difficulty differentiating treatment-induced
ciency is a crucial component of effective cancer treatment. Imaging necrosis from recurrent or progressive tumor on MR images.15 In
assessments, such as computed tomography (CT), magnetic reso- addition, after treatment with antiangiogenic agents, a decrease in
nance imaging (MRI), and positron emission tomography/CT (PET/ contrast enhancement does not reflect tumor regression.16–18 This
CT), are mainstream methods universally used to evaluate treatment type of response is because of a normalization of abnormally
responses. permeable microvessels, mostly noted with antiangiogenic treat-
Many approaches have been developed to objectively assess ment, leading to a rapid decrease of contrast enhancement of Gd-
treatment response, beginning with the original report by Moertel in enhanced MR images, but not reflecting a real decrease in tumor
1976 and the subsequent development of the World Health Organi- activity or size.19–21 Another major problem is underestimation of
zation (WHO) criteria in 1979, followed by publication of the Response the tumor invasion area because of a limitation of Gd-enhanced
Evaluation Criteria in Solid Tumors (RECIST) in 2000, and RECIST MR images, on which enhanced lesions can simply represent col-
1.1 in 2009.1–4 RECIST is widely used as an anatomic tumor response lapse of the blood–brain barrier. On 11C-methionine (11C-MET) PET
metric but is known to have limitations when tumors have obscure images, tracer uptake is sometimes observed in areas having no
margins or scar tissue is present after treatment. Moreover, some Gd-enhancement on MR images (Fig. 32.1). Thus, use of conven-
caution is required when using RECIST to predict outcomes of treat- tional MR techniques to monitor response is not appropriate,
ment with the novel molecularly targeted agents, because RECIST is especially for antiangiogenic therapies. To overcome these limita-
based on the reduction of morphologic size.5–10 These agents, which tions of conventional MRI, advanced PET imaging can potentially
tend to be more cytostatic than cytocidal, offer a substantial improve- assess biologic changes in tumors. Depending on the radiotracer
ment in outcome even without major shrinkage of tumors that would used, responses at the molecular level are visualized by PET
be characterized by a partial or complete RECIST response.11,12 which assess tumor metabolism and cell proliferation.
A B C
Figure 32.1. (A) Gd-enhanced MR image, (B) PET/MR fusion image, (C) 11C-MET-PET image of a 56-year-old man with glioblastoma. 11C-MET uptake was
observed outside the Gd-enhanced lesion, which indicated tumor invasion.
498

Chapter 32 Assessment of Response to Antitumor Treatment 499
PET with 18F-FDG directly reflects the glucose metabolic activity Early detection of treatment response has also been reported in
of tumor cells. 18F-FDG uptake has been shown to correlate with glioma patients after radiochemotherapy.39 Surgery and subsequent
tumor cell density22 and grading and malignant behavior of glio- radiochemotherapy was used to treat 22 patients with glioblas-
mas,23–25 and is predictive of patient outcome.26,27 In one report, tomas. The 18F-FET PET studies were performed before and 7 to 10
25 adult patients with recurrent high-grade gliomas were evaluated days after completion of therapy. Response was defined as a decrease
by 18F-FDG PET within 6 weeks of starting chemotherapy with of more than 10% in the maximal tumor-to-brain uptake ratio. There
bevacizumab and irinotecan. 18F-FDG PET was shown to be the were 16 early responders by 18F-FET PET (72.7%) and six nonre-
most powerful predictor of both progression-free survival and overall sponders (27.3%). Early responders, as revealed by PET, had a signifi-
survival (OS).28 However, variability of glucose uptake in recurrent cantly longer median disease-free survival (DFS) (10.3 versus 5.8
high-grade gliomas and low tumor-to-background ratios, because of months; p < 0.01) and OS (“not reached” versus 9.3 months; p < 0.001).
the high metabolic activity of healthy brain tissue, limit the useful-
ness of 18F-FDG PET to assess brain tumors.29 Another limitation is Monitoring Anticancer Immunotherapy
a treatment-associated inflammatory response leading to increased
18
F-FDG uptake into inflammatory cells. Increased 18F-FDG uptake
by Means of 11C-MET PET
in tumors was observed in a study using a rat model for intracere- Recent advances in tumor immunology have led to identification of a
bral gliosarcoma because of the presence of glucose-consuming number of tumor-associated antigens on cancer cell membranes. For
activated macrophages.30 example, the Wilms tumor gene (WT1) product is overexpressed in
Amino acid transport, as well as protein synthesis, were both malignant gliomas, and WT1 immunotherapy for patients with

demonstrated to be enhanced in most gliomas and can potentially recurrent glioblastoma is regarded as a safe therapy with a favorable
be used as imaging targets.31 Radiolabeled amino acids are more clinical response. The median survival after initial vaccination is
specific tracers for tumor detection and tumor delineation than 36.7 weeks, which is remarkably longer than that of 14.6 months
18
F-FDG because of their low uptake in normal brain tissue. after standard treatments for glioblastoma. The effects, based on the
Radiolabeled amino acid tracers are not taken up by glycolytic RECIST guidelines, of WT1 immunotherapy were evaluated by con-
inflammatory cells and, therefore, have been suggested to be trast-enhanced MRI. However, the RECIST-based response rate (com-
more appropriate to discriminate between recurrence or pro- plete response and partial response [CR+PR]) was only 9.5%, whereas
gression versus nonspecific therapy-related changes.32 Use of a the disease control rate was 57.1% of 21 patients studied, which
variety of radiolabeled amino acids, like 11C-MET, and aromatic indicated that use of RECIST criteria and contrast-enhanced MRI is
amino acid analogs, like 18F-fluoroethyltyrosine (18F-FET), not a sensitive method for evaluation of response to anticancer
18
F-fluorotyrosine (18F-TYR), 18F-fluoromethyltyrosine (18F-FMT), immunotherapy. Response evaluations of patients with malignant
and 18F-fluorodopa (18F-DOPA), has been proposed. Increased gliomas following immunotherapy targeting the WT1 gene product
uptake rates are related to increased transport mediated by type- were reported by PET-based criteria as well as size-based criteria.
L amino acid carriers. Uptake of 11C-MET correlates with cell pro- The Osaka group prospectively compared RECIST-based, 18FDG
liferation in vitro, Ki-67 expression, nuclear antigen expression, PET–based and 11C-MET–based evaluation of the effects of WT1
and microvessel density in areas of cell proliferation, suggesting peptide immunotherapy in patients with recurrent glioblastoma. Six
that 11C-MET may be a good marker of tumor proliferation and patients with recurrent glioblastoma following initial surgical resec-
neovascularization.33 tion, external radiation, and chemotherapy were enrolled. Inclusion
criteria were: (1) age ranging from 16 to 80 years; (2) expression of
Assessment of Therapeutic Response of Glioma: WT1 in the glioma cells, determined by immunohistochemistry;
(3) HLA type A*2402 positivity; (4) estimated survival of more than
Comparison of 18F-FET PET and MRI 3 months; (5) performance status from 0 to 2 (Eastern Cooperative
11
C-MET-PET can distinguish tumor progression from stable dis- Oncology Group); (6) no severe organ function impairment; and
ease with high sensitivity (90%) and specificity (92.3%) based on a (7) procurement of written informed consent from the patient. All
threshold of a 14.6% increase in 11C-MET uptake.34 Equivalent patients had histologically proven glioblastoma (Grade 4) based on
findings with 18F-FET PET were reported in patients with gliomas WHO criteria. Recurrence or progression of tumors was monitored
after radiotherapy, radiosurgery, and multimodal treatment such as by contrast-enhanced MRI during initial and maintenance therapy.
radioimmunotherapy.35 In contrast to the 92.9% specificity and No patient had chemotherapy or radiotherapy during the 4 weeks
100% sensitivity of 18F-FET PET, specificity of conventional MRI prior to WT1 immunotherapy. The patients were intradermally
alone was only 50%. After radioimmunotherapy, a threshold tumor- injected at 2-week intervals with an HLA-A*2402-restricted, modi-
to-background ratio of 2.4 for 18F-FET uptake provided the best fied 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant
differentiation between recurrence and reactive changes (sensitiv- at 1 mg/kg body weight. The patients underwent 11C-MET PET and
ity 82%, specificity 100%).36 In a prospective study of stereotactic 18
FDG PET before and after the WT1 vaccination. The 11C-MET and
sampling of 18F-FET-positive glioma recurrences in 17 patients with 18
FDG uptakes were measured 20 to 30 minutes and 60 to 70 min-
low-grade gliomas, 6 patients with anaplastic gliomas, and 8 utes after intravenous injection of 11C-MET and 18FDG, respectively.
patients with glioblastomas, the positive predictive value of 18F-FET The maximum uptake in the recurrent glioblastoma (% uptake com-
PET was 84%.37 18F-FET uptake in 11 patients with progressive pared to contralateral cerebral cortex) and the volume having
low-grade gliomas during temozolomide chemotherapy was quan- abnormally high accumulation (20% or more compared to contralat-
tified with PET as metabolically active tumor volume, and was com- eral cerebral cortex) were assessed in each PET study. Patients were
pared with the tumor volume on MR.38 Response was defined as a classified 4 weeks after initiation of vaccination by RECIST with MRI
10% reduction of the initial tumor volume, and eight patients had as follows: Partial response (PR, n = 1, survival period = 248 days),
metabolic responses. Three months after the start of chemotherapy, stable disease (SD, n = 4, alive at 453, 661, 936, and 960 days, or
the active 18F-FET volumes decreased to a mean of 44% from base- progressive disease (PD, n = 1, alive at 812 days), resulting in a
line in two patients. The first MRI volume responses were noted at response rate (CR + PR) of 18%. In the 11C-MET PET evaluation, the
6 months. Responders showed a volume reduction of 31% ± 23% maximum uptake of 11C-MET before therapy (220 ± 48%) was sig-
(mean ± SD) from baseline by 18F-FET PET, and 73% ± 26% by MRI. nificantly decreased after therapy (161 ± 50%, p < 0.01). The volume
The time to maximal volume reduction was 8 ± 4.4 months by of abnormally high accumulation (17.6 ± 10.9 mL) was significantly
18
F-FET PET and 15 ± 3 months by MRI. Therefore, metabolic vol- decreased after therapy (9.2 ± 7.3 mL, p < 0.01). The 18FDG PET
ume reduction estimated by 18F-FET PET was evident much earlier revealed lower accumulation of 18FDG in the tumor than in the con-
than tumor volume reduction by MRI. tralateral cortex in all patients. After vaccination, the maximum

A C E
Figure 32.2. (A, B) Contrast-enhanced MR images,

(C, D) 18F-FDG PET, and (E, F) 11C-MET-PET in a WT1
immunotherapy responder (63-year-old man, alive 826
days after treatment completion). (A, C, E) Before ther-
apy; (B, D, F) after therapy. The contrast-enhanced tumor
lesion expanded after treatment caused by peritumoral
edema. The FDG PET demonstrated a remarkable
increase in metabolically active volume corresponding to
morphologic changes observed on MR imaging. The MET-
B D F PET showed round-shaped uptake, indicating a decreased
volume of viable tumor cells.
uptake of 18FDG was unchanged in four patients, 30% decreased in greater than 25%. Treatment response was assessed by MRI at
one patient, and 50% increased in one patient (Fig. 32.2). Residual 6 weeks, according to the Response Assessment in Neuro-oncology
tumor cell volume could be more accurately estimated by means of criteria. Early and late changes in tumor 18F-FLT uptake were more
11
C-MET PET than 18FDG PET after WT1 immunotherapy. The sce- predictive of OS than MRI criteria (p < 0.001 and p = 0.01, respec-
nario of tumor volume expansion seen on contrast-enhanced MRI tively). 18F-FLT uptake changes were also predictive of progression-
and elevated 18FDG uptake may predominantly indicate an activated free survival (p < 0.001). On the basis of the 6-week 18F-FLT PET
host-immune system following WT1 immunotherapy. response, there were 16 responders (53%) and 14 nonresponders
To evaluate WT1 immunotherapy response in patients with (47%), whereas MRI identified nine responders (seven partial
recurrent malignant glioma, we further developed the parametric response, two complete response, 31%) and 20 nonresponders
response map (PRM) by means of 11C-MET PET evaluations.40 (13 stable disease, seven progressive disease, 69%). In seven of the
11
C-MET PET data before and after WT1 immunotherapy were reg- eight discrepant cases between MRI and PET, 18F-FLT PET demon-
istered onto pre- and post-WT1 contrast-enhanced T1-weighted strated response earlier than MRI. Among various outcome predic-
MR images, respectively, using normalized mutual information with tors, multivariate analysis identified 18F-FLT PET changes at 6 weeks
the VINCI image analyzing software from the Max Planck Institute as the strongest independent survival predictor (p < 0.001; hazard
for Neurological Research in Cologne, Germany. This data set delin- ratio, 10.051). New treatment strategies with antivascular agents
eated changes in maximal tumor length and tumor volume, and (e.g., the antivascular endothelial growth factor receptor-1 antibody,
PRM parameter changes, such that a negative PRM value resulted bevacizumab) are difficult to monitor reliably by conventional imag-
from a decrease in 11C-MET uptake after WT1 immunotherapy, ing techniques, because treatment-induced reduction of contrast
indicating treatment response. Study results indicated that changes enhancement predominantly represents reduced vascular permea-
seen on contrast-enhanced MRI in tumor length and volume did not bility.43 18F-FLT PET proved to be superior compared to contrast-
correlate with the OS period. Contrast-enhanced MRI findings prob- enhanced MRI in predicting treatment response of malignant
ably reflected immune reactions, such as increased capillary per- gliomas to bevacizumab plus chemotherapy.44
meability, rather than tumor viability. On the other hand, the PRM Dynamic 18F-FLT PET was performed in 15 patients with recur-
parameter derived from 11C-MET PET did predict the OS period. rent high-grade brain tumors; imaging was performed at baseline,
after one course of therapy (2 weeks), and at the end of therapy
Assessment of Therapeutic Response: Comparison (6 weeks) and 18F-FLT kinetics were investigated.45 The standard
3-compartment model was corrected for the blood volume fraction
of 18F-Fluorothymidine (18F-FLT PET) with MRI in tissue (Vb) and for metabolites, and the partial volume was used
A thymidine analog, 3′-deoxy-3′-18F-fluorothymidine (18F-FLT), has to estimate kinetic parameters. The largest change in kinetic
been developed to image tumor cell proliferation.41 18F-FLT is parameters occurred between baseline and 2 weeks of treatment.
transported into tumor cells via nucleoside transporters and is Significant changes were found for Vb, influx rate constant (Ki),
subsequently phosphorylated by thymidine kinase 1 to 18F-FLT volume of distribution, early SUV, and late SUV. After stratification
5-phosphate. In a previous report, 30 patients underwent 18F-FLT to OS, the patients with the best prognosis had a change at 2 weeks
PET before and 2 and 6 weeks after the start of bevacizumab com- of treatment that persisted at 6 weeks, whereas the patients with
bination therapy.42 A metabolic response was defined as a decrease short survival times had returned to baseline values at 6 weeks.
in standardized uptake values (SUVs) from baseline equal to or High correlations were found between SUV and Ki, indicating that,

Table 32. 1
Summary of PET Tracers used for the Evaluation of Brain Tumors to Antitumor Treatment
PET Tracer Tumor Type Timing of Evaluation and Treatment Findings

18
F-FDG Recurrent high-grade gliomas 6 wks after starting chemotherapy PET was the most powerful predictor of progression-free
survival and overall survival28
18
F-FET Gliomas (Grade 3 and Grade 4) More than 3 mos after radioimmunotherapy The best differentiation between recurrence and reactive
changes on PET (sensitivity 82%, specificity 100%)36
18
F-FET Low-grade gliomas 3 mos after the start of chemotherapy (temozolomide) PET responders showed a volume reduction to 31% ± 23%
(73% ± 26% by MRI)38
18
F-FET Glioblastomas 7–10 d after completion of surgery and Early PET responders had a significantly longer median
radiochemotherapy disease-free survival and overall survival39
11
C-MET Recurrent malignant gliomas 12 wks after WT1 immunotherapy The PET uptake volume was significantly decreased. PRM
parameter predicted the overall survival period40
18
F-FLT Recurrent malignant gliomas 2 and 6 wks after the start of bevacizumab therapy PET uptake was more predictive of overall survival than MRI42
18
F-FLT Recurrent high-grade gliomas 2 and 6 wks after the start of bevacizumab/irinotecan The largest change in PET kinetic parameters occurred
therapy between baseline and 2 wks of treatment45

18
F-fluciclatide Rat xenograft model 2–13 d after the start of sunitinib therapy Decrease in PET tumor uptake was earlier than any
volumetric changes47
in clinical practice, simple uptake measurements are sufficient for New Methods to Evaluate Therapeutic Efficiency
therapy monitoring and predicting short- and long-term survival.
RECIST is widely used as an anatomic tumor response metric, but
it is known to have limitations for tumors that have obscure margins
PET Imaging of aV b3-Integrin or when there is scar tissue after treatment.1–4 In patients with
Glycosylated arginine-glycine-aspartic acid peptide (18F-Galacto-RGD) esophageal cancer, measurement of the longest diameter of lesions on
was demonstrated to successfully identify the expression in glio- CT and resultant evaluation of treatment response are difficult. The
blastoma of the integrin αVb3, which is associated with tumor- general use of 18FDG PET for response evaluation to chemotherapy
induced angiogenesis via basic fibroblast growth factor, and which in esophageal cancer patients has been reported previously.51–53
is also found in small blood vessels, where it is thought to promote The following two novel methods will be the focus of this section:
extensive tumor progression.46 Assessment by the PERCIST criteria and evaluation of intratumor
Fluciclatide binds with a high affinity to αVb3-integrin and αVb5- heterogeneity by texture analysis of baseline PET scans.
integrin, which are highly expressed on tumors and in tumor neovas-
culature. In a rat xenograft model, 18F-fluciclatide detected changes Assessment by PERCIST
in tumor uptake after acute antiangiogenic therapy with sunitinib
markedly earlier than any significant volumetric changes were As mentioned in the introduction section of this chapter, PERCIST
observable.47 These results suggest that PET imaging of αVb3- has been recently proposed as the new standardized method to
integrin may provide clinically important information for monitor- assess chemotherapeutic response metabolically and quantita-
ing the response to antiangiogenic therapy. tively.14 Yanagawa et al.54 demonstrated that use of PERCIST was
In summary, PET can detect early metabolic responses to treat- the best method for evaluation of treatment response for patients
ment in brain tumors as well as precisely evaluate tumor extent and with esophageal cancer as it is closely related to prognosis.
activity, as compared to conventional MRI. PET is a suitable modality The method to evaluate therapeutic efficiency according to
for evaluating therapy response to antiproliferative drugs, antian- PERCIST is as follows.14,54 First, the entire tumor was manually
giogenic treatment strategies, and tumor progression (Table 32.1). enclosed using a volume of interest (VOI) to identify the pixel with
Further study is needed to determine the appropriate criteria and the maximum SUV in the tumor on PET. Second, the mean SUV of
timing for response evaluations and selection of the most suitable the tumor was measured using a maximal 1.2-cm diameter VOI,
tracer for each treatment type. which was placed on the hottest area within each tumor that
included the pixel with the maximum SUV. This mean SUV of the
tumor by the volumetric method corresponded to SUVpeak of the
Esophageal Cancer tumor. The SUVpeak was normalized to lean body mass (SULpeak =
Esophageal cancer has a high mortality rate. In the early stage, SUVpeak [lean body mass]/[total body mass]). Finally, it was
esophagectomy is selected as a treatment having curative poten- determined whether the SULpeak of the tumor was higher than
tial. Although surgery has remained the standard treatment for 1.5 times the liver SUL mean + 2SDs (in a 3-cm-diameter spherical
esophageal cancer, postoperative prognosis is unsatisfactory, with region of interest in the normal right lobe of the liver).14,54
5-year survival rates of 40% at most.48 Moreover, most patients at Results of some studies51–53 have demonstrated that the cutoff
presentation already have locally advanced esophageal cancer or values of maximum SUV reduction rates were useful for discrimi-
distant metastases. Therefore, multidisciplinary approaches, such nation of PET responders and nonresponders. However, these val-
as use of neoadjuvant chemotherapy (NAC) and/or radiotherapy ues varied, ranging from 35% to 70%. The main reason may be due
followed by surgery, are now frequently adopted in patients with in part to the wide variety of 18FDG PET evaluation criteria, timing
locally advanced esophageal cancer, resulting in improved prog- after start of therapy, techniques, and end points used. Thus, a
nosis for those who respond to induction therapy.49 standardized method should be established to evaluate therapeutic
On the other hand, some studies have suggested that patients response. Yanagawa et al.54 demonstrated that neither reduction
with locally advanced esophageal cancer who respond to chemora- rates of SULpeak by PET nor reduction rates of tumor diameter by
diotherapy might not receive any additional benefit from surgery.50 CT were useful for prediction of survival and recurrence. However,
Thus, appropriate selection of methods to evaluate therapeutic effi- patients with complete metabolic response (CMR) by PERCIST had
ciency is crucial for effective treatment. better prognosis: CMR is a complete resolution of 18F-FDG uptake

Table 32.2 In image processing algorithms, simplifying assumptions are

made about the uniformity of intensities in local image regions.
A Brief Account of Objective Therapeutic Responses However, images of real objects often do not exhibit regions of uni-
According to the Recist and Percist Criteria form intensities. Identifying the perceived qualities of texture in an
image is an important first step toward building mathematical mod-
Objective Therapeutic Responses According to the RECIST1–4 els for texture. Tixier et al.58 defined texture as a spatial arrange-
Complete response (CR) A disappearance of tumor foci for at least 4 wks ment of a predefined number of voxels allowing the extraction of
Partial response (PR) A decline of at least 30% in tumor diameters for complex image properties, and they defined a textural feature as a
at least 4 wks measurement computed using a texture matrix: The reader is
Stable disease (SD) Neither partial response nor progressive disease referred to the original article for more information. The method
Progressive disease (PD) At least a 20% increase in tumor diameters for used has two steps. First, matrices describing textures on images
at least 4 wks were extracted from tumors, and textural features were subse-
Objective Therapeutic Responses According to the PERCIST14 quently computed using these matrices. All parameters characterize
Complete metabolic Complete resolution of 18F-FDG uptake within mea- in some way tumor heterogeneity at the local and regional levels,
response (CMR) surable target lesion so that it is less than mean using texture matrices or global scales and image-voxel-intensity
liver activity and indistinguishable from surround- histograms. They assessed the predictive value of 18F-FDG uptake
ing background blood-pool levels. No new heterogeneity characterized by textural features extracted from pre-
18
F-FDG–avid lesions in pattern typical of cancer. therapy 18F-FDG PET images of patients with esophageal carcinoma,
Partial metabolic Reduction of minimum of 30% in target measurable as compared with the use of SUVmax and SUVmean; the correlation
response (PMR) tumor 18F-FDG SULpeak. Measurement is
commonly in same lesion as baseline but can
between image parameters and overall patient survival was not
be another lesion if that lesion was previously assessed in this study. Analysis of results from 41 patients with
present and is the most active lesion after newly diagnosed esophageal cancer treated with combined radio-
treatment chemotherapy (external-beam radiotherapy and chemotherapy
Stable metabolic disease Not CMR, PMR, or progressive metabolic disease with alkylatinlike agents [5-fluorouracil-cisplatin or 5-fluorouracil-
(SMD) carboplatin]) demonstrated that relationships between pairs of vox-
Progressive metabolic 30% increase in 18F-FDG SULpeak, or advent of new els, characterizing local tumor metabolic nonuniformities, were able
18
disease (PMD) F-FDG–avid lesions that are typical of cancer to significantly differentiate all three patient groups (nonresponders
and not related to treatment effect or infection [progressive or stable disease], partial responders, and complete
responders, p < 0.0006). Significant factors for prediction of response
to therapy included the size of nonuniform metabolic regions and
within the measurable target lesion, meaning that it is less than the the corresponding intensity of nonuniformities within these regions
mean liver activity (1.5 × [mean SUL of the liver] + 2SD) and indis- (p < 0.0002). Receiver operating characteristic curve analysis showed
tinguishable from the surrounding background blood-pool levels that tumor textural analysis can provide nonresponder, partial
with no new 18F-FDG–avid lesions in a pattern typical of cancer responder, and complete responder patient identification with
(Table 32.2). A PERCIST change was the most significant prognos- higher sensitivity (76% to 92%) than any SUV measurement. Tixier
tic indicator for predicting DFS (hazard ratio [HR]: 4.060; 95% CI: et al.58 concluded that textural analysis of the intratumor tracer
1.195 to 13.789; p = 0.025) and OS (HR: 8.953; 95% CI: 1.188 to uptake heterogeneity on baseline 18F-FDG PET scans can predict
67.506; p = 0.034) in the multivariate Cox proportional hazards response to combined chemoradiation treatment of esophageal
regression analysis.54 cancer patients, and that textural features from PET images provide
For example, even if the reduction rate (RR) in SUL is high, resid- useful information for personalizing patient management.
ual tumors after treatment often exhibit intense 18F-FDG uptake.
Moreover, even if the reduction of SUL is low, residual tumors show Lung Cancer
faint 18F-FDG uptake, which is less than the mean liver activity and
indistinguishable from the surrounding background blood-pool Lung cancer is the leading cause of cancer mortality worldwide.
levels. Therefore, reduction of SUL may not always correlate with The most common form of lung cancer is non–small-cell lung can-
prognosis. On the other hand, PERCIST might be more useful to cer (NSCLC). To improve the survival of patients with NSCLC, there
predict prognosis, because both the reduction of SUL and the value has been a focus on earlier diagnosis and, once cancer has been
of SUL after chemotherapy are evaluated (Fig. 32.3). Considering confirmed, on improved treatment selection and planning. At
that imaging, as a noninvasive procedure (generally, accurate infor- present, a multimodality approach that includes preoperative
mation about pathologic prognostic factors and resection level is chemoradiotherapy has been used in the clinical setting. Although
obviously difficult to obtain before surgery), is commonly and widely complete pathologic response to such NAC and radiotherapy is an
used to evaluate treatment response, PERCIST is considered to be important prognostic indicator for prolonged DFS, in fact, it is dif-
the best method for evaluation of treatment response in esophageal ficult to evaluate the pathologic factors before biopsy or surgery
cancer. has been performed.
Presently, the imaging techniques are the ultimate methods for
Evaluation of Intratumor Heterogeneity accurate assessment of the impact of preoperative chemotherapy
and/or radiotherapy in the clinical setting. As with other tumors,
by Texture Analysis in NSCLC, RECIST1–4 is widely used for evaluation of therapeutic
In many previous reports, the PET image index used for assess- efficiency. However, it is difficult to distinguish residual tumor from
ment of metabolic response was often the mean SUV or the SUV- necrosis or fibrosis59 on CT and/or MRI using RECIST because this
max. However, 18F-FDG tumor uptake is influenced by various is based on an anatomic tumor response metric. PET imaging,
conditions, such as increased metabolism, perfusion, cell prolif- because focused on functional information rather than anatomy,
eration, tumor viability, tumor aggressiveness, or hypoxia.55–57 might overcome these drawbacks and provide better accuracy in
Tixier et al.58 hypothesized that these physiologic parameters monitoring response, given that functional changes are expected to
might be responsible for tumor uptake heterogeneity, and, there- precede morphologic changes.
fore, they evaluated intratumor heterogeneity using a textural In recent years, there has been remarkable progress in treatment
analysis of baseline PET scans as a new parameter for the predic- of NSCLC. Epidermal growth factor receptor (EGFR) has emerged as
tion of therapy response in esophageal cancer. an important molecular target for advanced or recurrent NSCLC.

A C E

B D F
Figure 32.3. A 64-year-old man with cancer in middle/lower thoracic esophagus. A: CT (coronal image) before chemotherapy (5-fluorouracil, adriamycin, and
cisplatin) shows that the long axis of tumor is 72 mm. B: CT (coronal image) after chemotherapy shows that the long axis of tumor is 59 mm. The reduction rate is
18%. Objective therapeutic response by Response Evaluation Criteria in Solid Tumors (RECIST) is stable disease. Tumor SULpeak before chemotherapy is 7.96 by
(C) 18F-FDG PET and (E) 18F-FDG PET/CT. Tumor SULpeak after chemotherapy is 1.98 by (D) 18F-FDG PET and (F) 18F-FDG PET/CT. The reduction rate is 75%. Tumor
SUL is almost indistinguishable from surrounding background blood-pool levels. Objective therapeutic response by PET Response Criteria in Solid Tumors (PERCIST)
is complete metabolic response. There is a difference in response classification between RECIST and PERCIST.
Reversible EGFR tyrosine kinase inhibitors (TKI), such as gefitinib cancer.63 In particular, the widespread implementation of PET/CT
and erlotinib, were found to have antitumor activities in second- or with 18F-FDG has allowed not only evaluation of the primary
third-line therapy.60 On the other hand, it has been shown that anti- lesion, but also more accurate detection of both nodal and distant
angiogenic therapy targeting the vascular endothelial growth factor forms of metastatic disease.64
(VEGF) signaling pathway (e.g., bevacizumab) provides a survival When considering the effects of treatment for lung cancer, early
benefit in patients with solid malignancies, including NSCLC.61 How- prediction of tumor response is crucially important in patients with
ever, response to molecularly targeted agents, including the antian- advanced NSCLC. The majority of patients with advanced NSCLC
giogenic therapy, is not necessarily reflected by drug-induced changes undergo palliative therapy with platinum-based chemotherapy
in tumor size (Fig. 32.4).62 Therefore, appropriate selection of meth- regimens, which has been demonstrated to improve quality of life
ods for evaluation of therapeutic efficiency is crucial for effective and to prolong median OS by approximately 2 months.65
cancer treatment. Weber et al.66 examined whether changes in tumor glucose use
Use of various quantitative PET parameters measuring func- measured by PET with 18F-FDG allow prediction of tumor response
tional changes induced by treatment for lung cancer has been chal- and patient outcome after the first cycle of platinum-based chemo-
lenged by using PET imaging with a variety of radiolabeled tracers therapy (carboplatin/paclitaxel, cisplatin/vinorelbine, cisplatin/
other than 18F-FDG. Evaluation of therapeutic efficiency using PET/ docetaxel, and cisplatin/etoposide). This prospective study demon-
CT with 18F-FDG, 18F-FLT, and H215O are the focus of this section. strated that effective chemotherapy caused a rapid reduction of
tumor glucose use in 57 patients with advanced NSCLC. After one
Evaluation of Therapeutic Efficiency Using cycle of platinum-based chemotherapy (21 days), a metabolic
response seen by PET imaging was significantly correlated with
PET/CT with 18F-FDG best response to this chemotherapy regimen. In patients without a
PET with 18F-FDG has shown substantial promise during the past metabolic response, the response rate was only 4%, whereas it was
decade in aiding in the noninvasive preoperative staging of lung 71% in patients with a metabolic response. For patients with a

A C E
B D F
Figure 32.4. A 62-year-old woman with advanced lung cancer in right upper lobe. A: CT (axial image) before EGFR-TKI therapy (gefitinib: EGFR-TKI = the
epidermal growth factor receptor-tyrosine kinase inhibitor) shows that the long axis of tumor is 37 mm. B: CT (axial image) after EGFR-TKI therapy shows that the
long axis of tumor is 30 mm. Tumor SULmax before EGFR-TKI therapy is 4.1 by (C) 18F-FDG PET and (E) 18F-FDG PET/CT. Tumor SULmax after chemotherapy is
1.5 by (D) 18F-FDG PET and (F) 18F-FDG PET/CT. Reduction of SUVmax (63%) is greater than that of the long-axis size (18%).
metabolic response, the 1-year survival rate was 44%, whereas it tion of histopathologic response in the primary tumor and medi-
was only 10% in patients with no metabolic response. Weber et al.66 astinal lymph nodes and have prognostic value. The diagnostic
indicated that PET imaging might be used to predict the clinical information from serial PET/CT scans during the 3-month induc-
outcome of chemotherapy at an early stage of treatment. tion therapy phase is high enough to ascribe to this method a
In NSCLC, some suggestions regarding prediction of response substantial benefit for clinical patient management.69 Therefore,
to neoadjuvant treatment have been presented based on data from unsuccessful resections, performed in patients having residual
PET scans alone or on evaluation of PET and CT scans side by disease in multiple lymph node stations because of the off-chance
side.66,67 However, none of these investigations has included an of improving prognosis, may be avoided. Residual disease in the
analysis of responses of mediastinal lesions and the primary tumor, mediastinum might then be targeted by a high-dose conformal
because of the difficulty in detecting small mediastinal lymph node radiotherapy boost.
metastases by PET alone stemming from factors like elevated
background activity in the mediastinum or partial volume effects Evaluation of Therapeutic Efficiency Using
that reduce the value of SUVmax.68
PET/CT with 18F-FLT
However, Christoph et al.69 analyzed the value of PET/CT dur-
ing induction chemotherapy (CTx) followed by chemoradiotherapy Second-line chemotherapy regimens for treatment of NSCLC have
(CTx/RTx) for NSCLC for predicting the histopathologic response been established70 and new, targeted therapies, such as TKI, have
of the primary tumor and mediastinum and the prognosis of shown activity in patients who progressed after platinum-based
the patient. In this study, SUVmax was corrected for background chemotherapy.71
and partial volume effects according to the following formula: In one recent study assessing tumor response to gefitinib, Taka-
SUVmax,corr = background SUVmean + (measured SUVmax − hashi et al.72 demonstrated that early determination of SUVmax
background SUVmean)/recovery coefficient.55 Christoph et al.69 with 18F-FDG PET after 2 days of treatment could predict clinical
concluded that SUVmax,corr values from two serial PET/CT scans, outcome earlier than conventional CT evaluation in patients with
before and after three chemotherapy cycles or later, allow predic- lung adenocarcinoma. In this way, although determining the SUV

and percentage changes of SUVs during treatment are the measures Tab l e 3 2 . 3
used most widely for advanced NSCLC patients, use of various quan-
titative PET parameters other than SUV has been recently proposed Functional Imaging Modela
for measurement of treatment-induced functional changes. There
have been some previous reports on tumor treatment response Equation
evaluation of total lesion glycolysis (TLG) using 18F-FDG PET, or the
CPET (t) = (1 − VA − Vv) • F • CA(t)*e−(F/VT)t + VACA(t) + VVCV(t)
analogous evaluation of total lesion proliferation (TLP) using
3′-deoxy-3′-18F-fluorothymidine (18F-FLT-PET).73,74 Determining TLG CPET(t) Radioactivity concentration in tissue (Bq/cm3)
by 18F-FDG PET and TLP by 18F-FLT PET may be a promising CA(t) Arterial time–activity curve or image-derived input function (IDIF) (Bq/cm3)
approach, as these parameters represent tumor functional activity CV(t) Time–activity curve for the pulmonary circulation (Bq/cm3)
and volumetric data. Kahraman et al.75 reported on TLG and TLP for F Perfusion (mL/cm3/min)
response prediction and prognostic differentiation in patients with VT Distribution volume or partition coefficient of water in tumor tissue
advanced NSCLC treated with erlotinib. They assessed metabolic VA Arterial blood volume (mL)
response using different cutoff values for percentage changes in TLG Vv Pulmonary circulation blood volume (mL)
by 18F-FDG PET and in TLP by 18F-FLT PET, which were performed * Convolution integral method
in 30 patients having untreated stage IV NSCLC before the start of a
Standard single-tissue compartment model.
therapy, and 1 week (early) and 6 weeks (late) later. Patients with a From Van der Veldt AA, Hendrikse NH, Harms HJ, et al. Quantitative parametric perfusion images
metabolic response measured by early changes in TLP and late using 15O-labeled water and a clinical PET/CT scanner: Test–retest variability in lung cancer.
J Nucl Med. 2010;51:1684–1690.

changes in TLG and TLP had significantly better progression-free
survival than metabolically nonresponding patients. In cases where
use of a 45% cutoff value revealed no significant results, use of a
lower cutoff value, of 20% or 30%, for definition of metabolic Figure 32.5 shows data from a patient with advanced lung cancer
response resulted in better differentiation between metabolically who underwent dynamic PET/CT with H215O twice, before and after
responding and nonresponding patients. In this study of patients chemotherapy (carboplatin, paclitaxel, and bevacizumab).
with advanced NSCLC,75 lower absolute early and late residual TLG In general, antiangiogenic drugs such as bevacizumab are
and TLP levels under erlotinib treatment were more important assumed to contribute to improved delivery of subsequent chemo-
factors predicting prolonged progression-free survival than were therapy by transiently normalizing abnormal tumor vasculature.
absolute baseline TLG and TLP levels. There was a recent investigation of this concept using PET and
11
C-labeled docetaxel in 10 patients with NSCLC by Van der Veldt
et al.,81 who reported a rapid and significant reduction in perfu-
Evaluation of Therapeutic Efficiency Using sion and 11C-docetaxel uptake after treatment with bevacizumab,
PET/CT with H215O and suggested that the clinical relevance of these findings was
notable, because the study did not provide evidence for a substan-
VEGF, which is overexpressed in many human malignancies, is
tial improvement in drug delivery to tumors, but rather showed an
the most important factor for angiogenesis (formation of new blood
effect opposite to assumption. The group concluded that these
vessels), a critical determinant of growth and metastatic spread of
findings highlighted the importance of drug scheduling and advo-
tumors.76 Therefore, antiangiogenic therapy targeting the VEGF sig-
cated further studies to optimize scheduling of antiangiogenic
naling pathway provides a survival benefit in patients with solid
drugs.
malignancies, including NSCLC. Bevacizumab is a humanized mono-
clonal antibody that targets circulating VEGF and subsequently
prevents binding of VEGF to its receptors.61 Lymphoma
Response evaluation of antiangiogenic drugs, however, is often
Because malignant lymphomas are characterized by systemic
difficult using conventional CT because therapeutic efficiency is not
involvement, they are said to require exploratory examination of
necessarily reflected by drug-induced changes in tumor size.62 There-
the whole body. Diagnosing the extent of the lesions and staging
fore, new imaging tools are needed to accurately assess the efficacy
are necessary for deciding on the approach to treatment and pre-
of antiangiogenic drugs. Although Fraioli et al.77 demonstrated that
dicting prognosis. Diagnosis by measuring lesion size, done pri-
perfusion CT imaging may allow evaluation of lung cancer angiogen-
marily by CT, a morphologic diagnostic imaging method, is
esis following treatment, previous studies have shown that quantifi-
standard practice. However, as a result of the development and
cation of tumor perfusion using radioactive water (H215O) and PET is
widespread adoption of PET and combined PET/CT in recent
a promising method to monitor antiangiogenic treatment.78,79
years, it is now possible to obtain functional information as well
Van der Veldt et al.80 validated the quantitative accuracy of para-
as anatomical information, and opportunities to perform PET/
metric perfusion images in 11 patients who underwent dynamic
PET-CT to evaluate the extent and activity of malignant lymphoma
PET/CT with H215O twice on the same day. Parametric perfusion
lesions have increased.
images were computed using a basis function implementation of the
Most histologic types of malignant lymphomas accumulate the
standard single-tissue compartment model, compared between
glucose metabolism tracer 18F-FDG, because cell density is rela-
input functions derived from blood sampler data from the radial
tively high.82 These are often depicted by 18F-FDG PET/PET-CT,
artery and those derived from the ascending aorta as seen in the
which has a high lesion detection rate.83 In 2007, the International
images themselves (image-derived input function [IDIF]) (Table 32.3).
Working Group in the United States published the revised Interna-
Volumes of interest (VOIs) were delineated on low-dose CT and
tional Workshop Criteria (revised IWC), which include the use of
parametric perfusion images. As a result, there was good correla- 18
F-FDG PET. New criteria for evaluation of response to treatment
tion between perfusion values derived from the blood sampler
of malignant lymphomas by PET and guidelines related to PET
input function and IDIF (Pearson correlation coefficient, r = 0.964;
examinations were proposed, and firm criteria are anticipated.84
p < 0.001). The variability of tumor perfusion between a test and a
retest was 16% and 20% when delineated on low-dose CT and para-
metric perfusion images, respectively.80 Van der Veldt et al.80 con-
Staging of Lymphomas
cluded that it was feasible to assess tumor perfusion in patients with
NSCLC by dynamic H215O PET performed on a clinical PET/CT scan- It is well established that 18F-FDG PET is superior to65 gallium-
ner, and that the use of an ascending aorta time–activity curve as the citrate scintigraphy.85 Use of 18F-FDG PET has high sensitivity and
input function was an accurate alternative to arterial blood sampling. specificity for malignant lymphoma diagnosis, and PET has the

A C
Figure 32.5. A 64-year-old man with advanced

lung cancer in right upper lobe. A: CT (axial image)
before chemotherapy (carboplatin, paclitaxel, and
bevacizumab [antiangiogenic therapy targeting the
vascular endothelial growth factor signaling pathway])
shows that long axis of tumor is 38 mm, which is
almost the same on (B) CT (axial image) after che-
motherapy. However, by PET, H215O accumulation
B D (white circle) (D) after chemotherapy is lower than
that (C) before chemotherapy.
advantage of depicting lesions that are difficult to spot by other mended.84 Performing PET for diagnosis before treatment of these
diagnostic imaging methods, such as lesions invading liver or histologic types enables more precise assessments of responses to
spleen, and lesions in unexpected sites.86–88 Moreover, although treatment (Fig. 32.7). On the other hand, because relatively large
pathologic diagnosis by biopsy is essential for making a definitive amounts are also taken up by two other histologic types, follicular
diagnosis, PET, which makes it possible to conduct a whole-body lymphoma (FL) and mantle cell lymphoma (MCL), high rates of
evaluation in a single examination, also facilitates detection of lesion detection by PET have been reported.83 However, because
18
lesions suitable for biopsy. F-FDG accumulation by these histologic types is not uniform and
18
F-FDG accumulation by malignant lymphomas varies consid- no improvement in the survival rate in response to treatment can
erably according to the histologic type (Fig. 32.6). Two histologic be expected, performing PET to monitor progress is not strongly
types, diffuse large B-cell lymphoma (DLBCL) and Hodgkin lym- recommended at present.84 Because 18F-FDG accumulation is not
phoma (HL), have avid 18F-FDG uptake, and because complete uniform in any of the histologic types other than the two mentioned
cures can be expected, more accurate staging by PET is recom- above, the usefulness of PET to monitor treatment is uncertain, and
Figure 32.6. 18F-FDG accumulation in malignant lym-

phomas is variegated. A: Maximum intensity projection
(MIP) image of a diffuse large B-cell lymphoma case. The
invasive lesions in the left axillary lymph nodes and the
spleen have high 18F-FDG accumulation (SUVmax = 13.6).
Diffuse light accumulation in bone marrow was seen, but
the invasion by lymphoma cells was not confirmed by
subsequent bone marrow biopsy. B: MIP image of a
Grade 3 follicular lymphoma case. The invasive lesions in
abdominal lymph nodes have moderately strong 18F-FDG
accumulation (SUVmax = 6.2). C: MIP image of a mucosa-
associated lymphoid tissue lymphoma case. The nodal
A B C lesions appearing in the diaphragm (top and bottom)
have mild accumulation (SUVmax = 4.9).


Figure 32.7. A 72-year-old man with diffuse large B-cell
lymphoma presented for 18F-FDG PET/CT scans before and after
chemotherapy. This patient had bilateral widespread nodal
lesions with strong accumulation by 18F-FDG PET/CT (A) before
therapy; (B) scan after therapy revealed complete resolution of
disease. This patient continues to be in a complete remission A B
2 years after therapy.
performing PET is not recommended. Nevertheless, because 18F- masses and soft tissue densities on CT images, evaluations of com-
FDG PET is an excellent means of evaluating activity, PET diagnosis plete remission unconfirmed (CRu) are often made, and the actual
is said to be effective when assessing the response to treatment of response to treatment remains unclear.
only those cases in which it has been possible to confirm abnormal PET diagnosis based on cell metabolism, on the other hand,
accumulation at lesion sites by PET before treatment. makes it possible to confirm abnormal 18F-FDG accumulation at
However, caution is required, because PET diagnosis also has sites where residual tumor is present, and it is useful for distin-
limitations. PET is not very reliable for judging bone marrow infil- guishing this from posttreatment changes (Fig. 32.8). The ability
tration, irrespective of the histologic type of malignant lymphoma, to do so is also linked to being able to mitigate the risk of perform-
and evaluation by bone marrow biopsy is desirable.89 Lesions are ing excessive additional treatment. It has been reported that, in
poorly depicted by PET (false-negatives) in some tissue types, such patients with aggressive lymphomas, a comparison of IWC assess-
as mucosa-associated lymphoid tissue (MALT) lymphoma and ments (largely based on the size of the masses) with PET assess-
T-cell lymphoma (in which 18F-FDG PET has low sensitivity). There ments (based on 18F-FDG accumulation) revealed that even when
are limits to the use of PET to depict small lesions, under 1 cm in masses and soft tissue densities remained, the recurrence rate
diameter, and limits according to the morphology of the involve- was low if 18F-FDG accumulation was no longer seen.92
ment (influence of the partial volume effect of the PET scanner) In 2007, the revised IWC were published, and 18F-FDG PET
must also be kept in mind. Therefore, assessments need to be was included as a method to assess response to treatment. Per the
made in combination with other examination modalities, as appro- revised IWC, evaluations are made on the basis of a combination
priate.90 In addition, normal physiologic accumulation occurs in of lesion size and 18F-FDG accumulation after the completion of
organs such as the brain, liver, tonsils, and intestine, in the urinary treatment, but an assessment of complete remission (CR) is made
tract in association with excretion, and in noncancerous brown when abnormal FDG accumulation has completely disappeared,
adipose tissue and muscle, so care must be taken not to mistakenly even if lesions remain visible on CT scans. On the other hand,
diagnose these as abnormal accumulations. when new abnormal accumulation has developed, an assessment
of progression of disease (PD) is made. The revised IWC take into
account the impact on 18F-FDG accumulation of associated inflam-
Assessment of Treatment Response mation or necrosis after chemotherapy or radiotherapy, and there
The goal of treating malignant lymphomas is to induce a remis- is a rule regarding the optimal time for scanning: At least 3 weeks
sion, but additional treatment is necessary in cases in which a after the completion of treatment, but, if possible, after an interval
remission is not achieved, and so it is necessary to assess the of 8 to 12 weeks. There is also a report claiming that semiquanti-
response to treatment accurately. In the past the response of malig- tative evaluation by measuring the SUV, which indicates the
nant lymphomas to treatment was evaluated by using IWC on the degree of 18F-FDG accumulation, is useful; however, at present,
basis of morphologic methods, principally CT examinations.91 visual evaluation is sufficient, and abnormal accumulation is said
However, malignant lymphomas are often treated by combining to be present if accumulation is greater than that in the mediasti-
radiotherapy with chemotherapy as the principle treatment, and nal blood pool, which is used as the standard.84 In the revised IWC
under those circumstances scar tissue tends to form after treat- it is recommended that response to treatment be assessed by PET
ment. This residual mass, mainly composed of necrosis or fibrosis, for patients with DLBCL and HL (the two histologic types in which
is seen after therapy in one-third of patients with NHL and two- there is avid 18F-FDG accumulation and CR is considered the end-
thirds of those with HL.91,92 Consequently, even when treatment point of treatment), and that the status of the tumors after treat-
has been effective clinically, because of the presence of residual ment be determined accurately. For other histologic types, it is

A C E
B D F
Figure 32.8. A staging 18F-FDG PET/CT prior to chemoradiotherapy for a 51-year-old man with Hodgkin lymphoma—(A) and (B) CT images; (C and D) PET
images; (E and F) 18F-FDG PET/CT images. A, C, E: Images before treatment show strong accumulation in enlarged right axillary lymph nodes. B: The soft tissue
mass persisted after treatment but was smaller. D, F: Because there was no 18F-FDG accumulation at follow-up, the situation was defined as a complete response.
This patient continues to be in a complete remission 18 months after therapy.
recommended that PET be used to assess the response to treat- Although there are some reports that 18F-FDG PET/PET-CT pro-
ment only in cases in which it was possible to confirm 18F-FDG vides helpful information for recurrent search and prognostic value
accumulation at lesion sites by PET before treatment was started. in HL, aggressive NHL and FL, the role of the surveillance 18F-FDG
The number of cases in which a CR is achieved, according to PET/PET-CT is not established.90,92,95–97 The report of the large-scale
the revised IWC, which incorporates the use of 18F-FDG PET, is prospective cohort study is anticipated.
expected to increase, but caution is also necessary in regard to the In summary, 18F-FDG PET/PET-CT is a useful noninvasive imag-
problem of false positives in cases in which inflammation persists ing modality for staging, restaging, and assessment of response to
after treatment and in cases in which colony-stimulating factors, treatment in patients with malignant lymphoma. Interim and sur-
such as granulocyte colony-stimulating factor (G-CSF), have been veillance 18F-FDG PET/PET-CT scanning may improve malignant
administered. Assessments must be made after taking into account lymphoma patient outcomes.
the patient’s hematologic examination findings and medication
history, among other factors.
In recent years, it has been reported that early assessments of
Breast Cancer
response to treatment by PET during the treatment period were NAC has been used as a primary therapeutic strategy in patients
found to be associated with subsequent outcome.93,94 Because PET with locally advanced breast cancer. Evaluation of the response to
is capable of detecting changes in tumor metabolism that occur NAC is predominantly based on the changes in tumor size using
before morphologic changes develop, it has the advantage of the RECIST criteria, in which tumor size is measured in one dimen-
allowing assessment of response to treatment at an earlier stage, sion with the longest diameter in the plane of measurement. In
and is highly useful clinically. Nevertheless, there are the prob- some circumstances, it may be difficult to distinguish viable tumor
lems of the timing of performance of the examination, standard- tissue from necrotic or fibrotic scar tissue when using ultrasound
ization of the evaluation criteria, and false positives as a result of and mammography.98,99 In the newest version of the RECIST cri-
inflammation associated with treatment; at the present time the teria (version 1.1),4 PET may be considered to support CT for con-
usefulness of PET examinations during the course of treatment is firmation of complete response (CR). Specifically, similar to the use
uncertain. Reports of future results are eagerly awaited. of biopsy, 18F-FDG PET may be used to upgrade a response to a
CR in cases in which residual radiographic abnormality is thought
to represent fibrosis or scarring. However, many recent studies
Follow-Up Evaluation After Completion of Therapy have shown that 18F-FDG PET also allows assessment of tumor
Malignant lymphomas are characterized by repeated remissions biologic response at an early stage after the beginning of treat-
and relapses, and regular follow-up examinations are necessary. ment and that 18F-FDG PET allows noninvasive visualization and
Ordinarily, history taking, the physical findings, and hematologic quantitative assessment of many biologic processes that are mod-
examination findings, including soluble interleukin-2 receptor (sIL- ulated during therapy and that generally precede morphologic
2R) and lactate dehydrogenase (LDH) measurements, are said to be changes.100–104 Avril et al.105 reported a positive correlation between
useful. There seem to be many institutions where CT is performed as pretreatment 18F-FDG uptake and breast cancer cell proliferation.
an imaging examination, but no consensus has been achieved as to Recently, several studies have demonstrated a correlation between
the usefulness of performing regular follow-up imaging examinations. early changes in the SUVmax and the final pathologic response

after completion of NAC.101,106–109 Early prediction of the final tumors have low FDG uptake. Schwarz-Dose et al. reported that low
pathologic response to NAC might afford an opportunity to change early 18F-FDG uptake in ER-positive tumors was predictive of a
to a more effective therapy and thereby avoid the toxicity and cost poor response to NAC. Serial 18F-FDG PET studies have shown that
of ineffective therapy. Absence of residual cancer cells in the pri- an early increase in 18F-FDG uptake in response to an estrogen
mary tumor following NAC is strongly associated with improved agonist predicted the response to endocrine therapy and subse-
DFS and OS. However, the ability to implement early 18F-FDG PET quent patient outcomes,110,111 suggesting that this metabolic flare
as a surrogate marker for treatment efficacy in clinical practice could be a marker for the activation of estrogen signaling in the
remains unclear because of substantial heterogeneity of results tumor. The chemosensitivity of ER-positive tumors can vary but is
across studies. This may be, in part, because of the difference in mostly limited and pathologic CR (pCR) is rarely obtained in this
study design, including the timing of early 18F-FDG PET evaluation, group. Approximately 40% of patients with ER-positive breast can-
the histologic criteria, the phenotypic diversity of breast cancer, the cer do not show an objective clinical response to neoadjuvant endo-
definition of pathologic response, the method used for SUV deter- crine therapy. In the GeparTrio trial, pCR was obtained in 10% of
mination, the type of SUV, and the cutoff determination of SUV. the patients with positive hormonal status when compared with
In current clinical practice, immunohistochemistry is used to 43.2% in the group of negative hormonal receptor tumors. Because
define subgroups with different therapeutic responses and out- of low histologic CR of ER-positive patients, it is critical to identify
come. We will discuss three broad groups: Estrogen receptor factors that can predict chemosensitivity. The development of ER
(ER)-positive, human epidermal growth factor receptor type 2 imaging agents for PET, of which the most successful has been
18
(HER2)-positive, and triple-negative tumors (i.e., when ER, proges- F-16a-17b-fluoroestradiol (FES), appears to be worthwhile. Indeed,

terone receptor (PgR), and HER2 are all negative). Neoadjuvant the tumor uptake of FES appears to predict the clinical response to
endocrine therapy has gained wide acceptance for ER-positive endocrine therapy.
breast cancer because of its recognized efficacy in the adjuvant set- Approximately 20% of breast cancers overexpress HER2, a
ting and the fact that conventional cytotoxic chemotherapy may be finding that is associated with a positive response to the anti-
less effective in ER-positive breast cancer. Most hormone-positive HER2 antibody, Herceptin(trastuzumab) (Fig. 32.9). In the setting
A C E
B D F
Figure 32.9. A 71-year-old woman with right breast cancer. A: CT (axial image) before chemotherapy (5-fluorouracil, paclitaxel, and trastuzumab [molecularly
targeted agent that inhibits HER2 protein]) shows that the long axis of tumor is 60 mm. B: CT (axial image) after chemotherapy shows that the long axis of tumor
is 30 mm. Tumor SULmax before chemotherapy is 7.8 by (C) 18F-FDG PET and (E) 18F-FDG PET/CT. Tumor SULmax after chemotherapy is 1.7 by (D) 18F-FDG PET
and (F) 18F-FDG PET/CT. Reduction of SUVmax (78%) is greater than that of the long-axis size (50%).

