《Modern Breast Cancer Imaging》 - 240323 - 092230

Modern Breast
Cancer Imaging
Su Jin Kim Hsieh
Elizabeth Anne Morris
Editors
123
Modern Breast Cancer Imaging
Su Jin Kim Hsieh • Elizabeth Anne Morris
Editors
Modern Breast Cancer

Imaging
Editors
Su Jin Kim Hsieh Elizabeth Anne Morris
Breast Imaging Department Department of Radiology
Hospital Sírio-Libanês and Instituto de University of California Davis
Radiologia (INRAD), Hospital das Clinicas Sacramento, CA
HCFMUSP, Faculdade de Medicina, USA
Universidade de Sao Paulo
São Paulo, SP
Brazil
ISBN 978-3-030-84545-2 ISBN 978-3-030-84546-9 (eBook)

https://doi.org/10.1007/978-3-030-84546-9
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2022
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“To Mariana, Lucas and Pedro”
—Dr Su Jin Kim Hsieh
“For my two beautiful children, who are a
wonder” —Dr Elizabeth Anne Morris
Foreword
Breast cancer has haunted the female universe for millennia. And this agony has
been portrayed in many ways, both in history and in art. Sometimes in an accidental
way as in some well-known paintings and sculptures, while at other times directly,
as in hieroglyphic scripts that described it as an incurable disorder. Today, in the
third millennium of the Christian era, our knowledge about this disease has com-
pletely changed. We already have the sequencing of the main genes related to breast
cancer and specific targeted therapies, which totally altered its evolution. We know
that early detection is still the best way to increase the chances of cure and the pos-
sibility of less aggressive surgical and adjuvant treatments. Currently there are
imaging techniques capable of detecting increasingly smaller and biologically sig-
nificant tumors. And this was only achieved thanks to the tireless work of doctors
and scientists from different specialties, who joined together for a single objective:
to reduce mortality from breast cancer and provide a better quality of life for women
affected by it.
In the book Modern Breast Cancer Imaging, the editors, Su Jin Kim Hsieh and
Elizabeth Morris, both with extensive expertise in breast radiology and international
projection, brought a multidisciplinary approach to breast cancer, in the areas of
pathology, oncology, radiotherapy, and surgery, in addition to an extensive update
on diagnostic imaging applied to clinic. Divided into three large parts, the book
initially brings the main advances in science from a clinical and pathological point
of view. It covers from the molecular basis of breast cancer, risk factors, and genetic
testing to advances in surgical and pathological treatment. In Part II, the imaging
methods used in breast radiology, their indications and limitations, as well as their
future perspectives are discussed, mainly how to transpose the information obtained
to improve clinical outcomes. Part III presents the main clinical problems and how
imaging methods can help: from screening to diagnosis, including treatment and
follow-up of women diagnosed with breast cancer.
At last, despite breast cancer being one of the oldest and most studied diseases in
science, we do have a lot to evolve. Mainly because fear and prejudice against this
disease still exist, in the twenty-first century. And also, because we still witness
many lives lost, despite being a potentially curable disease. We currently live in the
vii
viii Foreword
era of personalized medicine, in which there is no single-treatment disease. There is

indeed a unique woman, with a unique history and genetic profile, who must be
accompanied individually. And this is the kind of treatment our women need and
deserve. And for this, the collaboration among the various professionals who are
part of a breast center is essential: radiologists, pathologists, breast surgeons, oncol-
ogists, and geneticists, among many other specialties. And it is this integration and
updating of knowledge and technology that this book brings in a spectacular way.
Linei Augusta Brolini Dellê Urban

Department of Breast Radiology
Clínica DAPI
Paraná, Brazil
Universidade Federal do Parana, UFPR
Paraná, Brazil
Brazilian College of Radiology, CBR
São Paulo, Brazil
Sociedad Iberoamericana de Imagen Mamaria (SIBIM)
São Paulo, Brazil
Preface
The field of breast imaging has been evolving very fast lately, especially concerning
breast cancer. Not only screening protocols have suffered some adjustments over
the past years, but also new imaging methods, software and even new types of pro-
cedures have emerged. New concepts regarding molecular and genetic basis and
therapeutic regimens have changed greatly.
The understanding of these new concepts become essential to give the patient the
best possible care, since the confection of a relevant and useful breast imaging
report from the radiologist, and also for the other professionals to understand what
type of imaging exams to order in each scenario and how to interpret the results.
Keeping up to date demanded a great deal of effort, considering the vast amount
of information in the literature, not only in the area of imaging, but also in other
fields such as pathology, surgery and oncology.
The idea of this book was to compile up-to-date and established information
about breast cancer in all these areas, in a multimodality approach. It is intended to
be useful for daily practice not only for breast radiologists, but also for everyone
who is in this field of medical practice.
This book has been written by very experienced and renowned professionals and
would not be possible without their valuable contributions!
Special thanks to Dr Morris, who believed in this project from the beginning!
São Paulo, Brazil Su Jin Kim Hsieh
ix
Contents
Part I Updates in Clinical and Pathological Aspects for Breast Cancer

1 Molecular Basis of Breast Cancer�� 3
Raquel Civolani Marques Fernandes
2 Risk Factors for Breast Cancer�� 17
Sergio Masili-Oku, Angela Trinconi, Gabriela Boufelli, and
Jose Roberto Filassi
3 Genomic Tests�� 31
Laura Testa and Renata Colombo Bonadio
4 Updates in Surgical Approaches for Breast and Axilla�� 39
Bruna Salani Mota, Rodrigo Goncalves, and Jose Roberto Filassi
5 Pathological Aspects for Diagnosis �� 47
Marcelo Abrantes Giannotti and Fernando Nalesso Aguiar
Part II Update in Imaging Method

6 Radiation Based Imaging: Digital
Mammography, Tomosynthesis�� 71
Almir Galvão Vieira Bitencourt and Carolina Rossi Saccarelli
7 Sonographic Based Imaging: Ultrasound, Color
Doppler, Elastography, and Automated Breast Imaging�� 97
Juliana Hiraoka Catani
8 Magnetic Resonance Imaging: Regular Protocols
and Fast Protocols�� 131
Joao V. Horvat and Sunitha B. Thakur
9 Nuclear Medicine Based Methods: PET FDG and Other Tracers�� 141
Marcelo Tatit Sapienza and Poliana Fonseca Zampieri
xi
xii Contents
10 Image-Guided Percutaneous Biopsies�� 161

Vitor Chiarini Zanetta
11 Breast Imaging Preoperative Localization Procedure�� 211
Heni Debs Skaf, Juliana Hiraoka Catani, and Vivian Simone De
Medeiros Ogata
Part III Different Clinical Scenario: Clinical Management

and Role of Imaging Modalities
12 Screening�� 247
Mila Trementosa Garcia, Laura Aguiar Penteado,
Flávia Abranches Corsetti Purcino, and Jose Roberto Filassi
13 Diagnostic�� 259
Karina Belickas Carreiro, Juliana Pierobon Gomes da Cunha,
Jose Roberto Filassi, and Caio Dinelli
14 Preoperative (Breast) �� 281
Jonathan Yugo Maesaka, Yedda Nunes Reis, and
15 Systemic Staging (Total Body – When, How)�� 297
Fabiano de Almeida Costa and Rudinei Diogo Marques Linck
16 Neoadjuvant Systemic Therapy�� 307
Ana Carolina de Ataíde Góes, Heni Debs Skaf, and Laura Testa
17 Postoperative Breast�� 331
Larissa Muramoto Yano and Monica Akahoshi Rudner
18 Radiation Therapy �� 415
Paula de Camargo Moraes
19 Adjuvant Therapy�� 435
20 Follow-Up After Treatment �� 439
Bruno Salvador Sobreira Lima, Fernanda Barbosa,
Maria Carolina Formigoni, Sergio Masili-Oku, and
21 Breast Cancer During Pregnancy and Lactation�� 447
Yoon Seung Chang and Monica Akahoshi Rudner
Index�� 463
Contributors
Fernando Nalesso Aguiar, MD Departamento de Patologia, Instituto do Cancer

do Estado de Sao Paulo ICESP, São Paulo, SP, Brazil
Fabiano de Almeida Costa, MD Departamento de Oncologia, Instituto do Cancer
do Estado de São Paulo ICESP, São Paulo, SP, Brazil
Ana Carolina de Ataíde Góes, MD Instituto de Radiologia INRAD, Hospital das
Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São
Paulo, SP, Brazil
Fernanda Barbosa, MD Departamento de Mastologia, Instituto do Cancer do
Estado de Sao Paulo ICESP, São Paulo, SP, Brazil
Almir Galvão Vieira Bitencourt, MD A.C.Camargo Cancer Center, São Paulo,
SP, Brazil
Diagnósticos da América SA, São Paulo, SP, Brazil
Renata Colombo Bonadio, MD Departamento de Oncologia, Instituto do Cancer
Gabriela Boufelli, MD Departamento de Mastologia, Instituto do Cancer do
Paula de Camargo Moraes, MD Instituto de Radiologia INRAD, Hospital das
Paulo, SP, Brazil
CDB (Centro Diagnóstico Brasil) – Grupo Alliar, São Paulo, SP, Brazil
Alta Medicina Diagnóstica – Grupo DASA, São Paulo, SP, Brazil
Karina Belickas Carreiro, MD Departamento de Mastologia, Instituto do Cancer
Juliana Hiraoka Catani, MD Instituto de Radiologia INRAD, Hospital das
Paulo, SP, Brazil
xiii
xiv Contributors
Yoon Seung Chang, MD Breast Imaging Section, Centro de Diagnósticos Brasil

(CDB – Alliar), São Paulo, SP, Brazil
Instituto de Radiologia INRAD, Hospital das Clinicas HCFMUSP, Faculdade de
Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
Juliana Pierobon Gomes da Cunha, MD Departamento de Mastologia, Instituto
do Cancer do Estado de Sao Paulo ICESP, São Paulo, SP, Brazil
Caio Dinelli, MD Instituto de Radiologia INRAD, Hospital das Clinicas
HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo,
SP, Brazil
Raquel Civolani Marques Fernandes, MD Hospital Beneficência Portuguesa de
São Paulo/Laboratório Bacchi, São Paulo, SP, Brazil
Pathology Department Director, Hospital Pérola Byington, São Paulo, SP, Brazil
Jose Roberto Filassi, MD, PhD Departamento de Mastologia, Instituto do Cancer
Maria Carolina Formigoni, MD Departamento de Mastologia, Instituto do
Cancer do Estado de Sao Paulo ICESP, São Paulo, SP, Brazil
Mila Trementosa Garcia, MD Departamento de Mastologia, Instituto do Cancer
Marcelo Abrantes Giannotti, MD Hospital Sírio Libanês and Departamento de
Patologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade
de Sao Paulo, São Paulo, SP, Brazil
Rodrigo Goncalves, MD Departamento de Mastologia, Instituto do Cancer do
Joao V. Horvat, MD Department of Radiology, Memorial Sloan Kettering Cancer
Center, New York, NY, USA
Bruno Salvador Sobreira Lima, MD Departamento de Mastologia, Instituto do
Rudinei Diogo Marques Linck, MD Departamento de Oncologia, Instituto do
Cancer do Estado de São Paulo ICESP, São Paulo, SP, Brazil
Jonathan Yugo Maesaka, MD Departamento de Mastologia, Instituto do Cancer
Sergio Masili-Oku, MD Departamento de Mastologia, Instituto do Cancer do
Vivian Simone De Medeiros Ogata, MD Instituto de Radiologia INRAD,
Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao
Paulo, São Paulo, SP, Brazil
Contributors xv
Bruna Salani Mota, MD Departamento de Mastologia, Instituto do Cancer do

Laura Aguiar Penteado, MD Departamento de Mastologia, Instituto do Cancer
Flávia Abranches Corsetti Purcino, MD Departamento de Mastologia, Instituto
do Cancer do Estado de Sao Paulo ICESP, São Paulo, SP, Brazil
Yedda Nunes Reis, MD Departamento de Mastologia, Instituto do Cancer do
Monica Akahoshi Rudner, MD Hospital Albert Einstein, São Paulo, SP, Brazil
Hospital Moriah and Prevent Senior, São Paulo, SP, Brazil
Carolina Rossi Saccarelli, MD Diagnósticos da América SA, São Paulo, SP, Brazil
Hospital Sírio-Libânes, São Paulo, SP, Brazil
Marcelo Tatit Sapienza, MD, PhD Departamento de Radiologia e Oncologia,
Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao
Paulo, São Paulo, SP, Brazil
Heni Debs Skaf, MD Instituto de Radiologia INRAD, Hospital das Clinicas
HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo,
SP, Brazil
Laura Testa, MD Departamento de Oncologia, Instituto do Cancer do Estado de
Sao Paulo ICESP, São Paulo, SP, Brazil
Sunitha B. Thakur, MD Department of Radiology, Memorial Sloan Kettering
Cancer Center, New York, NY, USA
Angela Trinconi, MD Departamento de Mastologia, Instituto do Cancer do Estado
de Sao Paulo ICESP, São Paulo, SP, Brazil
Larissa Muramoto Yano, MD Hospital Albert Einstein, São Paulo, SP, Brazil
Poliana Fonseca Zampieri, MD Departamento de Medicina Nuclear, Instituto do
Vitor Chiarini Zanetta, MD Department of Radiology, Instituto de Radiologia
INRAD, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade
de Sao Paulo, São Paulo, SP, Brazil
Part I
Updates in Clinical and Pathological
Aspects for Breast Cancer
Chapter 1
Molecular Basis of Breast Cancer
Raquel Civolani Marques Fernandes
1.1 Introduction
Breast cancer is the second most common cancer among women, after non-
melanoma skin cancer, with a one in eight probability of developing invasive carci-
noma in a US woman during her lifetime. In 2021, an estimated 281,550 new cases
of invasive breast carcinoma are expected to be diagnosed in American women,
along with 49,290 new cases of in situ breast cancer [1].
About 5–10% of breast cancer can be linked to a hereditary mutation of a known
gene, such as BRCA1 and BRCA2. On average, women with a BRCA1 mutation
have up to a 72% lifetime risk of developing breast cancer, while the risk is 69%
with BRCA2 mutation [2].
After the year 2000, with the sequencing of multiple types of tumors, the under-
standing of the molecular biology of breast cancer brought extremely important
knowledge, which changed the clinical practice of its treatment. It has been recog-
nized as a heterogeneous neoplasia by several biomarkers, now used in diagnosis,
prognosis, and treatment according to each subtype.
The heterogeneity of breast carcinomas is due to the involvement of different
genes, related to the proliferative activity, differentiation, and suppression of tumors,
several of them studied alone or in small groups, regarding the implication in carci-
nogenesis and/or as prognostic factors. However, the enormous heterogeneity and
the number of factors involved make interpretation difficult. With the development
of genome analysis technologies with the possibility of concomitant analysis of
thousands of genes, it was possible to identify intrinsic gene profiles in breast
R. C. M. Fernandes (*)
Hospital Beneficência Portuguesa de São Paulo/Laboratório Bacchi, São Paulo, SP, Brazil
Pathology Department Director, Hospital Pérola Byington, São Paulo, SP, Brazil
e-mail: [email protected]
© The Author(s), under exclusive license to Springer Nature 3

Switzerland AG 2022
S. J. Kim Hsieh, E. A. Morris (eds.), Modern Breast Cancer Imaging,
https://doi.org/10.1007/978-3-030-84546-9_1
4 R. C. M. Fernandes
tumors called basal; HER2-enriched; luminal A, B, and C; and normal breast type
according to the classification of Perou et al. [3–7]. These presentation profiles
showed consistency even in different study groups and using different array tech-
niques [4, 5, 8].
Over the past few years, there has been considerable effort to characterize and
classify breast cancer at the molecular level in order to effectively tailor treatment.
However, due to time and cost constraints, in the great majority of health-care sys-
tems, a surrogate molecular breast cancer classification is still largely based on
immunohistochemical (IHC) assessment of biomarkers: ER (estrogen receptor), PR
(progesterone receptor), HER2, and Ki-67. Nevertheless, the examination of global
patterns of gene expression (especially of genes involved in the regulation of cell
growth and other important aspects of cell behavior, such as invasion) has resulted
in the identification of intrinsic molecular subtypes of biological and clinical rele-
vance and of gene signatures predictive of outcome or response to therapy [9].
It is extremely important to remember that to avoid false-negative result for any
molecular or IHC study, the biopsy or surgical specimen must be properly fixed at
10% buffered formalin to ensure pH range 7.0 and 7.4 within 1 hour after resection
averting prolonged cold ischemic time, which may result in antigenic degradation.
Under- or over-fixation is not recommended. Fixation for at least 6 hours and a
maximum of 72 hours are recommendations from the College of American
Pathologists (CAP) [10].
1.2 C (Basal Carcinomas) and TNC (Triple

B
Negative Carcinomas)
BC is characterized by the high expression of several genes that characterize the

basal cells of the epithelium, which have the capacity to originate epithelial and
myoepithelial cells in the terminal lobular duct unit, including the basal cytokeratins
5/6 and 17. These basal cytokeratins indicate smooth muscle differentiation, present
in myoepithelial cells and their precursors [11]. Other markers can be used in order
to improve accuracy in determining the phenotype and the expected evolution for
these tumors, including expression of Epidermal growth factor receptor (EGFR) or
HER1, c-Kit, and vimentin. With the possibility of comparing the IHC profile and
the profile defined by the analysis of several genes, Nielsen et al. [12] demonstrated
that a panel composed of four markers—a negative estrogen receptor, positive
HER1, negative HER2, and a positive basal cytokeratin—could accurately identify
the genetically determined basal subgroup.
BC generally correspond to high-grade invasive carcinoma of no special type
(with or without medullary features) or metaplastic carcinoma [9].
Livasy et al. and Nielsen et al. also highlighted some morphological characteris-
tics frequently present in these tumor subtypes [12, 13], including high histological
and nuclear grade, high mitotic count, the presence of polygonal cells with abundant
1 Molecular Basis of Breast Cancer 5
eosinophilic or clear cytoplasm, geographic tumor necrosis, central scar, expansive

tumor borders, and increased immune cells.
TNC are defined by the lack of expression of hormone receptors and HER2 pro-
tein, and today, IHC examination is the most accessible and the best diagnostic
molecular tool for diagnosis [9]. Genetically, there is a 70–80% overlap between
BC and TNC. Although almost 70% of basal intrinsic molecular carcinomas have a
triple negative IHC profile, 20% of them have IHC expression of hormone recep-
tors, and 10% are HER2 enriched [14]. BC and TNC have more frequent metastases
to the brain and visceral organs than to the bone and nodes compared to ER-positive
carcinomas and high risk of early recurrence within 5 years and death [15].
As for the prognosis, it is important to remember that TNC are a heterogeneous
group of tumors. Among those with a favorable prognosis are low-grade adenosqua-
mous carcinoma, adenoid cystic carcinoma, and secretory carcinoma; among those
with intermediate prognosis is invasive carcinoma of no special type with medullary
features, and among the unfavorable ones are the high-grade invasive carcinoma of
no special type and metaplastic carcinoma [9].
The knowledge of the molecular biology of these tumors has been increasing
every year. While until the middle of the last decade no specific therapeutic target
was known, nowadays, antiandrogens, DNA damage response targeting, and
immune checkpoint inhibitors are some of the promising clinical approaches that
evolved from the concept that some tumors show poor prognosis due to overexpres-
sion of genes promoting proliferation and migration.
Lehman et al. in 2016 [16] updated the molecular classification of TNC through
the analysis of TNC gene expression profiles, previously proposed by the same
group in 2011. In this classification, four TNC subgroups were recognized, with
their own clinical and molecular characteristics: basal subtype 1 (BL1) and basal
subtype 2 (BL2), which have high proliferative activity with activation of various
pathways to stimulate the cell cycle and response to DNA damage; mesenchymal
subtype (M), which has activated signaling pathways of growth factors such as the
IGF pathway/mTOR, a part of them still with low expression of claudins; and the
luminal androgenic subtype (LAR), which has activation of signaling pathways
associated with the androgen receptor. In this work, the authors highlighted the dif-
ferences between age, grade, local and distant disease progression, and histopathol-
ogy among these subgroups, in addition to the different responses to neoadjuvancy,
depending on the subtype. Pathologic complete response (pCR) was reached in 41%
of BL1, 18% of BL2, and 29% of LAR.
It is important to note that the characteristics of each subgroup, especially BL1,
BL2, and M, can be modulated by the tumor microenvironment, with tumor-
infiltrating lymphocytes (TILs) playing a fundamental role in this modulation.
Programmed death ligand 1 (PD-L1) is an immunoregulatory molecule that lim-
its antitumor immune activity. Both TILs and PD-L1 status predicted pathologic
complete response (pCR) to neoadjuvant chemotherapy in univariate and multivari-
ate analysis. PD-L1 expression was associated with TNC and receptor-negative sta-
tus and high level of TILs [17].
In this scenario, immunotherapy with checkpoint inhibitors has made great prog-
ress. Early in 2019, atezolizumab, an anti-PD-L1 monoclonal antibody, was
approved in combination with nanoparticle albumin-bound (nab) paclitaxel, a form
of paclitaxel that does not require steroid premedication, for the treatment of patients
with locally advanced or metastatic TNC whose tumors are positive for PD-L1
expression (≥1%) on immune infiltrate, evaluated by the Ventana PD-L1 (SP142)
antibody [18].
The tumor mutational burden (TMB) is substantially lower in breast cancer than
in other solid malignancies such as lung cancer or melanoma, with low ability to
develop a competent immune response related only to this variant [19].
Along with BRCA1/2-mutation breast cancer, about 50% of sporadic TNC have
the BRCAness phenotype, which gives them, clinical and pathological characteris-
tics to be highlighted: large tumors (>2.0 cm), circumscribed with pushing borders,
sheets of pleomorphic tumor cells, syncytial-like growth pattern, brisk lymphocytic
stromal reaction, with geographic pattern necrosis or fibrosis, usually occurring in
young patients and high KI-67 levels.
They are frequently associated with TP53 gene mutation and EGFR expression,
deficient in homologous recombination and with sensitivity to (adenosine
diphosphate-ribose) polymerase inhibitors and platinum salts [20, 21].
1.3 Luminal Carcinomas (LC)
Luminal carcinomas represent a group of tumors that corresponds to approximately

75–80% of all breast carcinomas and show a differentiated epithelial cell profile,
with expression of estrogen and/or progesterone receptors and a better prognosis,
particularly the subtype A. These tumors express markers of the epithelial cells of
the ductal lining, such as luminal cytokeratins (8 and 18) and reflect a more advanced
stage in differentiation, constituting a more heterogeneous group depending on the
degree of differentiation. Fernandes et al. [22] showed that among the poorly dif-
ferentiated invasive breast carcinomas (Nottingham classification between 2 and 3
with a maximum of 10% of solid arrangement), the luminal subtype was the most
frequent (73 cases or 54.5%), followed by the triple-negative subtype (39 cases or
29.1%) and, more rarely, the HER2 subtype (22 cases or 16.4%).
The technology of DNA microarrays allowed subgroups of tumors to be ana-
lyzed in order to determine genes related to morphological characteristics of recog-
nized prognostic impact. Thus, RE-positive carcinomas were subdivided into high
and low genomic grade, determined by the expression of genes related to cell dif-
ferentiation and proliferation [23]. In this study, the genomic grade determines two
distinct subtypes of tumors in terms of evolution, regardless of the use of tamoxifen
and consistent with the luminal profiles A and B. Luminal A carcinomas are charac-
terized by a higher expression of ER, GATA3, and X-box-binding protein trefoil
factor 3, hepatocyte nuclear factor 3 alpha, and LIV-1, besides low genomic grade,
similar to the normal breast tissue. Luminal B carcinomas are generally
characterized by a lower expression of luminal-specific genes, a higher expression

of genes involved in mitosis and cell proliferation, and high genomic grade and can
also express in approximately 10–15% of cases, amplification and/or overexpres-
sion of the HER2 gene (ER+; PR+ and HER2+ or triple positive).
As to the IHC profile, the CAP and ASCO in the most recent update [24] main-
tained the definition of positive hormone receptor, any expression of ER or RP
greater than or equal to 1% (which would correspond to an Allred score of 2 or more
for the proportion of positive cells with any intensity of immunostaining) (Fig. 1.1).
They also recommend that the result of the hormone receptors status be reported
considering the average intensity and extent of immunostaining and not simply as
positive or negative. In the same issue, invasive carcinomas with 1 to 10% of cells
staining for ER (not PR) are reported as “low positive,” and the following report
comment is recommended: “The cancer in this sample has a low level (1–10%) of
ER expression by IHC.”
There are limited data on the overall benefit of endocrine therapies for patients
with low level of ER expression (1–10%), but they currently suggest possible ben-
efit, so patients are considered eligible for endocrine treatment. There are data that
suggest that invasive cancers with these results are heterogeneous in both behavior
and biology and often have gene expression profiles more similar to ER-negative
cancers. The “low positive” designation applies only to invasive carcinoma and is
not used for PR or ductal carcinoma in situ (DCIS).
When we attempt to correlate the histological with the molecular subtypes,
the main studies were almost completely limited to invasive breast carcinoma of
no special type, which can be of any molecular subtype, and did not take uncom-
mon histologies into account. Thus, molecular classification is more a descrip-
tion of the heterogeneity of invasive breast carcinoma of no special type rather
than an exhaustive representation of the entire breast cancer landscape. In this
scenario, Dieci et al. [25] studied the special molecular types and histological
subtypes, which represent 25% of all breast carcinomas. Some of the special
Fig. 1.1
Immunohistochemical
reaction illustrating
positive case for estrogen
receptor. Nuclear staining
in >1% of neoplastic cells
types with the best prognosis (pure mucinous and tubular carcinomas) presented
the lowest levels of gene copy number changes and corresponded to the luminal
subtype A.
In the 2013 St. Gallen consensus, the approximate cut-point in immunohisto-
chemistry to separate the luminal subtypes A and B was KI67 ≤20% and/or PR
<20% [26].
Currently, we also have genomic tests for HER-negative LCs, which can be used
to define treatment in cases of discordant clinical and genomic risks, formerly used
only to guide prognosis, such as the distance recurrence index determined by 21
genes [27] and the Amsterdam test of 70 genes [28]. These will be discussed in a
specific chapter.
As for the metastatic scenario, Chen et al. [29] provided a large single center
cohort to assess the frequency of receptor conversion in metastatic breast cancer.
The overall discordant rates were 18.3%, 40.3%, and 13.7% for ER, PR, and HER2,
respectively. The discordance was significantly higher for PR when compared with
ER and HER2. The conversion occurred significantly as a switch from positive to
negative receptor status when compared to the conversion from negative to positive
for all three receptors. Semiquantitative analyses revealed a significantly decreased
expression of both ER (25%) and PR (57%) in the metastases. There was a higher
rate of PR discordance in bone metastases when compared to other common organs
of relapse.
A positive ER status, in primary or metastatic breast cancer, was associated with
a prolonged metastasis-free survival when compared with ER-negative primary
tumors without conversion. Furthermore, a positive ER status in metastatic breast
cancer regardless of the primary tumor was associated with a superior overall sur-
vival when compared with an ER-negative tumor without conversion. Thus, recep-
tor conversion is a frequent event in the course of breast cancer progression and can
also be seen between different metastatic sites. Moreover, some conversions are of
prognostic significance. The findings may reflect tumor heterogeneity, sampling, or
treatment effect but may also indicate alteration in tumor biology. Repeat biomarker
testing is justified when making appropriate treatment plans in the pursuit of preci-
sion medicine.
Despite continuous expression of the ER, for unknown reasons, many ER+
breast cancers in the metastatic setting become refractory to the inhibition of estro-
gen action. Thirty-one biopsy samples collected after progression on hormonal
therapy from patients with metastatic ER+ breast cancer were subjected to targeted
DNA sequencing in a study [30]. ESR1 mutations (a total of 9/36 cases) were
detected at much higher rates than in those reported by TCGA. The mutations in
ESR1 clustered in the ligand-binding domain. Furthermore, analysis of the avail-
able paired primary samples showed that these mutations were an acquired event.
The mutations clearly occurred in a population of patients with hormone refractory
disease, and the biochemical and structural data demonstrated that these mutations
promoted the agonist conformation of ER in the absence of ligand. Furthermore, the
mutant ER isoforms were only partially inhibited by direct receptor antagonists
such as tamoxifen or fulvestrant and needed higher doses than those used clinically
to achieve full inhibition. Thus, ESR1 mutations have emerged as predictors of

acquired resistance to endocrine therapy and should help to select patients who are
potential candidates for chemotherapy or other targeted agents [31].
Nowadays, there are important biomarkers still on the same scenario, such as
genetic alterations of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian
target of rapamycin (mTOR) pathway, occurring in approximately 40% of patients
with hormone receptor-positive, HER2-negative breast cancer. Thus, outcomes
were not homogeneous, and it became evident that estrogen/ER signaling is more
complex than initially believed. Apparently, feedback loops with growth factor sig-
naling pathways play a vital role in resistance to antihormonal agents. Aberrant
PI3K/AKT/mTOR signaling pathway is one mechanism of endocrine resistance
acting via phosphorylation of the function domain 1 of the ER by S6 kinase 1, a
substrate of mTOR complex 1. Targeting this pathway has been shown to have
important clinical implications, demonstrated by the SOLAR-1 trial [32].
Dysregulation of the cell cycle is another important pathway targeted for drug
development that led to the regulatory approval of a new drug. Several genetic alter-
ations in key cell cycle regulatory proteins have been described in various cancers,
including breast cancer. Here, the cyclin-dependent kinases (CDKs) were studied as
targets of interest, especially CDK 4/6 molecule inhibitors [33].
1.4 HER2-Enriched Carcinomas
HER2 belongs to the family of four transmembrane receptors (HER1 or EGFR,

HER2, HER3, and HER4), which use tyrosine kinase activity as a trigger in cell
signaling. Other members of the tyrosine kinase growth factor receptor family are
the c-Kit and the vascular endothelial growth factor receptor (VEGFR), factors that
were initially studied in the assessment of breast cancer prognosis, and are now
known to use the same activation pathways as HER2. Positivity for HER2 seems to
be associated with relative but not absolute resistance to endocrine therapy in gen-
eral [34]. Studies have suggested that this effect is specific with ER, since the non-
genomic pathway of ER activity passes through the same pathways as HER, which
would justify the failure to respond to hormonal block and resistance to endocrine
therapy [35]. Retrospective results suggested that positivity for HER2 would be
associated with the response with anthracyclines; however, this effect could be sec-
ondary to the co-amplification of the topoisomerase II alpha gene (TOP2A), a direct
target of these agents and therefore another marker with therapeutic potential [36].
A subset of breast carcinomas (approximately 15%) overexpress human epider-
mal growth factor receptor 2 (HER2; Human Genome Organization (HUGO)
nomenclature ERBB2). Protein overexpression is usually due to gene amplification.
Assays for gene copy number, mRNA quantity, and protein generally give similar
results; gene amplification correlates with protein overexpression in about 95% of
cases. In a small subset of carcinomas (probably <5%), protein overexpression may
occur by different mechanisms. Overexpression is both a prognostic and predictive
factor [10]. HER2 status is primarily evaluated to determine patient eligibility for
anti-HER2 therapy. It may identify patients who have a greater benefit from
anthracycline-based adjuvant therapy.
HER2 status can be determined in formalin-fixed paraffin-embedded tissue by
assessing protein expression on the membrane of tumor cells using IHC or by
assessing the number of HER2 gene copies using in situ hybridization (ISH). When
both IHC and ISH are performed on the same tumor, the results should be corre-
lated. The most likely reason for a discrepancy is that one of the assays is incorrect,
but in a small number of cases, there may be protein overexpression without ampli-
fication, amplification without protein overexpression, or marked intratumoral het-
erogeneity. We must always keep in mind the intratumoral heterogeneity; when
there is a negative result in a small biopsy sample, repeated testing on a subsequent
specimen with a larger area of carcinoma sampled should be considered, particu-
larly if the tumor has characteristics associated with HER2 positivity (i.e., tumor
grade 2 or 3, weak or negative PR expression, increased proliferation index) [10].
When multiple invasive foci are present, the largest invasive focus should be tested.
Testing smaller invasive carcinomas is also recommended if they are of different
histologic type or higher grade.
The major challenge for the characterization of the HER2 group was the ade-
quate laboratory standardization. The American Society of Clinical Oncology
(ASCO) and CAP standardized criteria for positivity and laboratory control for
adequate testing [10]. The immunohistochemical criteria are illustrated in Table 1.1
(Figs. 1.2 and 1.3), remembering that all HER2 2+ tumors (equivocal) must be sub-
jected to ISH to confirm the real status of HER2. It is recommended that hormone
receptor and HER2 testing be performed in all primary invasive breast carcinomas
and in recurrent or metastatic tumors.
Fluorescence in situ hybridization (FISH), chromogenic in situ hybridization
(CISH), and silver-enhanced in situ hybridization (SISH) studies for HER2 deter-
mine the presence or absence of gene amplification. Some assays use a single probe
to determine the number of HER2 gene copies present, but most assays include a
chromosome enumeration probe (CEP17) to determine the ratio of HER2 signals to
copies of chromosome 17. Although 10% to 50% of breast carcinomas have more
Table 1.1 Reporting results of HER2 testing by immunohistochemistry

Result Criteria
Negative (score No staining or incomplete or faint membrane staining within ≤10% of tumor
0) cells
Negative (score Incomplete or faint membrane staining within >10% of tumor cells
1+)
Equivocal (score Weak to moderate complete membrane staining in >10% or intense complete
2+) membrane staining in ≤10% of tumor cells
Positive (score Intense complete membrane staining in >10% of tumor cells
3+)
Adapted from 2018 CAP/ASCO Update recommendations
Fig. 1.2
Immunohistochemical
reaction illustrating a
positive case (score 3+) for
HER2. Strong and
complete membrane
staining in >10% of
neoplastic cells
Fig. 1.3
Immunohistochemical
reaction illustrating an
equivocal case (score 2+)
for HER2. Weak to
moderate complete
membrane staining in
>10% of neoplastic cells
than two CEP17 copies, only 1% to 2% of carcinomas show true polysomy (i.e.,
duplication of the entire chromosome) (10).
Dual probe defines five groups by ISH: Group 1 = HER2/CEP17 ratio ≥2.0, ≥4.0
HER2 signals/cell; Group 2 = HER2/CEP17 ratio ≥2.0, <4.0 HER2 signals/cell;
Group 3 = HER2/CEP17 ratio <2, ≥6.0 signals/cell; Group 4 = HER2/CEP17 ratio
<2, ≥4.0 and <6.0 HER2 signals/cell; and Group 5 = HER2/CEP17 ratio <2.0, <4.0
HER2 signal/cell. Reporting results recommended by CAP/ASCO are shown in
Table 1.2.
Group 1 is positive, group 5 is negative, and groups 2, 3, and 4 require a new
count, together with immunohistochemistry and preferably by a second observer, to
determine whether the result is positive or negative, without further misunderstand-
ing after ISH. Regardless of the result, the group must be returned to the final report
after the ISH.
Table 1.2 Reporting results of HER2 testing by in situ hybridization (dual-probe assay)
Result Criteria (dual-probe assay)
Negative Group 5
Negative – results based on concurrent review of IHC Group 2 and concurrent IHC 0-1+ or 2+
Group 3 and concurrent IHC 0-1+
Group 4 and concurrent IHC 0-1+ or 2+
Positive – results based on concurrent review of IHC Group 2 and concurrent IHC 3+
Group 3 and concurrent IHC 2+ or 3+
Group 4 and concurrent IHC 3+
Positive – results based on concurrent review of IHC Group 1
Adapted from 2018 CAP/ASCO Update recommendations
The heterogeneity of HER2 breast cancer is a complex phenomenon. Before

discussing true heterogeneity, it is important to discard pre-analytical problems that
may have led to this result. Genomic heterogeneity refers to conditions where more
than one population of tumor cells exists within the same tumor. This can occur in
three separate manners: as discrete populations (clones) of amplified and non-
amplified tumor cells, diffuse intermingling of amplified and non-amplified cells
across the tumor, or as isolated 6 amplified cells in a predominantly non-amplified
tumor [10]. This intrinsic heterogeneity reflects the lack of complete response to
chemotherapy that these tumors present. lHC errors are more common in HER2
tumors, which had a low degree of amplification in the ISH [37].
As previously mentioned, there is biological resistance in positive hormonal
tumors, HER2 positive. HER2 can induce ER phosphorylation (via MAPK and
AKT) and cause hormonal resistance in these tumors. On the other hand, the ER
pathway is an escape pathway that can drive tumor cell growth and survival in the
presence of anti-HER2 therapy, via increased ER expression. In addition, non-
genomic ER (associated with the membrane) can induce HER2 phosphorylation,
causing resistance to anti-HER2 therapy [37–39].
Hou et al. [40], using the HER2 gene-protein assay (GPA) technique, simultane-
ously evaluated both HER2 gene signal and protein expression by means of a single-
slide dual assay and observed that post-neoadjuvant pCR dropped from 76% (cases
without heterogeneity for HER2) to 26% (cases with heterogeneity for HER2).
Another form of heterogeneity that occurs in these tumors is the conversion of
status between the primary and the metastatic tumor and the conversion after neo-
adjuvant chemotherapy. Changes between the primary and metastatic profiles are
expected in 10% of cases, most of them positive to negative. This is due to clonal
selection and changes induced by treatment. It is more common for cases with low
HER2 amplification, often HER2 2+ in immunohistochemistry [40–42]. Pusztai l
during the 2020 ASCO meeting [42] divided the predictive factors of response to
neoadjuvant treatment in HER2-positive breast carcinomas into two categories:
sensitivity markers, with greater chance of pCR, and resistance markers, with less
chance of pCR. Among the first are the ER-negative group, the intrinsic molecular
subtype HER2 enriched determined by PAM-50, tumors with intense immune

infiltration (high TILs), and those with a high level of HER2 expression (immu-
nohistochemistry, mRNA, copy number). Among the latter is the ER-positive
group, with PIK3CA mutation, PTEN loss, HER2 copy number ratio <4.0, and
focal HER2 positivity.
References
1. American Cancer Society. How common is breast cancer? Jan. 2021. Available at: https://
www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html.
2. National Cancer Institute. BRCA mutations: cancer risk and genetic testing. Jan. 2018. Available
at: https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet.
3. Perou CM, Sorlie T, Eisen MB, van de RM JSS, Rees CA, et al. Molecular portraits of human
breast tumours. Nature. 2000;406(6797):747–52.
4. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns
of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad
Sci U S A. 2001;98(19):10869–74.
5. West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R, et al. Predicting the clini-
cal status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci U S
A. 2001;98(20):11462–7.
6. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, et al. Breast cancer clas-
sification and prognosis based on gene expression profiles from a population-based study. Proc
Natl Acad Sci U S A. 2003;100(18):10393–8.
7. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation
of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S
A. 2003;100(14):8418–23.
8. Van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profil-
ing predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530–6.
9. WHO Classification of Tumours Editorial Board. Breast tumours, WHO classification of
tumours series, vol. 2. 5th ed. Lyon: International Agency for Research on Cancer; 2019.
10. Cancer Protocols Templates of College of American Pathologists. Available at: https://www.
cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates.
11. Birnbaum D, Bertucci F, Ginestier C, Tagett R, Jacquemier J, Charafe-Jauffret E. Basal and
luminal breast cancers: basic or luminous? (review). Int J Oncol. 2004;25(2):249–58.
12. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and
clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer
Res. 2004;10(16):5367–74.
13. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al. Phenotypic eval-
uation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006;19(2):264–71.
14. Stingl J, Caldas C. Molecular heterogeneity of breast carcinomas and the cancer stem cell
hypothesis. Nat Rev Cancer. 2007;7(10):791–9.
15. Thike AA, Cheok PY, Jara-Lazro AR, Tan B, Tan P, et al. Triple-negative breast cancer: clini-
copathological characteristics and relationship with basal-like breast cancer. Mod Pathol.
2010;23(1):123–33.
16. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of
triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy
selection. PLoS One. 2016;11(6):e0157368.
17. Wimberly H, Brown JR, Schlper K, Haack H, Silver MR, et al. PD-L1 expression correlates
with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast can-
cer. Cancer Immunol Res. 2015;3(4):326–32.
18. Schmid P, Adams S, Rugo HS, Schneeweiss A, et al. Atezolizumab and Nab-Pacltaxel in
advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.
19. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and sig-
nificance across 12 major cancer types. Nature. 2013;502(7471):333–9.
20. Tian T, Shan L, Yang W, Zhou X, Shui R. Evaluation of the BRCAness phenotype and its
correlation with clinicopathological features in triple-negative breast cancers. Hum Pathol.
2019;84:231–8.
21. Gross E, van Tinteren H, Li Z, Raab S, Meul C, Avril S, et al. Identification of BRCA1-like
triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplifica-
tion (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study. BMC
Cancer. 2016;16(1):811.
22. Fernandes RCM, Bevilacqua JLB, Soares IC, Siqueira SAC, Pires L, et al. Coordinated expres-
sion of ER, PR and HER2 define different prognostic subtypes among poorly differentiated
breast carcinomas. Histopathology. 2009;55(3):346–52.
23. Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, et al. Definition of clini-
cally distinct molecular subtypes in estrogen receptor-positive breast carcinomas through
genomic grade. J Clin Oncol. 2007;25(10):1239–46.
24. Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey AL, et al. Estrogen and
progesterone receptor testing in breast cancer: ASCO/CAP guideline update. J Clin Oncol.
2020;38(12):1246–66.
25. Dieci MV, Orvieto E, Dominici M, Conte P, Guarneri V. Rare breast cancer subtypes: histo-
logical, molecular, and clinical peculiarities. Oncologist. 2014;19(8):805–13.
26. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al.
Personalizing the treatment of women with early breast cancer: highlights of the St Gallen
International Expert Consensus on the primary therapy of early breast cancer 2013. Ann
Oncol. 2013;24:2206–23.
27. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant
chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med.
2018;379(2):111–21.
28. Cardoso F, van’t Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. MINDACT
Investigators. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N
Engl J Med. 2016;375(8):717–29.
29. Chen R, Qarmali M, Siegal GP, Wei S. Receptor conversion in metastatic breast cancer: analy-
sis of 390 cases from a single institution. Modern Pathol. 2020;33:2499–506.
30. Toy W, Shen Y, Won H, Green B, Sakr RA. ESR1 ligand-binding domain mutations in
hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.
31. Aftimos P Jr, AAAJ, Sotiriou C. Tumours of the breast. In: Coleman WB, Tsongalis GJ, editors.
Molecular pathology – the molecular basis of human disease. Academic Press; 2017. p. 583.
32. Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, et al. Alpelisib for PIK3CA-mutated,
hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–40.
33. Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene.
2014;33:1890–903.
34. Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative asso-
ciation between HER-2/neu and steroid hormone receptors in hormone receptor-positive pri-
mary breast cancer. J Natl Cancer Inst. 2003;95(2):142–53.
35. Ellis MJ. Neoadjuvant endocrine therapy for breast cancer: medical perspectives. Clin Cancer
Res. 2001;7(12 Suppl):4388s–4391s.
36. Villman K, Sjostrom J, Heikkila R, Hultborn R, Malmstrom P, Bengtsson NO, et al. TOP2A
and HER2 gene amplification as predictors of response to anthracycline treatment in breast
cancer. Acta Oncol. 2006;45(5):590–6.
37. Godoy-Ortiz A, Sanchez-Munoz A, Parrado MRC, Alvarez M, Ribelles N, et al. Deciphering