of neoadjuvant therapy, the addition of trastuzumab to conven- 65%, p = 0.001). Furthermore, the best correlation with pathology
tional cytotoxic chemotherapy improves the rate of CR and was yielded by employing a RR cutoff value of SUV between 55%
event-free survival. In a study by Buzdar et al.,112 the pCR rate and 65%.
was 65% in the patients receiving trastuzumab plus anthracy- MRI also provides functional imaging techniques, such as
clines and taxanes and was 26% for patients who did not receive dynamic contrast-enhanced MRI and diffusion-weighted imaging,
trastuzumab. A recent preclinical study showed a significant which all show promising results as surrogate markers of the
decrease in 18F-FDG uptake at 2 weeks after beginning trastu- response to neoadjuvant therapy in patients with breast cancer.
zumab therapy in tumors overexpressing HER2.113 However, Tateishi et al.119 reported that 18F-FDG PET/CT and dynamic contrast-
clinical information is lacking, because most of the clinical stud- enhanced MRI performed after two cycles of NAC allowed predic-
ies evaluating the role of 18F-FDG PET monitoring of neoadjuvant tion of the pathologic response in patients with breast cancer.
therapy did not study trastuzumab or did not independently ana- The sensitivities of %SUVmax (66.7%) at 18F-FDG PET/CT and
lyze patients receiving trastuzumab in association with chemo- dynamic contrast-enhanced MRI after two cycles of NAC were not
therapy when compared to patients receiving only conventional acceptable, but the specificities (96.4%) were high for stratifica-
chemotherapy.104 tion of pCR cases among patients with breast cancer.
Nearly 15% of breast cancers have a triple-negative phenotype. For the accurate evaluation for the prediction of response to
In contrast to the two preceding groups, no targeted therapy is NAC in patients with breast cancer, serial PET examinations
currently available for this tumor phenotype; thus, conventional should be performed in the same center with the same instrumen-
cytotoxic chemotherapy is used for triple-negative tumors. Patients tation, and standardization of procedures is needed (e.g., imaging
with triple-negative breast cancer have a higher pathologic response protocol, method of attenuation correction, and algorithm of
rate to anthracycline-based treatment when compared to patients reconstruction, etc.). New PET tracers might also play a role in the
with non–triple-negative breast cancer.114,115 The rate of disease prediction or early evaluation of the response to therapy. For
recurrence is high in this group despite high chemosensitivity. The example, 18F-FLT, an analog of thymidine, is the most extensively
poorer prognosis of triple-negative breast cancers might be related studied, and 18F-FLT uptake is dependent on the cellular activity
to a higher likelihood of relapse in those patients in whom pCR is of thymidine kinase.120,121 The combination of PET and other func-
not achieved.115 For patients with hormone-positive breast cancer, tional imaging techniques available in the field of breast cancer
obtaining pCR is less critical in terms of survival. (such as ultrasound and MRI) is another promising approach to
facilitate the monitoring of the response of breast cancer to neo-
18 adjuvant therapy.
Timing of F-FDG PET
Chemotherapy may cause an initial increase in 18F-FDG uptake
because of the activation of energy-dependent cellular repair
mechanisms. McDermott et al.106 performed 18F-FDG PET at base-
Conclusions
line, after one cycle, at the midpoint and at the endpoint of chemo-
In conclusion, the treatment response after chemotherapy, radio-
therapy. They suggested that the most appropriate time to evaluate
therapy, and their combination has been evaluated as tumor size
the response to chemotherapy with 18F-FDG PET was between the
change by CT and MRI and more recently as metabolic altera-
end of the first cycle and the midpoint of chemotherapy. Three
tions by 18F-FDG PET or PET-CT. New tracers more specific to
teams suggested that the optimal time to perform the early evalu-
viable residual cancer cells are now being developed, including a
ation was immediately before the third cycle.100,103,109 In a study by
marker of protein metabolism and nucleic acid metabolism.
Schwarz-Dose et al.,101 the authors reported that relative changes
Moreover, PERCIST has been proposed as a new standardized
in SUV after the first and the second cycle of chemotherapy are a
method for quantitative assessment of metabolic tumor response.
strong predictor of response irrespective of whether 18F-FDG PET
It is very important not only to select an effective treatment but
was performed after the first or second cycle. When comparing
also to evaluate treatment response appropriately, to better manage
different studies, we can observe that the decrement in the SUV
cancer patients for prolonged survival and for preserving quality
value occurs rapidly during the first part of treatment, and, even if
of life.
the decrease in SUVmax continues up until the end of chemo-
therapy, the curve tends to flatten out toward the end of it gradu-
ally. Therefore, performing 18F-FDG PET after the second cycle
might be a good compromise that still allows a switch to an alter- Future Considerations
native therapy at an early stage in the event that the tumor is not
responding to the regimen. Thus, assessment of tumor response As mentioned above, the current state of response to treatment
should not be performed until several weeks after initiation of evaluation in patients with cancers of the brain, lung, esophagus,
chemotherapy.116 and breast, as well as malignant lymphoma is summarized by the
Several meta-analyses have evaluated the accuracy of 18F-FDG type of PET tracers used. The current treatment for these tumors is
PET for the prediction of response to NAC in patients with breast diversified and it is necessary to select a tracer that can properly
cancer. Cheng et al.117 assessed the comparative utility of 18F-FDG evaluate the characteristics of the drug used, especially for molecular-
PET/CT and 18F-FDG PET and reported that the pooled sensitivity targeted drugs. In particular, hematopoietic system malignancies,
to predict histopathologic response in primary breast lesions such as malignant lymphoma, tend to be more highly susceptible to
was 0.847 and 0.826, respectively, whereas the specificity was chemotherapy than other solid cancers, so it is predicted that the
0.661 and 0.789, respectively. They concluded that 18F-FDG PET/ tumor metabolism changes rapidly with treatment. This feature
CT and 18F-FDG PET have reasonable sensitivity in evaluating the means that the choice of this therapy is spreading, and a technique
response to NAC in breast cancer; however, the specificity was to precisely evaluate early treatment response is needed. The clinical
relatively low. Wang et al.118 also reported similar results with significance of obtaining metabolic information by PET/CT in addi-
their meta-analysis; to predict the histopathologic response in pri- tion to anatomical information will become more and more impor-
mary breast lesions by 18F-FDG PET, the pooled sensitivity and tant in the future. Moreover, the definition of a responder, such as
specificity was 84% and 66%, respectively, and subgroup analysis reduced SUV, has varied among the many studies performed previ-
showed that performing a post-therapy 18F-FDG PET early (after ously. In the future, it is essential to optimize the timing for post-
the first or second cycle of chemotherapy) was significantly bet- treatment PET evaluation and the criteria used to define therapeutic
ter than that conducted at later time points (accuracy 76% versus effect.

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Chapter 33
Radionuclide Imaging for the Assessment of Toxicity

Due to Chemotherapy
Marcel P.M. Stokkel • Linda de Wit-van der Veen
Introduction affected.6–8 At this time, six different categories have been described:
hemodynamically mediated injury, tubular epithelial cell damage,
Drug toxicities and resistance are among the most important chal- tubulointerstitial disease, glomerular disease, renal vasculitis and
lenges encountered in delivering a curative dose during antineoplas- thrombosis, and finally, obstructive nephropathy.
tic treatment. Toxicities that affect one or more of the major organ
systems, for example, heart, lung, bone marrow, kidneys, and liver, Hemodynamically induced Renal Toxicity
are a rather common side effect of chemotherapeutics (Table 33.1). The kidneys receive approximately 20% to 25% of resting cardiac
Over two decades ago, the National Cancer Institute (NCI) intro- output.5,6 Blood flow and filtration pressure are regulated by affer-
duced the Common Terminology Criteria for Adverse Events (CTCAE ent and efferent arterioles to maintain urine production and excre-
version 4.0) to aid in the classification of the side effects associated tion. A regulatory mechanism based on natriuretic factors, the
with antineoplastic therapies. The severity of any event is graded sympathetic nervous system, and the renin–angiotensin system
from 1 to 5; one, being asymptomatic or mild symptoms, to five, (RAS) are the cornerstones of blood flow in the kidney. Hemody-
indicating death related to adverse event. Though this classification namically induced kidney failure results from a decrease in intra-
system is not discussed in further detail in this chapter, it is an glomular pressure caused by vasoconstriction of afferent arterioles
important tool to document toxicities in clinical trials. The CTCAE or vasodilation of efferent arterioles. Under normal circumstances,
does not, however, recommend techniques or methods to diagnose the RAS should compensate for this pressure decrease. However,
and monitor drug-related toxicity. agents such as angiotensin-converting enzyme inhibitors, nonsteroi-
In general, toxicities can be divided into two forms, those that dal anti-inflammatory drugs (NSAIDs), cyclosporines, and tacroli-
occur in an acute setting concomitant to the chemotherapy and mus may interfere with this compensating mechanism.4,9–11 Although
those that present as long-term side effects, possibly years after the site of interaction may differ per agent, the overall result is a
treatment. These late effects, in particular, are often either not decrease in filtration pressure. Patients at greatest risk for drug-
defined in a preclinical setting or have not been demonstrated induced renal failure are those with chronic kidney disease, ath-
during the initial clinical trials with a new drug, and therefore, erosclerotic cardiovascular disease, and elderly patients.
will only become apparent in the clinical setting in cancer survi-
vors. The NCI estimates that there were over 10 million cancer Tubular Epithelial Cell Damage
survivors in the United States in 2002.1,2 This improved patient
This is caused by either direct or ischemic effects of nephrotoxic
survival, combined with the aging population and the introduc-
drugs.6,12 This type of damage is usually located in the proximal and
tion of new targeted anticancer treatments, has led to interest in
distal tubular epithelia. When it is observed as cellular degeneration
long-term toxicity monitoring. This chapter will focus on nephro-
and sloughing from basement membranes, it is called acute tubular
toxicity, lung, liver, bone marrow, and cardiovascular toxicity, and
necrosis (ATN). ATN is the most frequently observed renal toxicity in
the evaluation of these toxicities using nuclear imaging tech-
clinical care, for which radiocontrast media, cisplatin, immunoglob-
niques.
ulins, and aminoglycosides are well-known causes.5,13–16 ATN caused
by such agents is dose dependent, which means that the higher the
Chemotherapy-Induced Nephrotoxicity dose, the higher the chance and severity.17 Obstruction of the tubular
lumen and back-leakage of the glomerular filtrate results in a reduc-
Mechanisms of Toxicity tion of GFR. Generally, glomeruli are spared; severe necrosis of
Drug-induced nephrotoxicity is a rather common complication of tubules and collecting ducts can be found in biopsy specimen. The
several chemotherapeutic agents.3 In an acute setting, drug-induced risk of ATN increases with aging, dehydration, previous irradiation,
toxicity has been implicated in 8% to 60% of all cases and, con- alcohol abuse, and concurrent use of other nephrotoxic drugs.18
sequently, it is recognized as a serious source of morbidity and
mortality.4,5 The mechanism of action differs among various agents
Tubulointerstitial Disease
or classes of chemotherapeutic agents. In general, nephrotoxicity is This condition includes damage to the renal tubules as well as the
categorized based on the histologic component of the kidney that is surrounding interstitial tissue.6,12,19 It is a nondose-dependent
Table 33.1
Forms of Chemotherapy-Induced Organ Toxicity According to Data in the Literature
Cardiotoxicity Nephrotoxicity Lung Toxicity Liver Toxicity Bone Marrow Toxicity
Left ventricular dysfunction Hemodynamically induced renal Diffuse alveolar damage Hepatocellular Myeloproliferative diseases
toxicity
Cardiovascular ischemia and Tubular epithelial cell damage Nonspecific interstitial pneumonia Cholestatic Myelodysplastic syndromes
thromboembolic events
Hypertension Tubulointerstitial disease Cryptogenic organizing pneumonia Fatty liver disease Aplastic anemia
Arrhythmias Glomerular disease Eosinophilic pneumonia Pseudocirrhosis Hemolytic anemia
Renal vasculitis and thrombosis Pulmonary hemorrhage Biliary sclerosis
Obstructive nephropathy Hepatovenous occlusive disease
514

Chapter 33 Radionuclide Imaging for the Assessment of Toxicity Due to Chemotherapy 515
toxicity in which a diffuse or focal infiltration of lymphocytes, plasma cause of an obstructive nephropathy is well known and is usually
cells, eosinophils, and neutrophils is observed in the interstitium.12,19 associated with pain, hematuria, and sometimes with infections.
In acute allergic interstitial nephritis, an allergic hypersensitivity Drug-induced nephrolithiasis is rare and has an estimated incidence
response is regarded as explanation for this phenomenon which less than 1%. An increased excretion of uric acid, a breakdown prod-
can be caused by analgesics, diuretics, and NSAIDs. Much of this uct of proteins, in combination with dehydration may increase the
reaction is reversible. Several drugs, however, may cause progres- risk on nephrolithiasis and subsequent kidney injury.6,27
sive and irreversible damage culminating in kidney failure. Lithium
and cyclosporine therapy are well-known causes of this phenome- The Role of Nuclear Medicine in the Detection
non with an increased risk in dehydrated patients. Nephrocalcino-
sis, characterized by extensive tubulointerstitial deposition of
and Follow-up of Nephrotoxicity
calcium phosphate, and papillary necrosis caused by analgesics, Radionuclide renal scintigraphy provides important functional data
such as aspirin and NSAIDs resulting in acute kidney injury.5,6,19,20 to diagnose and monitor chemotherapy-induced nephrotoxicity.29–31
The interval between exposure and toxicity may range from weeks Data related to this specific application, however, are scarce. The
to months whereas in case of analgesic nephropathy, end-stage most commonly used tracer for renography is Technetium-99m
renal disease may evolve over years. The exact mechanism of this (99mTc) mercapto acetyl triglycine (MAG3). See Table 33.2. After
form of nephropathy remains unclear, and is in many cases under- intravenous administration, approximately 45% of this tracer is
diagnosed as a cause of end-stage renal disease. The production of extracted by the proximal tubules. 99mTc-MAG3 has a higher extrac-
free, toxic radicals may be the initiating factor with accumulation tion fraction than diethylene triamine pentaacetic acid (DTPA) and,

of toxic metabolites, decreased blood flow, and impaired cellular therefore, it is a better diagnostic agent in patients with impaired
energy production as a consequence. function. The clearance of 99mTc-MAG3 is highly correlated with the
effective renal plasma flow and, consequently, it can be used as an
independent measure of renal function. Iodine-131 (131I) orthoiodo-
Glomerular Disease
hippurate (OIH) is a tracer that is also extracted by the proximal
Although chemotherapy-induced glomerular disease is rare, a vari- tubules, but because of the suboptimal imaging characteristics of 131I
ety of drugs have been implicated. Ampicillin, phenytoin, lithium, and its β-emission, it is rarely used. DTPA labeled with 99mTc is the
and NSAIDs have been known to cause proteinuria, a typical hall- second most frequently used radiopharmaceutical for renal scintig-
mark of glomerular injury.9,21,22 Glomerular injury is frequently raphy. 99mTc-DTPA is filtered by the glomerulus and can, therefore,
accompanied by interstitial nephritis, and it is most frequently be used to assess the glomerular filtration rate. Semiquantitative
caused by immune mechanisms rather than direct cellular toxicity. analyses of the scintigrams can be performed, providing measures
In NSAID-related glomerular injury, a T-lymphocytic interstitial of time to peak extraction (Tmax), the ratio of the activity at 20 min-
infiltrate is associated but the exact mechanism is not known. Pro- utes to the maximum activity and the rate of washout (activity at 20
teinuria usually resolves rapidly after discontinuation of the specific minutes) to the renal function (activity at 2 to 3 minutes). It is impor-
toxic agent whereas a course of corticosteroids may help resolve it tant that the patient is adequately hydrated when renal scintigraphy
more rapidly. Pamidronate, a bisphosphonate used to treat bone and its semiquantitative analysis is performed. Quite often, hydra-
metastases-related hypercalcemia, has also been associated with tion is suboptimal in cancer patients. Inadequate hydration results
focal segmental glomerulosclerosis. Patients receiving high doses or in retention of the radiopharmaceuticals in the tubular cells. Dimer-
prolonged therapy with this drug are at high risk.23 captosuccinic acid (DMSA) labeled with 99mTc is used for functional
imaging of the proximal renal tubular mass and provides high-qual-
ity images because of preferential cortical accumulation and limited
Renal Vasculitis and Thrombosis
excretion. This tracer is primarily used to assess residual damage
A large number of drugs have been associated with a vasculitis. and scar formation.
Allopurinol, propylthiouracil, hydralazine, and chemotherapeutic Functional imaging can also be performed with positron-
agents may induce systemic vasculitis with involvement of small- emitting radiopharmaceuticals. Tracers used for positron emission
and/or medium-sized renal arteries.24–26 Typical features are hema- tomography (PET) perfusion studies of the kidney include Oxygen-15
turia, proteinuria, hypertension, and reduced renal function. To (15O) labeled water and Rubidium-82 (82Rb). Glomerular filtration can
resolve the symptoms, the drugs must be discontinued and a course be imaged with either Gallium-68 (68Ga) 2-[2-[bis(carboxymethyl)
of prednisone may be necessary. Other drugs, such as interferon, amino]ethyl-(carboxymethyl)amino]acetic acid (EDTA) or Cobalt-55
tacrolimus, and mitomycin C may cause a thrombotic microangi- EDTA. An advantage of renal PET over scintigraphy is the possibility
opathy. Histologic examination may reveal endothelial proliferation of true quantification and a better assessment of renal blood flow. A
and thrombus formation as typical features of it. A dose-related major disadvantage of PET-based renal imaging in oncologic prac-
effect has been described in mitomycin C either with or without tice is the availability and costs of these tracers. At this time, there
the use of other chemotherapeutic drugs and its effect may be is insufficient data to determine the utility of PET tracer assessment
irreversible and severe. of renal viability and function.31
In clinical practice, the role of nuclear medicine is limited in the
assessment of chemotherapy-induced renal toxicity. Standard
Obstructive Nephropathy
laboratory tests include routine measurement of creatinine, cre-
This form of nephropathy can be subdivided into intratubular atinine clearance, and β-2 microglobulins, which can be used to
obstruction and nephrolithiasis.6,27 Intratubular obstruction can be establish a vascular, tubular, or glomerular origin of kidney failure.
caused by intratubular precipitation of tissue degradation products In contrast to renal scintigraphy, laboratory tests can be performed
or drugs and/or their metabolites. Acute uremic acid nephropathy several times per day and are less expensive. Based on these test
because of tumor degradation caused by chemotherapy is the most results, chemotherapy regimens are modified or discontinued
common cause of this type of nephrotoxicity. Oliguria or anuria usu- depending upon the severity of the nephrotoxicity. The choice of
ally develops rapidly. Rhabdomyolysis and precipitation of myoglob- radiopharmaceutical to be used is based on the type of damage. If
ulin is another frequently observed etiology. Drugs such as simvastatin tubular damage is suspected, 99mTc-MAG3 is the radionuclide of
or lovastatin are also known potentially nephrotoxic agents, espe- choice whereas in glomerular toxicity, 99mTc-DTPA might be a bet-
cially when used concurrently with cytochrome P450 inhibitors or ter option. In a study by Yetgin et al.,29 the role of MAG3 and DMSA
niacin.28 Other drugs, such as methotrexate, can also cause direct renal scintigraphy in the evaluation of kidney damage was
kidney injury by intratubular precipitation.6,21 Nephrolithiasis as a described. They studied 116 children treated with vincristine,

Ta b l e 3 3 . 2
Overview of Different Radiopharmaceuticals for Imaging

Chemotherapy-Induced Toxicity
Physical Quantification
Organ Radiopharmaceutical Half-life Cyclotron Absolute Target
Myocardium γ-camera
99m
Tc erythrocytes 6h — —a Erythrocytes (blood volume)
99m
Tc-HAS 6h —+ —a Erythrocytes (blood volume)
123
I-MIBG 16 h Generator —a Type 1 NA-reuptake channel
99m
Tc-myoview 6h + —a Myocardial perfusion
99m
Tc-tetrofosmin 6h + —a Myocardial perfusion
201
Tl-chloride 3d —+ Myocardial perfusion
111
In-antimyosin 2.3 d + Irreversible myocardial damage
111
In-trastuzumab 2.3 d + HER-2 receptor expression
123
I-BMIPP 16 h + Fatty acid metabolism
PET 2 min Myocardial blood flow
15
O-water 1.27 min Myocardial blood flow
82
Rb 3.3 d HER-2 receptor expression
89
Zr-trastuzumab 20 min Type 1 NA-reuptake channel
11
C-catecholamine
analogs
Kidney γ-camera
99m
Tc-MAGIII 6h —+ —+ Tubular cell
111
In-DTPA 2.3 d Generator + Glomeruli
99m
Tc-DMSA 6h Generator + Tubular cell
PET 2 min Generator + Renal perfusion
15
O-water 1.27 min Renal perfusion
82
Rb 68 min Glomerular filtration
68
Ga-EDTA 68 min Glomerular filtration
68
Ga-EDTA
Lung γ-camera
67
Ga-Citrate 6h —+ —+ Inflammation
99m
Tc-DTPA aerosol 16 h Pulmonary diffusion
123
I-MIBG 2h Endothelial function
PET Glucose metabolism
18
F-FDG
Liver γ-camera
99m
Tc-MIBI 6h — — Liver cell
99m
Tc-GSA 6h Asialoglycoprotein receptor
99m
Tc-IDA 6h Hepatobiliary tract
Bone marrow γ-camera
99m
Tc-sulfur colloid 6h —+ —+ RES
99m
Tc-nanocolloid 6h + + RES
111
In-chloride 2.3 d + + Erythropoietic
99m
Tc-WBC 6h + + RES
111
In-WBC 2.3 d + + RES
PET 8.2 d + + Erythropoietic
52
Fe 2h + + Glucose metabolism
18
F-FDG 2h Proliferation (DNA)
18
F-FLT 20 min Amino acid metabolism
11
C-methionine 20 min Fatty acid metabolism
11
C-acetate 20 min Cell proliferation
11
C-choline 2h Cell proliferation
18
F-choline
a
Quantification of cardiac function is possible when dedicated software systems are used.
b
NA stands for Noradrenaline.
daunorubicin, high-dose methylprednisolone or cytarabine, and authors concluded that 99mTc-DMSA detects tubular dysfunction
etoposide for acute lymphoblastic leukemia. 99mTc-MAG3 and prior to clinical deterioration and, therefore, suggested monitoring
DMSA scans were performed in 27 and 84 patients, respectively. patients treated with ifosfamide containing chemotherapy.
Abnormal results were obtained in 40% of the cases. The practical The role of renal scintigraphy in patients treated with chemo-
consequences of these findings were not discussed. It was sug- radiation for gastrointestinal malignancies has been reported in
gested that compared to abnormal serum biochemical tests, renal several case series. A decline in split renal function with a progres-
scintigraphy might be a better predictor of long-term outcome. In sive relative impairment of the involved kidney can be detected as
a study by Caglar et al.,30 a total of 13 patients treated with ifos- early as 6 months postradiation. In these studies, however, kidney
famide were evaluated with 99mTc-DMSA scintigraphy. Serial failure was more related to radiotherapy than to chemotherapy.
measurements were performed and a 25% decrease in renal In summary, the role of renal scintigraphy in oncologic practice
uptake was observed in five patients with nephrotoxicity. The is limited. Data in the literature is scarce.

Chemotherapy-Induced Lung Toxicity by proliferation of Masson bodies which are immature fibroblastic
plugs within alveolar ducts and alveolar spaces. Bleomycin, cyclo-
Many chemotherapeutic agents have been associated with pulmo- phosphamide, and methotrexate are the drugs most often associ-
nary toxicities.32 Approximately 10% of all patients treated with ated with COP. Dry cough, fever, and dyspnea are typical symptoms.
chemotherapeutic agents will develop an adverse event related to HRCT shows nodular areas of consolidation, centrilobular nodules,
the lungs. In some cases, the clinical presentation is acute whereas and branching linear opacities (tree-in-bud). Generally, it responds
in other cases, it is more insidious. The most commonly observed well to drug withdrawal but in some cases, corticosteroids are
symptoms are dyspnea, nonproductive cough, and fever. The onset required. Fibrosis is less commonly observed.36,37
may vary from weeks to years after treatment. In this respect, bleo-
mycin pulmonary toxicity is the most prevalent and well-described Eosinophilic Pneumonia and
chemotherapy-induced pulmonary disease; busulfan is the second
most common.32,33 Other agents, such as antimetabolites, nitrosa- Pulmonary Hemorrhage
mines, podophyllotoxins, and immune modulatory agents have These conditions are less commonly observed than the other forms
been associated with pulmonary toxicity. Bleomycin-induced lung of drug-induced toxicity. Eosinophilic pneumonia (EP) is character-
disease is associated with a significant decrease in 5-year overall ized by an accumulation of eosinophils and macrophages in the
survival in patients with Hodgkin lymphoma. The pathogenesis of alveoli and thickened septa. The most typical feature on chest
lung toxicity seems to be a combination of apoptotic dysfunction radiographs are homogeneous opacities that are typically located
and impaired repair. Apoptosis has two fundamental pathways: peripherally and in the upper lobes. Pulmonary hemorrhage (PH) is

the mitochondrial pathway and the death receptor. Anticancer a severe complication of cancer treatment. Amphotericin B, cyclo-
agents can activate proapoptic pathways resulting in an increased phosphamide, and mitomycin are associated with PH with acute
permeability of the mitochondrial outer membrane and the release respiratory distress as initial symptom. HRCT usually shows bilat-
of cytochrome C, leading to cell death.34 Regarding the second path- eral, scattered, or diffuse ground-glass opacity.37
way, epidermal growth factor (EGF) and vascular endothelial
growth factor (VEGF) signaling and angiogenesis may be the cor-
nerstone in the process of recovery. Inhibition of these factors The Role of Nuclear Medicine in the Detection
reduces the ability of pneumocytes to repair. and Follow-up of Lung Toxicity
In clinical practice, the role of nuclear medicine in the detection
Types of Lung Toxicity and follow-up of lung toxicity is limited. The standard diagnostic
There are several forms of lung toxicity. The clinical and radiologic procedure in patients presenting with symptoms of fever, cough,
manifestations generally reflect the underlying histopathologic and dyspnea includes a chest x-ray, arterial blood gas analysis, and
process. HRCT scanning. In most cases, the diagnosis is made, when the
symptoms occur shortly after the initiation of cancer treatment. In
patients in whom this correlation is less clear because of an
Diffuse Alveolar Damage extended time interval, bronchoscopy and biopsy may be required
This is the most common form of lung toxicity related to chemotherapy to establish a diagnosis. HRCT is of value to demonstrate fibrosis
and especially to the use of bleomycin, busulfan, carmustine, and and honey combing.
cyclophosphamide. The first phase is the so-called exudative One of the first tracers that has been studied extensively in this
phase, in which alveolar and interstitial edema is seen. The second respect is Gallium-67 (67Ga) citrate. Pulmonary uptake of 67Ga
phase, the reparative phase, is characterized by proliferation citrate has been described in a variety of disorders, such as inter-
of pneumocytes and fibrosis. This latter finding may either improve stitial pneumonia, sarcoidosis, pneumonia, toxicity to chemothera-
over time, but also may end in honeycomb lung. Diffusing capacity peutic agents, and in subradiographic interstitial inflammatory
for carbon dioxide may decrease, whereas radiologic evaluation reaction.38,39 See Table 33.2. Gallium scans have been reported as
with high-resolution computed tomography (HRCT) may reveal abnormal in pulmonary toxicity caused by amiodarone, busulfan,
bilateral ground-glass opacities. Although fibrosis at initial stage bleomycin, procarbazine, nitrofurantoin, pentazocine, cephalospo-
may be missed, follow-up CT scans may show progressive distor- rin, cyclophosphamide, and cocaine, even in the absence of radio-
tion of the architecture.35 graphic findings. In most of these cases, diffuse pulmonary uptake
is observed. This is a nonspecific finding. With the introduction of
HRCT, 67Ga citrate scintigraphy no longer used to assess lung toxic-
Nonspecific Interstitial Pneumonia
ity. In clinics where 67Ga may be in use to stage lymphoma, diffuse
In nonspecific interstitial pneumonia (NIP), infiltration of the inter- uptake on the scintigraphic images may be a feature of lung toxic-
stitium by mononuclear inflammatory cells is seen, in combination ity and should be recognized and reported. However, Fluor-18-
with mild interstitial fibrosis and hyperplastic pneumocytes. It has fluorodeoxyglucose (18F-FDG) PET scanning has generally replaced
67
been associated with amiodarone, methotrexate, and carmustine. Ga scintigraphy in many hospitals.
Docetaxel may cause an acute form of NIP, especially when coadmin- The clinical evidence on 18F-FDG PET imaging in lung toxicity
istered with gemcitabine. Paclitaxel has been described in a number is limited to retrospective studies or observational case series. In a
of case reports and clinical studies, but the overall incidence remains study by Kazama et al.,40 a total of 677 18F-FDG PET scans on 460
low. Targeted therapies with monoclonal antibodies against the patients with lymphoma, non-Hodgkin lymphoma (351), Hodgkin
VEGF receptor and EGFs tyrosine kinase inhibitors have been cor- disease (92), and 17 patients with both Hodgkin and non-Hodgkin
related with NIP in approximately 1% of the patients. In general, lymphoma were performed. In 51 patients, abnormal accumulation
diffusion capacity will decrease whereas HRCT scans show more dif- on both sides of the chest was reported. In 10 patients (six men
fuse areas of ground-glass opacity. Later in the course of this form of and four women, average age 47.3) representing 2.2% of cases,
lung damage, fibrosis can be observed, especially at the lung bases. probable drug toxicity was identified. In all 10 cases, diffuse and
subpleural-dominant FDG accumulation was seen on 18F-FDG PET
scans, and scattered or diffuse ground-glass opacities were
Cryptogenic Organizing Pneumonia
observed on chest CT. Four of the patients reported symptoms,
18
Cryptogenic organizing pneumonia (COP) was formerly known as F-FDG PET imaging may be able to detect pulmonary drug toxic-
bronchiolitis obliterans organizing pneumonia. It is characterized ity in asymptomatic patients but diffuse uptake appears to be a

nonspecific finding. In a case report by Yamane et al.,41 a 51-year- naive patients without evidence of pulmonary disease who were
old man presented who developed drug-induced pneumonitis dur- treated with bleomycin underwent 99mTc-DTPA scintigraphy. Scin-
ing chemotherapy for non-Hodgkin lymphoma. Pneumonitis was tigraphy was performed before the first cycle and every 3 weeks
detected earlier by 18F-FDG PET than by HRCT. Accordingly, the until the third month after the end of chemotherapy.48 Comparing
authors concluded that 18F-FDG PET imaging can be used to detect the pre- and posttreatment scans, the clearance was significantly
drug-induced pneumonitis at an earlier stage than HRCT. Buchler lower. The authors concluded that cumulative bleomycin doses are
et al.42 described a case in which 18F-FDG PET was used in a patient related to pulmonary epithelial permeability at a dose of 256.5 mg.
with Hodgkin disease who developed bleomycin lung toxicity fol- Since nonradioactive techniques have become available, this method
lowing the fourth cycle of chemotherapy. The 18F-FDG PET scan has not entered clinical practice.
performed 2 months after the acute presentation, showed diffuse
uptake of FDG in the lungs. Following treatment with corticoste-
roids, the FDG avidity in the lungs disappeared, whereas conven- Chemotherapy-Induced Liver Toxicity
tional CT scanning was not able to distinguish between residual
changes and active inflammation. The authors also concluded that The liver is the most important organ in drug metabolism. Many
18
F-FDG PET represents a useful diagnostic tool and demonstrates chemotherapeutic agents will be metabolized and excreted into the
the resolution of disease activity even in the presence of residual biliary tract and subsequently into the bowel. Consequently, dys-
pulmonary scarring. A comparable case was reported by Rohr et al.43 function of the liver may result in increased levels of many agents
stressing the fact that in patients with diffuse lung uptake on the causing greater toxicity to other organs such as bone marrow and
18
F-FDG PET scan should be evaluated for drug-induced toxicity. kidneys. On the other hand, some chemotherapeutic agents are
Kalkanis et al.44 retrospectively evaluated 18F-FDG PET scans of inactive after administration but become activated in tumor or
patients who have been treated with rituximab, a chimeric anti- other tissues following localization. If liver function is required for
CD20 monoclonal antibody widely used in the treatment of B-cell activation of the prodrug, liver impairment may reduce the chance
non-Hodgkin lymphomas (NHLs). In their case series, none of the of a meaningful response. Risk factors for drug-induced liver dis-
patients had pulmonary lymphoma or other pulmonary disease ease include age, gender, and familial predisposition. Pre-existing
before therapy and all remained asymptomatic during follow-up. liver impairment, however, due to alcohol abuse, for example, or
New pulmonary interstitial FDG uptake was detected on follow-up liver dysfunction due to metastatic disease and the use of concur-
18
F-FDG PET/CT between 1 and 3 months posttreatment. The rent medications may increase the risk of toxic effects and side
18
F-FDG PET findings preceded CT. FDG uptake was subpleural effects of chemotherapy.49–52 The most hepatotoxic agents described
with maximum standardized uptake value (SUV) from 2 to 5.84. in the literature are methotrexate, asparaginase, carmustine, and
Although rarely observed, diffuse FDG uptake should increase mercaptopurin. Less-toxic agents are capecitabine, dacarbazine,
awareness of toxicity and should not be confused with lymphoma etoposide, gemcitabine, and cyclophosphamide. Most agents are
activity. This data does not support the use of 18F-FDG PET imaging lipophilic compounds that are taken up rapidly by the liver and
in all patients suspected for having drug-induced lung toxicity when cannot be excreted without break down into smaller fragments. It
lung toxicity is diagnosed and a HRCT fails to demonstrate recovery, may disturb lipid metabolism resulting in steatosis in the liver.
18
F-FDG PET has a role in assessing disease activity. Because of this the liver becomes more vulnerable and repeated
99m
Tc-DTPA aerosol scintigraphy has been used to detect lung chemotherapy may finally induce irreversible hepatocellular dam-
toxicity. DTPA and other small molecules move across the alveolar age through recruitment of inflammatory cells and especially by
epithelium through paracellular pathways by passive diffusion after monocytes.
deposition on the alveolar surface. Increased surfactant over the Based on the biochemical alterations, liver toxicity can be sub-
alveolar epithelium lengthens the distance of diffusion pathway of divided into hepatocellular and cholestatic dysfunction. In hepato-
DTPA. In 1993, the first report on the use of 99mTc-DTPA aerosol cellular dysfunction, aspartate aminotransferase and alanine
scintigraphy in bleomycin-induced lung toxicity in patients with aminotransferase levels are elevated greater than two times the
germ cell tumor was presented by Ugur et al.45 Based on scintigra- upper limit of normal. In cholestatic dysfunction, alkaline phos-
phy, the percentage decrease in activity per minute (Kep) was eval- phatase and γ-glutamyltransferase are elevated greater than two
uated. Pretreatment Kep values (0.891 ± 0.286) were significantly times the upper limit of normal.
lower than those obtained following 180 and 360 mg bleomycin In the acute phase hepatocellular and cholestatic liver disease,
treatment (1.176 ± 0.336 and 1.389 ± 0.477, respectively; P < functional imaging may show minimal or no changes at all. Both
0.0005). The Kep values obtained with 180 and 360 mg bleomycin forms of liver disease may resolve after stopping treatment but
treatments were also significantly different (P < 0.005). Suga et al.46 occasionally acute (fatal) necrosis has been reported. Other drugs
reported on this effect in irradiated canine lung, in which 14 irradi- besides the chemotherapeutics, such as allopurinol and ketocon-
ated animals were studied. The histologic and bronchoalveolar azole, may induce fulminant liver necrosis. In general, the severity
lavage studies revealed an increase in alveolar surfactant material of liver disease is based on a combination of biochemical and clini-
without histologic changes in the alveolar structure. The radioaero- cal parameters. The Child-Turcotte-Pugh score is a combined mea-
sol is delivered via a ventilation circuit until a minimum count rate sure of ascites, encephalopathy, and biochemical indices that was
over the lung fields was obtained and the clearance study was originally developed to assess alcohol-related cirrhosis in the liver.53
started immediately after disconnection of the ventilation unit. In all This score is not used in current oncologic practice as the correla-
animals, the half-life of DTPA in the lung increased significantly tion with the Child-Turcotte-Pugh and clearance of chemotoxic
compared to the baseline study. In a subsequent study by Durmus- agents is weak. The model for end-stage liver disease (MELD) was
Altun et al.,47 99mTc-DTPA was evaluated in a rabbit model for the developed in 2000 and had been introduced for the selection of
detection of amiodarone-induced pulmonary toxicity. In this study, patients for liver transplantation.54 In the oncologic setting, it has
the radioearosol technique was compared to scintigraphic imaging only been used to identify patients with hepatocellular carcinoma
of Iodine-123-metaiodobenzylguanidine (123I-MIBG), a norepineph- for transplantation; not to assess prognosis in case of chemotherapy-
rine analog. 123I-MIBG has been used to study pulmonary endothe- induced liver toxicity. In patients with persistent biochemical altera-
lial function as the uptake patterns may reflect pulmonary tions, as well as in patients in whom recovery is observed after
endothelial cell injury. It was shown that the 123I-MIBG retention cessation of treatment, radiologic techniques can be used to assess
index, as well as the 99mTc-DTPA clearance time, was significantly morphologic alterations. The combination of biochemical informa-
higher in the amiodarone-induced pulmonary toxicity group com- tion and radiologic findings can be used to assess prognosis in
pared to the control group. Twelve nonsmoking chemotherapy general.

Hepatocellular and Cholestatic Dysfunction (P = 0.015). From these data, it was suggested that functional
imaging of hepatic uptake and excretory pathways may have
Fatty Liver Disease potential to predict irinotecan pharmacokinetics but further study-
Also known as steatosis hepatis, this is defined as accumulation of ing is required. Although 99mTc-MIBI seems to have potential to
fat globules in the hepatocytes. It may be observed during exten- study the ABCB1 transporter, it has never been used in oncology to
sive administration of irinotecan for liver metastasis of colorectal assess liver toxicity. It remains, however, of interest whether MIBI
cancer. It may progress to a severe form, steatohepatitis, a severe liver clearance can be regarded as indicator for liver toxicity or as
form with limited hepatic reserve. Although the final diagnosis is indicator for clearance of chemotherapeutic agents and, conse-
made by biopsy and histologic examination of the specimen, CT quently, a predictor of other toxic effects, such as neutropenia.
99m
may show fatty changes. Tc–labeled IDA derivates were initially reported by Loberg
et al.60 These lidocaine analogs are predominantly bound to albumin
and transported to the liver. Thereafter, it is dissociated in the
Pseudocirrhosis hepatic space of Disse after which the radiopharmaceutical is taken
Retraction of the capsule is observed in patients with metastases up by hepatocytes and follows the path of intracellular transit sim-
or primary tumors in the liver treated with chemotherapy. These ilar to bilirubin, toxins, or drugs. Without any transformation, IDA
findings may occur within 1 to 3 months after treatment and can derivates are excreted into the biliary tract and are ideal tracers for
be focal or more diffuse. It is probably due to nodular regenerative biliary tract imaging. In general, the uptake of IDA derivates is
hyperplasia. There is no association with treatment response, as it affected by high bilirubin plasma levels but 99mTc-mebrofenin is effi-

can be seen in tumors that are decreasing and increasing in size ciently excreted and, therefore, is considered as the most suitable.
and, therefore, it has no prognostic value. Hypoalbuminemia may hinder the uptake and increases the uri-
nary excretion of mebrofenin. Decreased liver uptake and increased
urinary excretion reflects impaired liver function. Uptake rates,
Biliary Sclerosis
time-to-peak, T1/2 peak values, and functional liver volumes can be
Chemotherapy related biliary sclerosis results either from toxic derived from dynamic image analysis.61–63 The clinical use of this
effects on the biliary system or ischemic changes secondary to fibro- tracer is mostly described in liver transplanted patients. In addition,
sis of the pericholangitic venous plexus, both of which can result in case series have been published on its value in patients with pri-
stricture of the duct. CT scanning demonstrates narrowing of the bile mary sclerosing cholangitis.64,65 These studies conclude that this
ducts with the extrahepatic ducts most commonly involved whereas technique is capable of assessing different aspects of liver function
the intrahepatic bile ducts are less involved. Clinically, it should be for the total liver, as well as for individual segments. Dynamic imag-
differentiated from jaundice observed in chemical hepatitis due to ing and serial scanning provides quantitative physiologic data that
chemotherapy in which case, only cessation of treatment is required may be useful in the longitudinal follow-up of patients with scleros-
whereas in biliary sclerosis stent placement may also be necessary. ing cholangitis. Nevertheless, although a role in the assessment of
Hepatoveno-occlusive disease is a serious complication charac- biliary sclerosis because of chemotherapy could be suggested, data
terized by obliteration of small hepatic venules with surrounding is not available because of the fact that ultrasonography is usually
fibrosis and clogging of the sinusoids with debris form cell necrosis. the procedure of choice.
The basic mechanism is thought to be damage of the endothelial 99m
Tc–labeled GSA was developed to visualize and quantify the
cells of central and sublobular veins in the liver.55,56 It is a common binding to asialoglycoprotein receptors expressed on hepatocytes,
finding in myeloablative chemotherapy with jaundice, ascites, and but not on other cells in the human body. This receptor consists of
hepatomegaly as typical features. Although CT scanning may reveal two subunits (type 1 and 2 hepatic lectins) and is expressed on the
nonspecific findings, Doppler ultrasonography will show decreased sinusoidal surface, close to the extracellular space of Disse.66 After
blood flow in the portal vein that can be observed within 3 weeks binding to the receptors, asialoglycoproteins are taken up via endo-
after initiation of treatment. cytosis and thereafter delivered to lysosomes where they are
degraded. In patients with chronic liver disease, the expression of the
The Role of Nuclear Medicine in the Detection receptors is diminished and, consequently, it was expected that
99m
Tc-GSA could be a noninvasive technique to assess liver function.
and Follow-up of Liver Toxicity Initial studies demonstrated a good correlation with the Child-Pugh
Functional imaging of the liver with radiopharmaceuticals aims to classification or other laboratory tests, such as bilirubin, antithrom-
provide a method to assess drug uptake and excretion by the liver. bin III, or prothrombin time.67,68 Several parameters from dynamic
Radiopharmaceuticals for this purpose include 99mTc-methoxyiso- scintigraphy have been described: Modified receptor index, hepatic
butylisonitrile (MIBI), 99mTc-DTPA-galactosyl human serum albu- uptake ratio, blood clearance ratio, blood clearance constant, and
min (GSA), and 99mTc-iminodiacetic acid (IDA) for hepatobiliary maximal removal rate seem to be good estimates of the total liver
scintigraphy. See Table 33.2. function.69,70 The advantage of this tracer is that the uptake is not
In the liver, biliary transporter-mediated excretion has a role in directly affected by elevated bilirubin levels. Its use has been exten-
drug clearance involving many enzymes including adenosine tri- sively studied in the preoperative assessment of liver function and
phosphate-binding cassette transporters such as the ABCB1, postoperative liver regeneration patients.71–73 Extrapolating from
ABCC1, ABCC2, and ABCG2. 99mTc-MIBI is a substrate for ABCB1 these data, 99mTc-GSA may have a role in differentiating reversible
enzyme in the liver, and consequently, it can be used as an indica- from irreversible liver damage. This was demonstrated in a study by
tor of drug clearance before therapy is initiated. This radionuclide Urganci et al.74 in which 99mTc-GSA uptake and subsequent
has been studied in patients treated with vinorelbine. It was shown endocytosis of labeled asialoglycoproteins distinguished between
that 99mTc-MIBI clearance was an independent predictor of this functional regions of hepatocytes and nonfunctional zones. In
chemotherapeutic agent clearance.57 Imatinib, a tyrosine kinase chemotherapy-induced liver toxicity, however, it has not been applied.
inhibitor, is an agent that is excreted in bile presumably via ABCB1.
In a study by Gurney et al.,58 99mTc MIBI liver clearance was stud-
ied in 22 patients treated with imatinib but the authors did not find
Chemotherapy-Induced Bone
a correlation between the clearance of both. Finally, in a study by Marrow Toxicity
Michael et al.,59 99mTc-MIBI was studied in patients treated with
irinotecan. 99mTc-MIBI excretion was prolonged in patients with Bone marrow is a compartment of bone in which hematopoietic
the ABCB1 exon 26 TT variant allele relative to the wild type cells are produced. Hematopoietic stem cells (HSCs) reside in

s pecific areas of this bone marrow. HSCs are able to proliferate Hemolytic Anemia
and differentiate into different cell lineages, such as the myeloid,
erythroid, and megakaryocytic lineages.75 HSCs, however, are also This hematologic disorder is not located in bone marrow but is a
capable of self-renewal to keep the number of HSC constant over result of an abnormal breakdown of red blood cells in either blood
time. This complete process and ultimate balance between these vessels or an overactive spleen. It can be either immune or nonim-
two aspects depend on many factors and can, therefore, be easily mune mediated or inherited. With the use of immune-modulatory
distorted by chemotherapeutic agents. Consequently, hematologic agents in cancer treatment, an increased risk of this phenomenon
toxicity is usually the limiting factor in chemotherapy. Indeed, is observed. Clinical symptoms are related to anemia, such as
depressed bone marrow reserve before initiating anticancer ther- fatigue and palpitations, whereas jaundice can be the first sign as
apy hampers the use of cytotoxic agents, thus influencing overall a result of increased hemoglobin degradation.89–92
morbidity and mortality. The induction of bone marrow disorders
by chemotherapy can be amplified by the additional use of radio- The Role of Nuclear Medicine in the Detection
therapy. These disorders may occur as acute effect during treat-
ment, but also months to years after completing treatment. In
and Follow-up of Bone Marrow Toxicity
general, acute side effects will show recovery after cessation of Regular peripheral blood counts and, occasionally, bone marrow
anticancer treatment but it may also go on to other bone marrow biopsies are standard techniques to evaluate the status and recov-
disorders. ery of chemotherapy-induced bone marrow toxicity. Despite the
fact that these procedures are easily performed in clinical practice,
they are regarded as indirect methods of systemic marrow status,
Types of Bone Marrow Toxicity limited by sampling errors and influenced by inflammatory
changes. A complete overview of status of the marrow is achieved
Myeloproliferative Diseases with nuclear medicine techniques. Because of the costs, most of
Myeloproliferative disease is a bone marrow disorder that resem- these techniques are not routinely applied in the acute phase of
bles a proliferation process of one or more cell lines resulting in an chemotherapy-induced bone marrow toxicity. PET tracers, how-
increased production of granulocytes, erythrocytes, or cells of the ever, can provide quantification and give better estimates of the
megakaryocytic cell line. Usually a combination of increased pro- bone marrow status.
liferative cell lines is observed. For example, polycythemia vera is The reticuloendothelial system (RES) is the compartment most
commonly associated with a mild increase in white blood cell readily imaged. This compartment consists of phagocytic cells that
(WBC) counts and myelofibrosis is frequently associated with an can be found in the reticular connective tissue and is imaged with
increase in immature WBC. Despite the increased proliferation, the radiolabeled colloids. 99mTc-sulfacolloids and 99mTc-nanocolloids are
cells show a relatively normal maturation at the initial stage of the most commonly used. After intravenous administration, both trac-
disease. However, myeloproliferative diseases usually show a step- ers are rapidly cleared from the plasma and taken up by the RES.
wise progression that leads to bone marrow failure due to myelo- Nanocolloids are smaller in size than other colloids and, conse-
fibrosis. The clinical outcome depends on the cell lineage involved quently, the uptake is high in bone marrow. See Table 33.2. The
in this myeloproliferative disease. The correlation between cancer normal pattern of bone marrow scintigraphy varies with age. In
treatment and induction of myeloproliferative disorders has been adults, there is homogeneous uptake in the axial skeleton and the
reported in the literature.76,77 Therapy-related myeloid neoplasms proximal long bones. In younger patients, activity is seen in the
are preferentially observed following the treatment with cytostatic juxta-articular areas.93 Colloid scintigraphy is not used in the fol-
drugs such as alkylating agents, topoisomerase II inhibitors, and low-up of chemotherapy-induced toxicity because the distribution
antimetabolites but have also been described in patients receiving pattern alone is not useful and quantitation is not readily per-
intensive immunosuppressive treatment, radiotherapy, or treat- formed. In patients treated with radiotherapy, however, well-
ment with radioiodine.78–81 demarcated defects in bone marrow can be observed.
Several tracers are available to image either the erythroid or
myeloid bone marrow. Indium-111 (111In) chloride is a tracer that
Myelodysplastic Syndromes binds to transferrin; marrow uptake probably reflects the distribu-
Myelodysplastic syndromes are bone marrow disorders in which tion of erythropoietic marrow. In patients with myelofibrosis or
dysplasia and ineffective hematopoiesis in one or several cell lin- chemotherapy-induced toxicity, an extension of 111In-chloride
eages can be observed. Differentiation into subgroups is based on uptake can be observed beyond the central skeleton.94–96 Increased
cytology and cytogenetic findings and typical groups are refractory uptake is seen especially in juxta-articular areas, such as the hips,
anemia and myelodysplastic syndrome. The primary form of this shoulders, and knees. Severely diminished uptake correlates with a
syndrome predominantly occurs in older adults. The secondary poor prognosis indicating the absence of bone marrow reserve.97,98
form of myelodysplastic syndrome is often a result of chemother- Because there is low uptake in erythrocytes and the radiation-
apy and/or radiotherapy. This form is not related to aging and absorbed dose is relatively high for a diagnostic study, 111In-
tends to be more severe than the primary form. The clinical pre- chloride is not generally used to assess bone marrow. Iron-52
sentation depends on the cell line involved in the syndrome but is (Fe-52), a cyclotron-produced PET tracer, identifies erythroid bone
usually predominated by anemia. The end stage of this syndrome, marrow by incorporation into hemoglobin. There are no data on its
however, results in pancytopenia.82 use in chemotherapy-induced abnormalities.
Radiolabeled WBCs are also useful as bone marrow tracers.
Labeling can be performed with 99mTc, 111In, or 99mTc–labeled
Aplastic Anemia monoclonal antigranulocyte antibodies. Radiolabeled WBCs and
This is characterized by an immune-mediated destruction of the antibodies have been used to identify granulocytic marrow ele-
stem cells resulting in an extremely low red blood cell count. It is a ments in the bone marrow but it is difficult to distinguish between
life-threatening disorder with a high mortality rate.83,84 In approxi- specific WBC localization and trapping by the RES. Consequently,
mately 50% of the patients the etiology is unknown. Exposure to imaging the bone marrow by these techniques is comparable to
certain drugs such as chloramphenicol, carbamazepine, and qui- radiocolloids. Antibodies identify an antigen on both circulating
nine, however, are associated with aplastic anemia. The clinical WBCs and mature myeloid cells in the marrow.99 With this tracer,
presentation is related to anemia, thrombocytopenia, and/or granu- bone marrow can be evaluated by identifying the distribution pat-
locytopenia.85–88 tern, identification of focal lesions, and calculating uptake ratios. In

patients with myelodysplastic syndrome, focal defects in uptake can these diagnoses is not always straight forward as type II injuries
be visualized whereas in myelofibrosis, diffusely decreased uptake can, when left untreated, also result in a cellular loss and ventricu-
is seen.93 Because of the cumbersome labeling techniques of WBCs lar dysfunction.112,113
and the costs of radiolabeled antibodies, its use in the assessment The fact that cardiac complications are exceptionally diverse is
of bone marrow toxicity and prognosis has been limited. in part explained by the so-called “multiple hit” theory.114 Prior to
18
F-FDG PET is routinely used in the evaluation of many onco- chemotherapy, all individuals have a risk for developing cardiovas-
logic and infectious diseases. Uptake of FDG in hematopoietic mar- cular events that depends on genetic factors (e.g., predisposition),
row and the uptake pattern show great variation with age and the cardiovascular risk factors (i.e., diabetes, hypertension, hyperlipid-
level of marrow function at the time of PET. Diffuse uptake may emia, elevated body mass index, etc.), and certain lifestyle choices
resemble bone marrow activation by either the presence of malig- (i.e., smoking, reduced physical activity, diet, etc.). The likelihood of
nancy or hematopoietic disease but may also result from recent developing cardiotoxicity during or following anticancer therapy
chemotherapy or the use of granulocyte-(macrophage) colony- increases depending on the type of therapy and the treatment
stimulation factors (G-CSF or GM-CSF).100–102 Consequently, 18F- regime. Furthermore, the limited ability of myocyte regeneration
FDG PET appears to be a sensitive tool to visualize bone marrow affects the capacity of these cells to cope with subsequent stressors
stimulation and to assess the reserve capacity. In case of myelodys- such as hypertension, coronary artery disease, radiation therapy,
plastic syndromes, diffusely increased activity is usually observed or other cardiotoxic drugs. Accordingly, combined regimens
in the skeleton. In contrast, decreased uptake throughout the skel- wherein chemotherapeutics, targeted therapies, and thoracic radi-
eton in combination with an increased uptake in the liver and ation are given concurrent or subsequent, commonly show the
spleen may be indicative for myelofibrosis.103 Although 18F-FDG

highest incidence of cardiotoxicity. In the following section, the
PET is not used on a routine basis to assess chemotherapy-induced main cardiotoxic entities, left ventricular dysfunction, cardiovascu-
bone marrow disorders, it has to be recognized that the marrow lar ischemia, thromboembolic events, hypertension, and arrhyth-
pattern and activity is observed on follow-up PET scans performed mias are described.
to monitor treatment outcome or to assess tumor recurrence.
The use of 3-deoxy-3-fluor-18 fluorothymidine (18F-FLT) in clin-
ical practice is increasing. Thymidine, a pyrimidine analog, is
Mechanisms of Toxicity
incorporated into DNA and after phosphorylation by TK1 remains Left ventricular dysfunction is one of the most profound manifes-
trapped in the cell and can, therefore, be regarded as proliferation tations of cardiotoxicity. It is defined as a (sub-)clinical reduction of
marker.104 Because of high proliferation activity in bone marrow, ejection fraction that is often, but not necessarily, accompanied by
high uptake of 18F-FLT is observed. In patients with leukemia, dif- symptoms of congestive heart failure (CHF), such as tachypnea, a
fuse increased uptake is seen, whereas in case of myelodysplastic gallop rhythm, tachycardia, and pulmonary edema. However, a
syndrome and myeloproliferative disorders, expansion of the bone consensus on an explicit definition and classification system of car-
marrow compartment is seen. Following G-CSF or GM-CSF admin- diac dysfunction had not been established. In an oncologic setting,
istration increased proliferation is expected and generalized two types of dysfunction can be discriminated, a transient decline
increased uptake is observed. In contrast, in myelofibrosis, bone in function (type II cardiotoxicity) and a persistent decline (type I
marrow expansion is observed but usually in combination with cardiotoxicity). This latter type is recognized as a serious source of
decreased uptake.105,106 Finally, radiotherapy either with or with- morbidity and mortality on long-term follow-up.
out chemotherapy affects bone marrow 18F-FLT uptake. Agool Ever since the introduction of anthracyclines (doxorubicine, epiru-
et al.107 found diminished uptake at irradiated sites consistent with bicine, idarubicine) in the 1960’s, they have been associated with
18
F-FDG; 18F-FLT can be used to assess bone marrow reserve as dose-dependent, progressive, nonreversible cardiac dysfunction.115,116
well as to assess long-term side effects of chemotherapy and/or Multiple pathways, ultimately leading to DNA damage and free
radiotherapy. Quantification of local or regional uptake provides radical formation, are believed to be responsible for the antineo-
noninvasive follow-up of bone marrow disorders induced by che- plastic effects of anthracyclines. Free radical formation is thought
motherapy. Other tracers that can also be used to visualize prolif- to induce irreversible, structural damage to the myocytes. Myocar-
eration, such as Carbon-11 (11C) methionine (i.e., amino acid dial biopsies after anthracycline therapy show (1) a loss and disor-
activity) and 11C- or 18F-choline (i.e., phospholipid metabolism in ganization of myofibrils, (2) enlargement of the endoplasmatic
cells), may have the potential to noninvasively assess bone marrow reticulum and mitochondria, and (3) increased numbers of vacu-
function.108–111 Their role is, however, still hypothetical without oles and lysosomes.116 Certain metabolites of anthracyclines have
confirmation in clinical practice. a poor clearance rate from cardiomyocytes, thus inducing long-
lasting changes in cellular architecture. These structural changes
are directly associated with cellular calcium-ion transport, energy
Chemotherapy-Induced Cardiotoxicity homeostasis, and proapoptic pathways in myocytes, consequently,
increasing myocardial stiffness and reducing conductance. In term,
Several chemotherapeutics have been associated with an increased this will initiate a vicious circle of distorted contractility–relaxation
risk of cardiovascular complications.2,112 Cardiotoxicity is roughly cycle, endothelial dysfunction, ventricular hypertrophy, myocardial
defined as damage to cardiomyocytes or the conductive system of ischemia, and persistent ventricular dysfunction.
the heart resulting in (sub-)acute or chronic events depending on Even low cumulative (i.e., lifetime) dosages, doxorubicin and
the development of the actual injury. In the acute setting, complica- epirubicin, have been shown to induce dilated CMP and CHF at
tions may include hypertension, repolarization abnormalities, long-term follow-up.117,118 Acute events occur infrequently (less
arrhythmias, pericarditis, and ischemia whereas chronic events than 1% of the patients) and manifest as a reversible decline in
are generally characterized by a decline in ventricular function contractility. The incidence of anthracycline-induced cardiotoxicity
that may develop into dilated cardiomyopathy (CMP). In general, is dose dependent, in which complication rates increase dispropor-
two major groups can be defined based on the histopathologic pro- tionally for high dosages with an applied cumulative dose limit of
cesses: (1) irreversible cardiovascular damage (type I) related to 400 to 500 mg/m2 for doxorubicin and 720 mg/m2 for epirubi-
an actual loss of cells and (2) reversible damage (type II ) as a cin.119 The 5-year incidence of CHF in adjuvant anthracycline
consequence of transient cellular dysfunction. Unlike type I regimes has been implicated in 2% to 20% of the patients. Despite
effects, which are dose dependent, type II effects are not dose the development of new generations of anthracyclines which have
related, do not affect all patients and when they occur, there is a resulted in a lowered incidence of cardiotoxicity incidence, ven-
broad range of clinical severity but is rarely lethal. Assignment of tricular dysfunction is still a serious side effect.

Nonanthracycline-based therapies like alkylators (e.g., cyclo- Though angina-like complaints are an important indicator of early
phosphamide, ifosfamide, cisplatin), microtubuli inhibitors (e.g., coronary damage, in many patients coronary damage initially
paclitaxel, docetaxel, vincristine), and antimetabolites (e.g., clofara- manifests as a subclinical disease.
bine, fluorouracil, capecitabine) have a lower incidence of ventricu- Fluorouracil, a pyrimidine base antimetabolite associated with
lar dysfunction compared to anthracyclines. A study of Goldberg thymidine syntheses, has been associated with angina pectoris,
et al.120 showed a dose-dependent incidence of 7% to 28% for car- vasospasm, arrhythmias, pericarditis, myocardial ischemia, and
diac events after cyclophosphamide therapy including pericardial even cardiogenic shock.132 Angina-like symptoms and myocardial
effusion, pericarditis, ventricular dysfunction, and heart failure. ischemia have also been reported in capecitabine use (also a
Paclitaxel and docetaxel have also been associated with an increased pyrimidine antimetabolite) in various case studies.133,134 Patho-
risk of developing heart failure (incidence 2% to 8%). Ventricular physiologic mechanisms such as coronary vasospasm, thrombosis,
dysfunction following nonanthracyclines is primarily triggered by endothelial dysfunction, and autoimmune activation have all been
endothelial injury or coronary spasm. Persistent coronary injury proposed as possible causes. Still, the underlying mechanisms of
may over time lead to diastolic dysfunction, increasing the risk of chemotherapy-induced ischemia and incidence of these complica-
myocardial infarction.121 In combined treatment regimen, an increase tions have yet to be confirmed. However, generally these events are
in the incidence of cardiac complications after nonanthracyclines thought to appear hours or days after infusion and are considered
has been shown which is consistent with the “multiple hit theory.”116,122 to be reversible, thus suggesting a type II cardiotoxicity. Ischemic
Although these combined regimes are associated with progressive ECG changes and elevations in serum cardiac markers (i.e., arte-
cardiac dysfunction, the precise pathogenesis of cardiotoxicity has rial natriuretic peptide and troponin I) are frequently observed.135
not been elucidated. In later stages, myocardial ischemia and infarction may lead to a
Ventricular dysfunction has also been regularly related to thera- permanent decline in cardiac function. These complications can
peutics that target the human epidermal growth factor receptor also be observed with other nonanthracycline chemotherapeutics
type 2 (ErbB2, or also known as HER2).123 Stimulation of this such as cisplatin, paclitaxel, and docetaxel.136 Consequently, it has
receptor pathway promotes cell proliferation and opposes cellular been advised to discontinue chemotherapy if patients develop
apoptosis. In 20% to 30% of breast cancer patients, overexpression angina-like symptoms.
of this pathway is associated with aggressive tumor phenotypes. In New therapies that inhibit tumor angiogenesis by affecting the
the cardiovascular system, the ErbB-Neuregulin-1 signaling path- VEGF signaling pathway are also associated with ischemic events.137
way is related to fetal cardiac development, repair after cardiovas- Within the cardiovascular system, the VEGF pathway is not only
cular stress, angiogenesis, and myofibril organization.123,124 Deletion essential for vessel growth but also affects the formation, matura-
of certain ErbB genes in mice has consistently resulted in the tion, and migration of hematologic cells, and regulates permeability
development of CMP.125 Trastuzumab (an anti-ERbB2 monoclonal of microvessels. In the myocardium, upregulation of VEGF is associ-
antibody)-related cardiotoxicity presents as an asymptomatic decline ated with conditions of cardiac stress and will initiate repair.138,139
in cardiac function. Sorafeni and sunitinib are both multikinase inhibitors that not only
The incidence seems to be higher in longer therapeutic target VEGF but also platelet-derived growth factor (PDGF), stem
regimes.126–128 The exact molecular pathways that induce cardiotox- cell factor Kit (tyrosine kinase) receptor, and hypoxia-inducible fac-
icity after ErbB2 inhibition are highly complex, however, and remain tor (HIF) pathway.140 Hence, multikinase inhibitors are actually not
largely unclear. Combinations of anthracyclines and trastuzumab single-targeted drugs but rather affect an array of physiologic and
adversely affect the risk of developing cardiac dysfunction, from pathologic cellular pathways that are not limited to tumor genesis
approximately 10% for anthracycline monotreatment to approxi- alone. The HIF pathway plays an important physiologic role in reg-
mately 30% in the combined regimes. Lapatinib (a kinase inhibitor ulating myocardial remodeling and vascular permeability after
that inhibits both ERbB1 and ERbB2), like trastuzumab, has also acute or chronic myocardial ischemia. Consequently, inhibition of
been used in patients with metastatic breast cancer overexpressing these cascades is related to a reduction in capillary density, ven-
ERbB2. It appears that incidence of cardiac symptomatic or asymp- tricular dysfunction, fibrosis, and eventually heart failure. Although
tomatic dysfunction related to lapatinib is lower (around 1%) than the incidence of cardiovascular ischemia associated with the anti-
those described in trastuzumab regimes. In this instance also, the VEGF monoclonal antibody bevacizumab is still reasonably low,
main symptom was a decline in systolic left ventricular function.129 arterial thrombosis has been described.137 As with the other tar-
It has been indicated that interruption of either trastuzumab or geted drugs, long-term follow-up studies are needed.
lapatinib after a significant decline in ventricular function may result Hypertension is often present in cancer patients and may well
in normalization of function in many patients.128,130 Although this be one of the most frequently observed comorbidities in therapeu-
observation suggests that the cardiotoxicity of ErbB2 inhibitors is tics that interfere with angiogenesis.141 Although epidemiologic
reversible, long-term follow-up studies are needed. data concerning hypertension is conflicting, roughly one in four
In a recent study by Russo et al.,131 it has been hypothesized patients is believed to develop hypertension. A study by Maitland
that renal dysfunction may increase the myocardial sensitivity to et al.142 suggested that if the systolic blood pressure is over
potentially cardiotoxic chemotherapeutics such as trastuzumab 200 mm Hg, or diastolic pressure is over 100 mm Hg, discontinu-
and anthracyclines. The renal-cardiac systems are connected by ation of targeted therapies like VEGF inhibitors should be consid-
the RAS which controls fluid volume, blood pressure, and cardiac ered. Elevated blood pressure due to inhibition of the VEGF
function. Overactivity of this hormonal system has been associated pathway is probably related to increased vascular stiffness, dis-
with both cardiac and renal diseases, and generally leads to an turbed endothelial function, and decreased production of vasodila-
imbalance in reactive oxygen species and nitric oxide, overactiva- tors like nitric oxide.137,143 The incidence and severity of a rise in
tion of the sympathetic nervous system, and activation of the blood pressure depends on the type of antiangiogenic agent, treat-
immune system. In turn, oxidative stress and activation of the ment regime, and underlying comorbidities. Incidences of 8% to
immune system are known to affect left ventricular function 45% for high-grade hypertension associated with VEGF inhibitors
adversely and may hasten the induction of renal dysfunction. have been reported. In combined treatment regimens, the inci-
Cardiovascular ischemia and thromboembolic events are regu- dence can rise to even 90%.144,145 Interpretation of these data, how-
larly the result of endothelial cell injury. These specialized cells ever, can be difficult as definitions, classification criteria, and
coordinate important activities such as coagulation, permeability, hypertension control vary among trails. Other, less frequently
immune response, inflammation, and angiogenesis. Consequently, observed side effects of VEGF inhibitors include thromboembo-
relatively small abnormalities in the endothelial lining can develop lism, ischemia, proteinuria, CHF, and supraventricular tachycar-
into coronary atherosclerosis, myocardial ischemia, and fibrosis. dia.137 Although some of these complications can be directly

related to poorly controlled hypertension, other signaling path- dose in critical organs while still assuring an optimal tumor dose.
ways may also be involved. These principles are described in detail by the “International Com-
Arrhythmias in cancer patients can be caused by pre-existing mission on Radiation Units and Measurements” (ICRU).153
cardiac conditions or radiotherapy which induces fibrosis within
the cardiac muscle resulting in disturbances in the conduction sys-
tem. These are common risk factors in the development of arrhyth- The Role of Nuclear Medicine in the Detection
mias during chemotherapy. The arrhythmias attributed to certain and Follow-up of Cardiotoxicity
chemotherapeutic agents often manifest in an acute or subacute
setting as prolongation of the QT interval, (supra-)ventricular Over the last decade, several clinical guidelines emphasized the
arrhythmias, or ventricular repolarization abnormalities on electro- need for monitoring cardiotoxicity.2,119,154,155 Timely detection of
cardiography (ECG). Paclitaxel is well known to induce reversible cardiotoxicity allows initiation of cardioprotective medication such
asymptomatic bradycardias even in patients without pre-existing as renin–angiotensin inhibitors, calcium channel blockers, diuret-
cardiac conditions supposedly related to either a direct effect on the ics, nitrates, and β-blockers at an early stage. Several clinical
cardiac conductive system, on the autonomic control or because of parameters have been identified that can be used for periodic eval-
release of histamines in a hypersensitivity reaction. The reported uation of various aspects of cardiac performance prior to, during,
incidence of paclitaxel-related bradyarrythmias varies greatly in and after therapy. These include physical assessment (i.e., ECG,
the literature from around 0.1% to 30%.136,146 blood pressure, exercise testing), cardiac output measures (i.e.,
Arsenic trioxide has been effectively used in patients with acute systolic and diastolic volume, stroke volume, ejection fraction), bio-
markers, and cellular metabolism imaging. In the last decade,

promyelocytic leukemia. It is known, however, to induce life-
threatening arrhythmias. ECG abnormalities such as QRS widening, these latter two methods have been used more frequently to mon-
ST depression, QT prolongation, torsade de points, atrioventricular itor cardiotoxicity in clinical trials. Cardiac troponin measurements
block, and tachycardia have all been described in the literature. to identify (sub-)acute damage to cardiomyocytes are recom-
Barbey et al.147 described the effects of arsenic trioxide on the con- mended because they are highly specific and highly sensitive for
ductive system in 99 patients. In 68% of the patients, a gradual this purpose.156 Nuclear imaging methods still have a prime role in
prolongation of the QT interval was observed. Two patients devel- both the detection and follow-up of cardiotoxicity (Table 33.2).
oped clinically significant arrhythmias during the study. In general,
QT prolongation is associated with an increased risk of developing
fatal cardiac arrhythmias including torsade de pointes, and sudden
Radionuclide Ventriculography
death. Therefore, appropriate monitoring of ECG abnormalities and Serial assessment of left ventricular function is at present the main
electrolyte disturbances has been advised during arsenic trioxide parameter to diagnose cardiotoxicity during and after anticancer
therapy. treatment especially in anthracycline-based regimes. Several
Targeted kinase inhibitors such as angiogenesis inhibitors and imaging-based techniques can be used to determine ventricular
the ERbB2 inhibitor lapatinib can also cause prolongation of the QT function, of which gated equilibrium radionuclide ventriculography
interval. For the multikinase inhibitors, sunitinib and sorafenib, a (e.g., multiple-gated acquisitions also known as MUGA) is the prime
dose-dependent prolongation of the action potential has been dem- scintigraphic method. The key principle of ventriculography is to
onstrated in a preclinical setting in canines and monkeys. Although image the blood pool over time with either 99mTc-labeled erythro-
in a preclinical setting, QT prolongation has not been demonstrated cytes or human serum albumin (HAS). Though erythrocytes can be
for lapatinib, it has been described in a clinical setting.129 The inci- labeled in vitro and in vivo, each procedure requires the so-called
dence of these side effects in a clinical setting needs to be established. “pretinning.” In this process, stannous pyrophosphate is used to
increase cell-labeling efficiency. Five to ten minutes after tracer
injection, planar images are acquired in a left anterior oblique
Thoracic Radiotherapy (LAO) projection.157 Concordant registration of an ECG signal allows
Although this chapter primarily focuses on the effects of chemo- for the allocation of counts into specific intervals within the cardiac
therapeutics, radiotherapy is a major factor in the “multiple hit” cycle. See Figure 33.1.
theory of cardiotoxicity development in an oncologic setting. The Quantitative analysis of cardiac function entails detection of the
adverse effects of thoracic radiotherapy on the cardiovascular sys- boundaries of the left and the right ventricular blood pool, which
tem have been demonstrated in long-term survivors of breast can- correspond with the endocardial borders. Based on these measures,
cer, esophagus carcinomas, lymphomas, and childhood cancers in a time versus count density curve can be derived that incorporates
which thoracic irradiation has been performed.148–151 In breast information on cardiac function (Fig. 33.2). Determinants of ven-
cancer, and especially left-sided breast cancer, irradiation has tricular function include systolic volume, diastolic volume, filling
shown to increase the prevalence of (acute) myocardial infarction, rates, emptying rates, stroke volume (diastolic volume minus systolic
pericardial diseases, and valvular heart disease. CHF, valvular volume), cardiac output (stroke volume times heart rate), and ejec-
heart disease, and pericardial diseases were frequently observed tion fraction (stroke volume divided by diastolic volume). Commer-
in the population with total fractionated doses >15 Gy. The aggre- cial software systems are available for semiautomated evaluation.
gated incidence of radiation-related cardiac disease is estimated to Normal values for the left ventricular ejection fraction (LVEF)
be 10% to 30% 5- to 10-year posttreatment.2 based on ventriculography range from 55% to 75%, with an LVEF
At therapeutic dosages, cardiotoxicity is mainly related to inflam- less than 50% indicating a lowered cardiac function. A decline
matory and thrombotic alterations in endothelial cells, leading to below 50%, or a drop is LVEF of more than 10% compared to base-
structural abnormalities within the microcirculation. High cardiac line, can be considered cardiac dysfunction.119 Seidman et al.126
dosages (single dose >15 Gy, fractionated dose >40 Gy) may even proposed a criteria to diagnose cardiac dysfunction in trastuzumab
result in acute pericarditis.152 The incidence of these events is pri- studies including (1) CMP characterized by a decline in LVEF (global
marily influenced by concurrent systemic therapies, irradiation tech- or septal), (2) signs or symptoms of CHF, (3) a decline in LVEF of at
nique, fractionation, and presence of pre-existing cardiovascular risk least 5% to less than 55% accompanied with signs or symptoms of
factors (i.e., smoking, reduced physical activity, elevated body mass CHF, or a decline in LVEF of at least 10% to less than 55% without
index, diabetes, hypertension, hyperlipidemia, etc.). Modern irra- symptoms. In general, this scintigraphic measure of LVEF is consid-
diation techniques such as intensity-modulated radiotherapy (IMRT) ered a robust and observer-independent measure although its
and computer-based dose optimization models are thought to result value partly depends on the software system used.157 The duration
in a lower risk of complications, as they can reduce the absorbed of follow-up, especially in patients that are nonsymptomatic, is

Myocardial Perfusion Imaging

Radionuclide myocardial perfusion imaging may also have a role
in the evaluation of drug-induced cardiovascular ischemia and
dysfunction.160–162 Cardiac perfusion can be evaluated by both
SPECT- and PET-based tracers. Since PET, however, involves more
complex imaging procedures, relative higher costs and a limited
8 9 10 number of large multicenter studies prepared to perform perfu-
6 7 sion PET, SPECT imaging is still the predominant technique to
4 5
3 assess cardiac perfusion and function in the clinical setting. SPECT
1 2
has proven to be highly sensitive to detect abnormal myocardial
Summed counts of frame 3 perfusion patterns while also providing information on left ven-
tricular function.165
Currently, the tracers used for myocardial perfusion SPECT
(MPS) are either Thallium-201 (201Tl) or 99mTc based. 201Tl chloride
exchanges between inter- and intracellular space by the Na/K-
pumps of the myocytes. Therefore, accurate timing of especially the
stress images is very important. The compounds 99mTc-tris(1,2
bis(dimethylphosphino)ethane), [99mTc-tetrofosmin], and 99mTc-
R-R interval hexakis-2-methoxy-2-methylpropyl isonitrile, [99mTc-sestamibi],
are both lipophilic cations that passively diffuse across myocyte
Figure 33.1. Principle of electrocardiography gating using 10 intervals or gating frames. cell membrane. Because of their relatively positive charge, they
Based on the time interval between subsequent R-peaks the duration in milliseconds of a single remain trapped in mitochondria of viable myocytes. Because of
frame is determined. The detection of an R-peak, which roughly matches with end-diastole, their widespread availability, shorter half-life, and more favorable
triggers the system to detect counts allocating them to frame one. Subsequently, counts are
allocated to frames two, three, four, and so on until a new R-peak is detected. Eventually, all energy peak of 99mTc, at present, these 99mTc compounds are gener-
counts in frame one over many heart cycles are summed resulting in a single image for frame ally being used as an alternative to 201Tl.166
one. This process is repeated for all frames, creating a set of images at different moments within To provoke an ischemic response in areas with abnormal coro-
the cardiac cycle. nary vasculature, stress is applied to the cardiac system, thus
increasing the overall oxygen demand. In the presence of diseased
coronary vasculature, the augmentation of blood flow is inade-
unclear. Whether the LVEF is the most appropriate measure for quate, resulting in regional ischemia. In the resting state, coronary
the early detection of left ventricular dysfunction is controversial. A blood flow will return to baseline and the supply–demand ratio is
decline in systolic function, and hence LVEF, is considered a late restored. As the distribution and accumulation of perfusion trac-
sign of cardiotoxicity, because of the physiologic capacity of the ers is highly related to the regional coronary blood flow, a differ-
heart to compensate for regional myocardial damage. In the case of ence in uptake patterns after stress and in resting state reveals
type II cardiotoxicity, detection of a reduction in cardiac function areas of ischemia (i.e., reversible defects). Areas that show reduced
requires that actual irreversible damage to the myocardium has tracer uptake in both poststress and rest images (i.e., fixed defects)
already occurred. Markers that focus on specific aspects of cardiac represent infarcted or scarred regions. This difference in stress-
function such as regional contraction patterns and filling or empty- rest blood flow in the presence of coronary artery disease is the
ing rates might provide more specific information.135,158,159 principal value of MPS. See Figure 33.3. All regional abnormalities
8000
Detected counts
EDV ESV
Baseline
7000
6000
5000
4000
3000
Post-trastuzumab
2000
1000
0
0 5 10 15 20 25 30
Frame number
Figure 33.2. Radionuclide ventriculography images of a patient at baseline and after trastuzumab treatment in end-systole (left) and end-diastole (right). The
quantitative evaluation of all frames of the cardiac cycle indicates a decline in left ventricular ejection fraction from 60% at baseline to 47% after the first cycle of
trastuzumab. This decline is primarily explained by an inadequate systolic function, as can be seen in the curve on the graph. EDV, end-diastolic volume; ESV, end-
systolic volume.

Oblique axis MPS images

1 3 5 7 9 11 13 15 17 19
Figure 33.3. Two-dimensional representations Stress

of slices perpendicular through the central axis of
the left ventricle (e.g., oblique views). Arrows indi-
1 3 5 7 9 11 13 15 17 19
cate perfusion defects in the poststress acquisition
(upper), whereas these defects are normal in the Rest
rest acquisition (bottom). This typical distribution
is indicative of ischemic heart disease. MPS, myo-
cardial perfusion SPECT.
in perfusion are defined with respect to the maximal tracer uptake myocardial adrenergic neuron activity is upregulated. Recently, it
in the entire myocardium and not as an absolute measure. Accord- has been postulated that adrenergic denervation precedes signifi-
ingly, each area of diminished uptake should be reported with cant perfusion defects and cardiac dysfunction.170,171 Given that
respect to severity, location, and extent.166 neurons are more sensitive to ischemia than myocytes, microvas-
Relevant variations within MPS protocols have been described cular dysfunction may lead to denervation and eventual ventricu-
in the recent guidelines.166 The basic elements of the protocols lar dysfunction. Accordingly, adrenergic denervation may also be

include stress induction, tracer administration, and acquisition. present in the early stages of chemotherapy- or radiotherapy-
Stress is preferably induced by bicycle or treadmill exercise. When induced cardiotoxicity.
a patient is not able to exercise or hemodynamic response is not A growing number of tracers have come up to assess various
sufficient, the so-called pharmacologic stress can be utilized. At pre- and postsynaptic processes. However, the majority of the PET
peak stress the tracer is injected intravenously. Images are acquired tracers are being used in a research setting. Some (i.e., 11C nor-
30 minutes to 2 hours after tracer injection. The majority of the adrenaline and 11C catecholamine analogs) even require an on-site
MPS studies are acquired using ECG gating to obtain functional cyclotron. At present, 123I-MIBG is the only clinically approved
evaluation of the heart.167 The principles of gating are similar to SPECT radiotracer available to assess adrenergic nerve function.
123
those described for radionuclide ventriculography. I-MIBG resembles the neurotransmitter norepinephrine with
Using specific software systems to delineate the endo- and epi- respect to its molecular structure, synaptic uptake, and intracellular
cardial borders, functional indices can be derived from these storage. Figure 33.4 provides a schematic overview of the kinetics
images. Frequently, an increased specificity of gated MPS is reported of 123I-MIBG in comparison with norepinephrine. An 123I-MIBG
which can be assigned to the more effective characterization of acquisition protocol consists of images obtained within minutes
abnormal perfusion patterns. Areas with moderate-to-severe isch- (early) and several hours after tracer injection (delayed).172 Anterior
emia or areas with infarction will display some degree of regional planar images are acquired to assess global 123I-MIBG uptake and
dysfunction. Consequently, combining visual interpretation of washout (i.e., the difference between early and delayed accumula-
perfusion patterns with functional indices increases the prognostic tion) from the cardiac region in relation to the nonspecific 123I-MIBG
value of MPS.168,169 uptake. To quantify the differences in 123I-MIBG uptake, regions of
interest are placed around the heart and in mediastinum. Early
Evaluation of Myocardial Adrenergic heart-to-mediastinum (HM) ratio reflects the blood flow and initial
uptake of 123I-MIBG by the uptake-1 mechanism (Fig. 33.5), whereas
Innervation the washout rate (WOR) is considered a measure for the integrity
An increase in adrenergic drive is one of the cardiac compensatory and activity of the neurons. Although the regional assessment of
mechanisms to preserve adequate cardiac output by increasing myocardial innervation using SPECT is less established than planar
heart rate, contractility, and conduction. In several cardiovascular imaging, it might be beneficial when innervation is heterogeneously
diseases, the circulating levels of norepinephrine, and hence, affected.
Diffusion
Injected
123
I-MIBG
MAO Metabolization NE Neuron
Ca++ transporter
NE transporter
α2 receptor
Storage in vesicles Vesicle migration
Uptake 1
Figure 33.4. The pathways shared by both norepinephrine (NE) and
123
iodine-123 metaiodobenzylguanidine ( I-MIBG) are shown in black. NE
Uptake 2
is synthesized within postganglionic neurons by a series of enzymatic
steps and eventually stored in vesicles. Once released, NE will interact α1 receptor β1 receptor β2 receptor
with adrenergic receptors, enter the neuron (uptake 1), enter the myo- NE transporter
cytes (uptake 2), or diffuse into the bloodstream. Intravenous-adminis- Metabolization NE
COMT
tered 123I-MIBG disperses through the bloodstream and will enter the Myocyte Diffusion to
neuron by uptake-1 pathway, whereafter it is stored in the vesicles and bloodstream
coreleased with NE after nerve excitement. These processes will result in
a physiologic washout of 123I-MIBG from the neurons over time. COMT, I-MIBG
123
Diffusion
catecholamine O-methyl transferase; MOA, monoamine oxidase. Norepinephrine (NE)

Figure 33.5. Normal early and delayed

iodine-123 metaiodobenzylguanidine (123I-
MIBG) uptake in a patient with diabetes but with-
out any other cardiovascular risk factors. In this
instance early heart-to-mediastinum (HM) ratio
was 1.91 and the delayed HM ratio was 2.18.
Moreover, physiologic uptake of 123I-MIBG can be
seen in the liver, thyroid gland, and lungs. In
severely abnormal 123I-MIBG distributions, the
heart will have an intensity that is visually roughly
similar to the mediastinum, with delayed HM
ratios ranging from 1.2 to 1.6.
Visual heterogeneity in regional 123I-MIBG uptake patterns and for quantification of tracer uptake in various therapies. 89Zr-
lowered HM ratios are associated with several cardiovascular dis- trastuzumab PET imaging has been applied to quantify tracer
eases.173,174 Anthracycline-induced heart failure has also been uptake in various organs, and hence, establish toxicity profiles.184,185
shown to induce abnormalities in adrenergic innervation in vari-
ous small-scale studies.175–177 A decrease in 123I-MIBG uptake is
hypothesized to precede a decline in LVEF, thus providing a method Conclusions
for early detection of cardiotoxicity.
The role of nuclear medicine in the assessment of toxicity caused
by chemotherapy is limited. In lung, liver, renal, and bone marrow,
Future Cardiovascular Tracers biochemical tests are usually used for the identification and follow-
111
In-antimyosin imaging has been used to study the actual degree up of toxicity and metabolic dysfunction of organs. In addition,
of irreversible myocardial damage, whether this is caused by apop- radiologic techniques, such as ultrasonography and HRCT, are
tosis or necrosis, in an early stage. Antimyosin, a myosin antibody, mainly used to differentiate between chemotherapy-induced abnor-
only binds to the intracellular myosin in myocytes if the cell mem- malities and other explanations, such as in lung and liver disorders.
brane is disrupted. Studies on doxorubicin-induced toxicity shows In chemotherapy-induced cardiotoxicity, the role of nuclear medi-
that antimyosin accumulation relates to the degree of damage. It cine is established. In this respect, regular measurements of the
precedes deterioration in cardiac function measured by ventricu- LVEF are used to monitor cardiotoxic chemotherapy guiding the
lography.176,178 After discontinuation of anthracycline therapy, anti- clinician in the proper direction. Although myocardial MIBG scintig-
myosin uptake remained abnormal for a number of years, raphy can be used for prognostic stratification in patients with a
supporting the hypothesis that type 1 cardiotoxicity develops as a persistent decreased LVEF, it is still not a common clinical practice.
progressive disease over time.
123
I-BMIPP (β-methyl-iodophenylpentadecanoic acid) is a fatty
acid analog that is used to image the degree of myocardial fatty Future Directions
acid metabolism. In general, an impaired uptake is highly sugges-
tive of regional myocardial dysfunction, even when wall function The future role of nuclear medicine in the assessment of toxicity is
and perfusion seem normal. Saito et al. found that 50% of the unclear. As biochemical tests are inexpensive and readily available
patients on a taxane–carboplatin combination treatment exhibited alternatives, the role of nuclear medicine will remain limited in
reduced fatty acid metabolism. Other studies in patients undergo- monitoring chemotherapy. However, as survival rates increase in
ing thoracic radiation and doxorubicin therapies also suggested a oncology, chemotherapy-induced long-term side effects and organ
relation between a reduction in fatty acid metabolism and cardio- failure will become more and more important issues to be assessed
toxicity.179,180 at an early stage. MIBG is an important tracer for prognostic strat-
111
In-trastuzumab, (111In-DTPA anhydride—trastuzumab), tar- ification in cardiology; other tracers may become available to eval-
gets the HER2 receptor. Several other radiolabeled antibodies uate lung, liver, and renal toxicity. The focus of research, however,
directed against the ErbB pathway have been described in the past. is not in this direction. With the development of new tracers, it may
Trastuzumab was the first clinically available in vivo imaging become a useful component of nuclear oncology practice.
tracer.181 It has been primarily used to evaluate receptor expres-
sion in tumors and assess the possibilities of radionuclide therapy
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P a r t I V
Investigative Methods for Studying

Tumor Biology and Microenvironment
Chapter 34
Radionuclide Imaging of Multidrug Resistance

Sabina Dizdarevic • A. Michael Peters
Introduction such as anticancer agents and toxins.7 Many tissues express P-gp
physiologically (Fig. 34.1),8,9 including the bronchopulmonary epi-
Treatment of patients with malignant tumors using a variety of che- thelium, hepatobiliary epithelium, renal tubular epithelium, GI
motherapeutic agents is sometimes rendered inadequate because tract, blood–brain barrier, and choroid plexus. P-gp in the apical
of the activation of a cellular biochemical mechanism that results in border of fetus-derived epithelial cells faces the maternal circula-
resistance to drugs to which the tumor had previously been sen- tion and is therefore optimally placed to protect the fetus against
sitive. Noninvasive imaging techniques have been developed that toxins.10 These tissues share the common property of a strategic
can identify this source of resistance to chemotherapeutic agents. location where they protect against the passage of xenobiotics.
Resistance of tumor cells to several structurally unrelated classes The differential expression of P-gp in many tissues, including cells
of natural products and drugs, including anthracyclines, taxanes, of the hematopoietic system, natural killer cells, antigen-presenting
and epipodophyllotoxins, is often referred as multidrug resistance dendritic cells, human peripheral blood mononuclear cells (PBMCs),
(MDR).1 and subpopulations of T and B lymphocytes, implies diverse
In tumor cell lines, MDR is associated with an ATP-dependent physiologic and pharmacologic roles.10,11
decrease in cellular drug accumulation attributable to overex-
pression of ATP-binding cassette (ABC) transporter proteins.
ABC transporters belong to the largest transporter gene family
and generally use energy derived from ATP hydrolysis for
translocation of different substrates across biologic membranes.
ABC transporters are classified into seven subfamilies based
on phylogenetic analysis and designated as ABCA to ABCG.2
ABC proteins that confer drug resistance include P-glycoprotein
(P-gp) (gene symbol ABCB1), the multidrug resistance protein 1
(MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2),
and breast cancer resistance protein (BCRP, gene symbol
ABCG2).
In addition to their role in drug resistance, there is compelling
evidence that in tissue defense, these efflux pumps have overlap-
ping physiologic functions. Collectively, they are capable of trans-
porting a large and chemically diverse range of toxins, including
bulky lipophilic cationic, anionic, and neutrally charged molecules
and many drugs in routine clinical use, as well as conjugated
organic anions, that encompass dietary and environmental car-
cinogens, pesticides, metals, metalloids, and lipid peroxidation
products.3
Single-nucleotide polymorphisms (SNPs) in ABC drug efflux
pumps may play a role in response to drug therapy and disease
susceptibility. The effects of various genotypes and haplotypes
(combinations of SNPs) on the expression and function of these
proteins are not yet entirely clear.4 The ABCB1 multidrug resistance
gene 1 (mdr1) encodes P-gp, a 170-kDa plasma membrane protein
that serves as an energy-dependent adenosine-5′-triphosphate Figure 34.1. Direction of substrate transport by P-glycoprotein (P-gp) located in various
organs of the human body. The solid arrows indicate the known direction of transport, whereas
(ATP) efflux pump.5 It has been termed a molecular “hydrophobic the dashed arrow indicates unclear direction of transport. P-gp is located in the lipid bilayer
vacuum cleaner” because it extracts substrates from the membrane (thick black line) that forms a barrier between various organs; red indicates vasculature, blue
and expels them to promote MDR.5,6 represents tissue, green represents tumor and white indicates excreta. CSF, cerebrospinal
fluid; MDR, multidrug resistance. (Modified from Szakács G, Paterson JK, Ludwig JA, et al.
By protecting tissues from toxic xenobiotics and endogenous
Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–234; Used in Kan-
metabolites, P-gp fulfils an important physiologic role. It also reg- nan P, John C, Zoghbi S, et al. Imaging the function of P-glycoprotein with radiotracers: Phar-
ulates the transport of various structurally unrelated substrates, macokinetics and in vivo applications. Clin Pharmacol Ther. 2009;86(4):368–377.)
530

Chapter 34 Radionuclide Imaging of Multidrug Resistance 531
Figure 34.2. Genetically determined P-glycoprotein (P-gp) expression:

Polymorphism in exon 26 at C3435T (silent polymorphism) influences the P-gp
expression. The C/C, T/C, and T/T genotypes are associated with increased,
intermediate, and low P-gp expression, respectively. High P-gp expressors
(C3435C/C) are linked to MDR. Low P-gp expressors (C3435T/T) are prone to
drug toxicity. SNP, single-nucleotide polymorphism.
A Role of MDR1 as a Modulator of of MDR1 makes cancer cells refractory to treatment with agents
that are P-gp substrates.
Health and Disease: Genetically The functional significance of MDR1 C3435T polymorphism
Determined Differences in with respect to imatinib treatment was studied in terms of hema-
PART IV • Investigative Methods for Studying

tologic and cytogenetic response. The frequency of the C/C genotype
P-Glycoprotein Expression was significantly increased in poor cytogenetic responders to an

extent that was inversely proportional to the degree of cytogenetic
The inter-individual variability of P-gp expression is linked to C3435T response. As a result of MDR, the C/C genotype is also associated
polymorphism of the human mdr1 gene which is located on the long with poor prognosis in ALL and AML.7,14
arm of seventh chromosome at q21.1 band position. It plays a sig- The effects of ABCB1 polymorphism on the handling of drugs
nificant role in ADME processes (absorption, distribution, metabo- that are P-gp substrates have also been shown to vary among
lism, and excretion) and drug–drug interactions. Variations in the races.16 Racial variability within C3434T has been demonstrated.
mdr1 gene product can directly affect therapeutic effectiveness, with Thus, there is a significantly higher frequency of the C/C genotype
overexpression of P-gp resulting in increased efflux of anticancer in West Africans and African Americans (83% and 61%, respec-
drugs and development of drug resistance. The mdr1 gene is highly tively17), compared to Caucasians (17.5%12 to 26%; p < 0.000117).
polymorphic and numerous SNPs have been identified, some of This could affect treatment with drugs that are P-gp substrates
which influence MDR1 expression levels.7 Polymorphism in exon (such as HIV-1 protease inhibitors and ciclosporine) and antican-
26 at C3435T (silent polymorphism) also influences the P-gp expres- cer drugs in African populations17 in whom there is a higher
sion. The C/C, T/C, and T/T genotypes are associated with increased, prevalence of the relevant diseases. The development of MDR not
intermediate, and low P-gp expression, respectively (Fig. 34.2).7,12 only reflects multiple genetic and epigenetic changes in cells
In the analysis of MDR1 variant genotype distribution in a large under cytotoxic conditions, but is also a normal physiologic
sample of Caucasian subjects, Cascorbi et al.13 demonstrated that response displayed by cells in their struggle to survive. The chal-
C3435T occurred in 53.9% of subjects heterozygously (T/C), whereas lenge of translating the concept of MDR modulation in vivo
28.6% of individuals were homozygous (T/T) carriers and 17.5% of involves a complex cellular interplay between both malignant and
the individuals were homozygous (C/C) carriers. In general, the prev- normal cells.18
alence of the T/T genotype in Caucasian individuals has been shown
to be between 24% and 29%.12,13
T/T Genotype: Link with Drug

In Vivo Imaging of ABC Transporters
Toxicity and Susceptibility to in Multidrug Resistance
P-Glycoprotein–Mediated Disease MDR and specific ABC transporters may be imaged with radiophar-
C3435T/T polymorphism is associated with low P-gp expression, and maceuticals that are MDR substrates or inhibitors. The most
hence lower protection against specific P-gp–dependent xenobiotics studied of these, and the first to be used, is 99mTc-sestamibi (hexakis-
and carcinogens and with a reduced efficiency to eliminate toxins. This methoxy-isobutyl isonitrile; MIBI), which is a substrate for P-gp,
results in higher intracellular concentrations of mutagens or toxins MRP1, MRP2, and BCRP and can therefore be used to image their
and thereby leads to DNA damage and accumulation of mutations. expression in vivo.19 99mTc-tetrofosmin and several other 99mTc-Q
This reduced capacity of detoxification may have implications for dis- complexes that are closely related to MIBI with respect to their
ease risk and therapeutic outcomes arising from the development of clinical applications are also transport substrates for P-gp and
drug toxicity. Thus, T/T individuals were found to be at increased risk MRP.1 Although tetrofosmin and MIBI do not have identical physi-
of chronic myeloid leukemia (CML),7 acute childhood lymphoblastic ologic properties, the available data suggest that the clinical imag-
leukemia (ALL),14 renal epithelial tumors,15 colorectal cancer, glioblas- ing and in vivo modulation of MDR function can be performed with
toma, breast cancer,7 and inflammatory bowel disease.12 either tetrofosmin or MIBI.20 Recent studies using the positron emit-
With respect to gender, the T/T genotype is more frequent in males. ter, 94Tc-MIBI and parallel previous studies with 99mTc-MIBI show
Tumor development in response to exposure to carcinogens was found essentially identical performance, thereby providing validation for
to be higher in males compared to females. The association with gen- micro-positron emission tomography (micro-PET).21
der is illustrated by male glioblastoma in relation to T/T genotype as Several 11C-labeled P-gp–avid radioligands developed for PET,
well as a greater risk of developing CML in males.7 including 11C-colchicine, 11C-verapamil, 11C-daunorubicin, 11C-paclitaxel,
and 11C-loperamide, have been evaluated in animals, but only 11C-vera-
C/C Genotype: Link with Multidrug pamil and 11C-loperamide22 have been extended to humans to investi-
gate MDR and quantify P-gp expression in the blood–brain barrier
Resistance and Poor-Risk Prognosis (Fig. 34.3).8,22 Other compounds that have been developed include
Increased C/C genotype is associated with MDR and therefore (67/68Ga-[3-ethoxy-ENBDMPI])(+) tracers (Fig. 34.4),23 4-18F-fluoropacl-
with poor disease prognosis. In cancer therapy, a high expression itaxel,24 and the positron-labeled P-gp inhibitor, 11C-tariquidar.25

532 Part IV Investigative Methods for Studying Tumor Biology and Microenvironment
A B C D
Figure 34.3. T1-weighted MR image (A) from representative subject and corresponding T2-weighted MR image (B) provide anatomic reference. C: 11C-verapamil
uptake image (SUV) before CsA treatment was acquired between 5 and 25 minutes after injection. D: 11C-verapamil uptake image after 1 hour of CsA infusion shows
general increase in verapamil uptake in all areas of brain after inhibition of P-gp by CsA. Color scale reflects SUV as shown by thermometer. (Reprinted with permission
from the Society of Nuclear Medicine from Muzi M, Mankoff D, Link J, et al. Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-Verapamil in the
brain: Studies of healthy humans. J Nucl Med. 2009;50:1267–1275. Figure 5.)
99m
Although many studies are currently focusing on functional Technetium-Sestamibi (MIBI) as an In Vivo
imaging of P-gp, other ABC drug transporters have also attracted Assay of ABC Transporters
interest. Thus, 99mTc-HIDA is transported only by MRP1, 2. Hepatic
99m
P-gp and MRP1, 2 could therefore be assessed by sequential use Technetium-MIBI is a lipophilic cationic radiotracer originally
of both MIBI and HIDA. Leukotrienes are substrates for MRP, so introduced for imaging myocardial perfusion. Chemical analysis
N-11C-acetyl-leukotriene E4 could possibly be used to noninvasively reveals a stable monovalent cation with a central Tc(I) core sur-
image MRP function.1 rounded by six identical MIBI ligands, coordinated through the
The above imaging techniques, tracers, and their relation to rel- isonitrile carbons in an octahedral geometry.6
99m
evant ABC substrates and genotypes are summarized in Table 34.1. Tc-MIBI is taken up by passive diffusion into cytoplasm and
accumulates in mitochondria. Following intravenous injection, the
tissue uptake is broadly dependent on tissue blood flow and cel-
lularity. Cellular transport of 99mTc-MIBI is affected by apoptosis, cell
proliferation, and angiogenesis. 99mTc-MIBI is therefore used to
image cellular metabolism in tumors.26,27 Tissue retention is vari-
able and markedly influenced by tissue expression of P-gp.6,28,29 The
mechanism of MIBI cellular uptake is clearly different from the
mechanism of elimination, which specifically reflects activity of drug
transporters, such as P-gp.
MIBI has been validated as a transport substrate for P-gp in cul-
tured MDR rodent29,30 and human tumor cells,31,6 as well as in cells
overexpressing the recombinant human mdr1 gene.32 Piwnica-
Worms et al.6 first demonstrated that 99mTc-MIBI is a substrate of
P-gp and that it can be used as a functional imaging agent for P-gp
in tumor xenografts in nude mice. They and others have shown that
tumor retention of 99mTc-MIBI correlates inversely with the degree of
P-gp expression and can be modified in vitro by P-gp antagonists.33
In rodent models, tumors that express P-gp eliminate 99mTc-MIBI
faster than those that do not.29,31 The hepatic and renal excretion
pathways of 99mTc-MIBI are mediated by P-gp and can be modu-
lated in humans following administration of cytotoxic drugs. Thus,
intravenous administration of a P-gp modulator delayed excretion
of MIBI from the liver and kidney in patients investigated for
MDR.34 In vitro MIBI studies have shown that P-gp inhibitors, such
as verapamil and ciclosporin, can reverse P-gp expression in ade-
nocarcinoma cells if given shortly before the administration of a
cytotoxic drug.35
Additional mechanisms of cell resistance, mainly involving alter-
ations of apoptosis, may also affect 99mTc-MIBI uptake in tumors. In
Figure 34.4. Micro-PET image of 68Ga-complex 1b in brains of FVB WT and mdr1a/1b (_/_) particular, overexpression of the antiapoptotic protein, Bcl-2, pre-
mice. After injection of mice with an intravenous bolus of radiopharmaceutical, images of abdo-
men, thorax, and head were obtained with micro-PET scanner. Representative coronal images vents tumor cells entering apoptosis and inhibits 99mTc-MIBI accu-
of WT (left) and mdr1a/1b (_/_) (right) mice obtained 5 minutes after injection are shown. mulation in mitochondria. So, although absent or reduced early
A body outline is included for orientation. (Reprinted with permission from the Society of Nuclear tracer uptake in breast carcinomas reflects the existence of a defec-
Medicine from Sharma V, Prior J, Belinsky M, et al. Characterization of a 67Ga/68Ga radio-
tive apoptotic program, an enhanced tracer clearance in 99mTc-MIBI–
pharmaceutical for SPECT and PET of MDR1 P-glycoprotein transport activity in vivo: Validation
in multidrug-resistant tumors and at the blood–brain barrier. J Nucl Med. 2005;46:354–364. positive lesions reflects the activity of drug transporters, such as
Figure 7.) P-gp. The existence of two different mechanisms underlying the

Tabl e 3 4 . 1
Spect and Pet ABC Substrates (S) and Inhibitors (I) and Their Relationships to Genes
Imaging Modality Radiopharmaceuticals ABC Transporter Gene Symbol

99m
SPECT Tc-MIBI (s) P-gp ABCB1 (mdr1)
MRP1,2 ABCC1,2
BCRP ABCG2
99m
Tc-tetrofosmin(s) P-gp ABCB1 (mdr1)
MRP1,2 ABCC1,2
99m
Tc-HIDA (s) MRP1,2 ABCC1,2
67
Ga-[3-ethoxy-ENBDMPI] (s) P-gp ABCB1 (mdr1)
MRP1 ABCC1
PET and micro-PET (μ) 94m
Tc-MIBI (s, μ) P-gp ABCB1 (mdr1)
MRP1,2 ABCC1,2
BCRP ABCG2
11
C-colchicines (i, μ) P-gp ABCB1 (mdr1)
11
C-verapamil (i) P-gp ABCB1 (mdr1)

11
C-loperamide (i) P-gp ABCB1 (mdr1)
11
C-paclitaxel (i, μ) P-gp ABCB1 (mdr1)

11
C-daunorubicin (i, μ) P-gp ABCB1 (mdr1)
4-18F-fluoropaclitaxel (i, μ) P-gp ABCB1 (mdr1)
11
C-tariquidar (i, μ) P-gp ABCB1 (mdr1)
68
Ga-[3-ethoxy-ENBDMPI] (s) P-gp ABCB1 (mdr1)
MRP1 ABCC1
N-11C-acetyl-leukotriene E4 (s) MRP2 ABCC2
predictive role of 99mTc-MIBI scan may be important to establish 99m

Tc-MIBI has also been used to image MDR in lung cancer,39
whether individual patients may benefit from P-gp inhibitors or brain tumors,40,41 gastric cancer,42 head and neck cancer,43 hepa-
Bcl-2 antagonists.36 tobiliary cancer,44 and hematologic malignancies.45
It has been demonstrated that preoperative washout rates of In lung cancer, the sensitivity, specificity, and accuracy of
99m 99m
Tc-MIBI from primary breast tumors correlated with levels of Tc-MIBI to identify responders to chemotherapy are 94%,
P-gp semiquantified by immunohistochemistry in the surgically 90%, and 92%, respectively.39 There is evolving evidence that
99m
resected specimens (Fig. 34.5). Tc-MIBI is cost-effective in predicting the response to chemo-
Imaging in patients with breast cancer demonstrated that therapy in patients with lung cancer39 and also for diagnosing
99m
Tc-MIBI washout rates from cancers overexpressing P-gp are breast cancer in patients with indeterminate mammography and
threefold faster than those from cancers not expressing P-gp.37,38 dense breasts.46
Early Late
Early Late
Figure 34.5. Images of breast cancer obtained 20 minutes (early) and

120 minutes (late) after injection of 99mTc-MIBI. A: A patient with tumor dis-
playing immunohistochemically negative P-gp expression showing tumor/
background (T/B) that increased from 1.65 to 1.99 between early and late
images. B: A patient with tumor displaying strongly positive P-gp expression
showing T/B that decreased from 2.25 to 1.52 between early and late images.
(Reprinted with permission from the Society of Nuclear Medicine from
Mubashar M, Harrington KJ, Chaudhary KS, et al. 99mTc-Sestamibi imaging in
the assessment of toremifene as a modulator of multidrug resistance in
patients with breast cancer. J Nucl Med. 2002;43(4):519–525.) B

In thyroid imaging, 99mTc-MIBI scintigraphy can be used to reli- P-gp had a mean progression-free survival of 19 months when
ably exclude thyroid cancer when ultrasound-guided fine-needle treated with chemotherapy, whereas in those expressing the
aspiration cytology (US-FNAC) is nondiagnostic thus avoiding more G1199A polymorphism, corresponding survival was only 2 months.8
invasive surgery and costs.47 It has, however, only recently been Other studies have shown a relation with C3435T polymorphism.
demonstrated that semiquantitative 99mTc-MIBI scintigraphy may All the factors mentioned above may influence imaging outcome in
preoperatively predict the malignant behavior of nononcocytic an individual patient, leading to controversial results, and so func-
follicular thyroid nodules indeterminate at fine-needle aspiration tional imaging of MDR remains under-utilized in clinical practice.
biopsy. Moreover, a good correlation was found between immuno-
histochemical apical expression of MRP1 and 99mTc-MIBI scintigra-
phy. A negative MIBI retention index correlated strongly with those Future Considerations
cases with high MRP1 expression. 99mTc-MIBI scintigraphy, there-
fore may provide information on the molecular expression of MRP1 Clinical trials better tailored to tumor types, genetic polymorphism,
in thyroid.48 and adequate dosing regimens need to be conducted because imag-
A potential role for 99mTc-MIBI scintigraphy has been investi- ing may be useful for selecting patients whose cancers express
gated in the management of hematologic malignancies, particularly MDR primarily through ABC-mediated mechanisms. For a proper
multiple myeloma (MM), in which it has been shown that the rate assessment of P-gp levels in tumors, patients should undergo two
of MIBI elimination can predict response to chemotherapy. Patients scans with a P-gp radioligand: At baseline and again after P-gp
showing disease progression at restaging had higher elimination inhibition. Patients whose tumors show enhanced uptake of the
rates (19.3 ± 9.8% versus 12.8 ± 6.9%, p < 0.05) than patients in radioligand following P-gp blockade would be suitable candidates
remission. Disease-free survival was significantly longer in patients for P-gp inhibitor trials (Fig. 34.6).8,51
with lower elimination rates. When patients treated with melphalan
were excluded from the analysis, 87.5% of patients in remission
had slow elimination.49 Before After
In general and in relation to a range of malignancies, patients XR9576 XR9576
whose tumors showed MIBI uptake responded well to chemother-
apy, whereas those whose tumors showed little or no uptake or a
rapid rate of MIBI washout did not respond well.8
Genetically determined responses to some anticancer drugs may
also influence anticancer treatment. It has been shown that imag-
ing the liver with 99mTc-MIBI may provide pretreatment indicators
of ABCB1-mediated hepatic drug clearance in cancer patients. MIBI
hepatic elimination (kH) was significantly reduced in patients with
SNPs in exons 21 and 26. The mean MIBI kH was respectively
1.90 times and 2.21 times higher in subjects homozygous for the
A (3)
wild-type alleles compared to those homozygous for these SNPs.50
History of ABC Drug Transporters and Imaging

Based on the premise that blockade of ATP-dependent drug efflux
pumps will enhance the effect of chemotherapy, there has been an
intense search for compounds able to reverse MDR in cultured
cells, animal models, and patients. There have been many attempts
to image these pumps using both single photon emission tomogra-
phy (SPECT) and PET tracers.39 However, administration of P-gp or
MRP1 modulators has failed to show any significant clinical benefit
in patient outcome, mainly because of toxicity (first generation) or B (5)
interaction with anticancer drugs and alteration in pharmacoki-
netics of the chemotherapy agents (second generation). These MDR
tracers have not, therefore, found routine clinical use.
Promising clinical trials have been conducted in acute myeloid
leukemia, breast cancer, and non-Hodgkin lymphoma, all of which
are known to express P-gp. Paradoxically, several studies focused
on MDR reversal in cancers in which resistance may not be P-gp
mediated. Several clinical trials, including the phase III trials of
tariquidar, not surprisingly yielded negative results in cancers in
which P-gp expression is generally low, such as small-cell lung can-
cer and non–small-cell lung cancer.8 Poor study design, regarding
either dosing regimens or patient selection, and genetic polymor- C (10)
phism of P-gp were further major reasons for negative results in
clinical trials using third-generation P-gp modulators. The two Figure 34.6. 99mTc-sestamibi images at baseline and after administration of XR95767 for
major phase III trials of tariquidar in patients with non–small-cell patients 3, 5, and 10. Patient numbers are shown in parentheses. A: Arrow identifies a left thigh
mass that had gone undetected until the whole-body 99mTc-sestamibi scan was performed (patient
lung cancer were terminated prematurely because of toxicity as a
3, renal cell carcinoma, 263% increase in tumor: Heart AUC 0- to 3-hour ratio). B: Arrow indicates
result of higher doses of chemotherapy than recommended. Fur- a soft tissue mass invading the iliac bone (patient 5, renal cell carcinoma, 18% increase in tumor:
thermore, the prevalence of various genetic polymorphisms of P-gp Heart AUC 0- to 3-hour ratio). C: Arrows indicate numerous bilateral lung metastases that are all
may have influenced results (both negatively and positively). Some more readily visualized after the administration of XR9576 (patient 10, adrenocortical carcinoma,
76% to 191% increase in tumor: Heart AUC 0- to 3-hour ratios. (Reprinted with permission from
SNPs and haplotypes of the mdr1 gene have been shown to alter
the American Association for Cancer Research: Agrawal M, Abraham J, Balis FM, et al. Increased
P-gp expression and activity both in vitro and in vivo. For example, 99mTc-Sestamibi accumulation in normal liver and drug-resistant tumors after the administration
patients with ovarian cancer who express the wild-type allele for of the glycoprotein inhibitor, XR9576. Clin Cancer Res. 2003;9:650–656.)