HER2 breast cancer disease: biological and clinical implications. Front Oncol. 2019;9:1124.
38. Turashvili G, Brogi E. Tumor heterogeneity in breast cancer. Front Med. 2017;4:article 227.
39. Griguolo G, Pascual T, Dierci MV, et al. Interaction of host immunity with HER2-targeted
treatment and tumor heterogeneity in HER2-positive breast cancer. J Immunother Cancer.
2019;7:90.
40. Hou Y, Nitta H, Wei L, Banks PM, Portier B, et al. Her2 intratumoral heterogeneity is indepen-
dently associated with incomplete response to anti-her2 neoadjuvant chemotherapy in HER2-
positive breast carcinoma. Breast Cancer Res Treat. 2017;166:447–57.
41. Schettini F, Pascual T, Conte B, Chic N, Braso-Maristany F, et al. Her2-enriched subtype and
pathological complete response in HER2-positive breast cancer: a systematic review and meta-
analysis. Cancer Treat Rev. 2020;84:101965.
42. Pusztai L. Molecular predictors of response to neoadjuvant Her2 targeted therapies. ASCO
Meeting, 2020.
Chapter 2
Risk Factors for Breast Cancer
Sergio Masili-Oku , Angela Trinconi , Gabriela Boufelli ,

and Jose Roberto Filassi
2.1 Introduction
Breast cancer is the second most common malignancy globally after lung cancer
and the most frequent cancer among women.
About 2 million new cases of cancer occur each year. In 2020, there were
2,261,419 new cases and 684,996 deaths due to breast cancer worldwide [1, 2]. The
incidence of breast cancer has been increasing in recent decades. In Brazil, the esti-
mate for the year 2020 is 66,280 new cases, with 16,927 deaths [3]. Due to its sig-
nificant incidence and prevalence, it is important to understand the risk factors for
its development and what can be done to reduce the risk of acquiring it.
Studies in the literature show that about 10% of breast cancer cases are related to
hereditary genetic mutations, while the other 90% occur randomly. Risk factors can
be related to age, sex, and reproductive cycle. There are also behavioral factors.
Other factors, such as precursor lesions and genetic mutations, must be evaluated.
2.2 Gender and Age
Breast cancer mainly affects women after 50 years old. Its incidence ranges from
14.5 to 55.6 (ASR-age standardized rate) per 100,000 women in Africa to 84.9
(ASR) per 100,000 in Brazil, 62.9 (ASR) per 100,000 in the United States, 93.6
(ASR) per 100,000 in the United Kingdom, and 99.1 (ASR) per 100,000 in France.
S. Masili-Oku (*) · A. Trinconi · G. Boufelli · J. R. Filassi

Departamento de Mastologia, Instituto do Cancer do Estado de Sao Paulo ICESP,
São Paulo, SP, Brazil
e-mail: [email protected]; [email protected]; [email protected]

Switzerland AG 2022
18 S. Masili-Oku et al.
The male sex corresponds to only 1% of cases, with one man per 100,000 standard
population. When it affects men, they are generally older and may present some
hormonal alteration, or it may be related to the BRCA2 gene mutation [4].
Regarding age, the incidence of breast cancer is higher among women after
menopause. In the United States, about 77% of cases occur in women after 50 years
of age, and the average age at diagnosis is 62 years old [5, 6]. In the United Kingdom,
between 2015 and 2017, about 85% of cases were diagnosed in women over
50 years old [7]. Therefore, the population at the most significant risk for breast
cancer are women over 50 years old, usually after menopause. They must undergo
screening with annual or biannual mammograms according to each country’s pro-
gram [1, 8].
2.3 Reproductive Factors
Early menarche, nulliparity, and late pregnancy are risk factors for the development
of breast cancer. In the literature, studies show a relationship between these factors
and the appearance of positive hormone receptor breast cancer, which is not related
to negative hormone receptor breast cancer. Probably the longer exposure time of
the breast tissue to the hormonal action, such as estrogen and progesterone, the
greater the likelihood of the appearance of breast neoplasms [9]. Thakur and col-
laborators [10] carried out a case-control study, which included 377 women with
breast cancer and 346 controls. In this study, early menarche (<12 years) increased
the risk for breast cancer by up to two times (odds ratio (OR) = 2.83, 95% confi-
dence interval (CI) = 1.02–7.86); the same was found for late menopause (>50 years)
(OR = 2.43, 95% CI = 1.2–4.9).
Huo and collaborators [11] also sought to assess menarche’s influence on the
onset of breast cancer. They carried out a case-control study, evaluating 819 patients
with breast cancer and 569 controls, and found that for every 2 years of delay in
menarche, there was a reduction in 7% risk of developing breast cancer.
2.4 Gestation and Lactation
Pregnancy and lactation are considered protective factors against developing breast
cancer, and the age of the pregnancy and the duration of lactation are responsible for
providing this protection. Ma and collaborators [12] evaluated that pregnancy
decreases the risk of developing breast cancer by 11%. Still, it presents itself as a
protective factor when it occurs before the age of 30 and can be a risk factor when
it occurs at a late age. Women who became pregnant after the age of 30 were 27%
more likely to have hormonal positive breast cancer than the patients who became
pregnant before the age of 30. This difference is probably due to the breast’s matura-
tion stages, as it completes its embryological development with pregnancy. The
2 Risk Factors for Breast Cancer 19
sooner this occurs, the less the chance of cellular changes that can be stimulated by
the hormonal action of pregnancy, leading to the onset of neoplasms [13]. Thakur
et al. [10], in a case-control study, found a risk of up to six times greater than having
breast cancer when pregnancy occurs at an older age (>30 years) (OR = 6.34, 95%
CI = 2.04–27).
A meta-analysis carried out by the collaborative group on hormonal factors of
the breast [14] evaluated the impact of pregnancy on breast cancer; forty-seven stud-
ies were carried out, were conducted in 30 countries, and compared 12,214 nulli-
gravid women with 16,900 women who had children but did not breastfeed. The
result found that the earlier the pregnancy occurred, the lower the relative risk of
developing breast cancer. The risk of developing breast cancer decreases by 7%
with each delivery, demonstrating that pregnancy is a protective factor against the
onset of breast cancer.
The practice of breastfeeding is a protective factor for breast cancer develop-
ment, but there is still no consensus on the ideal breastfeeding time for its preven-
tion [12, 15]. Huo and collaborators [11] found that every 12 months, lactation
reduces the risk of developing breast cancer by 7%. A meta-analysis carried out by
the collaborative group on hormonal factors of the breast [14] also identified breast-
feeding as a protective factor. Every 12 months of breastfeeding, there is a decrease
in the relative risk estimated at 4.5%.
2.5 Contraception and Hormone Replacement Therapy
Studies in the literature that have assessed the influence of hormonal contraceptives
on breast cancer have shown variable findings ranging from no increased risk to a
relative risk of 9.5, thus being a controversial subject [4, 16].
Marshbanks and collaborators [16] conducted a case-control study, evaluating
2282 women with breast cancer and 2424 women without breast cancer, and found
no association between the use of hormonal contraceptives and an increased risk of
developing breast cancer.
Mørch and collaborators [17], seeking a more recent analysis on the use of hor-
monal contraceptives and their relationship with breast cancer, conducted a cohort
study evaluating approximately 1.8 million women between 15 and 49 years old,
who were followed up by about 10.9 years. In this period, there were 11,517 cases
of breast cancer. The relative risk found for women who used contraceptives com-
pared to women who never used them was 1.20 (95% CI, 1.14–1.26). The risk
increased from 1.09 (95% CI, 0.96–1.23) in women with less than 1 year of use to
1.38 (95% CI, 1.26–1.51) in women over 10 years of using hormonal contracep-
tives. The absolute risk for using hormonal contraceptives was 13 (95% CI, 10–16)
per 100,000 women-years or approximately one extra breast cancer case for every
7690 women using hormonal contraceptives for 1 year. Therefore, the use of hor-
monal contraceptives should be discussed with the patient, individualizing personal
risk factors and deciding with her the use thereof.
Regarding hormone replacement therapy, the Women’s Health Initiative (WHI)

randomized clinical trial evaluated 16,608 postmenopausal women aged 50–79.
With an intact uterus, one arm of 8506 women that received 0,625 mg of conju-
gated equine estrogen and 2.5 mg of medroxyprogesterone acetate daily was com-
pared with the placebo group of 8102 women. A second arm of the study evaluated
10,739 hysterectomized women who received conjugated equine estrogen alone
versus the group that received the placebo. The first arm of the study was designed
for 8.5 years and was discontinued in 2002 (about 5.2 years) due to an increased risk
of breast cancer (HR 1.26) [18]. The second arm was stopped in 2004 due to
increased number of ischemic strokes (HR, 1.39; 1.10–1.77) [19]. In 2010, an anal-
ysis of the subgroups was carried out after discontinuation of hormone replacement
therapy, and this analysis showed that in hysterectomized patients, the use of iso-
lated estrogen (used for an average of 7.2 years) was a protective factor against the
appearance of breast cancer with HR 0.79 (0.65–0.97) [20], raising the hypothesis
that progesterone is more related to the risk of developing breast cancer.
Also, seeking to correlate the use of hormonal therapy (HT) with breast cancer,
the Collaborative Group on Hormonal Factors of the Breast carried out a meta-
analysis [21] comparing HT and breast cancer development. Fifty-three thousand
eight hundred sixty-five women were evaluated, and 17,830 of them used hormone
therapy (HT). The meta-analysis demonstrated a relative risk of 1.35 (1.21–1.49;
2p = 0.00001) for women who used TH for more than 5 years. The risk increased
with each year of using HT and returned to baseline 5 years after the end of treat-
ment, associating HT as a risk factor for breast cancer development. Hormone ther-
apy, then, is a risk factor for breast cancer development and should be used according
to each patient’s individual needs.
2.6 Obesity
Obesity has been described as a risk factor for the development of breast cancer.
Adipose tissue is an androgen producer and allows more significant hormonal action
in the breasts through their peripheral conversion [9].
Obesity is a risk factor for breast cancer in postmenopausal women. Kabat and
collaborators [22] evaluated obesity and metabolic syndrome as a risk factor for
breast cancer. An arm of the WHI study included 20,944 women with obesity and
metabolic syndrome. Blood glucose, triglycerides, HDL-cholesterol, blood pres-
sure, waist circumference, and body mass index (BMI) measurements were evalu-
ated. Women were classified according to their BMI (18.5–<25.0, normal weight;
25.0–<30.0, overweight; and ≥30.0 kg/m2, obese) and the presence of metabolic
syndrome (≥3 of the following: waist circumference ≥88 cm, triglycerides
≥150 mg/dL, HDL-C <50 mg/dL, glucose ≥100 mg/dL, and systolic/diastolic
blood pressure ≥130/85 mmHg or treatment for hypertension), yielding six groups:
metabolically healthy/normal weight (MHNW), metabolically unhealthy/normal
weight (MUNW), metabolically healthy/overweight (MHOW), metabolically
unhealthy/overweight (MUOW), metabolically healthy/ obese (MHO), and meta-

bolically unhealthy/ obese (MUO). These women were followed for 15 years, and
during this period, 1176 cases of invasive breast cancer were diagnosed. Obesity,
regardless of the metabolic part, has been associated with an increased risk of breast
cancer. Being obese and metabolically unhealthy was associated with a higher risk:
HR, 1.62 (95% CI, 1.33–1.96). These associations were strongest in women who
had never used hormone therapy. This study demonstrates that both obesity and the
metabolic part are related to the increase in breast cancer. These factors are modifi-
able with lifestyle changes, adequate diet, physical activity, and appropriate drug
treatment, decreasing the patient’s risk of breast cancer.
2.7 Alcohol and Smoking
Alcohol consumption and smoking are associated with the development of breast
cancer. The greater the consumption before pregnancy, the greater the risk [4]. Park
and collaborators [23] evaluated 85,089 women and alcohol consumption in a
cohort with women from different ethnicities in Hawaii and California, with an
average follow-up of 12.4 years. During this time, 3885 cases of breast cancer were
identified. The hazard ratios (HRs) found demonstrated that alcohol consumption
increases the risk of developing breast cancer compared to not consuming it. The
HRs were 1.23 (95% CI, 1.06–1.42), 1.21 (95% CI, 1.00–1.45), 1.12 (95% CI,
0.95–1.31), and 1.53 (95% CI, 1.32–1.77) for 5–9.9, 10–14.9, 15–29.9, and ≥30 g/
day of alcohol consumption, respectively.
A cohort between 1899 and 1975 with 302,865 Norwegian women evaluated the
effect of smoking on cancer and concluded that women who smoked had a 15%
increased risk of having breast cancer (HR = 1.15; 95% CI, 1.10–1.21) [24].
2.8 Thoracic Radiation Therapy
Chest radiotherapy performed to treat Hodgkin’s disease increases the risk of devel-
oping breast cancer. Studies have shown that this risk is greater the younger the
woman is when undergoing chest radiotherapy. The relative risk for developing
breast cancer for women who received chest radiotherapy between the ages of 15
and 19 is 30.7; between 20 and 24 years, the RR is 14.0; between 25 and 29 years
old, the RR is 5.5, and between 30 and 35 years old, the RR is 5.3. Thoracic radio-
therapy after age 35 does not seem to increase this risk [25].
The risk of developing breast cancer is also related to the time that elapses after
the end of chest radiotherapy. The RR is 2.9 after 5 years of the end of irradiation;
the peak is after 15 to 19 years when this risk reaches an RR of 11.1, and after 20 to
25 years, there is a drop to an RR of 8.0 [25].
Wolden and collaborators [26] evaluated 71 cases of breast cancer in 65 women

who had Hodgkin’s lymphoma. The average age for diagnosis of lymphoma was
24.6 years, and the average age for breast cancer diagnosis was 42.6 years. The rela-
tive risk for developing invasive breast cancer was 4.7 (95% CI, 3.4–6.0).
Cutuli and collaborators [27] also identified a relationship between exposure to
chest radiotherapy and breast cancer onset. When evaluating 117 women and two
men who had been treated for Hodgkin’s lymphoma, they found 133 diagnoses of
breast cancer, with less than 5% of the cancer cases appearing before 5 years after
the end of treatment and 27.8% of the patients between 11 and 15 years of therapy
and 30% after 20 years of treatment.
2.9 Precursor Injuries
The proliferative intraductal lesions usually have their origin in the terminal duct
lobular unit. They are composed of a heterogeneous group of lesions concerning
cytology and architecture. Their presence confers an increased risk of developing an
invasive lesion. The usual ductal hyperplasia, atypical hyperplasia, ductal carci-
noma in situ, columnar cell lesion, columnar cell lesion with atypia, lobular carci-
noma in situ, and flat epithelial atypia are part of this group. Since the increase in
risk for breast cancer is 1.5 times in the presence of usual ductal hyperplasia, this
rises to four to five times in ductal hyperplasia with atypia/columnar cell lesion with
atypia and eight to ten times in ductal carcinoma in situ/lobular carcinoma in
situ [28].
Atypical hyperplasia corresponds to a monotonous proliferation of epithelial
cells inside the mammary duct. Without breaching through the myoepithelial layer,
it does not compromise two consecutive mammary ducts and measures less than
2 mm. In terms of cytological characteristics, it is similar to low-grade ductal carci-
noma in situ. It is classified when atypical cells affect two consecutive whole ducts
and are present in an extension of 2 mm or more.
Columnar cell lesion with atypia is characterized by the proliferation of monoto-
nous, noncohesive cells that fill the mammary duct and compromise less than 50%
of the acini. In contrast, lobular carcinoma in situ is formed by these same cellular
changes that occupy more than 50% of acini [28, 29].
The greater access to breast screening programs and the more significant number
of mammograms performed have increased the diagnosis of atypia in percutaneous
biopsies performed for detected masses and microcalcifications found in imaging
exams. The presence of atypia in a breast biopsy, besides representing a greater risk
for this patient to develop breast cancer, implies the need for surgical excision for
the total removal of the lesion, since the percutaneous biopsy may underestimate the
presence of an invasive lesion in 15% to 30% [29].
As for the flat epithelial atypia (FEA), few data establish its risk for breast cancer
development as it is a rare finding. A study conducted by the Mayo Clinic [30]
evaluating 11,591 women with benign breast biopsies found 282 biopsies with
FEA. Of these, 130 were associated with atypical hyperplasia (AH) (46%), and the
others were associated with proliferative disease without atypia (PDWA). These
patients were followed for an average of 16.8 years. The standardized incidence
ratios (SIRs) were the following: SIR for breast cancer in women with AH + FEA
was 4.74 (95% confidence interval [95% CI], 3.17–6.81) versus 4.23 (95% CI,
3.44–5.13) for AH without FEA (P = 0.59). SIR for PDWA + FEA was 2.04 (95%
CI, 1.23–3.19) versus 1.90 (95% CI, 1.72–2.09) for patients with PDWA without
FEA (P = 0.76), so the risk of developing breast cancer was mainly attributed to the
presence of other hyperplasias with atypia rather than the presence of flat epithelial
atypia itself.
In the literature, there is a conundrum about the evolution of a precursor lesion to
an invasive breast cancer. It is known that breast cancer’s natural course does not
always follow this order: usual hyperplasia, atypical hyperplasia, ductal carcinoma
in situ, and then to an invasive ductal carcinoma. Some studies demonstrate a more
complex path, which does not follow these steps for the development of an invasive
breast cancer. To et al. [31] followed 146 women for 25 years, 111 with ductal car-
cinoma in situ (DCIS) and 35 with lobular carcinoma in situ (LCIS). Among these,
26 (19 from the DCIS group and seven from LCIS) developed invasive breast cancer
(17.8%), and 12 died of invasive cancer (8.2%). The average time for the diagnosis
of invasive cancer was 6.3 years. The probability of progressing to invasive breast
cancer was 10.0% in 5 years, 13.7% in 10 years, 17.6% in 15 years, and 19.7% in
20 years. Although 20% were related to the appearance of invasive cancer, in the
other 80%, this relationship was not clear, allowing the discussion that not all in situ
cancers evolve to invasive ones.
2.10 Hereditary Syndromes and Breast Cancer
Familial breast cancer is responsible for 5% to 10% of all breast cancers. Most of
these cases may be associated with mutations in the BRCA1 or BRCA2 genes [32].
The lifetime risk of developing breast cancer for a woman is approximately
12.9%. That is, one in eight women will be diagnosed with breast cancer at some
point in their lives, leading to the estimated prevalence of 3,577,264 women living
with breast cancer in the United States in 2017 [33].
Several factors suggest a genetic contribution to breast cancer, such as [34]:
1. Increased incidence among individuals with a family history of these cancers
2. Several family members affected by these and other types of cancer
3. A cancer pattern compatible with autosomal dominant inheritance
Didactically, we can classify cancer cases [35]:
(a) Sporadic: when there are no cases of the same type of cancer in two genera-
tions, that is, brothers, children, parents, aunts, and uncles, and both pairs of
unaffected grandparents.
(b) Familial: when there are two or more second-degree relatives with breast can-
cer, regardless of age, bilaterality, or other associated cancers. It corresponds to
about 25% of the total diagnoses. Its etiology is multifactorial or random.
(c) Hereditary: its genealogy leads us to think of an autosomal dominant distribu-
tion characterized by early age onset, a more significant number of cases with
bilaterality, and multiple primary cancers. It corresponds to about 10% of the
total cases.
2.11 Genes and Associated Syndromes
Breast and ovarian cancers are present in several autosomal dominant cancer syn-
dromes, although they are more strongly associated with highly penetrating patho-
genic variants in BRCA1 and BRCA2. Other genes, such as PALB2, TP53
(associated with Li-Fraumeni syndrome), PTEN (associated with Cowden syn-
drome), CDH1 (associated with diffuse gastric and lobular cancer syndrome), and
STK11 (associated with Peutz-Jeghers syndrome), confer risk for one or both can-
cers with relatively high penetrance [34].
2.11.1 Genes Associated with High Penetrance
(a) TP53
Mutations involving p53 are inherited in an autosomal dominant manner, which
results in a familial predisposition to various cancers, with an estimated risk of
breast cancer of around 49% at 60 years old and, according to several studies, a
large percentage of diagnoses in young people (about 30 years old). It is associated
with sarcomas, tumors of the central nervous system, leukemia, and adrenocortical
carcinoma.
(b) STK11
Characterized by mutations in the serine-threonine kinase STK11, Peutz-Jeghers
syndrome manifests itself by the appearance of hamartomas (perioral, hands, and
genitals) and polyps in the gastrointestinal tract, in addition to malignant tumors,
including uterus, ovary, and breast (relative risk, 15 times higher than the general
population) [36].
(c) PTEN
Mutations in the tumor suppressor gene PTEN constitute an autosomal dominant
inheritance known as Cowden syndrome, which is characterized by the develop-
ment of multiple hamartomas on the skin and mucous membranes and an increased
risk of developing thyroid, kidney, endometrial, and breast cancer (estimated risk of
85%) [37].
(d) BRCA
BRCA is a tumor suppressor gene responsible for maintaining the integrity of the
genome since it makes possible the recombination of homologous bases of DNA,
repairs the breakdown of the double helix, and controls DNA damage in the S
phase [38].
A recent study [39] estimated that about 72% of women who inherit a harmful
BRCA1 mutation and about 69% of women who inherit a harmful BRCA2 muta-
tion would develop breast cancer at the age of 80 years old.
It is estimated that in 20 years after the first diagnosis of breast cancer, about
40% of women who inherit a BRCA1 mutation and about 26% of women who
inherit a BRCA2 mutation will manifest cancer in their contralateral breast.
About 1.3% of women in the general population will develop ovarian cancer
at some point in their lives. On the other hand, it is estimated that approximately
44% of women who inherit a deleterious BRCA1 mutation and about 17% of
women who inherit a BRCA2 mutation will develop ovarian cancer at 80 years
old [40].
The BRCA mutation increases the risk for several other types of cancer, includ-
ing fallopian tube cancer and peritoneal cancer. Men with BRCA2 mutations are at
increased risk of breast and prostate cancer. Men and women with BRCA mutations
are at increased risk of pancreatic cancer [40].
Ashkenazi Jewish ancestry and Norwegian, Dutch, and Icelandic people have a
higher prevalence of deleterious BRCA1 and BRCA2 mutations than people in the
general population.
2.11.2 Genes Associated with Moderate Penetrance
(a) CHEK2
CHEK2 gene is a member of the Fanconi anemia (FA)-BRCA pathway and is
involved in both the checkpoint function and repair mediated by BRCA1 and p53.
CHEK * 1100delC mutations are associated with a three- to fivefold increase in
breast cancer. The cumulative risk of breast cancer at the age of 70 years old among
CHEK * 1100delC heterozygotes reaches 37% [41].
(b) PALB2
PALB2 is another gene on the FA-BRCA pathway. It encodes a protein that
binds closely to BRCA2, stabilizing it and allowing it to perform its repairing
functions. This interaction is essential for tumor suppression by BRCA2.
Germline mutations in PALB2 increase the chance of early-onset breast cancer,
with a five- to ninefold elevated risk. Unlike BRCA mutations, patients with a
PALB2 mutation do not experience a statistically significant increase in ovar-
ian cancer.
(c) ATM
Mutations in the ATM gene result in ataxia-telangiectasia, an autosomal reces-
sive neurodegenerative disease that causes cerebellar dysfunction and a weakened
immune response.
ATM protein is an essential kinase of the cell cycle within the FA-BRCA path-
way and, among its functions, phosphoryl BRCA1. Studies have shown that patients
with the ATM mutation have a breast cancer risk of approximately 2.37 [41].
2.12 Quantification of Mutation Risk
Risk assessment models have been developed to clarify the lifetime risk of develop-
ing breast cancer and the likelihood of having a pathogenic variant in BRCA1 or
BRCA2 (3). When this risk is greater than or equal to 10%, conducting genetic test-
ing should be suggested.
Among these risk calculators, we can mentio Claus and Gail’s models, which
estimate cancer-based risk only on personal and family characteristics.
To assess the probability of BRCA mutation, BRCAPRO, Penn II, Tyrer-Cuzick
model, and BOADICEA can be utilized.
2.13 Genetic Testing for High-Risk Patients
The BRCA mutation analysis can range from direct, including only a specific muta-
tion in BRCA1 or BRCA2 (single site analysis), to more complete tests that include
sequencing of the entire gene [41].
Given the number of genes associated with an increased risk of breast cancer,
several genes’ massive sequencing may be available. Such an option may be of
interest in patients whose family history is not very informative, that is, a restricted
or unknown family structure (for instance, in case of adoption).
The strategy is to offer the broadest genetic test to the family member affected by
the neoplasia and the guided analysis for the mutation then defined to the other fam-
ily members.
Possible results for genetic tests are:
(a) True positive: the identified mutation is associated with an increased risk
of cancer.
(b) True negative: no mutation is identified in an individual from a family known to
have a mutation.
(c) Meaningless: no mutation is identified in an individual whose family also has
no mutations.
(d) Uncertain meaning: a mutation has been identified; however, its clinical signifi-
cance is unknown at the moment.
According to genetic diagnoses, the National Comprehensive Cancer Network

(NCCN) guides the best practices for follow-up exams [42]. In general, the orienta-
tion is self-knowledge of the breasts from 18 years of age.
For women with BRCA mutation, the following are suggested:
• From 25 to 29 years old: screening with annual magnetic resonance imag-
ing (MRI).
• From 30 to 75 years old: screening with mammography (MG) and annual MRI.
• Over 75 years old: assess individual life expectancy.
• If there is previously treated breast cancer: annual MG and MRI.
• Risk-reducing breast surgery is based on awareness and discussion of risk
reduction.
• Bilateral salpingo-oophorectomy: for mutated BRCA1, it is most suitable
between 35 and 40 years old or if she has constituted offspring. For BRCA2,
surgery will be better indicated between 40 and 45 years old.
For men with BRCA mutation, the following are suggested:
• Annual self-examination and clinical breast examination from the age of
35 years old
• Annual MG if gynecomastia from 50 years old or 10 years before the youngest
affected family member
• From the age of 40 years old, prostatic evaluation, particularly for those with the
BRCA2 mutation
The other mutations mentioned above follow approximately the same scheme,
varying the initial period for starting breast screening tests and other associated
neoplasms.
Understanding genetic syndromes and their genes are essential to identify
patients subject to more intense surveillance.
BRCA1 and BRCA2 gene mutations correspond to the majority of hereditary
breast cancers. Identifying the high-risk patient is essential through a complete fam-
ily history and adequate identification of the patients who must undergo genetic
counseling for subsequent genetic testing.
References
1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating

the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J
Cancer. 2019;144(8):1941–53.
2. Sung H, Ferlay J, Siegel RL, Laversanne M, et al. Global Cancer statistics 2020: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J
Clin. 2021;0:1–41.
3. INCA INdC-. Câncer de mama 2020. Available at: https://www.inca.gov.br/tipos-de-cancer/
cancer-de-mama.
4. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for

breast cancer in the world. Breast Cancer (Dove Med Press). 2019;11:151–64.
5. Tamimi RM, Spiegelman D, Smith-Warner SA, Wang M, Pazaris M, Willett WC, et al.
Population attributable risk of modifiable and nonmodifiable breast cancer risk factors in post-
menopausal breast cancer. Am J Epidemiol. 2016;184(12):884–93.
6. DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin.
2014;64(1):52–62.
7. UK CR. Breast cancer risk Internet 2020. Available at: https://www.cancerresearchuk.
org/health-professional/cancerstatistics/statistics-by-cancer-type/breast-cancer/
incidence-invasive#heading-One.
8. Smart CR, Hendrick RE, Rutledge JH, Smith RA. Benefit of mammography screening in
women ages 40 to 49 years. Current evidence from randomized controlled trials. Cancer.
1995;75(7):1619–26.
9. Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman
ME. Etiology of hormone receptor-defined breast cancer: a systematic review of the literature.
Cancer Epidemiol Biomark Prev. 2004;13(10):1558–68.
10. Thakur P, Seam RK, Gupta MK, Gupta M, Sharma M, Fotedar V. Breast cancer risk fac-
tor evaluation in a Western Himalayan state: a case-control study and comparison with the
Western World. South Asian J Cancer. 2017;6(3):106–9.
11. Huo D, Adebamowo CA, Ogundiran TO, Akang EE, Campbell O, Adenipekun A, et al.
Parity and breastfeeding are protective against breast cancer in Nigerian women. Br J Cancer.
2008;98(5):992–6.
12. Ma H, Bernstein L, Pike MC, Ursin G. Reproductive factors and breast cancer risk according
to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies.
Breast Cancer Res. 2006;8(4):R43.
13. Aleitamento Materno MdO. 2006. Available at: https://www.febrasgo.org.br/images/arquivos/
manuais/Manuais_Novos/aleitamento_.pdf.
14. Cancer CGoHFiB. Breast cancer and breastfeeding: collaborative reanalysis of individual data
from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer
and 96973 women without the disease. Lancet. 2002;360(9328):187–95.
15. Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research
expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspec-
tive. Proc Nutr Soc. 2008;67(3):253–6.
16. Marchbanks PA, Curtis KM, Mandel MG, Wilson HG, Jeng G, Folger SG, et al. Oral contra-
ceptive formulation and risk of breast cancer. Contraception. 2012;85(4):342–50.
17. Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary
hormonal contraception and the risk of breast cancer. N Engl J Med. 2017;377(23):2228–39.
18. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks
and benefits of estrogen plus progestin in healthy postmenopausal women: principal results
from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–33.
19. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects
of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's
Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–12.
20. Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL,
et al. Menopausal hormone therapy and health outcomes during the intervention and
extended poststopping phases of the Women's Health Initiative randomized trials.
JAMA. 2013;310(13):1353–68.
21. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone
replacement therapy: collaborative reanalysis of data from 51 epidemiological studies
of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet.
1997;350(9084):1047–59.
22. Kabat GC, Kim MY, Lee JS, Ho GY, Going SB, Beebe-Dimmer J, et al. Metabolic obesity
phenotypes and risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomark
Prev. 2017;26(12):1730–5.
23. Park SY, Kolonel LN, Lim U, White KK, Henderson BE, Wilkens LR. Alcohol consumption
and breast cancer risk among women from five ethnic groups with light to moderate intakes:
the Multiethnic Cohort Study. Int J Cancer. 2014;134(6):1504–10.
24. Bjerkaas E, Parajuli R, Weiderpass E, Engeland A, Maskarinec G, Selmer R, et al. Smoking
duration before first childbirth: an emerging risk factor for breast cancer? Results from 302,865
Norwegian women. Cancer Causes Control. 2013;24(7):1347–56.
25. Bloom JR, Stewart SL, Hancock SL. Breast cancer screening in women surviving Hodgkin
disease. Am J Clin Oncol. 2006;29(3):258–66.
26. Wolden SL, Hancock SL, Carlson RW, Goffinet DR, Jeffrey SS, Hoppe RT. Management of
breast cancer after Hodgkin's disease. J Clin Oncol. 2000;18(4):765–72.
27. Cutuli B, Borel C, Dhermain F, Magrini SM, Wasserman TH, Bogart JA, et al. Breast can-
cer occurred after treatment for Hodgkin's disease: analysis of 133 cases. Radiother Oncol.
2001;59(3):247–55.
28. Board WCoTE. Breast Tumours. Lyon: International Agency for Research on Cancer; 2019.
29. Hartmann LC, Degnim AC, Santen RJ, Dupont WD, Ghosh K. Atypical hyperplasia of the
breast--risk assessment and management options. N Engl J Med. 2015;372(1):78–89.
30. Said SM, Visscher DW, Nassar A, Frank RD, Vierkant RA, Frost MH, et al. Flat epithelial
atypia and risk of breast cancer: a Mayo cohort study. Cancer. 2015;121(10):1548–55.
31. To T, Wall C, Baines CJ, Miller AB. Is carcinoma in situ a precursor lesion of invasive breast
cancer? Int J Cancer. 2014;135(7):1646–52.
32. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the
BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet. 1998;62:676–89.
33. Female breast cancer — cancer stat facts. Available at: https://seer.cancer.gov/statfacts/html/
breast.html. Accessed on 30/09/2020.
34. Genetics of Breast and Gynecologic Cancers (PDQ®)–Health professional version https://
www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq.
35. Lynch HT, Watson P, Lynch JF. Epidemiology and risk factors. Clin Obstet Gynecol.
1989;32(4):750–60.
36. Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, et al. Very high risk of cancer in
familial Peutz–Jeghers syndrome. Gastroenterology. 2000;119(6):1447–53.
37. Tan MH, Mester JL, Ngeow J, Rybicki LA, et al. Lifetime cancer risks in individuals with
Germline PTEN mutations. Clin Cancer Res. 2012;18(2):400–7.
38. De GrèveJ, Sermijn E, Brakeleer SD, et al. Hereditary breast cancer from bench to bedside.
Curr Opin Oncol. 2008;20:605–13.
39. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral
breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–16.
40. BRCA mutations: cancer risk and genetic testing fact sheet. Available at: https://www.cancer.
gov/about-cancer/causesprevention/genetics/brca-fact-sheet. Accessed on 30/09/2020.
41. Scalia-Wilbur J, Colins BL, Penson RT, Dizon DS. Breast cancer risk assessment: moving
beyond BRCA 1 and 2. Semin Radiat Oncol. 2016;26(1):3–8.
42. NCCN Guidelines. Available at: https://www.nccn.org/professionals/physician_gls/pdf/genet-
ics_bop.pdf. Accessed on 30/09/2020.
Chapter 3
Genomic Tests
3.1 Introduction
Localized hormonal receptor (HR)-positive breast cancer has a broad spectrum of

disease behavior, influenced by numerous factors. Clinical and pathological fea-
tures have a substantial impact on prognosis. For patients with a high risk of
recurrence, intensification of treatment using neoadjuvant or adjuvant chemother-
apy (CT) is usually recommended. Age, menopausal status, tumor size, lymph
node status, tumor grade, angiolymphatic invasion, and expression of hormone
receptor and HER2 are some of the factors influencing the risk of recurrence.
However, these factors alone do not provide a precise estimation of prognosis. On
the other hand, the indiscriminate use of chemotherapy is not appropriate since it
is associated with potentially severe adverse events, and many patients would be
cured without CT.
In this context, gene expression assays to assess patients’ prognosis were devel-
oped. These tests evaluate genes related to tumor proliferation, invasion, angiogen-
esis, and oncogenic pathways. The most widely used tests provide information on
recurrence risk based on the gene expression profile from tumor tissue, using micro-
array and reverse transcription polymerase chain reaction (RT-PCR) that assess
mRNA expression. The assays available differ from one other in terms of number of
genes evaluated, population in which the test was validated, number of risk catego-
ries provided, and validation as a predictor of chemotherapy benefit, as will be dis-
cussed ahead.
L. Testa (*) · R. C. Bonadio

Departamento de Oncologia, Instituto do Cancer do Estado de Sao Paulo ICESP,

Switzerland AG 2022
32 L. Testa and R. C. Bonadio
3.2 Gene Expression Assays
3.2.1 Oncotype DX
The Oncotype DX assay evaluates 21 genes (16 tumor associated and five controls)
and provides a recurrence score (RS) that ranges from 0 to 100. Depending on the
RS, patients are classified as low risk, intermediate risk, or high risk. Oncotype DX
was validated as a prognostication tool for estrogen receptor (ER)-positive early
breast cancer in various trials [1–4].
Among patients with node-negative ER-positive breast cancer enrolled in the
NSABP B-14 trial, recurrence scores (RS) of <18, 18–30, and ≥31 were associated
with 10-year distant recurrence rates of 6.8%, 14.3%, and 30.5%, respectively [1]. A
study with the population of another trial, the NSABP B-20, suggested that patients
in the low-risk category (RS < 18) derived no benefit from the addition of adjuvant
chemotherapy, while those with high risk (RS ≥ 31) had a significant reduction in
distant recurrence with chemotherapy. Finally, for patients in the intermediate-risk
category (RS 18–30), benefit from chemotherapy was uncertain [2].
The cutoff values for risk categories were refined in subsequent studies, and the
ability of Oncotype DX to predict chemotherapy benefit was evaluated prospec-
tively. The TAILORx trial enrolled patients with node-negative HR-positive breast
cancer, tailoring adjuvant systemic therapy according to RS. Patients with an RS
lower than 11 (low risk) were treated with endocrine therapy alone. Those with RS
greater than 25 (high risk) received chemotherapy plus endocrine therapy. Finally,
patients in the intermediate-risk category (RS 11–25) were randomized to receive
endocrine therapy alone or chemotherapy plus endocrine therapy. Results showed
similar outcomes from endocrine therapy and chemoendocrine therapy for patients
in the intermediate group [5]. The study confirmed that Oncotype DX can be used
to predict chemotherapy benefit.
Further analysis of the TAILORx trial suggested a different test behavior for
women younger than 50 years. For those in the intermediate-risk group, patients
with an RS of 16–25 seemed to benefit from chemoendocrine therapy. The absolute
distant recurrence rate decreased 1.6% for RS 16–20 and 6.4% for RS 21–25 at
9 years with the addition of chemotherapy. A question that remains is if this differ-
ence observed in younger women is due to the effect of chemotherapy itself or the
induction of menopause caused by it.
The RxPONDER trial evaluated the role of Oncotype DX for predicting che-
motherapy benefit for patients with one to three positive lymph nodes. Patients
with an RS ≤25 were assigned to receive either endocrine therapy or endocrine
therapy plus standard chemotherapy. No benefit was seen for chemotherapy in
postmenopausal women, but premenopausal women again had a different out-
come. Five-year invasive disease-free survival rates were 91.9% for endocrine
therapy plus chemotherapy vs 91.6% for endocrine therapy alone in the post-
menopausal patient subset and 94.2% vs 89.0% in the premenopausal patient
3 Genomic Tests 33
subset [6]. The question remains as to whether this is a direct benefit of chemo-
therapy or an indirect effect of ovarian suppression.
3.2.2 MammaPrint
The MammaPrint assay classifies HR-positive early breast cancer patients into two
categories, low risk and high risk, based on the evaluation of 70 genes. Retrospective
and prospective studies have validated MammaPrint as a prognostic tool for breast
cancer recurrence [7–9].
In the MINDACT trial, genomic risk based on MammaPrint was used together
with clinical risk to define the use of adjuvant chemotherapy for patients with
HR-positive breast cancer with negative lymph nodes or one to three positive lymph
nodes. The clinical risk was defined using Adjuvant! Online, a web-based tool that
provides recurrence risk according to clinical and pathological features [10].
Patients with low clinical and genomic risk received endocrine therapy alone, while
patients with high clinical and genomic risk received chemoendocrine therapy. The
cohort of patients with discordant results (low clinical risk and high genomic risk,
or high clinical risk and low genomic risk) were randomized to receive adjuvant
chemotherapy or not. The trial aimed to evaluate if patients with high clinical risk
and low genomic risk could be spared chemotherapy. Results showed that 5-year
distant metastasis-free survival (DMFS) rate was 94.7% (95% confidence interval
92.5–96.2%), which was considered satisfactory when compared with the noninfe-
riority boundary of 92% established by the study. Additionally, in this group, the
5-year distant metastasis rate of survival (DMRS) was similar in patients with che-
motherapy and without chemotherapy. The study suggested that MammaPrint can
be used for patients with high clinical risk to select patients for whom chemotherapy
can be avoided, although the trial was not powered for this comparison (yes versus
no chemotherapy) [11].
Similar to what was observed with both randomized Oncotype DX trials, sub-
group analysis of MINDACT suggested that for women younger than 50 years with
high clinical risk and low genomic risk, a relevant absolute difference of 5% in
8-year DMFS was observed with the addition of chemotherapy [12]. Thus, for
women younger than 50 years, additional studies are necessary to clarify the role of
genomic assays for predicting chemotherapy benefit.
3.2.3 Other Assays
EndoPredict assay analyzes 12 genes (eight cancer-related genes and four reference
genes), providing a risk score ranging from 0 to 15. The test also classifies patients
into low- and high-risk groups. Moreover, an EndoPredict clinical score is
generated by incorporating clinical factors (tumor size and nodal status).

EndoPredict’s prognostic value was validated in prospective-retrospective cohorts
of ER-positive patients with negative or positive lymph nodes [13–15].
Prosigna assay (or PAM50) uses 50 genes (plus eight reference genes) and
distinguished breast cancer molecular subtypes (luminal A, luminal B, HER2
enriched, normal-like, and basal-like), which correlate with disease behavior.
Moreover, a risk of recurrence (ROR) score is also provided by this test, ranging
from 0 to 100. Validation of its prognostic impact occurred in prospective-retro-
spective trials of postmenopausal ER-positive patients, containing both lymph
node-negative and positive cohorts [16–18]. Three risk group categories are pro-
vided for node-negative patients: low risk (ROR 0–40), intermediate risk (ROR
41–60), and high risk (ROR 61–100). For node-positive patients, only two cate-
gories are considered: low risk (ROR 0–40) or high risk (41–100). Prosigna’s
ability to predict late recurrences after adjuvant endocrine therapy has also been
shown [19].
The Breast Cancer Index (BCI) assay evaluates seven cancer-related genes plus
four reference genes, together with two other biomarkers (HOX-B13:IL17BR ratio
and Molecular Grade Index). Similar to Prosigna, BCI has been shown to predict
early and late recurrences in ER-positive lymph node-negative patients who received
adjuvant endocrine therapy in prospective-retrospective trials [20–23]. These results
generate the hypothesis that these tests (Prosigna and BCI) might help select patients
for extended endocrine therapy.
3.3 Concordance of Expression Assays
Although genomic tests available have similar objectives, they differ in terms of
genes evaluated and population in which the tests were validated. Importantly, dis-
cordances have been demonstrated among the tests. For instance, Barlett et al.
showed that in a cohort of patients with early breast cancer, the proportion consid-
ered as low/intermediate risk was 82.1%, 65.6%, and 61.4% with Oncotype DX,
Prosigna, and MammaPrint, respectively [24]. In another study, the concordance
between Oncotype DX and MammaPrint was only 0.64 [25].
These results are similar to what was observed in a review that summarized head-
to-head comparisons of Oncotype DX with other genomic tests. In this review, a
high-risk score was observed: 11.5% with Oncotype DX, 16.2% with BCI, 30.7%
with ROR (Prosigna), 63% with EndoPredict, and 45.8% with MammaPrint. Overall
discordance between Oncotype DX and other tests ranged from 42% to 66% [26].
Thus, genomic tests for recurrence risk are not interchangeable, and careful selec-
tion of the appropriate test for a patient is necessary. A summary of these tests’
characteristics is shown in Table 3.1.
3 Genomic Tests 35
Table 3.1 Summary of the characteristics of genomic tests for breast cancer recurrence risk
Type of
Number Risk Population Current validation
of genes categories evaluated validation studies
Oncotype DX 21 Low ER+/HER2- Prognostic Prospective-
Intermediate pT1-2 Predictive of retrospective
High pN0-1 chemotherapy [1–4]
benefit Prospective
randomized [5,
6]
MammaPrint 70 Low pT1-2 Prognostic Prospective-
High pN0-1 Predictive of retrospective
chemotherapy [7–9]
benefit Prospective
randomized [11]
EndoPredict 12 Low ER+/HER2- Prognostic Prospective-
High pT1-2 retrospective
pN0-1 [13–15]
Postmenopausal
Prosigna 58 Low ER+ Prognostic Prospective-
(PAM50) Intermediate pT1-2 retrospective
High pN0-1 [16–18]
Postmenopausal
Breast Cancer 11 Low ER+/HER2- Prognostic Prospective-
Index High pT1-3 retrospective
pN0 [20–23]
3.4 Conclusion
Genomic tests are adding valuable information on recurrence risk for ER/PR-positive
early breast cancer. Their use to estimate prognosis and predict the benefit of adju-
vant therapy has been increasing in clinical practice [27]. Nevertheless, some chal-
lenges still need to be faced.
Despite the number of tests available, they were validated in different scenarios
and are not totally concordant with one other. Carefulness is necessary for the
appropriate test selection for a patient. More prospective validation is still required
for some groups, such as premenopausal women and patients with positive lymph
nodes. Moreover, tests’ costs remain a barrier for wider access to these tests.
References
1. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recur-
rence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817–26.
2. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene expression and benefit of chemo-
therapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol.
2006;24(23):3726–34.
3. Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J, et al. Prediction of risk of distant
recurrence using the 21-gene recurrence score in node-negative and node-positive postmeno-
pausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.
J Clin Oncol. 2010;28(11):1829–34.
4. Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, et al. Prognostic and
predictive value of the 21-gene recurrence score assay in postmenopausal women with node-
positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis
of a randomised trial. Lancet Oncol. 2010;11(1):55–65.
5. Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Láng I, et al. Tailoring adjuvant
endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122–37.
6. Kalinsky K, Barlow W, Meric-Bernstam F, et al.. SWOG S1007: adjuvant trial randomized
ER+ patients who had a recurrence score < 25 and 1–3 positive nodes to endocrine therapy
(ET) versus ET + chemotherapy. Presented at: 2020 virtual San Antonio breast cancer sympo-
sium; December 8–11, 2020. Abstract GS3-00.
7. van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression
signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999–2009.
8. Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, Glas AM, et al. Validation and clinical
utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl
Cancer Inst. 2006;98(17):1183–92.
9. Bueno-de-Mesquita JM, van Harten WH, Retel VP, van't Veer LJ, van Dam FS, Karsenberg
K, et al. Use of 70-gene signature to predict prognosis of patients with node-negative
breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol.
2007;8(12):1079–87.
10. Olivotto IA, Bajdik CD, Ravdin PM, Speers CH, Coldman AJ, Norris BD, et al. Population-
based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol.
2005;23(12):2716–25.
11. Cardoso F, van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-gene signature as
an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717–29.
12. Cardoso F, van't Veer L, Poncet C, et al. MINDACT: long-term results of the large prospec-
tive trial testing the 70-gene signature MammaPrint as guidance for adjuvant chemotherapy in
breast cancer patients. J Clin Oncol. 2020;38(suppl; abstr):506.
13. Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, et al. A new molecular predictor
of distant recurrence in ER-positive, HER2-negative breast cancer adds independent informa-
tion to conventional clinical risk factors. Clin Cancer Res. 2011;17(18):6012–20.
14. Dubsky P, Filipits M, Jakesz R, Rudas M, Singer CF, Greil R, et al. EndoPredict improves
the prognostic classification derived from common clinical guidelines in ER-positive, HER2-
negative early breast cancer. Ann Oncol. 2013;24(3):640–7.
15. Martin M, Brase JC, Calvo L, Krappmann K, Ruiz-Borrego M, Fisch K, et al. Clinical valida-
tion of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2- breast cancer
patients: results from the GEICAM 9906 trial. Breast Cancer Res. 2014;16(2):R38.
16. Dowsett M, Sestak I, Lopez-Knowles E, Sidhu K, Dunbier AK, Cowens JW, et al. Comparison
of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant
recurrence after endocrine therapy. J Clin Oncol. 2013;31(22):2783–90.
17. Gnant M, Filipits M, Greil R, Stoeger H, Rudas M, Bago-Horvath Z, et al. Predicting distant
recurrence in receptor-positive breast cancer patients with limited clinicopathological risk:
using the PAM50 risk of recurrence score in 1478 postmenopausal patients of the ABCSG-8
trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2014;25(2):339–45.
18. Liu S, Chapman JA, Burnell MJ, Levine MN, Pritchard KI, Whelan TJ, et al. Prognostic and
predictive investigation of PAM50 intrinsic subtypes in the NCIC CTG MA.21 phase III che-
motherapy trial. Breast Cancer Res Treat. 2015;149(2):439–48.
19. Sestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, et al. Prediction of
late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients
from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone
3 Genomic Tests 37
or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol.
2015;33(8):916–22.
20. Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, et al. Prediction of late
distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective
comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the
TransATAC study population. Lancet Oncol. 2013;14(11):1067–76.
21. Sgroi DC, Carney E, Zarrella E, Steffel L, Binns SN, Finkelstein DM, et al. Prediction of
late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR bio-
marker. J Natl Cancer Inst. 2013;105(14):1036–42.
22. Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, et al. Breast
cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for
early- and late-distant recurrence. Clin Cancer Res. 2013;19(15):4196–205.
23. Sanft T, Aktas B, Schroeder B, Bossuyt V, DiGiovanna M, Abu-Khalaf M, et al. Prospective
assessment of the decision-making impact of the breast cancer index in recommending
extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer.
Breast Cancer Res Treat. 2015;154(3):533–41.
24. Bartlett JM, Bayani J, Marshall A, Dunn JA, Campbell A, Cunningham C, et al. Comparing
breast cancer multiparameter tests in the OPTIMA prelim trial: no test is more equal than the
others. J Natl Cancer Inst. 2016;108(9):djw050.
25. Denduluri N, Rugo H, Davis S, et al. Concordance between the 21-gene recurrence score
(RS) and the 70-gene profile (MP) in breast cancer (BC) patients (pts). J Clin Oncol.
2011;27_suppl:13.
26. Varga Z, Sinn P, Seidman AD. Summary of head-to-head comparisons of patient risk clas-
sifications by the 21-gene Recurrence Score® (RS) assay and other genomic assays for early
breast cancer. Int J Cancer. 2019;145(4):882–93.
27. Duffy MJ, Harbeck N, Nap M, Molina R, Nicolini A, Senkus E, et al. Clinical use of biomark-
ers in breast cancer: updated guidelines from the European Group on Tumor Markers (EGTM).
Eur J Cancer. 2017;75:284–98.
Chapter 4
Updates in Surgical Approaches for Breast
and Axilla
Bruna Salani Mota, Rodrigo Goncalves, and Jose Roberto Filassi
4.1 Introduction
Axillary surgery provides valuable staging information to guide the adjuvant treat-
ment of breast cancer and is key to the local control of axillary disease, being a
well-established procedure for the management of primary breast cancer.
However, the surgical management of the axilla has changed substantially in the
last three decades, from the axillary lymph node dissection (ALND), which has a
high morbidity and decreases the women’s quality of life, to a sentinel lymph node
biopsy for most patients.
This radical change in the surgical approach started in 1970; the Mayo Clinic
published strong evidence for the axillary nodal metastases predictive values. All
patients had undergone ALND, and the data showed 5-year survival rates of 86% in
node-negative patients compared to 50% in node-positive patients. After that, the
value of axillary clearance for all breast cancer surgery became questionable since
it did not influence the survival rates and increased the chances of lymphedema [1].
In 1994, Giuliano et al. [2], after the successful use of sentinel lymph node
biopsy (SLNB) for melanoma staging [3], published the first description of SLNB
for breast cancer treatment, with the potential of axillary staging with less morbid-
ity. Since then, its use has been widely accepted as the single axillary surgical pro-
cedure among all clinically node-negative (cN0) breast cancer patients and selected
patients with low-volume axillary metastases. Those results significantly impacted
breast cancer surgery management since it avoids as much as 70% of all complete
axillary node dissections.
B. S. Mota · R. Goncalves (*) · J. R. Filassi

e-mail: [email protected]; [email protected]

Switzerland AG 2022
40 B. S. Mota et al.
We will discuss in this chapter the surgical management of the axilla according
to the axillary stage: N (0), micrometastases (N1mic) or isolated tumor cells, clini-
cally N0 with macrometastases in the pathological exam, and clinically positive
axilla patients. This approach aims to facilitate the understanding of axillary treat-
ment in different scenarios.
4.2 xillary Management in Clinically Node-Negative

A
Patients with Invasive Breast Cancer
The effectiveness of SLNB in clinically N0 breast cancer patients has been proven
throughout the years with the publication of a comprehensive study assortment.
These trials all have demonstrated low rates of axillary recurrences (0.2–0.5%) [4–
7] when SLNB was compared to ALND (0–0.8%) in patients with a negative SLNB
who had no further surgery.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial is
the most extensive study, with 5611 participants, to compare survival and regional
control between SLNB alone and axillary lymph node dissection (ALND) in clini-
cally node-negative patients. Patients were assigned to SLNB plus ALND or SLNB
alone with ALND only if the sentinel node(s) was positive [5]. The latest report, in
2010, showed no difference in overall and disease-free survival between the two
groups with a median follow-up of 8 years. Axillary recurrence as a first disease
relapse event occurred in less than 1% of both the SLNB followed by ALND group
(0.4%) and the SLNB-only group (0.6%), p = 0.22 [8].
In 2017, a meta-analysis from the Cochrane database, including seven clinical
trials, compared ALND versus SLNB. There was no difference in overall survival in
the comparison between SLNB and ALND (HR 1.05, 95% CI 0.89 to 1.25; 6352
participants; three studies; moderate-quality evidence) [9].
4.3 xillary Management in Micrometastases (N1m1) or

A
Isolated Tumor Cells N (+1) Patients with Invasive
Breast Cancer
The pathology review of nodal specimens of SLNB negative patients in the NSABP
B-32 trial presented the question about the role of ALND in the axillary treatment
in micrometastases (N1m1) or isolated tumor cells N (+1) (ITC) patients. The abso-
lute reduction in overall survival in those patients with ITC or micrometastases was
only 1.2% in patients submitted to ALND in that trial [5].
The ACOSOG Z0010 trial confirmed that women with a low volume of nodal
metastases who underwent an SLNB plus ALND did not have significant benefit
in overall or disease-free survival over patients undergoing SLNB alone in this
4 Updates in Surgical Approaches for Breast and Axilla 41
multicentric prognostic study, which had 10.5% rates of occult sentinel node
metastases [10].
The International Breast Cancer Study Group (IBCSG) 23-01 trial answered the
question regarding the role of axillary surgery in breast cancer patients with N1mic
definitively. In this trial, clinically node-negative patients with an SLNB containing
micrometastases were randomized to ALND or no further axillary surgery. Thirteen
percent of patients who had an ALND presented additional involved axillary nodes.
However, 5-year disease-free survival did not significantly differ in the SLNB-alone
(87.8%) vs. the ALND (84.4%) group. In patients who did not undergo ALND, the
rate of disease recurrence was less than 1% [11].
4.4 xillary Management in Clinically Node-Negative

A
Patients and Macrometastases in the Pathology
with Invasive Breast Cancer
In the past, the standard of care for patients who had positive sentinel lymph nodes
with macrometastases (tumor deposits of more than 2.0 mm) was ALND to achieve
local control. However, with the increasing use and efficacy of adjuvant chemo-
therapy, hormonal therapy, and radiation, the scientific community started question-
ing the real importance of ALND in providing regional control.
The American College of Surgeons Oncology Group Z0011 trial recruited
patients with clinically T1 to T2, node-negative breast cancer selected to undergo
breast-conserving surgery and SLNB. All patients who had a positive SLNB by
routine H&E staining were randomized to ALND completion or no ALND and no
further axillary specific radiotherapy. Any patient with three or more positive senti-
nel nodes was excluded. Accrual to the study and event rates were lower than
expected, resulting in the trial’s early closure. All patients received whole-breast
irradiation, and almost all received adjuvant systemic therapy (58% chemotherapy,
46% hormonal therapy). Forty-one percent of the study patients had small volume
metastases (micrometastases or ITCs). In the cohort who did undergo an ALND,
additional positive axillary nodes were found in 27% of cases. At a median follow-
up of 6 years, there were no differences between the SLNB followed by ALND and
SLNB groups in the rates of overall locoregional recurrence (4.1% vs. 2.8%), breast
recurrence (3.6% vs. 1.9%), and axillary recurrence (0.5% vs. 0.9). The 10-year
follow-up publication confirmed the low rate of axillary recurrence of <2% in both
groups, denying any concerns that a spate of late axillary recurrences may be seen
with the SLNB-only group [12]. The trial’s major weakness focused on the design
of the radiotherapy fields; the tangential field whole-breast irradiation with high
tangents used in both groups resulted in a portion of the axilla receiving radiation in
patients on both arms of the study. However, trying to evaluate the radiotherapy as
a confounder, further statistical analysis did not show a significant difference
between treatment arms in the use of protocol-prohibited nodal fields [13].
The National Comprehensive Cancer Network (NCCN) guidelines adopted the

surgical strategy evaluated in the ACOSOG Z011 to avoid the ALND in the setting
of two or fewer metastatic lymph nodes on SLNB in patients with 5 cm or less
tumors who have no clinically suspicious axillary lymph nodes and who are under-
going breast-conserving surgery and subsequent whole-breast irradiation and sys-
temic therapy [14].
To investigate the same strategy of de-escalation of surgical treatment of the
axilla, the European Organization for Research and Treatment of Cancer (EORTC)
conducted and published the data from the AMAROS trial. This clinical trial
enrolled 1400 patients with T1-T2 tumors and with positive SLN that were random-
ized to ALND versus axillary radiation [15]. Approximately 82% of the 1425
patients with a positive SLNB underwent breast-conserving surgery. In both arms,
60% of the sentinel node metastases were macrometastases. There was no differ-
ence in the 10-year axillary recurrence, overall survival (OS), and disease-free sur-
vival (DFS) rates. The axillary recurrence rates were 1.82% (11 of 681) in patients
assigned to axillary radiotherapy versus 0.93% (seven of 744 patients) in those
assigned to ALND. The OS rates were 81.4% and 84.6% and DFS rates were 78.2%
and 81.7%, respectively [16].
There were a significant decrease in lymphedema with radiation and a nonsig-
nificant trend toward decreased shoulder mobility.
4.5 xillary Management in Clinically Node-Positive Patients

A
and Neoadjuvant Chemotherapy (NAC) Treatment
According to the American Joint Committee on Cancer, clinical examination or

imaging studies can identify positive axillary nodes. The core issue is detecting axil-
lary disease in patients who are candidates directly to ALND without SLNB or
planning to begin the treatment with neoadjuvant chemotherapy with a prospect of
axillary downstaging [17].
The axillary downstaging (pathological complete response (pCR)) rate after neo-
adjuvant treatment is 37% in the NSABP B-18. The highest pCR rates (97%) are in
patients with amplified HER2 disease, followed by estrogen receptor (ER)+/HER2+
with 70%, 47% in triple-negative and ER+ with 21% of pathological complete
response rates [18].
Based on this, an accurate axillary evaluation is essential to make the best clini-
cal decision. The NCCN recommends an axillary image with ultrasound (US) fol-
lowed by fine needle aspiration (FNA) or core biopsy of any suspicious nodes in
patients who would undergo neoadjuvant chemotherapy regardless of clinical axil-
lary status [14]. The clinical examination has a sensitivity of 8.3%, a specificity of
94.8%, and a negative predictive value (NPV) of 46.6%. The ultrasound alone
revealed a sensitivity of 23.9%, a specificity of 91.7%, and an NPV of 50.3%. The

association of both approaches (palpation and ultrasound) resulted in a sensitivity of
24.4%, a specificity of 91.4%, and an NPV of 50.3% [19].
Several clinical trials investigated the feasibility and accuracy of SLNB after
NAC for axillary staging in initially clinically node-negative breast cancer patients.
In 2016, a meta-analysis including 16 studies with 1456 patients showed an identi-
fication rate for SLNB of 96%, and the false-negative rate (FNR) was 6%. The nega-
tive predictive value (NPV) and accuracy were 94% and 98%, respectively [20].
Those values confirmed that SLNB is technically possible for axillary evaluation in
clinically node-negative breast cancer patients after NAC.
The SLNB in clinically node-positive disease at presentation has identification
rates ranging from 78% to 98% and false-negative rates as high as 40% in the initial
studies [21–24]. Therefore, the enthusiasm for exploring SLNB surgery after NAC
as a less aggressive alternative than ALND for those patients converted to clinically
node-negative has lead to essential publications in this field. The accuracy of SLNB
after neoadjuvant chemotherapy in clinically node-positive patients has been evalu-
ated in three prospective trials [25]. The American College of Surgeons Oncology
Group (ACOSOG) Z1071 trial reported a false-negative rate (FNR) of 12.6% for
SLND in patients with cN1 disease who had at least two sentinel lymph nodes
removed. A reduction in the false-negative rate was evident as the number of senti-
nel nodes removed increased: 31%, one node, and 21%, two nodes, dropping to a
clinically acceptable 9% only when three or more nodes were removed [26].The
mapping technique was the only factor found to impact SLN identification. The
SLN identification rate was 78.6% with blue dye alone, 91.4% with radiolabeled
colloid, and 93.8% with dual mapping agents. The patient features (age, body mass
index), clinical tumor characteristics, pathologic nodal response, and site of tracer
injection did not affect the SLN identification rate [25].
The European SENTinel NeoAdjuvant (SENTINA) trial and the Canadian
Sentinel Node Biopsy Following Neoadjuvant Chemotherapy (SN FNAC) trial sup-
ported these findings with slight differences between them [27, 28]. The dual-tracer
(blue dye and radioisotope) technique and removal of >2 SLNs were shown to lower
the FNR in all three trials. In the SENTINA trial, the sentinel node detection rate
was 80%, with a false-negative rate of 14%; it varied according to the number of
sentinel nodes removed: 24%, one node; 18%, two nodes; and less than 8% when
three or more nodes were removed [27]. The SN FNAC trial showed quite similar
false-negative rates, 18% with one node and 5% with two or more nodes.
The applicability of SLNB in treating clinically node-positive patients who
revert to clinically node-negative after neoadjuvant chemotherapy depends on the
dual-modality mapping with both blue dye and radiocolloid followed by removal of
three sentinel nodes to try to reduce the false-negative rates [26–28]. Added atten-
tion to avoid the false-negative rates is to use the clip to mark the metastatic axillary
node(s) guided by ultrasound before neoadjuvant therapy. This procedure ensures
that the positive node will be removed during the surgery, confirming the treatment
response. Caudle et al., in 2017, conducted a prospective study, including 208 par-
ticipants, using iodine-125 seed localization. The marked node was not recovered as
an SLN in 23% (31 of 134) of patients, including six with negative SLNs but metas-
tasis in the clipped node. A total of 120 patients still had residual disease; from
those, the clipped node showed metastases in 115 patients, resulting in a false-
negative rate of 4.2% [29].
The routine use of SLNB using iodine-125 seed localization has not been estab-
lished yet since there is an increase in treatment costs and questions regarding the
technique due to the need of specialized breast radiologists, notably experienced in
targeting techniques [29]. Otherwise, the trials published regarding this theme sup-
port the management of SLND with blue dye and radiocolloid with acceptable
false-negative rates.
Although there are increasing efforts to avoid the ALND in patients identified as
node-positive before systemic treatment that converted to negative after NAC, there
are still almost 40% of patients who have residual axillary disease and need ALND
following standard adjuvant treatment. The ALND is still the standard treatment in
this setting; there is no scientific data to support radiotherapy as a unique treatment
for this group of patients. The updated analysis of NSABP B-18 and B-27 neoadju-
vant trials showed high rates of locoregional recurrence (LRR) observed in patients
with pathologically positive nodes at surgery. The 10-year cumulative incidence of
LRR was 12.3% for mastectomy patients and 10.3% for lumpectomy plus breast
radiotherapy patients. The independent predictors of LRR in lumpectomy patients
were age, clinical nodal status (before NAC), and pathologic nodal status/breast
tumor response. In mastectomy patients, predictors of LRR were clinical tumor size
(before NAC), clinical nodal status (before NAC), and pathologic nodal status/
breast tumor response. The risk of LRR was increased by 2.71 times if residual axil-
lary disease was present [30].
The Alliance A11202 study is a randomized clinical trial that evaluates the role
of axillary radiotherapy (axilla, supraclavicular nodes, and internal mammary
nodes) compared to ALND in patients who remain node-positive after NAC irre-
spective of the breast surgery type. The main outcome of this trial is recurrence-free
survival rate in a non-inferiority design.
We will still observe extraordinary advances and practice changes in axilla man-
agement for the next decades due to preoperative image improvement and profile
signatures. There are two exciting trials in the recruitment phase: the SOUND trial
[31] and the SWOG RxPONDER trial [32]. In the first one, the research question is
based on patients with a low burden of axillary disease, with a hypothesis that the
results of SLNB are unlikely to alter adjuvant treatment decisions. Regarding this,
the patients will be randomized to perform SLNB versus ultrasound only. The sec-
ond protocol, SWOG RxPONDER trial, will assess gene expression profiling’s abil-
ity in the setting of lymph node positivity to identify patients with excellent predicted
long-term survival with adjuvant hormonal treatment alone in which chemotherapy
would not confer any additional benefit.
References
1. Fisher B, Montague E, Redmond C, Barton B, Borland D, Fisher ER, et al. Comparison of rad-
ical mastectomy with alternative treatments for primary breast cancer. A first report of results
from a prospective randomized clinical trial. Cancer. 1977;39(6 Suppl):2827–39.
2. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymph-
adenectomy for breast cancer. Ann Surg. 1994;220(3):391–8. discussion 398–401.
3. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of
intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4):392–9.
4. Mansel RE, Fallowfield L, Kissin M, Goyal A, Newcombe RG, Dixon JM, et al. Randomized
multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast
cancer: the ALMANAC trial. J Natl Cancer Inst. 2006;98(9):599–609.
5. Krag DN, Julian TB, Harlow SP, Weaver DL, Ashikaga T, Bryant J, et al. NSABP-32: phase
III, randomized trial comparing axillary resection with sentinal lymph node dissection: a
description of the trial. Ann Surg Oncol. 2004;11(3 Suppl):208S–10S.
6. Zavagno G, De Salvo GL, Scalco G, Bozza F, Barutta L, Del Bianco P, et al. A randomized
clinical trial on sentinel lymph node biopsy versus axillary lymph node dissection in breast
cancer: results of the Sentinella/GIVOM trial. Ann Surg. 2008;247(2):207–13.
7. Veronesi U, Paganelli G, Viale G, Luini A, Zurrida S, Galimberti V, et al. A randomized com-
parison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med.
2003;349(6):546–53.
8. Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP, et al. Sentinel-
lymph-node resection compared with conventional axillary-lymph-node dissection in clini-
cally node-negative patients with breast cancer: overall survival findings from the NSABP
B-32 randomised phase 3 trial. Lancet Oncol. 2010;11(10):927–33.
9. Bromham N, Schmidt-Hansen M, Astin M, Hasler E, Reed MW. Axillary treatment for oper-
able primary breast cancer. Cochrane Database Syst Rev. 2017;1:CD004561.
10. Giuliano AE, Ballman K, McCall L, Beitsch P, Whitworth PW, Blumencranz P, et al.
Locoregional recurrence after sentinel lymph node dissection with or without axillary dissec-
tion in patients with sentinel lymph node metastases: long-term follow-up from the American
College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 randomized trial. Ann Surg.
2016;264(3):413–20.
11. Galimberti V, Cole BF, Viale G, Veronesi P, Vicini E, Intra M, et al. Abstract GS5-02: axillary
dissection vs. no axillary dissection in patients with cT1-T2cN0M0 breast cancer and only
micrometastases in the sentinel node(s): ten-year results of the IBCSG 23-01 trial. Cancer Res.
2018;78(4 Supplement):GS5-02-GS5-02.
12. Giuliano AE, Ballman KV, McCall L, Beitsch PD, Brennan MB, Kelemen PR, et al. Effect of
axillary dissection vs no axillary dissection on 10-year overall survival among women with
invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) random-
ized clinical trial. JAMA. 2017;318(10):918–26.
13. Haffty BG, McCall LM, Ballman KV, McLaughlin S, Jagsi R, Ollila DW, et al. Patterns of
local-regional management following neoadjuvant chemotherapy in breast cancer: results
from ACOSOG Z1071 (Alliance). Int J Radiat Oncol Biol Phys. 2016;94(3):493–502.
14. Gradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast cancer,
version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw.
2020;18(4):452–78.
15. Straver ME, Meijnen P, van Tienhoven G, van de Velde CJH, Mansel RE, Bogaerts J, et al.
Sentinel node identification rate and nodal involvement in the EORTC 10981-22023 AMAROS
trial. Ann Surg Oncol. 2010;17(7):1854–61.
16. Rutgers EJ, Donker M, Poncet C, Straver ME, Meijnen P, van de Velde CJ, et al. Abstract
GS4-01: radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer
patients: 10 year follow up results of the EORTC AMAROS trial (EORTC 10981/22023).
Cancer Res. 2019;79(4 Supplement):GS4-01-GS4-01.
17. Singletary SE, Connolly JL. Breast cancer staging: working with the sixth edition of the AJCC
Cancer staging manual. CA Cancer J Clin. 2006 Jan;56(1):37–47; quiz 50–1.
18. Mamtani A, Barrio AV, King TA, Van Zee KJ, Plitas G, Pilewskie M, et al. How often does
neoadjuvant chemotherapy avoid axillary dissection in patients with histologically confirmed
nodal metastases? Results of a prospective study. Ann Surg Oncol. 2016;23(11):3467–74.
19. Schwentner L, Helms G, Nekljudova V, Ataseven B, Bauerfeind I, Ditsch N, et al. Using ultra-
sound and palpation for predicting axillary lymph node status following neoadjuvant chemo-
therapy - results from the multi-center SENTINA trial. Breast. 2017;31:202–7.
20. Geng C, Chen X, Pan X, Li J. The feasibility and accuracy of sentinel lymph node biopsy in
initially clinically node-negative breast cancer after neoadjuvant chemotherapy: a systematic
review and meta-analysis. PLoS One. 2016;11(9):e0162605.
21. Lee S, Kim EY, Kang SH, Kim SW, Kim S-K, Kang KW, et al. Sentinel node identification
rate, but not accuracy, is significantly decreased after pre-operative chemotherapy in axillary
node-positive breast cancer patients. Breast Cancer Res Treat. 2007;102(3):283–8.
22. Shen J, Gilcrease MZ, Babiera GV, Ross MI, Meric-Bernstam F, Feig BW, et al. Feasibility
and accuracy of sentinel lymph node biopsy after preoperative chemotherapy in breast cancer
patients with documented axillary metastases. Cancer. 2007;109(7):1255–63.
23. Alvarado R, Yi M, Le-Petross H, Gilcrease M, Mittendorf EA, Bedrosian I, et al. The role for
sentinel lymph node dissection after neoadjuvant chemotherapy in patients who present with
node-positive breast cancer. Ann Surg Oncol. 2012;19(10):3177–84.
24. Newman EA, Sabel MS, Nees AV, Schott A, Diehl KM, Cimmino VM, et al. Sentinel lymph
node biopsy performed after neoadjuvant chemotherapy is accurate in patients with docu-
mented node-positive breast cancer at presentation. Ann Surg Oncol. 2007;14(10):2946–52.
25. Boughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, Wilke LG, Taback B, et al. Factors
affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast
cancer patients enrolled in ACOSOG Z1071 (Alliance). Ann Surg. 2015;261(3):547–52.
26. Boughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, Wilke LG, Taback B, et al. Sentinel
lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast can-
cer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310(14):1455–61.
27. Kuehn T, Bauerfeind I, Fehm T, Fleige B, Hausschild M, Helms G, et al. Sentinel-lymph-node
biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA):
a prospective, multicentre cohort study. Lancet Oncol. 2013;14(7):609–18.
28. Boileau J-F, Poirier B, Basik M, Holloway CMB, Gaboury L, Sideris L, et al. Sentinel node
biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN
FNAC study. J Clin Oncol. 2015;33(3):258–64.
29. Caudle AS, Yang WT, Krishnamurthy S, Mittendorf EA, Black DM, Gilcrease MZ, et al.
Improved axillary evaluation following neoadjuvant therapy for patients with node-positive
breast cancer using selective evaluation of clipped nodes: implementation of targeted axillary
dissection. J Clin Oncol. 2016;34(10):1072–8.
30. Mamounas EP, Anderson SJ, Dignam JJ, Bear HD, Julian TB, Geyer CE Jr, et al. Predictors
of locoregional recurrence after neoadjuvant chemotherapy: results from combined analy-
sis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol.
2012;30(32):3960–6.
31. Gentilini O, Veronesi U. Abandoning sentinel lymph node biopsy in early breast cancer? A
new trial in progress at the European Institute of Oncology of Milan (SOUND: sentinel node
vs observation after axillary UltraSouND). Breast. 2012;21(5):678–81.
32. Ramsey SD, Barlow WE, Gonzalez-Angulo AM, Tunis S, Baker L, Crowley J, et al. Integrating
comparative effectiveness design elements and endpoints into a phase III, randomized clini-
cal trial (SWOG S1007) evaluating oncotypeDX-guided management for women with breast
cancer involving lymph nodes. Contemp Clin Trials. 2013;34(1):1–9.
Chapter 5
Pathological Aspects for Diagnosis
Marcelo Abrantes Giannotti and Fernando Nalesso Aguiar
5.1 Pre-analytical Procedures
Fixation of biopsies and surgical specimens in neutral buffered 10% formalin must
be immediate, and an adequate volume of fixative (at least ten times the volume of
the specimen – for biopsy fragments, about 10 ml) should be used for histological,
immunohistochemical, in situ hybridization, and molecular studies (e.g., Oncotype
DX). Large specimens should be sectioned in slices with a maximum thickness of
10 mm for adequate fixation.
Bar code identification and individual analysis in each step of histological pro-
cessing are recommended to avoid errors.
5.2 Radiological-Pathological Correlation
The pathologist must have access to lesion imaging characteristics and clinical data.
If the purpose of the biopsy is to study calcifications, the identification and segrega-
tion of biopsy fragments with calcifications may facilitate analysis and radiological-
pathological correlation. Some rules are recommended to avoid mistakes:
M. A. Giannotti (*)
Hospital Sírio Libanês and Departamento de Patologia, Hospital das Clinicas HCFMUSP,
Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
F. N. Aguiar
Departamento de Patologia, Instituto do Cancer do Estado de Sao Paulo ICESP,

Switzerland AG 2022
48 M. A. Giannotti and F. N. Aguiar
1. To be considered adequate, the diagnosis of a benign lesion must explain the

radiological findings. Eventually, some benign lesions may have suspicious
aspects in image exams like microcalcifications or irregular masses, but before
accepting a benign diagnosis, it is necessary to verify if the lesion was correctly
sampled. Common suspect calcified benign lesions include fibroadenomatoid
changes, columnar changes, cysts, and steatonecrosis. Suspect irregular lesions
can be related to mastitis, diabetic changes, radial scars, desmoid fibromatosis,
and granular cell tumors.
2. If there is a very high radiological probability of malignancy, a benign diagnosis
should be dealt with caution, and surgical biopsy should be considered.
3. Invasion is detected when normal tissue (ducts, terminal ductal lobular unit
(TDLU), adipose tissue) is infiltrated by carcinoma. Papillary (e.g., solid papil-
lary carcinoma and encapsulated carcinoma) and sclerosing lesions may have
findings similar to invasive carcinomas, and in order to avoid false-positive diag-
nosis, sampling the interface between the lesion and normal tissue is
recommended.
4. “If it is malignant, is it primary?” Beware when diagnosing a “triple negative”
carcinoma of the breast! Metastatic carcinomas and other epithelioid neoplasias
(e.g., melanoma and high-grade lymphomas) are always a challenge, and immu-
nohistochemistry should be employed if there is some doubt. The presence of in
situ carcinoma and hormonal receptor positivity are suggestive of breast origin,
but other tumors can also be estrogen positive (e.g., ovary carcinoma).
Information of previous and coexisting diseases should always be informed to
the pathologist.
5.3 Fibroepithelial Lesions
Fibroadenomas and phyllodes tumors are lesions that exhibit proliferation of epithe-
lial and stromal cells. The architectural aspects of stromal growth can be divided
into two patterns. In the peri-canalicular pattern, the stroma grows around rounded
tubules, while in the intracanalicular pattern, the stroma compresses the ducts and
forms arciform slit-like structures with epithelial revestment. In phyllodes tumors,
this intracanalicular pattern is exaggerated and associated to stromal hypercellular-
ity, with formation of leaf-like structures.
Fibroadenomas are benign lesions, may be multiple, and may increase with hor-
monal stimuli. If asymptomatic, excision of fibroadenomas is not required.
Phyllodes tumors are classified according to some histological findings: its cel-
lularity, atypia, the presence of stromal overgrowth (i.e., areas greater than a lower
magnification field with only stromal component), growth pattern (permeative x well
defined), the presence of malignant heterologous elements, and, mainly, by their
mitotic count. Although benign phyllodes tumors and fibroadenomas may have
molecular differences [1], they share molecular alterations (e.g., MED12-mutant
pathway) and recurrence rates, even when margins are positive [2]. In core needle
5 Pathological Aspects for Diagnosis 49
Fig. 5.1 Phyllodes tumor.

Leaf-like structures and
cellularity variation
Table 5.1 Differences between fibroadenomas and phyllodes tumors

Histological Phyllodes tumors
characteristics Fibroadenoma Benign Borderline Malignant
Mitotic count Very low/absent Less than 5/10 5–10/10HPF More than 10/10
HPF HPF
Stromal Absent Absent Absent/focal Often present
overgrowth
Heterologous Absent Absent Absent (unless May be present
component liposarcoma-like)
Atypia Absent Absent Mild-moderate Marked
Borders Well defined Well defined May be focally Permeative
permeative
Cellularity Scant to mild, Mild Mild to moderate, Marked,
uniform heterogenous heterogenous
Frequency Common Uncommon Rare Rare
* HPF = High-power field.
biopsies, the differences between them may be difficult to distinguish. Malignant

and borderline tumors can be very heterogeneous, and final classification is some-
times possible only after complete excision (Fig. 5.1 and Table 5.1).
5.4 Papillary Neoplasms
Papillary lesions are characterized by fibrovascular cores covered by epithelial cells.

When benign, myoepithelial cells are present. Malignant lesions can be classified as
papillary ductal carcinoma in situ (DCIS), encapsulated, solid, and invasive. Ductal
carcinoma in situ can also involve papillary lesions. Although encapsulated papil-
lary carcinoma and solid papillary carcinoma usually do not have myoepithelial
cells, they are considered in situ lesions and should be treated surgically.
Pure invasive papillary carcinoma is rare. The majority of invasive lesions related
to encapsulated and in situ papillary carcinoma is carcinoma of no special type
Table 5.2 Differences between papillary lesions

Clinical and radiological
Histology findings
Intraductal Broad fronds, epithelial and myoepithelial Single nodule (central
papilloma cells around the fronds, epithelial papilloma); incidental or
hyperplasia with UDH features calcifications (peripheral
multiple papillomas)
Papilloma with Broad fronds, myoepithelial cells present. If high-grade DCIS is present,
DCIS Epithelial hyperplasia with features of calcifications and nodules may
DCIS be present
Papillary DCIS Slender fronds. Myoepithelial cells absent Similar to other types of DCIS
in the fronds, present at the periphery
Encapsulated Slender fronds; well-developed capsule. Single nodule
papillary Myoepithelial cells absent
carcinoma
Solid papillary Solid pattern with delicate vascular septa. Nodule. May be multiple
carcinoma Myoepithelial cells absent
Invasive papillary Infiltrative growth. Frond stroma with Single nodule
carcinoma high cellularity. Myoepithelial cells
absent. High-grade cytological findings
may be present
DCIS ductal carcinoma in situ
(NST). Metastatic lesions should be excluded when invasive papillary carcinoma is

diagnosed. Immunohistochemistry always shows diffuse estrogen receptor positiv-
ity in breast papillary carcinomas, and if this marker is negative, other primary
lesions must be investigated.
The table below summarizes the differences between them (Table 5.2).
5.5 enign High-Risk Lesions and Precursors, Including

B
Classic Lobular Intraepithelial Neoplasia
With the improvement of biopsy devices, i.e., vacuum-assisted biopsies (VAB), the
ratio of false-negative results in percutaneous biopsies has been reduced, and surgi-
cal approach to avoid underestimation is no longer recommended for some high-
risk lesions [3], i.e., lesions with risk for subsequent development of breast cancer
lower than 2.5-fold. When appropriate sampling is achieved on a percutaneous
biopsy, patients diagnosed with papilloma, radial scar, mucocele-like lesion, flat
epithelial atypia, lobular atypical hyperplasia, and classic in situ lobular carcinoma
may be spared of surgical intervention. It is very important, however, before adopt-
ing a conservative approach, to verify if pathological and radiological aspects are
compatible; for example, the diagnosis of in situ lobular carcinoma in a nodular
lesion on mammogram should be considered inappropriate. The sampled proportion
of the lesion should also be regarded. Large lesions, i.e., larger than 10 mm, will
probably benefit from surgical approach. It is recommended that the pathologist

specify the amount of lesion represented in the biopsy so that the radiologist can
estimate how much lesion was excised.
5.6 typical Ductal Hyperplasia and Low-Grade

A
Carcinoma In Situ
Definition: Atypical ductal hyperplasia is characterized by epithelial proliferation

similar to low-grade ductal carcinoma in situ (monomorphic cells with distinct bor-
ders, spaces with polarized cells, absence of streaming and overlapping) that does
not meet the criteria of at least two TDLUs involved and 2 mm in size, necessary to
the diagnosis of DCIS (Fig. 5.2). The difference between these diagnoses, therefore,
is mostly quantitative.
Even with new biopsy devices, the underestimation rates of atypical ductal
hyperplasia are not negligible, and surgery is recommended for the majority of
cases. However, some very small lesions and atypical incidental findings (not related
to the radiological findings) may be conservatively conducted [3]. Therapeutic deci-
sion in these cases will probably be influenced by the results of trials like COMET,
LORD, and LORIS that study low-grade carcinoma in situ prognosis comparing
conservative conduct to surgery.
Whenever high-grade atypia is found, even in very small lesions, the diagnosis
of ADH is not adequate, and the diagnosis should alert for the possibility of high-
grade ductal carcinoma in situ in the surroundings.
5.7 Intermediate and High-Grade Ductal Carcinoma In Situ
DCIS of intermediate grade is composed of cells without the polarization seen in

low-grade DCIS nor the highly atypical cells seen in high-grade DCIS. The cells
usually show mild to moderate variability in size and shape and also present
Fig. 5.2 Atypical ductal

hyperplasia, micropapillary
Fig. 5.3 Ductal carcinoma in situ (DCIS) of intermediate nuclear grade (grade 2)
Fig. 5.4 Ductal carcinoma in situ (DCIS) of high nuclear grade (grade 3)
variably prominent nucleoli [4] (Fig. 5.3). Necrosis and microcalcifications in simi-
lar patterns seen in low- or high-grade DCIS may be present. By sharing some his-
tological characteristics with low- and/or high-grade DCIS, it is no surprise that
intermediate-grade DCIS has the least agreement between pathologists [5]. Studies
show that the agreement is better when only two categories, low or high grade, are
considered [6, 7]. Molecular studies support this as the intermediate-grade DCIS
separates into these two and not into an individual category [8].
In summary, DCIS of intermediate grade can show any histological characteris-
tics and immunohistochemical profile, overlapping with low- or high-grade DCIS.
High-grade DCIS presents highly atypical cells with pleomorphic nuclei, irregu-
lar contours, clumped chromatin, and prominent nucleoli [4]. Comedonecrosis is
frequently seen, although not obligatory. Mitotic figures are common. High-grade
DCIS may present as a mass or calcifications on mammography and as an enhance-
ment on magnetic resonance imaging (MRI) [9] (Fig. 5.4).
5.8 Pleomorphic Lobular Carcinoma In Situ (PLCIS)
The pleomorphic LCIS variant has inactivation of e-cadherin which can be con-
firmed by immunohistochemistry, lacking membrane expression of e-cadherin and
B-catenin and showing cytoplasmic expression of p120 [10]. Histologically, they
are more similar to high-grade DCIS, showing higher nuclear grade and
comedonecrosis [11, 12] (Fig. 5.5). Compared with classic LCIS, PLCIS shows less
expression of hormone receptors (estrogen and progesterone) and more chance of
overexpression of HER2 [10, 11, 13].
PLCIS shares some genetic similarities with classic LCIS, including 16q loss
and 1q gain, but might show a higher number of genetic alterations like gain of 16p,
loss of 8p, and amplification of cyclin D1 gene [11, 14]. Biological behavior of
PLCIS is more similar to high-grade DCIS [15].
5.9 Biomarkers in Ductal Carcinoma In Situ
Expression of hormonal receptors, at least estrogen receptor (ER), by immunohisto-

chemistry is evaluated and recommended in all cases of DCIS, especially because
they provide possibility of treatment with hormonal therapy [16]. Although not
obligatory, HER2 evaluation in DCIS can help to understand its biological behavior
and better plan its treatment as DCIS shows the same molecular classes seen in
invasive carcinomas [17, 18] and more aggressive behavior in HER2 over-express-
ing DCIS [19] (Fig. 5.6).
Fig. 5.5 Pleomorphic lobular carcinoma in situ (PLCIS)
Fig. 5.6 Estrogen receptor expression and HER2 overexpression at immunohistochemis-

try in DCIS
The most studied characteristic of DCIS is the prediction of progression to inva-

sive carcinoma. Several clinical studies and algorithms are known in this regard
[20–23], although none can predict exactly the probability of invasion. With the
improvement in the knowledge on breast carcinogenesis together with molecular
technologies, other factors have been studied in DCIS, especially regarding the evo-
lution or association with invasive carcinoma, including epithelial, myoepithelial,
and microenvironment components and also combinations of those [24, 25].
The use of molecular or immunohistochemical methods to divide DCIS into
classes [17, 26, 27] has provided some information as which is more (luminal-
HER2) or less (triple-negative) prevalent when invasive carcinoma is present [28];
also high-grade DCIS, which includes HER2-expressing DCIS, is more associated
with enhancement on MRI [29, 30]. The major genetic, molecular, and histological
differences in the epithelial cells occur during progression from normal breast tissue
to in situ carcinoma, and those are very similar to invasive carcinoma cells [31–33].
Although it is probably not the main driver in the progression to invasive carcinoma,
there are some studies that show differences between cells in those components and
possible markers helping in this prediction [34, 35].
With the improvement in the knowledge on breast carcinogenesis, the microen-
vironment became an integral part of the process of invasion, and it is reflected in
numerous recent studies about microenvironment components. Stromal expression
profile shows more differentially expressed genes between normal and DCIS-
associated stroma than DCIS and invasive-associated stroma [36], although pure
DCIS stroma is also different than stroma with DCIS and invasive carcinoma [37].
The vascular component of DCIS is also different compared to normal and also
invasive carcinoma [38, 39]. The immune component of microenvironment also
shows differences like more tumor-infiltrating lymphocytes (TILs) in DCIS with
more DNA copy number aberration load [40] that histologically reflects in more
TILs in high grade with HER2 overexpression and lack of ER and RP expression
[41]. There are some promising studies regarding B lymphocytes in TILs, with
some tumors having poor prognosis, but still they need large validation [16]. Another
important component located between the DCIS neoplastic epithelial cells and the
stroma is the basal membrane and myoepithelial cells; both need to be transposed
for a diagnosis of invasive carcinoma [42]. Until recently, the general thought was
that it was only a physical barrier, but now studies have shown that they are also an
active part in the process of tumor suppressor function [43]. Also, DCIS-associated
myoepithelial cells show different gene expression compared to normal breast tis-
sue [44]. There is evidence that those gene expression differences may translate to
immunohistochemical visible phenotypic alterations [45]. Based on that, it is likely
that it can act as thermometers of what is happening on that interface, helping to
evaluate risk of invasion in DCIS associated with other factors [24, 25].
Although there is no definite answer to which DCIS will or will not invade the
adjacent stroma, the future looks promising in the discovery of more data that will
help evaluate this risk even better.
5.10 Invasive Carcinoma of No Special Type
Previously known as invasive ductal carcinoma, invasive carcinoma of no special type