Two studies using 99mTc-sestamibi following administration of for the mdr1 gene may be associated with altered oral bioavailabil-
tariquidar or valspodar have shown the utility of this approach. ity of MDR1 substrates, drug resistance, and a susceptibility to
Another ongoing study is using MIBI to monitor progress through- some human diseases. The challenge of translating the concept of
out the trial.8 MDR modulation in vivo involves a complex cellular interplay
Prolonged exposure of cells to P-gp inhibitors may cause phys- between both malignant and normal cells. Integration and correla-
iologic upregulation of P-gp.52 As many inhibitors are also modu- tion of functional SPECT or PET imaging findings with mdr1 gen-
lators, initial downregulation may be followed by upregulation, otype and clinical data may contribute to efficient management by
resulting in acquired drug resistance to P-gp inhibitors. Func- selecting cancer patients with the appropriate molecular phenotype
tional imaging may be used to monitor physiologic prolonged P-gp for maximal individual therapeutic benefit, as well as those who are
response to P-gp inhibitors, in addition to an acute response. nonresponders. A role for functional imaging of classical mecha-
Ongoing research has led to the development of a third genera- nisms of MDR with an emphasis on readily available 99mTc-MIBI
tion of MDR modulators, some of which have demonstrated encour- scintigraphy has been described. MIBI scintigraphy has been shown
aging results compared with earlier modulators. They are less toxic, to be a noninvasive cost-effective in vivo assay of ABC transporters
more P-gp specific, and do not affect the pharmacokinetics of anti- associated with MDR in cancer, including P-gp, multidrug-resistant
cancer drugs. Some MDR-reversing strategies aim to destroy protein 1 (MRP1) and breast cancer resistance protein (BCRP).
mRNAs for ABC drug transporters, inhibit transcription of ABC Functional imaging can investigate a relationship between genetic
transporter genes, or block ABC transporter activity using monoclo- polymorphisms of P-gp and its function in vivo. Individualized
nal antibodies. There is an optimistic view that much more can be treatment could be provided to cancer patients because MDR levels

achieved in developing agents for reversing ABC transporters.53 It in tumors could be determined before or during chemotherapy
is therefore likely that with the development of more potent P-gp treatment by radionuclide imaging of ABC protein transporters.

inhibitors, effective imaging agents that are analogs of ABC trans- New imaging agents for molecular targets such as VEGF and
porters will emerge. HER2 receptors may potentially be combined with MDR imaging
In the post-genomic era of individualized medicine, ABC imag- substrates to more accurately predict the therapeutic response to
ing may be helpful to adjust the treatment dose in individual anticancer drugs, guiding individualized treatment while minimiz-
patients. More research is needed to identify patients, through ing the health economic cost of ineffective therapy in an era of
imaging, who are susceptible to drug toxicity side effects, to provide personalized medicine.
information concerning dose adjustment, and to allow better deci-
sion making when considering therapy with anticancer drugs that
are ABC transporter substrates. References
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C h apt e r 3 5
Radionuclide Imaging of Tumor Hypoxia and Its

Clinical Implications
Gang Niu • Xiaoyuan Chen
Introduction the influence of other hypoxic-related biologic phenomena may

happen at hypoxia levels that are less severe and in the range of
Hypoxia is a pathologic condition in which tissues lack oxygen 5 to 20 mm Hg.8
required for normal cell metabolism. In tumors, hypoxia occurs Hypoxia-induced expression of certain genes may also result in
when the size of a tumor results in an imbalance between oxygen a drug-resistant phenotype by expansion of populations of cells
supply and consumption. In locally advanced solid tumors, the O2 with altered biochemical pathways.9 For example, hypoxia is selec-
consumption rate of neoplastic (as well as stromal) cells may out- tive for cells that have lost sensitivity to p53-mediated apoptosis
weigh a restricted oxygen supply and result in the development of and for cells that are deficient in DNA mismatch repair, which may,
tissue areas with very low O2 levels. After several decades of pre- in turn, be resistant to platinum-based chemotherapeutic agents.10,11
clinical and clinical investigations, there is now a consensus that Transient hypoxia has been reported to cause amplification and

the prevalence of hypoxic tissue areas (i.e., areas with O2 tensions increased expression of the genes encoding P-glycoprotein and
[pO2 values] ≤ 2.5 mm Hg) is a characteristic of locally advanced dihydrofolate reductase, which induce drug resistance to substrates

solid tumors and a relevant pathophysiologic feature. Accumulating of P-glycoprotein and to folate antagonists, respectively.12 Transient
evidence has shown that up to 50% to 60% of locally advanced solid hypoxia associated with glucose deprivation can also disrupt protein
tumors may exhibit hypoxic and/or anoxic tissue areas that are het- folding in the endoplasmic reticulum, which may confer resistance
erogeneously distributed within the tumor mass.1 Variability in oxy- to topo-isomerase II–targeted drugs and enhance P-glycoprotein
genation among tumor sites is greater than intratumor variability. expression and multidrug resistance.13 In the presence of oxygen,
Local recurrences have a higher hypoxic fraction than the primary many anticancer drugs generate free radicals that damage DNA.
tumor. However, there is no clear-cut difference in the oxygenation These drugs accept electrons from biologic sources and then trans-
status between primary and metastatic malignancies.1 fer the electrons to oxygen.14 For example, doxorubicin undergoes
Hypoxia in solid tumors is mainly caused by rapid proliferation chemical reduction to a semiquinone radical, which in turn reduces
and severe structural and functional vascular abnormalities.2 It has oxygen to a superoxide that may contribute to cytotoxicity.15 Thus,
been found that intratumoral vessels have significant structural at low oxygen concentrations, the cytotoxicity of drugs whose activ-
abnormalities. They are dilated, saccular, tortuous, and heteroge- ity is mediated by free radicals is decreased.16
neous in their spatial distribution3 which contributes to perfusion- Consequently, hypoxia represents a compelling therapeutic
limited O2 delivery. This type of hypoxia is also called “acute hypoxia” target.17 The currently developed small molecule drugs to kill hypoxic
because it is usually transient. Hypoxia in tumors can also be caused cells include bioreductive prodrugs that are activated selectively
by an increase in diffusion distances which is termed “diffusion- under hypoxic conditions and drugs that inhibit molecular targets in
limited hypoxia,” also known as “chronic hypoxia.”1 In addition to hypoxic cells. The former category mainly is comprised of five differ-
enlarged diffusion distances, adverse diffusion geometry can also ent chemical moieties, including nitro groups, quinones, aromatic
cause hypoxia. Tumor-associated or therapy-induced anemia can N-oxides, aliphatic N-oxides, and transition metals. The compounds
contribute to the development of hypoxia, known as “anemic have the potential to be metabolized by enzymatic reduction under
hypoxia.” This type of hypoxia is particularly relevant in tumors or hypoxic conditions, and thus provide the basis for the design of bio-
tumor areas exhibiting low perfusion rates.4 reductive prodrugs to exploit tumor hypoxia.18 On the other hand,
Cells exposed to hypoxia respond by reducing their overall pro- the identification of molecular mechanisms that mediate cellular
tein synthesis which in turn leads to restrained proliferation and responses to hypoxia has stimulated interest in targets that might
subsequent cell death. Sustained hypoxia can also change the cell compromise the survival of hypoxic cells if inhibited. The two main
cycle distribution and the relative number of quiescent cells leading oxygen-responsive signaling pathways that mediate adaptation to
to alterations in response to radiation and many drugs. Hypoxia ini- hypoxia are centered on the hypoxia-inducible factor (HIF) family of
tiates both p53-dependent and p53-independent apoptosis path- transcription factors19 and the unfolded protein response (UPR).20
ways including those involving genes of the BCL-2 family. At the In view of the major role hypoxia plays in tumor development
same time, hypoxia-induced proteome and/or genome changes may and resistance to therapy, the ability to detect hypoxia within
promote tumor progression via mechanisms enabling cells to over- tumors has significant implications for cancer management and
come nutritive deprivation, to escape from the hostile environment, therapy. Currently, the gold standard for in vivo measurement of
and to favor unrestricted growth. Sustained hypoxia may also lead to tumor oxygenation is the Eppendorf needle electrode system,
cellular changes resulting in a more clinically aggressive phenotype.5 which allows for direct measurement of pO2 in tumors. However,
In 1953, Gray et al.6 first demonstrated that the presence of it is an invasive procedure that often requires ultrasound-guided
hypoxic cells in solid tumors was associated with treatment failure placement of the electrode. Its use, therefore, is limited to easily
following radiotherapy. Later on, it has been demonstrated that accessible tumors. Thus, evaluation of hypoxia in the clinic is
hypoxic cell radioresistance is a result of lack of oxygen in the shifting to monitoring endogenous markers, especially the tran-
radiochemical process by which ionizing radiation is known to scriptional targets of the HIFs, and exogenous 2-nitroimidazole
interact with cells.7 The magnitude of this effect is well described probes, such as pimonidazole, that bind covalently to SH-containing
by the oxygen enhancement ratio (OER), which is typically in the molecules (thiols) in hypoxic tissue.21,22 These differences in oxygen
order of 2.7 to 3. The phenomenon is most clearly seen after large concentration have important implications for hypoxic cell target-
single doses of radiation but also exists in fractionated radiother- ing as well as differences in the spatial distribution, duration of
apy. It is often observed in solid tumors, whereas normal tissues hypoxia, and the genetic and environmental context in which
tend to have sufficient oxygen to sustain radiation sensitivity. The hypoxia occurs. In particular, these factors will dictate the choice
level of hypoxia that results in radioresistance is 5 mm Hg or less, of hypoxia-targeted therapy that best complements existing agents
which is at the more extreme end of the hypoxic scale, whereas used to treat the nonhypoxic tumor cell population.17 However, the
537

understanding of tumor hypoxia and physiologic hypoxia in some measurement or indirect measurement of tumor oxygenation.
normal tissues is far from complete. This chapter summarizes the Most of these techniques are still immature for clinical application.
noninvasive imaging of hypoxia and the potential clinical applications. For example, electron paramagnetic resonance (EPR) spectroscopy
uses the spin of unpaired electron species to obtain images and
spectra. It is now being evaluated in animals to provide a quantita-
Invasive Measurement of Hypoxia tive measure of oxygenation in tissues.39 Although this method has
a lot of potential to be developed as a tumor oximeter, particularly
A variety of techniques are being proposed to assess hypoxia and to monitor changes after tumor oxygenation,40 development of a
the apparent extent of hypoxia in human tumors. These methods suitable paramagnetic marker that has low toxicity for human is
can be broadly categorized into direct measurements and indirect currently unavailable. The lack of appropriate EPR instrumenta-
measurements according to different principles and ability to quan- tion in the clinic also prevents widespread implementation of this
tify tissue oxygenation. Direct measurements, including polaro- otherwise promising technique.41
graphic needle electrode, phosphorescence imaging, near-infrared Tumor vascular pO2 can also be measured by phosphorescence
spectroscopy (NIRS), blood oxygen level dependent (BOLD) and 19F imaging following the injection of an albumin bound metal–
magnetic resonance imaging (MRI), and electron paramagnetic res- porphyrin complex (Oxyphor) into the vasculature. For instance,
onance (EPR) imaging can detect oxygen partial pressure (pO2), oxy- Lebedev et al.42 described a general approach to construct phos-
gen concentration or oxygen percentage.23 Indirect measurements, phorescent nanosensors with tunable spectral characteristics,
including measuring exogenous and endogenous hypoxia markers, variable degrees of quenching, and a high selectivity for oxygen.
can provide parameters related to tissue or tumor oxygenation.24 The performance of the probes was demonstrated in measuring
The invasive polarographic electrodes have been extensively vascular pO2 in the rat brain with in vivo microscopy. NIRScan also
used to measure pO2 in human tumors and animal studies since the be used to analyze tumor oxygenation in vivo through recording
1990s.25,26 Regarded as the gold standard, these electrodes have the spectral changes by hemoglobin in the vasculature. An animal
been applied to more easily accessible tumors such as head and study by Kim and Liu43 showed good efficacy for NIRS compared
neck cancer, cervical cancer, soft tissue sarcomas of the extremities, to electrode measurements in assessing tumor hypoxia. However,
astrocytic brain tumors, lung cancer, pancreatic cancer, prostate low spatial resolution, light scattering, limited path length, low sen-
cancer, and lymph node metastases. The typical pretreatment sitivity, and being easily affected by the environment limit clinical
median pO2 is 11.2 mm Hg (range: 0.4 to 60 mm Hg)25 and values translation of both phosphorescence imaging and NIRS.
obtained by such measurements can predict treatment response27
and the metastatic potential of tumors.28 Currently, the polaro-
graphic electrode can be used under CT or ultrasound guidance to
Photoacoustic Imaging
assay the pO2 of a tumor in deep-seated organs and obtain overall Photoacoustic tomography (PAT), also referred to as optoacoustic
tumor oxygen status.29 However, insertion of an electrode into the tomography or thermoacoustic tomography, is a hybrid noninva-
tumor disrupts tissues, making it difficult to distinguish necrotic sive imaging modality that combines high optical contrast and high
areas to discern the patterns of hypoxia. Moreover, the technique ultrasonic resolution.44,45 PAT involves optical irradiation, ultra-
requires great expertise and has a large interobserver variability. sonic detection, and image formation. The tissue is usually irradi-
Indirect methods utilize exogenous probes to measure molecu- ated by a short-pulsed laser beam to produce thermal and acoustic
lar reporters of oxygen. These reporter agents usually form stable impulse responses. Locally absorbed light is converted into heat,
adducts with intracellular macromolecules when the oxygen pres- which is further converted to a pressure rise via thermoelastic
sure is less than 10 mm Hg.30 2-nitroimidazole derivatives such expansion of the tissue. The initial pressure rise, determined by the
as misonidazole (1-(α-methoxymethylethanol)-2-nitroimidazole),31 local optical energy deposition and other thermal and mechanical
pimonidazole (1-(2-nitro-1-imidazolyl)-3-N-piperidino-2-propan- properties, propagates in the tissue as an ultrasonic wave, which
olol),32 and EF5 (nitroimidazole[2-(2-nitro-1H-imidazol-1-yl)- is referred to as a photoacoustic wave. The photoacoustic wave is
N-(2,2,3,3,3-pentaflouropropyl) acetamide)33 have been used. detected by ultrasonic transducers placed outside the tissue, pro-
Immunohistochemical (IHC) staining with specific antibodies ducing electric signals. The electric signals are then amplified, dig-
against hypoxia marker adducts in situ can provide quantitative itized, and transferred to a computer to form an image.46
information on the relative oxygenation at cellular resolution.30,34 This technique can assess relative changes in concentrations of
For example, in one animal study, 120 mg/kg of pimonidazole was both oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin
intravenously administrated followed by antibody staining against (Hb).47 Wang et al.48 implemented PAT to image cerebral blood oxy-
pimonidazole. The result showed that pimonidazole staining was genation of rats in vivo and the results showed that PAT can image
decreased when pO2 returned to normal by carbogen reoxygen- the change of the alternation from hyperoxia to hypoxia. However,
ation.35 IHC methods are particularly useful for in vitro studies, at this time, there is no report related to clinical application, pri-
including assays of human biopsy specimens. Many studies have marily because of the depth limitation of this technique.
confirmed that these exogenous markers for areas of chronic
hypoxia are more sensitive under severely hypoxic conditions than
the polarographic needle electrode.33,36
BOLD Magnetic Resonance Imaging
HbO2 is diamagnetic and Hb is paramagnetic.49 Microscopic field
gradients in the vicinity of red blood cells and vessels are modu-
Noninvasive Imaging of Hypoxia lated by changes in Hb concentration. Paramagnetic Hb can
increase the transverse relaxation rates of the surrounding protons
Although the polarographic electrode and IHC staining can pro- whereas HbO2 does not.50 Such magnetic field perturbations within
vide relatively accurate measurement of tumor oxygenation, these a voxel (volume element) cause a loss of phase coherence and
methods have a selection bias and only identify partial, rather therefore lead to signal attenuation in gradient echo or T2* (appar-
than complete information of the entire tumor region.37 Therefore, ent spin–spin relaxation time)-weighted sequences. This phenom-
there has been growing interest in using noninvasive functional enon has been called BOLD contrast.51 BOLD-MRI uses endogenous
and molecular imaging techniques which can yield a plethora of signals coming from Hb as image contrast to reflect the changes in
high quality experimental data per protocol by increasing the the blood oxygenation, and has been shown to have potential to
number of times that quantitative data can be collected.38 To date, diagnose tumor hypoxia.52 The relationship between BOLD-MRI
several imaging techniques have been developed using either direct signal and vascular oxygenation allows investigators to directly

Chapter 35 Radionuclide Imaging of Tumor Hypoxia and Its Clinical Implications 539
NO2
OH NO2
NO2 H
N N
HO N 18F N N
18F N O
N 18F
OH
18F-FMISO 18F-FETNIM 18F-FETA
NO2 NH2 HN S S NH
F F H
18F N O Cu
N N HN N N N
F F18 N N
F O
Figure 35.1. Structures of hypoxia positron emission tomography (PET) 18F-EF5 18F-FAZA Cu-ATSM
imaging agents.

estimate pO2. Many studies have been undertaken to investigate PET Imaging
the effects of carbogen breathing in mice and oxygenation in tumor

models by BOLD-MRI.53,54 A recently reported preclinical study Detection of tumor hypoxia with radionuclides was first demon-
demonstrated that under short-term generalized hypoxia induced strated in 1981 by autoradiography with 14C-misonidazole, which
by inhalation of 8% oxygen, BOLD contrast was measured as high selectively bound to metabolizing hypoxic cells within the tumor.69
as 25% from vessels at 9.4 T using a simple gradient echo (GRE) So far, the intensively investigated hypoxia imaging markers
pulse sequence.54 The major disadvantage of BOLD-MRI, like in the include 2-nitroimidazoles, nucleoside conjugates, and Cu(II)-
case of phosphorescence and near-infrared fluorescence imaging, diacetyl-bis(N4-methylthiosemicarbazone) (Cu(II)-ATSM).70–72 The
is that the data provide the change of oxygen tension in vascula- structures of most popular hypoxia imaging probes are shown in
ture but not in the tissue. Furthermore, BOLD-MRI is not a quanti- Figure 35.1.
tative method and can be easily affected by many factors including
flow, hematocrit concentration, pH, and temperature.52,55 2-Nitroimidazoles
19 The mechanism by which 2-nitroimidazoles are reduced and
F Magnetic Resonance Imaging retained in hypoxic tissues has been summarized previously.41 In
19
F has 100% natural abundance, a spin of 1/2, and a gyromag- brief, 2-nitroimidazole tracers are readily diffusible through cell
netic ratio of 40.08 MHz/T, which is slightly lower than that of 1H membranes and undergo reversible reduction by intracellular
(42.58 MHz/T), resulting in 83% of the sensitivity of 1H.56 Addition- reductases to yield nitroimidazole radical anions, which are then
ally, the chemical shift of 19F is sensitive to the molecular environ- rapidly reoxidized to neutral molecules that diffuse out of the cell.
ment of its nucleus because of the seven outer-shell electrons of If the concentration of oxygen in tumor tissue is low, oxidation
19
F atom as compared to only one electron of 1H. Finally, in contrast competes with the irreversible binding of the radical anion to other
to the prominent 1H signal from mobile water in biologic tissue, only substrates which forms irreversible compounds with cellular mac-
a trace amount of 19F (<1 μM) is present in tissue. Moreover, these romolecular components.73 Therefore, with decreasing intracellu-
19
F atoms are immobilized in a solid phase in the teeth and bones, lar concentration of oxygen, the tracer accumulates within the
resulting in virtually zero background 19F MR signal in vivo.57 hypoxic tissue. There are several features that make 2-nitroimid-
19
F MRI uses mainly perfluorocarbons (PFCs) or fluorinated azoles the most dominant hypoxia imaging agents. First, the reduc-
nitroimidazoles as the contrast agents for hypoxia imaging. PFCs tion of the nitro group on the imidazole ring is accomplished by
are highly hydrophobic but offer exceptional oxygen solubility.58 The tissue nitroreductases that are plentiful and do not represent a
19
F spin lattice relaxation rate of PFCs varies linearly with the dis- rate-limiting factor.74 Second the ideal octanol–water partition
solved oxygen concentration. Thus, the 19F-based oximetry allows coefficient75 and low nonspecific protein-binding guarantee that
measurements of vascular oxygenation in vivo.59 To date several their biodistribution is not complicated by reduced blood flow.76
PFCs have been tried, for example, hexafluorobenzene (HFB)60 and Furthermore, the pO2 where nitroimidazoles are retained in cul-
perfluoro-15-crown-5-ether (PF15C5),61,62 which can be injected tured cells is in the same range as that where the OER is observed.
either intravenously or intratumorally. The use of 19F MR is pro- These features enable 2-nitroimidazoles to be trapped at a level
gressing rapidly toward detecting changes in tumor oxygenation in proportional to the intracellular demand for O2 and is not limited
response to radio-sensitizing and oxygen-augmenting treatments.63 by blood flow, meeting the design requirements for a hypoxia
The disadvantages of 19F MRI are that the measurements are subject imaging agent.41
to flow artifacts and the oxygen sensitivity of some 19F MR imaging
18
compounds can be easily affected by temperature, dilution, pH, Imaging Tumor Hypoxia with F-FMISO
18
common proteins, and blood.64 After intravenous injection, majority F-labeled misonidazole (18F-FMISO) is the first-generation nitro-
of the PFC contrast agent is extensively ingested by the reticuloen- imidazole marker and the most commonly used hypoxia PET imag-
dothelial system (RES), and the slow clearance can have adverse ing agent.77 18F-FMISO is only sensitive to the presence of hypoxia
effects. Intratumoral injection can also be risky as PFC emulsion in viable cells. Studies have shown that significant 18F-FMISO
could be accidentally injected into tumoral vein, leading to embo- uptake requires a hypoxic level of less than 10 mm Hg.78 With an
lism.65 Another type of probes that had been tried for detecting image-guided robotic system, the oxygen tension (pO2) in rodent
tumor oxygenation by 19F MRI are fluorinated-2-nitroimidazole tumor xenografts was measured using interstitial probes guided by
18
compounds including hexafluoromisonidazole (CCI-103F),66 EF5,67 F-FMISO PET images. The 18F-FMISO image intensities were
and SR-4554.68 SR-4554 has shown good result at detecting hypoxia inversely correlated with the measured pO2.79 However, another
in a phase I study by Lee et al.68 and it can be further developed for comparison study showed no correlation between data from
18
the detection of tumor hypoxia in certain patients. F-FMISO PET and polarographic oxygen-sensitive electrodes.80

18
F-FMISO has been found to reflect hypoxia in glioma, head
15 ID%/g
and neck cancer, renal tumor, and non–small-cell lung cancer.78,81,82
In a clinical study by Rajendran et al.83 in glioblastoma multiforme
(GBM) patients, both posttherapy FMISO and FDG images showed
increased uptake and retention, suggesting that reoxygenation did
not occur. Koh et al.84 found that treated non–small-cell lung carci-
nomas exhibited increased oxygen and decreased hypoxia distri-
bution, as indicated by sequential FMISO imaging.
Because tumor hypoxia is closely related to radioresistance,
pretreatment or serial 18F-FMISO PET imaging has been performed
to determine prognosis or dose planning of radiation therapy.85,86
Pretreatment FMISO uptake and retention correlated with survival
data, allowing clinicians to better predict the failure of tumor 0 ID%/g
response to treatment.83,87 In one study, pretreatment 18F-FMISO A Day 0 Day 1 Day 3 Day 7 Day 14
PET was performed on 17 patients with untreated head and neck
squamous cell carcinoma (HNSCC). Local control rates with radio-
therapy were significantly lower in the tumor group with high 15 Control VEGF121/rGel
uptake of 18F-FMISO compared to the tumor group with low uptake
**
of 18F-FMISO using either SUVmax or tumor-to-muscle ratio (TMR)
*
as the hypoxic indicator.88 Combined 18F-FMISO PET imaging and 10
ID%/gmax
intensity-modulated radiotherapy (IMRT) planning permitted
delivery of higher doses to hypoxic regions, increasing the predicted
TCP (mean 17%) without increasing expected complications.89
Increased equivalent uniform dose (EUD) of the hypoxic volumes 5
has also been confirmed.90 However, the changes in spatial distri-
bution of tumor hypoxia, as detected in serial FMISO PET imaging,
compromised the coverage of hypoxic tumor volumes achievable 0
by dose-painting IMRT. B Day 0 Day 1 Day 3 Day 7 Day 7
In addition, 18F-FMISO PET imaging has been applied to moni- Figure 35.2. A: Representative decay-corrected whole-body coronal micro-PET images of
tor tumor response to various antiangiogenesis therapeutics.91–94 mice bearing MDA-MB-435 breast cancer at 2.5 hours after intravenous injection of 18F-FMISO
Treatment with DMXAA (5,6-dimethylxanthenone-4-acetic acid, (1.11 MBq/mouse) on days 0, 1, 3, 7 and 14 after the treatment was initiated. The tumors are
indicated by arrows. Increased tumor uptake of 18F-FMISO was observed on day 1 and day 3
Vadimezan), an antivascular compound, resulted in a marked but was restored to the baseline level on day 7. Upper panel: Control; Lower panel: VEGF121/rGel
reduction in the 18F-FMISO mean standardized uptake value treatment. B: Quantitative micro-PET region of interest analysis of tumor uptake for 18F-FMISO
(SUVmean) in approximately half of the treated tumors. The reduc- (*p < 0.05, **p < 0.01). (Reproduced with permission from Yang M, Gao H, Sun X, et al.
tion in SUVmean correlated with a decrease in the fraction of Multiplexed PET probes for imaging breast cancer early response to VEGF/rGel treatment. Mol
Pharm. 2011;8:621–628. Copyright 2011. American Chemical Society.)
tumor area staining positive for both EF5 and pimonidazole. Com-
pared with untreated controls, tumors with decreased SUVmean
had significantly fewer perfused microvessels. Thus, a reduction in
18
F-FMISO SUVmean after DMXAA treatment was indicative of uptake, retention, and clearance of the tracer upon injection. Clinical
reduced perfusion and therefore delivery of 18F-FMISO, rather than studies on static 18F-FMISO PET for head and neck cancer patients
a reduction in tumor hypoxia.91 A total of 13 patients with locally revealed that 18F-FMISO image 90 to 140 minutes after injection led
advanced HNSCC underwent 18F-FMISO PET scans before and after to an operational definition of tumor hypoxia corresponding to a
neoadjuvant chemotherapy (NAC). All PET indexes of 18F-FMISO tumor-to-blood activity concentration ratio of greater than 1.2 to
significantly decreased after NAC. Although hypoxic volume (HV) in 1.6.35,70,83 However, the physiologic clearance of 18F-FMISO from
primary tumor and a few indices before NAC in responders was highly perfused normal tissue may result in the same tumor-to-
lower than that in nonresponders, none of the change in indices blood ratio (T/B), which is comparable to hypoxic tumor at the time
were statistically significant.93 In another preclinical study, two of patient imaging. At 90 to 180 minutes after injection, the activity
doses of 12 mg/kg VEGF121/rGel, administered intraperitoneally, concentration in normal tissue continually decreases as a function
resulted in initial delay of tumor growth but the growth resumed of time, whereas in hypoxic tumor it increases as a function of time.
4 days after tumor treatment was stopped. 18F-FMISO uptake was The possibility of a cross-over point between the decline in activity
increased in the treated tumors at day 1 and day 3, compared to from a well-perfused tissue region and the increasing activity from
the control group. At days 7 and 14, 18F-FMISO uptake restored to a predominantly hypoxic one can result in an ambiguity in the inter-
the baseline level (Fig. 35.2).94 pretation of single time-point imaging. With dynamic contrast-
Inconsistent results and controversies still exist in 18F-FMISO enhanced (DCE) MRI using Magnevist (Gd-DTPA) and dynamic
PET imaging. The uptake of 18F-FMISO has a wide variation among 18
F-FMISO PET, it has been demonstrated that tumor vasculature is
patients and different types of tumors. In many cases, no correla- a major determinant of early 18F-FMISO uptake.96 Consequently, some
tion was found between patient diagnosis and the degree of reduc- investigators proposed that data acquisition of 18F-FMISO should be
tion in FMISO uptake and retention. For example, in a prospective done 4 hours post injection to gather the optimal contrast, preferably
study, neither the presence nor the absence of hypoxia, defined by allowing further analysis, for example, hypoxic sub volume definition
positive 18F-FMISO findings on the midtreatment PET scan, corre- for therapy planning.97
lated with patient outcome.95 The variability in spatial uptake has Compared with static imaging, dynamic imaging followed by
been confirmed with two 18F-FMISO PET scans 3 days apart in kinetic analysis has certain advantages. It can be used to quanti-
patients with head and neck cancer by a voxel-by-voxel analysis.90 tatively calculate the perfusion/clearance rates. Furthermore,
To overcome this problem, serial images performed during the dynamic imaging facilitates the separation of specific signal from
course of treatment, rather than baseline volumes, would be most nonspecific signal and thus can be applied to accurately measure
helpful in planning to boost radiation therapy to persistent hypoxic the binding potential of an agent.98 Dynamic imaging with
18
subvolumes. In addition, the time frame is also very important for F-FMISO has been performed either with a mathematical phan-
18
F-FMISO PET imaging because it is a very dynamic process for the tom or head and neck cancer patients.99,100 A generic irreversible

one-plasma, two-tissue compartmental model was used to analyze Tabl e 3 5 . 1

the pharmacokinetic parameters including a potential tumor
hypoxia index (Ki). There is a positive correlation of 0.86 between List of Hypoxia Imaging Tracers with Abbreviations
the average tumor-to-background (T/B) and average hypoxia
index (Ki) of the region of interest. However, the direct correlation Abbreviation Full Name References
between the T/B and hypoxia of the individual pixel is not obvious
because of the statistical photon counting noise in PET and the ATSM Diacetyl-bis(N4-methylsemicarbazone) 116
amplification of noise in kinetic analysis.100 EF3 2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropro- 111
In patients with newly diagnosed GBM, the volumetric analysis pyl)acetamide
demonstrated that the viable hypoxic tissue assessed by 18F-FMISO EF5 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3- 112,113
PET is related to the neovascularization in Gd-enhanced MRI and pentafluoropropyl) acetamide
the tumor aggressiveness assessed by 11C-MET PET.101 Moreover, FAZA Fluoroazomycin arabinoside 117
the intratumoral 18F-FMISO uptake pattern matched perfectly with FETA Fluoroetanidazole 110
endogenous markers including hypoxia-responsive element (HRE) FETNIM Fluoroerythronitroimidazole 108,109
FMISO Fluoromisonidazole 70
driven HSV1-TKeGFP and CA9.102 It has also been reported that the
FRAZ 1-α-D-(2-deoxy-2-fluororibofuranosyl)- 115
uptake volume of FMISO was larger in GBM than in non-GBM,
2-nitroimidazole
which may distinguish GBM from lower-grade glioma.103 Swansan IAZA Iodoazomycin arabinoside 118
et al.104 performed T1Gd, T2 MRI, and 18F-FMISO PET studies on a IAZG Iodoazomycin galactoside 119

total of 24 patients with glioblastoma preceded surgical resection or IAZGP β-D-iodinated azomycin galactopyranoside (200)
biopsy. On 18F-FMISO PET images, the HV generally occupied a IAZP Iodoazomycin pyranoside 120

region straddling the outer edge of the T1Gd abnormality and into IAZXP Iodoazomycin xylopyranoside 120
the T2. A significant correlation between HV and the volume of the NEFA 2-Fluoro-N-(2-(2-nitro-1H-imidazol-1-yl) 114
T1Gd abnormality that relied on the existence of a large outlier was ethyl)acetamide
observed, indicating hypoxia may drive the peripheral growth of NEFT 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 114
glioblastomas.104,105 2-fluoroacetate
In addition to identifying tumor hypoxia, differentiating between
chronic and acute hypoxia, is a worthwhile challenge for noninva-
sive imaging. Wang et al.106 have developed an iterative optimiza-
tion method to delineate chronic and acute hypoxia based on the found to be hypoxia-specific. The increased uptake of 18F-EF5 was
18
F-FMISO PET serial images. They assume that chronic hypoxia is related to the extent of malignancy and high risk of metastasis in
the same in the two scans and has a gaussian distribution, whereas cancer patients.112 Thus, the technique could be useful to identify
acute hypoxia varies in the two scans and is best represented by high-risk patients in clinical trials to determine whether early che-
Poisson distributions. The model calculation generates the amount motherapy will influence the occurrence of metastasis.125 One draw-
of acute hypoxia, which differed among patients, ranging from back of EF5 is the complex labeling chemistry and consequently low
approximately 13% to 52%, with an average of approximately 34%. radiochemical yield.126
However, this model was not confirmed with a follow-up study by Among the second generation of nitroimidazoles, 18F-FAZA has
comparing microscopic fluorescent staining results with the frac- shown promise to assess tumor hypoxia. It has faster diffusion into
tions of acute hypoxia in individual tumors assessed by the model cells and faster clearance from the normal tissues than 18F-FMISO.127
using xenografts of two tumor types. The method needs to be fur- Two-dimensional spatial distribution of 18F-FAZA, demonstrated by
ther tested in both experimental and clinical studies.107 autoradiography, showed a highly significant colocalization with
fluorescence images from pimonidazole.128,129 18F-FAZA PET imag-
18 18
Imaging Tumor Hypoxia with F-EF5 and F-FAZA ing in seven patients with high-grade gliomas showed very high
Quite a few second-generation nitroimidazoles for tumor hypoxia tracer uptake in all patients, indicating that 18F-FAZA is a promising
imaging have been developed including 18F-FETNIM (fluoroery- agent for assessing the hypoxic fraction of this tumor type.130
thronitroimidazole),108,109 18F-FETA (fluoroetanidazole),110 18F-EF3 In patients with head and neck cancer, the T/M ratio generally
(2-(2-nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)acetamide), 111 decreased within the first 60 minutes of the dynamic sequence
18
F-EF5,112,113 18F-NEFA (2-fluoro-N-(2-(2-nitro-1H-imidazol-1-yl) whereas generally increasing at later time points. The mean T/M
ethyl)acetamide), 18F-NEFT (2-(2-methyl-5-nitro-1H-imidazol- ratio at 2 hours p.i. was 2 ± 0.3. However, the tumor volume display-
1-yl)ethyl 2-fluoroacetate),114 and 18F-FRAZ (1-α-D-(2-deoxy- ing a T/M ratio above 1.5 was highly variable.72 In another study,
2-fluororibofuranosyl)-2-nitroimidazole).115 The full names of there was substantial uptake in the primary tumor and/or the lymph
these tracers are listed in Table 35.1. In general, these new mark- nodes in the neck in six out of nine patients with HNSCC, primary
ers are more water soluble and resistant to degradation by most lung tumors in 7 out of the 13 lung cancer patients. No side effects
physiologic oxidation mechanisms. For example, both 18F-FMISO of the administration of 18F-FAZA were observed.130 In CT26 colon
and 18F-EF3 exhibited similar pharmacokinetics and biodistribu- carcinoma models, it was found that the crucial 18F-FAZA uptake
tion in mice and accumulated in tumors in a hypoxia-dependent phase is during the first hour after 18F-FAZA injection and was not
manner. However, more nonspecific activity was observed with affected by pure oxygen breathing.131
18
F-FMISO at late time points after tracer injection in normal tis- Using 18F-FAZA to determine the predictive value for success of
sues.111 However, another study found that 18F-EF3 is not superior radiotherapy in combination with tirapazamine, a specific cytotoxin
to 18F-FMISO for PET-based hypoxia evaluation as measured in a for hypoxic cells, has been evaluated in EMT6 tumor-bearing nude
rat rhabdomyosarcoma tumor model.121 mice. An additive beneficial therapeutic effect of tirapazamine to RT
EF5 was reported to be the most stable 2-nitroimidazole deriva- was observed only in hypoxic tumors but not in normoxic tumors.117
tives studied to date.122 EF5 distributes evenly throughout soft tissue In a clinical study, 18 patients with advanced squamous cell head
within minutes of injection. Its concentration in blood over the typ- and neck cancer were imaged with 18F-FAZA PET and CT. The
ical time frame of the study (approximately 3.5 hours) was nearly results demonstrated the feasibility of using 18F-FAZA PET to guide
constant, consistent with a previously determined EF5 plasma half- hypoxia-directed intensity-modulated radiotherapy in head and
life of approximately 13 hours. Elimination was primarily via urine neck cancer.132 Moreover, 18F-FAZA PET analysis showed that pre-
and bile.123 18F-EF5 was used in several human trials to determine treatment tumor hypoxia was prognostic of a satisfactory radiation
its feasibility as a hypoxia imaging agent (Fig. 35.3).124 18F-EF5 was response. Both 18F-FAZA PET and pO2 electrode showed that the

Figure 35.3. PET and CT images of one patient with 18F-EF5,

18
F-FDG, and 15O-H2O. 18F-EF5 images are made at 3 hours after
injection. Arrow indicates the primary tumor, and arrowhead
indicates the metastatic lesion. (Reprinted with permission from
SNMMI from Komar G, Seppanen M, Eskola O, et al. 18F-EF5: a
new PET tracer for imaging hypoxia in head and neck cancer.
J Nucl Med. 2008;49:1944–1951.)
more hypoxic tumors had significantly less tumor control.133 complexed with copper. Because of the simplicity of chemistry,
Another clinical study confirmed that PET imaging with 18F-FAZA Cu(II)-ATSM is gaining acceptance in diagnostic imaging of
is feasible in patients with cervical cancer. However, because of the hypoxia.116 Cu(II)-ATSM is a simple molecule and its biochemical
limited number of patients, the predictive and prognostic value of interaction with cells is similarly simple, mainly based upon redox
18
F-FAZA remains to be clarified.134 chemistry. In living cells, Cu(II)-ATSM undergoes reduction and is
Integrin αvβ3, a marker of angiogenesis, is highly expressed on rapidly cleared from the aerobic cells but become trapped in the
proliferating and activated endothelial cells associated with neovas- hypoxic cells, thus can differentiate between dead, hypoxic, non-
cularization in malignant tumors, but not in quiescent blood ves- functional, and viable tissue.138
sels. PET imaging with arginine-glycine-aspartic acid (RGD)-based Dearling and Packard139 suggested that the trapping mecha-
peptides has been used to visualize and quantify integrin αvβ3 nism is biphasic. The first phase is a reduction/oxidation cycle
expression levels in vivo and to further evaluate the neoangiogen- involving thiols and molecular oxygen. This is followed by interac-
esis in tumors. Under room air conditions, roughly 60% of the tion with proteins in the mitochondria leading to more permanent
tumor surface displayed a spatial coupling of 18F-FAZA and retention of the tracer.139 Recently, with a unique cell culture model,
125
I-Gluco-RGD uptake. However, the remaining approximately 40% mitochondrial xenocybrids, Donnelly et al.140 confirmed that com-
of the tumor surface showed discordant 18F-FAZA and 125I-Gluco- promised electron transport chain (ETC) function, caused by the
RGD uptake, indicating that hypoxia and angiogenesis are not nec- absence of O2 as the terminal electron acceptor or dysfunction of
essarily spatially linked to each other.135 individual components of the ETC, is an important determinant in
In a feasibility study to assess hypoxia kinetic models using driving the intracellular dissociation of Cu(II)-ATSM that increases
voxel-wise cross-analysis between the uptake of the perfusion cellular retention of Cu.140 Consequently, the high dynamic range of
tracer 15O-H2O and the hypoxia tracer 18F-FAZA, the compartment Cu(II)-ATSM uptake is representative of a narrow range of low oxy-
model, Thorwarth model, Patlak plot, Logan plot, and Cho model gen tension whose values are dependent on microenvironment
were applied to model the process of tracer transport and accumu- acidity, whereas FMISO uptake is representative of a wide range of
lation under hypoxic conditions. The results demonstrated that pO2 values that are independent of acidity.141
hypoxia kinetic modeling delivered different information from Both in vitro and in vivo data showed that high MDR1-express-
static measurements. The reversible two-compartment model gave ing tumors showed lower tracer activity on 64Cu-ATSM PET images,
better correspondence to the initial assumptions than the other indicating the expression of MDR1 glycoprotein may affect the
models.136 However, with three squamous cell carcinoma tumor retention of 64Cu-ATSM in the tumors.142 Cu(II)-ATSM has also been
models, late time 18F-FAZA PET images provided an accurate mea- applied as a marker of intracellular overreduced states for disor-
sure of hypoxia against which kinetic model estimates can be vali- ders with mitochondrial dysfunction, such as MELAS, Parkinson’s
dated. Tumor TACs varied widely (ranging from distinctly wash-out disease, and Alzheimer’s disease.143 Moreover, inhibition of fatty
to accumulative type) among tumor types although pimonidazole acid synthesis resulted in significant increase in 64Cu-ATSM reten-
staining revealed extensive hypoxia in all models.137 tion in prostate tumor cells in vitro under anoxia over 60 minutes.
Thus, the translation of Cu-ATSM to the imaging of prostate cancer
may be limited by the overexpression of fatty acid synthase associ-
Dithiosemicarbazones ated with prostatic malignancies.144
Dithiosemicarbazones were initially discovered for their antioxi- Most clinical copper-ATSM studies have used the agent labeled
dant properties in the 1960s that were enhanced when they were with the short-lived positron-emitting radionuclide of copper,145

60
Cu (half-life, 0.395 hours; β+-decay, 92.5%; electron capture, SPECT Imaging of Hypoxia
7.5%).146 To enable copper-ATSM to be translated for use in PET
centers that do not have an in-house cyclotron, copper-ATSM Single photon emission computed tomography (SPECT) uses single
labeled with one of the longer-lived positron-emitting nuclides, 64Cu photon-emitting radionuclide-labeled hypoxia-specific compounds
(half-life, 12.7 hours; β+-decay, 17.4%; β−-decay, 38.5%; electron to generate a signal from hypoxic areas of tumors.63 123I was initially
capture, 43%) or 61Cu (half-life, 3.33 hours; β+-decay, 62%; electron used for this purpose. In one study, 123I-iodoazomycin arabinoside
capture, 38%),145,147 is required. The longer half-lives of 64Cu and (123I-IAZA) was used in 51 human patients with malignancies and
61
Cu allow for production at a regional center and distribution to the results demonstrated hypoxia in small-cell lung cancer and
PET facilities in a fashion similar to that for 18F-labeled radiophar- squamous cell carcinoma of head and neck.163 The radiopharmaco-
maceuticals. The preparation of 62Cu (half-life, 0.16 hours; β+-decay, kinetics and the radiation dosimetry of 123I-IAZA confirmed that
123
98%; electron capture, 2%), via a 62Zn/62Cu generator system, has I-IAZA can be used for clinical hypoxia tissue imaging.118,164
been reported and commercialized148,149 and offers an additional Because 123I-IAZA has inconsistent uptake in various tumors, modi-
method for radiolabeling copper-ATSM for use in humans. fied iodinated azomycin arabinosides.165 IAZA, iodoazomycin pyran-
Studies in animal tumor models have shown good correlations oside (IAZP), β-D-iodinated azomycin galactopyranoside (IAZGP),
between tumor uptake of 64Cu-ATSM and oxygen electrode mea- and iodoazomycin xylopyranoside (IAZXP) have been developed
surement. The imaging results were also comparable with 18F-FMISO and evaluated as newer agents based on the azomycin-nucleoside
PET.150 However, 64Cu-ATSM tumor uptake was found to be less sen- structure.120 125I-IAZGP in FM3A mouse tumors 24 hours after
sitive to oxygen level change whereas 18F-FMISO tumor uptake was administration showed high accumulation within tumors.166
99m
Technetium [99mTc]-labeled nitroimidazoles and nonnitroimid-

more responsive to changing levels of hypoxia.151 The regional com-
parisons between 64Cu-ATSM (10 minutes) and 18F-FDG (1 hour) azoles identified as BMS-181,321, BRU 59–21, N2IPA, and 99mTc-
HL91 have been used to study tumor hypoxia.120 BMS-181,321 was

resulted in a very poor correlation between the regional uptake of
the two agents. The comparison between 18F-FLT and 64Cu-ATSM the first 99mTc-labeled 2-nitroimidazole widely studied for the detec-
showed a strong relationship between the two tracers.152 tion of ischemic and hypoxic myocardium. BMS-181,321 is unsta-
Tumor uptake of Cu-ATSM, as assessed by PET, has been con- ble, has a high partition coefficient, slow clearance from the blood
firmed as a clinically important biomarker of prognosis in several and high background levels in normal tissues, and thus was not
human cancers. Cu(II)-ATSM was first used in human study in 2000 optimal for tumor hypoxia imaging.167 BRU 59–21 has greater stabil-
in normal subjects and patients who had lung cancer.153 In all lung ity in vitro and more rapid clearance in vivo than BMS-181,321.
cancer patients, 62Cu-ATSM showed high uptake and a plateau can be This compound had shown good retention in tumors compared to
reached within a few minutes after tracer injection. The maximum muscle and blood and is suitable for tumor hypoxia imaging, as
tumor-to-background ratio of 62Cu-ATSM was up to 9.33.153 60Cu- confirmed by pimonidazole staining.168 Yutani et al. found that there
ATSM has also been applied to detect hypoxia and to assess the rela- is a very good correlation between 99mTc-HL91 retention and hypoxia,
tionship between Cu(II)-ATSM uptake and response to therapy and/or as measured by the polarographic electrode. 99mTc-HL91 accumu-
recurrence.154,155 The toxicology and pharmacology data demon- lated to significantly higher levels in hypoxic tumor areas and 99mTc-
strated that 64Cu-ATSM has an appropriate margin of safety for clini- HL91 uptake was strongly correlated with the expression of GLUT1
cal use compared with 60Cu-ATSM. Besides, the image quality with in the viable cancer cell area.169,170
64
Cu-ATSM was better than that with 60Cu-ATSM because of lower
noise. The pattern and magnitude of tumor uptake of 60Cu-ATSM and
64
Cu-ATSM on studies separated by 1 to 9 days were similar.156 Endogenous Hypoxia Markers
60
Cu-ATSM PET may be predictive of survival and, possibly,
tumor response to neoadjuvant chemoradiotherapy in patients with Endogenous molecular markers represent proteins and genes
rectal cancer. In patients with locally invasive (T2–T4) primary or whose expressions are associated with hypoxia. A wide range of
node-positive rectal cancer, both overall and progression-free sur- potential markers have been studied over the last several years
vivals were worse with hypoxic tumors (tumor-to-muscle activity and have been found to be useful to monitor hypoxia.171 Because
ratio >2.6) than with nonhypoxic tumors (tumor-to-muscle activity the biology of tumor hypoxia in tumors is rather complicated and
ratio ≤2.6).157 In patients with lung cancer of pathohistologically dif- no single marker characterizes prognosis in clinical practice,
ferent types, the intratumoral distribution patterns of 62Cu-ATSM attempts have been made to combine various markers to create a
and 18F-FDG were different between SCC and adenocarcinoma in hypoxia-prognostic profile.172
lung cancers, indicating that intratumoral regions of high glucose
metabolism and hypoxia could differ with the pathohistologic type
of lung cancer.158 In addition, Cu(II)-ATSM PET has been shown to
Hypoxia-Inducible Factor 1 (HIF-1)
distinguish patients likely and unlikely to respond to conventional HIF-1 is one of the most intensively studied oxygen response path-
therapies for cancers of the lung146 and uterine cervix.159 ways in molecular biology. HIF-1, activated by hypoxia, regulates
It was found that the Auger radiation emitted by 64Cu can cause genes that are involved in cell metabolism, angiogenesis, invasion,
DNA damage and induce apoptosis in hypoxic cells, thus 64Cu-ATSM metastasis, and apoptosis. HIF-1–induced cellular changes are
can serve as both an imaging and a therapy agent.160 Although Cu- extremely important diagnostic and therapeutic features of cancer
ATSM may be a valid hypoxia agent for some tumor types, the effi- cells, particularly in cancers refractory to therapy. The transcrip-
cacy varies among different tumors and may be tumor-type specific.154 tion factor HIF-1 is a heterodimer consisting of an oxygen-sensitive
α-subunit (HIF-1α) and the constitutively active β-subunit (HIF-1β).173
Under normoxic conditions, prolyl hydroxylases (PHDs) hydroxylate
Galactopyranoside
proline sites in the oxygen-dependent degradation domain (ODD) of
The iodinated analogs 124I-iodoazomycin galactopyranoside (IAZG) the HIF-1α protein, and further binding of the von Hippel–Lindau
and 124I-iodoazomycin galactoside have also been developed as protein (VHL) leads to the ubiquitination and proteasomal degrada-
hypoxia radiotracers and have shown good tumor contrast in tion of HIF-1α. In addition, oxygen-dependent hydroxylation of three
several xenograft models.161 However, compared with 18F-labeled residues within HIF-1α affects the ability of this complex to activate
compounds, deiodination, long half-lives of 124I, low positron abun- transcription.174
dance, high positron energy and accompanied high-energy γ-rays Under hypoxic conditions, HIF-1α is stabilized by hypoxia upon
resulted in varied biodistribution, poor image resolution, and activation of HIF-1. This leads to increased levels of HIF-1α and
higher radiation exposure for 124I-labeled imaging tracers.119,162 reductions in hydroxylation, ubiquitination, and degradation of the

protein. Accumulated HIF-1 binds to the HRE and triggers the conditions was demonstrated in different types of cancer where a
recruitment of coactivators essential for transcriptional activation, more general staining pattern is observed.187
thereby promoting the transcription of numerous genes including Dubois et al. imaged CA IX with fluorescently labeled sulfon-
VEGF, VEGFR2, MMP2, and the genes encoding the glucose trans- amides to distinguish hypoxic and (re)oxygenated cells in a tumor
porters. Several cofactors are involved in the transcriptional regula- xenograft model. The in vivo imaging results confirmed previous
tion of various target genes, and the first main inhibitory pathway in vitro data that CA IX binding and retention require exposure to
of HIF-1α is factor inhibiting HIF-1 (FIH-1). The hydroxylation of hypoxia.188 The G250 monoclonal antibody against CA IX has
the C-terminal transactivation domain (CAD) of HIF-1α by FIH-1 been evaluated in renal-cell carcinoma xenografts and resulted in
inhibits binding of the HIF-1 complex with p300/CBP, which is a a significant inhibition of tumor growth.189 G250-based radioim-
cofactor necessary for transcription. Certain receptors of the tyro- munoimaging has been used in phase II clinical trials for primary
sine kinase family, like insulin-like growth factor receptor (IGFR), and metastatic lesion detection and guiding radioimmunotherapy
epidermal growth factor receptor (EGFR), and HER2/neu, can acti- after G250 was labeled with effective therapeutic radioisotopes
vate HIF-1α and regulate the transcriptional activity through the including 177Lu, 90Y, or 186Re.190 Using phage display technology,
PI3K/Akt/mTOR pathway.173 HIF-1α overexpression is present in a Ahlskog et al.191 described the generation of high-affinity human
wide variety of malignant tumors such as clear cell carcinoma, monoclonal antibodies (A3 and CC7) specific to human CA IX,
ovarian carcinoma, gastric carcinoma, breast cancer, soft tissue which may serve as broadly applicable reagents for the noninva-
sarcoma, bladder cancer, head and neck cancer, rectal, lung cancer, sive imaging of hypoxia and for pharmacodelivery applications.
and cervical carcinoma.175,176 Some studies showed that high level Although the combination of CA IX and a proliferation marker can
of HIF-1α expression indicates poorer outcomes.177 Because of the identify cells that are proliferating under hypoxic conditions,192,193
widespread overexpression of HIF-1 and its influence on multiple there is no correlation between the amount of CA IX and direct
cellular functions, HIF-1 has become a promising diagnostic and oxygen measurement with the needle electrode.194
therapeutic target as an endogenous hypoxia-related marker. Many additional hypoxia-related markers have been reported
Optical imaging methods have played an important role in eval- to be induced by hypoxia and expressed in hypoxic human tumors.
uating hypoxia, especially in the evaluation of biopsy specimens. For example, both VEGF and glucose transporters (GLUTs) were
Several elegant methods have been developed to directly measure upregulated by increased HIF-1 activity under hypoxia condi-
HIF-1 activity by the introduction of transgenes with HREs as pro- tion.195–197 Imaging strategies targeting to these proteins have also
moter sequences coupled to reporter genes such as luciferase178,179 been intensively investigated to reflect tumor vasculature and pro-
or green fluorescent protein (GFP).180 In these studies, a luciferase liferation. A direct relationship between pO2 measurements and
reporter gene under the regulation of an HIF1-dependent pro- protein expression, however, has not been established.198,199
moter has been developed. It can express a 100-fold increase of
luciferase response to hypoxia and has been used to evaluate the
efficacy of hypoxia-directed therapy in animals.181 Shinae et al. Conclusions
developed an imaging probe for HIF-1–active cells with a PTD–ODD
fusion protein. Because PTD–ODD fusion proteins underlie the Among the various techniques to measure tumor hypoxia, PET
same ODD control as HIF-1α, they are expected to be colocalized imaging with hypoxia-specific probes is definitely the most inten-
with HIF-1α.182 The group first constructed PTD–ODD-enhanced sively investigated. Several imaging agents, such as 18F-FMISO,
18
GFP labeled with near-infrared fluorescent dye Cy5.5 for use as a FAZA, and Cu(II)-ATSM, have been extensively applied in the
model protein. The results showed that the imaging probe perme- clinic and the data so far supports the promising potential of PET
ated cell membrane with high efficiency, and its stability was con- imaging in hypoxia evaluation. Consequently, noninvasive mea-
trolled in an oxygen concentration-dependent manner. The probe surement of hypoxia in solid tumors is predictive of drug resis-
accumulated in hypoxic tumor cells with HIF-1 activity, and in con- tance and radioresistance, dose painting, and monitoring tumor
trast to the surrounding cells that were under aerobic conditions, response early after the onset of the treatment. These approaches
the hypoxic tumor cells with HIF-1 activity were thus imaged with are promising although inconsistency and controversy still exist.
good contrast.182 Viola et al.183 also used bioluminescence imaging More accurate and comprehensive evaluation of tumor hypoxia is
to noninvasively image the upregulation of HIF-1α in vivo after che- expected with novel imaging probes, advanced or combined imag-
motherapy. These imaging tools are useful for studying the biology ing instruments, and better alignment of microscopic observation
of hypoxia and mechanisms of response to experimental therapy and macroscopic evaluation.
but the heterogeneity of the gene response makes HIF-1 a complex
target.
However, many studies showed only weak correlation between Future Considerations
HIF-1α expression and oxygen electrode or PET imaging measure-
ments.184,185 For example, the HIF-1α–positive tumor section sur- The ideal technique for hypoxia measurement should be clinically
face was much smaller than the tumor section surface of increased safe, readily available, minimally invasive, with high resolution, and
18
F-FAZA uptake, suggesting that both markers are identifying disease-of-use. With the number of techniques available to measure
tinctly different biologic processes associated with hypoxia.135 hypoxia, including polarographic needle electrode methods, IHC
Moreover, the HIF-1α–positive tumor cell fraction was not signifi- staining, PET, MRI, optical imaging with NIR fluorescence or biolu-
cantly influenced by breathing conditions and covered between minescence, it is crucial to determine the pros and cons of each
0% and 35% of the total tumor section surface. method before clinical application. There are many PET imaging
probes available, each with its own merits and shortcomings. Thus,
more preclinical animal experiments and clinical data are required
Carbonic Anhydrase IX to identify which method best defines hypoxia. Furthermore, a
One downstream target of HIF-1 is carbonic anhydrase IX (CA IX). technique to differentiate acute from chronic hypoxia is needed.
CA IX is one of the 14 members of the CA family, existing in cyto- Tumor tissue oxygenation is very heterogeneous, both spatially
solic, membrane-associated, mitochondrial, and secreted carbonic and temporally. Heterogeneity has an important impact on appli-
anhydrases.186 CA IX is a membrane-associated enzyme involved cation of the imaging techniques to stratify patients and predict
in the respiratory gas exchange and acid–base balance. The pres- outcomes. Consequently, an effective way to assess heterogeneity
ence of CA IX is limited in normal tissue in gastric mucosa, small has to be established. Synergistic effect of multimodality imaging
intestine, and muscle. The overexpression of CA IX under hypoxic and multiplexed imaging may be helpful to address the heterogeneity

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C h apt e r 3 6
Radionuclide Imaging of Tumor Cell Apoptosis

Paola A. Erba • Chiara Manfredi • H. William Strauss • Giuliano Mariani
Introduction All these steps that allow the cell to die without inducing inflam-
matory response make apoptosis different from necrosis, which is
The term “apoptosis” refers to the biologic process of programmed characterized by the primary loss of cell membrane function and
cell death, an active process requiring energy and regulated by the integrity, with consequent release into the environment of cyto-
activation of specific genes, whose transcription and translation plasm components causing local inflammation (Fig. 36.1).22
into active proteins determine death of the cell. The word “apopto- It was subsequently observed that apoptosis occurs physiologi-
sis” derives from two Greek roots, “apo” (which means from) and cally in many circumstances, both during embryologic develop-
“ptosis” (which means falling). It was first coined by Kerr et al.1 ment23 and in adult life. In embryos, apoptosis is a mechanism that
over 40 years ago while investigating the rapid involution of hepatic limits excessive proliferation (mitosis) during organogenesis. In
parenchyma in response to acute surgical interruption of the portal adults, apoptosis regulates proliferation of immune cells and death
venous blood supply to the liver.2 They demonstrated that cells because of viral infection, serving as a mechanism of defense from
the outer injuries. For instance, neoplastic transformation can be

within the ischemic hepatic lobes, interspersed among islands of
normal tissue, transformed into small round vesicles of cytoplasm considered as a condition characterized by a high rate of cell pro-
liferation not counterbalanced by a corresponding higher of apop-

that often contained specks of condensed nuclear chromatin. These
vesicles were then taken up and ingested by surrounding cells as tosis level.
well as by specialized (professional) mononuclear phagocytes. In physiologic conditions, the apoptotic machinery can be acti-
Although it was clear that these were dying cells, the process vated by different stimuli such as cytokines, severe DNA damage
profoundly differed from necrosis because of the following: (i) the with no possibility of repair, decline of growth factors, low ATP
lack of adjacent inflammation; (ii) the mitochondria and ribosomes supply, and various physical or chemical stimuli.24 On the other
contained in the round vesicles remained intact throughout the hand, causes of impaired activation of physiologic apoptosis can be
process; and (iii) the aggregation of vesicles into clusters, which found in specific mutations of cell cycle checkpoints where specific
strongly suggested the “budding” or formation of these structures proteins are downregulated.
from the surface of the dying cell. Apoptosis is a highly complex mechanism that can be activated
This new type of cell death contrasted with typical necrosis, in by different signals that lead to the activation of specific apoptotic
which dying cells lose membrane integrity, begin to swell up, then pathways but focus on the same end-point targets consisting of
they spill their contents into surrounding tissues, thus causing local DNA fragmentation (with DNA laddering at 180- to 200-bp intervals),
inflammation. Because the cells that Kerr observed in the liver formation of the apoptotic body, and subsequent phagocytosis. The
actually decreased in size as they died, this type of cell death was two different basic pathways activating apoptosis can be summa-
also defined as “shrinkage necrosis.” Phenotypic appearance of rized as follows (Fig. 36.2):
apoptosis was soon reported to occur also within histologic speci- • The extrinsic pathway represented by the tumor necrosis fac-
mens of basal cell carcinoma,3 within cancer specimens obtained tor (TNF)-related apoptosis-inducing ligand (TRAIL) and its net-
from sites treated with radiotherapy, and within the adrenal cortex work of receptors.25
of rats treated with prednisolone.4 In addition, apoptosis associ- • The intrinsic pathway including the mitochondrial pathway and
ated with regression of experimental rat breast carcinoma after the endoplasmic reticulum pathway.26,27
removal of the ovaries5 was also demonstrated.
However, the biologic mechanisms and pathways that drive A specific family of cysteine–aspartate-specific proteases called
apoptosis were at that time unknown. Continued investigation has caspases plays a crucial role in the execution of apoptosis (Fig. 36.3).
shown that the histologic changes of apoptosis are preceded by an These proteases are activated by specific cleavage at an aspartic
initiation stage called the “lag or trigger phase”6–9 and multiple acid residue. Caspase family includes 14 different components that
triggers of apoptosis have now been identified, such as withdrawal are present in virtually all cells.28 Caspases are activated by proteo-
of growth factors, DNA damage, immune reactions, ionizing radi- lytic cleavage of the zymogen through a reaction where the initiator
ation, chemotherapy, and ischemic injury.10–13 These and other caspases activate the executioner caspases. The executioner cas-
triggers can start a cascade of events that lead to the morphologic pases are the effector molecules responsible for the phenotypic
changes of apoptosis. The lag time between exposure to the appearance of apoptotic cells. Such activation may occur in response
trigger(s) and the time when morphologic signs of apoptosis can to different stimuli, including developmental signals, as well as vari-
be observed highly variable as it heavily depends on cell type, type ous forms of persistent cellular stress or injury.29
of trigger(s), intensity and exposure, duration of trigger, and local Initiator caspases, caspase-8, -9 and -10, activate the execu-
environmental conditions.14 tioner caspases. Caspase-3, -6 and -7, the executioner caspases,
have multiple intracellular targets, including inactivation of DNA
repair enzymes and activation of DNA cleavage. Initiator caspases
Apoptosis have long prodomains, whereas executioner caspases have short
prodomains. The prodomain of the initiator caspases contains
The apoptotic process can be divided into four different phases15,16: protein–protein interaction motifs for binding to upstream adaptor
Initiation, execution, recognition/phagocytosis of the apoptotic bod- molecules.
ies, and removal. All these phases, characterized by specific events, Caspase regulation is under dual control by both activating
are morphologically defined by cell shrinkage and by a specific pat- factors (Apaf-1 and cytochrome c) and inhibiting factors (inhibitor
tern of chromatin condensation, resulting in a dense crescentic of apoptosis proteins, IAPs), whose activity is in turn regulated by
mass close to the nuclear margin.17,18 Budding of the apoptotic bod- a complex network of upstream signaling pathways. Each caspase
ies and the expression of new molecules on the cell surface serve as is also associated with a specific inhibitor, allowing the system to be
recognition signal for phagocytes to engulf the apoptotic cell, which strictly regulated by several positive and negative feedback mecha-
thus dies without inflicting damage to viable neighboring cells.19–21 nisms. The final enzyme activated within the cascade is caspase-3,
549

Figure 36.1. Schematic representation of the phenotypic cellular events leading to necrosis (upper pathway) or to apoptosis (lower pathway) following a variety
of initiators. (From Galluzzi L, Vitale I, Abrams JM, et al. Molecular definitions of cell death subroutines: Recommendations of the Nomenclature Committee on Cell
Death 2012. Cell Death Differ. 2012;19:107–120, with permission.)
which is activated both in the extrinsic pathway (by activation of from the exoplasmic to the cytoplasmic leaflet if PS appears in the
the FAD CD95 receptor) and the intrinsic (mitochondrial) pathway exoplasmic leaflet. APLT is a member of the family of P4-type
and it is responsible for the activation of the target protein leading ATPases, a class of ATPases that mediate in an ATP-dependent
to DNA cleavage or disassembling of the cytoskeleton. manner the transbilayer movement of phospholipids.34 APLT activ-
After activation of caspase-3, the morphologic events of apopto- ity is present mostly in blood cells (including erythrocytes, leuko-
sis quickly follow, resulting in the orderly breakdown of cellular cytes, platelets, and nucleated cells in the bone marrow),35 where
proteins (including the cytoskeleton and nuclear matrix), and in the they reside in the membrane and in trans-Golgi and Golgi-derived
activation of poly-ADP-ribose polymerase (PARP), an enzyme that secretory vesicles. Once established, PS asymmetry between the
facilitates the degradation of nuclear DNA into 50- to 300-kb-sized inner and outer leaflets of the plasma membrane is stable and is
pieces (DNA ladder formation). These morphologic events are col- maintained by “translocase,”36 whereas “floppase” maintains an
lectively called the “execution phase.” The hallmark of the start of asymmetric distribution of different phospholipids.37–39
the execution phase is redistribution and exposure of phosphatidyl- APLT activity is required again if disturbances caused by, for
serine (PS) on the outer layer of the cell membrane (Fig. 36.4).30 example, membrane fusion processes during endo- and exocytosis
PS is a negatively charged aminophospholipid present in all cells occur. Inhibition of APLT activity only results in a slow rate of PS
that constitutes approximately 2% to 10% of total cellular lipid. exposure,40 thus indicating that PS asymmetry of the plasma mem-
Mammalian cells synthesize PS predominantly by converting phos- brane is important for cell homeostasis. Certain conditions can
phatidylcholine (PC) and phosphatidylethanolamine (PE) through a cause translocation of PS to the outer leaflet of the plasma mem-
serine exchange reaction. The enzymes PS-synthase 1 and 2, pres- brane, where it may initiate and participate in humoral and cellular
ent in the endoplasmic reticulum, catalyze the conversion having processes such as blood coagulation and phagocytosis. In this pro-
PC and PE as the substrates, respectively. PS appears to be crucial cess a third enzyme, “scramblase,”41 together with the simultane-
to the cell and, as such, is produced by different biosynthetic routes ous calcium ion–dependent deactivation of “translocase” and
that can compensate each other to maintain a certain minimal level “floppase,” is needed to redistribute phospholipids on the plasma
of PS in case one route fails.31,32 Several transport mechanisms membrane. Scrambling (a rapid, ATP-independent and nonphos-
including vesicular transport and lipid-transfer protein-mediated pholipid-species–selective event) causes randomization of the phos-
lipid-exchange between juxtapositioned bilayers33 allow PS to reach pholipids over the two membrane leaflets. Scramblase operates in
the cell membrane, where it is subject to the action of the amino- erythrocytes,42 in activated platelets,43 and in apoptotic cells.44
phospholipid transporter (APLT), which translocates PS rapidly Phospholipid scramblase 1 (PLSCR1) seems to be the protein more

Chapter 36 Radionuclide Imaging of Tumor Cell Apoptosis 551

Figure 36.2. A: Extrinsic apoptosis. Upon binding
of the FAS ligand (FASL), the cytoplasmic tails of FAS
(also known as CD95, a prototypic death receptor)
trimers recruit several proteins, including FAS-asso-
ciated protein with a death domain (FADD), cellular
inhibitor of apoptosis proteins (cIAPs), c-FLIPs, and
procaspase-8 (or -10). This event results in activation
of caspse-8 and -10, according to a sequence that
has been denominated “death-inducing signaling
complex” (DISC). Nevertheless, within the DISC, there
are some proteins that exert prosurvival functions
(c-FLIPs and cIAPs). When lethal signals prevail, acti-
vated caspase-8 can directly trigger the caspase
cascade by proteolytic maturation of caspase-3 (in
type I cells) or can stimulate mitochondrial outer
membrane permeabilization (MOMP) by cleaving the
BH3-only protein BID (in type II cells). Dependence
receptors such as DCC or UNC5B, which relay lethal
signals in the absence of their ligand (netrin-1),
can also initiate extrinsic apoptosis, by activating
caspase-9, through the assembly of a DRAL- and
TUCAN- (or NLRP1-) or by the dephosphorylation-
mediated activation of death-associated protein
kinase 1 (DAPK1) by UNC5B-bound protein phospha-
tase 2A (PP2A), respectively. DAPK1 can mediate
the direct activation of executioner caspases or favor
MOMP. (continued ) A
often involved in phospholipid scramble of the membrane.45 that is independent of cell type and of cell-death–inducing trigger51
However, cells are able to scramble plasma membrane phospholip- and is phylogenetically conserved.52
ids in the absence of PLSCR1,46 and the level of PLSCR1 expression In the early phases of apoptosis, before the start of autodiges-
is not correlated with the capacity to externalize PS during apopto- tion of DNA and the self-packaging of intracellular contents, cells
sis.47 No other candidate mechanisms have been hypothesized, can also be directly engulfed by phagocytes. It is currently unclear
thus indicating complexity of phospholipid scrambling and, possi- which of these modes of apoptotic cell removal dominates in vivo.
bly, diversity in scrambling mechanisms.48 The mode of removal may in fact depend on the actual local condi-
Translocation of PS to the membrane exoplasmic leaflet does tions surrounding unwanted cell(s).
not compromise the barrier function of the membrane. Once in the
exoplasmic leaflet, PS may participate in a variety of processes
depending on type and localization of the PS-exposing cell. Cell sur-
Modulators of Apoptosis
face expression of PS has been found with aging erythrocytes, acti- Apoptosis can be regulated by different modulators such as ions,
vated platelets, activated macrophages, endothelial cells of tumor genes, proteins, and cellular organelles (mitochondria or endoplas-
blood vessels, apoptotic cells, apoptotic bodies, and cell-derived mic reticulum). Calcium ions are constantly required during the
microparticles. apoptotic process and are necessary to activate endonucleases,
The exposure of PS functions as target for the so-called profes- transglutaminase-specific proteases, reorganization of the cytoskel-
sional phagocytes, such as monocytes and macrophages or, at a eton, and scramblase.
slower pace, adjacent stromal cells such as fibroblasts and vascu- Besides calcium ions, different proteins can determine whether
lar smooth muscle cells that are responsible for ingesting the small apoptosis proceeds or stops. This is the case for the Blc-2 family,
membrane-bound packets called “apoptotic bodies.” Inhibition of composed by proteins subdivided into two groups on the basis of
PS exposure greatly impairs phagocytic capacity of the activated their proapoptotic or antiapoptotic activity, respectively.
macrophages.49 First described for apoptotic lymphocytes,50 PS Similarly, as the Bcl-2 family components, p53 protein (so
exposure is recognized as a ubiquitous phenomenon of apoptosis denoted because its molecular weight is 53 kDa and also called

Figure 36.2. (Continued ) B: Intrinsic apoptosis.

Multiple intracellular stress conditions (e.g., DNA dam-
age, cytosolic Ca2+ overload) generate prosurvival and
prodeath signals and converge to a mitochondrion-
centered control mechanism. If lethal signals prevail,
MOMP leads to dissipation of the mitochondrial trans-
membrane potential (Δym), arrest of mitochondrial ATP
synthesis, and Δym-dependent transport activities.
Moreover, uncoupling of the respiratory chains leads to
overgeneration of reactive oxygen species (ROS), and
release into the cytosol of proteins that are normally
confined within the mitochondrial intermembrane
space (IMS). In particular, cytochrome c (CYTC) and
the cytoplasmic adaptor proteins APAF1 and dATP
drive the assembly of the apoptosome, a multiprotein
complex that triggers the proteolytic caspase-9 →
caspase-3 cascade. (From Galluzzi L, Vitale I, Abrams
JM, et al. Molecular definitions of cell death subrou-
tines: Recommendations of the Nomenclature Com-
mittee on Cell Death 2012. Cell Death Differ. 2012;
B 19:107–120, with permission.)
Figure 36.3. Cross-talk between the inflammatory and apoptotic caspase

network, illustrating the analogies and overlaps between formation of the
inflammasome and apoptosome. Bold arrows are established links, and dashed
arrows indicate possible interactions not yet fully established.


Figure 36.4. Schematic representation of phosphatidylserine (PS)

redistribution on the cellular membrane and formation of blebs during
apoptosis. PC, phosphatidylcholine; PE, phosphatidyl-ethanolamine. (From
Blankenberg FG, Norfray JF. Multimodality molecular imaging of apoptosis
in oncology. AJR Am J Roentgenol. 2011;197:308–317, with permission.)
“the Genome Guardian”) plays a crucial role in the activation or and TRADD) at their intracellular site, the death domain (DD). The
inhibition of the apoptotic process. The p53 protein is normally complex is able to recruit procaspase-8 that, once activated, in turn
involved in cell cycle progression, senescence, DNA metabolism, activates procaspase-3, or cleavage of the proapoptotic protein Bid,
angiogenesis, and cellular differentiation. In particular, p53 plays a that belongs to Bcl-2 family. Bid is activated by proteolysis and is
crucial role in blocking the cell cycle progression and/or in induc- able to penetrate into the mitochondria, thus determining release of
ing apoptosis in response to cellular stress or DNA damage.53 In cytochrome c in the cytosol.
physiologic conditions, the transcription of p53 is downregulated Among the intracellular factors, p53 is activated by severe DNA
by the transcription factor Mdm2 (murine double minute 2), which damage, such as exposure to x-ray, chemotherapeutic agents, and
inhibits the activation and accelerates the degradation of p53 upon various physical or chemical agents. For example, the rapid activa-
binding; however, if DNA is damaged, specific protein kinases tion of p53 caused by ionizing radiation is mediated by the ataxia-
(depending on the type and severity of damage) phosphorylate p53 telangiectasia–mutated (ATM) kinase. Upon activation, p53 and its
and disrupt its binding with Mdm2, thus prolonging its biologic downstream effectors (e.g., p21) regulate different responses,
half-life. The activation of p53 determines either a mechanism including cell cycle checkpoints, apoptosis, and stress-induced pre-
repairing DNA damage, or (for more severe DNA damage) activates mature senescence (SIPS). In most human cell types, the primary
apoptosis. response triggered by moderate doses of DNA-damaging agents is
Cytochrome c is also crucially important for apoptosis. Because not apoptosis but a sustained proliferation block.55–58 The prolif-
it is normally located in the inner mitochondrial membrane, its eration block triggered by ionizing radiation predominantly
release indicates that an irreversible stage of apoptosis has been induces SIPS in p53-proficient cultures,59 whereas it induces the
reached. Cytochrome c binds to APAF1 and to caspase-9 forming formation of multinucleated and polyploid giant cells in p53-
a complex called “apoptosome” that, together with ATP, induces deficient cultures.60 Evidence is emerging that such responses may
activation of the executioner caspase-3. represent cell survival mechanisms consequent to treatment with
Mitochondria represent the core subcellular organelles in the ionizing radiation. If DNA damage is severe and not repairable by
execution of apoptosis. There are different proteins or factors that the repair machinery, p53 is able to induce apoptosis by increasing
are normally located in the inner layer of the mitochondrial mem- the levels of Bax (a proapoptotic protein belonging to the Bcl-2
brane. Among these, it is important to mention the apoptotic inducer family), thus altering the Bcl2/Bax ratio. Upon activation, Bax
factor (AIF), which is responsible for a caspase-independent apop- moves from the cytoplasm onto the mitochondrial membrane,
totic pathway. The mechanism by which AIF and cytochrome c are where it induces formation of a pore that causes the release of
released from mitochondria is not well defined. AIF-dependent cytochrome c from the mitochondria. The process continues on
apoptosis seems to be activated in ATP deprivation conditions.54 with formation of the apoptosome and subsequent activation of
procaspase-3.
The third apoptotic pathway is activated by damage/stress of the
Induction of Apoptosis endoplasmic reticulum (ER). In fact, also on the ER surface there
Apoptosis can be activated either by extracellular or by intracellular are various proteins involved in apoptosis. Caspase-12 (a murine
factors, depending on the specific signal, for example depletion of a caspase not yet identified in human tissues) is specifically associ-
growth factor. Extracellular factors correspond to specific ligands ated with the ER stress, and its activation occurs as a response
that activate a specific apoptotic pathway by binding to their spe- to ER stress either by the activation of calpain or by cleavage of
cific receptor(s), which are therefore called “death receptors.” These caspase-7. An additional mechanism of induction can be linked to
receptors, normally located on the cell membrane, are members of IRE-1, that can aggregate procaspase-12 at the ER membrane sur-
the TNFR family, such as Fas APO-1 and Fas CD95, TNF receptor-1 face; recruiting of the cytosolic protein adaptor TRAF2 results in
(TNFR-1), DR-3 (TRAMP), DR-4 (TRAIL-R1), and DR-5 (TRAIL-R2). cleavage and activation of caspase-12, presumably via an induced
When a “death ligand” (TNF or CD95L) binds to its specific proximity mechanism. Combination of caspase-12 with caspase-
receptor, the activated receptor recruits the adaptor proteins (FADD 9 mediates a new intrinsic apoptosis pathway, apoptosome- and

mitochondria-independent. Nevertheless, an ER-dependent apop- but can also be activated by the adaptor proteins at the cytoplas-
totic pathway can be activated also by a different protein, BAP31; this mic site of the death receptors described above.
protein is normally located on the ER transmembrane space, where Although activation of a particular caspase following an apop-
it normally acts by binding with nascent membrane proteins in tran- totic stimulus is mostly tissue-specific, caspase-3 is ubiquitous.
sit between the ER and cis-Golgi network and exists in a complex Caspase-3 is activated in the final phase of apoptosis, causing DNA
with procaspase-8 and the antiapoptotic regulators Bcl-2 or Bcl-x. cleavage.
ER stress or other apoptotic signals lead to the cleavage of BAP31, Caspases can act on different substrates, mostly intracellular sig-
with formation of the p20 fragment that initiates the following cas- nal transporters. The most important and more extensively investi-
cade: release of Ca2+ from the ER, upatake of Ca2+ into the mitochon- gated substrate is PARP-1, a conserved multi-domain enzyme that is
dria causing release of cytochrome c and initiation of apoptosis. present in virtually all eukaryotes (except in yeast). PARP-1 is nor-
Furthermore, caspase-8 can cleave BAP31 at the ER and thus stimu- mally stored into the nucleus in an enzymatically inactive form
late Ca-dependent mitochondrial fission and enhances the release of bound to chromatin, with a density of 1 every 20 nucleosomes.
cytochrome c. Thus, the caspase-derived fragment of BAP31 may When DNA damage occurs, PARP-1 catalyzes the cleavage of its sub-
coordinate cell death signals between the ER and mitochondria. strate NAD into nicotinamide and ADP-ribose and polymerizes long
ADP-ribose chains onto core histones, linker histone H1, and many
Regulation of Apoptosis by the Bcl-2 other nuclear proteins (heteromodification), as well as onto itself
(automodification). The final target of this chain is to activate the
Family Proteins repair system in case of mild DNA damage; whereas, in severe DNA
The Bcl-2 family is composed of about 30 different members that damage, a different mechanism leading to cellular death is acti-
result from the interaction of about 25 genes and can be classified vated. Other substrates for caspases are pRB, NuMA, DNA-PK. pRb
on the basis of their proapoptotic or antiapoptotic activities. The is the product of the retinoblastoma gene determining cell cycle
presence of four conservative domains (BH1–BH4) permits to clus- arrest; denomination of this gene derives from the childhood cancer
ter these proteins into a single family, the denomination of which retinoblastoma, because of somatic mutation of both alleles of the
derives from the prototype protein, Bcl-2 (the 26-kDa product of gene. Nuclear mitotic apparatus (NuMA) and DNA-PK, a critical
the bcl-2 gene). In particular, the BH4 domain is present in all the component of the nonhomologous end-joining pathway, influence
antiapoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w, whereas which pathway is ultimately utilized for repair.
the BH3 domain is typical of the proapoptotic proteins such as Bax,
Bad, Bak, and Bok. Most of these proteins (that have at their
C-terminus a group of hydrophobic amino acids permitting anchor- Apoptosis and Disease
age to membranes) are localized on the outer mitochondrial mem-
brane and enable MOMP; alternative locations are in the endoplasmic Control of apoptosis is critical for normal tissue development, and
or nuclear membrane. tissue homeostasis, whereas inhibition of apoptosis contributes to
In normal condition the Bcl-2 protein is mostly localized in the the development and progression of cancer.62,63 Recognition and
cytosol but, in response to an apoptotic stimulus, it moves onto clearance of PS-expressing cells are extremely efficient in healthy
the external mitochondrial membrane, where its overexpression tissues, which therefore contain, if any, a low steady-state level of
enhances resistance to apoptosis61 by maintaining impermeability PS-expressing cells. Different pathologic conditions can shift the
and the membrane potential of mitochondria. However, the activa- balance between appearance and clearance of PS-expressing cells
tion of Bax or Bak disrupts mitochondrial permeability, with con- toward a sustained presence of PS-expressing cells as well as of cell
sequent release of cytochrome c and Smac/DIABLO from the remnants, such as apoptotic bodies and cell-derived microparticles
mitochondria and formation of the apoptosome complex. Follow- in tissues. Many tissues can tolerate a surprisingly high level of cell
ing an appropriate injury, Bax (which is normally confined in the death, because they compensate for the loss of cells through
cytosol) binds to the mitochondrial membrane by its hydrophobic increased cell proliferation and regeneration.64 For example, a full-
anchorage and induces pore formation; thereafter, the voltage- sized mammalian liver can regenerate after as much as 75% of the
dependent anion channel is responsible for selective translocation whole organ has been removed.65 Depending on the type of tissue
of AIF, cytochrome c, and SMAC/Diablo to the cytosol. damage, these regeneration processes involve several steps, includ-
Bid, Bax, and Bad are also crucially important for perpetuating ing wound healing, the formation of proliferative blastema cells,
apoptosis. Bid is cleaved by caspase-8, and the fragment containing differentiation, and patterning.66 As hypothesized as early as
the BH3 domain activates release of cytochrome c. Bid functions as 1988,67 work in several model organisms has revealed that, unex-
a proapoptotic factor acting in two ways: The first mimics the Bax pectedly, apoptosis may also drive cell proliferation during tissue
pathway (pore formation), whereas the second one inhibits forma- regeneration.68–76 In particular, the proliferation component of
tion of the Bcl-XL-Apaf-1 complex. Bad activates the apoptotic regeneration, including the formation of blastema cells, is under the
pathway because its phosphorylated form binds to and inhibits the control of apoptotic cells through a series of events that has been
antiapoptotic Bcl-x and Bcl-2 proteins, thus allowing the continua- termed “apoptosis-induced compensatory proliferation.”77
tion of the apoptotic cascade. However, mitogenic signaling by apoptotic cells may contribute
The Bcl-2 family includes members that exert their activity in also to the development of neoplasms. The old concept that tumors
the cytoskeleton too, where the final target is disassembling of the resemble wounds that do not heal78,79 has more recently been sup-
microtubules operated by the Bim protein, which is normally ported by the observation that several pathways involved in tissue
sequestered as a microtubule-associated dynein motor complex. By regeneration and stem cell self-renewal play prominent roles in
moving to the mitochondria during apoptosis, Bim enhances the human cancer as well.80–85 Therefore, even if wound healing, inflam-
proapoptotic activity and induces release of cytochrome c from the mation, tissue stress, or tissue damage on one hand promote a cer-
mitochondria. tain degree of apoptosis in cancer cells, on the other hand these
dying cells may release mitogens that promote malignant growth.
Activation of Caspases as Even if the release of mitogens by apoptotic cells is not sufficient per
se to promote the overall growth of a tumor, it may nevertheless
Apoptosis-Specific Proteases stimulate proliferation of cancer stem cells86 or provide a support-
Caspases are normally present in cells in their inactive form as ive microenvironment facilitating tumor growth.87 This process
zymogene. They are activated by specific cleavage by Apaf-1 which is, could contribute to regrowth and relapse after favorable response
in turn, activated by the cytochrome c released from mitochondria, of cancer to therapy, and also to distant seeding of metastases.

This possibility deserves serious consideration for several reasons. versibly committed to apoptosis. The ability of radiolabeled annexin
First, virtually all cancer cells have acquired at least some degree of V to bind to “stressed” cells with relatively low levels of PS exposure
resistance toward apoptosis, and hence they have features of the also implies that annexin V imaging may be extremely sensitive and
so-called “undead” cells.88 Second, most existing anticancer thera- can thus be used to identify tissues or organs at risk for irreversible
pies, including radiation and chemotherapy, kill cancer cells by injury, such as seen in hypoxic-ischemic injury101 or chronic heart
apoptosis, and hence are expected to induce a “compensatory pro- failure,102 or at sites of active disease that can be seen in infec-
liferation” response. Third, it has been demonstrated that compen- tion,103,104 unstable atherosclerotic plaques,105 allograft rejection,106
satory growth is at the base of oncogenic cooperation between or autoimmune disorders.107 Therefore, imaging based on radiola-
genetically distinct cells in a Drosophila tumor model.89 Therefore, beled annexin V could be useful for the serial assessment of acute
the combination of apoptosis resistance and strong, therapy-induced and chronic disorders of organs or tissues at risk for permanent
cellular stress and damage may lead to the expansion of cancer stem damage in which prompt treatment may prevent irreversible cell
cells and hence increase the likelihood of tumor regeneration and injury and death.
development of secondary tumors. Thus, development of a cancer Most chemotherapy agents cause tumor cell death by inducing
(dysregulation leading to abnormal cell accumulation) and its suc- apoptosis, whereas resistance to anticancer treatment is believed to
cessful treatment (iatrogenic modification stimulating tumor cell involve mutations that lead to deregulated cell proliferation and
removal) may represent the two opposite sides of the apoptosis coin. suppression of the mechanisms that control apoptosis.108 Defects in
Dysregulation of apoptosis can cause either the accumulation of the apoptotic pathways are also responsible for resistance to ther-
unwanted cells (as it may happen in cancer) or the premature removal apy, and new therapeutic approaches attempting to reactivate these

of useful and/or essential cells (as it may happen in Alzheimer’s pathways bypassing the block are currently being explored.109
disease or in some autoimmune rheumatologic disorders). Analysis of timing, tissue localization, and extent of cell death

Externalization of PS on the outer leaflet of the cell membrane induced by anticancer drugs is helpful for assessing the efficacy of
does not only occur in apoptosis, as other forms of cell death can therapy.110,111 In solid tumors, assessment of drug-induced apopto-
also demonstrate this feature. PS externalization occurs in necrosis/ sis can be performed using biopsy material of paired tumor sam-
oncosis, mitotic catastrophe, cell senescence, pyroptosis, PARP-1- ples (before and after therapy) and several biopsy cores. However,
mediated cell death, and autophagy.90 In particular, autophagy levels of cell death observed in tissue sections are variable, both at
(type II cell death, also known as “self-eating”) exhibits consider- baseline and following therapy. This variability is likely to reflect
able overlap with apoptosis.91 Autophagy is initiated by derepres- tumor heterogeneity and the presence in the tumor of different
sion of the mammalian-cell target of rapamycin (mTOR Ser/Thr clones with different rates of spontaneous cell death and different
kinase), followed by formation of the Beclin-1-class III phosphati- sensitivities to the drug used. Pharmacokinetics of a chemothera-
dylinositol 3-kinase complex. This complex mediates the formation peutic drug as well as the inherent kinetics of cell death processes
of isolation membranes that engulf cytoplasmic material, thus pro- clearly also affect the results at any given time point. Imaging tech-
ducing autophagosomes. Bcl-2 and Bcl-XL are regulators of beclin-1, niques are therefore potential alternatives to serial tumor biopsy,
and constitute therefore a link with apoptotic cell death.92 Autopha- because they may integrate the overall response of a tumor and can
gosomes fuse then with lysosomes to create autolysosomes. In the therefore be less affected by tumor heterogeneity at the microscopic
autolysosome, the inner membrane and the luminal contents of the level. Modulating the apoptotic pathway offers special opportunities
autophagic vacuole are degraded without eliciting inflammation. for targeted therapeutic interventions, as direct imaging of caspase
The main role of autophagy is to remove unneeded, senescent, or activity or PS expression can be used for noninvasive monitoring of
damaged cytoplasmic contents and to allow a cell to survive peri- early drug responses to drugs.
ods of cellular famine through the autodigestion of intracellular
DNA/RNA, proteins, and lipids into free nucleotides, amino acids,
and fatty acids. Autophagic cell death can also represent an alter- Detecting Apoptosis
native to apoptosis, if this latter mechanism is damaged/inhibited.
A related form of cell death involves lysosomal stress followed Several approaches can be used to specifically stain cell suspen-
by lysosomal membrane permeabilization and release of cathepsin sions and histologic specimens for detecting apoptosis. The most
that causes generalized proteolysis. Details of when and how this widely used are based on assays for terminal deoxynucleotidyl-
process occurs are still poorly understood, but it causes expression transferase (Tdt)-dUTP nick end labeling (TUNEL), originally intro-
of PS on cell membranes to ligands. duced by Gavrieli et al. in 1992.6 TUNEL is based on the specific
Recently, reversible PS externalization in a process independent binding of TdT to the 3′-OH ends of fragmented DNA. After proteo-
of cytochrome c release, caspase activation, or DNA fragmentation lytic treatment of histologic sections, TdT incorporates X-dUTP
was demonstrated.93 However, it accounts for lower levels of PS (X = biotin, DIG, or fluorescein) at sites of DNA breaks. Terminally
exposure as compared with apoptosis and other forms of cell modified nucleotide avidin peroxidase can then amplify the signal
death.94,95 The relatively low levels of PS exposure observed with and allows the evaluation of labeled cells under light/fluorescent
reversible PS externalization can readily be counteracted by microscopy, flow cytometry, or via immunohistochemistry. Another
removal of the physiologic stressor (nitric oxide, p53 activation, DNA-based method is the detection of the internucleosomal frag-
allergic mediators, or growth factor deprivation). If the stress mentation produced by endonucleases at expected intervals of 180
remains uncorrected, the cell may undergo apoptosis. The ability to to 200 bp.112 Standard DNA extraction techniques are used to
identify cells with low, potentially reversible levels of PS exposure obtain the nucleic acids from either cells or homogenized tissue.
may explain the uptake of PS-ligands outside regions of apoptosis DNA is then submitted to electrophoresis in an agarose gel to dem-
(as seen histologically by TUNEL staining), for example, in patients onstrate the characteristic DNA ladder pattern.
with hypoxic-ischemic reperfusion injury of the heart96,97 or
brain.98–100 In fact, even in regions with apoptosis/ischemic injury,
more annexin V-positive cells after the administration of radiola-
PS-Binding Compounds
beled annexin V as compared to apoptotic nuclei at TUNEL staining Because PS externalization represents the hallmark of apoptosis, a
have been demonstrated.97 These observations suggest that annexin variety of PS-binding compounds have been extensively investi-
V uptake after ischemic reperfusion injury may be also because of gated for imaging, including proteins,113 peptides,114–117 and small
large numbers of stressed cells (not necessarily committed to apop- chemical entities.118 Peptides and small chemical compounds have
tosis) with relatively low levels of PS expression in contrast to the the advantage of being quickly and efficiently cleared from the blood
relatively fewer cells with high levels of PS exposure that are irre- circulation. Therefore, in principle they exhibit optimal properties

Figure 36.5. Three-dimensional structure of annexin V. (From Extracellular Matrix Proteins,

http://www.bbm1.ucm.es/public_html/res/prot/extmat.html; accessed January 2, 2013.)
Figure 36.6. Binding of annexin V to phosphatidylserine (PS) expressed on the outer layer of
as imaging probes, because their signal-to-background ratio is favor- cell membrane. Binding to PS occurs only after formation of a trimer structure of annexin V.
(Reproduced from “Annexins: Molecular Structure to Cellular Function.” Barbara AS, ed. Austin,
ably affected by this kinetic profile. However, the main disadvantage TX: Landes Bioscience, 1996, with permission.)
of these compounds is their low affinity for PS. On the other hand,
proteins exhibit higher affinities for PS, but they are usually cleared
from the blood circulation with slower kinetics because of their range of labeled forms of annexin V to image PS expression using
higher molecular weight. optical, radionuclide, and magnetic resonance imaging.127 Initially,
annexin V was coupled to fluorescent dye molecules and used as an
apoptosis detection reagent for fluorescence microscopy and flow
Annexin V cytometry.14 Subsequently, annexin V was coupled to a radionuclide
Annexin V, a 36-kDa vesicle-associated protein, is perhaps the most (99mTc) or iron oxide nanoparticles128 to detect apoptosis noninva-
widely investigated PS-targeting moiety. It is a nonglycosylated sin- sively in animals129 and in patients130,131 using radionuclide imaging
gle chain protein that belongs to the annexin supergene family. Its techniques or magnetic resonance, respectively.
polypeptide is organized in an N-terminal tail with a C-terminal Photonic imaging methods have also been used to image annexin
core containing four domains that form the annexin core, a slightly V labeled with fluorochromes132 or near-infrared (NIR) fluoro-
bent surface with a convex shape that interacts with the PS- chromes.133 Furthermore, Schellenberger et al.134 described labeling
containing phospholipid membrane (Fig. 36.5).119,120 Annexin V binds of annexin V with superparamagnetic iron oxide (SPIO) nanoparti-
to PS in a Ca2+-dependent manner, with nanomolar affinity. Ca2+ cles, for MR detection. Gd-containing annexin V-coated liposomes
ions bind to the annexin core surface at type II Ca2+-binding sites121 for positive or bimodal MR contrast have also been developed135,136
and form the prime contact by coordinating carbonyl and carboxyl as well as multimodal contrast agents for combined MRI and fluo-
groups of the protein and phosphoryl moieties of the glycerol back- rescent imaging.136
bone of membrane phospholipids (Fig. 36.6).120 The domains are Most preclinical noninvasive imaging of PS expression has been
composed mainly of α-helices and the Ca2+-binding sites protrude carried out with radionuclide and magnetic resonance imaging. In
as loops. The overall binding affinity for PS arises from collabora- fact, low tissue penetration of photons and autofluorescence of
tion among the Ca2+-binding sites of the four domains, with a dom- extracellular matrix components have so far hampered develop-
inant role for domain 1.122 In solution annexin V is a monomer, but ment of noninvasive optical imaging of PS expression. Recently,
once bound to PS-expressing membrane three monomers build a near-infrared fluorescent (NIRF) probes and fluorescence-mediated
trimer by protein–protein interaction; in turn, trimers assemble in tomography (FMT) have been developed, thus making noninvasive
a two-dimensional lattice covering the PS-expressing surface by optical imaging feasible.137 Second-generation annexin A5 has
trimer-trimer interactions (Fig. 36.7).123 Therefore, such two- been coupled to the NIRF probe Vivo-750 via thiol chemistry and
dimensional protein network of annexin V at a PS-expressing cell employed successfully to quantify the anticancer effect of cytotoxic
surface determined internalization of annexin V124 by a unique compounds in a mouse cancer model using noninvasive FMT.
pathway of pinocytosis. This pathway is initiated by disassembly of
the cortical actin network underlying the PS-exposing membrane
Radionuclide Labeling of Annexin V
patch. Annexin V then binds to PS and crystallizes on the cell sur-
face as closely packed trimers that cause the underlying membrane Radiolabeling of rh-annexin V with 99mTc-pertechnetate can be
to bend inward. The invaginated membrane patch then closes on performed by the penthioate radioligand (N2S2) method.138 This
itself and is transported into the cytosol in a microtubule-dependent method starts with the chelation of 99mTc in the presence of stan-
manner. This pathway does not seem to be related to clathrin- or nous gluconate to yield 99mTc-gluconate, which is then reacted with
caveolin-mediated endocytosis, as it is neither actin-driven nor pre- acidified penthioate ligand (tetrafluorophenyl 4,5-bis-(S-1-ethoxy-
ceded by membrane ruffling.125 ethylmercaptoacetamido) pentanoate, TFP) under heating to form a
Recombinant human (rh) annexin V exhibits PS-binding prop- stable 99mTc-N2S2 complex. The technetium diamide dimercaptide
erties identical to those of annexin V purified from human tissue.126 N2S2 ester complex is then randomly conjugated to the N-H groups of
Availability of recombinant annexin V spurred synthesis of a wide lysine of the protein at basic pH. However, the N2S2 labeling method


Figure 36.7. Structural modifications of
annexin V, enabling its binding to phosphati-

dylserine expressed on the outer layer of the
cell membrane. Upper panels: Trimer of the
annexin V-calcium complex represented in
the solid state from the top (upper left) and
from the side (upper right) of the three-fold
axis. The protein backbone is in blue, calcium
ions are in magenta, and sulfate ions are ren-
dered as balls and sticks. Subunits within the
trimer are arranged so that the ion channels
within each subunit are parallel to the three-
fold axis. Lower panels: Annexin trimer in
presence of zinc ions rather than calcium
ions, represented in the solid state from the
top (lower left) and from the side (lower
right) of the three-fold axis. In this case the
three subunits arrange to form a propeller-like
structure, with more globular trimer–trimer
arrangement, is more globular; orientation of
the ion channels is not parallel, and thus can-
not interact with the phospholipid bilayer
simultaneously. (Source: http://www.chem.
sc.edu/faculty/lebioda/projects/anxV.htm;
accessed January 2, 2013).
is cumbersome, has low labeling efficiency (30% to 40%), and entails adversely affecting its binding affinity for PS.128,143–146 These pro-
a high nonspecific excretion of radioactivity into the bowel via bili- teins have an endogenous site for 99mTc chelation consisting of six
ary excretion. For these reasons, an improved labeling method amino acid tags added at the N-terminus, followed by the 1 to 320
using the bifunctional agent hydrazinonicotinamide (HYNIC) was amino acid sequence of wild-type annexin V, with only the amino
selected for clinical trials.139 In this procedure, HYNIC (succinimidyl acid cys-316 mutated to serine. 99mTc chelation is thought to occur
[6-hydrazinopyridine-3-carboxylic acid]), also known as (succinimidyl via formation of an N3S structure involving the N-terminal cysteine
[6-hydrazinonicotinic acid]), is used to randomly modify the accessi- and the immediately adjacent amino acids. The purified protein is
ble N-terminal groups in the lysine residues of rh-annexin V. The then reduced and stored for later labeling with 99mTc using gluco-
resultant compound can then be lyophilized and stored indefinitely heptonate as an exchange reagent. Both the V-117 and V-128 vari-
for labeling with 99mTc. Labeling of reconstituted HYNIC-annexin V is ants have major advantages over HYNIC-annexin V, including a
performed simply by reacting the conjugate with 99mTc-pertechnetate 50% to 75% lower renal accumulation and a markedly improved in
in the presence of stannous tricine for 5 to 10 minutes at room tem- vivo localization to sites of apoptosis in animal models.140 Using
perature. Similarly as the penthioate radioligand (N2S2 method), related annexin mutants, it has been found that all four calcium-
99m
Tc-HYNIC-annexin V shows the greatest accumulation in the kid- binding sites are needed for full in vitro and in vivo binding of
neys, liver, and urinary bladder. However, 99mTc-HYNIC-annexin does annexin V. Mutation (loss of function) of any one of the four calcium-
not undergo any bowel excretion, thus resulting in excellent imaging binding sites decreases apoptosis-related in vivo localization of the
profile for the abdominal region. Unfortunately, 99mTc-HYNIC-annexin tracer by 25%, and any two site mutations result in a 50% decline
V exhibits high accumulation in the renal cortex, thus limiting visu- of uptake. The adverse effects of the random modification of annexin
alization of pararenal structures.138 V have also been observed with 111In-DTPA-PEG-annexin V.147 Fur-
However, because the N-H groups of lysine are also present on ther work has also established that random modification of the
the surface of the annexin V core, radiolabeling may compromise lysine residues of annexin V with HYNIC, mercaptoacetyltriglycine
its binding to PS.140 Therefore, to avoid reduction of binding affinity, (MAG3), or fluorescein isothiocyanate decreases by 50% nonspecific
annexin V variants have been generated for site-directed labeling at liver uptake of such form of annexin V compared with self-chelating
the concave side of the molecule using thiol chemistry. Thiol-linkage (site-specific) protein, as also does conjugation with biotin. Despite
sites have been obtained either in extensions of the N-terminus141,142 its prolonged circulation time, the uptake of 111In-DTPA-PEG-
or between the N-terminal tail and the concave side of annexin V, annexin V in a mammary carcinoma was not increased relative
and successfully coupled with a number of compounds without to a nonspecific control protein pegylated in the same manner.