(NST) is a diagnosis of exclusion. It is an invasive carcinoma that does not present
enough histological features (more than 90% of the tumor) to be classified as any of
the special types like lobular, metaplastic, tubular, and apocrine [46] (Fig. 5.7). It is
the most common histological subtype of breast carcinoma, and all should be graded
according to Nottingham criteria (see table below) (Table 5.3), which has direct cor-
relation with prognosis, grade 3 carcinomas being the more aggressive ones [47].
Since the classic work of Perou [48] demonstrating the existence of different
molecular classes of breast carcinomas, histologic grading is not the only important
factor in its evaluation. Molecular classes also show differences in prognosis and
Fig. 5.7 Invasive carcinoma of no special type
Table 5.3 Nottingham criteria for invasive carcinomas of no special type (NST)
Feature Score
Tubule and gland formation
Majority of tumor (>75%) 1
Moderate degree (10–75%) 2
Little or none (<10%) 3
Nuclear pleomorphism
Small, regular, uniform cells 1
Moderate increase in size and variability 2
Marked variation 3
Mitotic count (dependent on microscopic field
area)
Low 1
Moderate 2
High 3
Total score (add the scores) Final grading
3–5 Grade 1
6 or 7 Grade 2
8 or 9 Grade 3
predictive factors [49]. Although the gold standard for identification of these classes
is the molecular tests, in practice, immunohistochemical profile shows a good cor-
relation with those [50, 51]. Based on that, the main molecular classes of invasive
breast carcinoma can be correlated as this:
• Luminal A or B: carcinomas that express hormone receptors (ER and/or PR),
without overexpression of HER2; the division between A and B has many
options, but most incorporate Ki67 and the level of progesterone receptor expres-
sion – we follow this group criteria [52] (Table 5.4).
• Hybrid luminal/HER2: carcinomas that express hormone receptor (ER and/or
PR) associated with overexpression of HER2 (Fig. 5.8).
• HER2: carcinomas that overexpress HER2 without expression of hormone
receptors.
• Triple negative (TN): carcinomas that do not express hormone receptors
nor HER2.
Invasive carcinomas of no special type are present in all of those groups, even
though we can see some patterns of characteristics in some of them. Luminal A
carcinomas are mostly Nottingham grade 1 with some grade 2. Hybrid, HER2, and
Table 5.4 Immunohistochemical profile and its correlation with molecular classes of invasive
breast cancer
Luminal A All of:
ER positive
HER2 negative
And at least one of:
Ki67 <14%
Ki67 14–19% and PR ≥20%
Luminal B (HER2 negative) All of:
ER positive
HER2 negative
And at least one of:
Ki67 14–19% and PR negative or <20%
Ki67 ≥20%
Fig. 5.8 Estrogen receptor expression and HER2 overexpression at immunohistochemistry in

invasive carcinoma
TN are mostly grade 2 or 3 [53]. Special histological types show a more specific
association with those classes: classic invasive lobular carcinoma is almost always
luminal, predominantly A, and Nottingham grade 1 or 2. Pleomorphic lobular car-
cinoma can be luminal B (majority), but also hybrid, HER2, or even TN, being most
Nottingham grade 2 or 3. Metaplastic and medullary carcinomas are TN and
Nottingham grade 2 or 3. Some special types of carcinomas, such as adenoid cystic
and secretory, can be TN and have a Nottingham low grade, but they are rare
carcinomas.
With the improvement in the knowledge on breast carcinomas, its histological
evaluation must have complementary immunohistochemistry to better understand
its biology, predict the behavior, and offer adequate treatment.
5.11 acroscopic Evaluation of the Breast Specimen,

M
Including Those with Neoadjuvant Treatment
General rules for evaluation of breast specimens are well established and available
in various publications like the College of American Pathologists [54] and other
papers [55–57]. Here, we would like to reinforce some fundamental aspects in an
attempt to better evaluate and obtain the best possible report for the other specialties
that receive the anatomopathological summary.
The pathologist must have access to all data regarding the clinical, imaginologi-
cal, and histological aspects about the specimen that he is evaluating. Most hospitals
have integrated systems available to the pathologist, but in other scenarios, that may
not be available. In this case, the pathologist must be proactive in looking for those
data before evaluating and processing the specimen, as the optimal strategies in
choosing which areas to evaluate happen in that first time – subsequent new cuts can
be problematic as the tissue has already been cut before and its recomposition is
difficult and also add to the delay in delivering the final pathological report.
Another extremely important factor in the evaluation of these specimens is the
adequate fixation which does not mean just placing the specimens in formalde-
hyde, but it implies making sure that it can reach all areas of the specimen.
Without an adequate fixation, morphological and biomarker evaluation will suf-
fer [58, 59]. In larger specimens, it is necessary to make sections prior to fixation,
so the maximum thickness should be of 10 mm or less. If the pathology labora-
tory is not integrated with the operating room or if the pathologist is not present
at the surgery to make an evaluation and make the sections, the surgeon can do it
himself.
With all specimen-related information and an adequate fixation, the pathologist
can make optimal sections to provide the best anatomopathological report.
Low-grade DCIS specimens normally do not present any macroscopic lesions,
so small specimens are entirely included for analysis and larger specimens can have
only selected areas included, which should be chosen based on the lesion radiologic
characteristics.
High-grade DCIS usually presents a macroscopic lesion, so the selection of the

areas for microscopic analysis is clearer. Those which have a more extensive lesion
on the radiologic exam than a visible macroscopically one - usually lesions with low
cellularity and little desmoplasia - the area chosen for analysis should be bigger to
not miss any lesion.
Most invasive carcinomas are macroscopically visible, the exception being some
cases of low-grade carcinomas with little or no stromal reaction, as classic lobular
carcinoma. At least one section per centimeter of the lesion is recommended for
adequate analysis of the tumor, with the aid of radiologic data for those that do not
appear macroscopically. Radiologic data can also help identify other lesions, such
as in situ carcinoma, adjacent to or in other areas of the specimen, so the pathologist
must have access and seek this data.
Invasive carcinomas might regress with neoadjuvant treatment, impacting sur-
vival rates [60]. Those with no response to treatment can be processed as stated
above. The ones with clinical and/or radiologic response, complete or partial, pro-
vide a more complex challenge to the pathologist. Again, all the clinical, radiologic,
and pathological information about the tumor is necessary for a better macroscopic
evaluation and adequate selection of the areas for analysis. Triple-negative carcino-
mas and those that overexpress HER2 have a better chance to regress or even show
complete pathological response [61–63]. At macroscopic evaluation, the patholo-
gist can already see signs of regression and make adequate sections of the visible
remaining areas of the tumor and also of the areas with regression (Fig. 5.9). Most
carcinomas that have hormone receptor expression without overexpression of HER2
do not show great response to neoadjuvant treatment [61, 64, 65]. Knowing that,
even with clinical and/or radiologic indication of partial regression, the pathologist
must include sections that comprehend the initial area of the carcinoma so it can be
adequately measured in microscopy. That is even more important in breasts with
dense parenchyma or classic lobular invasive carcinomas.
If possible, all macroscopically free axillary lymph nodes should be processed as
sentinel, i.e., maximum thickness of 2.0 mm, so any area with metastasis or regres-
sion will not be missed [55]. When the metastasis is macroscopically visible, only
representative sections can be included.
Fig. 5.9 Breast and lymph node with histological features of post-neoadjuvant chemotherapy
regression
5.12 Special Subtypes
Before a diagnosis of invasive ductal carcinoma is rendered, the pathologist should

verify if the clinical and morphological characteristics of the lesion do not corre-
spond to one of the special subtypes.
The most common special subtype is invasive lobular carcinoma (approx. 15%
of breast carcinomas) that is related to CDH1 gene mutation and loss of e-cadherin
expression. Consequent to loss of cell-to-cell adhesion, invasive lobular carcinoma
acquires different radiological findings and, not infrequently, are hard to find in
screening tests (up to 19% false-negative rates) (Fig. 5.10). In spite of low nuclear
grade and estrogen positivity, distant metastasis to bone, gastrointestinal tract (GIT)
and ovary are more frequent than those of NST carcinoma. The incidence of contra-
lateral tumors is also higher in this subtype. Cases with greater degree of atypia are
classified as pleomorphic and exhibit association with pleomorphic LCIS.
Some of the special subtypes are related to better prognosis, e.g., mucinous
(Fig. 5.11), cribriform, and tubular, and are usually estrogen positive, while others
are worse, e.g., invasive micropapillary carcinomas that have higher lymph node
metastasis rates. Radiological characteristics also differ among subtypes. Mucinous
carcinomas may appear as benign masses on mammograms because of their regular
margins, while most tubular carcinomas are spiculated. The table below summa-
rizes these findings (Table 5.5).
Fig. 5.10 Invasive lobular

carcinoma. Isolated cells in
desmoplastic stroma
Fig. 5.11 Mucinous

carcinoma. Small groups
of neoplastic cells
embedded in mucus
60
Table 5.5 Main characteristics of special subtypes of invasive carcinomas

Subtype Clinical Radiological Immunohistochemical Molecular Prognosis
Lobular Bilateral 5–19% False-neg mammo (up to Loss of e-cadherin CDH1 More long-term events (distant
Larger tumors 19%); irregular poor defined ER+ PIK3CA metastasis and recurrences) than
Higher rate of margins HER2- IBC-NST
node metastasis
Tubular and Age median 63 Small spiculated ER+ – Favorable
cribriform Small lesion HER2-
Mucinous Age median 71 Well circumscribed ER+ Low level of Favorable (unless assoc.
HER2- instability micropapillary pattern)
Micropapillary Frequent axillary Dense irregular tumors Peripheral MUC1+ PIK3CA, TP53, Higher recurrence rate; overall
metastasis GATA3, MAP2K4 similar to IBC-NST
Apocrine Median age Poorly circumscribed tumors ER- TP53, PIK3CA/ –
higher than AR+ PTEN/AKT
IBC-NST HER2+ (30–60%)
Metaplastic (high Advanced stage – ER- Complex Worse than IBC-NST
grade) Less node HER2- TP53, RB1,
metastasis CK5/6+ ARID1A, PI3K,
MAPK, WNT
M. A. Giannotti and F. N. Aguiar
A very aggressive breast carcinoma subtype is inflammatory carcinoma. Its inci-

dence is higher in young women and among afro-descendants. The symptoms are
similar to inflammatory diseases, with rapid enlargement and skin changes.
Histologically, lymphovascular emboli are found, but their absence does not pre-
clude this diagnosis. They are more frequently negative for hormonal receptors and
are more HER2 positive than usual carcinomas.
5.13 Special Methods
5.13.1 Immunohistochemistry
Immunohistochemistry is the most used technique, and usual antibodies are well
described in the carcinoma section. It is also used to help pathologists decide
between typical and atypical hyperplasias, to define invasion (Fig. 5.12), and to
subclassify carcinomas. Besides HER2 therapy, immune-checkpoint therapy is also
based on immunohistochemical assays. The table below shows some of the most
used antibodies (Table 5.6).
5.13.2 In Situ Hybridization
In situ hybridization allows the search of genetic alterations in slides from paraffin-
embedded biopsies. In breast pathology, the main utility is to verify HER2 equivo-
cal staining cases. The number of genes per cell and the ratio of genes and
Fig. 5.12 P63 labeling

myoepithelial cells in a
papilloma
Table 5.6 Most common antibodies used for breast tumor evaluation
Antibody Utility
P63, calponin, SMA, p40 Identify myoepithelial cells
CK5/6 ADH versus UDH
MUC1 Peripheral in micropapillary carcinoma
Cytokeratins Diagnosis of spindle cell metaplastic carcinoma
E-cadherin, B-catenin, Loss of expression in ILC
GP120
GATA3, mammaglobin, Breast primary tumors
Sox10
Pax-8, Melan A, TTF1, Cdx2 Identification of metastasis to the breast
PD-L1 Identify cases that benefit from immuno-therapy (e.g.,
atezolizumab)
*ADH = Atypical Ductal Hyperplasia, UDH = Usual Ductal Hyperplasia, ILC = Invasive Lobular
Carcinoma
centromeres are calculated. Amplified cases are those with HER2/centromere ratio
higher than 2.0 and more than 4.0 signals per cell [66].
5.14 Next-Generation Sequencing (NGS)
Next-generation sequencing is already feasible in many centers. The possibility of

identification of mutations in up to 500 genes is a fantastic tool, and target specific
drugs are already a reality. PIK3CA pathway inhibitors, for example, may be used
in cases with diagnosed mutations. The same paraffin-embedded tissue used for
routine histological analyses can be used to these molecular tests. Besides detecting
specific gene mutations, investigation of tumor mutational burden and of genetic
stability is also a promising tool [67].
References
1. Ng CCY, Md Nasir ND, Loke BN, Tay TKY, Thike AA, Rajasegaran V, et al. Genetic differ-
ences between benign phyllodes tumors and fibroadenomas revealed through targeted next
generation sequencing. Mod Pathol. 2021;34:1320.
2. Lu Y, Chen Y, Zhu L, Cartwright P, Song E, Jacobs L, et al. Local recurrence of Benign,
Borderline, and malignant Phyllodes tumors of the breast: a systematic review and meta-anal-
ysis. Ann Surg Oncol. 2019;26(5):1263.
3. Raza S. Management of high-risk breast lesions: counterpoint—time for personalized surveil-
lance. Am J Roentgenol. 2020;216:1434.
4. Lakhani SR, Eliis IO, Schnitt SJ, Tan PH, van de Vijver MJ. WHO classification of tumors of
the breast, vol. 4. Lyon: IARC Press; 2012. p. 240.
5. van Dooijeweert C, van Diest PJ, Willems SM, Kuijpers CCHJ, Overbeek LIH, Deckers
IAG. Significant inter- and intra-laboratory variation in grading of ductal carcinoma in situ of
the breast: a nationwide study of 4901 patients in the Netherlands. Breast Cancer Res Treat
[Internet]. 2019 [cited 2020 Feb 1];174(2):479–88. Available at: http://www.ncbi.nlm.nih.gov/
pubmed/30539380
6. Alghamdi SA, Krishnamurthy K, Garces Narvaez SA, Algashaamy KJ, Aoun J, Reis IM,
et al. Low-grade ductal carcinoma in situ. Am J Clin Pathol [Internet]. 2020;153(3):360–7.
Available at: https://academic.oup.com/ajcp/article/153/3/360/5643824
7. van Bockstal M, Baldewijns M, Colpaert C, Dano H, Floris G, Galant C, et al. Dichotomous
histopathological assessment of ductal carcinoma in situ of the breast results in substantial
interobserver concordance. Histopathology [Internet]. 2018;73(6):923–32. Available at: http://
doi.wiley.com/10.1111/his.13741
8. Hannemann J, Velds A, Halfwerk JBG, Kreike B, Peterse JL, van de Vijver MJ. Classification
of ductal carcinoma in situ by gene expression profiling. Breast Cancer Res. 2006;8(5):1–20.
9. Shehata M, Grimm L, Ballantyne N, Lourenco A, Demello LR, Kilgore MR, et al. Ductal
carcinoma in situ: current concepts in biology, imaging, and treatment. J Breast Imag.
2019;1(3):166–76.
10. Dabbs DJ, Schnitt SJ, Geyer FC, Weigelt B, Baehner FL, Decker T, et al. Lobular neo-
plasia of the breast revisited with emphasis on the role of E-Cadherin immunohistochem-
istry. Am J Surg Pathol [Internet]. 2013;37(7):e1–11. Available at: http://journals.lww.
com/00000478-201307000-00001
11. Wen HY, Brogi E. Lobular Carcinoma In Situ. Surg Pathol Clin [Internet]. 2018;11(1):123–45.
Available at: https://linkinghub.elsevier.com/retrieve/pii/S1875918117301435
12. Ginter PS, D’Alfonso TM. Current concepts in diagnosis, molecular features, and manage-
ment of lobular carcinoma in situ of the breast with a discussion of morphologic variants. Arch
Pathol Lab Med [Internet]. 2017;141(12):1668–78. Available at: http://meridian.allenpress.
com/aplm/article/141/12/1668/65743/Current-Concepts-in-Diagnosis-Molecular-Features
13. Shamir ER, Chen Y-Y, Chu T, Pekmezci M, Rabban JT, Krings G. Pleomorphic and florid lob-
ular carcinoma in situ variants of the breast. Am J Surg Pathol [Internet]. 2019;43(3):399–408.
Available at: http://journals.lww.com/00000478-201903000-00013
14. Chen Y-Y, Hwang E-SS, Roy R, DeVries S, Anderson J, Wa C, et al. Genetic and phenotypic char-
acteristics of pleomorphic lobular carcinoma in situ of the breast. Am J Surg Pathol [Internet].
2009;33(11):1683–94. Available at: http://journals.lww.com/00000478-200911000-00015
15. Foschini MP, Miglio R, Fiore R, Baldovini C, Castellano I, Callagy G, et al. Pre-
operative management of Pleomorphic and florid lobular carcinoma in situ of the breast:
report of a large multi-institutional series and review of the literature. Eur J Surg Oncol
[Internet]. 2019;45(12):2279–86. Available at: https://linkinghub.elsevier.com/retrieve/pii/
S0748798319305487
16. Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL,
et al. Estrogen and progesterone receptor testing in breast cancer: American Society of
Clinical Oncology/College of American Pathologists Guideline Update. Arch Pathol Lab
Med [Internet]. 2020;144(5):545–63. Available at: http://meridian.allenpress.com/aplm/
article/144/5/545/427509/Estrogen-and-Progesterone-Receptor-Testing-in
17. Tamimi RM, Baer HJ, Marotti J, Galan M, Galaburda L, Fu Y, et al. Comparison of molec-
ular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res
[Internet]. 2008;10(4):R67. Available at: http://breast-cancerresearch.biomedcentral.com/
articles/10.1186/bcr2128
18. Mardekian SK, Bombonati A, Palazzo JP. Ductal carcinoma in situ of the breast: the impor-
tance of morphologic and molecular interactions. Human Pathol. 2016;49:114–23.
19. Miligy IM, Toss MS, Gorringe KL, Lee AHS, Ellis IO, Green AR, et al. The clinical and bio-
logical significance of HER2 overexpression in breast ductal carcinoma in situ: a large study
from a single institution. Br J Cancer [Internet]. 2019;120(11):1075–82. Available at: http://
www.nature.com/articles/s41416-019-0436-3
20. Sue GR, Lannin DR, Killelea B, Chagpar AB. Predictors of microinvasion and its prognos-
tic role in ductal carcinoma in situ. Am J Surg [Internet]. 2013;206(4):478–81. Available at:
https://linkinghub.elsevier.com/retrieve/pii/S0002961013002882
21. Badve S, A’hern RP, Ward AM, Millis RR, Pinder SE, Ellis IO, et al. Prediction of local recur-
rence of ductal carcinoma in situ of the breast using five histological classifications: a com-
parative study with long follow-up. Human Pathol [Internet]. 1998;29(9):915–23. Available at:
22. Silverstein MJ, Lagios MD. Choosing treatment for patients with ductal carcinoma in situ: fine
tuning the University of Southern California/Van Nuys prognostic index. J Natl Cancer Inst -
Monographs. 2010;41:193–6.
23. Silverstein MJ. The University of Southern California/Van Nuys prognostic index for duc-
tal carcinoma in situ of the breast. Am J Surg [Internet]. 2003;186(4):337–43. Available at:
24. Hilson JB, Schnitt SJ, Collins LC. Phenotypic alterations in ductal carcinoma in situ-associ-
ated myoepithelial cells. Am J Surg Pathol [Internet]. 2009;33(2):227–32. Available at: http://
journals.lww.com/00000478-200902000-00008
25. Aguiar FN, Cirqueira CS, Bacchi CE, Carvalho FM. Morphologic, molecular and microen-
vironment factors associated with stromal invasion in breast ductal carcinoma in situ: role of
myoepithelial cells. Breast Dis. 2015;35(4):249–52.
26. Livasy CA, Perou CM, Karaca G, Cowan DW, Maia D, Jackson S, et al. Identification of a basal-
like subtype of breast ductal carcinoma in situ. Human Pathol [Internet]. 2007;38(2):197–204.
Available at: https://linkinghub.elsevier.com/retrieve/pii/S004681770600534X
27. Meijnen P, Peterse JL, Antonini N, Rutgers EJT, van de Vijver MJ. Immunohistochemical cate-
gorisation of ductal carcinoma in situ of the breast. Br J Cancer [Internet]. 2008;98(1):137–42.
Available at: http://www.nature.com/articles/6604112
28. Doebar SC, van den Broek EC, Koppert LB, Jager A, Baaijens MHA, Obdeijn IMAM, et al.
Extent of ductal carcinoma in situ according to breast cancer subtypes: a population-based
cohort study. Breast Cancer Res Treat. 2016;158(1):179–87.
29. Chou S-HS, Gombos EC, Chikarmane SA, Giess CS, Jayender J. Computer-aided hetero-
geneity analysis in breast MR imaging assessment of ductal carcinoma in situ: correlating
histologic grade and receptor status. J Magn Resonan Imag [Internet]. 2017;46(6):1748–59.
Available at: http://doi.wiley.com/10.1002/jmri.25712
30. Esserman LJ, Kumar AS, Herrera AF, Leung J, Au A, Chen Y-Y, et al. Magnetic reso-
nance imaging captures the biology of ductal carcinoma in situ. J Clin Oncol [Internet].
2006;24(28):4603–10. Available at: http://ascopubs.org/doi/10.1200/JCO.2005.04.5518
31. Porter D, Lahti-Domenici J, Keshaviah A, Bae YK, Argani P, Marks J, et al. Molecular markers
in ductal carcinoma in situ of the breast. Mol Cancer Res. 2003;1:362.
32. Hernandez L, Wilkerson PM, Lambros MB, Campion-Flora A, Rodrigues DN, Gauthier A,
et al. Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent
invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection. J
Pathol [Internet]. 2012;227(1):42–52. Available at: http://doi.wiley.com/10.1002/path.3990
33. Aguiar FN, Mendes HN, Bacchi CE, Carvalho FM. Comparison of nuclear grade and immuno-
histochemical features in situ and invasive components of ductal carcinoma of breast. Revista
Brasileira de Ginecologia e Obstetrícia [Internet]. 2013;35(3):97–102. Available at: http://
www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-72032013000300002&lng=en&nr
m=iso&tlng=en
34. Pareja F, Brown DN, Lee JY, da Cruz PA, Selenica P, Bi R, et al. Whole-exome sequencing
analysis of the progression from non–low-grade ductal carcinoma in situ to invasive ductal
carcinoma. Clinical Cancer Res [Internet]. 2020;26(14):3682–93. Available at: http://clincan-
cerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-19-2563
35. Aguiar F, Mendes H, Cirqueira C, Bacchi C, Carvalho F. Basal cytokeratin as a potential marker
of low risk of invasion in ductal carcinoma in situ. Clinics [Internet]. 2013;68(5):638–43.
Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654300/?report=classic
36. Vargas AC, Reed AEM, Waddell N, Lane A, Reid LE, Smart CE, et al. Gene expression
profiling of tumour epithelial and stromal compartments during breast cancer progression.
Breast Cancer Res Treat [Internet]. 2012;135(1):153–65. Available at: http://link.springer.
com/10.1007/s10549-012-2123-4
37. Sharma M, Beck AH, Webster JA, Espinosa I, Montgomery K, Varma S, et al. Analysis of
stromal signatures in the tumor microenvironment of ductal carcinoma in situ. Breast Cancer
Res Treat [Internet]. 2010;123(2):397–404. Available at: http://link.springer.com/10.1007/
s10549-009-0654-0
38. Muggerud AA, Hallett M, Johnsen H, Kleivi K, Zhou W, Tahmasebpoor S, et al.
Molecular diversity in ductal carcinoma in situ (DCIS) and early invasive breast cancer.
Mol Oncol [Internet]. 2010;4(4):357–68. Available at: http://doi.wiley.com/10.1016/j.
molonc.2010.06.007
39. Lee S, Stewart S, Nagtegaal I, Luo J, Wu Y, Colditz G, et al. Differentially expressed genes
regulating the progression of ductal carcinoma in situ to invasive breast cancer. Cancer
Res [Internet]. 2012;72(17):4574–86. Available at: http://cancerres.aacrjournals.org/cgi/
doi/10.1158/0008-5472.CAN-12-0636
40. Hendry S, Pang J-MB, Byrne DJ, Lakhani SR, Cummings MC, Campbell IG, et al. Relationship
of the breast ductal carcinoma in situ immune microenvironment with clinicopathological and
genetic features. Clin Cancer Res [Internet]. 2017;23(17):5210–7. Available at: http://clincan-
cerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-17-0743
41. Pruneri G, Lazzeroni M, Bagnardi V, Tiburzio GB, Rotmensz N, DeCensi A, et al. The preva-
lence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in
situ of the breast. Ann Oncol. 2017;28(2):321–8.
42. Man Y, Tai L, Barner R, Vang R, Saenger JS, Shekitka KM, et al. Cell clusters overlying
focally disrupted mammary myoepithelial cell layers and adjacent cells within the same duct
display different immunohistochemical and genetic features: implications for tumor progres-
sion and invasion. Breast Cancer Res [Internet]. 2003;5(6):R231. Available at: http://breast-
cancer-research.biomedcentral.com/articles/10.1186/bcr653
43. Gudjonsson T, Adriance MC, Sternlicht MD, Petersen OW, Bissell MJ. Myoepithelial
cells: their origin and function in breast morphogenesis and neoplasia. J Mammary Gland
Biol Neoplas [Internet]. 2005;10(3):261–72. Available at: http://link.springer.com/10.1007/
s10911-005-9586-4
44. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular char-
acterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.
45. Hilson JB, Schnitt SJ, Collins LC. Phenotypic alterations in ductal carcinoma in situ-associ-
ated myoepithelial cells. Am J Surg Pathol. 2009;33(2):227–32.
46. Lokuhetty D, White VA, Watanabe R 1966-, Cree IA, WHO Classification of Tumours
Editorial Board, International Agency for Research on Cancer. Breast tumours.
47. Elston CW, Ellis IO. pathological prognostic factors in breast cancer. I. The value of histological
grade in breast cancer: experience from a large study with long-term follow-up. Histopathology
[Internet]. 1991;19(5):403–10. Available at: http://doi.wiley.com/10.1111/j.1365-2559.1991.
tb00229.x
48. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular por-
traits of human breast tumours. Nature [Internet]. 2000;406(6797):747–52. Available at: http://
www.nature.com/articles/35021093
49. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns
of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad
Sci [Internet]. 2001;98(19):10869–74. Available at: http://www.pnas.org/cgi/doi/10.1073/
pnas.191367098
50. Cheang MCU, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. Ki67 index, HER2 sta-
tus, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst [Internet].
2009;101(10):736–50. Available at: https://academic.oup.com/jnci/article-lookup/
doi/10.1093/jnci/djp082
51. Nielsen TO. Immunohistochemical and clinical characterization of the basal-like subtype of
invasive breast carcinoma. Clinical Cancer Res [Internet]. 2004;10(16):5367–74. Available at:
http://clincancerres.aacrjournals.org/cgi/doi/10.1158/1078-0432.CCR-04-0220
52. Maisonneuve P, Disalvatore D, Rotmensz N, Curigliano G, Colleoni M, Dellapasqua S, et al.
Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-
negative) intrinsic breast cancer subtypes. Breast Cancer Res [Internet]. 2014;16(3):R65.
Available at: http://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr3679
53. Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchió C, Reis-Filho JS. Breast can-
cer precursors revisited: molecular features and progression pathways. Histopathology.
2010;57(2):171–92.
54. Protocol for the Examination of Resection Specimens From Patients With Invasive Carcinoma
of the Breast [Internet]. 2020. Available at: www.cap.org/cancerprotocols.
55. Bossuyt V, Provenzano E, Symmans WF, Boughey JC, Coles C, Curigliano G, et al.
Recommendations for standardized pathological characterization of residual disease for
neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration. Ann Oncol.
2015;26(7):1280–91.
56. Pinder SE, Rakha EA, Purdie CA, Bartlett JMS, Francis A, Stein RC, et al. Macroscopic
handling and reporting of breast cancer specimens pre- and post-neoadjuvant chemotherapy
treatment: review of pathological issues and suggested approaches. Histopathology. Blackwell
Publishing Ltd. 2015;67:279–93.
57. Marchiò C, Maletta F, Annaratone L, Sapino A. The perfect pathology report after neoadjuvant
therapy. J Natl Cancer Inst - Monographs. 2015;2015(51):47–50.
58. Khoury T. Delay to formalin fixation (cold ischemia time) effect on breast cancer molecules.
Am J Clin Pathol. Oxford University Press. 2018;149:275–92.
59. Carson FL. Formaldehyde as a fixative for light and electron microscopy. Micros Today.
2000;8(5):30–1.
60. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological com-
plete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analy-
sis. Lancet [Internet]. 2014;384(9938):164–72. Available at: https://linkinghub.elsevier.com/
retrieve/pii/S0140673613624228
61. Battisti NML, True V, Chaabouni N, Chopra N, Lee K, Shepherd S, et al. Pathological
complete response to neoadjuvant systemic therapy in 789 early and locally advanced
breast cancer patients: the Royal Marsden experience. Breast Cancer Res Treat [Internet].
2020;179(1):101–11. Available at: http://link.springer.com/10.1007/s10549-019-05444-0
62. Gianni L, Pienkowski T, Im Y-H, Roman L, Tseng L-M, Liu M-C, et al. Efficacy and safety of
neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or
early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase
2 trial. Lancet Oncol [Internet]. 2012;13(1):25–32. Available at: https://linkinghub.elsevier.
com/retrieve/pii/S1470204511703369
63. Santonja A, Sánchez-Muñoz A, Lluch A, Chica-Parrado MR, Albanell J, Chacón JI, et al.
Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant
chemotherapy. Oncotarget [Internet]. 2018;9(41):26406–16. Available at: https://www.onco-
target.com/lookup/doi/10.18632/oncotarget.25413
64. Cottu P, D’Hondt V, Dureau S, Lerebours F, Desmoulins I, Heudel P-E, et al. Letrozole and
palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer.
Ann Oncol [Internet]. 2018;29(12):2334–40. Available at: https://linkinghub.elsevier.com/
retrieve/pii/S0923753419342358
65. Haque W, Verma V, Hatch S, Suzanne Klimberg V, Brian Butler E, Teh BS. Response rates
and pathologic complete response by breast cancer molecular subtype following neoadjuvant
chemotherapy. Breast Cancer Res Treat [Internet]. 2018;170(3):559–67. Available at: http://
link.springer.com/10.1007/s10549-018-4801-3
66. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human
epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical
Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J
Clin Oncol. 2018;36(20):2105.
67. Colomer R, Mondejar R, Romero-Laorden N, Alfranca A, Sanchez-Madrid F, Quintela-
Fandino M. When should we order a next generation sequencing test in a patient with cancer?
EClinicalMedicine. 2020;25:100487.
Part II
Update in Imaging Method
Chapter 6
Radiation Based Imaging: Digital
Mammography, Tomosynthesis
Almir Galvão Vieira Bitencourt and Carolina Rossi Saccarelli
6.1 Introduction
Mammography is the most used imaging method for breast cancer screening in
average-risk women. In fact, it is still the mainstay of breast cancer screening
because it is broadly available, with established quality assurance, and has demon-
strated within multiple historic randomized controlled trials to reduce breast cancer
mortality in this population [1–4]. One of the main advantages of mammography
over other modalities is the ability to identify calcifications, which are the only ini-
tial manifestation in about 30–50% of non-palpable breast cancers, especially in
ductal carcinoma in situ (DCIS). However, mammography sensitivity for breast
cancer detection varies with breast density and is lower for women with heteroge-
neously dense or extremely dense fibroglandular tissue [5].
Radiation-based breast imaging has undergone an impressive evolution in the
past decades [6, 7]. The transition from conventional screen-film mammography to
full-field digital mammography (DM) allowed higher accuracy for women younger
than 50 years and women with heterogeneously dense or extremely dense breasts,
in addition to improvement in mammography workflow, lower radiation dose, and
faster localization procedures [8, 9]. More recently, digital breast tomosynthesis
(DBT), which is an evolution of DM, has improved both screening and diagnostic
A. G. V. Bitencourt (*)
A.C.Camargo Cancer Center, São Paulo, SP, Brazil
C. Rossi Saccarelli
Hospital Sírio-Libânes, São Paulo, SP, Brazil

Switzerland AG 2022
72 A. G. V. Bitencourt and C. Rossi Saccarelli
imaging by decreasing the confounding effect of overlapping tissue, improving

lesion detection, characterization, and localization [10, 11].
In this chapter, we will briefly discuss the technique of modern radiation-based
breast imaging methods (DM and DBT), their indications, and basic interpretation.
6.2 Technique
Radiation-based breast imaging is formed by recording pattern of X-rays transmit-

ted through the volume of the breast into an image receptor with high spatial resolu-
tion. While DM provides two-dimensional (2D) images based on stationary X-ray
emission, DBT provides multiple projection images that are acquired, while the
X-ray source makes an angular scanning motion and the acquired projections are
reconstructed to provide sections parallel to the film. Although DBT images are
acquired in low doses, the combination of DM and DBT approximately doubles the
radiation exposure to the patient. Synthetic 2D mammography from DBT images
has been developed to reduce the radiation dose with comparable diagnostic accu-
racy to DM; however, its use depends on the radiologists’ learning curve [12].
Standard views in both DM and DBT include craniocaudal (CC) and mediolat-
eral oblique (MLO) views (Fig. 6.1), which comprise routine screening exams.
Diagnostic mammography sometimes requires obtaining additional views to further
characterize inconclusive findings, which include:
a b
Fig. 6.1 Example of standard mammography views: (a) craniocaudal (CC); (b) mediolateral
oblique (MLO)
6 Radiation Based Imaging: Digital Mammography, Tomosynthesis 73
• True lateral view: it is used to determine the exact location of a lesion, to guide
stereotactic percutaneous procedures, and to evaluate calcifications of probable
intracystic nature; it can be performed in mediolateral (ML) or lateromedial
(LM) views; in both, the device will be positioned at 90° (it is usually positioned
at 45° on MLO view) (Fig. 6.2).
• Magnification view: it is mandatory for the evaluation of the morphology and
distribution of calcifications; the breast is positioned on a device which brings
the breast closer to the X-ray source and allows the acquisition of magnified
images (1.5–2x larger) of the region of interest (Fig. 6.3).
• Spot compression view: it is used on DM to perform a focal compression over
asymmetries and masses, which is used to separate overlapping structures and
improve lesion characterization (Fig. 6.4); this additional view is becoming less
frequently used after the advent of DBT.
Fig. 6.2 Example of true

lateral view on left
mammography showing a
circumscribed small mass
in the posterior third of the
upper quadrants
Fig. 6.3 Example of

magnification view on left
mammography showing
large rod-like calcifications
Fig. 6.4 Example of spot

compression view on right
mammography showing an
irregular mass with
microlobulated margins
a b
Fig. 6.5 Example of regular and rolled CC view on left mammography. Regular CC view (a)
showed an asymmetry in the outer quadrants (arrow), which was not characterized on rolled CC
view (b), corresponding to overlapped breast tissue
• Rolled CC view: it should be performed to confirm the presence and location of

a lesion only visible in CC, which often turns to be not a true lesion, but a result
of overlapped tissues in the standard view; as the spot compression, this addi-
tional view is also much less used after the advent of DBT (Fig. 6.5).
• Exaggerated CC views: also called the “Cleopatra view”; it should be performed
to access deep and lateral tissue in the outer quadrants of the breast or axillary
tail (Fig. 6.6).
• Cleavage view: also called the “valley view”; it should be used for the evaluation
of lesions in the posterior and medial portion of both breasts (Fig. 6.7).
• Axillary view: it allows to characterize structures in the axillary tail, such as level
I and II lymph nodes, palpable lesions, and metallic clips (Fig. 6.8).
a b
Fig. 6.6 Example of regular and exaggerated CC view on left mammography. Regular CC view
(a) partially showed an asymmetry in the posterior third of the outer quadrants (arrow), which was
better characterized on exaggerated CC view (b)
• Tangential view: it is useful to differentiate cutaneous from intraparenchymal

calcifications and masses (Fig. 6.9); also less used after DBT, since the slices can
demonstrate that the lesion is on the skin.
• Eklund technique: it is aimed at patients who have silicone implants and consists
of posterosuperior displacement of the implants simultaneously to an anterior
traction of the breast, allowing better visualization of the anterior breast tissue
(Fig. 6.10).
a b
Fig. 6.7 Example of cleavage view on mammography. Regular CC view (a) showed an asymme-
try in the inner quadrant of the right breast (arrow). Cleavage view (b) confirmed the finding and
also showed a contralateral symmetric finding, compatible with sternalis muscle (anatomic variant)
6.3 Indications
Mammography is considered the best imaging modality for average-risk screening

because it is the only method that has proven to be cost-effective and has shown a
reduction in breast cancer mortality [2]. However, the sensitivity of screening mam-
mography depends on factors such as the patient’s age, density of breast tissue, and
use of hormone replacement therapy. Thus, for young patients or those with dense
breasts that are at higher risk of breast cancer, other imaging methods can be associ-
ated with mammography, with the aim of increasing the sensitivity of the screening.
The recommendations of different societies differ in relation to the periodicity
(annual or biannual), age of beginning and stopping population screening [13–18].
Virtually all specialty societies recommend mammographic screening for women
between 50 and 69 years old, with an interval never exceeding 2 years. In women
Fig. 6.8 Example of right

axillary view with spot
compression showing
typical lymph nodes
Fig. 6.9 Example of

tangential view on left
mammography,
demonstrating cutaneous
calcifications (arrows)
a b
Fig. 6.10 Example of standard mammography views (a) and mammography views using Eklund
technique (b) in a patient with breast implants
between age 40 and 49, the indication for screening is controversial, because in this
population the incidence of cancer is lower and there is a higher frequency of dense
breasts, reducing the effectiveness of screening. However, several studies have
proven the benefit of mammographic screening also in this age group, especially
with DM and DBT. For women under the age of 40 years, without a high risk of
developing breast cancer, mammographic screening is not recommended due to the
low frequency of the tumor, lower sensitivity of the mammogram, and greater radio-
sensitivity of the parenchyma. For women over age of 70, the decision to suspend
screening should be individualized, considering global health, comorbidities, and
life expectancy.
Several studies have demonstrated the benefit of DBT over DM for breast cancer
screening, especially in women with dense breasts, with an increased rate of breast
cancer detection, an increase in the positive predictive value of patients summoned
for reassessment, and a reduction in the recall rates [19–24]. DBT also allows better
a b c d
Fig. 6.11 Example of architectural distortion in the upper outer quadrant of the left breast (circle),
better seen on tomosynthesis images ((b): MLO view; (d): CC view) than digital mammography
images ((a): MLO view; (c): CC view), which was confirmed as an invasive lobular carcinoma
characterization of margins and location of breast lesions due to the elimination of

tissue overlap, especially in spiculated lesions (Fig. 6.11).
In addition to breast cancer screening, DM or DBT is also indicated for evalua-
tion of patients with clinical complaints (e.g., palpable lump, pain, or nipple dis-
charge), complementary assessment of breast lesions identified in other imaging
methods, staging and therapeutic planning for patients with diagnosed breast can-
cer, and to guide percutaneous biopsy and preoperative location of lesions identified
on mammography, especially microcalcifications [25].
6.4 Interpretation
Both DM and DBT reports should follow the American College of Radiology –
Breast Imaging Reporting and Data System (ACR-BI-RADS®) lexicon and must
include indication of the exam, breast composition, and comparison with previous
exams [26]. The report must also include an assessment category and manage-
ment recommendation based on the relevant findings described on the exam and
their probability of malignancy.
6.4.1 Breast Composition
Breasts can be presented to mammography in four composition subtypes: almost

entirely fatty breasts; breasts with scattered areas of fibroglandular density; hetero-
geneously dense breasts, which may obscure small masses; and extremely dense
breasts, which lower the sensitivity of mammography (Fig. 6.12). Heterogeneously

and extremely dense breasts may require supplemental imaging to avoid false-
negative results, even on DBT.
6.4.2 Masses
They are three-dimensional findings and must be described according to the shape
(oval, round or irregular), margins (circumscribed, obscured, indistinct, microlobu-
lated and spiculated), and density in relation to the normal fibroglandular tissue
(fat-containing, low, equal, or high density) (Figs. 6.13, 6.14, and 6.15).
a b c d
Fig. 6.12 Examples of different composition subtypes on mammography: (a) almost entirely fatty
breast; (b) breast with scattered areas of fibroglandular density; (c) heterogeneously dense breast;
(d) extremely dense breast
Shape
Oval Round Irregular