Table 36.1
Summary of the Main Studies on the use of Radiopharmaceuticals to Evaluate Apoptosis Either In Vitro or In Vivo
Authors Experimental Timing After

(Reference) Radiopharmaceutical Model Apoptotic Stimuli Main Findings
Collingridge [125/124I]SIB-annexin V RIF-1 cells into 48 h after 5-FU single Uptake of [125I]SIB-annexin V was 2.3-fold higher in 5-FU–treated
et al.154 C3H/HeJ mice dose i.p. (165 mg/kg) tumors compared to control tumors
Khoda et al.155 99m
Tc-HYNIC-annexin + 201Tl H1299 in an ICR 48 h after 9 Gy irradiation Uptake in the 9-Gy irradiated mice was three to four times higher
nu/nu mice than that of control mice
125
Watanabe I-annexin V Ependymoblastoma After 5-Gy irradiation Peak apoptosis within 6 h increasing with radiation dose up to 5 Gy;
et al.156 no significant apoptosis increase for radiation doses above 5 Gy
Guo et al.157 99m
Tc-HYNIC-annexin V EL4 in mice After 2–8-Gy irradiation Apoptosis two times and five times more than observed in the control
group after irradiation with 2- and 8-Gy doses
Mareková et al.158 99m
Tc-annexin V HL-60 in mice Irradiation Percentage of apoptosis was higher at 48 h than 24 h after
Lin et al.159 99m
Tc(I)-his(6)-annexin A5 C57BL/6J mice 10-Gy irradiation Splenic uptake showed from three- to five-fold higher than those of
the sham-irradiated mice from 45- to 165-min post injection.
Intestinal uptake showed from ca. two- to three-fold higher. Positive
correlation with caspase-3 active immunohistochemistry
Greupink et al.160 99m
Tc-HYNIC-cys-AnxA5 — Cycloheximide and Cycloheximide treatment increased accumulation in liver and spleen
castration over controls, which correlated well with TUNEL staining. Increase
in TUNEL-positive prostate epithelial cells observed following
castration was not paralleled by greater 99mTc-HYNIC-cys-AnxA5
accumulation
Therefore, any specificity for PS in the tumor had been lost, prob- of radiolabeled annexin V when designing imaging trials for assess-
ably because the annexin V was heavily modified on amino groups ing with this agent tumor response to therapy.153 Several studies in
to attach enough PEG. Annexin V has also been proven to be quite different animal models confirm a wide variability in the time
heat-labile, as it loses most of its activity with heating at 56°C for course of radiolabeled annexin V uptake following a single admin-
10 minutes148 (whereas being quite stable at 37°C), thus precluding istration of chemotherapeutic agents (Table 36.1).154–160
99m
the use of many different types of labeling chemistries. Tc-HYNIC-annexin V is currently being investigated in Phase
Several approaches to label annexin V with fluorine-18 (18F)149 II/III trials,161 as several studies have confirmed the potential clinical
for PET imaging have been developed. One method has used N- utility of 99mTc-HYNIC-annexin V in determining the efficacy of che-
succinimidyl 4-fluorobenzoate to synthesize F-annexin V. The fluorine- motherapy.131,162–164
labeled agent has lower uptake in the liver, spleen, and kidney than In this regard, even the rate of spontaneous apoptosis assessed
HYNIC-annexin V. Another method involves site-specific derivatiza- by a pretreatment 99mTc-HYNIC annexin-V scan may be useful to
tion with an 18F-maleimide-labeled compound of mutant annexin predict subsequent response to chemo- and radiotherapy.165 In
V-117 or annexin V-128.142 However, both methods need more pre- fact, although the baseline tumor uptake of 99mTc-HYNIC annexin
clinical investigations before further development as imaging agents V differs significantly from patient to patient, in general patients
for apoptosis in patients. displaying tumor progression or stable disease exhibited a higher
Other radionuclide derivatives of annexin V have been devel- than background uptake in their tumor tissue, whereas patients
oped, including annexin V-labeled 123I150 or 124I151 and 64Cu-labeled responding to treatment display a comparable or lower than the
streptavidin for PET imaging after pretargeting of PS with bioti- background uptake in their tumor.
nylated annexin V.152 Kartachova et al.166 found that the degree of tumor response to
platinum-based chemotherapy in NSCLC patients correlated with
Pilot Clinical Applications of Imaging Apoptosis the percentage increase in tumor uptake of 99mTc-HYNIC-annexin V
versus baseline evaluated 48 hours after the first injection of cis-
with Radiolabeled Annexin V platin. Patients achieving only disease stabilization exhibited a
Using SPECT imaging with 99mTc-rh-annexin V, Belhocine et al.130 slightly increased, unchanged, or even a slightly decreased annexin
investigated 15 patients with either primary or metastatic lung can- V tumor uptake, whereas in patients with progressive disease a
cer lesions before and after chemotherapy. In this pilot study, a marked decrease of annexin V tumor uptake was observed. The
negative scan after therapy (i.e., no change in tumor uptake versus same group evaluated patients with primary untreated head and
the pretreatment baseline scan) correlated well with a lack of treat- neck squamous cell carcinoma with 99mTc-HYNIC annexin V SPECT
ment response in six of eight patients; the remaining two patients before treatment.167 On univariate as well as multivariate analysis,
(with metastatic breast cancer) actually had a clinically significant only the 99mTc-HYNIC-annexin V tumor-to-background ratio of the
response to Taxol-based chemotherapy despite no change in 99mTc- primary tumor distinguished using a cutoff value of 2 was predic-
rh-annexin V uptake. All seven patients with increased tumor tive of recurrence-free survival and of overall survival. When lymph
uptake versus baseline (i.e., positive annexin V study) had an objec- node status was considered (N0 versus N1-N2-N3 disease) 99mTc-
tive response to chemotherapy (tumor shrinkage of tumor). Such HYNIC-annexin V tumor-to-background ratios were included in the
increase in annexin V uptake was observed 40 to 48 hours after multivariate model, both N status and the 99mTc-HYNIC-annexin V
chemotherapy in five of these seven patients (1 NHL, 1 HL, 1 SCLC, tumor-to-background ratios of the primary tumor showed an inde-
and 2 NSCLC), whereas it was observed at 20 to 24 hours post pendent association with overall survival.
treatment in the remaining two patients (1 NSCLC and 1 SCLC). Treatment-induced changes of 99mTc-HYNIC-rh-annexin V uptake
These findings suggest some variability in the optimal timing for in patients with head and neck squamous cell carcinoma evaluated
imaging with annexin V following antitumor treatment, thus before and within 48 hours after the first course of cisplatin-based
emphasizing the need to define the best timing for administration chemoradiation (with a radiation dose to the tumor of 6 to 8 Gy)

was determined in primary tumor, lymph node metastases, and

normal tissue included in the irradiation field. Patients with primary
tumors with a high 99mTc-HYNIC-rh-annexin V uptake also had
high 99mTc-HYNIC-rh-annexin V uptake in lymph node metastases.
Treatment-induced increment in uptake of 99mTc-HYNIC-rh-annexin
V in primary tumors and in lymph node metastases showed large
interpatient differences. A high correlation was observed on a patient-
to-patient basis between the maximum δ-uptake induced by treat-
ment both in the primary tumor and in the lymph node metastases.
However, in this small series of patients the treatment-induced
increment in 99mTc-HYNIC-rh-annexin V uptake in primary tumor
did not predict outcome: No correlation between 99mTc-HYNIC-rh-
annexin V uptake and early response was observed. In addition,
99m
Tc-HYNIC-rh-annexin V uptake also did not predict the locore- A B
gional control rates within the first 2 years of follow-up, possibly
because of advanced stages of head and neck squamous cell car-
cinoma with large and necrotic tumors. Treatment-induced 99mTc-
HYNIC-rh-annexin V uptake in relation to radiation dose in the

parotid glands was observed, indicating early treatment-related
apoptosis in a normal tissue at mean radiation doses as low as 3 to

8 Gy and one course of cisplatin.168 The uptake of 99mTc-HYNIC-rh-
annexin V in the parotid glands showed a radiation dose-response
relationship: Glands that had received higher doses of radiation
demonstrated increased 99mTc-HYNIC-rh-annexin V uptake. Already
after a low dose (6 to 8 Gy), parotid glands may be affected, thus sug-
gesting early start of loss of parotid gland function. This is in agree-
ment with observations in experimental rodent and monkey models
in which apoptosis was induced early, after doses of up to 5 Gy.169,170
It has also been recently reported that the uptake of annexin V
in normal tissues, such as the spleen and bone marrow (that are C D
susceptible to drug-induced injury), is not significantly changed
following chemotherapy or prior administration of radiolabeled Figure 36.8. Patient with non-Hodgkin lymphoma in the left side of the neck. Axial fused
SPECT/CT images clearly show increase in 99mTc-annexin V uptake from weak prior to radio-
annexin V within a 48-hour period.171 Furthermore, the biodistri- therapy (A) to intense (B) early after starting the first course of radiotherapy. On baseline CT
bution of radiolabeled annexin V in the kidneys, liver, and whole (C) and on CT obtained 4 weeks after radiotherapy (D) a complete response is seen (circle).
body remained unchanged after chemotherapy or prior adminis- (Image courtesy of Dr. Renato A. Valdés Olmos, Nuclear Medicine Division, Diagnostic Oncology, The
tration of the same tracer. Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.)
Kartachova et al.172 systematically explored how to best assess
chemotherapy-induced increases in annexin V uptake. SPECT
studies in 38 patients with lymphoma (n = 31), NSCLC (n = 4), and of enhanced permeability and retention (caused by leaky vessels
head and neck squamous cell carcinoma (n = 3) were analyzed for and poor lymphatic drainage in tumors) that may mask small vari-
maximal counts per pixel in the tumor volume (Cmax) for every ations in specific annexin V uptake because of cell death.174 Thus,
target lesion in addition to grading on a visual four-grade score enhanced permeability and retention175 together with the effects of
(i.e., Cmax/expressed as percentages of baseline values: Grade-1, anticancer drugs on the vasculature might result in altered tracer
decrease >25%; grade 0, 1% to 25% decrease; grade +1, 1% to 25% accumulation. In fact, using a 11C-labeled Sel-tagged annexinV ([11C]-
increase; grade +2, >25% increase; visual analysis: 0 = absent, 1 = Anx5-ST)176,177 in a SCID mice implanted with human squamous
weak, 2 = moderate, 3 = intense). Both the quantitative and visual carcinoma cells, a trend to reduced [11C]-AnxA5-ST uptake 72 hours
assessments of increments in annexin V uptake after treatment after treatment with doxorubicin has been observed.178 In this
correlated well with therapeutic outcome as evaluated by RECIST regard, doxorubicin has been reported to affect endothelial cell
criteria. Excellent intra- and interobserver reproducibility was function179 and the actual imaging readout for assessing the specific
found, thus suggesting that chemotherapy-induced increases in uptake of annexin V should therefore be estimated as the difference
annexin V uptake evaluated by SPECT can be employed for the between [11C]-Anx5-ST uptake and uptake of a size-matched control
early noninvasive assessment of anticancer treatment efficacy (24 ligand ([11C]-mTrx-GFP-ST) after treatment, rather than simply the
to 48 hours after initiation of therapy), weeks before actual tumor uptake of [11C]-Anx5-ST post-doxorubicin versus baseline. Whether
shrinkage can be detected by conventional imaging. Examples of changes in passive, nonspecific tracer accumulation have influ-
clinical imaging in lymphoma patients exhibiting different responses enced the adequacy of other studies with annexin V ligands to
to radiation therapy are shown in Figures 36.8–36.10, obtained reveal therapy-induced cell death cannot be excluded.
when imaging apoptosis with 99mTc-HYNIC-annexin V. The relationship between annexin V SPECT imaging and [18F]
Semiquantitative 99mTc-HYNIC-annexin V tumor uptake (expressed FDG uptake has not been systematically compared in clinical trials.
as percent fraction of injected activity) in visible tumor lesions divided Studies in tumor models, however, have demonstrated that an
by the tumor volume derived from SPECT imaging has been found to enhanced apoptotic reaction (increased uptake of radiolabeled
correlate linearly with the histologic score of Fas ligand expression, annexin V) is correlated with decreased [18F]FDG uptake 48 hours
whereas no correlation was found with the histologic score of matrix after the start of cytotoxic chemotherapy.180 In a clinical trial of
metalloproteinase-9, as well as with the number of tumor-infiltrating 45 patients with breast cancer receiving three administrations of
lymphocytes (CD45 staining) or microvessel density.173 neoadjuvant chemotherapy, a significant reduction in [18F]FDG
Annexin V imaging can be problematic for detecting modest uptake was associated with a marked increase in the fraction of
responses to therapy, such as those often seen clinically in patients TUNEL-positive (apoptotic) tumor cells.181
with solid tumors. In fact, several factors complicate imaging of Because apoptosis is an energy-dependent process (at least ini-
tumor cell death, such as nonspecific tracer uptake in tumors because tially), glucose demand may actually increase temporarily following

A B
Figure 36.9. Patient with non-Hodgkin

lymphoma in the left axilla. Axial fused SPECT/
CT images show slight increase in 99mTc-
annexin V uptake from moderate prior to radio-
therapy (A) to moderately intense (B) early
after starting the first course of radiotherapy.
On baseline CT (C) and CT obtained 4 weeks
after radiotherapy (D) a partial response was
observed (circle). (Image courtesy of Dr. Renato
A. Valdés Olmos, Nuclear Medicine Division,
Diagnostic Oncology, The Netherlands Cancer
C D Institute–Antoni van Leeuwenhoek Hospital,
Amsterdam, The Netherlands.)
effective antitumor treatment.182 One example of such occurrence for targeting PS exposure in apoptotic cells, using bacteriophage dis-
can be the “metabolic flare” often observed on [18F]FDG PET imag- play technology. Optical imaging after the systemic administration of
ing following hormonal therapy for estrogen receptor–positive the fluorescein-labeled CLSYYPSYC peptide to tumor-bearing nude
human breast cancer.183 mice (H460-cell xenograft model) treated with a single dose of camp-
In conclusion, several issues limit clinical use of radiolabeled tothecin indicated satisfactory homing of the peptide in the tumor.117
annexin V probes. The main concern is suboptimal pharmacokinet- ApoSense molecules are small nonpeptidic fluorescent com-
ics of radiolabeled annexin V, resulting in high background activity pounds developed on the basis of the γ-carboxyglutamic acid (Gla)
in the abdominal region. Another concern is the partial inability of structure. In response to apoptosis, these molecules exhibit selec-
annexin V probes to distinguish apoptosis from necrosis, because tive membrane binding, transmembrane transport, and accumula-
PS is exposed also during necrosis because of disruption of plasma tion in the cytoplasm of apoptotic cells, being instead excluded from
membrane integrity. Finally, the optimal time window for detecting viable cells.186,187 Besides the fluorescence feature, some of these
treatment-induced apoptosis in cancer patients has yet to be ApoSense molecules contain a fluorine atom, which facilitates
defined.184 In this regard, it should be emphasized that evaluating radiolabeling with 18F for PET imaging. Recently, synthetic zinc(II)-
the time course of 99mTc-annexin V uptake is critical for any given dipicolylamine also showed some potential to image apoptotic and
clinical condition, because treatment-induced apoptosis may differ necrotic cells in vivo.188 However, further characterization of these
from tumor type to tumor type and possibly also from one chemo- apoptosis imaging probes is required to fully explore the potential
therapy agent to another agent. The clinical setting is also quite of these low–molecular-weight alternatives to annexin V.
different from the experimental animal models, where the various Besides annexin V, other proteins also bind to PS with high affin-
parameters determining detection of treatment-induced apoptosis ity. For example, the C2A domain (14.2 kDa) of another vesicle-
can be strictly controlled, including possible coadministration of dif- associated protein, synaptotagmin I, binds with nanomolar affinity
ferent pro- or antiapoptotic stimuli.185 to negatively charged phospholipids in membranes, including PS, in
a calcium-dependent manner.
Imaging Apoptosis with Phosphatidylserine-
Binding Peptides and Small Molecules Molecular Imaging of PS with Synaptotagmin I
Compared to protein probes, peptides and small molecules have As a whole molecule, synaptotagmin I is not suitable for imaging
some favorable characteristics, including fast clearance from the cir- because of its transmembrane domain. Using recombinant technol-
culation, efficient tissue penetration, and high target-to-nontarget ogy, the soluble PS-binding C2A domain was expressed by Esche-
ratios. Consequently, several peptide sequences have been screened richia coli as a fusion protein with Gluthation-S-transferase (GST).


A B

C D
Figure 36.10. Patient with non-Hodgkin lymphoma in the left groin. Axial fused SPECT/CT images show no changes in 99mTc-annexin V uptake prior to radio-
therapy (A) and early after starting the first course of radiotherapy (B). On baseline CT (C) and CT obtained 4 weeks after radiotherapy (D) no response was observed
(circle). (Image courtesy of Dr. Renato A. Valdés Olmos, Nuclear Medicine Division, Diagnostic Oncology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek
Hospital, Amsterdam, The Netherlands.)
Although the affinity for binding PS is higher for C2A (Kd = 20 to been coupled with fluorescein isothiocyanate via random chemical
40 nM) than for the fusion protein C2A-GST (Kd ≅ 115 nM), C2A-GST linkage.195 In principle, lactadherin has several advantages as a PS
was developed as a ligand because labeling of C2A reduces its PS- imaging agent over annexin V and synaptotagmin I, as its binding
binding affinity.189 Labeling of GST-C2A likely occurred predomi- to membranes is directly proportional to PS content and indepen-
nantly at the GST moiety. C2A-GST conjugated with fluorochromes, dent from both phosphatidylethanolamine and Ca2+.195 The draw-
radionuclides, and superparamagnetic iron oxide particles using back of lactadherin is its posttranslational modification, which
random chemical linkage retains its PS-binding properties.190,191 precludes expression of functional lactadherin by recombinant
Whether site-directed chemical linkage will yield a superior PS technology in an E. coli system.
imaging ligand has not been clarified so far.
On the other hand, C2A has been labeled with 99mTc for SPECT
Caspase
imaging of apoptosis in NSCLC patients treated with paclitaxel,
showing significantly increased tumor uptake post therapy.192 Caspase peptide substrates containing either a radionuclide (e.g.,
99m
Tc-C2A-GST has also been employed in a reperfused acute myo- an 18F-labeled caspase-inhibiting analog196), or a bioluminescence
cardial infarction rat model. Ex vivo and in vivo data indicate that label197 or a far-red198 or near-infrared optical fluorochrome199 have
both specific binding and passive leakage contribute to the accu- been developed to detect apoptosis. Using firefly luciferase-based
mulation of the radiotracer in the area at risk.191 Finally, a recent bioluminescence imaging in nude mice, Laxman et al.197 developed
in vitro study suggested that the C2A derivative binds more spe- a caspase-cleavable reporter probe able to detect tumor apoptosis
cifically to apoptotic and necrotic cells than does annexin V.193 following chemotherapy. Although not relevant clinically, optical
imaging techniques may become particularly useful in the screen-
ing of targeted drugs in preclinical studies.
Molecular Imaging of PS with Lactadherin By high-throughput screening and further structural optimiza-
PS imaging with lactadherin purified from bovine milk has so far tion, several isatin (1H-indole-2,3-dione) sulfonamide analogs were
been limited to in vitro studies only.194 In particular, lactadherin has identified to have nanomolar potency in inhibiting the executioner

caspases, caspase-3, and caspase-7.200 For example, small-animal A DEVD-containing cyclic luciferase to detect caspase activation
PET using 1-[4-(2-18F-fluoroethoxy)-benzyl]-5-(2-phenoxymethyl- has also been reported.209 Two fragments of DnaE intein were fused
pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (18F-WC-II-89) revealed to neighboring ends of firefly luciferase connected with a DEVD
high uptake of the radiotracer in the liver of a cycloheximide-treated sequence. After translation into a single polypeptide in living cells, the
rat, relative to the untreated control.196 Because caspases are intracel- amino and carboxy terminals of luciferase were conjugated by pro-
lular targets, the radiolabeled imaging probes are usually lipophilic or tein splicing, which resulted in a closed circular polypeptide chain.
contain a cell-penetrating moiety to achieve target access, which When the substrate sequence was digested by caspases, luciferase
dampens the enthusiasm for these probes.201 Another problem for was changed into an active form and restored its activity. Rather than
caspase-based imaging is that caspase inhibitors usually lack selec- modifying the reporter gene to respond to caspases, luciferase
tivity, as they are also effective inhibitors of various cathepsins. reporter gene substrate can also be modified to reflect caspase activ-
Recently, Bogyo’s group identified irreversible inhibitors and active ity. One such example is a proluminescent, caspase-activated DEVD-
site probes of the caspases (activity-based probes) that showed both aminoluciferin reagent (Caspase-Glo 3/7; Promega).210,211
broad and narrow selectivity within this family of proteases. Further
optimization identified sequences with lower legumain reactivity and
complete lack of reactivity toward the cathepsins.202 Optical imaging Imaging Mitochondrial Membrane Potential
probes have been developed by conjugating such activity-based Another approach to detecting apoptotic cell death is to target the
probes with near-infrared fluorescent tags and with a cell-permeable collapse of mitochondrial membrane potential (Δym), a hallmark
peptide sequence. of the initiating phase of apoptosis. Phosphonium cations are
sufficiently lipophilic to permeate the membrane lipid bilayer and
Activatable Probes for Caspases accumulate in cells as a function of the transmembrane voltage
gradient. Because of the high mitochondrial membrane potential,
The high background activity of caspase imaging with directly most of the phosphonium cations accumulate within mitochondria.
labeled probes can be overcome by activatable probes, which typi- A PET agent, 18F-fluorobenzyl triphenylphosphonium, demon-
cally consist of three functional components. For example, a cas- strated good uptake in H345 cells. Selective collapse of Δym caused
pase-activatable probe, TcapQ(647), was synthesized so to include a a substantial decrease in cellular uptake of 18F-fluorobenzyl triphe-
Tat-peptide–based permeation peptide sequence, an effector cas- nylphosphonium, compared with controls.212 In an orthotopic
pase recognition sequence (Asp-Glu-Val-Asp, DEVD), and a flanking prostate tumor model, docetaxel caused a marked decrease (52.4%)
optically activatable pair comprising a far-red quencher (QSY 21) of 18F-fluorobenzyl triphenylphosphonium tumor uptake within
and a fluorophore (Alexa Fluor 647). Under baseline conditions, 48 hours, whereas [18F]FDG uptake was much less affected (12%).213
high quenching efficiencies resulting in low background fluores- Compared with the transient nature of PS externalization, loss of
cence were observed. On exposure to executioner caspases, Δym is an ongoing process not limited to a time window, which may
TcapQ(647) was specifically cleaved, thereby releasing the fluoro- allow time-independent detection of apoptosis. However, “negative”
phore from the quencher and enabling imaging of apoptosis. In vivo contrast because of decreased accumulation of the imaging probes
experiments demonstrated the ability of TcapQ(647) to detect para- in apoptotic cells and cellular efflux mediated by the multidrug-
site-induced apoptosis in human colon xenograft and liver abscess resistance proteins may limit its clinical application.214
mouse models.203 Cell-permeable polymeric nanoparticles have also
been prepared for apoptosis imaging. The close spatial proximity of
the near-infrared fluorochromes in polymeric nanoparticles resulted Conclusions
in an autoquenched state and strong near-infrared fluorescence sig-
nal emitted in apoptotic cells.204 Theranostic agents that combine Despite almost two decades of intensive investigations, there is still
therapeutic components and a caspase-activatable imaging moiety no fully validated method for radionuclide imaging of apoptosis in
have also been reported.205 Most activatable probes use the sub- humans. Although several radiopharmaceuticals have been pro-
strate DEVD to achieve caspase-3 cleavage after being internalized posed for this purpose, none of them have been licensed for human
into lysosomes. Legumain is a lysosomal cysteine protease that plays use. 99mTc-annexin V is perhaps the radiotracer that has been more
a pivotal role in the endosomal/lysosomal degradation system. extensively used in Phase II trials (for instance, in patients with
Cathepsins also become activated at the low pHs found in lyso- NSCLC), but its validation as a prognostic imaging agent to predict
somes. Thus, both cathepsins and legumain will digest DEVD and response to antitumor treatment has not been completed. This
restore the optical signal even in nonapoptotic cells.202 Such cross- delay in the clinical applications of an approach that holds such a
reaction may result in nonspecific activation of the activatable high promise based on the results obtained both in vitro and in
probes and thus increase the background activity of in vivo imaging. animal tumor models is caused by several factors; in particular, the
Key issues for future development of activatable probes include how lack of GMP-grade annexin V kits for clinical imaging trials after
to improve internalization and how to reduce noncaspase cleavage. Theseus Imaging Corporation (Cambridge, MA) has closed its oper-
ation. It had limited clinical use of the tracer. This problem, together
with the suboptimal biodistribution profile of 99mTc-HYNIC-annexin
Reporter Gene Imaging of Caspase Activity
V, has stimulated several attempts to synthesize new radiolabeled
Bioluminescence imaging has been employed to image apoptosis moieties to image apoptosis and perform preclinical characteriza-
with several seminal apoptosis-responsive reporter gene con- tion. However, biologic characterization of the new molecules has
structs.206,207 One reporter gene contains firefly luciferase gene not progressed sufficiently to pass the preclinical investigation
flanked by ER (residues 281–599 of the modified mouse estrogen phase. No new radiopharmaceutical has reached the clinical
receptor sequence) with DEVD linker. A caspase-3–specific cleavage phase. Among all the radiolabeled agents, 99mTc-annexin V-128 is
of the recombinant product results in the restoration of luciferase currently under development for human use. Expectation is high
activity in cells undergoing apoptosis.207 Ray et al. developed a also for the 18F-labeled ligand of Caspase-3, [18F]fluoroethylazide
fusion protein construct by combining three different reporter pro- (an isatin sulfonamide).
teins (red fluorescent protein, firefly luciferase, and HSV1-sr39 trun- This scenario is further complicated by the complex clinical set-
cated thymidine kinase), linked through a caspase-3–recognizable tings, where apoptosis imaging would be helpful. There is much
polypeptide linker. Upon apoptosis induction with 8-μM staurospo- wider variability in the clinical settings than the experimental set-
rine, the fusion protein showed a significant increase in firefly lucif- tings, where most of the factors can be strictly controlled; for
erase and red fluorescent protein activity in 293 T cells.208 instance, to monitor the time course of the various events leading

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C h apt e r 3 7
Radionuclide Imaging of Tumor Angiogenesis

Zhao-Hui Jin • Takako Furukawa • Tsuneo Saga
Introduction targets specific molecules in the angiogenic pathway, also known

as targeted angiogenesis imaging. Recent advances in nuclear med-
icine imaging technology, including PET and single photon emission
Angiogenesis is a tightly regulated process involving the formation
computed tomography (SPECT), have enabled direct angiogenesis
of new blood vessels from pre-existing vasculature.1 Angiogenesis
imaging with high sensitivity and improved spatial resolution. These
is fundamental to embryogenesis, uterine maturation, placental
techniques have become the predominant strategy for noninvasive
development, corpus luteum formation, and wound healing.1,2
in vivo visualization, quantitation, and monitoring of tumor angio-
Angiogenesis is also characteristic of pathologic processes includ-
genesis and antiangiogenic treatment efficacy.19
ing neoplasm, psoriasis, endometriosis, arthritis, macular degen-
This chapter introduces the most extensively studied biomark-
eration, regional ileitis, atherosclerosis, and chronic inflammatory
ers and development of corresponding radionuclide-based probes
diseases.3–5 In 1971, Folkman,6 an American medical scientist best
for nuclear medicine imaging of tumor angiogenesis (Table 37.1).
known for his research on tumor angiogenesis, proposed that
The main tools for nuclear medicine imaging are PET and SPECT,

tumor cells were capable of stimulating endothelial cell prolifera-
each with advantages and shortcomings, and each of the radio-
tion by means of a soluble “tumor angiogenesis factor,” and empha-
nuclides in PET or SPECT radiopharmaceuticals has a specific

sized the importance of angiogenesis in tumor growth, leading to
decay mode, physical half-life, chemical properties, and method
extensive research to understand and control the angiogenic path-
of production. Detailed descriptions can be found in recent
ways in tumors. Angiogenesis is jointly regulated by the nature of
reviews.20,21
each tumor and a complex network of several cell types, various
growth factors/receptors, extracellular matrix (ECM) proteins/
proteases, and signaling pathways involved in endothelial prolif- Tabl e 3 7 . 1
eration, migration, and tube formation and function.5,7,8 Tumor
angiogenesis has been accepted as an important target and indica- Representative Molecular Probes Developed
tor of therapeutic outcome and prognosis, because it is a key fea- for Tumor Angiogenesis Imaging
ture of malignant solid tumors and plays a critical role in tumor
growth, invasion, and metastasis.9,10 A large number of angiogen-
esis inhibitors have been developed, based on cells, genes, mono- Biomarker Molecular Probe
clonal antibodies (mAbs), proteins, peptides, or small molecules,
αvβ3 Integrin Peptide *[18F]Galacto-RGD
for differentially blocking the multiple and complex steps of angio- *[18F]Fluciclatide
genesis, whereby the formation of new blood vessels can be sup- *[18F]RGD-K5
pressed and growth or spread of tumors can be stopped or *[18F]FPPRGD2
slowed.7,10,11 Several angiogenesis inhibitors such as bevacizumab *68Ga-NOTA-RGD
(Avastin), sorafenib (Nexavar), and sunitinib (Sutent) for the treat- *99mTc-NC100692
ment of certain types of cancer have been approved by the Food *99mTc-3PRGD2
64
and Drug Administration (FDA) in the United States and many Cu-cyclam-RAFT-c(-RGDfK-)4
other countries; many other drugs are in active clinical trials.10,12 VEGF Antibody or antibody 124/125
I, 153Sm or 99mTc-VG76e
As clinical practice and research proceed, it is critical to identify fragment *124I-HuMV833
noninvasive biomarkers for patient selection/stratification, dose *125I, 111In, or 89Zr-bevacizumab
89
and dosage optimization, prediction/monitoring of treatment Zr-ranibizumab
response, and detecting early signs of drug resistance that may be VEGFR-2 Natural ligand VEGF 123/125
I-VEGF121
acquired by activation or upregulation of an alternative path- isoform or its *123/125I-VEGF165
64
way.13,14 Unlike cytotoxic chemotherapeutic drugs, angiogenesis derivative Cu-DOTA-VEGF121 (or VEGFDEE)
99m
inhibitors are typically cytostatic; that is, they slow or stop tumor Tc-HYNIC-VEGF
64
growth rather than causing tumor shrinkage. Therefore, routine Cu, 68Ga, or 18F-scVEGF
11
Small molecule tyrosine C-PAQ
methods for evaluating chemotherapeutic efficiency, including 11
kinase inhibitor C-Vandetanib (or chloro-Vandetanib)
changes in tumor volume or morphology detected by computed 5-125I-iodo-sunitinib
tomography (CT) and magnetic resonance imaging (MRI), may 18
F-SKI-249380
not be suitable for assessing the response to antiangiogenic Antibody 99m
Tc-chitosan-DC101
treatment.15
ED-B Antibody or antibody *123I-L19(scFv)2
Great advances in imaging instrumentation have made possi- fragment 99m
Tc-L19-AP39
ble the noninvasive molecular imaging of tumor angiogenesis in 76
Br-L19-SIP
vivo; thus, tumor angiogenesis can be assessed and evaluated 124
I-L19-SIP
indirectly or directly.16–18 Indirect angiogenesis imaging is nontar- 125
CD105 Antibody I-MAEND3
geted, measuring differences in perfusion, vessel permeability, and 99m
Tc-E9
blood volume between tumor and normal vasculature. Contrast- 111
In-MJ7/18
enhanced or dynamic contrast–enhanced CT and MRI can be 64
Cu-DOTA-TRC105
used to evaluate or quantify perfusion and vascular permeability. 64
Cu-NOTA-TRC105
Positron emission tomography (PET) with oxygen-15 (15O) water, 89
Zr-Df-TRC105
carbon-11 (11C)-carbon monoxide (CO) or C15O can be used to visu- Endostatin Natural ligand 99m
Tc-EC-endostatin
alize and quantify tumor blood volume. Ultrasound with contrast- receptors endostatin
enhanced microbubbles also shows promise to evaluate tumor
blood volume. By contrast, direct tumor angiogenesis imaging Note: The mark * indicates the molecule has been tested in clinical trials.
567

αvβ3 Integrin as a Marker for groups to explore optimal tracers for tumor angiogenesis imaging.
Some of these have already entered clinical trials, and some prom-
Tumor Angiogenesis ising agents are undergoing preclinical studies.
Integrins, a family of transmembrane glycoproteins and cell adhe-

sion receptors,22 mediate cell–cell and cell–matrix interactions23 and RGD-Based Tracers in Clinical Trials
outside-in/inside-out modes of signal transduction.24,25 An integrin
contains two noncovalently associated α and β subunits; in mam- [18F]Galacto-RGD
mals, 19 α and 8 β subunits have been characterized, forming 24 [18F]Galacto-RGD was developed by Haubner et al.41 at the Univer-
distinct integrin heterodimers through different subunit combina- sity of Munich by introducing a sugar amino acid (SAA) (7-amino-
tions.26,27 The vitronectin receptor, αvβ3 integrin, is one of the most L-glycero-L-galacto-2,6-anhydro-7-deoxyheptanoic acid) to the cyclic
interesting and extensively studied members of the integrin family, RGD pentapeptide to form cyclo(-Arg-Gly-Asp-D-Phe-Lys(SAA)-) to
with important roles in tumor growth, invasion, metastasis, and increase hydrophilicity, reducing hepatobiliary excretion, and allow-
angiogenesis.26,28 It is highly expressed on activated endothelial cells ing fluorine-18 (18F, commonly used positron emitter for clinical
during angiogenesis and on some types of tumor cells, such as inva- patients, half-life: 110 minutes) labeling with 4-nitrophenyl 2-18F-
sive melanoma, glioblastoma, osteosarcoma, neuroblastoma, and fluoropropionate. In vitro binding assays using the isolated immo-
carcinomas of different origins.26,28,29 αvβ3 Integrin is important for bilized integrin receptors (αIIbβ3, αvβ5, and αvβ3) demonstrated the
tumor angiogenesis imaging because of its high expression levels, αvβ3 integrin-binding specificity of [18F]Galacto-RGD, which exhibited
but also because the activation state of αvβ3 occurs during the final 200- to 1,200-fold greater affinity for αvβ3 than for αvβ5 and αIIbβ3.
stage of angiogenesis. The latter is especially helpful when using it The in vivo αvβ3 integrin-targeting specificity of [18F]Galacto-RGD was
as a biomarker for monitoring tumor response to angiogenesis tested by using αvβ3-positive M21 and αvβ3-negative M21-L human
inhibitors. As explained by Choyke,30 “There are multiple mecha- melanoma xenografts. Tracer uptake in M21 is approximately four
nisms by which new vessels can be generated; inhibition of one times greater than in M21-L between 60 and 120 minutes post
pathway can lead to compensation by another. An imaging agent injection (p.i.); this was confirmed by a competitive blocking assay
that targets the ‘final common pathway’ of angiogenesis would be with excess αv-selective peptide cyclo(-Arg-Gly-Asp-D-Phe-Val-).
more widely useful than a highly specific agent that is relevant only Published in 2005,42 the first study of PET imaging with [18F]
under certain circumstances; integrins hold promise clinically, pre- Galacto-RGD (133 to 200 MBq) was performed in 19 patients
cisely because they seem to be part of this final common pathway.” with metastatic malignant melanoma (seven patients), sarcoma
Many integrins, including αvβ3, bind to their natural ligands: A (ten patients), or osseous metastases (two patients), and demon-
wide variety of ECM proteins such as fibronectin, vitronectin, osteo- strated rapid blood clearance and primarily renal excretion of this
pontin, fibrinogen, collagens, and laminin via the common tripeptide tracer. Dynamic scanning revealed that tumor tracer uptake peaked
sequence Arg-Gly-Asp (single letter coding: RGD).31,32 However, the at ∼10 minutes p.i., followed by a plateau with no or minimal reduc-
specificity of the receptor–ligand recognition and binding is also tion in radioactivity until 60 minutes p.i. [18F]Galacto-RGD uptake in
attributed to sequences neighboring the RGD, as well as its constitu- 29 tumor lesions had a mean standardized uptake value (SUV) of
tive spatial conformation.33,34 Cyclic pentapeptides containing the 3.7 ± 2.3 (ranging from 1.2 to 9) at 72 minutes p.i., indicating great
RGD (cRGD) are optimized synthetic ligands possessing a high affin- inter- and intraindividual diversity of αvβ3 expression in cancer
ity and selectivity for αvβ3 integrin.35,36 Based on this lead structure, patients. The tumor-to-blood (T/B) and tumor-to-muscle (T/M) ratios
a series of cRGD-containing radiolabeled tracers have been devel- increased over time, with peak ratios of 3.1 ± 2 and 7.7 ± 4.3,
oped for the purpose of tumor angiogenesis imaging.37,38 In addition, respectively, at 72 minutes p.i. Nearly 80% of the 29 lesions could be
other RGD-based peptidomimetics or peptide sequences obtained visualized by PET imaging.
from phage-display peptide library screening have also been devel- To determine the clinical correlation of [18F]Galacto-RGD uptake
oped.38,39 The most published preclinical and clinical studies on the with αvβ3 integrin expression (distribution pattern and levels), or
use of radiolabeled tracers for detection of αvβ3 integrin are based microvessel density (MVD), a clinical study was performed in 19
on RGD peptides. patients with solid tumors (musculoskeletal system, ten patients;
melanoma, four patients; head and neck cancer, two patients; glio-
blastoma, two patients; and one breast cancer patient) who were
RGD-Based Radionuclides for examined with [18F]Galacto-RGD PET before surgical removal of
the tumor lesions.43 Twenty-six specimens were collected from rep-
Angiogenesis Imaging Via Targeting resentative areas with low and high SUVs and then snap frozen.
of αvβ3 Integrin Immunohistochemical staining revealed no αvβ3 expression in nor-
mal tissue and in the two lesions without tracer uptake whereas all
The first generation of RGD-based tracers was developed by lesions with enhanced uptake showed immunohistochemical αvβ3
Haubner et al.40 They modified the lead cyclo(-Arg-Gly-Asp-D-Phe- expression. In benign lesions (pigmented villonodular synovitis,
Val-) peptide to retain high selectivity and affinity for αvβ3 through neurofibroma, and inflammatory tissue), αvβ3 was located only on
substitution of D-Phe or Val with tyrosine (Tyr) to allow electro- the vasculature, whereas in malignant tumors, the patterns of αvβ3
philic radiohalogenation by the iodogen method. This led to two expression varied considerably. In lymph-node metastasis and
iodine-125 (125I, γ-ray emitter, half-life: 59.4 days)-labeled tracers, cutaneous metastasis from melanoma, αvβ3 was predominantly
125
I-3-iodo-D-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) and 125I-3-iodo- located on tumor cells. In squamous cell carcinoma of the head and
D-Tyr5-cyclo(-Arg-Gly-Asp-D-Phe-Try-). In vitro binding assays of neck (SCCHN), αvβ3 was located on the neovasculature. In the other
isolated and immobilized integrin receptors revealed that the two tumor entities, αvβ3 was located on the neovasculature and on
modes of tyrosine replacement and subsequent radiolabeling had tumor cells in varying degrees. SUVs and T/B ratios significantly
no influence on αvβ3 affinity and selectivity; however, 125I-3-iodo- correlated with the intensity of immunohistochemical αvβ3 staining
D-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) showed better αvβ3-specific (Spearman’s r = 0.92 and 0.94, respectively; p < 0.0001) and with
tumor-targeting efficiency in vivo. Both tracers had fast elimina- the MVD of αvβ3-positive vessels (Spearman’s r = 0.84 and 0.90,
tion kinetics, resulting in a rapid decrease in tumor tracer accu- respectively; p < 0.0001).
mulation and predominant hepatobiliary excretion, leading to A clinical trial investigated the efficacy of [18F]Galacto-RGD PET
high radioactivity accumulation in the liver and intestine. These to image αvβ3 expression on the neovasculature in SCCHN
promising results and serious limitations inspired many research patients.44 Eleven patients with primary SCCHN diagnoses were

Chapter 37 Radionuclide Imaging of Tumor Angiogenesis 569
terminus to stabilize the peptide against degradation by carboxy-

peptidases and prolonging the circulation life span, thereby
increasing tumor uptake and retention.48
[18F]Fluciclatide has entered clinical trials to evaluate safety and
metabolic stability and to determine the pharmacokinetic and
tumor-targeting efficacy.49,50 However, the limitation of [18F]flucicla-
tide is the relatively high radioactivity in the liver and gastrointes-
tinal tract because of the hepatobiliary excretion.49,50 Dynamic PET
scan was performed in seven patients with metastatic breast can-
cer after receiving [18F]fluciclatide (198.8 to 292.1 MBq), and all 18
tumors could be visualized either as a distinct increase in radioac-
A C tive accumulation in comparison with the surrounding normal tis-
sue (Fig. 37.2A, B) or, in the case of liver metastases, as regions of
deficient accumulation (Fig. 37.2C) because of the high background
activity in normal liver tissue.50 Compared with the rapid uptake of
[18F]Galacto-RGD in tumors, which peaked at 10 to 15 minutes
p.i.,42,44 the PEGylated [18F]fluciclatide accumulated in tumor
lesions gradually, reaching a plateau by 50 to 60 minutes p.i. A

two-tissue reversible model was established as the best quantita-
tive methodology for analysis of [18F]fluciclatide PET data, suggest-

ing that the k(3)/k(4) ratio is a reasonable measure of specific
binding, and for tumor/healthy tissue differentiation.51 In addition,
clinical trials in patients with malignant melanoma, renal cell car-
cinoma (RCC), and renal oncocytoma (the most common benign
B D solid renal tumor) are ongoing52 It is worth noting that it would be
valuable if [18F]fluciclatide PET imaging can distinguish RCC from
Figure 37.1. Patient with a squamous cell carcinoma of the head and neck in the right oncocytoma because in clinical practice it is not always possible to
mandible (arrows, A and B). [18F]Galacto-RGD PET (A) and PET/MRI image fusion (B) show do so with ultrasonography, CT scanning, or MRI.
heterogeneous intense tracer accumulation in the lesion, whereas there is only low background Another important application of [18F]fluciclatide PET is to
uptake in parts of the oral cavity and very low uptake in the parotid glands and in muscle tissue.
Immunohistochemical evaluation of αvβ3 expression at low-power magnification (C) and at monitor tumor response to antiangiogenic therapy as reported by
high-power magnification (D) shows intense staining of the neovasculature (arrows) without Battle et al.53 In their experimental study in mice bearing αvβ3
staining of the tumor cell complexes. SUV, standardized uptake value. (Reprinted from Beer AJ, highly expressing U87MG tumor models, sunitinib (60 mg/kg orally
Grosu AL, Carlsen J, et al. [18F]galacto-RGD positron emission tomography for imaging of αvβ3 daily, two 5-day cycles with 2 days free between cycles), the FDA-
expression on the neovasculature in patients with squamous cell carcinoma of the head and
neck. Clin Cancer Res. 2007;13:6610–6616, with permission from AACR.) approved multitargeted receptor tyrosine kinase (RTK) inhibitor,
enrolled. Ten of twelve tumors could be detected (Fig. 37.1), and

the other two tumors (<5 mm) failed for delineation. Tumor kinet-
ics were consistent with a two-tissue compartmental model with
reversible specific binding. Immunohistochemistry confirmed αvβ3
expression in all tumors with αvβ3 being located on the microves-
sels in all specimens (see Fig. 37.1) and with only one tumor show-
ing αvβ3 expression on both tumor cells and vasculature. This study
suggests the feasibility of performing angiogenesis assessments
A
with [18F]Galacto-RGD PET in SCCHN, which might be useful for
planning and response evaluation of antiangiogenic therapies
combined with chemotherapy and/or radiotherapy.
A breast cancer clinical trial was performed in 16 patients with
invasive ductal carcinoma.45 [18F]Galacto-RGD PET performed well
for primary tumor detection but did not show sufficient sensitivity
for lymph-node staging. Immunohistochemical staining in primary
tumors revealed αvβ3 expression predominantly on endothelial B
cells, but also on tumor cells. This work indicates the ability of [18F]
Galacto-RGD PET to detect primary breast cancer, but also sug-
gests that when assessing angiogenesis of breast cancer using αvβ3
as a biomarker, the results must be interpreted carefully, as part
of the signal might come from the tracer binding on tumor cells
themselves. Similar findings were obtained in patients with malig-
nant glioma.46
C Spleen Spleen
[18F]Fluciclatide
[18F]Fluciclatide, also known as 18F-AH111585, is under develop- Figure 37.2. 18F-AH111585 PET of metastatic lesions and corresponding CT images
showing increased signal in periphery of lesions in patient with lung and pleural metastases
ment as a monomeric cyclic RGD-based radioligand for αvβ3 inte- (A), intralesion heterogeneity of uptake within pleural metastasis in PET image, which was not
grin with the core sequence ACDCRGDCFCG, originally discovered demonstrated as necrosis on corresponding CT section (B), and liver metastases imaged as
in a phage-display library.47 [18F]Fluciclatide was designed by cycli- hypointense lesions because of high background signal (C). High uptake in spleen is possibly
because of blood pooling. See also color bar for PET images. (Reprinted with permission of the
zation and introduction of multiple disulfide bridges to stabilize the
Society of Nuclear Medicine from Kenny LM, Coombes RC, Oulie I, et al. Phase I trial of the
molecule with minimal disruption of the RGD pharmacophore, and positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer
by introduction of a polyethylene glycol (PEG)-like spacer at the C patients. J Nucl Med. 2008;49:879–886.)

inhibited tumor uptake of [18F]fluciclatide and significantly reduced

the tumor MVD obtained at the end of therapy, but without signifi-
cant changes in tumor volumes. Earlier work done by Morrison
et al.54 also showed the promise of [18F]fluciclatide PET for monitor-
ing response to treatment with different antiangiogenesis drugs,
low-dose paclitaxel (a mitotic inhibitor with antiangiogenic activity
at low doses) and ZD4190 (a substituted 4-anilinoquinazoline acting
as an RTK inhibitor-type angiogenesis inhibitor) as well as different
tumor models in mice, mouse Lewis lung carcinoma (LLC), and
human lung adenocarcinoma Calu-6, both of which have estab-
lished low levels of tumor-cell αvβ3 expression.
[18F]RGD-K5
2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-18F-
fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-
trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-
(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-penta-
azacyclopentadecan-2-yl) acetic acid ([18F]RGD-K5), a click-chemistry–
derived, RGD-based cyclic peptidomimetic tracer, was developed as
an αvβ3 integrin marker for PET.38,55 It contains a metabolically stable,
yet highly polar 1,2,3-antitriazole moiety that increases the tracer’s A
excretion via the renal pathway, thus circumventing unwanted liver
uptake. Compared with [18F]Galacto-RGD, the preparation of [18F]
RGD-K5 is simple and straightforward using click chemistry, con-
sisting of a single reaction that can be readily automated.56 Although
[18F]RGD-K5 was designed to target αvβ3 integrin, it may also bind
other integrins because the selectivity of RGD-K5 toward αvβ3 integ-
rin is only 2.3 to 3.4-fold higher versus related integrins.57
Whole-body PET/CT on four healthy humans receiving 583 ± 78
MBq [18F]RGD-K5 demonstrated its safety, favorable pharmacoki-
netic characteristics with metabolic stability, rapid blood clear-
ance, and predominant renal excretion.55 It was also shown that
the biodistribution and dosimetry of [18F]RGD-K5 in monkeys can
adequately predict similar data in humans.55 B
The initial evaluation of [18F]RGD-K5 PET compared with 18F-
FDG PET was performed in 12 patients with breast cancer.38 More
Figure 37.3. Clinical-grade [18F]FPP(RGD)2 (518 MBq/14 mCi) injected intravenously to a
than 77% of 157 FDG-positive lesions could be detected on [18F] healthy human volunteer. Images include a coronal fusion PET/CT image (A, left side) and
RGD-K5 PET, and no correlation was observed with tracer uptake. maximum intensity projection (MIP) image (A, right side) as well as serial MIP images (B).
Tumor uptake of [18F]RGD-K5 did not correlate with MVD, one of (A) was obtained 1 hour post injection and has the major organs of uptake labeled as follows: 1,
the histologic parameters of angiogenesis. Further study on the brain ventricles; 2, lung; 3, liver; 4, gallbladder; 5, bowel; 6, urinary bladder; 7, salivary glands/
oropharynx; 8, thyroid glands; 9, spleen; and 10, kidneys. The renal and hepatobiliary clearance
correlation between the intratumoral distribution of [18F]RGD-K5 routes of [18F]FPP(RGD)2 are evident. Above the diaphragm, there is only very limited uptake. The
and αvβ3 integrin localization, as well as the correlation of tracer combined image in (B) shows the temporal stability of [18F]FPP(RGD)2 at five time-points post
uptake with integrin expression may help determine the efficacy injection. (With kind permission from Springer Science and Business Media: Chin FT, Shen B,
of this tracer for tumor angiogenesis imaging. Liu S, et al. First experience with clinical-grade [18F]FPP(RGD)2: An automated multi-step radio-
synthesis for clinical PET studies. Mol Imaging Biol. 2012;14:88–95.)
[18F]FPPRGD2 glioblastoma multiforme (GMB).62 [18F]FPPRGD2 PET/CT and 18F-

18 18 18
[ F]FPPRGD2, 4-nitrophenyl 2- F-fluoropropionate ( F-NFP)- FDG PET/CT were performed within 2 weeks for each patient, and
labeled PEGylated dimeric RGD peptide, PEG3-E[c(RGDyk)2], was brain MRI was added for suspected recurrent GBM patients. Vital
developed at Stanford University Medical Center and approved by signs, electrocardiogram, and blood examination indicated the
the FDA as an Investigational New Drug (IND 104150). It was safety of [18F]FPPRGD2. There was consistent distribution in all
designed by using the dimeric cRGD peptide and PEG3 as the space patients with primary clearance through the kidneys and hepatobi-
linker between two cRGD motifs to enhance receptor-binding affin- liary system. Intense uptake of [18F]FPPRGD2 was observed in the
ity.58 Compared with the monomeric peptide tracer [18F]Galacto- three primary breast lesions at 45 minutes p.i., with SUVmax values
RGD, [18F]FPPRGD2 showed high αvβ3 affinity to human glioblastoma ranging from 8.1 to 9.4 (average: 8.75 ± 0.9), compared to 18F-FDG
U87MG cells in vitro and high αvβ3-specific tumor uptake with com- uptake with SUVmax 11.9. Eleven metastatic breast cancer lesions
parable tumor contrast in U87MG tumor-bearing mice.58 also showed intense uptake of [18F]FPPRGD2, with SUVmax values
Mittra et al.59 reported a pilot study of [18F]FPPRGD2 PET in ranging from 4.8 to 9.4 (average: 7.12 ± 1.9), compared with 18F-
five healthy volunteers, showing the safety, favorable dosimetry, FDG uptake with SUVmax values ranging from 2.2 to 4.8 (average:
and pharmacokinetics of this tracer. [18F]FPPRGD2 PET is suitable 3.13 ± 1.4). Among the five patients suspected of developing recur-
for brain, lung, and breast cancers. For reliable and routine clini- rent GMB, one patient had recurrent GBM identified only on the [18F]
cal PET studies, Chin et al.60 developed an automated multistep FPPRGD2 PET. Another patient had recurrent GBM identified on
radiosynthesis of clinical-grade [18F]FPPRGD2 with favorable bio- [18F]FPPRGD2 PET and brain MRI but not on 18F-FDG PET. Another
distribution in human studies, with low background signal in the patient had recurrent GBM identified on all three scans. The remain-
head, neck, and thorax (Fig. 37.3). ing two patients had no recurrent GBM as determined by [18F]
Stanford University Medical Center recruited six female patients FPPRGD2 PET, 18F-FDG PET, and brain MRI. Uptake of [18F]FPPRGD2
with breast cancer61 and five patients with suspected recurrent in the three recurrent GBM lesions showed SUVmax values of 2.3 to

2.9 (average: 2.6 ± 0.3). [18F]FPPRGD2 uptake was seen in the brain uptake (5.1 ± 1%ID/g) and high T/B and T/M ratios of 10.3 ± 4.8
ventricles and at the edge of the surgical incision (wound repair) in and 9.3 ± 3.9 at 1 hour p.i., with predominant renal excretion.66
all patients, but was not noted in the normal brain. These findings The highest radioactivity accumulation was in the kidneys (5.3 ±
show that [18F]FPPRGD2 PET is a promising candidate for detection 1.3%ID/g at 1 hour p.i.) and relatively lower levels were observed
of primary and metastatic breast cancers, as well as recurrent GBM in the liver, intestines, lung, spleen, and heart (<2.5 %ID/g at 1 hour
lesions. Further evaluation with larger cohorts will verify these pre- p.i.). PET imaging clearly visualized tumors at 1 and 2 hour p.i.
liminary data and clarify the relationship between tracer uptake and Whole-body distribution of 68Ga-NOTA-RGD (172.4 ± 20.5 MBq)
histologic localization of αvβ3 integrin to explore the potential of [18F] in humans and mice was similar, and radiation dosimetry studies
FPPRGD2 for angiogenesis imaging. indicate the acceptable effective radiation dose of 68Ga-NOTA-RGD
The utility of [18F]FPPRGD2 PET to monitor tumor response to in humans.67 The first clinical trial of 68Ga-NOTA-RGD PET was
antiangiogenic therapy was investigated in mice bearing αvβ3- performed in six patients with liver metastasis from colorectal can-
positive human MDA-MB-435 breast tumors.63 The mice received 3 cer.38 18F-FDG and 68Ga-NOTA-RGD PET/CT were performed before
days (days 1 to 3) of treatment with ZD4190 (100 mg/kg/day, oral). combination therapy with the chemotherapeutic drug FOLFOX and
Compared to the almost unchanging [18F]FPPRGD2 uptake in the the antiangiogenesis drug bevacizumab. All six patients showed
control tumors between days 0 and 7, [18F]FPPRGD2 uptake in hypermetabolic lesions on 18F-FDG PET/CT. For 68Ga-NOTA-RGD
ZD4190-treated tumors decreased significantly relative to the base- PET, mildly elevated tracer uptake in liver metastases was seen in
line level (day 0) by 26.74% ± 8.12% on day 1 and by 41.19% ± 6.63% three of six patients; the others were negative. Finally, only patients
on day 3, then returned to baseline on day 7, at which time the with elevated 68Ga-NOTA-RGD uptake showed at least a partial

tumor volume of ZD4190-treated mice was significantly lesser than response to therapy indicating the potential of 68Ga-NOTA-RGD
that of the control mice. In parallel, ZD4190 suppressed expression PET to predict response to chemotherapy combined with an anti-

of αvβ3 integrin on tumor vasculature and on tumor cells on days 1 angiogenesis drug. Collectively, these reports suggest that
68
and 3, but not day 7. Unlike ZD4190, treatment with Abraxane (an Ga-NOTA-RGD should be evaluated further as a promising radio-
FDA-approved nanoparticle albumin-bound paclitaxel: 25 mg/kg pharmaceutical for tumor angiogenesis imaging.
every other day, three doses, intravenous) did not induce significant
changes of αvβ3 integrin expression on the tumor cells.64 The decreased 99m
Tc-NC100692
tumor uptake of [18F]FPPRGD2 in the Abraxane-treated group corre-
lated with the decreased expression of αvβ3 integrin on vascular Technetium-99m (99mTc, generator-produced, widely used γ-ray emit-
endothelial cells. The collapse of microvessel cavities observed in ter, half-life: 6 hours)-labeled NC100692, 99mTc-Diamine dioxime-
Abraxane-treated tumors further confirmed the antiangiogenic effects Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys-polyethylene glycol has been
of Abraxane. Together, these studies illustrate that [18F]FPPRGD2 is a developed and is in active clinical trials for breast cancer detection.
promising PET tracer that allows noninvasive evaluation of the effi- NC100692 is a cyclic RGD-containing peptide with a PEG chain
cacy of antiangiogenesis therapy, but it should be noted that some linked to the C-terminal amino acid and a 99mTc-binding chelator
angiogenesis inhibitors may directly influence integrin expression on linked to the N-terminal amino acid.68 A phase I study of 31 healthy
tumor cells, which would make data analysis complicated. volunteers demonstrated the acceptable pharmacokinetics of 99mTc-
One major disadvantage of [18F]FPPRGD2 and other 18F-labeled NC100692 with rapid blood clearance, prominent renal excretion,
RGD peptides is the multistep, time-consuming, and low-yield syn- and relatively high background activity in the liver and intestines.68
thetic procedures, hindering their widespread use as routine tracers Scintigraphy with 99mTc-NC100692 identified 19 of 22 primary
in the clinic. A recent report65 suggested that [18F]AlF-NOTA-PRGD2 is lesions (86%) (561 to 747 MBq, imaged 40 to 150 minutes p.i.)69
a promising alternative to [18F]FPPRGD2, with the former radiolabel- and was feasible for detection of lung and brain metastases from
ing process via a recently introduced kit formulation method using an breast and lung cancer in 25 patients (800 to 1,100 MBq, imaged
18
F-fluoride–aluminum complex, simplifying the 18F-labeling proce- 45 to 75 minutes p.i.).70 Although the utility of 99mTc-NC100692 for
dure to facilitate clinical translation. When studied in mice bearing detection of angiogenesis was shown in murine models of hind leg
U87MG tumors, [18F]AlF-NOTA-PRGD2 had pharmacokinetics and ischemia,71 its value as a marker of angiogenesis in breast cancer
quantitative parameters for αvβ3 integrin-targeting efficiency compa- remains to be determined in patients.
rable to those of [18F]FPPRGD2.
99m
Tc-3PRGD2
68
Ga-NOTA-RGD 99m
Tc-3PRGD2 is a dimeric cyclic RGD peptide (3PRGD2 = PEG4-
Gallium-68 (68Ga, generator-produced positron emitter, half-life: E[PEG4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13-tetraoxapen-
68 minutes)-labeled tracer, 68Ga-1,4,7-Triazacyclononane-1,4-7- tadecanoic acid) labeled with 99mTc using HYNIC (6-(2-(2-
triaceticacid-isothiocyanatobenzyl-c(Arg-Gly-Asp-d-Tyr-Lys) sulfonatobenzaldehyde)hydrazono)) as a bifunctional coupling
(68Ga-NOTA-RGD), was introduced by Jeong et al.66 using agent and tricine and TPPTS (trisodium triphenylphosphine-
2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4-7-triacetic 3,3′,3′′-trisulfonate) as coligands to prepare 99mTc complexes. Opti-
acid (SCN-Bz-NOTA) as a bifunctional chelator for labeling the mization of dimeric cyclic RGD peptides has been explored by
c(RGDyK) monomer with 68Ga. 68Ga offers an advantage for clini- inserting various pharmacokinetic modifiers (PKMs) between the
cal translation over other cyclotron-produced positron emitters RGD motifs; Shi et al.72 developed 99mTc-3PRGD2 using two PEG4
including the most frequently used 18F because it can be obtained linkers as the PKM and with high αvβ3 integrin–binding affinity
from commercially available 68Ge/68Ga generator systems. The and high tumor contrast resolution in a nude mouse model. This
production of 68Ga is also cost effective because the parent nuclide SPECT tracer was developed in kit form by the Medical Isotopes
68
Ge has a long half-life of 271 days, allowing its use as a genera- Research Center of Peking University.73 The first clinical trial of
tor for more than 1 year. The short half-life of 68Ga (68 minutes) scintigraphic imaging using 99mTc-3PRGD2 was performed in
and its hydrophilic nature makes it suitable for labeling of small 21 patients with 21 solitary pulmonary nodules (SPNs) (lesion size
peptides like the c(RGDyK) monomer, with fast pharmacokinetics ranging from 1 to 3 cm) based on CT scans, the current standard
in vivo. Moreover, labeling of NOTA-RGD with 68Ga is simple and imaging procedure for SPN evaluation.74 Thoracic planar and
straightforward, and may be achieved by incubating the reaction SPECT sequential acquisitions were obtained at 45 and 75 minutes
mixture at room temperature for only 10 minutes. p.i. of 99mTc-3PRGD2 (939 ± 118 MBq). All 15 malignant tumors
A biodistribution study of 68Ga-NOTA-RGD in human colon can- including adenocarcinoma, squamous cell carcinoma, and small
cer SNU-C4 xenograft-bearing mice showed high tumor tracer cell carcinoma were detected, and all of them were confirmed to

radiolabeling with 64Cu via the bifunctional chelator, cyclam

(1,4,8,11-tetraazacyclotetradecane) conjugated onto the opposite
face of the RAFT.77,78 This PET probe was developed by a collabora-
tion of the Molecular Imaging Center of the National Institute of
Radiological Sciences in Japan (NIRS) and the Département de Chi-
mie Moléculaire at the University Joseph Fourier in France (UJF).
RAFT-c(-RGDfK-)4 was designed and developed by Dumy et al.79 at
UJF based on the concept that multiple presentation of ligands in a
A D single construct may significantly improve targeting. The advantages
of RAFT-c(-RGDfK-)4 over other multimeric cRGD polymers are that
the required chemistry is regio- and chemoselective, and the synthe-
sis and purification of the final product are perfectly controlled at
gram scale. In addition, the RAFT architecture allows spatial separa-
tion between the two functional groups, RGD ligands, and the radio-
tracer 64Cu. Moreover, it is interesting because four cRGD motifs are
simply and separately grafted onto the RAFT without using space
linkers, allowing presentation of four RGD motifs in an area of ±0.7
B nm2, a high density of ligands on such a small surface.80 The mecha-
E nistic study of RAFT-c(-RGDfK-)4 interaction with αvβ3 integrin clearly
revealed the relationships between multimeric presentation,
increased affinity, and subsequent integrin-mediated and clathrin-
dependent co-internalization.81 In addition to the benefits of RAFT-c(-
RGDfK-)4, radiolabeling with 64Cu is also an advantage, because 64Cu
is a promising biomedical radioisotope. The positron energy spec-
trum of 64Cu is comparable to that of 18F, allowing high spatial resolu-
tion in PET imaging; its relatively longer half-life permits PET
evaluation of slow biokinetics of multimeric ligands, and moreover,
64
Cu can be produced on a small biomedical cyclotron. In comparison
C with other 18F-labeled RGD peptides including galacto-RGD, flucicla-
tide, and FPPRGD2, the radiolabeling procedure for 64Cu-cyclam-
Figure 37.4. Example of a true-positive 99mTc-3P4-RGD2 scintigraphy based on an optimal cut- RAFT-c(-RGDfK-)4 is easy, mild, and straightforward: The mixture of
off value of two by visual scores. A: A solitary pulmonary nodule (SPN; indicated by arrow) was peptide and 64Cu only needs to be incubated at 37°C for less than 60
identified on CT scan. B, C: High uptake of the radiotracer was observed on the SPN. The T/N ratio minutes. Specific radioactivity as high as ∼37 MBq/nmol with a label-
is 2.30. D: Histopathology staining indicated that the SPN is an adenocarcinoma. E: Immunohisto-
ing efficiency >99% can be achieved in the production of 64Cu-cyclam-
chemistry demonstrates intense ανβ3 expression in tumor vessels. (With kind permission from
Springer Science and Business Media: Ma Q, Ji B, Jia B, et al. Differential diagnosis of solitary RAFT-c(-RGDfK-)4, making purification unnecessary and reducing
pulmonary nodules using 99mTc-3P4-RGD2 scintigraphy. Eur J Nucl Med Mol Imaging. 2011;38: radioactive exposure.82 Although cyclam is not a new chelating agent,
2145–2152.) it is well suited for labeling with 64Cu in the case of RAFT-c(-RGDfK-)4.
64
Cu-cyclam-RAFT-c(-RGDfK-)4 has high affinity and selectivity
show positive expression of αvβ3 integrin. In one example of lung for αvβ3 in vitro and αvβ3-specific tumor-targeting efficiency with
adenocarcinoma with high tracer uptake, immunohistochemistry good PET imaging quality.78 A preclinical study in murine tumor
demonstrated intense αvβ3 staining in the tumor vessels (Fig. 37.4). xenografts demonstrated a strong and positive linear correlation
Two of the six benign lesions, which were highly suspicious of between tumor uptake of 64Cu-cyclam-RAFT-c(-RGDfK-)4 and cor-
malignancy on CT scan and showed relatively high tracer uptake, responding αvβ3 integrin expression levels quantified by SDS-PAGE/
were histopathologically diagnosed as tuberculoma and inflamma- autoradiography.78 A subsequent study in mice bearing human
tory pseudotumor, with αvβ3 integrin expression identified pre- hepatocellular carcinoma HuH-7 xenografts, which expressed αvβ3
dominantly on the endothelium of newly formed blood vessels. A at negligible levels on the tumor cells but were αvβ3-positive on the
multicenter study of 70 patients further demonstrated the suitabil- endothelial cells of murine origin, demonstrated that 64Cu-cyclam-
ity of this tracer for the detection of lung cancer at 1 hour p.i.75 In RAFT-c(-RGDfK-)4 PET enables clear visualization of tumor angio-
addition, a very recently published clinical study showed the genesis by targeting the αvβ3 expressed on the vasculature and helps
potential of 99mTc-3PRGD2 SPECT for detection of radioactive monitor the antiangiogenic effect of a novel multitargeted tyrosine
iodine-refractory (RAIR) differentiated thyroid cancer (DTC), and kinase inhibitor (TKI), TSU-68.82 TSU-68 significantly slowed tumor
found a correlation between the mean T/B ratios and mean lesion growth and reduced MVD; these findings were consistent with a
growth rates, which may indicate active angiogenesis and malig- significant reduction in the tumor 64Cu-cyclam-RAFT-c(-RGDfK-)4
nant phenotypes of RAIR DTC.76 However, the efficacy of 99mTc- uptake (Fig. 37.5A, B, G, H ). Moreover, a linear correlation was observed
3PRGD2 SPECT for angiogenesis imaging must be validated by between tumor MVD and the corresponding SUV (r = 0.829,
exploring the correlations between tumor tracer uptake and αvβ3 p = 0.011 for SUVmean; r = 0.776, p = 0.024 for SUVmax) deter-
expression, and between tracer uptake and MVD. mined by quantitative PET. Autoradiography and immunostaining
showed that the distribution of intratumoral radioactivity and tumor
vasculature corresponded (see Fig. 37.5C–F). This proof-of-concept
Promising RGD-Based Tracers Under study clearly shows that 64Cu-cyclam-RAFT-c(-RGDfK-)4 is a promis-
Preclinical Development ing candidate for PET imaging of tumor angiogenesis.
64 RAFT-c(-RGDfK-)4 is also flexible and can be conjugated with a
Cu-Cyclam-RAFT-c(-RGDfK-)4 variety of substances such as fluorescent dye for optical imaging,83
64
Cu-cyclam-RAFT-c(-RGDfK-)4 (molecular weight ∼ 5 kDa) is a cop- other radioisotopes in addition to 64Cu for nuclear medicine
per-64 (64Cu, a promising positron emitter, half-life: 12.7 hours)- imaging,84,85 or oligonucleotides or peptides for drug delivery.86
labeled tetrameric cyclic RGD peptide with four cyclo(-RGDfK-) Indium-111 (111In, γ-ray emitter, half-life: 2.8 days) or 99mTc-labeled
monomers grafted onto the upper face of a cyclic decapeptide scaf- RAFT-c(-RGDfK-)4 have been reported for the purpose of SPECT
fold regioselectively addressable functionalized template (RAFT) and imaging of angiogenesis.84,87

A B

C D E F
(HA′) (HB′)
p = 0.003 p = 0.0007 p = 0.0014
G H
Figure 37.5. Transverse and coronal PET images of s.c. HuH-7 tumor-bearing mice at 3 hours after i.v. injection of 64Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq)
on the day after daily intraperitoneal injections of (A) vehicle alone (50 μL of DMSO) or (B) TSU-68 (75 mg/kg/day in 50 μL of DMSO) for 14 days (n = four mice
for each group). The arrows indicate the tumor location. Representative autoradiographic examination (C, E) and CD31 immunofluorescence staining (D, F) with
the same whole-tumor sections from (C, D) vehicle-treated and (E, F) TSU-68–treated tumors excised after PET imaging. G: Microvessel density (MVD), HA′
SUVmean, and HB′ SUVmax were compared in TSU-68–treated and vehicle-treated tumors. All data presented in (A–H) are from the same set of experimental
groups. SUV, standardized uptake value. (With kind permission from Springer Science and Business Media: Jin ZH, Furukawa T, Claron M, et al. Positron emission
tomography imaging of tumor angiogenesis and monitoring of antiangiogenic efficacy using the novel tetrameric peptide probe 64Cu-cyclam-RAFT-c(-RGDfK-)4.
Angiogenesis. 2012;15(4):569–580.)
Finally, because 64Cu-cyclam-RAFT-c(-RGDfK-)4 is predominantly

eliminated through the kidneys, common for radiolabeled peptides
αvβ3 Integrin–Targeted Radiolabeled
or antibodies, relatively high renal radioactivity accumulation Nanoparticles
because of proximal tubular cell reabsorption of the tracer and reten-
tion of radiolabeled metabolite, is a limitation for 64Cu-cyclam-RAFT- αvβ3 Integrin is highly expressed on activated endothelial cells during
c(-RGDfK-)4 when imaging lesions located in the abdominal area. angiogenesis, but also on some types of tumor cells. Therefore, αvβ3
However, this problem can be solved by reducing renal uptake of integrin expression levels in a tumor may predominantly be associ-
RAFT-c(-RGDfK-)4 labeled with fluorescent dye or 111In by co- or pre- ated with its vasculature or with the mixture of vasculature and αvβ3-
injection of Gelofusine, the succinylated gelatin plasma expander.88 positive tumor cells. For the latter case, molecular imaging of tumor

angiogenesis via detection of αvβ3 expression does not reflect the expression in human tumor xenograft models.100,101 VG76e-based
extent of angiogenesis. αvβ3 Integrin–targeted radiolabeled RGD- tracers specifically bound VEGF, with maximum tumor uptake at
conjugated nanoparticles (100 to 250 nm in diameter), which can be 24 and 48 hours after injection.100 However, high levels of radioac-
confined to the circulatory system when vascular integrity is not tivity accumulated in other organs, especially the blood and plasma.
124
severely disrupted, may allow visualization and quantitation of tumor I-VG76e PET imaging in HT1080-26.6 human fibrosarcoma-
angiogenesis by targeting only the vascular αvβ3 integrin.89,90 αvβ3- bearing mice clearly showed localization to the tumor 24 hours after
Targeted 111In perfluorocarbon nanoparticle,89 64Cu-labeled DOTA- tracer injection.100 Additional areas of high radioactivity were visible
QD (quantum dot)-RGD,91 125I-labeled cyclic RGD-PEGylated gold in the thoracic cavity, abdominal cavity, and bladder.
nanoparticle,92 and 64Cu-labeled RGD-PEGylated single-walled car-
bon nanotubes (SWNTs)93 have been introduced by different research
124
groups, with the first two agents mainly localized in the tumor vascu- I-HuMV833
lature. However, nonspecific tumor uptake because of the enhanced HuMV833 is a humanized IgG4κ-type mouse monoclonal antibody
permeability and retention (EPR) effect should also be considered.94 that recognizes human VEGF121 and VEGF165.102 In a phase I clinical
Other issues such as chemical structure definition, quality control, trial, PET imaging with 124I-labeled HuMV833 was performed in 20
toxicity, stability, pharmacokinetics, and biodistribution have not yet patients with progressive solid tumors that were not amenable to
been characterized. standard therapy.103 The data did not clearly indicate whether
HuMV833 showed specific targeting of the tumor tissue. Instead,
the authors observed a strikingly wide variation of 124I-HuMV833
Angiogenesis Imaging Via Targeting uptake and/or clearance in tumor tissues between and within
patients and individual tumors whereas most normal tissues
the VEGF/VEGFR Pathway cleared the antibody at approximately equal rates.
The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-

E, snake venom VEGF, and placental growth factor, all of which share Radiolabeled Bevacizumab and the Fab
a common VEGF homology and are encoded by individual genes.95 Fragment, Ranibizumab
These members bind differentially to three subtypes of transmem-
brane tyrosine kinase VEGF signal-transducing receptors (VEGFRs): Subsequent studies of VEGF imaging have focused on the use of
VEGFR-1 (also known as Flt-1 [Fms-like tyrosine kinase-1]), VEGFR-2 bevacizumab, a humanized IgG1-type variant of anti–VEGF-A
(also known as Flk-1 [fetal liver kinase-1] and, in humans, kinase monoclonal antibody A.4.6.1 that binds all VEGF isoforms.104 Beva-
insert domain-containing receptor [KDR]), and VEGFR-3.95 VEGF-A cizumab was approved for first-line treatment of metastatic colorec-
(VEGF) is a homodimeric, disulfide-bound glycoprotein that exists in tal cancer in combination with 5-fluorouracil–based chemotherapy,
at least four main isoforms of 121, 165, 189, and 206 amino acids and for initial systemic treatment of non–small-cell lung cancer in
generated by alternative mRNA splicing.95–97 VEGF121 is acidic, non- combination with carboplatin and paclitaxel.104,105 Bevacizumab
heparin and nonheparan sulfate proteoglycan (HSPG) binding, and is was labeled with 125I, 111In, or zirconium-89 (89Zr, positron emitter,
freely diffusible. VEGF189 and VEGF206 are highly basic and bind to half-life: 3.27 days) and demonstrated VEGF-specific tumor uptake
HSPGs with high affinity, and both are almost completely sequestered in human tumor xenograft models.105,106 Scintigraphic imaging
in the ECM. VEGF165 is the predominant isoform in vivo. It is also using 111In-bevacizumab and PET imaging using 89Zr-bevacizumab
secreted and diffusible, but carries a heparin-binding domain that provided clear tumor visualization beginning on day 3 after tracer
can result in cell association, leading to a significant portion remain- injection, and image quality improved by day 7. 111In-Bevacizumab
ing bound to the cell surface and ECM. and 89Zr-bevacizumab showed similar biodistribution in major nor-
VEGF, synthesized and secreted by many cell types in several mal tissues, with high radioactivity accumulation in the blood, lung,
embryonic and adult tissues (e.g., the lung, kidney, heart, brain, and and heart at 24 hours p.i. that decreased over time, and high radio-
spleen) and by a variety of tumor cells, plays key roles in the regula- activity accumulation in the spleen and liver at later time points. In
tion of developmental vasculogenesis, angiogenesis, and differentia- addition, radioactivity accumulation in the bone was much higher
tion of progenitor endothelial cells, functioning mainly by interacting for 89Zr-bevacizumab than 111In-Bevacizumab at day 7 p.i. In com-
with VEGFR-1 and VEGFR-2.97,98 VEGFR-2 is expressed in vascular parison with 89Zr-labeled human IgG and antihuman IgG staining
and lymphatic endothelial cells but several types of nonendothelial in a tumor slice from mice receiving 89Zr-bevacizumab, the study
cells such as hematopoietic stem cells, megakaryocytes, and some found that radiolabeled bevacizumab binds primarily to VEGF in
tumor cells also express VEGFR-2.95,98,99 Binding of VEGF to tumor blood vessels, but binding to VEGF in the ECM around tumor
VEGFR-2 on endothelial cells starts a tyrosine kinase signaling cas- cells could not be demonstrated.106 Another study examined uptake
cade that stimulates production of factors that differentially stimu- of 111In-bevacizumab in mouse tumors of human melanoma Mel57
late vascular permeability and activate or regulate endothelial cell (originally VEGF-negative) transfected with various VEGF isoforms
proliferation, survival, migration, and differentiation during angio- (VEGF121, VEGF165, and VEGF189).107 Tumors expressing VEGF121 did
genesis. Upregulated expression of VEGF/VEGFR-2 by tumor cells/ not show specific uptake, whereas tumors expressing VEGF165 and
endothelial cells frequently occurs in many human solid tumor VEGF189 were clearly visualized by γ-camera imaging. This suggests
types, and is associated with tumor progression, metastasis, and that the accumulation of radiolabeled bevacizumab in the tumor is
angiogenesis, and is implicated in poor prognosis, thus making them because of the interaction with VEGF-A isoforms VEGF165 and
rational targets for cancer detection and therapy. VEGF189 associated with the tumor cell surface and/or ECM.
One clinical study investigated the correlation between tumor
accumulation of 111In-bevacizumab and VEGF expression in 12
Radionuclide Tracers for Angiogenesis Imaging patients with colorectal cancer liver metastases.108 Enhanced
Using Radiolabeled Anti-VEGF Antibodies tracer uptake in the liver metastases was observed in nine of the
patients. Antibody accumulation in these lesions varied consider-
Radiolabeled VG76e ably, and no clear-cut correlation was achieved between the level
VG76e is an IgG1-type mouse monoclonal antibody that recognizes of tracer accumulation and the level of VEGF expression in the
the human VEGF121, VEGF165, and VEGF189 isoforms.100 Labeling of tissue as determined by in situ hybridization and ELISA. But in
VG76e with iodine-124 (124I, positron emitter, half-life: 4.2 days), 125I, another clinical setting, 111In-bevacizumab SPECT was performed
samarium-153 (153Sm), or 99mTc was reported for detection of VEGF in nine patients with stage III/IV melanoma, and tracer uptake


Figure 37.6. A: Transverse and coronal
VEGF-SPECT images at days 0, 2, 4, and 7 p.i.
of the tracer. Over time, 111In-bevacizumab
accumulates in the tumor with optimal tumor-to-
background ratio 4 days p.i. B: Transverse and
coronal CT images and VEGF-SPECT/CT fusion
4 days p.i. (Reprinted from Nagengast WB,
Hooge MN, van Straten EM, et al. VEGF-SPECT
with 111In-bevacizumab in stage III/IV melanoma
patients. Eur J Cancer. 2011;47:1595–1602,
B with permission from Elsevier.)
was compared to VEGF levels in resected melanoma lesions.109 contrast were observed at 24 hours. A biodistribution study showed
Twelve nodal lesions were detected by both FDG-PET and CT, all rapid blood clearance of 89Zr-ranibizumab from 8.44 ± 2.19%ID/g
of which could be visualized by 111In-bevacizumab SPECT; day 4 at 1 hour p.i. to 0.38 ± 0.38%ID/g at 24 hours p.i., at which time the
after tracer injection was determined to be the optimal timing for blood accumulation of 89Zr-bevacizumab remained high at 9.54 ±
visualization and quantification of 111In-bevacizumab uptake in 5.12%ID/g, demonstrating the improved pharmacokinetics of the
the tumor (Fig. 37.6). At baseline, 111In-bevacizumab tumor Fab derivative of bevacizumab.112 The VEGF-binding specificity of
uptake varied three-fold and 1.6 ± 0.1-fold between and within 89
Zr-ranibizumab was supported in comparison with the low tumor
patients, respectively. After a therapeutic dose of bevacizumab, uptake of 89Zr-Fab-IgG control and by a competitive blocking assay
there was a 21% ± 4% reduction in tracer uptake. 111In-bevaci- using increasing doses of unlabeled ranibizumab. The potential of
89
zumab tumor uptake measured after treatment correlated with Zr-ranibizumab as a tumor-imaging agent to determine the effi-
VEGF expression in the resected tumor lesions. cacy of sunitinib was also shown in mice bearing SKOV-3, A2780,
89
Zr-bevacizumab PET was useful for monitoring tumor response or Colo205 (a human colorectal adenocarcinoma cell line) tumors.
to VEGF-dependent antiangiogenic treatment with HSP90 inhibitor
NVP-AUY922 in mice bearing A2780 human ovarian cancer xeno-
grafts.110 Compared to pretreatment values, 2 weeks of NVP- Radionuclide Tracers for Angiogenesis
AUY922 treatment decreased tumor uptake of 89Zr-bevacizumab by Imaging by Targeting VEGFR-2
44.4% (p = 0.0003), coinciding with a significant reduction in tumor
VEGF levels and MVD. The long circulating serum half-life (21 days)
VEGF-Based Tracers
of bevacizumab is a limitation for dynamic imaging studies because VEGF165 and VEGF121 are secreted by different cell types and repre-
maximum signal is observed as late as 4 to 7 days p.i. Ranibizumab sent the predominant isoforms of VEGF, whereas the other isoforms
(molecular weight: 48 kDa), an mAb fragment (Fab) derivative of are primarily expressed in membrane-bound form.113 Compared to
bevacizumab (molecular weight: 148 kDa) was developed111 and VEGF121, VEGF165 is less soluble and contains an extra domain for
labeled with 89Zr (89Zr-ranibizumab) to improve the pharmacoki- heparin binding, resulting in increased nonspecific binding and low
netics of 89Zr-bevacizumab.112 PET of mice bearing SKOV-3 (a tumor-to-background ratio. VEGFR-2 is overexpressed in vascular
human adenocarcinoma cell line) tumors performed at 1, 3, 6, and endothelial cells of various human tumors and tumor cells.99 Inhibi-
24 hours p.i. of 89Zr-ranibizumab showed clear tumor visualization tion of VEGFR-2 function inhibits tumor growth and metastasis.
within 3 hours; the highest tumor tracer uptake and greatest tumor Therefore, determination of VEGFR activity is of central interest for

research in the field of tumor angiogenesis and for diagnosis and This study demonstrates that even in the same tumor model,
treatment of tumors. VEGF acts directly on endothelial cells by VEGFR-2 expression differs dramatically between stages of tumor
binding to VEGFR-1 and VEGFR-2. Because VEGF is the natural growth. In another study of similar design, 64Cu-DOTA-VEGF121 PET
ligand for VEGFR-2, VEGF or derivative-based tracers may have imaging was performed in mice bearing a relatively larger number
high receptor-binding affinity and be less immunogenic than exog- (n = 15) of various-sized U87MG tumors, followed by western blot-
enous molecules. However, because it is also the ligand for VEGFR-1, ting and immunofluorescence staining of tumor tissues.120 Tumor
which is highly expressed in the kidneys, nonspecific accumulation uptake of 64Cu-DOTA-VEGF121 peaked when the tumor size was
is a major concern.114 about 100 to 250 mm3. Both smaller and larger tumors had lower
tracer uptake, indicating a narrow range of tumor size with high
VEGFR-2 expression. All tumors shared low VEGFR-1 expression.
Radioiodinated VEGF121 and VEGF165 Most importantly, the tumor uptake value obtained from PET imag-
Human recombinant VEGF121 and VEGF165 were labeled with 123I by ing at 4 hours p.i. showed a good linear correlation with the relative
electrophilic radioiodination using the chloramine T method, and tumor tissue VEGFR-2 expression as measured by western blotting.
the in vitro binding properties were analyzed using human umbili- Histology of the frozen tumor tissue verified the imaging results.
cal vein endothelial cells, several human tumor cell lines, a variety The highest accumulation of radioactivity from 64Cu-DOTA-
of primary human tumors, and adjacent nonneoplastic tissues, as VEGF121 was observed in the kidneys, mainly because of VEGFR-1
well as normal human peripheral blood cells.115 Significantly greater binding, as this receptor is highly expressed in the kidneys.64Cu-
specific binding was observed for 123I-VEGF165 and 123I-VEGF121 DOTA-VEGFDEE was developed as a solution for this problem.121
in a variety of human tumor cells/tissues compared with corre- Alanine-scanning mutagenesis revealed that Arg(82), Lys(84), and
sponding normal tissues or peripheral blood cells. Compared to His(86) are critical for binding of VEGF to VEGFR-2, whereas
123
I-VEGF121, 123I-VEGF165 bound to a higher number of different Asp(63), Glu(64), and Glu(67) are required for binding to VEGFR-1.122
tumor cell types with higher capacity. 123I-VEGF165 scintigraphy and Based on this finding, the D63AE64AE67A mutant of VEGF121
SPECT were evaluated in 18 patients with gastrointestinal tumors.116 (VEGFDEE), in which Asp(63), Glu(64), and Glu(67) of VEGF121 were
Intravenous injection of 123I-VEGF165 (184 ± 18 MBq) did not cause mutated to Ala, conjugated with DOTA, and labeled with 64Cu
side effects. Among the 40 lesions detected by CT/MRI, 23 (58%) (64Cu-DOTA-VEGFDEE) for PET imaging.121 In comparison with
64
could be visualized 0.5 to 3 hours after tracer injection. In patients Cu-DOTA-VEGF121, 64Cu-DOTA-VEGFDEE had comparable tumor-
with pancreatic adenocarcinomas, primary tumors were visualized targeting efficacy but reduced renal accumulation because of its
in seven of nine. Malignant liver lesions can be visualized by 20-fold lower affinity for VEGFR-1.
123
I-VEGF165 SPECT; however, benign liver hyperplasia appeared as
a cold spot. In a follow-up study, nine patients with biopsy-proven 99m
pancreatic carcinomas received 123I-VEGF165 scintigraphy; seven of
Tc-HYNIC-VEGF
99m
nine primary lesions could be clearly visualized within 30 minutes Tc-HYNIC-VEGF was developed based on the construction and
after injection and remained detectable at 3 hours p.i.117 No substan- expression of VEGF121 fused with a cysteine-containing peptide tag
tial uptake by normal gastrointestinal tissue was noted. 123I-VEGF165 (C-tag).123 C-tagged-VEGF allowed site-specific conjugation of the
showed rapid clearance from the circulation, as radioactivity in the biofunctional chelator hydrazine nicotinamide (HYNIC)-maleimide
blood rapidly decreased to less than 4% ± 2% of the injected activity for 99mTc labeling. The site-specific strategy may overcome the prob-
within 30 minutes, and approximately 86% ± 6% of the injected activ- lem of random labeling usually associated with reduced receptor-
ity was recovered in the urine by 24 hours p.i. Main 123I-VEGF165- binding activity, high liver uptake, or complicated probe design.
99m
retaining tissues in humans include the thyroid, spleen, lungs, liver, Tc-HYNIC-VEGF SPECT imaging of 4T1 murine mammary
and kidneys. A very recent clinical report suggested 123I-VEGF165 carcinoma-bearing mice showed that the tumor can easily be visual-
receptor scintigraphy may be useful for visualization of highly malig- ized 1 hour after tracer injection, and that 99mTc-HYNIC-VEGF pref-
nant osteosarcoma and/or metastasis and the angiogenic activity of erentially accumulates at the tumor rim, where the most extensive
the tumor.118 Although promising results have been obtained for angiogenesis takes place.123 SPECT imaging with 99mTc-HYNIC-VEGF
123
I-VEGF165 in the clinical setting, another study comparing the bio- can also readily detect the effects of cyclophosphamide treatment
distribution of 125I-VEGF121 and 123I-VEGF165 in an LS180 human on 4T1 tumors. One week of cyclophosphamide therapy resulted
colon cancer xenograft model in mice suggested that VEGF121 would in reduced tracer uptake, corresponding with reduced VEGFR-2
be the more appropriate targeting molecule of VEGFRs in terms of expression as determined by immunohistochemistry.
low background activity.119 However, prolonged elevated radioactiv-
ity in the circulation is a major limitation of 125I-VEGF121, whereas
prominent 125I-VEGF165 radioactivity accumulation was observed in
scVEGF-Based Radiotracers
the stomach because of deiodination. The similarities and differ- scVEGF is an engineered 28-kDa single-chain VEGF composed of
ences between VEGF121 and VEGF165 in terms of their in vivo behav- two repeated 3- to 112-amino acid fragments of VEGF121 with a
ior may be attributable to their distinct binding affinity to different 15-amino acid N-terminal Cys tag containing a unique cysteine
VEGFRs with different tissue distributions. residue for site-specific attachment of a variety of agents such as
64
Cu,124 68Ga,125 18F,126 etc. for nuclear imaging. In addition, incor-
64 64 poration of PEG as a linker between the protein and chelator pro-
Cu-DOTA-VEGF121 and Cu-DOTA-VEGFDEE longed blood clearance, leading to higher tumor accumulation and
Human recombinant VEGF121 was randomly conjugated with reduced renal uptake. The advantages of radiolabeled scVEGF-
DOTA (4.3 ± 0.2 DOTA molecules per VEGF121) and labeled with based tracers to image tumor VEGFR-2 expression in clinical set-
64
Cu.114 DOTA-VEGF121 has VEGFR-2-binding affinity comparable tings should be determined with respect to in vivo stability,
to that of VEGF121. 64Cu-labeled DOTA-VEGF121 was stable in mouse targeting efficiency and specificity, pharmacokinetics, the correla-
serum after 24-hours incubation at 37°C. PET of mice bearing tion between tracer uptake and receptor expression levels, and the
U87MG tumors of different sizes revealed rapid (within 2 hours), ease of radiolabeling and cost.
specific, and prominent uptake of 64Cu-DOTA-VEGF121 (∼15 %ID/g)
in small U87MG tumors (tumor volume: 64.9 ± 24.6 mm3; high
VEGFR-2 expression and high MVD) but significantly lower and
VEGFR-2-Targeting Radiotracers
sporadic uptake (∼3 %ID/g) in large U87MG tumors (tumor volume: VEGFR-2 is a transmembrane tyrosine kinase VEGF signal-
1,164.3 ± 179.6 mm3; low VEGFR-2 expression and low MVD). transducing receptor. Many small molecules have been developed to

block the intracellular tyrosine kinase at the adenosine triphos- carcinoma patient with miliary lesions in both lungs, diffuse activity
phate–binding site99; some of which, such as sorafenib and sunitinib, accumulation was revealed in both lungs. No selective accumula-
have been approved by the FDA as antiangiogenesis drugs for cancer tion was observed in the brain of a patient with a benign brain tumor
therapy. Preparation and evaluation of radiolabeled TKIs or analogs (pilocytic astrocytoma) (see Fig. 37.7C, D). The differences in tracer
such as 11C-PAQ,127 11C-labeled Vandetanib or chloro-Vandetanib,128 uptake correlated with the different levels of ED-B expression dem-
5-125I-iodo-sunitinib,129 and 18F-SKI-249380130 have been reported onstrated by immunohistochemical staining. This clinical work
for VEGFR-2 imaging. In mice bearing B16F10 melanoma xeno- shows the ability of 123I-labeled L19(scFv)2 to noninvasively detect
grafts, enhanced radioactivity accumulation of 11C-PAQ was observed aggressive primary tumors and metastases in patients by targeting
in the VEGFR-2–positive area of the tumor; however, strong accumu- ED-B expression around the tumor vasculature.
lation was also found in the lungs, kidneys, and liver.127 Although
radiolabeling of TKI is emerging as a new strategy for VEGFR-2
imaging, much more evidence is necessary to confirm the in vivo Radiotracers for ED-B Imaging
targeting efficiency and specificity for tumor VEGFR-2 expression. in Preclinical Studies
Radiolabeling of anti–VEGFR-2 antibody is also an approach for 99m
VEGFR-2 imaging. DC101, a rat antimouse VEGFR-2 monoclonal
Tc-L19-AP39
antibody, inhibits angiogenesis and suppresses tumor growth and Because of the thiophilic nature of Tc(V), a free sulfhydryl group
metastasis.131–133 DC101 was conjugated with chitosan, a linear poly- must be introduced into the protein sequence for stable radiometal
saccharide composed of D-glucosamine and N-acetylglucosamine binding. In Berndorff et al.’s147 work, the amino acid sequence

subunits with numerous D-glucosamine groups for ligand conjuga- (Gly)3-Cys-Ala was genetically inserted at the C-terminus of
tion, and labeled with 99mTc.134 γ-Camera imaging of mice bearing scFv(L19), resulting in a recombinant protein named AP39, which

B16F10 and HeLa tumor models demonstrates the potential of is suitable for direct labeling with 99mTc. In F9 tumor-bearing mice,
99m
Tc-chitosan-DC101 for VEGFR-2 imaging, with T/M ratios >3 a 99m
Tc-L19-AP39 showed high tumor uptake with a maximum of
couple of hours after tracer injection135 Human/mouse cross-reactive 8.7%ID/g after 5 hours, decreasing to 2.8%ID/g 24 hours after
anti–VEGFR-2 antibodies136 available for radiolabeling are awaiting injection, and fast blood clearance, leading to a T/B ratio of 6.4,
further evaluation with VEGFR-2 imaging in clinical settings. 3 hours after injection, increasing to 17.2 after 24 hours, with very
low radioactivity accumulation in nontarget organs with the excep-
tion of the kidneys because of the major renal elimination pathway
The Extra Domain B of Fibronectin of this radiotracer. Scintigraphic images also showed that the
tumor could be clearly visualized at 3, 5, and 24 hours after tracer
(ED-B) as a Marker of Tumor injection. Their work shows the feasibility of SPECT imaging of
Angiogenesis tumor angiogenesis with 99mTc-L19-AP39 radiotracer.
Fibronectin is a large glycoprotein widely distributed in the ECM, and 76

Br-L19-SIP
exists in several isoforms (e.g., III CS, ED-A, ED-B).137,138 The ED-B
(extra domain B), a sequence of 91 amino acids identical in mice, L19-SIP was labeled with bromine-76 (76Br, positron emitter, half-
rats, and humans, is a marker of angiogenesis and tissue remodeling life: 16.2 hours) via enzymatic radiobromination using bromoper-
because it plays an important role in endothelial cell proliferation oxidase/H2O2.148 The labeling yield was >55% under mild reaction
and vascular morphogenesis, and is abundantly expressed around conditions (0°C for 80 minutes). Biodistribution and small-animal
the vasculature of tumors in the exponential growth phase, but not imaging studies (PET and CT) in mice with F9 tumors showed
in the slow-growth phase or other tissues undergoing angiogenesis, high and persistent tumor uptake of 18.1 ± 7.6, 9.3 ± 3.5, and
but is undetectable in mature normal tissues.139–142 High levels of 14.3 ± 1.6 %ID/g at 5, 24, and 48 hours p.i., respectively, and clear
ED-B expression have been detected in a variety of human cancers tumor visualization. Other ED-B–expressing organs, especially the
and metastases such as breast and lung cancers, high-grade astrocy- uterus, also showed high tracer uptake of 13.5 ± 6.3, 9.3 ± 3.5,
toma (but not low-grade), glioblastoma, and liver metastases.140,141,143 and 6 ± 1 %ID/g at 5, 24, and 48 hours p.i. However, slow renal
First identified by Pini et al.,144 the human recombinant single- clearance and persistent radioactivity predominately in the blood
chain antibody fragment L19, scFv(L19), selectively binds ED-B with and stomach was also observed, partially because of 76Br-L19-SIP
high affinity. Microautoradiography of an F9 tumor (a fast-growing debromination in vivo. 76Br-L19-SIP PET is a valuable tool for
murine teratocarcinoma expressing high levels of ED-B) dissected tumor angiogenesis imaging by targeting the angiogenesis-
from a mouse after injection with 125I-labeled scFv(L19) clearly associated expression of ED-B fibronectin. Further efforts to reduce
showed radioactivity accumulation in the tumor blood vessels but debromination of 76Br-L19-SIP are necessary.
not in the vessels of the normal surrounding tissue.145 No radioactiv-
ity accumulation was observed in the vessels of other organs (liver, 124
I-L19-SIP/ 131I-L19-SIP
lung, muscle, spleen, kidney, brain, and skin). Afterward, several
other scFv(L19) derivatives were constructed such as a dimeric scFv L19-SIP was labeled with 124I produced in a GMP compliant facility
[(scFv)2], a human bivalent “small immunoprotein” (SIP, approxi- or with commercially available 131I by using a modified version of
mately 80 kDa), and a complete human IgG1,146 based on which a the IODO-GEN method, and overall labeling efficiency, radiochemi-
variety of radiotracers have been designed, synthesized, and char- cal purity, and the immunoreactive fraction were ∼80%, 99.9%,
acterized for their tumor-targeting efficiency and pharmacokinetics. and >90% for both 124I-L19-SIP and 131I-L19-SIP.149 In human
An initial clinical study published in 2003 reported scintigraphic SCCHN FaDu xenograft-bearing mice, biodistribution data showed
imaging of ED-B expression using iodine-123 (123I, γ-ray emitter, half- that the tumor uptake of 124I-L19-SIP was 7.3 ± 2.1, 10.8 ± 1.5, 7.8 ±
life: 13.2 hours)-labeled L19(scFv)2 (185 to 518 MBq) in 20 patients 1.4, 5.3 ± 0.6, and 3.1 ± 0.4%ID/g at 3, 6, 24, 48, and 72 hours
with brain, lung, and colorectal cancer.143 No side effects were p.i., respectively, resulting in increased T/B ratios ranging from 6
observed. Sixteen of the patients showed different levels of tracer at 24 hours to 45.9 at 72 hours p.i., and increased T/M ratios from
accumulation in the primary tumor or metastases 6 hours after 22.6 at 24 hours to 119 at 72 hours p.i. At 24 hours p.i., tumor-to-
tracer injection. For example, a strong and selective radioactivity major normal organ ratios were generally >4 except for the blad-
accumulation was observed in the liver lesions of a patient with liver der; importantly, the tumor-to-liver and tumor-to-kidney ratios
metastases of colorectal cancer, and in the tumor mass of a patient were 18.5 and 6.2, revealing the highly sensitive and selective
with recurrent glioblastoma (Fig. 37.7A, B). In a small-cell lung receptor-targeting efficiency and optimum pharmacokinetics of

A B
C D
Figure 37.7. Localization of 123I-L19(scFv)2 in brain tumors. SPECT γ-camera transaxial section (A) and MRI (B), from a patient with a recurrent glioblastoma
lesion growing around the postoperatory cavity. SPECT transaxial scans (C) and CT (D) from a patient with a low-grade pilocytic astrocytoma, which could be
removed only subtotally by surgery. Residual tumor tissue adjacent to the brainstem is indicated by the arrow (D). CT had to be performed for this patient, because
a metallic implant prevented MRI. (Reprinted from Santimaria M, Moscatelli G, Viale GL, et al. Immunoscintigraphic detection of the ED-B domain of fibronectin, a
marker of angiogenesis, in patients with cancer, with permission from AACR. Clin Cancer Res. 2003;9:571–579.)
124
I-L19-SIP. Fully concordant labeling and biodistribution results such as CD31 and von Willebrand factor, CD105 expression serves
were obtained with 124I- and 131I-L19-SIP. PET imaging with as a better prognostic marker of patient outcomes.150 CD105
124
I-L19-SIP (3.7 MBq) revealed clear delineation of tumors, even expression determined by immunohistochemical staining in
those ∼50 mm3 and no adverse uptake in other organs (Fig. 37.8). gastrointestinal, breast, lung, brain, ovarian, endometrial, pros-
This study revealed the promise of 124I-L19-SIP PET for tumor tate, and head and neck malignancies was consistently associated
angiogenesis imaging and for predicting 131I-L19-SIP biodistribu- with lower patient survival rates, and in gastrointestinal, breast,
tion as a guide to 131I-L19-SIP radioimmunotherapy. Further stud- prostate, and head and neck malignancies, CD105 expression was
ies should be conducted to characterize the correlation between associated with the presence of distant metastases.150 Overexpres-
124
I-L19-SIP uptake and ED-B expression levels in tumors. sion of CD105 was also reported to be a useful predictor of recur-
rence of resected gastric cancer and may be specifically associated
with the development of locoregional recurrence and hematoge-
CD105 as a Marker of Tumor nous metastasis.152 CD105 expression thus seems to have prog-
Angiogenesis nostic value in a variety of solid cancers, and has become a
powerful therapeutic target of tumor angiogenesis. Moreover,
CD105 (also known as endoglin) is a homodimeric transmem- CD105 expression is mainly restricted to vascular endothelial
brane glycoprotein expressed on activated vascular endothelial cells; in solid malignancies, CD105 is almost exclusively expressed
cells of newly formed blood vessels.150,151 It is an accessory protein on endothelial cells of both peri- and intratumoral blood vessels
of the transforming growth factor-β receptor system. The patterns and on tumor stromal components.153 Hence, CD105 can be con-
of CD105 and CD31 expression were evaluated and compared in sidered one of the most suitable markers for evaluating tumor
primary colon adenocarcinomas and normal colonic mucosa.150 angiogenesis.
Whereas anti-CD31 antibodies equally stained blood vessels in
normal and malignant colon, CD105 expression was observed
primarily in malignant lesions, with little to no expression in the
Radiotracers for Targeting CD105
vessels of nonmalignant mucosa. Several research groups have Monoclonal anti-CD105 antibodies MAEND3, E9, and MJ7/18 were
reported that, compared to some traditional vascular markers initially radiolabeled with 125I,154 99mTc,155 and 111In,156 respectively,

A B C

Figure 37.8. Serial PET images of FaDu
xenograft-bearing nude mouse injected with
124
I-L19-SIP (3.7 MBq, 25 μg). At 1 (A, D), 2 (B,
E) and 3 (C, F) weeks after tumor implantation
124
I-L19-SIP was administered, and 48 hours
later coronal images were acquired. Image
planes have been chosen where the left tumor
(upper, A–C) or right tumor (lower, D–F) is
optimally visible. The thyroid (arrow) is visible
because this organ was not blocked by potas-
sium iodide in this experiment. (With kind
permission from Springer Science and Busi-
ness Media: Tijink BM, Perk LR, Budde M, et al.
124
I-L19-SIP for immuno-PET imaging of tumour
vasculature and guidance of 131I-L19-SIP radio-
immunotherapy. Eur J Nucl Med Mol Imaging. D E F
2009;36:1235–1244.)
and tested for tumor angiogenesis imaging in experimental tumor CD105-positive 4T1 tumors at 24 and 48 hours after 64Cu-DOTA-
models with encouraging results. TRC105 (also known as c-SN6j) TRC105 injection, and tumor activity uptake was 8 ± 0.5, 10.4 ±
is a human/murine chimeric IgG1 monoclonal antibody that binds 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 hours p.i., higher than
human and murine CD105 (with lower affinity for the latter) and most organs at later time points, which provided good tumor
inhibits angiogenesis and tumor growth.157,158 Compared to other contrast. Tumor tracer uptake was CD105-specific, which was
anti-CD105 antibodies, TRC105 has very high affinity to human validated by blocking experiments, control studies with an iso-
CD105. Very recently, a phase I first in human study in 50 patients type-matched 64Cu-DOTA-cetuximab that binds to human epider-
with advanced refractory solid tumors was reported, and subse- mal growth factor receptor, and in vitro/ex vivo immunostaining
quent phase II clinical studies are ongoing to evaluate TRC105 studies. Predominant radioactivity accumulation in normal
alone and in combination with other agents in a wide variety of organs was observed at 24 hours and in the liver and spleen,
cancer types.159 Developing and clinical translation of radiola- both of which were CD105-negative, suggesting that tracer
beled TRC105-based tracers should be helpful for patient stratifi- uptake in the liver and spleen was largely unrelated to CD105
cation, monitoring treatment response, and drug evaluation for binding and more likely related to nonspecific capture by the
dose and dosing regimen in TRC105-based clinical trials. Mean- reticuloendothelial system, hepatic clearance, and possible tran-
while, efforts to determine the value of CD105-targeted tumor schelation of 64Cu. Zhang et al.161 from the same group reported
angiogenesis imaging are also necessary. Currently, CD105-targeted the development of 64Cu-labeled TRC105 using a different chela-
radiotracers are mostly focused on the use of TRC105 which tor NOTA which was performed and evaluated in the same exper-
is under development by Weibao Cai and colleagues at the imental settings including the labeling conditions used for
64
University of Wisconsin-Madison. At this time, there have not been Cu-DOTA-TRC105. Tumor-targeting efficacy did not significantly
clinical trials for CD105 SPECT or PET imaging. differ between the two bifunctional chelators. The major differ-
ences between 64Cu-DOTA-TRC105 and 64Cu-NOTA-TRC105 were
TRC105-Based Radiotracers observed in their accumulation levels in some normal organs,
with the latter showing particularly higher activity in the blood
in Preclinical Studies but lower activity in the liver and spleen. Detailed comparison of
Hong et al.160 reported the first successful PET imaging study of the agents suggests 64Cu-NOTA-TRC105 may have higher stabil-
CD105 expression using TRC105 conjugated to the biofunctional ity, longer circulation half-life, and better tumor contrast at 24 or
chelator DOTA and labeled with 64Cu. 64Cu labeling (reaction tem- 48 hours. However, the authors also stated that DOTA is a univer-
perature: 40°C; reaction time: 30 minutes) was achieved with sal chelator which can complex with a wide variety of imaging
high yield and specific activity. PET imaging clearly visualized and therapeutic radioisotopes; the same DOTA-TRC105 conjugate

expression (levels and pattern) in tumors is anticipated to explore

the clinical potential of CD105-targeted angiogenesis imaging by
TRC105-based radiotracers.
Endostatin Receptors as Possible

Markers of Tumor Angiogenesis
Endostatin was discovered in 1997 by O’Reilly et al.163 in Judah
Folkman’s laboratory as an endogenous inhibitor of tumor
angiogenesis and growth. It was isolated from a murine heman-
gioendothelioma and identified as a naturally occurring 20-kDa
C-terminal proteolytic fragment of type XVIII collagen, an
important proteoglycan in epithelial and endothelial basement
membranes. Endostatin may bind and interact with several
membrane proteins including α5β1, αvβ3, and αvβ5 integ-
rins,5,163,164 heparin/heparan sulfate,164,165 and VEGFR-2,166
A which are possible endostatin receptors. The mechanisms of
endostatin in tumor angiogenesis are complicated and not fully
understood167,168 but appear to mediate many aspects of the
VEGF/VEGFR-2 pathway,166 cell cycle pathway,169 and proapop-
totic pathway.170 Endostatin may significantly affect approxi-
Tumor
mately 12% of genes used by human endothelial cells.171
Recombinant human endostatin has been evaluated in clinical
trials as a broad-spectrum angiogenesis inhibitor for several
types of cancer including pancreatic endocrine tumors and car-
cinoid tumors,172 as well as stage IIIB–IV non–small-cell lung
cancers (NSCLCs)173 without causing severe adverse effects or
drug resistance. Addition of endostatin to the standard chemo-
therapeutic regimen in advanced NSCLC patients resulted in
significant and clinically meaningful improvement in response
rate, median time to progression, and clinical benefit compared
with the chemotherapeutic regimen alone.
As early as in 2002, it was proposed that endostatin imaging
B
may facilitate understanding of antiangiogenic drugs.174 Cur-
Figure 37.9. Small-animal PET imaging of 4T1 tumor-bearing mice. A: Serial coronal PET rently, there are limited reports on endostatin-based molecular
images at 5, 24, 48, 72, and 96 hours after injection of 89Zr-Df-TRC105, 2 mg of TRC105 before
89 imaging in tumor angiogenesis. Yang et al.175 reported the 99mTc-
Zr-Df-TRC105 (i.e., blocking), or 89Zr-Df-cetuximab. Tumors are indicated by arrowheads.
B: Representative PET/CT images of 89Zr-Df-TRC105 in 4T1 tumor-bearing mice at 48 hours labeled endostatin γ-camera imaging of rat with RBA CRL-1747
p.i. (With kind permission from Springer Science and Business Media: Hong H, Severin GW, Yang breast cancer tumors and assessment of the antiangiogenic
Y, et al. Positron emission tomography imaging of CD105 expression with 89Zr-Df-TRC105. Eur effect of endostatin or the chemotherapeutic drug paclitaxel.
J Nucl Med Mol Imaging. 2012;39:138–148.)
Endostatin was conjugated with L, L-ethylenedicysteine (EC)
and labeled with 99mTc to form the endostatin-based SPECT
probe. Scintigraphic imaging showed that the tumor could be
can therefore be employed for imaging and therapeutic applica- visualized 0.5 to 4 hours after 99mTc-EC-endostatin injection
tions, with the use of appropriate isotopes, without altering its (3.7 MBq), compared with 99mTc-labeled EC chelator alone (3.7
pharmacokinetics and tumor-targeting efficacy. The choice of MBq) (Fig. 37.10). Tumor uptake of 99mTc-EC-endostatin could
64
Cu-DOTA-TRC105 or 64Cu-NOTA-TRC105 may depend on the be efficiently blocked with preinjection of excess unlabeled end-
application, imaging alone or imaging plus radioimmunotherapy ostatin, revealing the receptor-binding specificity, which was
(e.g., with yttrium-90 (90Y) and/or lutetium-177 [177Lu]). For imag- supported in comparison with a nonspecific peptide tracer,99mTc-
ing alone, the localization of lesions is also a factor in choosing a EC-K1XaK2tPA. One week of endostatin or paclitaxel treatment
suitable radiotracer. resulted in decreased tumor uptake of 99mTc-EC-endostatin and
Cai’s group developed another TRC105-based PET probe by reduced tumor volume. There was a positive correlation
conjugating the biofunctional chelator p-isothiocyanatobenzyl- between tumor uptake of 99mTc-EC-endostatin and expression of
desferrioxamine (Df-Bz-NCS) to TRC105 for 89Zr labeling.162 The angiogenic factors including VEGF, basic fibroblast growth fac-
longer decay half-life of 89Zr (3.3 days) makes long-term tracing of tor, and interleukin-8. An optical imaging study in mice with
TRC105 possible. Also evaluated in the same experimental set- Lewis lung carcinoma xenografts demonstrated the efficiency of
tings as those used for 64Cu-DOTA-TRC105 and 64Cu-NOTA- near-infrared Cy5.5-labeled endostatin for tumor detection.176
TRC105,89Zr-Df-TRC105 showed superb stability, excellent tumor The intratumoral binding site for endostatin was located in the
contrast at 24 hours and later time points until 96 hours p.i., and tumor vasculature and colocalized with CD31-positive endothe-
much higher tracer uptake in the tumor than in all major organs lial cells. These studies show the promise of endostatin-based
including the liver and kidney (Fig. 37.9). The CD105 specificity of imaging as a surrogate approach for tumor angiogenesis imag-
89
Zr-Df-TRC105 was confirmed by competitive blocking with ing, which would be helpful for unraveling the mysteries of
TRC105 2 hours before the tracer injection, which significantly endostatin as reviewed by Fu et al.177 and may be useful for
reduced tracer uptake in the tumor at all time points examined, selection of patients who will benefit from endostatin, and for
and further supported in comparison with the isotype-matched monitoring the efficacy of antiangiogenic treatment. Further
control, 89Zr-Df-cetuximab (see Fig. 37.9). Forward quantitative development of endostatin-based radiopharmaceuticals are
correlation and colocalization study of tracer uptake and CD105 needed.