Margins
Fibroglandular
Tissue
Circunscribed Obscured Indistinct Microlobulated Spiculated
Fig. 6.13 Illustration of mass shape and margins according to the BI-RADS fifth edition
a b c
d e f
Fig. 6.14 Examples of masses with different shapes and margins on mammography: (a) round
shape and circumscribed margins; (b) oval shape and circumscribed margins; (c) oval shape and
obscured margins; (d) irregular shape and microlobulated margins; (e) irregular shape and indis-
tinct margins;(f) irregular shape and spiculated margins
a b c d
Fig. 6.15 Examples of masses with different densities on mammography: (a) fat-containing oval
masses; (b) low-density oval mass; (c) equal-density (isodense) oval mass; (d) high-density irreg-
ular mass
6.4.3 Calcifications
Their morphology and distribution in the breast parenchyma must be taken into
account. According to their distribution (Fig. 6.16), they should be classified as:
• Diffuse, when they are present in the entire breast.
• Grouped, when at least five calcifications are observed in a space of less than
1 cm2, with the upper limit of 2 cm.
• Regional, when they occupy an area greater than 2 cm.
• Linear, suggesting ductal involvement.
• Segmental, inferring involvement of a ductal tree.
According to the morphology, calcifications should be classified as typically
benign (skin, vascular, coarse or popcorn-like, large rod-like, rim, dystrophic, milk
of calcium, and suture) or suspicious (amorphous, coarse heterogeneous, fine pleo-
morphic, fine linear, or fine linear branching) (Figs. 6.17 and 6.18). Round or
a b c d e
Fig. 6.16 Illustration of calcification distribution according to the BI-RADS fifth edition: (a)
grouped; (b) regional; (c) diffuse; (d) linear; (e) segmental
a b
c d
Fig. 6.17 Examples of typically benign breast calcifications on mammography: (a) skin lucent-
centered calcifications; (b) vascular calcifications in blood vessels; (c) coarse or popcorn-like cal-
cifications, typical of involuting fibroadenomas; (d) large rod-like intraductal calcifications; (e)
rim “eggshell” calcification; (f) dystrophic calcifications; (g) suture calcifications; (h) milk of cal-
cium sedimented calcifications in macro- or microcysts, usually more clearly defined on the true
lateral view
e f
g h
Fig. 6.17 (continued)
a b c d
Fig. 6.18 Examples of calcifications with suspicious morphology on mammography: (a) coarse
heterogeneous calcifications; (b) amorphous calcifications; (c) fine pleomorphic calcifications; (d)
fine linear and fine linear branching calcifications
punctate calcifications are classified based on their distribution into benign (scat-
tered or diffuse distribution), probably benign (grouped), or suspicious (linear or
segmental distribution) (Fig. 6.19).
a b
c d
Fig. 6.19 Examples of round and punctate (<0.5 mm) calcifications with different distributions on
mammography: (a) scattered isolated round calcifications (typically benign); (b) diffuse small
punctate calcifications (typically benign); (c) grouped round calcifications (probably benign); (d)
segmental round calcifications (suspicious)
6.4.4 Architectural Distortion
This finding may be related to previous surgeries and the presence or absence of
other associated findings such as nodules or microcalcifications (Fig. 6.20). If there
is no personal history of surgery, trauma, or radiation therapy, any architectural
distortion should be considered suspicious for malignancy. These findings are par-
ticularly best characterized on DBT (Fig. 6.11) [27].
6.4.5 Asymmetries
According to the ACR-BI-RADS® classification, they should be named as:

a b
Fig. 6.20 Examples of architectural distortions on mammography: (a) postoperative changes; (b)
invasive lobular carcinoma
• Asymmetry: Lesion seen in only one breast and in only one incidence of the
mammographic exam. About 80% of the asymmetries are images formed by the
overlapping of the breast tissue and complementary views such as magnification
and compression or even the repetition of the exam can be sufficient to define
whether the lesion is an image overlay or not (Fig. 6.21).
• Global asymmetry: They are seen in only one breast but in both views (caudal
skull and oblique mediolateral) and occupy an area larger than one quadrant,
being benign in most cases, except when there is an associated clinical symptom
(Fig. 6.22).
• Focal asymmetry: Lesion seen in only one breast but in both views, occupying an
area smaller than one quadrant. If there is no correspondent on ultrasound, they
are considered ACR-BI-RADS® 3 because they have a malignancy index below
1%, when they are not associated with other suspicious findings (Fig. 6.23).
• Developing asymmetry: It has the same concept as a focal asymmetry, but it is
more dense or larger when compared to the previous exam (Fig. 6.24). Therefore,
for its characterization, it is mandatory to have a previous exam for comparison,
and it has a malignancy index of 13 to 27% and should always be submitted to a
histological study (ACR-BI-RADS 4) [28].
6.4.6 Intramammary Lymph Node
They are regular nodules with a fatty central hilum, often appear close to the ves-
sels, and can present in any location of the breast, being more common in the upper
outer quadrant (Fig. 6.25) [29].
Fig. 6.21 Example of

asymmetry in the upper
quadrants of the left breast
(arrow), not seen on
CC view
Fig. 6.22 Example of global asymmetry in the right breast

Fig. 6.23 Example of focal asymmetry in the upper outer quadrant of the right breast (arrows)
a b
Fig. 6.24 Example of developing asymmetry in the central portion of the right breast (arrow in a),
not seen on prior exam (b)
6.4.7 Skin Lesions
Skin breast lesions are usually associated to benign conditions; however, they may
mimic breast lesions at mammography (Fig. 6.26). Placement of a metallic marker
on skin lesions identified prior to mammography is essential to reduce additional
Fig. 6.25 Example of

typical intramammary
lymph node in the right
breast
a b
Fig. 6.26 Example of cutaneous cyst mimicking a mass in the left breast. (a) CC view with no
marker. (b) CC view with metallic marker in the skin lesion
workup. On the other hand, breast cancer may present as a superficial lesion, and
thus, any new, increasing, or suspicious superficial finding, not related to known
skin lesions, should undergo additional imaging for further characterization [30].
6.4.8 Single Dilated Duct
It is a rare finding (Fig. 6.27), but it can be associated with DCIS. Recent studies
have suggested that the positive predictive value of this findings is low and ultra-
sound should be performed to better assess ductal content [31].
6.4.9 Associated Findings
They are the result of the effect that a lesion can cause in the surrounding tissues, includ-
ing skin thickening and retraction, nipple retraction, trabecular thickening (edema), axil-
lary adenopathy, architectural distortion, and calcifications (Figs. 6.28 and 6.29).
6.4.10 Location of Lesions
Lesions identified on DM or DBT should be located in relation to its laterality,

quadrant (or clock face), depth (anterior, middle, or posterior), and distance from
the nipple. It is important to remember that the location of a lesion in the MLO view
a b
Fig. 6.27 Example of single dilated duct in the right breast. (a) MLO view of both breasts. (b)
Spot compression view of the right breast
Fig. 6.28 Example of a malignant tumor with associated findings in the left breast, characterized
by skin and trabecular thickening (edema) and axillary adenopathy
may be different in the true lateral view. Thus, it is important to know how to prop-
erly locate the lesions, both for correlation with other imaging methods and to indi-
cate an additional incidence in the correct topography, when necessary. In general,
lesions located in the inner quadrants tend to have an upper location in the true lat-
eral view, when compared to the MLO view, while lesions located in the outer
quadrants tend to have a lower location in the true lateral view.
6.4.11 ACR-BI-RADS® Final Assessment
Based on the positive predictive values of each finding, final assessment should be
categorized in:
• BI-RADS 1 (negative; normal exam).
• BI-RADS 2 (benign findings): it includes typically benign calcifications, round
or punctate calcifications with diffuse distribution, fat-containing masses or
masses with typically benign calcifications (e.g., popcorn-like, rim or milk of
calcium), architectural distortion related to prior surgery, asymmetry or global
asymmetry with no other findings, and intramammary lymph node.
• BI-RADS 3 (probably benign; <2% likelihood of malignancy): it includes round
or punctate calcifications with grouped or regional distribution, oval masses
with circumscribed or obscured margins, and focal asymmetry with no other
associated findings.
• BI-RADS 4 (suspicious; 2–95% likelihood of malignancy): calcifications
with suspicious morphology, linear or segmental distribution, masses with
irregular shape or non-circumscribed margins, architectural distortion not
related to prior surgery, developing asymmetry, and other asymmetries with
other suspicious findings. This category can be further subdivided into 4A,
a b
Fig. 6.29 Examples of nipple retraction on mammography: (a) postoperative changes; (b) inva-
sive ductal carcinoma
4B, and 4C, with 2–10%, 10–50%, and 50–95% likelihood of malignancy,
respectively.
• BI-RADS 5 (highly suggestive of malignancy; >95% likelihood of malignancy):
more than one suspicious (BI-RADS 4) feature associated to additional findings.
• BI-RADS 6 (known biopsy-proven malignancy).
• BI-RADS 0 (incomplete; needs additional imaging evaluation or prior exams for
comparison).
6.4.12 Recommendation
Usually, routine screening is recommended for BI-RADS categories 1 and 2 exams.

Short interval (6 months) follow-up is recommended for BI-RADS category 3
exams, and tissue diagnosis (biopsy) is recommended for BI-RADS categories 4
and 5 exams. The fifth edition of the BI-RADS Atlas allows to disconnect the final
assessment category from the recommendation in selected cases [32]. For example,
in a patient with a palpable mass with normal mammography, it is possible to report
the exam as negative (BI-RADS 1) and suggest complementation with other imag-
ing tests if there is clinical suspicion. It is also possible to suggest appropriate treat-
ment for benign lesions (BI-RADS 2) or with probably benign findings (BI-RADS
3), such as inflammatory cysts and abscesses, or to suggest follow-up for suspicious
lesions (BI-RADS 4) in patients with known benign conditions, such as mastitis and
steatonecrosis.
For follow-up of probably benign lesions (BI-RADS 3), the mammography
should be repeated in 6 and 12 months of the initial examination, and in the case of
stability, control can be performed 24 months after the initial examination (it is no
longer necessary to perform follow-up exam 18 months after the initial examination
if the findings are stable after the initial 12 months).
The presence of unilateral abnormal axillary lymph nodes, without known
inflammatory or infectious etiologies, may be related to occult breast carcinoma and
should be considered suspect (category BI-RADS 4). Ideally, ultrasound should be
performed to confirm the finding as unilateral and suspicious. Bilateral lymph node
enlargement with no known cause, especially if it is a new finding, could also be
considered a suspicious finding.
6.5 Conclusions
Radiation-based breast imaging is still the most used method for screening and
diagnostic workup in clinical practice. The advent of DM and DBT has improved
mammography quality and results. Mammography findings should be reported
according to the BI-RADS lexicon, which is widely available and universally
accepted.
References
1. Myers ER, Moorman P, Gierisch JM, et al. Benefits and harms of breast cancer screening.
JAMA. 2015;314:1615. https://doi.org/10.1001/jama.2015.13183.
2. Mainiero MB, Moy L, Baron P, et al. ACR appropriateness criteria ® breast cancer screen-
inG. J Am Coll Radiol. 2017;14:S383–90. https://doi.org/10.1016/j.jacr.2017.08.044.
3. Helvie MA, Bevers TB. Screening mammography for average-risk women: the controversy
and NCCN’s position. J Natl Compr Cancer Netw. 2018;16:1398–404. https://doi.org/10.6004/
jnccn.2018.7081.
4. Saccarelli CR, Bitencourt AGV, Morris EA. Is It the era for personalized screening? Radiol
Clin N Am. 2021;59:129–38. https://doi.org/10.1016/j.rcl.2020.09.003.
5. Vourtsis A, Berg WA. Breast density implications and supplemental screening. Eur Radiol.
2019;29:1762–77. https://doi.org/10.1007/s00330-018-5668-8.
6. Joe BN, Sickles EA. The evolution of breast imaging: past to present. Radiology.
2014;273:S23–44. https://doi.org/10.1148/radiol.14141233.
7. Garcia EM, Crowley J, Hagan C, Atkinson LL. Evolution of imaging in breast cancer. Clin
Obstet Gynecol. 2016;59:322–35. https://doi.org/10.1097/GRF.0000000000000193.
8. Lewin JM, D’Orsi CJ, Hendrick RE. Digital mammography. Radiol Clin N Am.
2004;42:871–84. https://doi.org/10.1016/j.rcl.2004.06.004.
9. Bick U, Diekmann F. Digital mammography: what do we and what don’t we know? Eur
Radiol. 2007;17:1931–42. https://doi.org/10.1007/s00330-007-0586-1.
10. Kopans DB. Digital breast tomosynthesis from concept to clinical care. Am J Roentgenol.
2014;202:299–308. https://doi.org/10.2214/AJR.13.11520.
11. Nguyen T, Levy G, Poncelet E, et al. Overview of digital breast tomosynthesis: clinical cases,
benefits and disadvantages. Diagn Interv Imaging. 2015;96:843–59. https://doi.org/10.1016/j.
diii.2015.03.003.
12. Abdullah P, Alabousi M, Ramadan S, et al. Synthetic 2D mammography versus standard 2D
digital mammography: a diagnostic test accuracy systematic review and meta-analysis. Am J
Roentgenol AJR. 2020;20:24204. https://doi.org/10.2214/AJR.20.24204.
13. Oeffinger KC, Fontham ETH, Etzioni R, et al. Breast cancer screening for women at average
risk. JAMA. 2015;314:1599. https://doi.org/10.1001/jama.2015.12783.
14. Siu AL. Screening for breast cancer: U.S. Preventive Services Task Force recommendation
statement. Ann Intern Med. 2016;164:279. https://doi.org/10.7326/M15-2886.
15. Monticciolo DL, Newell MS, Hendrick RE, et al. Breast cancer screening for average-risk
women: recommendations from the ACR commission on breast imaging. J Am Coll Radiol.
2017;14:1137–43. https://doi.org/10.1016/j.jacr.2017.06.001.
16. Sardanelli F, Aase HS, Álvarez M, et al. Position paper on screening for breast cancer by
the European Society of Breast Imaging (EUSOBI) and 30 national breast radiology bod-
ies from Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic,
Denmark, Estonia, Finland, France, G. Eur Radiol. 2017;27:2737–43. https://doi.org/10.1007/
s00330-016-4612-z.
17. Qaseem A, Lin JS, Mustafa RA, et al. Screening for breast cancer in average-risk women: a
guidance statement from the American College of Physicians. Ann Intern Med. 2019;170:547.
https://doi.org/10.7326/M18-2147.
18. Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 201930(8):1194–220. https://
doi.org/10.1093/annonc/mdz173.
19. Sharpe RE, Venkataraman S, Phillips J, et al. Increased cancer detection rate and variations
in the recall rate resulting from implementation of 3D digital breast tomosynthesis into a
population-based screening program. Radiology. 2016;278:698–706. https://doi.org/10.1148/
radiol.2015142036.
20. Rose SL, Shisler JL. Tomosynthesis impact on breast cancer screening in patients younger than
50 years old. Am J Roentgenol. 2018;210:1401–4. https://doi.org/10.2214/AJR.17.18839.
21. Alsheik NH, Dabbous F, Pohlman SK, et al. Comparison of resource utilization and clini-
cal outcomes following screening with digital breast tomosynthesis versus digital mammog-
raphy: findings from a learning health system. Acad Radiol. 2019;26:597–605. https://doi.
org/10.1016/j.acra.2018.05.026.
22. Conant EF, Barlow WE, Herschorn SD, et al. Association of digital breast tomosynthesis vs
digital mammography with cancer detection and recall rates by age and breast density. JAMA
Oncol. 2019;5:635.
23. Dang PA, Wang A, Senapati GM, et al. Comparing tumor characteristics and rates of breast
cancers detected by screening digital breast tomosynthesis and full-field digital mammogra-
phy. Am J Roentgenol. 2020;214:701–6. https://doi.org/10.2214/AJR.18.21060.
24. Bahl M, Mercaldo S, Dang PA, et al. Breast cancer screening with digital breast tomosyn-
thesis: are initial benefits sustained? Radiology. 2020;295:529–539 https://doi.org/10.1148/
radiol.2020191030.
25. Jackson VP. Diagnostic mammography. Radiol Clin N Am. 2004;42:853–70. https://doi.
org/10.1016/j.rcl.2004.06.002.
26. Sickles EA, D’Orsi CJ, Mendelson EB, Morris E, et al. ACR BI-RADS® mammography. In:
ACR BI-RADS® Atlas, breast imaging reporting and data system. 5th ed. Reston; 2013.
27. Durand MA, Wang S, Hooley RJ, et al. Tomosynthesis-detected architectural distortion: man-
agement algorithm with radiologic-pathologic correlation. Radiographics. 2016;36:311–21.
https://doi.org/10.1148/rg.2016150093.
28. Chesebro AL, Winkler NS, Birdwell RL, Giess CS. Developing asymmetries at mammography:
a multimodality approach to assessment and management. Radiographics. 2016;36:322–34.
29. Bitencourt AG, Ferreira EV, Bastos DC, et al. Intramammary lymph nodes: normal and abnor-
mal multimodality imaging features. Br J Radiol. 2019;92:20190517. https://doi.org/10.1259/
bjr.20190517.
30. Giess CS, Raza S, Birdwell RL. Distinguishing breast skin lesions from superficial breast
parenchymal lesions: diagnostic criteria, imaging characteristics, and pitfalls. Radiographics.
2011;31:1959–72. https://doi.org/10.1148/rg.317115116.
31. Choudhery S, Simmons C, Woodard GA, et al. Outcomes of solitary dilated breast ducts
in symptomatic and asymptomatic patients. Br J Radiol. 2020;93:20191039. https://doi.
org/10.1259/bjr.20191039. https://doi.org/10.1001/jamaoncol.2018.7078
32. Rao AA, Feneis J, Lalonde C, Ojeda-Fournier H. A pictorial review of changes in the BI-RADS
fifth edition. Radiographics. 2016;36:623–39. https://doi.org/10.1148/rg.2016150178.
Chapter 7
Sonographic Based Imaging:
Ultrasound, Color Doppler, Elastography,
and Automated Breast Imaging
Juliana Hiraoka Catani
Abbreviations
ABUS Automated breast ultrasound

HHUS Handheld ultrasound
MRI Magnetic resonance imaging
ROI Region of interest
SE Strain elastography
SWE Shear wave elastography
US Ultrasound
7.1 Introduction
Ultrasound (US) is an interactive, dynamic, and real-time method that has become
an indispensable resource for breast assessment, both together and complementary
to mammography and magnetic resonance imaging (MRI). In the past, only mam-
mography has been useful for population-based screening. However, high-resolution
and quality-controlled ultrasound can further improve early cancer detection.
US has been used to classify benign, solid lesions with a negative predictive
value of 99.5% [1].
US advantages include:
(a) No exposure to radiation and its related risks
J. H. Catani (*)
Instituto de Radiologia INRAD, Hospital das Clinicas HCFMUSP, Faculdade de Medicina,
Universidade de Sao Paulo, São Paulo, SP, Brazil

Switzerland AG 2022
98 J. H. Catani
(b) No tissue injury from US waves

(c) No contraindications
Ease of use and real-time imaging capability make breast ultrasound a method of
choice for guiding breast biopsies and other interventions.
The limitations include:
(a) Inability to identify and characterize calcifications.
(b) Diagnostic performance is operator dependent.
(c) Large, mobile breasts will be difficult to scan thoroughly.
Currently accepted clinical indications include palpable lump; axillary adenopa-
thy; first diagnostic approach for clinical abnormalities under 40 and in pregnant or
lactating women; suspicious abnormalities at mammography or MRI; nipple dis-
charge; recent nipple inversion; skin retraction; breast inflammation; surgical scar
abnormalities; abnormalities in the presence of breast implants; screening high-risk
women and locoregional staging of a known breast cancer when MRI is not per-
formed; guidance for percutaneous interventions; and monitoring breast cancer
neoadjuvant therapy. US can also be used as an adjunctive modality for breast can-
cer screening in women with dense breast tissue and negative mammography.
The ultrasound device emits and receives high-frequency electromechanical
waves (ultrasound) that are generated by the piezoelectric crystals contained in the
transducer. According to the impedance of each tissue, images in gray scale (B
mode) are generated.
For the examination, proper positioning is essential, aiming at reducing breast
thickness and mobility.
7.2 Scanning Technique
For positioning, the patient should lie down in the supine position with the chest
undressed and with arms relaxed and flexed behind the head to flatten the breast. It
might be necessary to roll the patient slightly to access the breast evenly.
The scan with the transducer should be done in at least two orthogonal planes,
including the peripheral regions of the breasts and lymphatic drainage pathways. As the
lactiferous ducts are arranged radially in the nipple, and the lesions tend to grow along
the ducts, the radial scan is favored by being anatomically guided (Figs. 7.1 and 7.2).
Medial structures should generally be scanned in the supine position, and lateral
structures including the armpit should generally be scanned with the patient in the
contralateral oblique position. This allows for the elimination of possible artifacts
secondary to inadequate compression of the breast tissue.
7.2.1 The Ideal Image
When examining the breast, a 12- to 18-MHz multifrequency linear transducer is

commonly used (a minimum frequency of 10 MHz is required) [2, 3] and provides
7 Sonographic Based Imaging: Ultrasound, Color Doppler, Elastography, and… 99
Fig. 7.1 Radial and

anti-radial scanning
Fig. 7.2 Longitudinal and

transverse scan
excellent spatial and soft tissue resolution, allowing for substantially improved dif-
ferentiation of subtle shades of gray, margin resolution, and conspicuousness of the
lesion at the bottom of normal breast tissue [2, 4–8].
The initial gain settings must be adjusted so that the fat at all levels is displayed
as medium level gray (calibrated by the superficial fat to the breast area).
The echogenicity of the structures is determined by comparison with the echo-
genicity of the fat. In comparison with breast fat, most solid masses are hypoechoic
and simple cysts anechoic, while skin, Cooper’s ligaments, and fibrous tissue are
echogenic.
100 J. H. Catani
Gentle pressure should be applied to the transducer during the examination. The
smaller the thickness of the tissue, the higher the image resolution. The increase in
pressure can have a beneficial effect on the acquired image, which can reduce arti-
factual shadows, as well as making it difficult to evaluate compressible structures
(ducts and vessels).
7.2.2 Anatomy
The region of interest in the breast comprises the portion from the skin surface (a)
and subcutaneous tissue (b) to the pleural surface/posterior chest wall (Fig. 7.3).
The areolopapillary complex is formed by the areola, papilla, and lactifer-
ous ducts.
The mammary zone (c) is formed by glandular and adipose tissue and Cooper’s
ligaments, where most of the breast ducts and lobules are located, and therefore the
main area of breast diseases.
The retromammary zone (d) is formed by retromammary fat, pectoral muscle,
ribs, and pleural surface.
The axillary region is the pyramidal space inferior to the glenohumeral joint, at
the junction between the arm and thorax, and contains many neurovascular struc-
tures, including the axillary artery, axillary vein, brachial plexus, and lymph nodes.
The anatomical repair used to classify lymph node levels in the axilla is the pec-
toralis minor muscle (highlighted in red in Fig. 7.4), being:
• Level I: lateral to the pectoralis minor muscle
• Level II: between the medial and lateral borders of the pectoralis minor muscle
• Level III: medial to the pectoralis minor muscle
Fig. 7.3 (a) – Skin surface. a

(b) – Subcutaneous tissue.
(c) – Mammary zone. b
(d) – Retromammary zone
c
d
7.2.3 Harmonic
The harmonic image can also be applied to better characterize a cyst or a subtle
solid mass. The generation of harmonic images allows the higher harmonic waves
to be selected and used to create the grayscale images with fewer artifacts [9].
Low-frequency surface reverberation echoes are thus reduced, allowing better
characterization of simple cysts (particularly if small) by eliminating artificial inter-
nal echoes often seen in fluids (Fig. 7.5).
Fig. 7.4 Pectoralis minor muscle (highlighted in red, left axilla)
Fig. 7.5 Cyst with harmonic resource (left) and without harmonic resource (right), showing atten-
uation of internal echoes and confirming that it is a simple cyst
102 J. H. Catani
Harmonic imaging also improves lateral resolution and can improve the contrast
between adipose tissue and subtle lesions, allowing for better definition of lesion
margins and posterior shading.
7.2.4 Compound Imaging
Compound imaging shows improved image quality compared with conventional

ultrasound, primarily because of reduction of speckle, clutter, and other acoustic
artifacts.
The compound imaging feature acquires images at multiple angles from an
insonation plane, reducing artifact echoes and increasing the image contrast, but
there is a loss of image quality from the deepest planes (Fig. 7.6).
7.3 Doppler Evaluation
The evaluation through color mapping on the breast is based on the argument that
malignant or inflammatory lesions can cause angiogenesis and these vessels are
identified on the periphery or inside the lesions.
Currently, both power and color Doppler are complementary tools to the gray-
scale image, although power Doppler mode is favored for being more sensitive
when viewing small vessels, and factors such as flow direction and spectral evalua-
tion are not relevant.
Fig. 7.6 Left – B mode. Right – compound imaging

Malignant breast lesions typically produce pro-angiogenic factors that stimulate

neoangiogenesis and the growth of new irregular and branching vessels. Aggressive
malignant lesions can exhibit little or no blood flow due to small lesions (bigger
lesions tend to show more vascularization), the presence of posterior acoustic shad-
owing, and necrotic anechoic areas. Benign lesions usually do not show irregular
branching, chaotic vessels, or formation of sinusoids and arteriovenous shunts [2, 3].
The evaluation of masses must be correlated with ultrasound findings, emphasiz-
ing that no vascular pattern is specific to a particular diagnosis.
The technique consists of visualizing the area of interest with the Doppler mode,
performing small compression on the breast, as small vessels may not be identified
with too much pressure from the transducer.
The demonstration of central or penetrating vascularization of irregular branch-
ing within a solid mass raises suspicion of malignant neovascularization [2, 3].
Color Doppler and power US are also useful for evaluating cysts and complex
cystic masses that contain a solid component. The demonstration of flow within an
apparently simple cyst, a complicated cyst, or a complex mass confirms the pres-
ence of a suspect solid component, which requires biopsy. The twinkle artifact seen
with color Doppler is useful for identifying a biopsy marker or subtle echogenic
calcifications.
By ACR BI-RADS, the findings on color Doppler mapping are classified as
(Figs. 7.7, 7.8, and 7.9):
(a) Absent
(b) Internal vascularization
(c) Peripheral vascularization
It is important to note that these findings can overlap and sometimes benign
lesions have internal and exuberant vascularization and malignant lesions can pres-
ent absent or peripheral vascularization (Fig. 7.10).
Fig. 7.7 Absent, when no

vessel is identified in the
region of interest, common
in simple cysts and some
benign masses
104 J. H. Catani
Fig. 7.8 Internal

vascularization, when
vessels (sometimes more
than one) are identified
inside the lesion, the most
common finding in
malignant neoplasms
Fig. 7.9 Peripheral

vascularization, when
vessels are found
surrounding the lesion,
more common in
inflammatory processes
and benign solid masses
Fig. 7.10 New, solid, hypoechoic, oval, and circumscribed mass, with peripheral and central vas-
cularization, and branched vessels on color Doppler. Patient underwent a percutaneous biopsy and
was diagnosed with adrenal carcinoma metastasis
7.4 Elastography
Ultrasound elastography is an established method for characterization of focal

lesions in the breast and can be used to measure tissue stiffness with the potential to
improve specificity in the diagnosis of breast masses. There are two forms of elas-
tography available: strain (SE) and shear wave (SWE).
This technique assesses tissue elasticity, which is the tendency of tissue to resist
deformation with an applied force, or to return to its original shape after removal of
the force [9–11].
Obtaining a good grayscale image is essential before changing to the elastogra-
phy mode since SE and SWE images are often generated based on raw data from
grayscale images.
Ultrasound elastography has 86.5% sensitivity, 89.8% specificity, and 88.3%
diagnostic accuracy in the differentiation of benign from malignant solid breast
masses [12].
Elastography is a useful complementary tool for undetermined breast lesions
categorized as BI-RADS 4A or BI-RADS 3 or for cystic lesions but cannot avoid
investigation if ultrasound features are clearly suspicious.
Some benign lesions can be poorly deformable, such as fibrous fibroadenomas or
scars. The presence of implants can also change the strain of breast tissue around the
implant, complicating elastography assessment.
The bull’s eye cyst pattern can be seen with lesions that appear solid and suspi-
cious on B-mode imaging. It occurs because of the fluid movement, and there is no
correlation between images.
In ACR BI-RADS, the elastography findings are divided into:
(a) Stiff or hard.
(b) Intermediate.
(c) Soft, and this relationship is made with adjacent adipose tissue.
7.4.1 Strain Elastography
In this technique, a normal stress is applied to tissue (gentle compression or natural

movement such as heartbeat, vascular pulse, or breathing), and the normal strain is
measured. Under an equal amount of stress, a stiff region experiences less strain
than the surrounding soft tissue.
For breast imaging, the region of interest (ROI) should extend anterior-posteriorly
from the subcutaneous fat tissue to the pectoralis muscle, excluding the thoracic
cage, and the width should be adjusted to keep the lesion of interest within 25% of
the ROI width [13].
The information obtained with strain elastography provides qualitative informa-
tion (hard, intermediate, soft).
106 J. H. Catani
Tsukuba Scoring System

A color-coded scoring system has been proposed by Itoh et al. [12], most com-
monly used for SE. The strain in lesion tissue is displayed in a color-coded image.
The scoring system assigns a score from 1 to 5 (Fig. 7.11) with the risk of malig-
nancy increasing from 1 to 5 (Fig. 7.12):
The risk of malignancy increases from 1 to 5.
7.4.2 Shear Wave Elastography
In contrast to strain imaging, SWE employs a higher intensity pulse to generate

shear waves in the parallel or perpendicular dimensions.
a b
c d
Fig. 7.11 (a) Score 1: complete deformability of lesion. (b) Score 2: most of the lesion is deform-
able although there are areas which are not deformable. (c) Score 3: presence of stiff area in center
with peripheral deformability of lesion. (d) Score 4: no deformability throughout the entire lesion
only. (e) Score 5: no deformation throughout the entire lesion or in adjacent tissue
Fig. 7.12 Solid, hypoechoic, irregular, and microlobulated lesion on the grayscale B-mode image
(right). Color mapping SE image (left) showing the same lesion shaded in blue color (hard lesion
in the color scale used)
With the use of light transducer pressure, automatic transient pulses can be gen-
erated by the US probe, inducing shear waves transversely oriented in the tissue.
The system captures the speed of these shear waves, which move faster in hard tis-
sue compared to soft tissue.
To measure the elasticity quantitatively in SWE for breast lesions, the most com-
mon practice is to place a 2- to 3-mm circular ROI over the stiffest part of the lesion,
including the immediately adjacent stiff tissue or halo [14].
Shear wave elastography provides quantitative information because tissue elas-
ticity can be measured in meters per second or kilopascals, a unit of pressure. A
value of over 80 kPa or velocity results of over 2 m/s are considered suspicious
(Figs. 7.13 and 7.14).
7.5 Automated Breast Ultrasound
Automated breast ultrasound (ABUS) is used as a supplement to mammography for

screening in asymptomatic women with dense breasts. It is an effective screening
modality with diagnostic accuracy comparable to that of handheld ultrasound
(HHUS) [10, 15].
108 J. H. Catani
Fig. 7.13 Solid, hypoechoic, irregular, and microlobulated lesion on the grayscale B-mode image
(right), poorly deformable in color-mode SWE (left)
Fig. 7.14 Velocities measured in the lesions are very high (>3 m/s), which suggests a malig-
nant lesion
ABUS consists of a US scanner and special stationary device with a transducer,

which moves automatically in a scan box. The slice thickness is adjustable from
0.5 mm to 8.0 mm, and up to 448 axial slices are acquired [10, 15].
The sequence of the technique consists of three steps: patient positioning, image
acquisitions, and interpretation of data.
The patient lies down in the supine position with the ipsilateral hand raised above
the head. A rolled towel is placed under each shoulder to help stabilize the breast
with the nipple pointing to the ceiling. A hypoallergenic lotion is spread out evenly
on the breast with an additional amount on the nipple area. A nipple marker is
placed in every examination for accurate correlation of the reformatted views.
The exam is performed in anteroposterior, medial, and lateral views routinely
and in the superior or inferior view additionally in cases of large breasts. Image
acquisition in six views takes approximately 10–15 min.
The optimal image quality should be guaranteed for screening. However, the
image quality and ultrasonic resolution diminish with poor contact, marked shad-
owing due to fibrotic breasts, and artifacts.
ABUS presents some limitations such as inability to assess vascularity and tissue
elasticity and exclusion of axillary regions from the field of view. ABUS screening
is also limited by its high recall rate and biopsy rate with low positive predictive
value (PPV), similar to HHUS screening.
The most common artifacts in ABUS are:
(a) Corrugation, which is due to respiratory motion; this artifact can be avoided
when women breathe calmly and do not speak or cough.
(b) Dropout shadowing deep to the skin, caused by insufficient lotion application
and extreme compression.
(c) Nipple shadow and reverberation artifacts frequently occurred with ABUS.
(d) Skip artifacts present as a transverse anechoic line at the location of change in
tissue stiffness due to a mass and can be used to detect isoechoic masses.
(e) In the study by Vourtsis and Kachulis [13], a “zigzag” sign was produced by
disruption of the scanning process in 61.5% of women with palpable lesions.
Studies have shown that ABUS is a standardized and reproducible imaging
modality that surmounts the limitations of HHUS, while offering valuable impact in
the detection of breast lesions, and differentiates malignant from benign lesions,
with a high inter-observer reliability [10, 13, 15, 16].
7.6 Correlation with Other Imaging Methods
When looking for a lesion initially identified on mammography or MRI, careful

correlation must be made with the depth of the lesion and surrounding anatomical
structures.
The location of the lesion can be affected by the patient’s position, which differs
during mammography, US, and MRI exams (Figs. 7.15 and 7.16).
110 J. H. Catani
Fig. 7.15 When performing the correlation with mammography and MRI, take into account loca-
tion (superficial, medium, and deep thirds), dimensions, shape, and margin
Fig. 7.16 Oily cysts in the posterior third of the right breast seen on mammography and their cor-
respondence in the ultrasound study, next to the pectoral muscle
If a mass identified on mammography or magnetic resonance imaging is com-

pletely surrounded by adipose or fibroglandular tissue, on US, it must also be sur-
rounded by hypoechoic tissue or echogenic fibroglandular tissue, respectively.
Lesions detected by MRI images are usually hidden in mammography, but many
can be detected with the US. Along with the additional characterization of a lesion
detected by MRI, US can be used to guide the intervention toward lesions initially
detected in MRI (Fig. 7.17).
Likewise, careful attention is needed to the region of clinical interest when exam-
ining a palpable abnormality to ensure that the correct area is scanned. The exam-
iner should place a finger on the palpable abnormality and then position the
transducer directly over the region.
7.7 Exam Documentation
According to ACR BI-RADS®, the documentation must contain the breast that is
being studied, the laterality, and the place of the “body mark,” thus reducing any
errors in laterality and quadrant (Fig. 7.18).
When documenting findings, the adjustment of focus and gain and frequency
must be made and must contain images with and without measures to allow the
evaluation of margins in still images. The location should be noted in laterality,
quadrant, and/or clock face notation on the breast [9].
The size of the lesion should be measured in three dimensions, first reporting the
longest diameter and the rest in the orthogonal plane (Figs. 7.19 and 7.20). The
measurement can be made in millimeters or centimeters, rounding to just one deci-
mal place [7].
In the presence of multiple cysts, documentation of the largest cyst in each breast
and the measurement of its largest dimension can be made. In the presence of a
normal lymph node, the same documentation can be performed.
Measure the longest axis (1) and perpendicular to the first (2). The third measure
(3) should be taken from a plane orthogonal to the first image.
Fig. 7.17 Non-mass enhancement associated with architectural distortion in the posterior third of
the outer quadrants of the left breast in the mammary zone (surrounded by fibroglandular tissue)
and its ultrasound correspondence (“second-look” ultrasound)
112 J. H. Catani
Fig. 7.18 US
documentation with
laterality, quadrant, and
body mark
Fig. 7.19 Mass documentation in two plans without and with measures
The distance between the papilla and the lesion, and from this to the skin, is use-
ful information and easy to identify by any operator, facilitating eventual localiza-
tion during surgery and for evolutive control (Fig. 7.21).
A color Doppler/power Doppler image is recommended to assess the vascular-
ization of the documented lesion (Fig. 7.22).
The documentation on breast screening without changes should contain the four
quadrants and the retroareolar region.
Fig. 7.20 Incorrect

measurement, not
respecting the largest axis
of the lesion
Fig. 7.21 Distance

between the mass and the
papilla (1) and the skin (2)
a b
Fig. 7.22 Isoechoic mass that is difficult to characterize in B mode (a), but well delimited with the
use of power Doppler (b)
Axilla documentation is not mandatory under the American College of Radiology

(ACR) but can be performed as a courtesy when performing breast exams.
The ultrasound evaluation of breast implants must be performed in two separate
steps, with adjustments of focus, gain, and depth for the evaluation of the paren-
chyma and later for the evaluation of the implant (Figs. 7.23 and 7.24).
114 J. H. Catani
7.8 BI-RADS® Lexicon
1. Breast composition
Can be homogeneous background – fat or fibroglandular or heterogeneous back-
ground echotexture (Figs. 7.25, 7.26, and 7.27).
Fig. 7.23 Adjustment of

focus and depth for
evaluation of the breast
parenchyma
Fig. 7.24 Adjustment of

focus and depth for
evaluation of the implant
Fig. 7.25 Homogeneous

background
echotexture – fat
Fig. 7.26 Homogeneous

background
echotexture –
fibroglandular
Fig. 7.27 Heterogeneous

background echotexture
2. The characteristics of a mass that must be evaluated and included in the report
include:
(a) Shape
Shape can be oval, round, or irregular (Figs. 7.28, 7.29, and 7.30).
(b) Margin
Can be circumscribed or non-circumscribed (indistinct, angular, microlobu-
lated, or spiculated) (Figs. 7.31, 7.32, 7.33, 7.34, and 7.35).
(c) Orientation (in relation to the skin surface)
Parallel or non-parallel (Figs. 7.36 and 7.37).
(d) Echogenicity
Can be anechoic, hyperechoic, hypoechoic, isoechoic, complex cystic solid,
or solid, heterogeneous (Figs. 7.38, 7.39, 7.40, 7.41, 7.42, and 7.43).
(e) Posterior features
116 J. H. Catani
Fig. 7.28 Oval
Fig. 7.29 Round
Fig. 7.30 Irregular

Fig. 7.31 Circumscribed
Fig. 7.32 Non-circum-

scribed – indistinct

scribed – angular
118 J. H. Catani

scribed – microlobulated

scribed – spiculated
Fig. 7.36 Parallel

Fig. 7.37 Non parallel
Fig. 7.38 Anechoic
Fig. 7.39 Hyperechoic

120 J. H. Catani
Fig. 7.40 Hypoechoic
Fig. 7.41 Isoechoic
No posterior features, enhancement, shadowing, or combined pattern

(Figs. 7.44, 7.45, and 7.46).
3. Calcifications
Can be in a mass, outside a mass or intraductal (Figs. 7.47, 7.48, and 7.49).
4. Associated findings
(a) Architectural distortion (Fig. 7.50).
(b) Ductal changes (Fig. 7.51).
(c) Skin changes
(i) Skin thickening (Fig. 7.52).
(ii) Skin retraction (Fig. 7.53).
Fig. 7.42 Complex cystic

solid
Fig. 7.43 Solid,

heterogeneous
Fig. 7.44 No posterior

features
122 J. H. Catani
Fig. 7.45 Enhancement
Fig. 7.46 Shadowing
Fig. 7.47 Calcifications in

a mass
Fig. 7.48 Calcifications

outside of a mass
a b
Fig. 7.49 A 75-year-old patient undergoing breast cancer screening. Linear calcifications on the
right papilla on mammography (a). US shows hyperechoic foci within the papilla (b). In color
Doppler (c), these foci have a “twinkle” artifact
(d) Edema (Fig. 7.54).

(e) Vascularity
(i) Absent
(ii) Internal vessels
(iii) Vessels in rim
(f) Elastography assessment
(i) Soft
(ii) Intermediate
(iii) Hard
124 J. H. Catani
Fig. 7.50 Architectural

distortion after breast
conservation surgery
Fig. 7.51 Duct ectasia
Fig. 7.52 Skin thickening

Fig. 7.53 Nipple

retraction secondary to an
irregular mass
Fig. 7.54 Skin and

parenchymal edema
5. Special cases
(a) Simple cyst (Fig. 7.55).
(b) Clustered microcysts (Fig. 7.56).
(c) Complicated cyst (Fig. 7.57).
(d) Mass in or on skin (Fig. 7.58).
(e) Foreign body, including implants (Fig. 7.59).
(f) Lymph nodes: intramammary, axillary (Fig. 7.60).
(g) Vascular abnormalities (Fig. 7.61).
(h) Postsurgical fluid collection (Fig. 7.62).
(i) Fat necrosis (Fig. 7.63).
126 J. H. Catani
Fig. 7.55 Cyst
Fig. 7.56 Clustered

microcysts
7.9 Report and Assessment
The preparation of the ultrasound report must contain the indication of the exam, the
breast composition, a brief description of the lesion according to ACR BI-RADS,
comparison with previous exams, final impression, and recommendation.
The report should conclude a summary of relevant US findings with a final
assessment using BI-RADS® US categories 1–6 and the phrases associated
with them.
If report of a US examination is integrated with a concurrently mammographic
examination, the combined final assessment should reflect the highest likelihood of
malignancy assessed by the two exams [7].
Fig. 7.57 Complicated cyst
Fig. 7.58 Skin lesion. Ultrasound demonstrates skin thickening with increased vascularity
7.9.1 BI-RADS® Categories
1. Category 0: incomplete – need additional imaging evaluation.