99mTc-EC 99mTc-EC-Endostatin
0.5 2 4h 0.5 2 4h
Figure 37.10. Scintigraphic images of mammary-tumor–bearing rats following administration of Tc-EC-endostatin and Tc-EC (100 μCi/10 μg/rat, i.v.) at
99m 99m
0.5 to 4 hours on day 14 after inoculation of tumor cells. Tumor, located in right hind leg, was well visualized with 99mTc-EC-endostatin. (From Yang DJ, Kim KD,

Schechter NR, et al. Assessment of antiangiogenic effect using 99mTc-EC-endostatin. Cancer Biother Radiopharm. 2002;17:233–245. The publisher for this copy-
righted material is Mary Ann Liebert, Inc. publishers.)

Conclusions Application of angiogenesis imaging probes for internal radia-
tion therapy by replacing radionuclides from γ-emitters/positron
As angiogenesis in solid tumors plays a critical role in cancer pro- emitters to β-emitters/α-emitters (e.g., 131I, 90Y, 177Lu, 64Cu/Astatine-
gression, invasion, and metastasis, it presents a primary target for 211) is also important, as is research on the reduction of normal
cancer diagnosis and treatment. Now several antiangiogenic drugs tissue uptake of the probes to increase therapeutic gain.
are currently available for clinical use. The need for reliable methods The process of angiogenesis plays an important role in tumor
to predict treatment outcome and/or evaluate treatment effective- progression and many other pathologic states such as atheroscle-
ness at an early stage is ever increasing. Tumor characterization by rosis, arthritis, and chronic inflammation. Application of angio-
in vivo imaging is physically easy on patients and nuclear medicine genesis imaging to these pathologies will also be beneficial.
imaging has the potential to provide direct information on the pres-
ence and change of neovasculature in tumors that would be valuable
for treatment planning. Many radiolabeled tracers for angiogenesis Acknowledgments
imaging have been developed that target molecules associated with
angiogenesis, such as αvβ3 integrin, VEGF, and so on. Some that We thank Professor Yasuhisa Fujibayashi and the other members
were developed earlier are already in clinical trials. More refined of the Molecular Imaging Center, NIRS, for kindly supporting this
designs that have been developed recently are in preclinical evalua- work.
tions. It should be noted, however, that the target molecule is not
entirely specific for angiogenesis in tumors, that is, it is expressed
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C h apt e r 3 8
Radionuclide Imaging of Tumor Cell Proliferation

Sridhar Nimmagadda • Anthony F. Shields
Introduction s ynthesis of RNA after replacement of the deoxyribose. Accordingly,

for more than five decades Tdr labeled with either 3H or 14C and
Uncontrolled proliferation is a hallmark of cancer. Monitoring and more recently other nonradioactive click chemistry–based analogs
quantification of this uncontrolled growth for diagnostic and thera- such as 5-ethynyl-2′-deoxyuridine (EdU) have become a standard to
peutic purposes has long been a primary interest of the imaging characterize proliferation.7 Interestingly, Tdr is not essential for DNA
community.1 Proliferation can be monitored in several ways based synthesis. It is introduced into DNA synthesis by an endogenous pro-
on identifying the active biologic process required for cell growth cess called the de novo pathway. It is synthesized by methylation of
that is, carbohydrate metabolism, DNA synthesis, amino acid metab- dUMP and converted to dTMP by an enzyme called thymidylate
olism, lipid metabolism to name a few. Glucose metabolism, as synthase (TS) (Fig. 38.1). TS is a key enzyme for the de novo synthe-
monitored using 18FDG PET, is the mainstay of nuclear medicine sis of pyrimidines. TS catalyzes the reductive methylation of dUMP,
PET imaging.2 However, high 18FDG uptake is nonspecific because derived from either the deamination of dCMP (catalyzed by dCMP
deaminase), or from the hydrolysis of dUTP (catalyzed by dUTPase),

of inflammation or immune cell proliferation in the tumors. High
intense glucose metabolism in tissues like the brain and radioac- by N5, N10-methylene tetrahydrofolate to result in 2′-deoxyTdr-5′-O-
monophosphate (dTMP).8 dTMP is further di- and triphosphorylated

tivity in the bladder caused by excretion of tracer may also inter-
fere with the interpretation in the brain or prostate, respectively. to dDTP and dTTP by Tdr monophosphate kinase (TMPK) and nucle-
Importantly, cells tend to maintain glucose metabolism even after otide diphosphate kinase (NDPK), respectively. All the Tdr kinase
cessation of replication therefore complicating assessment of the family members require ATP and magnesium for the catalytic addi-
effectiveness of therapeutic agents. tion of phosphate groups. The formed dTTP is incorporated into DNA
Amino acid and lipid precursors can also be used to quantify by DNA polymerase. This de novo pathway is tightly autoregulated
cell growth. Both of these precursors, however, tend to have more by different anabolic and catabolic processes including the end prod-
than one metabolic pathway.3,4 Therefore, it is sometimes difficult uct dTTP. The formed dTTP inhibits several enzymes involved in its
to assess the uptake observed in the tumors as a measure of pro- synthesis process including (1) aspartate transcarbamylase involved
liferation. Despite these limitations, recent developments in this in the synthesis of carbamoyl aspartic acid, a precursor for all pyrim-
category such as utilization of [18F]FACBC and [11C/18F]choline, idine nucleotides; (2) deoxyuridine kinase involved in the synthesis
respectively have gained attention for imaging of prostate and of dUMP; (3) deoxycytidine monophosphate deaminase involved in
other cancers.5,6 Recently, [11C]choline-PET received FDA approval the synthesis of dUMP; (4) cytidine diphosphate reductase involved
to detect recurrent prostate cancer underscoring the importance of in the synthesis of dCDP (Fig. 38.1).9 Our understanding of these
the availability of an armamentarium of complementary imaging processes played an important role in the development of imaging
agents for a thorough cancer diagnosis. agents and how therapeutic agents modulate these processes is
further exploited for proliferation-based therapeutic monitoring.
When Tdr is introduced exogenously, it is rapidly transported
Radiolabeled Thymidine (Tdr) as a across the cell membrane by both equilibrative (ENT1 and ENT2)
and concentrative (CNT1 and CNT3) transporters that produce
Proliferation Imaging Agent equilibration within seconds.10 Once intracellular, the Tdr DNA
incorporation time course is determined by the nature of the sys-
One of the first biologic processes to be halted in response to a cel- tem with dTMP formation as the rate-limiting step and dTTP as the
lular insult is DNA synthesis. An unambiguous way to assess pro- largest fraction of metabolite composition. In the case of exogenous
liferation, therefore, would be to monitor the DNA synthesis. In TdR, TK1 catalyzes the transfer the γ-phosphate group of ATP to the
addition, nucleosides, particularly thymidine (Tdr) and its analogs, 5′-hydroxyl group of Tdr resulting in dTMP. Expression of TK1 is
are unique because of their involvement in the DNA salvage path- strictly cell cycle regulated and increases markedly during S-phase
way. Of all the nucleic acid bases, Tdr is the only one that is selec- followed by a rapid decline as cells enter G2-phase.11 Increased
tively incorporated into DNA and not into RNA. Hence, retention of human TK1 activity is observed and proposed as a prognostic
this radiolabeled base reflects the level of DNA synthesis and cell marker in several cancers.12 Because of a high proliferation rate,
replication. Cytosine, adenosine, and guanosine are used in the cancer cells often express high levels of TK1, which can be used for
CA X
OMP TdR
Orotic acid
dUTP CH3 TP TK
X
TMPK NDPK
Uridine TS dTMP dDTP
Figure 38.1. Thymidine synthesis and metab- UMP UDP dUDP dUMP dTTP
olism. Biochemical de novo pathways leading to
the DNA synthesis. Double arrows indicate revers- NH3 X
UTP
ible processes, catalyzed not necessarily by the
same enzyme. The sites of dTTP inhibition path- X dUR DNA
ways are shown in X. Enzymes discussed in this
chapter that play a role in proliferation imaging
are shown in blue. CA, carbamyl aspartic acid.
CTP CDP X dCDP dCMP dCR
(Modified from Loffler M, Zameitat E. Pyrimidine RNA dCTP
Biosynthesis. In: William JL, Lane MD, eds. Ency-
clopedia of Biological Chemistry. New York, NY: Cytidine
Elsevier; 2004:600–605.)
585

*CH3
O O
NH
*CH *CH3
3
NH NH
N O
HO N O N O
H H
O
OH O O
*CH3 *CH3
OH OH
CO2 + NH3 + NH2
NH2 N O
BAIB H
Figure 38.2. [11C]Thymidine catabolism leading to radioactive metabolites. BAIB, β-aminoisobutyric acid.
the detection of tumors and metastases by means of positron-labeled For detailed molecular characterization of Tdr metabolism,
tracers.13 However, considering only 8% to 20% of the cells are in many of the early studies, both in vitro and in vivo, measured the
S-phase but every cell has active glucose metabolism, the absolute retention of the radiolabel, either 3H- or 14C-Tdr, after the extrac-
accumulation of TK1-catalyzed radioactivity, though highly specific, tion of macromolecules. These extraction processes were done by
is relatively low compared to 18FDG accumulation within the tumors. acid precipitation of the DNA from mixtures of disrupted cellular
One of the issues encountered with labeled thymidine is that, contents and usually removed small molecules, including Tdr itself
exogenously introduced Tdr could be metabolized before it gets and its metabolic breakdown products. Studies were also per-
into the cell by thymidine phosphorylase (TP). TP is involved in formed using fixed tissues, where fixed cells retained labeled DNA.
catalyzing the phosphorolysis of the nucleosidic linkage of pyrimi- Such detailed characterization is not possible in vivo with PET,
dine 2′-deoxynucleosides with the formation of the pyrimidine because PET cannot distinguish the molecular form of the radio-
and 2-deoxy-a-D-ribofuranose-1-phosphate.14 Because this phos- tracer detected. In PET, all of the radioactivity present in a given
phorolysis reaction is reversible, the catabolic function of TP is volume element is measured irrespective of the associated molecu-
inhibited by excess thymine and enhanced by low Tdr levels. The lar entity. These issues were encountered when 11C-Tdr was used
formed thymine undergoes further degradation to dihydrothymine, to measure DNA synthesis. The initial synthesis of 11C-Tdr was
β-ureiodoisobutyric acid (BUIB), β-aminoisobutyric acid (BAIB), achieved by introducing the radiolabel at the methyl position by
carbon dioxide, and water (Fig. 38.2). Although the steps involving enzymatic conversion of deoxyuridine-5′-phosphate to [11C]thymi-
TP occur in many tissues where TP is expressed, including intes- dylate. Further alkaline phosphatase treatment of [11C]thymidylate
tines, liver, bone marrow, kidney, brain, etc., the steps involving the resulted in [11C]-Tdr.19 Evaluation in a VX2 rabbit tumor model
formation of BAIB, CO2, NH3, and water preferentially occur in liver, showed clear tumor uptake of radioactivity. However, longer syn-
spleen, and kidneys. By regulating nucleotide pools, TP plays a thesis time and poor yields limit routine use of this method. Later
critical role in maintaining nucleic acid homeostasis by ensuring in the 1980s, improved synthesis and evaluation of 11C-Tdr was
the correct supply of deoxyribonucleoside triphosphates (dNTPs) achieved through the production and introduction of a radiolabel
for DNA replication and repair.15,16 To prevent the TP-associated using 11C-CH3I in the methyl position.20 Comparison of in vivo stud-
catabolism, nucleoside analogs with greater stability are developed ies of 11C-Tdr with other labeled Tdr analogs (3H and 14C) demon-
by substituting the 2′ or 3′ hydroxyl group of the sugar with a fluo- strated similar results that is, a minor fraction of radioactivity
ride as in the case of 3′-fluoro-3′-deoxy-thymidine (FLT) (Fig. 38.3). incorporated into DNA with a major fraction present in metabo-
Clearly, knowledge of TP levels in tumors will be useful for ther- lites. Further HPLC analysis of metabolites demonstrated that
apeutic dosing and better interpretation of nucleoside-PET images. within 2 minutes post injection, 11C-Tdr is degraded into thymine
Grierson et al., developed 5′-deoxy-5′-[18F]fluorothymidine (18F-DFT) and later into other smaller metabolites BAIB, CO2, and NH3, which
as a probe for intracellular TP expression imaging. The tracer are excreted (Fig. 38.2). Extensive metabolism of 11C-thymidine
uptake did not show a correlative uptake with TP expression levels demands complicated image analysis and this detailed analysis of
in A459 and U937 cell lines, reason being that initial metabolite metabolites by HPLC certainly improved the modeling of imaging
formed resulted in a diffusible secondary metabolite allowing kinetics.21–23 In the 1990s, developments in radiosynthesis allowed
efflux of radioactivity from the cells.17 Recent developments include the synthesis of [2-11C]Tdr radiolabeled at the 2′-position of the
the synthesis of 5-fluoro analog of (5-chloro-6-[(2-iminopyrrolidin- pyrimidine ring.24 The advantage of this radiolabeled analog is that,
1-yl)methyl]uracil) (TPI), a known inhibitor of TP, was shown to the principal metabolite, [11C]CO2, is readily transported into and
have an IC50 value of 9 nM for [3−H]TdR cleavage inhibition by washed out of tissues. It can be quantified and modeled more
human TP. The presence of a fluoride functional group suggests a readily than BAIB.25–27 Initial studies with this agent identified 11 of
potential radiopharmaceutical for TP expression imaging.18 14 untreated brain tumors with an average uptake approximately

Chapter 38 Radionuclide Imaging of Tumor Cell Proliferation 587
O O
*CH3 *CH3
NH NH
*
N O N O
HO HO
O S
OH OH
TdR 4DST
O O O
H3C H3C *Br

NH NH NH

N O N N

O O
HO HO HO
O O O
F* F*
F* OH OH
Figure 38.3. Thymidine analogs. Molecular structures of FLT FMAU FBAU
thymidine-based agents used for proliferation imaging.
twice that of normal brain.28 However, no correlation was seen trapped intracellularly. Unlike thymidine, the presence of
between tumor grade and radioactivity uptake. In another study, 3′-fluorine in FLT makes it not only resistant to degradation by TP
Eary et al.29 compared [11C]Tdr-PET imaging, FDG, and MRI in but also less susceptible to incorporation into DNA by DNA poly-
13 patients. Comparison of PET scans with MRI showed different merases. Therefore, the majority of the intracellularly trapped
uptake patterns in about half of the patients, indicating that differ- radioactivity represents the sum of the activities of its specific trans-
ent information was being obtained. Even though proliferation port and phosphorylation. Based on these observations, initial
images would be expected to match clinical progression, it was not radiosynthesis of 18F-FLT was achieved through a displacement of
observed in all cases. This preliminary application of a kinetic model 3′-O-nosyl group on the precursor protected with dimethoxy ben-
of brain tumor proliferation showed promising results and sug- zoyl and dimethoxy trityl groups.35 Other improved syntheses were
gested an improved ability to delineate active tumor from treatment later developed using 5′-O-(4,4′-dimethoxy-trityl)-2,3′-anhydro-Tdr
effects. Nevertheless, both [11C] radiolabeled analogs of thymidine or 5′-O-benzoyl-2,3′-anhydro-Tdr as precursors.36,37 FLT was ini-
required quantification of labeled metabolites for comprehensive tially developed as an antiviral agent; however, its use was discon-
interpretation of time–activity curves and DNA incorporation. tinued because of hematologic and hepatic toxicity and peripheral
Several factors including (1) fast metabolism of Tdr limiting the neuropathy.38 One of the advantages of PET and SPECT imaging
amount of radiolabel available for DNA incorporation; (2) complex agents is that, at tracer doses, toxicity is not an issue. Nonetheless,
metabolite analysis and extensive modeling effort required for an NCI sponsored safety trial did not show any detectable toxicity
interpretation of images and (3) the short half-life of 11C limited symptoms at a maximum injected dose of 6.1 μg.39
the routine clinical use of 11C-Tdr. These studies not only demon- The suitability of 18FLT as a proliferation imaging agent was
strated the potential of proliferation imaging with [11C]Tdr-PET but demonstrated in an elegant study by Rasey et al.,40 in which 18FLT
also illustrated the need for metabolically stable Tdr analogs, pref- uptake was correlated with TK1 activity in A549 lung carcinoma
erably labeled with 18F, for successful in vivo proliferation imaging cells. Using growth arrested and actively proliferating cells, the
applications. authors demonstrated that growth arrested cells take up little
18
FLT whereas actively growing cells show increased 18FLT uptake.
Increased 18FLT uptake is correlated with increased TK1 activity
Development and Evaluation of and S-phase cell fraction. In comparative studies, [14C]deoxyglu-
18 cose showed that 18FLT uptake is better correlated with growth
F-Labeled Nucleoside Analogs changes than glucose utilization suggesting that 18FLT is perhaps a
as Proliferation Imaging Agents better measure of proliferation than 18FDG. However, correlation of
18
FLT uptake in vivo in rodents with TK1 activity is not always
Nucleoside analogs with nonalcohol functional groups in the 2′- or straightforward. Rodents have a 10-fold higher serum level (1 μM)
3′-position are generally stable from degradation by TP.30 Initial of Tdr compared to humans (0.1 μM).41 Therefore, in addition to
screening of several analogs with 2′-fluorine substitution of the Tdr being a better substrate for TK1 injected 18FLT has 10-fold
sugar in dog plasma demonstrated greater stability than Tdr. How- higher competition from endogenous Tdr for TK1 activity to be
ever, most of these agents are also substrates for mitochondrial phosphorylated and trapped intracellularly.
thymidine kinase TK2.31–33 FLT demonstrated high substrate speci- Interestingly, dogs have similar serum Tdr levels as humans. Ini-
ficity to TK1 and is a poor substrate for TK2.31–33 FLT is taken up tial studies of 18FLT in dogs demonstrated a clear uptake of radioac-
by tumor cells similar to thymidine,34 phosphorylated by TK1 and tivity in bone marrow of the spine, which is a highly proliferative

tissue. Confirming the previous in vitro results, very little uptake 7

was observed in the heart which has very high levels of TK2. An
initial report of 18FLT in humans clearly showed uptake in the non– 6
small-lung cancer lesion and marrow.13 High uptake was also
observed in the liver in humans that was not observed in dog studies. 5
F-FLT SUV
This could be attributed to the intraspecies differences in glucuroni-
dation of 18FLT. Further metabolite analysis performed showed that 4
18
FLT was conjugated in the liver with glucuronide and rapidly
excreted in urine. In spite of glucuronidation, in humans, nearly 60% 3
18
to 70% of the extracted 18FLT is intact. Based on these observations,
Mean
a robust mechanism-based 4-compartment kinetic model has been 2
developed and validated in human.42,43 Sampling and metabolite
analysis at five time points is sufficient to derive a 18FLT flux param- 1
eter with compartmental analysis.44 Analysis of 18FLT metabolites
from in vitro studies showed that 18FLT and 18FLT-MP are primary
0
metabolic species. The di- and triphosphate products were also
0 10 20 30 40 50 60 70
reported in smaller fractions.45 As mentioned previously, one impor-
tant aspect of 18FLT is that it is not incorporated into DNA and is Proliferative activity (%Ki-67 positive cells)
therefore only a surrogate marker of DNA synthesis based on TK1 Figure 38.4. Comparison of 3′-fluoro-3′-deoxy-thymidine (FLT) retention and Ki-67 mea-
activity. Factors that may confound the 18FLT uptake are changes in surement in patients with lung cancer. (Based on graph from Buck AK, Halter G, Schirrmeister
H, et al. Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG. J Nucl Med.
nucleoside transporter expression and the contributions from the sal- 2003;44:1426–1431.)
vage and de novo pathways including the removal of the phosphate
by nucleotidases. Because most 18FLT is trapped inside cells as 18FLT-
MP, dephosphorylation of 18FLT-MP is a possibility and needs to be grade, mitotic index, and gene expression profiles (genomic grade
accounted for during kinetic analysis. In addition, many parameters index, [GGI]).50 Overall, in patients with node-positive breast cancer
such as the plasma thymidine levels, degradation of the tracer by GGI appeared to provide the best marker of disease-free survival. A
plasma proteins, and uncoupling of TK1 activity from the cell cycle recent meta-analysis has compared 18FLT uptake and Ki-67 from
in P53 mutated tumors46 may affect tracer uptake. 27 studies.51 Overall, they found the average Ki-67 expression using
surgical or biopsy specimens, has high correlation with 18FLT uptake
18 (r = 0.70, p < 0.001). The maximum Ki-67 value from biopsies did
FLT PET and Pathology Comparisons not correlate with 18FLT uptake, presumably because of sampling
issues. The maximum Ki-67 from surgical specimens, however, did
Increased tumor proliferation has been assessed by many meth- correlate with 18FLT uptake. They reported that in brain, lung, and
ods using pathologic specimens. These began using simple mea- breast cancer there was enough data to validate 18FLT imaging to
surement of the mitotic index in tumors, but this simply determines predict Ki-67 levels.
the fraction of cells in M-phase and does not take into account the
rate of proliferation. With the production of thymidine labeled
with long-lived tracers (e.g., 3H and 14C) autoradiography was used Role of 18FLT in Therapeutic Monitoring
to measure the fraction of cells in S-phase, or the labeling index
(LI). This approach, although frequently used in preclinical stud- The value of 18FLT-PET as a predictor of anticancer treatment
ies, has never been routinely used clinically, because the tracers response has been demonstrated in various cell culture and tumor
need to be injected intravenously followed by biopsy and labori- models. Often, a decrease in 18FLT uptake in response to therapy is
ous tissue processing and measurements. The approach that has reported both in cell culture systems and mouse models. The sensi-
gained the most use is the assessment of the nuclear antigen Ki-67 tivity and superiority of 18FLT over 18FDG in detecting early thera-
in tumors using immunohistochemical methods.47 Ki-67 is absent peutic changes induced by cytotoxic chemotherapy, radiotherapy, or
in cells in G0 but it is present in proliferative cells, in other cell chemoradiotherapy has been well characterized.52,53 Similar results
cycle phases. This method has now become routine at many med- were also observed with specifically targeted therapeutic agents
ical centers. When tumor proliferation with PET tracers, such as such as Aurora kinase inhibitors that fall into the general category
18
FLT, was being evaluated, among the first studies was its com- of antimitotic agents. Pharmacodynamic effects of antimitotic agents
parison with Ki-67 to determine the association between these are somewhat difficult to assess because the traditional biomarker,
approaches. Both of these approaches have been found to be the mitotic index, is different from one cell line to another in the
highly correlated, in many cancers, such as lung cancer, but not in duration of mitotic arrest as well as the mitotic slippage-based
all tumors (Fig. 38.4).48 It is important to understand what is being mechanism.54,55 Aurora A and B kinases are frequently expressed in
measured, and the limitations of each method. human tumors. They belong to the serine/threonine kinase family
The measurement of Ki-67 is done using fixed tissues stained for and are essential for the formation of normal mitotic spindles and
immunochemistry and detects the presence of the antigen, which is function of centrosomes. Inhibition or depletion of Aurora Kinase A
associated with cell proliferation. There are technical issues associ- has been shown to result in inappropriate chromosomal segrega-
ated with staining for Ki-67.49 Although a number of antibodies have tion and G2-M arrest resulting apoptosis.56 Similarly, Aurora Kinase
been developed over the years to assess Ki-67, MIB-1 has become B plays an important role in mitosis and functions in both chromo-
the standard (Dako, Glosstrup, Denmark). It is routinely used by some attachment and orientation. Because of these important roles,
most investigators in clinical services and has been the best vali- Aurora kinases are considered important therapeutic targets and
dated. The tissue must be fixed, stored, and sectioned in a consistent several agents are in clinical trials.56 Alisertib (MLN8237), an Aurora
manner and then stained using an approach such as avidin-biotin Kinase A inhibitor, is a potent inhibitor of cell division in vitro and
with immunoperoxidase. Although the fraction of stained cells shows growth inhibition in various tumor xenografts.57 In an effort
should be quantitated. The choice of areas for measurement, method to identify pharmacodynamic imaging biomarkers for alisertib
of interpretation, and use of a cut-point for staining intensity all therapy, Manfredi et al., assessed 18FLT-PET uptake compared to
require consideration. Comparisons of Ki-67 measurements have mitotic index, spindle bipolarity, and chromosome alignment assays
been performed with multiple other approaches, such as histologic in HCT116 colon cancer xenografts. Although there was no change

Tabl e 3 8 . 1
Tabulated Summary of FLT-PET for Therapeutic Monitoring in Preclinical

and Clinical Studies
Therapeutic Agent Clinical

Target/Paradigm Used Tumor Model Reference Studies Reference
C-MET BAY 853474 Gastric cancer (Hs746T) 58,59 Yes, Glio- 60

Crizotinib Gastric cancer (GTL-16) blastoma
Glioblastoma (U87)
EGFR Erlotinib NSCLC (HCC827, PC9, 61,62 Yes, NSCLC 63,64
Gefetinib and H1975)
Bcl-x(L) ABT-263 NSCLC (H1650) 62 No —
NPM-ALK HSP90 inhibitor NVP- Anaplastic large-cell 65 No —
fusion protein- AUY922, and the lymphoma (SUDHL-1
dependent signal mTOR inhibitor and Karpas299)
transduction everolimus
Aurora Kinases A MLN8237, AZD1152, Colon cancer (HCT116, 57,66,67 No —

and B CCT120202 SW620)
PI3K/mTOR BEZ235, everolimus Gastric cancer (N87, 68–70 No —

MKN45, and MKN28)
Ovarian cancer (SKOV3)
Lymphoma (Granta-519)
CTLA-4 Tremelimumab None X Yes 71
Checkpoint kinase 1 PF-00477736 Colorectal cancer 72 —
(COLO205)
ENT1 Knockout mice and NSCLC (A549) 73 No —
nitrobenzylmercap-
topurine ribonucleo-
side phosphate
HER-2 Trastuzumab MMTV/HER2 or BT474 74 No —
tumors
VEGFR Sunitinib malate Yes, RCC 75
Mitogen-activated PD0325901 SKMEL-28, BT-474 76,77 No —
protein kinase
(MEK)
Tubulin JAC106 Colorectal cancer 78,79 No —
(SW620) and
fibrosarcoma
Immune response Dendritic cell (DC) — Yes, 80
vaccine Mela-
noma
TK1 flare because of 5-FU Colorectal cancer (HCT8, 81,82 No —
TS inhibition HT-29)
FGFR PD173074 SCLC (H-510 and H-69) 83 No —
α-Folate receptor BGC 945 KB 84 No —
Insulin-like growth BMS-754807 NSCLC (H292) 85 No —
factor-1 receptor
HSP-90 AUY922 Anaplastic large-cell 65 No —
lymphoma (SUDHL-1
and Karpas299)
Cyclin D–dependent PD-0332991 Yes, mantle 86
kinase 1 cell
lymphoma
Colorectal
cancer
in tumor volumes over the course of 3 weeks of treatment, the phorylation is the primary trapping mechanism, it is postulated that
authors demonstrate that 18FLT uptake and, therefore, cell prolifera- the role of transport predominates resulting in an increase, rather
tion, significantly decreased within 7 days of treatment.57 These than decrease, in 18FLT uptake is referred to as “flare effect.”81 In
observations also show potential of alisertib in clinical trials. Similar response to de novo DNA synthesis inhibition such as TS inhibition
observations have been made in preclinical studies with therapeu- that results in short thymidine supplies, tumor cells respond through
tics targeting HSP90, histone deacetylase, epidermal growth factor a temporary compensatory mechanism by increasing the TK1 activ-
receptor, and mitogen-activated protein kinase as summarized in ity that may result in flare response. However, this posttherapeutic
Table 38.1.58–62,64–80,82–86 flare response window is rather short, generally 14 to 24 hours,
Although in most cases, decrease in 18FLT uptake is observed until the thymidine pool requirement by the salvage pathway
following treatment, when thymidine synthesis is blocked by could not be met and results in DNA synthesis arrest. Indeed, sig-
antimetabolites such as 5-fluorouracil (5-FU) and methotrexate, an nificant flare response of 18FLT uptake was observed in response
increase in 18FLT uptake can be observed. Though TK1-based phos- to 5-FU and methotrexate treatment in esophageal squamous cell

carcinoma cell lines.87 A similar increase in 18FLT uptake was also In an effort to develop imaging agents that can accurately reflect
observed in human breast cancers as early as 1 hour after admin- DNA synthesis, 76Br- or 18F-labeled 1-(2′-deoxy-2′-fluoro-1-β-D-
istration of capecitabine.88 arabinofuranosyl)-5-bromouracil (FBAU) was synthesized and
Endogenous plasma and tumor thymidine levels could also influ- studied for use as a proliferation marker96–101 in mice, rats, and
ence the tracer uptake as there is a considerable competition from dogs. The rationale for studying FBAU is that, similar to Tdr and its
the natural TK1 substrate, thymidine. This was elegantly demon- analogs, it will be phosphorylated by cytosolic Tdr kinases and sub-
strated by Wang et al. in a series of imaging experiments correlated sequently incorporated into newly synthesized DNA. Such cellular
with metabolite measurements and ex vivo histology. These studies trapping of the tracer combined with labeling with a long-lived iso-
show that, even in rapidly growing tumors, 18FLT uptake is not pro- tope (76Br; 16.7 hours) would be a good indicator of DNA synthesis
portional to TK1 expression. This discordance was caused by high for protracted studies that is not possible with currently available
intrinsic plasma or tumor thymidine levels suggesting that careful imaging agents. However, 18FBAU is relatively a poor substrate for
consideration should be given to plasma and tumor thymidine levels TK1 in comparison to 18FLT or Tdr which results in low tumor-to-
while interpreting PET images. Because most therapeutic assess- background ratios in in vivo studies.101
ment studies often use baseline scans, these interpatient differences Recently, Toyohara et al. described the evaluation of a thymi-
might influence imaging results. dine analog 4′-[methyl-11C]thiothymidine ([11C]4DST). In [11C]4DST,
Another important aspect that could confound 18FLT uptake is replacement of the 4′-position oxygen with sulfur was shown to
the deregulation of TK1 from cell cycle in P53 mutated tumors. P53 prevent cleavage of deoxyribose from the nucleoside by TP confer-
is considered a guardian of the genome and many cancers harbor ring resistance to degradation. Initial stability studies in mice
P53 mutations. Under wild-type p53 conditions, DNA damage showed the molecule to be stable with >97% as the parent molecule
leads to p53-mediated negative regulation of TK1 followed by cell at 60 minutes post injection. In vivo biodistribution in the EMT-6
cycle arrest at the G1/S-phase leading to cell death or senescence tumor model showed the majority of activity in the spleen, duode-
and reduced FLT uptake. However, in p53-deficient tumors, DNA num, thymus, and tumor with little activity in nonproliferative tis-
damage results in halting of the cell cycle progression at the G2/S sue. Further tissue extraction studies showed 50% to 80% of the
checkpoint, rather than G1/S checkpoint, allowing accumulation of radioactivity in the rapidly proliferating tissues was present in the
TK1 in S-phase resulting in an increase in FLT uptake. These DNA fractions. In response to a DNA synthesis inhibitor treatment,
changes may result in dramatic differences in FLT uptake in p53 reduced uptake in the tumor was also observed confirming the spec-
wild type and null tumors as illustrated by Schwartz et al. and ificity of the tracer for DNA synthesis.102 11C-labeled analog was syn-
others.46,89 These studies suggest factors confounding 18FLT uptake thesized using 11C-CH3I chemistry and a tributyltin precursor. Initial
in tumors are not fully understood and require further investigation. clinical studies in brain tumor patients showed high tumor, bone-
marrow, and liver uptake. Very little uptake was observed in the
heart suggesting that 4DST is not a good substrate for TK2.103 In
contrast to mouse studies, glucuronidation and high liver uptake was
Alternative Tdr Analogs for observed in humans with only 30% as intact molecule and several
Proliferation Imaging hydrophilic metabolites. In another study of 18 non–small-cell lung
cancer (NSCLC) patients, correlation coefficient between SUVmax
Although 18FLT is very promising as a proliferation imaging agent, and Ki-67 index was higher with 11C-4DST than that of FDG.104
it is poorly incorporated into DNA and therefore does not reflect Though promising, the metabolism observed indicates that a thor-
DNA synthesis. Several 2′-substituted analogs that could be incor- ough kinetic and compartmental analysis is necessary and the role of
porated into DNA exist. 11C90,91 and 18F-labeled 1-(2′-deoxy-2′- 4DST in monitoring antiproliferative therapy is yet to be established.
fluoro-beta-D-arabinofuranosyl)thymine (FMAU)92,93 have been
studied in humans. FMAU was initially developed as an antiviral
agent and is a slightly better substrate for TK2 than TK1. Similar to σ-Receptors
Tdr, FMAU is phosphorylated by Tdr kinases, and incorporated into
DNA by DNA polymerases because of the presence of 3′-hydroxyl The TK1-based assessment of proliferative status of the tumors pri-
group but it is not a substrate for TP. In vitro studies have shown marily works in cells that are in S-phase and use salvage pathway
that the amount of FMAU incorporation into DNA was proportional but does not account for cells that exclusively rely on de novo path-
to DNA synthesis.94 FMAU was initially labeled in good yield with way, uncoupled cell cycle-TK1 activity or the presence of quiescence
11
C in the 5-methyl position of the pyrimidine ring using the 11CH3I cells. Solid tumors, as they increase in size, can outgrow their blood
chemistry. Studies in beagle dogs showed clear tumor accumulation supply and become hypoxic and nutrient deprived. During the
of radioactivity and correlation with BrdU staining demonstrating hypoxic state, proliferative cells (P cells) can exit the cell cycle and
potential for imaging cellular proliferation. The 18F-labeled version enter a prolonged quiescence (Q) state. A quiescent tumor cell can
of FMAU was achieved through a complicated 4-step synthesis remain undifferentiated for a long time and can be recruited back
involving initial fluorination of the sugar followed by condensation into a P-cell state once the conditions of hypoxia and/or nutrient
with the thymine precursor. In vivo studies in normal dogs using deprivation are eliminated. Quiescence cells play a significant role in
18
F-FMAU showed substantial quantities of radioactivity in the acid tumor resistance to therapy. Accumulating evidence suggests that
precipitable large molecular fraction suggesting FMAU incorpora- σ2 receptor may serve as an imaging biomarker of cell proliferation
tion into DNA.92 In addition, 18F-FMAU studies in humans provide based on its expression in proliferating cells. This receptor is a
a clear visualization and uptake of activity in tumors of the brain, 21.5-kDa protein that has not been sequenced or cloned. Its role in
thorax, prostate, and bone indicating that it might be useful as a proliferation is not yet clearly established. Its natural ligand is yet to
direct marker to monitor DNA synthesis.93 Although FMAU uptake be determined. The initial characterization and overexpression of
is seen within the marrow of dogs, uptake within the normal human σ2 receptor in cancer cell lines was demonstrated by differential
marrow has not been seen.92,93 Studies using human cell lines in binding observed with two antagonists to its sister σ1 receptor.105
culture demonstrate that FMAU retention increases as cells are The σ2 receptor is reported to be expressed 10-fold higher in prolif-
stressed, whereas 18FLT retention declines in the same setting.95 erating cells compared to quiescent cells and is regulated in a man-
This reflects the phosphorylation of FMAU by mitochondrial TK2 ner similar to other proliferation markers such as Ki-67. Because
and suggests that FMAU may be more relevant application to mea- tumor cells cycle between P and Q states, low radioactivity uptake in
sure oxidative stress rather than proliferation. Further studies are tumors as determined by σ2 receptor quantitation may provide a
warranted. window into the quiescent status of the tumor cells suggesting that

OCH3 OCH3
O*CH3 O
H
N O
N
N N OCH3
H
O
σ1 = 3078 nM
CH3 σ2 = 10.3 nM
σ1 = 92.5 nM CH3
A σ2 = 3.1 nM B
*F
OCH3
O O

N

N OCH3
H
[18F]18
CH3 σ1 = 330 nM
C σ2 = 7 nM
Figure 38.5. Molecular structures of various σ2 receptor ligands and their Ki values. Where applicable, radiolabelled position on the analogs is shown as an *.
its expression could be used as a proliferation marker.106–108 In vitro Although uncertainties remain about the functional role of σ2
receptor-binding studies on brain and liver tissues suggest that receptor in cell cycle and tumor biology, accumulating evidence
receptor is localized in the endoplasmic reticulum, mitochondria, suggests that its expression correlates well with proliferation sta-
and plasma membrane. Studies with σ2 receptor binding fluores- tus of the tumors and may provide complementary information to
cent probes in combination with cell organelle compartmentalizing that of thymidine analogs.
tracker dyes in cancer cells show that this receptor is localized in
mitochondria, lysosomes, endoplasmic reticulum, and the cytoplas-
mic membrane.109 Time lapsed confocal microscopy studies revealed Assessment of Treatment Response
a rapid internalization of the bound probe with nearly 40% of the
receptors internalized by receptor-mediated endocytosis with T1/2 of
with Proliferative Imaging Agents
16 seconds which could have therapeutic implications.
Based on the high correlation observed between σ2 receptors
Brain Tumors
18
and proliferative status of solid tumors significant efforts have been FLT PET has been utilized to help detect and assess the prognosis
invested into the developing imaging agents. Currently available in patients with high-grade brain tumors.115 Grade III and IV lesions
agents fall into two broad categories namely the 9-azabucyclo[3.3.1] are usually visualized whereas grade II lesions may not show
nonanes (granatane) and the benzamides (Fig. 38.5). Of these two, increased tracer retention. Measurement of the proliferative volume
the benzamides have been more amenable to modifications and (PV), using an adaptive approach taking into account the signal-
several 11C-labeled derivatives were synthesized. Initial evaluation to-background ratio, has demonstrated information predictive of
of these analogs (Fig. 38.5B) showed high affinity for σ2 receptors. survival in patients with gliomas.116 Receiver operating characteris-
The short half-life of 11C and reduced tumor-to-background ratios tic curve (ROC) analysis resulted in a cut-off volume of 11.4 mL
observed because of high lipophilicity of the compounds under- whereas patients with a PV of less than 7.4 mL had prolonged
scored the need for the development of more hydrophilic 18F-labeled survival and those with a volume of over 24 mL had short survival
agents.110 Further structure–activity modifications resulted in the and none over 2 years.
18
development of 2-fluoroethoxy analog (Fig. 38.5C), with a Ki of FLT PET imaging of patients with gliomas has also been utilized
6.95 ± 1.63 nM for the σ2 receptor and a σ1/σ2 selectivity ratio of to assess the response to treatment in 31 patients treated with beva-
48. Biodistribution studies of this analog in female Balb/c mice- cizumab usually given with irinotecan (Fig. 38.6).117,118 Imaging was
bearing EMT-6 tumor allografts demonstrated 1.14 ± 0.10% ID/g done at baseline and after 2 and 6 weeks of treatment. Using an ROC
in the tumor and acceptable tumor/normal tissue ratios at 1 and analysis, the optimal cut-off was 25% to define responders based on
2 hours post i.v. injection. Blocking studies further confirmed that the change in SUVpeak (1 cm circular region of interest). Both follow-
uptake was indeed σ2 receptor specific.111 This agent is currently in up scans predicted the overall survival ( p < 0.001) although the base-
clinical investigation in cancer patients (NCT00968656). In addi- line to 6-week scans appear to be slightly better at predicting overall
tion to the analogs mentioned above, several analogs labeled with survival (OS) (HR: 7.869 and 5.416, respectively) and improved pro-
either 76Br, 123I, 125I, or 99mTc have also been synthesized and evalu- gression-free survival (PFS). The OS was 3.3 times longer in those
ated as potential PET or SPECT imaging agents for proliferative with a PET response (12.5 versus 3.8 months, p = 0.001) whereas
index of tumors.112–114 Fluorescent probes developed have already comparison with MRI response, also done around 6 weeks, was sig-
contributed to the understanding of the σ2 receptor localization and nificant but not as useful in predicting OS (12.9 versus 9, p = 0.05).
intracellular processing.108,109 18
FLT PET imaging at 6 weeks provided the best predictor of OS and

A B C
Figure 38.6. Images obtained from two patients

with glioblastoma multiforme demonstrating de
creased 3′-fluoro-3′-deoxy-thymidine (FLT) uptake
in a responding patient when comparing baseline
(A) with scans at 2 weeks (B) and 6 weeks (C).
The nonresponding patient (baseline D) demon-
strated no significant change in SUV on the scan at
2 weeks (E) or 6 weeks (F), although the uptake is
clearly increased in the final scan. (Reprinted by
permission of the Society of Nuclear Medicine from
Schwarzenberg J, Czernin J, Cloughesy TF, et al.
3′-Deoxy-3′-18F-Fluorothymidine PET and MRI for
Early Survival Predictions in Patients with Recur-
rent Malignant Glioma Treated with Bevacizumab.
D E F J Nucl Med. 2012; 53(1): 29–36.)
PFS in a multivariate analysis. Although this early study is intriguing Lung Cancer
and provided a useful predictive marker, its limitations must also be
considered. 18FLT does not cross the intact blood–brain barrier, EGFR inhibition using gefitinib was evaluated by Sohn et al.63
hence uptake in tumors depends on breakdown of this barrier and using 18FLT PET for the assessment of patients with lung cancer
tracer delivery, as well as trapping by TK1 within the tumor. To over- with scans before and 7 days after the start of therapy (Fig. 38.7).
come this issue, one needs to obtain dynamic images and use kinetic In the 28 patients analyzed, they compared the results of PET to
modeling to fully assess the flux of 18FLT into brain tumors.43,119 CT obtained 6 weeks after the start of therapy. SUVmax declined
delivery of 18FLT to the tumor might be further altered because the by a mean 36% in responders (mean SUVmax 3.2 decreased to 2)
antivascular agent bevacizumab also alters blood flow and/or vessel compared to a 10.1% increase in nonresponders (Fig. 38.8). Using
permeability, further altering delivery of 18FLT unrelated to prolifera- ROC analysis, they found that a decline of 10.9% in 18FLT SUVmax,
tion. No kinetic modeling was done as part of this study to take these resulted in 92.9% positive and negative predictive values. 18FLT
issues into account but the changes in simple measurement of SUV PET responders had a median time to progression of 7.9 months,
were predictive nonetheless of OS and PFS. compared to 1.2 months in nonresponders (p = 0.0041).
Responder Nonresponder
CT
Basleline At 6 weeks Basleline At 6 weeks
Figure 38.7. 3′-Fluoro-3′-deoxy-thymidine

(FLT) of patients with lung cancer treated
PET with gefitinib comparing FLT assessment
7 days after the start of therapy to CT done at 6
weeks. A: A responding patient with a decline in
SUVmax from 4.8 to 2.3, and (B) a nonre-
sponder with SUVmax increasing from 7.2 to 8.
(Reprinted from Sohn HJ, Yang YJ, Ryu JS,
et al. [18F]Fluorothymidine positron emission
PET-CT tomography before and 7 days after gefitinib
treatment predicts response in patients with
advanced adenocarcinoma of the lung. Clin
Cancer Res. 2008, 14:7423–7429, with
permission of the American Association for
A Day 0 Day 7 B Day 0 Day 7
Cancer Research [AACR].)

60 cancers in 15 of 17 patients. 18FLT had two false-positive patients,

one of which was found to be associated with inflammation. In the
40 initial development of 18FLT, it was thought that one advantage
% Decrease of SUVmax
would be that there would be minimal tracer uptake in inflamma-

20 tory lesions, which certainly had been a problem with 18FDG. In
>10.9 patients with head and neck cancer FDG uptake in inflammatory
0 nodes in follicular dendritic cells in secondary lymphoid follicles
Sens: 92.2 and was associated with GLUT1 expression.125 In a study of FLT
−20 imaging prior to neck dissection increased 18FLT uptake was seen
Spec: 92.2 in 9 of 10 patients, but six of these were false positives based on
−40 pathology.126 In addition to PET imaging, these patients had the
thymidine analog iododeoxyuridine (IUdR) injected just before sur-
−60 gery. Lymph nodes were evaluated by staining for IUdR and Ki-67
DP SD PR and they found increases in both markers in the germinal centers
caused by B cells. Hence, proliferation of immune cells can also be
Nonresponder Responder detected with FLT imaging, as it is with 18FDG, and this limitation
Figure 38.8. Percent change in SUVmax by FLT PET in patients with lung cancer treated with needs to be considered.
gefitinib. Imaging was done prior to and 7 days after the start of treatment. Patients had disease To be able to utilize 18FLT PET imaging to assess treatment
status, disease progression (DP), stable disease (SD), and partial response (PR), determine on

response, the quantitative measurements must be reproducible. In
CT at 6 weeks. (Based on a graph from Sohn HJ, Yang YJ, Ryu JS, et al. [18F]Fluorothymidine
positron emission tomography before and 7 days after gefitinib treatment predicts response in
general, the simple measurement of SUV has been utilized to mea-

patients with advanced adenocarcinoma of the lung. Clin Cancer Res. 2008;14:7423–7429, sure treatment response, although dynamic imaging may be par-
with permission of the American Association for Cancer Research [AACR].) ticularly useful if there are differences in metabolism, delivery, or
clearance of the tracer. Most commonly SUV measurements are
obtained about 60 minutes after injection for convenience, as is
Although 18FLT use appears promising for evaluation of EGFR routinely done in for clinical 18FDG measurements. Fortunately, the
inhibition, it should also be noted that 18FDG can also be used to exact timing for 18FLT imaging is not at issue, because a study has
assess such treatment.120 Imaging was done at baseline and again shown that the measurement of SUV at 55 to 60 minutes, obtained
around days 14 and 56 after the start of erlotinib in the study by as part of a dynamic scan, produced uptake that was highly cor-
Mileshkin et al. The scans at both time points were quantitated using related with results obtained at around 100 minutes as part of a
the SUVmax and a partial metabolic response (PMR) was defined as whole-body scan (SUVmax Spearman’s r: 0.97, p < 0.0001).127
a decrease of equal or greater than 15%. PMR for 18FLT at days 14 Furthermore, SUV measurements were found to correlate with
and 56 was associated with improved PFS; hazard ratio for respond- both kinetic analysis using compartmental models and graphical
ers compared with nonresponders 0.41, p: 0.02; HR: 0.38, p: 0.02, (Patlak) approaches (correlation coefficient: 0.91 and 0.99, respec-
respectively. The trend was slightly better for 18FDG PET done at the tively).128 In this study they also compared baseline scans to those
same time points (HR: 0.28, p < 0.001; HR: 0.32, p: 0.01, respec-

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Nuclear

Cumali Aktolun, MD, MSc

(c) 2015 Wolters Kluwer. All Rights Reserved.

© 2015 by Wolters Kluwer Health

Two Commerce Square

Library of Congress Cataloging-in-Publication Data

Nuclear oncology (Aktolun)

(c) 2015 Wolters Kluwer. All Rights Reserved.

To Mustafa Kemal Ataturk, the founder of Republic of

(c) 2015 Wolters Kluwer. All Rights Reserved.

Gad Abikhzer, MDCM, NM Stefano Arcangeli, MD

(c) 2015 Wolters Kluwer. All Rights Reserved.

Christina Blümel, MD Jean-Francois Chatal, MD, PhD

(c) 2015 Wolters Kluwer. All Rights Reserved.

Timothy R. DeGrado, PhD Paola A. Erba, MD

(c) 2015 Wolters Kluwer. All Rights Reserved.

Per Hellman, MD, PhD Kemal Metin Kir, MD

Kayako Isohashi, MD, PhD Cinzia Landolfi, MD

Revathy B. Iyer, MD William D. Leslie, MD, MSc, FRCPC

(c) 2015 Wolters Kluwer. All Rights Reserved.

Roberto Luksch, MD Gang Niu, MD, MS

(c) 2015 Wolters Kluwer. All Rights Reserved.

Elgin Ozkan, MD Gregory C. Ravizzini, MD

Giovanna Pepe, MD Babak Saboury, MD, MPH

Marc Peeters, MD, PhD Hideo Saji, PhD

(c) 2015 Wolters Kluwer. All Rights Reserved.

Ettore Seregni, MD Drew A. Torigian, MD, MA

(c) 2015 Wolters Kluwer. All Rights Reserved.

Leonie Wyffels, PharmD, PhD Lucia Zanoni, MD

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

Cumali Aktolun and Stanley J. Goldsmith

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10 Liver Tumors 124 28 Sentinel Lymph Node Detection and Imaging in

(c) 2015 Wolters Kluwer. All Rights Reserved.

40 Radionuclide Imaging of Integrins 616

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PART I • Organ Malignancies

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and cellular uptake that may involve transmembrane transport into

Single-Photon Emission Tomography/Computed

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PART I • Organ Malignancies

(c) 2015 Wolters Kluwer. All Rights Reserved.

Figure 1.3. Newly diagnosed tumors, show-

(c) 2015 Wolters Kluwer. All Rights Reserved.

PART I • Organ Malignancies

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

PART I • Organ Malignancies

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

PART I • Organ Malignancies

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

PART I • Organ Malignancies

(c) 2015 Wolters Kluwer. All Rights Reserved.

Radiolabeled Peptides for Targeted

(c) 2015 Wolters Kluwer. All Rights Reserved.

Introduction roduced in the follicular cells. Increasing serum Tg after thy-