2. Category 1: negative – 0% likelihood of malignancy – routine screening is
recommended.
128 J. H. Catani
Fig. 7.59 Breast implant

rupture
Fig. 7.60 Abnormal

lymph node
Fig. 7.61 An 8-month-old with circumscribed, hypoechoic, and heterogeneous mass in the upper
outer quadrant of the left breast. Color Doppler shows high flow in the entire lesion with a vascular
pedicle, consistent with arteriovenous malformation
3. Category 2: benign – 0% likelihood of malignancy – routine screening is

recommended.
4. Category 3: probably benign – ≤2% likelihood of malignancy – follow-up is
recommended (6 months, 12 months, 24 months, optional 36 months).
5. Category 4: suspicious – >2% but <95% likelihood of malignancy – tissue sam-
pling is recommended.
Fig. 7.62 Postsurgical

fluid collection
Fig. 7.63 Irregular mass in a patient with a history of surgical manipulation, requiring further
evaluation with mammography. The correlation with mammography showed that it was
steatonecrosis
BI-RADS subdivides category 4 assessments by likelihood of malignancy

into categories 4A (>2% to ≤10%), 4B (>10% to ≤50%), and 4C (>50%
to <95%).
6. Category 5: highly suggestive of malignancy – ≥95% likelihood of malignancy –
tissue sampling is recommended.
7. Category 6: known biopsy-proven malignancy – surgical excision when clini-
cally appropriate.
130 J. H. Catani
References
1. Stavros AT, Thickman D, Rapp CL, Dennis MA, Parker SH, Sisney GA. Solid breast nod-
ules: use of sonography to distinguish between benign and malignant lesions. Radiology.
1995;196(1):123–34.
2. Watanabe T, Kaoku S, Yamaguchi T, Izumori A, Konno S, Okuno T, Tsunoda H, Ban K,
Hirokaga K, Sawada T, Ito T, Nakatani S, Yasuda H, Tsuruoka M, Ueno E, Tohno E, Umemoto
T, Shirakawa T. Multicenter prospective study of color Doppler ultrasound for breast masses:
utility of our color Doppler method. Ultrasound Med Biol. 2019;45(6):1367–79. https://doi.
org/10.1016/j.ultrasmedbio.2019.01.021. PMID: 30905536.
3. Cho N, Jang M, Lyou CY, Park JS, Choi HY, Moon WK. Distinguishing benign from malig-
nant masses at breast US: combined US elastography and color doppler US–influence on radi-
ologist accuracy. Radiology. 2012;262(1):80–90. https://doi.org/10.1148/radiol.11110886.
PMID: 22084209.
4. Hooley RJ, Scoutt LM, Philpotts LE. Breast ultrasonography: state of the art. Radiology.
2013;268(3):642–59. https://doi.org/10.1148/radiol.13121606. PMID: 23970509.
5. https://www.acr.org/-/media/ACR/Files/Practice-Parameters/US-Breast.pdf. Assessed 15
Dec 2020.
6. Monticciolo DL, Newell MS, Moy L, Niell B, Monsees B, Sickles EA. Breast cancer screen-
ing in women at higher-than-average risk: recommendations from the ACR. J Am Coll
Radiol. 2018;15(3 Pt A):408–14. https://doi.org/10.1016/j.jacr.2017.11.034. PubMed PMID:
29371086.
7. Mendelson EB, Bõhm-Vélez M, Berg WA, et al. ACR BI-RADS® ultrasound. In: ACR
BI-RADS® atlas, breast imaging reporting and data system. Reston: American College of
Radiology; 2013.
8. Leung JW, Sickles EA. Multiple bilateral masses detected on screening mammography:
assessment of need for recall imaging. AJR Am J Roentgenol. 2000;175(1):23–9. https://doi.
org/10.2214/ajr.175.1.1750023. PMID: 10882241.
9. Barr RG. Breast elastography: how to perform and integrate into a “best-practice” patient
treatment algorithm. J Ultrasound Med. 2020;39(1):7–17. https://doi.org/10.1002/jum.15137.
PMID: 31617225.
10. Vourtsis A. Three-dimensional automated breast ultrasound: technical aspects and first results.
Diagn Interv Imaging. 2019;100(10):579–92. https://doi.org/10.1016/j.diii.2019.03.012.
PMID: 30962169.
11. Hao SY, Jiang QC, Zhong WJ, Zhao XB, Yao JY, Li LJ, Luo BM, Ou B, Zhi H. Ultrasound
elastography combined with BI-RADS-US classification system: is it helpful for the diag-
nostic performance of conventional ultrasonography? Clin Breast Cancer. 2016;16(3):e33–41.
https://doi.org/10.1016/j.clbc.2015.10.003. PMID: 26639065.
12. Itoh A, Ueno E, Tohno E, Kamma H, Takahashi H, Shiina T, Yamakawa M, Matsumura
T. Breast disease: clinical application of US elastography for diagnosis. Radiology.
2006;239(2):341–50. https://doi.org/10.1148/radiol.2391041676. PMID: 16484352.
13. Vourtsis A, Kachulis A. The performance of 3D ABUS versus HHUS in the visualisation and
BI-RADS characterisation of breast lesions in a large cohort of 1,886 women. Eur Radiol.
2018;28(2):592–601. https://doi.org/10.1007/s00330-017-5011-9. PMID: 28828640.
14. Youk JH, Gweon HM, Son EJ. Shear-wave elastography in breast ultrasonography: the state
of the art. Ultrasonography. 2017;36(4):300–9. https://doi.org/10.14366/usg.17024. PMID:
28513127; PMCID: PMC5621798.
15. Kim SH. Image quality and artifacts in automated breast ultrasonography. Ultrasonography.
2019;38(1):83–91. https://doi.org/10.14366/usg.18016. PMID: 30139244; PMCID:
PMC6323315.
16. Kaplan SS. Automated whole breast ultrasound. Radiol Clin N Am. 2014;52(3):539–46.
https://doi.org/10.1016/j.rcl.2014.01.002. PMID: 24792655.
Chapter 8
Magnetic Resonance Imaging: Regular
Protocols and Fast Protocols
Joao V. Horvat and Sunitha B. Thakur
8.1 Introduction
Breast cancer diagnosis on magnetic resonance imaging (MRI) relies on the estab-
lishment of standard features for imaging acquisition. Patient positioning, temporal
and spatial resolution, and pulse sequences should be standardized to provide high-
quality images for adequate interpretation. The protocol should consist of sequences
that can be obtained from different equipment within the same institution. The
sequences obtained must provide images that are familiar to the radiology staff and
that satisfy certain imaging interpretation objectives, such as differentiating cystic
from solid lesions [1].
The imaging acquisition must not be extensively long. Long protocols can cause
discomfort to the patient and may result in interruptions during the examination or
patient motion that decreases the image quality. Long protocols reduce the number
of patients that can be scanned within a certain amount of time, which may result in
the elevation of costs. On the other hand, time should not be the most important fac-
tor in a protocol. If essential sequences are left out in a protocol, misdiagnosis may
occur [2].
A reliable protocol must provide images that maintain a high sensitivity for the
diagnosis of breast cancer and that are capable of differentiating between benign
and malignant lesions [3]. Lesion morphology on gadolinium contrast-enhanced
sequences is essential for this accomplishment. For malignant lesions, there are
several morphological features that must be demonstrated, including shape, margin,
internal enhancement pattern, and the presence of tumoral necrosis. Features that
are typical of benign lesions such as the presence of fat should be clearly evident. A
J. V. Horvat (*) · S. B. Thakur

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Switzerland AG 2022
132 J. V. Horvat and S. B. Thakur
given protocol should be capable of preoperatively demonstrating local and regional

staging for patients with breast cancer. The presence of chest wall invasion or axil-
lary nodal disease may directly impact treatment management. These structures
must be included in the field of view during the examination [4].
Standardization of MRI protocols is essential for patient care. Individuals with
breast cancer may undergo a number of examinations in the same institution for a
period of months to several years. Radiologists must be capable of comparatively
evaluating these studies. This is of paramount importance, especially for the assess-
ment of response to neoadjuvant treatment and to detect recurrence. Thus, protocols
should remain unchanged as long as possible, unless modifications are proven to be
highly necessary in order to improve diagnostic accuracy [1].
8.2 Standard Examination
The standard MRI examination consists of utilizing 1.5, 3, or 7 T equipment with a

dedicated breast coil that frequently has between four and 16 channels. The patient
lies in the prone position with the breasts hanging in the recesses of the coil. Care
should be taken to make the breasts hang as free and straight as possible and to
avoid much contact of the breasts with the surfaces of the coil as imaging artifacts
may occur. Breasts are scanned from the clavicle to the inframammary fold. The
axilla and the anterior chest wall should also be included in the examination. An
intravenous access for the administration of gadolinium contrast media should be
obtained. For contrast-enhanced sequences, a gadolinium-based agent should be
administered at a dose of 0.1 mmol/kg of body weight with an injection rate of
2–3 mL/s followed by a 10–20 mL saline flush [5].
Although protocols may vary among institutions, there are universal goals that a
given protocol must achieve. For an optimal diagnostic performance, a protocol
must be able to detect enhancing lesions that measure 5 mm or more. A high signal-
to-noise ratio and a high spatial resolution are necessary to demonstrate with fine
detail lesion shape and margins. Acquisition slice thickness should be smaller than
3 mm, in-plane pixel resolution should be ≤1.0 mm, and interslice gap should be
≤0 mm [6]. A standard protocol usually includes T1-weighted and T2-weighted
sequences and subtraction and 3D maximum intensity projection (3D MIP) post-
processed images. Signal intensity of the most common structures in the breast on
different MRI sequences is demonstrated in Table 8.1.
The sequences may be acquired in the axial, coronal, or sagittal planes or a com-
bination of them. The advantage of the axial plane is a faster acquisition time and
the possibility of comparing both breasts on the same image, facilitating lesion
detection. Some breast imaging services may add other sequences to the protocol to
improve accuracy, such as diffusion-weighted images with post-processed apparent
diffusion coefficient (ADC) maps.
8 Magnetic Resonance Imaging: Regular Protocols and Fast Protocols 133
Table 8.1 Most common signal intensity of different structures in the breast on MRI sequences
Complicated Benign Malignant Lymph nodes
Sequence Fluid cysts Fat tumors tumors (cortex)
T2 with fat sat High Low to high Low Low to high Low High
T1 without fat Low Low to high High Low Low Low
sat
T1 with fat sat Low Low to high Low Low Low Low
T1 post Low Low to high Low Low to high High High
contrast
Subtraction Low Low Low Low to high High High
8.3 T2-Weighted Images
T2-weighted images with fat suppression are the most important sequence for the
detection of fluid [7]. Some facilities may opt to utilize a short tau inversion recov-
ery (STIR) sequence instead with the same objective. Simple cysts present typical
high signal intensity on T2 and have absence of internal enhancement on T1-weighted
contrast-enhanced images. Complicated cysts may present high protein or hemor-
rhagic fluid content that may reduce T2 and increase T1 signal intensity. Subtraction
images may be helpful in demonstrating the absence of internal enhancement within
a complicated cyst.
T2-weighted images with fat suppression may aid in the identification of a solid
portion on the wall of a cyst or a mass inside a fluid-filled duct. Cystic areas inside
a mass are also visible on T2. The presence of tumoral necrosis is associated with
poor prognosis and may also be identified as cystic areas with high signal intensity
inside a tumor. Likewise, the presence of perilesional edema on T2-weighted images
is also associated with malignancy and poor prognosis. Breast cancer on T2-weighted
images usually presents low signal due to its high cellularity. Enhancing circum-
scribed masses that are T2 bright are most frequently benign [8]. Some tumors, on
the other hand, may have a different biological profile and present high signal inten-
sity on T2, like mucinous carcinomas [9].
Sequences without fat suppression, either T1 or T2, may be used to evaluate fat-
containing lesions. Fat necrosis and mammary hamartoma, also known as fibroad-
enolipoma, can be easily detected as they present internal high signal similar to
adjacent fatty tissue [10]. Due to its high resolution, radiologists may use this
sequence to better visualize the margins of a mass, especially if it is surrounded by
fat. Similarly, fat surrounding axillary lymph nodes may facilitate their identifica-
tion and the diagnosis of nodal disease. Lastly, the distinction between a breast mass
and an intramammary lymph node is not always easy. The identification of a fatty
hilum in a sequence without fat suppression together with other morphological fea-
tures may indicate that it corresponds to an intramammary lymph node. Some breast
imaging services opt to include in their protocol only T2-weighted images with fat
suppression. As there is need for a sequence without fat suppression for the reasons
mentioned, a T1-weighted sequence without fat suppression may be used instead.
8.4 T1-Weighted Images
Contrast-enhanced T1-weighted images are the core of breast cancer diagnosis on

MRI. Most tumors present early and intense enhancement to gadolinium-based con-
trast media that is visually distinguishable from breast parenchyma and benign
lesions. T1-weighted sequences are usually performed with fat suppression, but
some breast imaging services may opt to utilize sequences without fat suppression.
The advantage of fat suppression is to erase all of the high signal that comes from
breast fatty tissue in order to better demonstrate enhancement to contrast media and
to identify other lesions that might have high signal on unenhanced images [11].
Enhancing masses and non-mass enhancements are the main imaging findings on
breast MRI. T1-weighted images must clearly demonstrate the morphology of
enhancing lesions. For masses, shape and margins are the most important morpho-
logical features for imaging interpretation. For non-mass enhancements, distribution
is a key factor. Some patterns like segmental distribution are frequently associated
with malignancy. Given that lymph nodes enhance to gadolinium-based agents, con-
trast-enhanced sequences can be used to demonstrate nodal enlargement and cortical
thickening, which are often associated with axillary metastatic disease. T1-weighted
images can also be useful in the evaluation of pectoralis major muscle or skin malig-
nant infiltration. The presence of abnormal enhancement in these structures is associ-
ated with neoplastic invasion.
Breast fibroglandular tissue may present background parenchymal enhancement
to contrast media. The enhancement is symmetric, often seen in the periphery of the
parenchyma, and shows persistent increase in signal intensity after gadolinium
injection. In some patients, this enhancement may be markedly intense and jeopar-
dize the identification of lesions, resulting in a decrease in sensitivity for the diagno-
sis of breast cancer. Occasionally, background enhancement may be highly
heterogeneous and asymmetric, which can be confounded with a suspicious non-
mass enhancement.
T1-weighted sequences consist of one acquisition before the administration of
contrast agent and from one to seven or more contrast-enhanced dynamic phases
that are repeatedly acquired in a certain time interval. There is no consensus on the
number of phases that are adequate for a full multiparametric protocol. The first
phase is acquired between 90 and 120 s after contrast injection followed by addi-
tional phases. Dynamic contrast-enhanced (DCE) acquisition is usually completed
4–7 min after contrast injection in most protocols. Nowadays, protocols often con-
sist of one to three contrast-enhanced phases. Protocols that utilize more than one
contrast-enhanced phase can demonstrate the enhancement kinetic curves of breast
masses, while protocols that utilize a single post-contrast acquisition are more often
seen in a screening scenario where abbreviated imaging studies are done.
8.5 Subtraction, Enhancement Curve, and 3D MIP
Post-processed images are extremely valuable in the analysis of breast MRI studies.
Subtraction images correspond to the deletion of signal of the unenhanced
T1-weighted sequence from a given contrast-enhanced phase. The result is the sub-
traction of all T1 signal except the signal from contrast enhancement. Subtraction
images are capable of demonstrating only structures that truly present enhancement
to gadolinium. There are, on the other hand, certain situations where the subtracted
signal may not be optimal. Patient motion between pre- and post-contrast sequences
may cause uneven subtraction. This may result in areas of false enhancement dem-
onstrated in the subtraction images. When patient motion is suspected, visual com-
parison between pre- and post-contrast T1-weighted sequences is necessary to
evaluate if it has occurred. Nowadays, there are several softwares that are capable of
automatically correcting patient motion.
Variations in signal intensity between dynamic contrast-enhanced phases can be
post-processed and graphically evaluated. Once a mass is visualized, it is possible
to position a region of interest over it and create an enhancement kinetic curve.
Three distinct enhancement curve patterns can be identified: persistent, plateau, and
washout. Most malignant masses present a rapid increase in signal intensity fol-
lowed by a contrast washout with a decay in signal intensity [12]. Most benign
lesions, on the other hand, present a slow and persistent increase in signal intensity
in the first 5 min after contrast injection [13].
3D MIP images have a significant contribution to the detection of breast cancer.
They are obtained from subtracted images that are post-processed to create a three-
dimensional volumetric display of both breasts. 3D MIP can better demonstrate
abnormal enhancement with the comparison between both sides. Not only it is used
to highlight malignancies, but it can also be useful in the comprehension of their
position and distribution within the breast and the proximity to the papilla, skin, and
chest wall.
8.6 Diffusion-Weighted Images
Diffusion-weighted images (DWI) are sometimes included in the standard protocol

as it has been demonstrated to improve specificity in the evaluation of breast masses.
This sequence can demonstrate features of breast tumors without the need of contrast
injection. DWI demonstrates the diffusivity of water molecules in a tissue within a
period of time [14, 15]. Two or more time points (b-values) are used to evaluate this
diffusivity. A low b-value of 0 and a high b-value of 600–1500 s/mm2 are typically
used. Diffusion is reduced in the presence of high cellularity often found in malig-
nant tumors that corresponds to high signal intensity on DWI. Previous studies have
demonstrated that DWI may improve lesion diagnosis, especially in the differentia-
tion between benign and malignant masses [16]. Traditional DWI sequences have
limited spatial resolution and are prone to artifacts that may jeopardize imaging
interpretation [17]. Recent improvements in technique such as the use of readout-
segmented echo planar imaging or multi-shot multiplexed sensitivity- encoding
(MUSE) reduce these artifacts and improve lesion characterization [18, 19].
Post-processing images from the DWI sequence may be achieved with the cre-
ation of ADC maps that can be used to calculate the numerical amount of restriction
in a mass. High-cellularity lesions present high diffusion restriction that is repre-
sented as low signal on ADC maps [20]. By drawing a region of interest on a lesion,
ADC values can be calculated. Mean ADC values that are lower than 1.3 × 10−3 mm2/s
are associated with malignancy.
8.7 Breast Implants
Breast implants have become widely present in our society. MRI is the best modal-
ity for the evaluation of implant ruptures and other implant-related abnormalities.
The vast number of different types of implants is specially challenging for radiolo-
gists. Implants may be filled with saline or silicone, which have different signal
intensities on MRI. They may have one, two or, more lumens. They may present
inner structures such as seals, valves, cannulas, markers, and chips that may cause
confusion during imaging interpretation. Nevertheless, a standardized protocol to
evaluate breast implants is necessary despite these variations [21].
Protocols to evaluate breast implants may be used alone or in addition to the
standard protocol. Patients who are having an examination for the sole reason of
evaluating implant rupture may opt not to receive intravenous contrast media. For
these patients, a combination of unenhanced sequences of the standard protocol and
sequences for implant evaluation should be used.
The sequences for implant evaluation consist of T2-weighted images with fat
suppression and silicone or water suppression. These two sequences should be done
in the same axis, as comparison between the two is of paramount importance. The
suppression of silicone and water makes it possible for radiologists to evaluate
abnormalities on the contours or within the implants that could be an indication of
intracapsular rupture. The signal shift of silicone on the sequences with and without
silicone suppression can demonstrate its presence within the breast parenchyma or
inside internal mammary or axillary lymph nodes. Additionally, peri-implant fluid
may be better depicted on the sequences with silicone suppression [22].
8.8 Abbreviated Protocol
Because of the high sensitivity of MRI for the detection of breast cancer, several
studies have been conducted to evaluate its use in screening. There are a number of
obstacles in MRI screening, including equipment lower availability, need of
intravenous contrast media, higher costs, and longer examination and reading times.
To overcome some of these factors, abbreviated protocols with shorter examination
times and with a reduced number of sequences have been proposed [23]. The main
objective of these protocols is to maintain high sensitivity for breast cancer diagno-
sis [24]. Some protocols are proposed only to be used for patients with a previous
full imaging protocol study, while others are used on the patient’s first breast MRI
examination [25].
The majority of abbreviated protocols consists of dynamic contrast-enhanced
images with fat suppression. One pre-contrast and one post-contrast sequences are
acquired followed by post-processed images, including subtraction and 3D
MIP. Some authors have included other sequences such as more than one contrast-
enhanced phase or T2-weighted images that may improve lesion characterization
but increase examination and reading times. Since breast cancers usually present
rapid contrast enhancement, images obtained 90–120 s after the injection of gado-
linium depict the majority of malignancies on MRI.
8.9 Ultrafast Breast MRI
On MRI post-contrast sequences, breast malignant tumors enhance early, fast and
avidly to gadolinium-based contrast agent. To evaluate the first stages of contrast
inflow of breast lesions, ultrafast sequences were developed and have been investi-
gated in several studies that were recently published. These sequences have high tem-
poral resolution with an imaging acquisition of the whole breast that takes less than
7 s. Multiple repeated sequences can be obtained after contrast media injection or after
it reaches the aorta. Kinetic curves of the first 1–2 min of contrast enhancement can
demonstrate how early and intense a lesion enhances, and measurements of the
enhancement curve slope can be obtained [26, 27]. These measurements have been
used to improve specificity in the differentiation between benign and malignant lesions
[28]. Some authors have proposed that ultrafast breast MRI can substitute the delayed
standard dynamic contrast-enhanced sequences and reduce examination time [17].
8.10 Conclusion
Standardization of imaging protocols is necessary for consistent lesion detection

and characterization. Protocols must be able to provide essential information to the
radiologist in order to make the correct diagnosis. Protocols should not be exten-
sively long but must include all the sequences needed to identify the most frequent
breast lesions. Novel protocol proposals have been created to optimize lesion evalu-
ation and to make breast MRI screening programs feasible and cost-effective.
Abbreviated and ultrafast breast MRI have proven to be useful in clinical practice,
maintaining high sensitivity for the diagnosis of breast cancer.
References
1. Newstead GM. MR imaging in the management of patients with breast cancer. Semin
Ultrasound CT MR. 2006;27(4):320–32.
2. Clauser P, Mann R, Athanasiou A, Prosch H, Pinker K, Dietzel M, et al. A survey by the
European Society of Breast Imaging on the utilisation of breast MRI in clinical practice. Eur
Radiol. 2018;28(5):1909–18.
3. Huang W, Fisher PR, Dulaimy K, Tudorica LA, O’Hea B, Button TM. Detection of breast
malignancy: diagnostic MR protocol for improved specificity. Radiology. 2004;232(2):585–91.
4. Thompson JL, Wright GP. The role of breast MRI in newly diagnosed breast cancer: an
evidence-based review. Am J Surg. 2020;221(3):525–8.
5. Yitta S, Joe BN, Wisner DJ, Price ER, Hylton NM. Recognizing artifacts and optimizing breast
MRI at 1.5 and 3 T. AJR Am J Roentgenol. 2013;200(6):W673–82.
6. Radiology ACo. Breast MRI clinical image review category D: spatial and temporal resolution
2019 [MRI and breast MRI accreditation]. Available at: https://accreditationsupport.acr.org/
support/solutions/articles/11000070275-breast-mri-clinical-image-review-category-d-spatial-
and-temporal-resolution
7. Santamaría G, Velasco M, Bargalló X, Caparrós X, Farrús B, Luis FP. Radiologic and
pathologic findings in breast tumors with high signal intensity on T2-weighted MR images.
Radiographics. 2010;30(2):533–48.
8. Lee JY, Jang M, Kim SM, Yun B, Jang JY, Ahn HS. Preoperative magnetic resonance imaging
characteristics of oval circumscribed fast enhancing lesions in patients with newly diagnosed
breast cancer. Medicine (Baltimore). 2018;97(19):e0704.
9. Pintican R, Duma M, Chiorean A, Fetica B, Badan M, Bura V, et al. Mucinous versus
medullary breast carcinoma: mammography, ultrasound, and MRI findings. Clin Radiol.
2020;75(7):483–96.
10. Taboada JL, Stephens TW, Krishnamurthy S, Brandt KR, Whitman GJ. The many faces of fat
necrosis in the breast. AJR Am J Roentgenol. 2009;192(3):815–25.
11. Carbonaro LA, Pediconi F, Verardi N, Trimboli RM, Calabrese M, Sardanelli F. Breast MRI
using a high-relaxivity contrast agent: an overview. AJR Am J Roentgenol. 2011;196(4):942–55.
12. Partridge SC, Stone KM, Strigel RM, DeMartini WB, Peacock S, Lehman CD. Breast DCE-
MRI: influence of postcontrast timing on automated lesion kinetics assessments and discrimi-
nation of benign and malignant lesions. Acad Radiol. 2014;21(9):1195–203.
13. Schnall MD, Blume J, Bluemke DA, DeAngelis GA, DeBruhl N, Harms S, et al. Diagnostic
architectural and dynamic features at breast MR imaging: multicenter study. Radiology.
2006;238(1):42–53.
14. Iacconi C, Thakur SB, Dershaw DD, Brooks J, Fry CW, Morris EA. Impact of fibroglandular
tissue and background parenchymal enhancement on diffusion weighted imaging of breast
lesions. Eur J Radiol. 2014;83(12):2137–43.
15. Durando M, Gennaro L, Cho GY, Giri DD, Gnanasigamani MM, Patil S, et al. Quantitative
apparent diffusion coefficient measurement obtained by 3.0Tesla MRI as a potential noninva-
sive marker of tumor aggressiveness in breast cancer. Eur J Radiol. 2016;85(9):1651–8.
16. Horvat JV, Durando M, Milans S, Patil S, Massler J, Gibbons G, et al. Apparent diffusion coef-
ficient mapping using diffusion-weighted MRI: impact of background parenchymal enhance-
ment, amount of fibroglandular tissue and menopausal status on breast cancer diagnosis. Eur
Radiol. 2018;28(6):2516–24.
17. Mann RM, Cho N, Moy L. Breast MRI: state of the art. Radiology. 2019;292(3):520–36.
18. Naranjo I, Gullo R, Morris E, Larowin T, Fung M, Guidon A, et al. High-spatial-resolution
multishot multiplexed sensitivity-encoding diffusion-weighted imaging for improved qual-
ity of breast images and differentiation of breast lesions: a feasibility study. Radiol Imaging
Cancer. 2020;2(3):e190076.
19. Bogner W, Pinker K, Zaric O, Baltzer P, Minarikova L, Porter D, et al. Bilateral diffusion-
weighted MR imaging of breast tumors with submillimeter resolution using readout-segmented
echo-planar imaging at 7 T. Radiology. 2015;274(1):74–84.
20. Horvat JV, Bernard-Davila B, Helbich TH, Zhang M, Morris EA, Thakur SB, et al. Diffusion-
weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping as a quantitative
imaging biomarker for prediction of immunohistochemical receptor status, proliferation rate,
and molecular subtypes of breast cancer. J Magn Reson Imaging. 2019;50(3):836–46.
21. Maijers MC, Niessen FB, Veldhuizen JF, Ritt MJ, Manoliu RA. MRI screening for silicone
breast implant rupture: accuracy, inter- and intraobserver variability using explantation results
as reference standard. Eur Radiol. 2014;24(6):1167–75.
22. Brenner RJ. Evaluation of breast silicone implants. Magn Reson Imaging Clin N Am.
2013;21(3):547–60.
23. Greenwood HI. Abbreviated protocol breast MRI: the past, present, and future. Clin Imaging.
2019;53:169–73.
24. Gao Y, Heller SL. Abbreviated and ultrafast breast MRI in clinical practice. Radiographics.
2020;40(6):1507–27.
25. Oldrini G, Derraz I, Salleron J, Marchal F, Henrot P. Impact of an abbreviated protocol for
breast MRI in diagnostic accuracy. Diagn Interv Radiol. 2018;24(1):12–6.
26. Mori N, Abe H, Mugikura S, Takasawa C, Sato S, Miyashita M, et al. Ultrafast dynamic
contrast-enhanced breast MRI: kinetic curve assessment using empirical mathematical model
validated with histological microvessel density. Acad Radiol. 2019;26(7):e141–e9.
27. Shin SU, Cho N, Kim SY, Lee SH, Chang JM, Moon WK. Time-to-enhancement at ultra-
fast breast DCE-MRI: potential imaging biomarker of tumour aggressiveness. Eur Radiol.
2020;30(7):4058–68.
28. Onishi N, Sadinski M, Gibbs P, Gallagher KM, Hughes MC, Ko ES, et al. Differentiation
between subcentimeter carcinomas and benign lesions using kinetic parameters derived from
ultrafast dynamic contrast-enhanced breast MRI. Eur Radiol. 2020;30(2):756–66.
Chapter 9
Nuclear Medicine Based Methods: PET
FDG and Other Tracers
Marcelo Tatit Sapienza and Poliana Fonseca Zampieri
9.1 Introduction
9.1.1 Basic Aspects of 18F-FDG-PET
Positron emission tomography (PET) allows the assessment of different metabolic

parameters based on the detection of in vivo biodistribution of intravenously admin-
istered compounds, labeled with positron-emitting isotopes. Short-lived positron
emitters are used to label several organic molecules, without interfering in their
biological properties. During image acquisition, the positron emitted by the radio-
pharmaceutical interacts with an electron, and both undergo annihilation, emitting
two gamma rays in opposite directions. In a typical PET equipment, these rays are
detected simultaneously by scintillation crystals arranged like a ring around the
patient in the detector system (Fig. 9.1). PET/CT cameras integrate PET imaging to
a computed tomography (CT), adding the anatomical and morphological informa-
tion of the CT to the functional information of PET. More recently, PET/MRI scan
has also become available, allowing the integration of PET and magnetic resonance
imaging (MRI) in a single study. This chapter will mainly review the application of
PET/CT in breast cancer but will also discuss some aspects of PET/MR.
Fluorodeoxyglucose (FGD) is the most studied radiopharmaceutical in the eval-
uation of breast cancer. The FDG molecule is a glucose analog, in which a hydroxyl
M. T. Sapienza (*)
Departamento de Radiologia e Oncologia, Hospital das Clinicas HCFMUSP, Faculdade de
P. F. Zampieri
Departamento de Medicina Nuclear, Instituto do Cancer do Estado de Sao Paulo ICESP,

Switzerland AG 2022
142 M. T. Sapienza and P. F. Zampieri
Fig. 9.1 Two gamma rays

are emitted after a positron
annihilation and detected
simultaneously by the
detectors in a PET
equipment
18F
511keV
511keV
H2C OH
Hexokinase Glycolysis
H O H
GLUT
OH H 18
F-FDG 18
F-FDG-6P
OH OH
18
F
H
Fig. 9.2 FDG is transported by GLUTs and metabolized in FDG-6P by hexokinase but does not
follow the subsequent glycolysis steps, being accumulated in the cell
group has been replaced by fluorine-18, obtained in a cyclotron. The uptake of 18F-
FDG by tumor cells occurs through non-insulin-dependent glucose transport sys-
tems (GLUTs 1 and 4) and, like glucose, undergoes phosphorylation due to
hexokinase. Phosphorylated FDG does not progress in the metabolic pathway
beyond this step and remains trapped in the tumor cell (Fig. 9.2). Most breast can-
cers present increased metabolic activity, although there are variations according to
tumor characteristics and histology, to be discussed below.
9 Nuclear Medicine Based Methods: PET FDG and Other Tracers 143
PET/CT study is usually acquired 60 min after administration of 18F-FDG to the

fasting patient, who needs to remain at rest during the interval. Visual analysis is the
basis for interpreting a PET/CT study. Semiquantitative measures can help to com-
pare or monitor the degree of metabolic uptake, the most used being the SUV – stan-
dardized uptake value. SUV refers to the activity in a given volume of interest in
relation to the total activity administered, corrected by the patient’s weight.
 MBq 
Tissue activity concentration  
 mL  × body weight g
SUV = ( )
Injected dose ( MBq )
Other tissues also show physiological uptake of FDG. Among the organs with
intense physiological uptake of 18F-FDG is the brain, impairing the ability to detect
metastases at this site. Activity in the kidneys, ureters, and bladder resulting from
the excretion of the radiopharmaceutical generally does not interfere with the inter-
pretation of the study. It should also be remembered that inflammatory changes with
infiltration by macrophages or granulation tissue (e.g., postoperative) have high
metabolic activity and may lead to a false-positive study. Other causes of false-
positive studies in the breast include benign conditions such as breast changes in
pregnancy and lactation (Fig. 9.3), gynecomastia, mastitis, fat necrosis (Fig. 9.4),
fibroadenoma, intraductal papilloma, and atypical ductal hyperplasia [1].
a b
Fig. 9.3 FDG PET scan of a 39-year-old breastfeeding patient demonstrating diffuse intense
activity in both breasts on MIP (a) and axial PET/CT (b), without tomographic lesions (c)
a b
Fig. 9.4 Restaging FDG PET/CT scan in a patient suspected of having recurrent breast carci-
noma. Axial fusion (a) and dedicated CT (b) images show areas of fat necrosis with increased
FDG uptake
9.2 18F-FDG-PET/CT Indications in Breast Cancer
The National Comprehensive Cancer Network (NCCN) Guidelines do not indicate

PET/CT in the staging of clinical stages I and II or operable stage III breast cancer.
FDG PET/CT is suggested to be most helpful in situations where standard staging
studies are equivocal or suspicious, especially in the setting of locally advanced or
metastatic disease [2]. Regarding surveillance, the American Society of Clinical
Oncology and NCCN guidelines recommend only regular history, physical exami-
nation, and mammography for breast cancer routine follow-up. Systematic 18F-FDG
PET/CT is not indicated [3].
Although not appropriate for all patients with breast cancer, the use of 18F-FDG
PET/CT can have an impact on patient care in multiple settings, including initial
staging, treatment response assessment, and evaluation of suspected recurrence [4].
Influence of Histologic Subtypes and Receptor Status
Breast cancer is considered as a group of diseases with different molecular charac-
teristics that originate in breast epithelial tissue but have different prognosis, pat-
terns of recurrence, and dissemination after primary multidisciplinary treatments,
leading to significant changes in diagnostic and therapeutic approaches [5].
18
F-FDG uptake depends on the histologic and biologic characteristics of the
breast tumor and is influenced by its receptor status, grade, and histologic type [3,
4]. Invasive carcinoma of no special type (NST) exhibits higher uptake than invasive
lobular carcinoma (ILC) [3, 6]. Lobular breast cancers may be occult at FDG PET
even with large dimensions [4]. This is probably due to the lower density of tumor
a b c
d e
Fig. 9.5 Restaging with PET/CT in a patient with triple negative breast cancer presenting with
reduction of strength in the left hemibody. MIP (a), sagittal PET/CT fusion (b), and axial PET/CT
fusion (c–e) images show multiple metastasis with intense FDG uptake on the central nervous
system, lungs, liver, and bones
cells in lobular carcinomas, lower expression of GLUT1, lower proliferation rates,

and diffuse infiltrative tumor growth patterns into surrounding tissue, which may
lead to false-negative scans [3]. Untreated osseous metastases from ILC are more
likely sclerotic and missed by FDG PET than IDC metastases, showing a lower
avidity and uptake similar to the background. In addition, ILC differs from NST in
its patterns of metastatic spread, with a greater propensity to metastasize to the gas-
trointestinal tract and retroperitoneum, which are areas often difficult to assess with
FDG PET as they are common sites of physiologic and variable FDG avidity [4].
Estrogen receptor (ER)-negative tumors and grade 3 cancers have significantly
higher FDG avidity than ER-positive tumors and lower-grade malignancies [4].
Also, triple negative breast cancers demonstrate particularly elevated uptake of fluo-
rodeoxyglucose (FDG) on PET. They are also known to result in early metastatic
disease and have a propensity for extra skeletal metastases, increasing the impor-
tance of imaging for systemic staging [6] (Fig. 9.5).
Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are
characterized by a high expression of HER2 gene, which promotes tumor growth
and progression and therefore tends to be more aggressive and FDG avid. Poorly
differentiated tumors are more aggressive tumors and are more FDG avid [7]. There
is also a positive correlation between the tumor proliferation index (Ki-67 expres-
sion) and the intensity of 18F-FDG uptake [3].
Question Is the sensitivity of FDG PET similar for lobular and invasive carcinoma
of no special type breast cancer? Why?
9.2.1 Primary Breast Tumor Detection and Staging (T)
FDG PET/CT is not indicated for screening in early-stage cancers [8]. Although it
offers the opportunity to provide an overview of disease in a single procedure, the
recommendation against the use of PET scanning is supported by many factors [3,
8]: it has low sensitivity for the primary breast tumor, and neither FDG PET nor CT
is sensitive enough to detect breast cancers smaller than 1 cm [4]; the SUV in small
lesions is susceptible to the partial volume averaging effect, which may lead to a
lower value. This is further hampered by potential breathing motion artifact, as the
PET acquisition is performed at tidal volume breathing [8]; 18F-FDG imaging has
lower sensitivity than the sentinel node technique in assessing axillary lymph node
involvement, and the risk of distant metastases in early-stage cases is also low [3].
In addition to that, there is a high rate of false-positive scans in early-stage cancers,
leading to unwarranted patient anxiety and delay of care in those patients [3].
However, in high-risk patients like those with inflammatory (T4d) or locally
advanced breast cancer (LABC), the role of 18F-FDG imaging in detecting local and
distant metastasis has been highlighted [3]. FDG PET is helpful in local staging and
particularly helpful in evaluation of internal mammary nodes and distant nodal
metastasis [7]. It also helps to evaluate the equivocal findings on standard imaging
and, in some cases, can detect unknown sites of distant metastasis even though the
standard imaging is negative for lesions [7].
Any FDG-avid breast focus found during staging or surveillance of an extra-
mammary malignancy should be thoroughly investigated in patients with reason-
able life expectancy [8] (Fig. 9.6). These lesions have a 30–40% chance of being
a b
c d
Fig. 9.6 FDG PET/CT used to stage lung cancer. Lung CT demonstrates partially cavitated pul-
monary nodule (arrowhead in a), and PET/CT shows a solid nodule on the left breast (arrows in b,
c, and d) with FDG uptake, which was later diagnosed as ductal invasive carcinoma by biopsy
malignant, including previously unsuspected primary breast malignancies, metasta-

ses to the breast, and breast lymphoma [4]. The likelihood that the lesion is a pri-
mary breast cancer is approximately 6%, and more than half of these will be
early-stage disease, with potential for cure [8].
Question An intense area of FDG uptake was detected in the breast of a patient
during the investigation of a solitary pulmonary nodule. Considering that FDG PET
is not indicated for detecting a primary breast tumor, do you think this finding
should be further evaluated?
9.2.2 Nodal Staging (N)
For the evaluation of locoregional nodal metastases, it is useful to make a distinction

between axillary and regional extra axillary nodes [4]. Axillary lymph node status is
one of the main prognostic factors in breast cancer. If there are no palpable lymph
nodes on clinical examination, the currently accepted approach for axillary staging
is sentinel lymph node biopsy. This technique has the advantage of detecting even
micrometastases (<2 mm) or isolated tumor cells [9]. The sentinel lymph node
biopsy predicts the state of axillary disease with an accuracy greater than 95%. FDG
PET/CT has poor sensitivity for axillary nodal metastases compared with sentinel
lymph node biopsy, because clinically relevant axillary nodal metastases are often
subcentimeter in size. But the specificity of FDG PET/CT for axillary nodes has
been shown to be far better than its sensitivity. Thus, the presence of an FDG-avid
axillary node is likely to represent nodal malignancy [4].
Locoregional extra axillary nodes, including internal mammary, infraclavicular,
and supraclavicular nodes, may be clinically occult and less commonly identified by
sentinel node evaluation (Fig. 9.7). It is in this group of nodes where FDG PET/CT
evaluation begins to show value in patient staging through the detection of unsus-
pected extra axillary nodal metastases [4]. Axillary node clearance by axillary dis-
section is usually limited to levels I and II. 18F-FDG uptake suggesting involvement
at level III (infraclavicular) or in extra axillary locoregional nodes (supraclavicular
or internal mammary) may have important implications in surgical management and
in the design of radiation therapy fields [3, 9].
Question A patient with a palpable axillary node had an FDG PET study acquired
prior to the surgery. Intense FDG uptake was noted in multiple axillary nodes and
also in the internal mammary node. What is the practical implication of this finding?
9.2.3 Metastatic Staging (M)
The most common sites of distant metastasis in breast cancer are bones, lungs, liver,
and brain, and the conventional imaging studies for detecting distant metastasis
include contrast-enhanced CT, bone scintigraphy, and MRI [10]. FDG PET/CT has
a b
Fig. 9.7 Restaging with PET/CT in a patient with breast cancer presenting rising levels of CA
15-3. MIP (a), axial PET/CT fusion (b), and axial CT (c) images show intense FDG uptake in
internal mammary lymph node (arrows in a, b, and c)
higher sensitivity than conventional modalities for detection of unsuspected distant

metastasis in patients with locally advanced breast cancer, changing the patient’s
stage and converting patient’s management from curative-intent therapy by surgery
with or without neoadjuvant therapy to palliative systemic therapies [4].
Groheux et al. compared a conventional staging approach including bone scan-
ning, chest radiography or dedicated CT, and liver ultrasound or contrast-enhanced
CT for abdomen–pelvis with a single session of staging with 18F-FDG PET/CT. 18F-
FDG PET/CT outperformed conventional imaging for bone, distant lymph nodes,
and liver metastases, whereas CT was more sensitive for lung metastases [3]. PET
lacks sensitivity for detection of infracentimetric pulmonary nodules because of the
partial-volume effect and respiratory movements. Careful scrutiny of CT images
from PET/CT can reveal small nodules without 18F-FDG uptake. However, CT per-
formed during free breathing is less efficient than standard diagnostic thoracic CT [3].
For evaluation of bone metastasis in breast cancer patients, both bone scintigra-
phy and FDG PET/CT are convenient whole-body imaging tools [11]. FDG PET
acts as a tumor-specific tracer and reflects the glucose usage by tumor cells in viable
metastatic lesions, while bone scintigraphy mainly reflects the response of sur-
rounding bone to cancer. Bone scan may fail to show early response to effective
therapy and may even show a “flare” related to bone healing. Similar findings may
occur with other modalities including CT [11, 12]. Metabolic flare may be seen at
FDG PET, with temporarily increasing FDG avidity after successful therapy; how-
ever, it occurs in the first 1–2 weeks and, thus, is not a confounding issue on scans
a b c
Fig. 9.8 Metastatic disease in a patient with biopsy-proven breast cancer. Arrows in sagittal PET
(a) and sagittal CT (b) demonstrate FDG uptake in lytic bone lesions, with no uptake in 18F-NaF
(sodium fluoride) (c)
that are normally performed months after initiating therapy. Rather, FDG metabolic
flare may be an indicator of future response to therapy [4].
PET is generally considered to be superior to CT and bone scintigraphy in detect-
ing lytic or mixed bone metastases and bone marrow metastases (Fig. 9.8), but a
multimodality approach is recommended for the investigation of bone metastases
due to the low sensitivity of PET in detecting sclerotic bone metastases in some
cases. In addition, sclerotic lesions without FDG accumulation can be detected on
CT images of a PET/CT study [13].
FDG PET is not as sensitive as MRI in the evaluation of brain metastases.
Cerebral cortex is highly FDG avid, and metastases often appear as focal areas of
hypometabolism, which may also be seen in non-neoplastic entities. Some lesions
do manifest as focal areas of hypermetabolism, although this can be difficult to
detect in the setting of normal physiologic gray matter metabolism [14]. Furthermore,
inflammatory tissue can also exhibit high FDG tracer uptake, diminishing diagnos-
tic specificity [15].
Question Why, despite the high global sensitivity for breast cancer metastases,
PET FDG is not indicated for the detection of brain lesions?
9.2.4 Recurrence
Breast cancer recurrence can be suggested by clinical symptoms, radiologic find-

ings, or rising levels of tumor markers (carcinoma antigen 15-3, carcinoembryonic
antigen or cancer antigen 125) [3]. 18F-FDG PET/CT has a high diagnostic accuracy
in detecting breast cancer recurrence in case of elevated levels of serum tumor
markers, and it can be used in addition to conventional imaging techniques [16]
(Figs. 9.9 and 9.10). The European Society for Medical Oncology (ESMO) guide-
lines and NCCN suggest that FDG PET/CT can be useful for identifying the site of
relapse when traditional imaging methods are equivocal or conflicting, because it
allows better discrimination between posttreatment scar or fibrosis and viable tumor
tissue [17]. Moreover, this imaging modality can improve the identification of iso-
lated locoregional relapse as well as isolated metastatic lesions, that is, a situation
where patients may benefit from a more aggressive multidisciplinary approach [17].
PET/CT is also efficient in patients with suspected recurrence but with negative
tumor marker results [3].
a b
Fig. 9.9 PET/CT in a patient with breast cancer presenting rising levels of tumor markers. MIP
(a), axial PET/CT fusion (b), and axial CT (c) images show FDG uptake on mediastinal soft tissue
mass (arrows in a, b, and c)
a b
Fig. 9.10 PET/CT in a patient suspected of having recurrent breast carcinoma due to back pain.
Sagittal PET/CT fusion (a) and sagittal CT (b) images show mixed bone lesion on the vertebral
body of L4, consistent with metastatic disease
9.2.5 Response Assessment to Neoadjuvant

Chemotherapy (NAC)
Breast cancer response to NAC has traditionally been assessed by conventional

imaging modalities, which sometimes have difficulties in differentiating fibrosis
from residual tumors. 18F-FDG PET/CT and enhanced MRI are used in this clinical
setting [18]. Studies using 18F-FDG PET/CT to monitor early tumor responses to
NAC showed a moderate accuracy to identify pathological responses in breast can-
cer patients, with better results than mammography, sonography, and MRI in pre-
dicting pathologic complete response (pCR) during NAC for locally advanced
breast cancer [19].
18
F-FDG PET/CT can differentiate changes in tumor glucose metabolism before
morphologic changes. The decrease in 18F-FDG uptakes in tumors after chemo-
therapy is an indicator to assess the treatment response in triple-negative breast
cancer (TNBC) and HER2-positive subtypes [18, 20]. Enhanced MRI can provide
information on lesion microvasculature and depict changes in the physiologic char-
acteristics of tumors [18]. PET/MRI holds the promise to improve therapy-response
evaluation because it has the high sensitivity of PET and the high specificity of the
MRI component [18].
9.2.6 Response Assessment in Metastatic Disease
Accurate assessment of treatment response is vital to provide the most effective

therapy as well as to avoid unnecessary treatment escalation [21]. The current stan-
dard of measuring treatment response in metastatic breast cancer relies on size mea-
surements of tumors, usually on CT [4]. Nonetheless, there are some inherent
limitations in the size criteria. Distinguishing viable from nonviable residual tumor
tissue is often difficult, and osseous metastases are in general nonmeasurable [22].
Metabolic changes measured by FDG PET may better predict treatment response
than anatomic changes because PET/CT can differentiate active tumors from post-
therapeutic changes and assess metabolic activity in osseous metastases [4, 22].
18
F-FDG PET/CT seems to be accurate in directing treatment of metastatic bone
disease as it reflects tumor activity, which is structurally difficult to be assessed by
CT scan alone or by bone scintigraphy (Fig. 9.11). The latter reflects bone reaction
against metastatic tumor that increases as the disease responds to treatment [21].
FDG PET was able to distinguish responders from nonresponders after distinct
and varied courses of hormonal and chemotherapies of breast cancer metastases [4].
Riedl et al. showed that metabolic assessment by FDG PET/CT was a better predic-
tor of both progression-free and disease-specific survival than Response Evaluation
Criteria in Solid Tumors (RECIST) evaluation on CT, and this difference would
alter overall patient management in 25% of the patients, reducing the morbidity and
costs of ineffective therapies in clinical practice [22].
a b
c d
Fig. 9.11 Response assessment in a patient with metastatic breast cancer after chemotherapy.
Pretreatment FDG PET/CT images (a and b) show intense bone lesion FDG uptake in the sternum.
(b) Follow-up FDG PET/CT images after chemotherapy (c and d) show significant decrease in the
intensity and extent of FDG uptake in the sternum
Question Is FDG PET a good method to assess whether a persistent residual mass
after therapy corresponds to a viable tumor or fibrosis?
9.3 Prognostic Value
FDG PET has been found to have also a role in predicting the prognosis of breast
cancer [23], indicating those patients more likely to progress, also with a correlation
between SUV measurement and histologic grade, proliferation index, and triple-
negative status [3]. High uptake reflects aggressive tumors and has poor prognosis
[7]. Although SUVmax is one of the most widely used parameters in clinical set-
tings, it does not show the uptake of the entire tumor mass and may not reflect the
intratumor heterogeneity sufficiently [23]. Therefore, there has been an increasing
interest in volumetric parameters such as metabolic tumor volume (MTV) and total
lesion glycolysis (TLG), which are becoming easier to measure due to commer-
cially available softwares [23]. The metabolic parameters SUVmax, MTV, and TLG
of the lesion before treatment are related to the recurrence rate. The higher the meta-
bolic parameters of the primary lesion, the greater the possibility of recurrence and
distant metastasis [24].
9.4 Other PET Technologies and Tracers
9.4.1 PET/MR and Positron Emission Mammography (PEM)
After the rapid incorporation of PET/CT into clinical practice for staging and prog-
nostic evaluation of breast cancer patients, hybrid PET/MRI equipment was devel-
oped. MRI provides not only high resolution but also high contrast images and the
possibility of better tissue characterization with the combination of different pulse
sequences. MRI sensitivity in the detection of breast lesions is well established,
especially for patients with limitations in conventional mammographic/ultrasound
evaluation, such as young women, dense breasts, and multifocal/multicentric
lesions. Incorporation of metabolic information by FDG PET can increase the spec-
ificity of the method, but care must be taken with false-negative results in cases of
small tumors (<1–2 cm) and histologic variations such as tubular carcinoma, well-
differentiated, or in situ ductal carcinomas.
PET/MR for breast imaging includes specific position and pulse sequences.
PET/MR mammography is acquired in the prone position with the breast hanging
and allows better identification of lesions in the breast and regional lymph nodes
[25]. MR imaging sequences usually include a T2 fat-suppressed sequence, a T1
non-fat-suppressed sequence, and post-contrast T1 sequences. Even though there is
no increase in radiation dose, the additional time spent on a PET/MRI exam should
be considered in obtaining additional images. Among the additional MR sequences

that may be indicated for FDG PET/MR mammography, diffusion-weighted imag-
ing (DWI) is probably the most useful. Restricted diffusion and a low apparent dif-
fusion coefficient (ADC) are observed in tissues with high cellularity, and this
finding may provide prognostic information on breast cancer patients, although
false-negative results may occur due to the association of necrotic tissues with
aggressive tumors. Prognostic information obtained from DWI and FDG uptake
may be incremental, as they reflect different biological properties of the tumor and
are not directly correlated, even though when considered as isolated parameters,
FDG uptake has a higher prognostic value than ADC values [26, 27].
Whole-body PET/MR is limited in the detection of breast lesions. A PET/MR
mammography, with the acquisition of prone breast imaging using a breast coil, has
better results in local assessment for determining the local extent of malignant
lesions and for surgery planning [28, 29]. Another option is the fusion of breast PET
and MR based on software. Post-acquisition fusion of PET/CT and MRI, guided by
landmarks, has shown significant increases in specificity and positive predictive
value (PPV) for breast lesions, as compared to MR alone [30].
MRI is generally considered to be of low effectiveness in preoperative lymph
node evaluation. The same limitations of the PET component described in PET/CT
apply to PET/MR. A PET/MR mammography allows better discrimination of lymph
nodes than a whole-body study; however, the method is not able to detect minimal
infiltrations and therefore does not replace a sentinel lymph node biopsy. Despite
the limited sensitivity, there are situations in which a patient with locally advanced
disease or during follow-up can benefit from the PET/MR study by detecting the
metabolic alteration in lymph nodes that are not enlarged or by detecting previously
unsuspected locoregional extra-axillary lymph node metastases [31]. Local staging
may be well addressed by hybrid whole body PET/MR, combining the high sensi-
tivity of MR for multifocal disease with the high sensitivity of PET for axillary
nodal disease [32].
Regarding distant metastases detection, whole-body PET/MRI combination of
structural and functional information in a single study may be valuable [33].
However, it is not yet clear whether there are advantages over performing sequential
PET/CT and MRI studies. In the detection of distant metastasis, the MR component
of a whole-body PET/MR will improve detection of lesions in the brain, liver, and
bones and decrease the sensitivity for small lung lesions as compared to CT.
Low sensitivity of whole-body PET for breast cancer is due to the limited resolu-
tion of the method (5–6 mm). Resolution and lesion detectability can be improved
using positron emission mammography (PEM). However, limitations arising from
histological types with low metabolic activity are only partially resolved with these
devices. PEM equipment consists of detectors arranged as plates, which compress
the breast and allow the acquisition of images with greater spatial resolution and
better sensitivity. There is also the configuration with the breast hanging through an
opening in the examination table, with the PET detector ring positioned below. Both
systems have limitations for lesions close to the thoracic wall.
PET mammography reports are preferentially described with a standardized

interpretation lexicon similar to BI-RADS. Sensitivity and specificity of the method
are higher than MR in a direct comparison and can contribute to a reduction in
unnecessary biopsies [34]. Even without the CT exposure, administration of FDG
implies in a whole-body radiation exposure more than ten times higher than that
from a two-view screen film mammography [34]. Also, the technical complexity of
the method, including those related to maintaining a nuclear medicine facility,
makes it difficult to include PET mammography as a tool for screening or in pri-
mary patient evaluation.
Question Will PET/MR be a suitable equipment for breast cancer screening in the
foreseeable future?
9.4.2 Non-FDG Tracers for Breast Cancer
While 18F-FDG remains the most widely used radiopharmaceutical in PET studies,
other tracers available or under development have a great prospect of clinical appli-
cation in breast cancer imaging. New radiotracers allow a noninvasive method not
only for staging but also for assessment of receptor status, metabolic activity, and
proliferation [35]. The clinical introduction of these radiopharmaceuticals depends
on factors such as local production and availability, clinical validation, and national
regulatory agencies approval.
18
F-NaF (sodium fluoride) presents high affinity for areas of bone remodeling,
determined by the fluoride ion exchange in hydroxyapatite crystals. Its higher and
faster uptake, together with the improved resolution of PET in relation to scintigra-
phy, allows a higher sensitivity than a bone scan, especially for osteoblastic metas-
tasis (Fig. 9.12). However, there is still a need for further cost-benefit analysis
before the recommendation to replace the methods [36].
18
FMISO and 18FAZA are hypoxia markers that have prognostic value. Hypoxia,
in addition to radioresistance, is associated with greater tumor aggressiveness and
worse response to treatment, and a boost in hypoxemic tumors may allow optimiza-
tion of radiotherapy results [37].
18
F-FLT (fluorothymidine) is a labeled nucleotide that traces DNA synthesis and
correlates with Ki-67 expression, used as an imaging proliferation marker. FLT PET
may be used in the assessment of early response to chemotherapy and endocrine
therapy [38].
18
F-FES (fluoroestradiol) and other receptor tracers
18
F-FES is currently used to evaluate the estrogen receptor status in breast cancer
patients, with the advantage of a simultaneous evaluation of multiple sites and of
sites not accessible to a biopsy. Visual and semiquantitative measures (SUV) in a
FES PET/CT can identify patients that will most likely benefit from endocrine
a b c d
Fig. 9.12 18F-NaF PET shows multiple areas of increased radioactivity (a, b, and d), predomi-
nantly in the axial skeleton, consistent with osseous metastases. CT image (c) shows both lytic and
sclerotic bone metastases, demonstrating fluoride uptake only on sclerotic lesions
therapy [39, 40]. Clinical trials are currently under way to assess the value of FES
PET/CT as predictive marker of response to endocrine therapy.
18
F-Fluoro Furanyl Norprogesterone (18F-FFNP) is a progesterone receptor
tracer, also under evaluation to determine its value as a predictor of response to
hormone therapy [41].
89
Zr-trastuzumab is one of many different tracers developed to study human epi-
dermal growth factor type 2 (HER2) receptor status. HER2 PET is a possible method
to predict response to trastuzumab-based therapy [41, 42].
Question FES PET can be used to evaluate hormone receptor status. Which lesions
should be presumed to respond to hormonal therapy, those with high or with low
radiopharmaceutical uptake?
9.5 Conclusion
18
F-FDG PET/CT is indicated for distant metastases detection in patients with
advanced breast cancer, particularly when other methods are inconclusive. It is also
indicated to detect suspected recurrence. New tracers and equipment may increase
the future role of PET imaging in breast cancer patients.
References
1. Dong A, Wang Y, Lu J, Zuo C. Spectrum of the breast lesions with increased 18F-FDG uptake
on PET/CT. Clin Nucl Med. 2016;41:543–57. https://doi.org/10.1097/rlu.0000000000001203.
2. Rashmi Kumar JB. NCCN Guidelines Version 6.2020 Breast Cancer. Version 6.2020 —
September 8, 2020. NCCN Guidelines Version 6.2020 Breast Cancer. Version 6.2020 —
September 8, 2020. [cited 2020 Sep 27]. Available at: https://www.nccn.org/professionals/
physician_gls/pdf/breast.pdf
3. Groheux D, Cochet A, Humbert O, Alberini J-L, Hindie E, Mankoff D. 18F-FDG PET/CT for
staging and restaging of breast cancer. J Nucl Med. 2016;57:17S–26S. https://doi.org/10.2967/
jnumed.115.157859.
4. Ulaner GA. PET/CT for patients with breast cancer: where is the clinical impact? Am J
Roentgenol. 2019;213:254–65. https://doi.org/10.2214/ajr.19.21177.
5. Hortobagyi GN, Connolly JL, D’Orsi CJ, Edge SB, Mittendorf EA, Rugo HS, et al. AJCC cancer
staging manual. Breast. 2017;2017:589–636. https://doi.org/10.1007/978-3-319-40618-3_48.
6. Provenzano E, Ulaner GA, Chin S-F. Molecular classification of breast cancer. PET Clin.
2018;13(3):325–38.
7. Lebron L, Greenspan D, Pandit-Taskar N. PET imaging of breast cancer. PET Clin.
2015;10:159–95. https://doi.org/10.1016/j.cpet.2014.12.004.
8. Benveniste AP, Marom EM, Benveniste MF, Mawlawi O, Fox PS, Yang W. Incidental primary
breast cancer detected on PET–CT. Breast Cancer Res Treat. 2015;151:261–8. https://doi.
org/10.1007/s10549-015-3402-7.
9. Yararbas U, Avci NC, Yeniay L, Argon AM. The value of 18F-FDG PET/CT imaging in breast
cancer staging. Bosn J Basic Med Sci. 2018;18(1):72–9.
10. Paydary K, Seraj SM, Zadeh MZ, Emamzadehfard S, Shamchi SP, Gholami S, et al. The
evolving role of FDG-PET/CT in the diagnosis, staging, and treatment of breast cancer. Mol
Imaging Biol. 2019;21:1–10. https://doi.org/10.1007/s11307-018-1181-3.
11. Park S, Yoon J-K, Lee SJ, Kang SY, Yim H, An Y-S. Prognostic utility of FDG PET/CT and bone
scintigraphy in breast cancer patients with bone-only metastasis. Medicine. 2017;96:e8985.
https://doi.org/10.1097/md.0000000000008985.
12. Peterson LM, O’Sullivan J, Wu Q, et al. Prospective study of serial 18F-FDG PET and
18F-fluoride PET to predict time to skeletal-related events, time to progression, and survival in
patients with bone-dominant metastatic breast cancer. J Nucl Med. 2018;59:1823–30. https://
doi.org/10.2967/jnumed.118.211102.
13. Aliyev A, Aksoy SY, Özhan M, Ekmekçi̇oğlu Ö, Vatankulu B, Kocael PÇ, et al. The role of
FDG PET/CT in detection of distant metastasis in theinitial staging of breast cancer. Turk J
Med Sci. 2016;46:349–60. https://doi.org/10.3906/sag-1409-1.
14. Fink KR, Fink JR. Imaging of brain metastases. Surg Neurol Int. 2013;4(Suppl 4):S209–19.
15. Galldiks N, Langen K-J, Albert NL, Chamberlain M, Soffietti R, Kim MM, et al. PET imag-
ing in patients with brain metastasis—report of the RANO/PET group. Neuro-Oncology.
2019;21:585–95. https://doi.org/10.1093/neuonc/noz003.
16. Göktaş İ, Cayvarlı H. The role of F-FDG PET/CT in evaluating elevated levels of tumor mark-
ers in breast cancer. Mol Imaging Radionucl Ther. 2018;27(1):3–9.
17. Piva R, Ticconi F, Ceriani V, Scalorbi F, Fiz F, Capitanio S, et al. Comparative diagnostic accu-
racy of 18F-FDG PET/CT for breast cancer recurrence. Breast Cancer. 2017;9:461–71. https://
doi.org/10.2147/bctt.s111098.
18. Liu Q, Wang C, Li P, Liu J, Huang G, Song S. The role of18F-FDG PET/CT and MRI in
assessing pathological complete response to neoadjuvant chemotherapy in patients with breast
cancer: a systematic review and Meta-analysis. Biomed Res Int. 2016;2016:1–10. https://doi.
org/10.1155/2016/3746232.
19. Tian F, Shen G, Deng Y, Diao W, Jia Z. The accuracy of 18F-FDG PET/CT in predicting
the pathological response to neoadjuvant chemotherapy in patients with breast cancer: a
meta-analysis and systematic review. Eur Radiol. 2017;27:4786–96. https://doi.org/10.1007/

s00330-017-4831-y.
20. Grapin M, Coutant C, Riedinger J-M, Ladoire S, Brunotte F, Cochet A, et al. Combination of
breast imaging parameters obtained from 18F-FDG PET and CT scan can improve the predic-
tion of breast-conserving surgery after neoadjuvant chemotherapy in luminal/HER2-negative
breast cancer. Eur J Radiol. 2019;113:81–8. https://doi.org/10.1016/j.ejrad.2019.02.005.
21. Al-Muqbel KM, Yaghan RJ. Effectiveness of 18F-FDG-PET/CT vs bone scintigraphy in treat-
ment response assessment of bone metastases in breast cancer. Medicine. 2016;95:e3753.
https://doi.org/10.1097/md.0000000000003753.
22. Riedl CC, Pinker K, Ulaner GA, Ong LT, Baltzer P, Jochelson MS, et al. Comparison of FDG-
PET/CT and contrast-enhanced CT for monitoring therapy response in patients with meta-
static breast cancer. Eur J Nucl Med Mol Imaging. 2017;44:1428–37. https://doi.org/10.1007/
s00259-017-3703-7.
23. Pak K, Seok JW, Kim HY, Nguyen TL, Kim K, Kim SJ, et al. Prognostic value of meta-
bolic tumor volume and total lesion glycolysis in breast cancer: a meta-analysis. Nucl Med
Commun. 2020;41:824–9. https://doi.org/10.1097/mnm.0000000000001227.
24. Qu Y-H, Long N, Ran C, Sun J. The correlation of F-FDG PET/CT metabolic parameters, clin-
icopathological factors, and prognosis in breast cancer. Clin Transl Oncol. 2020;23(3):620–7.
https://doi.org/10.1007/s12094-020-02457-w.
25. Heusner TA, Kuemmel S, Umutlu L, Koeninger A, Freudenberg LS, et al. Breast cancer stag-
ing in a single session: whole-body PET/CT mammography. J Nucl Med. 2008;49:1215–22.
https://doi.org/10.2967/jnumed.108.052050.
26. Razek AAKA, Khalek AA, Gaballa G, Denewer A, Nada N. Invasive ductal carcinoma: cor-
relation of apparent diffusion coefficient value with pathological prognostic factors. NMR
Biomed. 2010;23:619–23. https://doi.org/10.1002/nbm.1503.
27. Kitajima K, Yamano T, Fukushima K, Miyoshi Y, Hirota S, Kawanaka Y, et al. Correlation of
the SUVmax of FDG-PET and ADC values of diffusion-weighted MR imaging with patho-
logic prognostic factors in breast carcinoma. Eur J Radiol. 2016;85(5):943–9.
28. Grueneisen J, Nagarajah J, Buchbender C, Hoffmann O, Schaarschmidt BM, Poeppel T,
et al. Positron emission tomography/magnetic resonance imaging for local tumor staging in
patients with primary breast cancer. Investig Radiol. 2015;50:505–13. https://doi.org/10.1097/
rli.0000000000000197.
29. Sasaki M, Tozaki M, Kubota K, Murakami W, Yotsumoto D, Sagara Y, et al. Simultaneous
whole-body and breast 18F-FDG PET/MRI examinations in patients with breast cancer: a
comparison of apparent diffusion coefficients and maximum standardized uptake values. Jpn J
Radiol. 2018;36:122–33. https://doi.org/10.1007/s11604-017-0707-y.
30. Moy L, Noz ME, Maguire GQ Jr, Melsaether A, Deans AE, Murphy-Walcott AD, et al. Role
of fusion of prone FDG-PET and magnetic resonance imaging of the breasts in the evalua-
tion of breast cancer. Breast J. 2010;16(4):369–76. https://doi.org/10.1111/j.1524-4741.2010.
00927.x.
31. Moon E-H, Lim ST, Han Y-H, Jeong YJ, Kang Y-H, Jeong H-J, et al. The usefulness of F-18
FDG PET/CT-mammography for preoperative staging of breast cancer: comparison with con-
ventional PET/CT and MR-mammography. Radiol Oncol. 2013;47(4):390–7.
32. Melsaether A, Moy L. Breast PET/MR imaging. Radiol Clin N Am. 2017;55:579–89. https://
doi.org/10.1016/j.rcl.2016.12.011.
33. Cho I-H, Kong E-J. Potential clinical applications of 18F-Fluorodeoxyglucose positron emis-
sion tomography/magnetic resonance mammography in breast cancer. Nucl Med Mol Imaging.
2017;51:217–26. https://doi.org/10.1007/s13139-016-0446-5.
34. Narayanan D, Berg WA. Use of breast-specific PET scanners and comparison with MR imag-
ing. Magn Reson Imaging Clin N Am. 2018;26(2):265–72.
35. Ulaner GA, Riedl CC, Dickler MN, Jhaveri K, Pandit-Taskar N, Weber W. Molecular imag-
ing of biomarkers in breast cancer. J Nucl Med. 2016;57:53S–9S. https://doi.org/10.2967/
jnumed.115.157909.
36. Arvola S, Jambor I, Kuisma A, Kemppainen J, Kajander S, Seppänen M, et al. Comparison of

standardized uptake values between 99mTc-HDP SPECT/CT and 18F-NaF PET/CT in bone
metastases of breast and prostate cancer. EJNMMI Res. 2019;9(1):6. https://doi.org/10.1186/
s13550-019-0475-z.
37. Daimiel I. Insights into hypoxia: non-invasive assessment through imaging modalities
and its application in breast cancer. J Breast Cancer. 2019;22:155. https://doi.org/10.4048/
jbc.2019.22.e26.
38. Kostakoglu L, Duan F, Idowu MO, Jolles PR, Bear HD, Muzi M, et al. A phase II study of
3’-Deoxy-3’-18F-Fluorothymidine PET in the assessment of early response of breast cancer to
neoadjuvant chemotherapy: results from ACRIN 6688. J Nucl Med. 2015;56:1681–9. https://
doi.org/10.2967/jnumed.115.160663.
39. Linden HM, Stekhova SA, Link JM, Gralow JR, Livingston RB, Ellis GK, et al. Quantitative
fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment
in breast cancer. J Clin Oncol. 2006;24:2793–9. https://doi.org/10.1200/jco.2005.04.3810.
40. van Kruchten M, de Vries EG, Brown M, de Vries EF, Andor WJ, Rudi AJ, et al. PET imaging
of oestrogen receptors in patients with breast cancer. Lancet Oncol. 2013;14:e465–75. https://
doi.org/10.1016/s1470-2045(13)70292-4.
41. Website. [cited 2020 Aug 15]. Available from: (NCT02398773 and NCT 02455453, available
at https://clinicaltrials.gov)
42. Gebhart G, Lamberts LE, Wimana Z, Garcia C, Emonts P, Ameye L, et al. Molecular imag-
ing as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to
predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial. Ann Oncol.
2016;27:619–24. https://doi.org/10.1093/annonc/mdv577.
Chapter 10
Image-Guided Percutaneous Biopsies
Vitor Chiarini Zanetta
10.1 Historical Perspective
The history of percutaneous breast biopsies is intrinsically associated with the

development of mammography in the twentieth century as a diagnostic tool and the
identification of non-palpable breast abnormalities, some of which are malignant
tumors being detected prior to becoming palpable lesions. The cognizance that early
detection improves survival rates urged the adoption of mammography as a screen-
ing tool for asymptomatic women in the 1970s. However, a drawback was quickly
noted. Owing to the overlap between benign and malignant features in imaging,
most of these clinical occult lesions are in fact benign lesions, and surgery was often
needed to provide a definitive diagnosis. This meant a significant burden for the
majority of women undergoing additional investigation as surgical biopsies are
morbid and expensive procedures.
This problem was first addressed in the late 1980s with the development of ste-
reotactic biopsy, using x-rays and triangulation to accurately sample lesions with
needle biopsy, seeking to obviate unnecessary surgeries. In the early 1990s, core
needles began to be used in stereotactic biopsy, showing encouraging results [1, 2].
In 1993, the first study evaluating the efficiency of ultrasound (US)-guided large
core percutaneous breast biopsy in 181 cases was published, with 100% agreement
between 49 malignant biopsy results and surgery, and no cancers were found during
follow-up of the remaining 132 cases [3]. In the following years, stereotactic and
ultrasound-guided procedures were endorsed by research, and percutaneous biopsy
began to present as a reliable and safe alternative to open surgery [4]. In the last
20 years, technology has made tomosynthesis and magnetic resonance imaging
V. C. Zanetta (*)
Department of Radiology, Instituto de Radiologia INRAD, Hospital das Clinicas HCFMUSP,
Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil

Switzerland AG 2022
162 V. C. Zanetta
(MRI)-guided biopsies possible, increasing the range of lesions that are amenable to
percutaneous biopsy, while the development of more efficient sampling needles,
including larger core needles and vacuum-assisted devices, has improved diagnostic
accuracy.
Currently, the goal of the breast team is to obtain a definitive, nonoperative diag-
nosis of all potential breast abnormalities in a timely and cost-effective way [5]. The
standard approach to potential breast abnormalities is the “Triple Assessment”
derived from clinical evaluation, radiological information, and pathological assess-
ment. When there is agreement between these three assessments, the level of diag-
nostic accuracy exceeds 99%. For cases without clinical information, such as
nonpalpable breast lesions, similar levels of accuracy have been achieved by com-
bining only imaging tests and pathological evaluation [5].
10.2 nderstanding Imaging-Guidance and Needle

U
Selection: Practical Considerations
Preferences for guidance methods and needle types for specific breast lesions vary
across institutions. A major factor in choosing the adequate imaging modality to
guide a biopsy procedure is lesion visibility. Breast lesions may be better depicted
at one modality over another, to the point that some highly suspicious lesions in one
modality may be completely invisible in another method.
For lesions that are well seen in all different modalities, the order of choice
among imaging methods will usually be ultrasound, mammography, and MRI. It is
easy to understand this order when comparing modalities. Ultrasound-guided biop-
sies have several advantages, including real-time sampling, lower cost, and the
absence of radiation or gadolinium injection, and are more comfortable for patients
when compared to MRI and mammographic guided procedures. These last two
methods require breast compression and immobile position in order to target the
lesion and complete the sampling, occasionally lasting more than 30 minutes.
Whenever a suspicious lesion is first seen at mammography or MRI, a targeted
ultrasound can be performed to look for a possible correlate, and if found, ultra-
sound is used to guide the procedure. Likewise, stereotactic and tomosynthesis-
guided biopsies must be preferred instead of MRI-guided procedures, given the
technical difficulties associated with MRI biopsy, higher costs, and limitations
related to contrast injection.
Usually masses, cysts, and every other lesion detected on ultrasound will be sub-
mitted to ultrasound-guided biopsy. Calcifications, breast asymmetries, and archi-
tectural distortions without a sonographic correlate will undergo
mammography-guided biopsy, and non-mass enhancements, foci, and masses with-
out correlation in other modalities will undergo MRI-guided biopsy. It is thus criti-
cal to perform an adequate imaging workup before any procedure to ensure accurate
targeting, safety of the procedure, and cost-effectiveness.
10 Image-Guided Percutaneous Biopsies 163
There are currently three different options of biopsy needles that are used for
sampling breast lesions: fine needle aspiration (FNA), conventional core needle
biopsy (CNB), and vacuum-assisted core needle biopsy (VAB). Although all imag-
ing modalities can guide procedures using any kind of needles, VAB is preferably
guided by mammography and MRI, while ultrasound is used for all types of biop-
sies and needles. This matter will be further discussed.
10.3 Pre-biopsy Assessment
Prior to any percutaneous breast biopsy, there are several common steps that should
be undertaken regardless of the procedure. It is critical to ensure that complete
imaging workup has been performed, to obtain confirmation that the lesion is real
and requires tissue sampling, as well as to select the proper imaging guiding method.
For instance, the radiologist should review all available images and assure that the
lesion is not actually a benign finding with incomplete workup, such as skin calcifi-
cations without proper tangential mammographic views demonstrating them or fat
necrosis presenting as a suspicious complex mass on ultrasound without proper
mammographic correlation, that would reveal benign lucent-center calcification. If
there is any concern about the biopsy need due to incomplete workup or doubts
about what imaging guidance method is appropriate, additional studies may be per-
formed, such as additional mammographic views or a second-look ultrasound look-
ing for a sonographic correlate.
10.4 atient Preparation, Biopsy Risks, and General

P
Post-biopsy Information
The patient should be oriented to keep normal activities and medications until the
day of the procedure; no fasting is required. Discontinuing blood thinning medica-
tions is a controversial topic. Blood thinning medications may increase the risk of
bleeding and hematoma formation due to biopsy; however, there are potential life-
threatening risks in stopping them, such as myocardial infarction and stroke. Current
literature supports that it is safe to perform percutaneous breast biopsy under medi-
cations known to impact bleeding, such as aspirin and anticoagulants [6]. Decisions
regarding discontinuing blood thinning medications should be made on a case-by-
case basis and shared with referring physician. If the radiologist opts for cessation,
it is necessary to ensure adequate timing for normalization of coagulation and, if
needed, check laboratory tests such as international normalized ratio (IRN) before
performing the procedure.
On the day of the procedure, the patient should be instructed to avoid applying
deodorant, lotion, or powder in the chest and axilla, since these may cause
164 V. C. Zanetta
calcification-like artifacts in the image. The patient should be questioned about

allergies related to medications used during the procedure and metal allergies for
clip placement. The chance of pregnancy should also be assessed given the potential
risks of ionizing radiation, MR field strength, and gadolinium injection.
All percutaneous breast biopsies require oral and written informed consent
clearly informing about the (1) purpose of the procedure, (2) benefits, (3) risks, and
(4) alternatives to diagnosis:
1. The purpose of the procedure is to obtain a satisfactory sample of tissue to evalu-
ate a breast abnormality. A comprehensible explanation of how the procedure is
performed should be given. The patient should be aware that the target may not
be sampled, neither completely removed, and occasionally, the biopsy will not
be performed due to non-visualization.
2. Percutaneous breast biopsy is a minimally invasive way of obtaining diagnosis
of a breast abnormality and to provide the referring physician adequate informa-
tion for patient care. It should be noted that depending on the result, additional
surgery may be needed, and in case of inadequate sampling, a re-biopsy or surgi-
cal biopsy may be needed.
3. Complications in percutaneous breast biopsy are rare. The risks associated with
the procedure are vasovagal reactions, hematoma formation, unstoppable bleed-
ing requiring surgical intervention (extremely rare), infection, pneumothorax,
pseudoaneurysm formation, implant rupture, and milk fistula in lactating
patients. The post-biopsy marker (clip) placement should be addressed, inform-
ing that a tiny marker may be placed in the biopsy site, facilitating correlation
between different imaging modalities and preoperative lesion localization.
Occasionally, the clip may migrate to a different location. Potential complica-
tions related to post-biopsy markers, such as allergy, are restricted to few case
reports, and the metallic marker will not trigger security metal detectors.
4. Surgical biopsy is usually the only alternative in obtaining tissue diagnosis.
Once the procedure is finished, the patient should be discharged with information
on how to obtain the final diagnosis, contact information for problems and concerns,
and general postprocedural orientations: avoid extreme physical activity in the fol-
lowing 4 or 5 days, appropriate care instructions for the sterile dressing, possible
occurrence of minor bleeding or bruising, as well as the appearance of a small lump
at the biopsy site and how to be vigilant for infection signs or abnormal bleeding.
Pre-biopsy assessment:
–– Lesion is real.
–– Lesion is suspicious.
–– Modality and needle selection are adequate.
–– Patient preparation and informed consent.
Post-biopsy orientations:
–– How to obtain the final diagnosis.
–– Patient education for surveillence of normal and abnormal post-biopsy healing.
–– Contact information for problems or concerns.
10.5 Considerations Regarding Clip Placement
The radiologist may choose to deploy a post-biopsy marker (clip) at the biopsy site
to facilitate the subsequent location. These markers are designed to be seen at dif-
ferent imaging modalities, allowing accurate localization of the biopsy site. Post-
biopsy markers are useful for several reasons:
1. Correlation of imaging findings between MRI, US, and mammography. This is
especially useful to check for accurate targeting when the lesion was first iden-
tified in one modality and biopsied using another one, for instance, a suspi-
cious MRI finding, submitted to a second-look ultrasound-guided biopsy. A
post-biopsy non-enhanced MRI T1-weighted sequence can be used to check
for the marker location and whether it matches the original diagnostic MRI
location.
2. Tissue markers allow for reliable re-identification of a biopsy site. Tissue mark-
ers are considered vital when the target is no longer visible after biopsy, for
instance, after complete removal during percutaneous biopsy and the histologic
results warrant surgical excision. In addition, re-identification of the biopsy
assists in evaluation for sampling error and imaging-pathology concordance.
3. Malignant lesions submitted to neoadjuvant chemotherapy may reduce to the
point of complete radiological response, becoming invisible in control examina-
tions. The post-biopsy marker is usually a reliable landmark to guide additional
surgical excision. For large lesions, more than one marker may be used for lesion
extent bracketing.
4. Dealing with breasts containing multiple sampled lesions is facilitated when
biopsy markers are used, clearly demonstrating which lesions have already been
sampled. Multiple biopsy sites may require different management, and biopsy
markers streamline this assessment. Post-biopsy markers are available in several
different shapes, and specific clips can be used to mark different targets
(Fig. 10.1).
Clips are frequently made of titanium or stainless steel. Other materials include
metal alloys and non-metallic alternatives, such as carbon-coated ceramic. Metallic
clips produce a susceptibility artifact on MRI, being easily identified, whereas non-
metallic clips may be less evident. On the other hand, metallic clips cause an artifact
on tomosynthesis that may obscure subtle findings.
Clips are available either alone, as bare clips, or associated with other materials,
such as bio-absorbable materials or non-absorbable polymers. Examples of associ-
ated materials include beta glucan, polyethylene glycol (PEG)-based hydrogel,
bovine collagen, polyvinyl alcohol (PVA) polymer, polyglycolic acid (PGA) micro-
fiber pad, PGA microfiber–PVA polymer combinations, starch pellets, polylactic
acid–PGA pellets, and suture-like netting [7]. These associated materials are
designed by vendors to improve or confer the clips certain features, such as improved
hemostasis, ultrasound visualization, or reduced clip migration.
166 V. C. Zanetta
a b
c d
Fig. 10.1 Malignant mass marked for neoadjuvant chemotherapy, with two different clips. (a, b)
sonography views of the markers before starting chemotherapy. One of the markers was deployed
at the center of the mass (a) and the other at the posterior and lateral edge (b), to mark lesion
extent. (c) Post-neoadjuvant chemotherapy mammography; the two markers are easily identified
and no residual lesion is seen. (d) MRI T1W axial image; notice the different susceptibility arti-
facts produced by each different clip
10.6 Clip Placement Complications
The clip must be deployed at the biopsy site and must remain close to it to mark
location accurately. Complications with clip placement are related to inaccurate
deployment away from the lesion, mechanical failure to deploy the clip (rare), and
clip migration, which may occur immediately after the procedure or later. Clip
migration is the most frequent cause of clip displacement, and there are several
reasons that can account for it:
1. The accordion effect: in procedures that require breast compression, such as
mammography or MRI-guided biopsy, the clip might not adhere to the biopsy
site and can be moved away from the biopsy site during compression release.
The displacement of the clip in those cases occurs in the direction of the needle
track (usually the Z axis, which will be further explained in the following
sections).
2. Clip migration in fatty tissue: predominantly fatty tissue breasts are more likely
to present clip migration within or outside the biopsy cavity, which is unrelated
to breast compression.
3. Bleeding – post-procedure continuous bleeding may displace a clip that is not
firmly attached to the biopsy cavity.
4. Hematoma – hematoma formation may prevent adequate clip attachment (float-
ing clip inside the biopsy cavity) or even cause significant mass effect displacing
the clip.
5. Changes in the biopsy site – Any factor that can modify the biopsy site may be
responsible for clip migration, such as air reabsorption in the biopsy cavity or
breast surgery.
Obtaining proper imaging documentation after clip deployment is essential. For
ultrasound-guided procedures, it is critical to seek real-time visualization of the
echogenic clip being deployed, while for MRI or mammography-guided proce-
dures, post-procedure imaging provides immediate clip identification.
Regardless of the method being used to guide the procedure, it may be useful to
obtain post procedure two orthogonal (craniocaudal (CC) and mediolateral (ML))
mammographic views to document clip location. Although uncommon, delayed
migration may occur, and immediate post-clip documentation is critical to assess
the extent of migration and accurate target location.
10.7 Ultrasound-Guided Biopsy
Ultrasound can guide fine-needle aspiration (FNA), CNB, and VAB. Currently,
US-guided CNB is the most popular modality of breast tissue sampling and consid-
ered very safe, diagnostically accurate, and cost-effective compared to other modal-
ities. In everyday practice, US-guided biopsy is the first option for sonographically
visible lesions. In the following sections, we will discuss the three main types of
US-guided procedures: FNA, CNB, and VAB.
All US-guided procedures can be performed either by a single operator or two
operators. A single operator uses the free-hand technique, in which one hand holds
the transducer in place while the “free hand” performs needle manipulation. Two
operators may be helpful for challenging cases such as lesions too close to a blood
vessel or in a very deep location, where one operator holds the transducer in place
while the other is responsible for needle handling and sampling.
10.8 Fine-Needle Aspiration (FNA)
Fine-needle aspiration is performed with small disposable needles, usually 21–25

gauge, in a relatively rapid and simple way under ultrasound guidance. FNA is usu-
ally readily available and very well tolerated by patients, with no or minimal pain
168 V. C. Zanetta
during the procedure, even when no local anesthesia is used. Prior to the develop-
ment of core biopsy in the 1990s, FNA was the standard test used for breast lesion
assessment. However, FNA has several limitations compared to core biopsy and has
been progressively replaced by the latter. FNA retrieves small amount of tissue,
samples are frequently non-diagnostic or inadequate, and cytologic analysis is lim-
ited in differentiating invasive and in situ carcinoma, as well as tumoral subtype.
Currently, FNA is still employed in specific scenarios, especially for the evalua-
tion of metastasis in axillary lymph nodes, workup of breast cysts, and evaluation of
peri-implant effusions suspected of breast implant–associated anaplastic large cell
lymphoma (BIA-ALCL). Rarely, FNA might be preferred for very superficial or
deep lesions.
10.8.1 Axillary Assessment
Axillary management is an evolving and complex subject, and it is beyond the scope
of this chapter to conduct a thorough discussion of axillary management and the
role of image-guided biopsy of lymph nodes (see Chap. 4).
Staging of axillary lymph nodes is an important prognostic factor, and sentinel
lymph node biopsy (SLNB) is the standard procedure to define axillary status.
SLNB could be skipped in cases of positive image-guided biopsy of axillary nodes,
leading straight to complete axillary dissection.
This paradigm has changed since the ACOSOG Z0011 study. The ACOSOG
Z0011 trial showed that for clinical T1–T2 N0 invasive breast cancer patients, with
up to two positive sentinel nodes in SNLB, there is no need for complete dissection
of axillary nodes for patients undergoing conservative surgery and whole breast
radiotherapy. In this setting, the role of preoperative axillary imaging has been ques-
tioned. Nevertheless, axillary image-guided biopsy with FNA or CNB still plays an
important role in assessing axillary status in the clinically node-positive axilla and
also in determining patients with extensive axillary disease burden, who may still
benefit from additional axillary management. In addition, assessment of nodal sta-
tus with ultrasound-guided biopsy should be considered for patients eligible for
neoadjuvant chemotherapy, as SLNB can be plagued by a high false-negative rate
afterward. Although with inferior diagnostic accuracy than CNB, FNA is still a
reasonable option to assess lymph nodes, being less traumatic and more affordable.
10.8.2 Cysts
FNA is indicated for symptomatic large simple cysts, without a true solid compo-
nent or other associated suspicious features (Fig. 10.2).
a b
c d
Fig. 10.2 (a–d) Consecutive images of a US-guided simple cyst FNA
Usually, simple cysts are easily aspirated, leaving no residual lesions in the imag-
ing evaluation. For most of the cases, non-bloody and non-purulent aspirates are
deemed benign and can be discarded. However, purulent aspirates should be sent for
microbiologic analysis and culture, while bloody aspirates should be sent for cyto-
logic evaluation. In the last case, it is also important to place a post-biopsy marker,
especially if no residual lesion is visible.
Occasionally, cysts may be complicated and filled with echogenic material from
pus, clot, or debris. If ultrasound and Doppler evaluation cannot discern whether the
echogenic material is actually a solid component, FNA may be indicated to differ-
entiate them. True complicated cysts will likely disappear, while true solid compo-
nents will persist. It should be noted that if a true solid component is present, this
should be submitted for histologic analysis preferably with VAB. Nevertheless,
whenever US evaluation confirms a solid component within a cystic mass by flow
detection on Doppler, FNA should not preclude histologic analysis by VAB or
CNB [8].
170 V. C. Zanetta
10.8.3 reast Implant–Associated Anaplastic Large Cell

B
Lymphoma (BIA-ALCL)
BIA-ALCL is a recently recognized complication of texturized breast implants,

usually presenting as late-onset effusion (85%), or less frequently as a mass (15%).
Although patients with mass should undergo histologic analysis either by percuta-
neous biopsy or surgical excision, up to 85% of the cases are associated with late-
onset effusion, defined as effusion occurring more than 1 year after breast
augmentation. Whenever a suspected effusion is present, FNA is indicated, seeking
to obtain at least 50 mL of effusion fluid for cytologic analysis and immunopheno-
typing, culture, cell counting, and protein [9].
10.8.4 Challenging Lesion Location
When compared to CNB, FNA maintains better tactile sensitivity, is considered

easier to perform, and is less traumatic. Thus, FNA may be preferred for lesions just
under the skin to avoid unwarranted skin trauma and also to sample lesions near the
chest wall.
10.8.5 Diagnostic Accuracy and Availability
Although inferior to CNB, FNA is still a reasonable diagnostic option. A meta-

analysis showed the sensitivity of FNA to be 74%, with a specificity of 96%. While
CNB showed a sensitivity of 84% and a specificity of 98%. The area under the curve
of CNB and FNA was high (98% vs 94%, respectively), confirming that both meth-
ods have excellent test performances [10]. The authors of this meta-analysis did not
evaluate the impact of nondiagnostic insufficient samples, which is a major disad-
vantage of FNA. In another meta-analysis assessing the diagnostic value of FNA,
although satisfactory samples of sensitivity and specificity of the test remained high
(92% and 94%, respectively), the pooled proportion of unsatisfactory samples that
were subsequently upgraded to cancers was 27.5% [11]. Since FNA is less expen-
sive, it still plays an important diagnostic role in limited resource locations, such as
developing countries [11].
10.9 Technique
The patient is positioned in a supine or supine oblique position, with the ipsilateral
arm raised behind the head. Usually, the oblique position is preferred for lateral
lesions, as well as axillary targets, especially in large breasts. In these situations, the
Skin entry
Skin entry
Fig. 10.3 Breast illustration for adequate needle entry point. (a) For superficial lesions, a closer
entry point from the lesion is desired, while for deep lesions (b), a farther entry point is required to
allow the needle to be parallel to the chest wall while sampling
oblique position may facilitate lesion visualization and improve needle path, allow-
ing it to pass parallel to the chest wall.
The skin is cleansed, the transducer is properly covered with a sterile cover, and
sterile gel is used to allow ultrasound imaging.
Planning the needle trajectory and skin entry site is one of the most crucial steps
in the procedure. In general, the needle is better visualized while perpendicular to
the transducer beam, and the needle tip should not be pointing to the chest wall to
avoid unwarranted trauma (Fig. 10.3). Given the breast natural curvature, superficial
lesions are better approached by a closer entry skin point in relation to the lesion,
while deep lesions require a farther entry point. These considerations are valid for
all US-guided procedures, including all types of biopsy needles, such as CNB and
VAB, although different adjustments are required according to the needle length.
Once proper skin entry point has been selected, proceed applying local anesthe-
sia, such as lidocaine, to decrease discomfort or pain during the procedure. The
sampling needle attached to a 10–20-ml disposable syringe should be gently intro-
duced and accurately placed within the lesion. The tip of the needle should be seen
inside the target. For solid lesions, sampling is performed while applying suction to
the syringe and using small and rapid back and forth stroke movements for cell
harvesting. Coupling the syringe with a pistol-grip mechanic syringe holder
(Fig. 10.4) is not required but highly recommended as it eases maintaining a nega-
tive pressure, allowing the operator to be more accurate during the back and forth
movements.
172 V. C. Zanetta
Fig. 10.4 Syringe attached

to the pistol-grip mechanic
syringe holder
a b
Fig. 10.5 After removing the needle and drawing air into the syringe, the operator replaces the
needle onto the syringe and squirts one drop in the center of a slide (a). A second slide is used to
gently spread the sample and make the smear (b)
Whenever suitable material is collected, the negative pressure is relieved and the
needle withdrawn. Handling and preparation of the sampled cytologic material is as
important as targeting.
If an on-site cytotechnologist or pathologist is not available, the operator must be
familiar with pathology service standards and be able to prepare the direct smears
on slides (Fig. 10.5) or any other desired preparation, such as cell blocks. If a slide
is being submitted to fixation, it is imperative to be as expedite as possible, since
delayed fixation may impair cellular preservation.
It is recommended to perform multiple needle passes, aiming to sample different
portions of the target lesion to improve representativeness and diagnostic accuracy.
A cytotechnologist or pathologist present on-site during the procedure can assist
and ensure adequate sample collection.
10.10 Complications and Post-care
FNA is minimally invasive, usually very well tolerated by patients, and considered
a safe breast procedure. Patients are released after the procedure and do not require
further care. Rarely, the procedure may be complicated with pain, bleeding, or
infection. Even rarer is the occurrence of pneumothorax, which is usually treated

conservatively without drainage.
10.10.1 ltrasound-Guided Core Needle Biopsy

U
and Vacuum-Assisted Biopsy
Core needle biopsies can be divided into two main groups: conventional core needle
biopsy (CNB) and vacuum-assisted biopsy (VAB), which, although both use hollow
needles to obtain the samples, are substantially different systems.
Conventional US-guided core needle biopsy (CNB) uses a hollow needle to
retrieve tissue samples and overpowered FNA with its higher diagnostic accuracy,
capability of differentiating in situ and invasive carcinomas, tumor grade, subtype,
and receptor status. The procedure is currently the most popular modality of breast
tissue sampling.
CNB uses a spring-loaded mechanism to obtain the samples with 18–12G nee-
dles. They are available as automatic or semiautomatic devices (Figs. 10.6 and 10.7).
The mechanism for cutting and collecting each sample is similar for both: the
needle contains an outer cutting cannula and an inner stylet, with a notch for speci-
men collection. With the inner stylet retracted, the needle tip is first placed adjacent
to the target border. The inner stylet is advanced inside the target. Once the inner
trocar is in place, the outer cannula is rapidly advanced, cutting and storing each
sample in the inner trocar notch. The whole needle is then withdrawn from the
breast, and the sample is collected after being exposed in the trocar notch (Figs. 10.8,
10.9, 10.10, and 10.11).
The main difference between automatic and semiautomatic devices is to the
advancement of the inner trocar. In semiautomatic devices, the inner trocar is manu-
ally advanced inside the lesion by the operator. Once the operator triggers (needle
firing), the outer cutting cannula is spring deployed (one-stage mechanism). In auto-
matic needles, the needle tip is positioned adjacent to the lesion border, and once the
operator triggers, the inner trocar is spring deployed inside the lesion, followed by
automatic spring deployment of the outer cutting cannula (two-stage mechanism).
Since the inner trocar of the most commonly used 14-gauge needle has a throw of
2.2 cm, before firing the needle, the operator has to ensure the presence of adequate
tissue beyond the lesion to avoid unwarranted trauma to the surroundings.
Because the procedure has to be repeated for each sample and requires multiple
passes, a coaxial device may be used to facilitate repeated access to the biopsy site.
The semiautomatic method allows for a steady and operator-controlled advance-
ment of the inner trocar, with real-time tracking of the needle tip. Thus, it is popular
in challenging cases such as sampling of subtle atypical axillary lymph nodes,
where it is possible to avoid the vascular hilum and better target the suspicious cor-
tex, lesions near vascular structures or next to breast implants, avoiding unwar-
ranted rupture of the implant shell. Nevertheless, the automatic procedure is slightly
174 V. C. Zanetta
Fig. 10.6 Examples of automatic core biopsy devices: (a) Max-Core™ Disposable Core Biopsy
(Bard Medical Division, Covington, GA, USA). (b) Magnum Reusable Core Biopsy Instrument
(Bard Medical Division, Covington, GA, USA). (c) BioPince™ Full Core Biopsy (Argon Medical
Devices, Inc., Athens, TX, USA). (d) Pro-Mag™ Ultra (Argon Medical Devices, Inc., Athens,
TX, USA)
Fig. 10.7 Examples of a

semiautomatic biopsy
devices. (a)
SPEEDYBELL™
(BIOPSYBELL Srl.,
Mirandola, MO, Italy). (b)
VELOX™ (Medax Srl
Unipersonale, San b
Possidonio, MO, Italy)
Fig. 10.8 Core needle

a
sampling mechanism
illustration. (a) Needle tip
is positioned next to the
target border. (b) The inner
stylet is advanced inside
the target, exposing the
sampling notch. (c) The
outer cannula is rapidly
b
advanced, cutting and
storing each sample in the
inner trocar notch
a b
Fig. 10.9 (a) Semiautomatic needle device with the inner stylet retracted. (b) After pushing the
plunger (arrowhead), the inner stylet is advanced, exposing the sampling notch. (c) In detail, the
sampling notch (arrow) and outer cutting cannula (void arrow)
176 V. C. Zanetta
a b
c d
e f
Fig. 10.10 Core biopsy of a lymph node with a semiautomatic device. (a) Ultrasound shows the
abnormal cortical thickening (void arrow) and vascular hilum (arrow) of the target lymph node. (b)
The needle is introduced fully retracted until reaching the border of the cortex. (c) Gradual and
controlled advancement of the inner stylet, piercing the cortical and avoiding the vascular hilum.
(d) The inner stylet fully extended while the sampling notch placed in the region of interest. (e) 90°
rotation of the transducer confirming in both planes the accurate position of the sampling notch. (f)
Post-fire with advancement of the outer cutting cannula over the sampling notch, colleting
the sample
a b
Fig. 10.11 Core biopsy of irregular mass with an automatic device (a) Pre-fire – the needle is
introduced until the tip is positioned near the border of the mass. (b) Post-fire – both the inner stylet
and outer cutting cannula have been spring deployed
more comfortable for the operator and less likely to displace the lesion as the inner
trocar advances. Especially for hard lesions surrounded by breast soft tissue, the
vigorous mechanical inner trocar throw in automatic devices is more likely to pierce
the lesion instead of displacing it forward.
Vacuum-assisted breast biopsy (VAB) uses a vacuum-powered biopsy probe to
obtain samples from larger core needles, available in a variety of sizes, needle
gauges range from 14- to 7-gauge. The needle sampling chamber is positioned into
or underneath the lesion, and after activation, the system continuously opens the
needle sampling chamber while using suction to pull the tissue into it; a rotating
cutting device advances through this tissue, closing the sampling chamber and aspi-
rating the sampled material through the probe into a collection chamber. This pro-
cess is repeated several times. The operator holds the probe in place and may rotate
it to acquire samples from different locations, requiring only one needle pass for the
whole procedure (Figs. 10.12 and 10.13).
a b
c d
Fig. 10.12 (a) VAB needle with a sampling chamber positioned underneath the lesion. (b) Vacuum
pulls the lesion inside the sampling chamber. (c) Cutting cannula advances and shaves part of the
lesion. (d) The specimen is aspirated (e) followed by retraction of the cutting cannula, uncovering
the sampling chamber for the next sample
178 V. C. Zanetta
a b
c d
Fig. 10.13 VAB of an irregular mass. (a) A mass is situated near a breast implant. (b) The VAB
needle is introduced until the sampling chamber is located underneath the target, being careful not
to pierce the breast implant. Once in position, sampling is performed with (c) retraction of the cut-
ting cannula, lesion aspiration, and (d) advancement of the cutting cannula
10.10.2 Sampling Considerations
Adequate sampling requires not only accurate targeting of the lesion but also repre-
sentative and satisfactory sampling; in other words, adequate sampling requires
samples of sufficient quality from the most suspicious parts of the lesion.
Adequate sampling is ultimately related to operator skills and needle selection.
While the operator is responsible for adequately targeting the lesion, needle selec-
tion impacts the amount of tissue retrieved per biopsy and the quality of each sample.
10.11 Quantity and Quality of the Sample
The amount of tissue retrieved per biopsy and its quality are dependent on needle
gauge as well as the method of choice: VAB vs CNB. Larger core needles yield
larger sample sizes, and for the same needle gauge, vacuum-assisted biopsy obtains
larger amounts of tissue when compared to CNB. For instance, the average speci-
men weight for the 14-gauge CNB sample is 17 mg, while per VAB, it is 37 mg. An
11-gauge VAB probe is capable of obtaining on average 94 mg per sampling, which
is over five times the amount of tissue retrieved by the 14-gauge CNB [12]. In addi-
tion, another key factor is the quality of the sampled material. VAB devices can
provide superior quality samples using suction, avoiding fragmented or floating
specimens that are worse for pathologic assessment. For instance, bleeding in the
biopsy cavity during the procedure may occur to varying degrees and can be severe
during a CNB, leading to the removal of a blood clot instead of an actual tissue. An
interesting feature available in most VAB devices is manual aspiration of the biopsy
cavity. Applying suction to the biopsy site can draw blood from the biopsy cavity,
improving actual tissue sampling instead of blood clots.
10.12 Adequate Targeting
A skilled operator should sample different portions of the lesion and consider the
minimum amount of required tissue for a definitive diagnosis, which is dependent
on lesion type and size. For instance, when sampling a complex solid cystic mass,
the main objective should be to target the solid portion, and when sampling a very
heterogeneous lesion, the goal is to obtain fragments from different parts of the
lesion. Due to the risk of carcinoma in situ, non-mass lesions require greater sam-
pling for a definitive diagnosis. This is also true for irregular areas of distortion,
comprising a differential diagnosis of sclerosing adenosis, radial scar, and invasive
carcinoma [13].
There is no consensus on the number of fragments that must be retrieved during
a standard CNB. The American College of Radiology suggests that at least three to
six fragments should be obtained from each lesion. However, instead of looking for
a fixed number of fragments, the operator should seek for adequate quality of the
samples obtained according to the lesion type.
10.13 Choosing Between VAB and CNB
The two main advantages of VAB are the convenient single-pass procedure and
capability of acquiring high-quality samples. A study by the American Society of
Breast Surgeons Mastery of Breast Surgery Registry showed that larger core nee-
dles and tethered vacuum-assisted biopsy are associated with lower re-biopsy rates.
One potential drawback from VAB devices is its higher cost per procedure when
compared to standard CNB, although this might be balanced when comparing the
cost per diagnosis, since VAB is more accurate [13].
Although the benefits of performing VAB in stereotactic biopsy for calcified
lesions have been extensively shown in the literature, the evidence supporting VAB
instead of CNB for US-guided biopsies, mainly for solid masses, is less clear. For
biopsy of solid masses, both methods have shown excellent diagnostic performance,
and CNB is a reasonable option in most scenarios. The operator should take into
consideration its familiarity with each method, the type of the lesion, and cost of
each method. In addition, while CNB is restricted to diagnostic purpose, VAB has
been playing an increasing role as a therapeutic procedure, which will be further
discussed below.
180 V. C. Zanetta
US-guided VAB should be considered for:

1. Re-biopsies after a non-concordant CNB or FNA findings.
2. Sampling of complex lesions (containing solid and cystic components).
3. Small lesions, usually under 5 mm, which may be challenging to perform
with CNB.
4. Sampling of cluster of microcalcifications visible on US.
5. VAB may also be a better option for diffuse non-mass lesions, where a large
sampling is indicated.
6. Therapeutic VAB.
10.13.1 Therapeutic VAB
VAB is also suitable for therapeutic removal of benign breast lesions, such as fibro-
adenomas. In such cases, the operator seeks the complete removal of a symptomatic
benign entity, thus avoiding excisional surgery. Moreover, VAB has an increasing
role in the management of benign lesions with heterogeneity in histological find-
ings, such as papillary lesions.
Papillary lesions are a broad category ranging from definitely benign papilloma
to lesions containing varying degrees of atypia, in situ and invasive carcinoma. One
of the problems dealing with papillary lesions is that atypical cells can be found
only in part of the lesion, as small foci, or even in adjacent areas outside the lesions
themselves. Thus, although most papillary lesions are benign, CNB tends to mislead
the pathologist and is associated with underestimation. For papillary lesions diag-
nosed through CNB, the risk of malignant upgrade on surgery has been reported as
high as 15.7% [14].
Although surgical excision is still appropriated to atypical papilloma and malig-
nant papillary lesions, most papillary lesions are in fact benign papilloma, which
frequently present as a small intraductal solid mass and bloody nipple discharge.
Surgical excision for papilloma without atypia diagnosed by VAB may not be nec-
essary, since pathologic underestimation of heterogeneous lesions is reduced in
biopsies with larger gauge needles, such as VAB. Moreover, VAB can be a therapeu-
tic option when complete removal of the lesion is achieved, resolving the nipple
discharge in symptomatic cases. An ongoing research has shown that if complete
removal of papilloma has been achieved by VAB and no atypia is found, the upgrade
rate to malignancy is close to 0% [15]. This approach to use VAB instead of surgery
for papilloma without atypia may also be suitable for papilloma first diagnosed by
standard CNB, where VAB could be used as a final diagnostic and therapeutic tool
(Fig. 10.14).
This trend to de-escalate treatment with complete removal of the lesion by VAB
has been expanding to other histological diagnosis with uncertain malignant poten-
tial and may be appropriate for selected cases of flat epithelial atypia, classic lobular
neoplasia, radial scar, and benign phyllodes tumor [15, 16].
a b
c d
Fig. 10.14 Diagnostic and therapeutic VAB for an intraductal papilloma. (a) Intraductal solid
mass in a patient presenting with bloody nipple discharge. (b) Color Doppler detected flow within
the lesion, confirming the solid nature of the mass. (c) Complete removal of the intraductal mass
with US-guided VAB. (d) Post-biopsy marker deployed immediately after the procedure. (e)
Biopsy site 4 years after the procedure, with no residual lesion
10.13.2 VAB and CNB Technique
The initial planning of both VAB and CNB is very similar to FNA. The patient is
positioned in a supine or supine oblique position, with the ipsilateral arm behind the
head. The oblique position is preferred for lateral lesions, as well as axillary targets,
especially in large breasts, improving lesion visualization and needle trajectory,
allowing it to pass parallel to the chest wall.
Similar to FNA, the skin is cleansed and asepticized, the transducer is properly
covered with a sterile cover, and sterile gel is used to allow ultrasound imaging of
the targeted lesion. Once the initial preparations are complete, the operator has to
plan the skin entry point of the needle and its trajectory, taking into account the
lesion depth and location. The optimal needle visualization is obtained with a per-
pendicular angle between the needle and the transducer beam. Superficial lesions
are best approached by a skin entry point closest to the transducer, while deep
lesions require a farther entry point (Fig. 10.3).
182 V. C. Zanetta
Fig. 10.15 Skin entry

point anesthesia
a b
Fig. 10.16 (a) Scalpel incision in the skin and (b) core needle introduction
The entry skin point is anesthetized with lidocaine or other local anesthetic
(Fig. 10.15). The needle trajectory should also be anesthetized with lidocaine alone
or in combination with epinephrine, and the anesthetic liquid can be used to lift
lesions close to the chest wall or breast implants. While delivering anesthesia, the
operator uses this opportunity to confirm that the planned entry site in the skin and
needle trajectory is optimal for performing the biopsy.
A small incision is made in the skin with a scalpel blade, and a needle is inserted
under real-time guidance into the desired location for specimen collection
(Fig. 10.16). VAB needles are ideally placed underneath the lesion, allowing the
suction of the vacuum to assist in the lesion sampling, while CNB needles should
pierce the lesion in each sampling (multiple passes). Once sampling is adequate, a
marker should be deployed inside the lesion or in its original location in case of
complete lesion removal with VAB.
Direct compression and ice should be applied to the breast for hemostasis for
about 10 minutes. The most frequent biopsy complication is related to persistent
bleeding and hematoma formation. Since VAB yields more tissue per biopsy, there
may be more tissue damage and bleeding, although the suction during the procedure
is an effective measure to minimize hematomas in most cases. Usually 10 minutes
of direct compression is sufficient for adequate hemostasis for both VAB and CNB;
however, additional compression for 20 minutes or longer may be required in refrac-
tory cases. Continuous bleeding that requires surgical intervention is extremely
rare. Albeit rare, other possible complications include infection, pneumothorax, and
pseudoaneurysm formation. Implant rupture and milk fistula in lactating patients
may occur, although they do not represent a threat but rather an inconvenient
outcome.
Once hemostasis is achieved, a sterile dressing is applied to the skin wound, and
the patient may be submitted to mammographic CC and ML views to document
post-biopsy clip location. A compression bandage can be used for a few hours to
further enhance hemostasis, and the patient is discharged after receiving general
post-procedure orientations.
10.14 Mammography-Guided Biopsy
There are two methods of percutaneous mammography-guided breast biopsy: ste-

reotactic and digital breast tomosynthesis (DBT)-guided biopsy. Stereotactic biopsy
emerged first in the 1980s. The development of stereotactic biopsy was a huge
breakthrough for diagnostic evaluation of suspicious breast lesions only seen at
mammography.
Indications for stereotactic-guided and DBT-guided biopsies are identical,
although the latter method is able to characterize and sample lesions not seen by
standard 2D mammography, which will be further detailed in the following sec-
tions. Mammography-guided biopsies are mainly indicated to sample suspicious
findings as calcifications, masses, architectural distortions, and focal and develop-
ing asymmetries not seen on ultrasound evaluation. In everyday practice, most ste-
reotactic biopsies are related to clustered microcalcifications, since the individual
calcifications are smaller than 0.5 mm and rarely seen on ultrasound.
For mammography-guided biopsies, although FNA and standard CNB can be
performed, VAB is the current state of the art for the procedure. FNA does not have
a reliable sensitivity in such procedures, and CNB is related to higher rates of re-
biopsy due to insufficient sampling and image-pathology discordance, especially
for calcifications [17, 18]. The vacuum system and larger gauge needles are associ-
ated with higher-quality samples, while the greater volume of tissue collected by
VAB minimizes sampling error and compensates sampling error due to patient
movement or due to deep injection of anesthetic. A recent meta-analysis has shown
that VAB is related to lower Ductal carcinoma in situ (DCIS) underestimation rate
compared to CNB (22.98% by CNB and 11.05% by VAB, p < 0.001) with higher
rates of calcification retrieval (RR = 0.89, 95% CI 0.81 to 0.98, p = 0.02) [19]. The
sensitivity and negative predictive value of VAB have been reported as high as
>99% in a large retrospective study [17].
184 V. C. Zanetta
10.15 Stereotactic Biopsy
Stereotactic biopsy uses spatial triangulation and basic trigonometry to precisely

target a breast lesion seen on mammography, providing coordinates in all axes
(width, X; length, Y; and depth, Z) and allowing correct placement of the biopsy
needle inside the breast for sampling.
Conventional 2D mammographic views alone cannot provide depth information.
However, depth calculation is possible after adding a second view from a different
position, based on the parallax principle. Stereotactic biopsy uses two different
views of the target lesion, each one with different x-ray tube angulations, known as
“stereopair,” usually 15° off the midline. Bear in mind that the breast is fixed in
place, while the x-ray tube is angled around a fixed center of rotation (Fig. 10.17).
The different angulations between the images of the stereopair are responsible for
the apparent change in the position of the lesion. The apparent change in position of
an object in relation to a reference point from two different views is known as paral-
lax shift. The target lesion does not actually move; however, it is projected at
Fig. 10.17 The different

Image receptor
angulations of the x-ray
tube are responsible for the
apparent change in position
of the target at the image
receptor, which is known Breast support
as the parallax principle
Lesion
Compression
paddle
+15˚ –15˚
different locations in each image. Using trigonometry and the apparent shift of the
target lesion, the computer software is able to calculate the depth of the target lesion
and provide coordinates in all axes.
10.16 Upright Add-On and Prone Table Biopsy Systems
Both stereotactic biopsy and DBT biopsy systems are offered by vendors as either
dedicated prone tables or as add-on units to standard mammogram devices
(Fig. 10.18).
In dedicated prone tables, the system is designed solely for breast biopsies. The
patient is in prone position on the table, with the target breast inserted through a
table opening. Under the table, the breast is compressed by a fenestrated compres-
sion paddle for needle introduction and tissue sampling.
On the other hand, upright add-on units are attached to a diagnostic mammogra-
phy unit; the patient is positioned either in a lateral decubitus on a table or in an
upright position seated on a chair, while the breast is compressed by a fenestrated
compression paddle for sampling. The patient is able to see the whole procedure,
including the needle manipulation and tissue sampling, which can increase vasova-
gal reactions.
The major advantage of the prone table system is that it is more comfortable for
the patients; however, these systems are more expensive and cannot be used for
routine mammographic imaging. The prone table system has a weight limit, which
can preclude its use for overweight patients who exceed the limit. Also, targeting of
far posterior lesions may be difficult as the breast cannot be pulled down enough
a Prone b Lateral c Upright
Image detector
Compression Biopsy x-ray

paddle needle tube
Fig. 10.18 (a) A dedicated prone table; the patient lies prone on the table, with the target breast
inserted through a hole in the table. Under the table, the breast is compressed with a fenestrated
paddle, through which the biopsy needle is inserted. (b, c) Conventional mammography unit with
an add-on device for biopsy; the patient can be positioned either in a lateral decubitus or upright
(seated)
186 V. C. Zanetta
through the table opening, often requiring the arm-through-the-hole technique.

Upright add-on systems have the advantages of being less expensive, the mammo-
graphic unit can be used for routine mammographic examinations, and the system
does not have a standard weight limit as the patients are placed on tables or chairs
not attached to the system itself. In addition, far posterior lesions are more easily
accessed. However, as previously explained, upright systems are known to be
related to increased vasovagal reactions, which can impair the procedure.
10.17 The Procedure
The first step is to select the most appropriate approach for breast compression
and needle introduction. The operator should review the CC and ML views and be
attentive to two factors: conspicuity of the lesion in both views and in which view
the lesion is more superficial to the skin. Ideally, the radiologist chooses the inci-
dence in which the lesion is most superficial on the skin, as long as it is well
visualized. In some situations, the operator has to choose one or the other
(Fig. 10.19).
For instance, a lesion located at the junction of the inner quadrants has the medio-
lateral view as the shortest skin to lesion approach; however, if this lesion is best
seen at the craniocaudal view, being very subtle at the lateromedial view, the opera-
tor may choose the CC approach to avoid sampling error.
After selecting the biopsy approach, the patient is positioned on the available
biopsy system (prone or upright), and the technologist acquires a scout view visual-
izing the lesion through a fenestrated compression paddle. This preliminary image
is acquired with the x-ray tube perpendicular to the breast (angle of 0°) to position
the lesion at the center of the field of view (FOV). This step may be hard, long, and
strenuous, especially for subtle findings in large breasts, given the small FOV of the
a b
Fig. 10.19 Approach selection for a pleomorphic cluster of calcifications. (a) ML view and (b)
CC view. The cluster of calcifications (circle) is closer to the inferior skin than the medial (arrows)
and is well seen in both views; thus, the best approach is caudocranial
a b c
Fig. 10.20 (a) Scout image; (b, c) the “stereopair”
fenestrated paddle. If needed, the radiologist may help in positioning, using what-
ever helpful landmarks are available, such as blood vessels or coarse calcifications
near the lesion to guide the correct positioning. The available screen in the proce-
dure room does not have the same resolution as the dedicated breast workstations
used for reporting, and therefore, the findings usually become less evident.
After finding the lesion, it is also important to check if there is any major blood
vessel overlapping the lesion, a situation that will require repositioning, for instance,
with maneuvers such as rolling.
Once the lesion is properly found and centered, the two views of the “stereopair”
are obtained. Each stereopair view is 15° off the scout view, one angled to the left
and the other angled to the right (+15° and −15°) (Fig. 10.20).
The radiologist should mark the target on each of the stereopair views so the
software can calculate X-Y and Z coordinates. Using the Z coordinate (depth), the
thickness of the breast, and the needle measurements, the radiologist has to check
the “stroke margin” to ensure that the tip of the needle will not hit the posterior
aspect of the breast (Fig. 10.21).
After targeting, the coordinates are transferred to the computer connected to the
needle probe holder. The system automatically drives the needle to the desired loca-
tion in the horizontal and vertical planes (X and Y coordinates), while advancing the
needle in depth (Z-axis) is performed manually by the operator. The radiologist
should disinfect the skin through the fenestrated paddle and administer local subcu-
taneous and deep anesthesia with lidocaine alone or in combination with epineph-
rine. For accurate local administration of anesthesia, it is helpful to manually
advance the tip of the needle close to the skin to ensure the entry point is being
numbed and seek for the needle trajectory for the deep anesthesia. A small scalpel
incision (2–3 mm) is made in the skin, and the needle is manually advanced to the
target. Once the needle is in place, the operator may request pre-fire images, two
stereopair angulated views (+15 and −15 degrees) to ensure that the lesion has not
moved due to anesthesia injection or inadvertent patient movement. The radiologist
may obviate the pre-fire images if there is confidence that no movement has
occurred. The needle is then fired deeper into the breast, and two post-fire stereopair
188 V. C. Zanetta
Fig. 10.21 Once in proper Post-fire Pre-fire

pre-fire position, the needle
is fired into the tissue to
avoid displacing the lesion.
The distance of the
post-fire needle tip to the
image detector is the Stroke
“stroke margin” Stroke 12 mm
margin
Target
Detector
or breast Compression
platform plate
Compression thickness
a b c
Fig. 10.22 (a, b) Post-fire stereopair images; part of the calcifications are obscured by the needle,
with the sampling chamber correctly placed. (c) The specimen radiograph shows multiple frag-
ments with pleomorphic calcifications
images are usually obtained to ensure the sampling chamber is within the target
lesion (Fig. 10.22).
Generally, samples are obtained in a clockwise fashion if the needle is right in
the center of the target; however, obtaining post-fire images can tailor sampling; for
example, if more calcifications are seen under the sampling chamber, more samples
should be obtained with the sampling chamber directed downward.
Usually, from 6 to 12 tissue fragments should be obtained. However, the number
of fragments is variable and depends on the radiologist’s discretion, needle gauge,
and lesion size. For calcified lesions, radiographs of the sample should be obtained
a b c
Fig. 10.23 (a) Biopsy probe slightly pulled back showing adequately deployed clip. (b, c) Post-
biopsy clip documentation in CC and ML views
to confirm calcification retrieval and accurate targeting (Fig. 10.22c). There is no

consensus about the optimal number of fragments in the literature; however, it has
been suggested that for a larger needle gauge, such as 9G, nine fragments are opti-
mal for diagnosis [20], while for a smaller needle gauge, such as 11G, at least 12
fragments should be retrieved [21]. The European Society of Breast Imaging sug-
gests that at least 12 fragments should be retrieved [5].
Once sampling is finished, a marker should be deployed at the biopsy cavity
through the biopsy probe. The probe should be slightly pulled back in order to con-
firm its placement with additional stereotactic views (Fig. 10.23).
If the marker is not seen, the probe is reinserted into the target’s coordinates, and
a second marker is deployed. Once adequate marker deployment has been ensured,
the probe is withdrawn and the breast slowly released from compression to avoid
clip migration (“accordion effect”).
The main complications related to stereotactic biopsy are vasovagal reactions,
bleeding, and hematoma formation, as seen in other breast procedures.
Direct compression and ice should be applied to the breast for hemostasis for at
least 10 minutes. Once adequate hemostasis is achieved, a sterile strip dressing is
applied to the skin incision to aid wound healing. Post-biopsy CC and ML views
should be obtained to document the biopsy site, to confirm adequate sampling with
partial or complete removal of the target lesion, and to document the location of the
post-biopsy marker (Fig. 10.23b, c). Occasionally, the marker may be displaced
from the biopsy site. This displacement usually occurs within the needle track; for
instance, if the approach was either medial or lateral to the breast, the marker may
be displaced lateral or medial to the biopsy cavity, while a craniocaudal approach
may present superior or inferior displacement of the clip in relation to the biopsy
cavity. In such cases, the radiologist should describe in the final report the amount
of displacement of the marker in relation to the target site in centimeters as well as
provide useful landmarks that can assist later localization of the biopsy site.
A compression bandage may be used for a few hours to further enhance hemo-
stasis, and the patient is discharged with general post-procedure orientations.
190 V. C. Zanetta
Table 10.1 Positive predictive value for architectural distortions seen only on tomosynthesis
Author AD only seen on DBT Malignant outcome PPV (%)
Alshafeiy TI et al. 59 6 10.2
Partyka L et al. 9 4 44
Patel BK et al. 34 9 26
AD architectural distortion, PPV positive predictive value
10.18 Digital Breast Tomosynthesis-Guided Biopsy
Digital breast tomosynthesis (DBT) has been increasingly used since the first device
received its Food and Drug Administration (FDA) approval in 2011. The technology
uses an x-ray tube that moves in an arc over the compressed breast and captures
several images of each breast from different angles, which are reconstructed by
software into a set of “three-dimensional” images. Also, acquired data can be col-
lapsed into a single synthesized 2D image, which may obviate the need for conven-
tional 2D images, reducing radiation dose in half. The three-dimensional set of
images is converted into 1-mm sections of the breast, reducing tissue overlapping,
improving analysis of the margins, facilitating the identification of subtle findings
such as architectural distortions, and providing the location of lesions visible only
in one mammographic view [22]. Studies have shown that DBT reduces false-
positive and recall rates while improving cancer detection [8, 23, 24]. Its adoption
by medical facilities has been increasing and replacing older mammographic 2D
units (conventional full field digital mammography and computed radiography
units). To illustrate, on December 1, 2017, 3866 certified facilities had DBT units in
the United States of America (USA), and this number jumped to 6.111 on June 1,
2020. Currently, over 70% of all US certified facilities [25] have already adopted at
least one DBT unit.
With increasing number of examinations being done with DBT technology, we
have been facing a growth of findings visible only on DBT. There is still an ongoing
debate of the positive predictive value of these findings; however, initial data sug-
gests that biopsy is required. For architectural distortions (AD) seen only on DBT,
10–44% had a malignant biopsy outcome [26–28] (Table 10.1).
10.19 DBT Versus Stereotactic Guided Biopsy
DBT biopsy is critical for tissue sampling of findings only seen on DBT, such as
AD, asymmetries, and some masses. Prior to DBT biopsy development, findings
seen only on DBT had to be surgically excised after preoperative localization; thus,
DBT biopsy reduces the costs and morbidity related to surgical excision. Moreover,
even for noncalcified lesions seen at 2D mammography, DBT biopsy usually depicts
these findings better than digital mammography (DM), which translates into better
confidence in targeting.
Table 10.2 Comparison of technical success rate, mean procedure time, and radiation exposure
between digital breast tomosynthesis and stereotactic biopsy
Mean procedure time Median number of
Author Technical success rate (min) images acquired
PSVAB DBTVAB PSVAB DBTVAB
Schrading 154/165 51/51 (100%) 27 13 8 5
et al. (93%)
Bahl et al. 410/431 695/700 27 12 12 3
(95.1%) (99.3%)
Ariaratnam N/A 38/38 (100%) N/A 15 N/A N/A
et al.
PSVAB prone stereotactic vacuum-assisted biopsy,. DBTVAB digital breast tomosynthesis vacuum-
assisted biopsy
In addition, DBT biopsy obviates the need for the stereopair images, with direct
depth calculation (Z-axis), decreasing procedure time and radiation exposure. A
large retrospective study conducted by Bahl et al. comparing 706 DBT-guided biop-
sies in upright positions with 439 stereotactic biopsies in prone tables suggested that
DBT biopsy prevailed over stereotactic as a faster procedure (12 vs 27 min), with
lower radiation dose (3 vs 12 exposures) and greater technical success (99.3% vs
95.1%) [29]. Those findings are similar to those of smaller earlier studies comparing
DBT and stereotactic guided biopsies [30, 31] (Table 10.2).
10.20 The Procedure
Overall, aside from lesion identification and targeting, DBT-guided biopsy is very
similar to the standard stereotactic biopsy. The choice of approach is identical,
requiring the needle to go through the shortest distance to the skin or use the inci-
dence that provides the best conspicuity of the lesion.
The patient is positioned according to the available system (upright or prone),
and tomosynthesis images or a 2D scout image is obtained by the technologist cen-
tralizing the lesion within the FOV. Once the lesion is accurately identified, a tomo-
synthesis scout image is obtained. The radiologist scrolls through the slices until he/
she finds the slice where the lesion is more conspicuous (Fig. 10.24).
In the computer screen, the target is marked and the software readily calculates
the Cartesian coordinates X, Z, and Y. It is important to emphasize when going
through the images, the radiologist should be aware if there are no vessels along the
needle path, and if applicable, repositioning should be done. The breast can be
rolled to remove the vessel from the path or change the approach view, such as
orthogonal view.
After the proper coordinates are obtained, the radiologist has to ensure that there
is sufficient tissue beyond the lesion for the needle to be fired within the breast
without hitting the posterior aspect of the breast and also that the skin is not included
in the sampling chamber of the needle. This has become very easy and intuitive with
192 V. C. Zanetta
Fig. 10.24 DBT-guided

biopsy of an architectural
distortion. Once proper
scout has been done, a
tomosynthesis set of
images are obtained. The
radiologist scrolls the
images until he/she reaches
the slice where the lesion
is most conspicuous
(arrow)
newer software that displays a graphical representation of the needle inside the
breast, as shown in Fig. 10.25.
Once targeting has been completed, the coordinates are sent to the computer
attached to the needle probe. Asepsis of the skin, anesthesia, scalpel incision, and
needle introduction are conducted similarly to stereotactic biopsy. Once in target,
pre-fire images may be obtained, which can be either 2D stereopair angulated views
(+15 and −15 degrees) or a pre-fire tomosynthesis image set. At this stage, it is
crucial to check if there was patient movement after the lesion coordinates were
obtained. After firing the needle, a post-fire tomosynthesis set or a 2D stereopair
post-fire images may be obtained at the discretion of the radiologist; however, the
stereopair adds more radiation than the tomosynthesis set of images (Fig. 10.26).
The handling of the probe for tissue sampling, the number of fragments required,
the specimen radiographs, the procedure complications, and the post-procedure
care are no different from what has been described for stereotactic biopsy. However,
post-biopsy documentation to ensure the correct sampling with the marker in place
is performed with a single set of tomosynthesis images (Fig. 10.27).
10.21 echnical Challenges and Possible Solutions (DBT

T
and Stereotactic Biopsy)
10.21.1 Subtle Findings
Subtle findings may be hard to locate within the small field of view of the biopsy
equipment. To overcome this problem, before positioning the patient on the stereo-
tactic table, the lesion can be localized using a full-field 2D mammography and an
alphanumeric grid. The alphanumeric grid is used to place a metallic marker (BB)
overlying the skin, which can then be used during the procedure as a landmark to
find the target lesion [32] (Fig. 10.28).
Fig. 10.25 The Hologic Affirm® Prone Biopsy System uses pre-programmed needle parameters
to display a graphical representation of the selected needle, the target location, the compression
paddle, and the image receptor. In an intuitive fashion, it is possible to see all relevant spatial rela-
tionships: the location of the marked target (green), the length of the needle inside the breast (blue),
the distances between the point of entry of the skin and the beginning (white) and middle (light
gray) of the sampling chamber, as well as the distance between the needle tip and the image recep-
tor (dark gray)
Fig. 10.26 Post-fire

tomosynthesis showing the
needle sampling chamber
in an accurate position to
sample an architectural
distortion
194 V. C. Zanetta
a b c
Fig. 10.27 Comparison of pre- and post-biopsy images to verify sampling accuracy. (a) Pre-
biopsy tomosynthesis slice demonstrating the architectural distortion to be sampled; (b) post-biopsy
tomosynthesis slice showing adequate sampling with the clip at the desired location; and (c) pre-
biopsy 2D mammography for comparison. Note that the architectural distortion is barely seen
without tomosynthesis
a b
Fig. 10.28 (a) Full-field 2D mammography and alphanumeric grid used to locate subtle calcifica-
tions. (b) Magnified view after placing the marker overlying the skin. The BB can later be used as
landmark to find the clustered calcifications
10.21.2 Far Posterior Lesions
Targeting deep lesions can be challenging, especially in prone tables. Occasionally,

the breast cannot be sufficiently pulled down through the hole, and the lesion is not
included in the field of view. If available, upright add-on systems are better suited
for far posterior lesions.
There are several techniques that can be used to target far posterior lesions.
Repositioning with lower breast compression and lateral or MLO approach can
increase the inclusion of posterior and axillary tissue. For prone tables, the patient
can be slightly rolled onto her side while placing her entire arm, shoulder, and breast
through the table hole (arm-through-the-hole technique) [33].
10.21.3 Thin Breasts
During breast compression, a minimum thickness of the breast is required to fit the
needle, including its tip and sampling chamber. A minimum thickness of 30 mm is
required for standard VAB or 20 mm for a shortened sampling chamber needle, also
called petite needle (Fig. 10.29).
If there is not enough room for the needle, the stroke margin becomes negative. In
cases where even a petite needle is not enough, the operator can attempt to roll the
standard sampling chamber
I
m shortened sampling chamber
a
g
e
r
e
c
e
p
t
o
r
20mm
30mm
Fig. 10.29 Illustration showing the differences between standard and shortened sampling cham-
ber needles
196 V. C. Zanetta
Fig. 10.30 Lateral arm

approach for a very thin
breast. The needle is
manually inserted along
the horizontal axis (X) into
the breast
breast or tape up the breast against the chest wall in order to bulge the breast anteri-
orly through the opening of the paddle to increase thickness. Rarely, very thin breasts
may require adding another biopsy paddle between the posterior aspect of the breast
and the image receptor. In cases where the stroke margin is only slightly negative,
injecting superficial anesthetic to increase the skin wheal can add a few millimeters.
If available, the operator can opt to use a lateral arm extension device to perform the
insertion of the needle between the image receptor and the compression paddle, i.e.,
orthogonal to the compressed breast. In the lateral arm approach, the needle is inserted
horizontally (X) into the breast; thus, the stroke margin is greatly improved (Fig. 10.30).
10.22 Superficial Lesions
To avoid unwarranted trauma of the skin, superficial lesions can be sampled with a
shortened sampling chamber needle. In addition, although the software calculates
the coordinates so that the target is right in the center of the sampling chamber,
I
m
a
g
e
r
e
c
e
p
t
o
r
Proximal edge
of the sampling
chamber
Z+ Z
Fig. 10.31 Illustration showing the position of the sampling chamber and the skin at the calcu-
lated depth (Z) for the target. The operator can further introduce the needle (Z+) so the sampling
chamber is able to sample the lesion at its proximal edge while avoiding the skin
sampling occurs throughout the whole sampling chamber. Taking into account the
length of the sampling chamber and its relationship to the target allows the needle
to advance a few millimeters to avoid skin trauma, while sampling is done at the
beginning of the sampling chamber (Fig. 10.31).
10.23 MRI-Guided Biopsy
Of all imaging modalities, breast MRI has the highest sensitivity for detecting breast
cancer. Two meta-analyses showed a sensitivity of 90–92% and a specificity of
70–72% [34, 35]. Thus, although MRI is very sensitive, up to 30% of suspicious
findings are in fact benign, and histologic confirmation is required for a definitive
evaluation of suspicious findings (BIRADS 4 and 5). The main indication for breast
MRI-guided procedure is BIRADS 4 and 5 lesions that are not amenable to biopsies
guided by ultrasound or mammography.
198 V. C. Zanetta
10.23.1 Second-Look Ultrasound

and Second-Look Mammography
MRI-guided biopsy is an expensive and time-consuming procedure; it requires

intravenous gadolinium injection and can be limited in deep or axillary lesions. The
procedure may be time-consuming and uncomfortable for patients. Ultrasound sam-
pling, whenever possible, should be the first option. Even in cases where breast
ultrasound has already been performed, it may be useful to obtain a second-look
ultrasound before undergoing breast MRI-guided biopsy.
A second-look ultrasound is a targeted examination with a purpose of finding a
corresponding lesion on ultrasound. It should be performed using information from
the MRI examination, such as lesion location and characteristics and available ana-
tomic landmarks, taking into account imaging differences between the two modali-
ties, including different breast position (supine vs prone) and related tissue
deformation [36]. If a positive correlation is found, an ultrasound-guided biopsy is
performed. It should be noted that the second-look ultrasound is often a challenging
examination, requiring an experienced operator. The successful rate of positive cor-
relation reported in the literature is markedly heterogeneous, ranging from 23% to
82%, and can be dependent on several factors, such as operator’s experience, lesion
type, size, depth, and size of the breast.
In 2009, Nakano et al. [37] described the use of a sonographic system that
enables real-time sonography with MR navigation. Since then, several vendors have
offered systems with different names that permit co-registration and allow synchro-
nization of sonographic and MR images during real-time sonography [38]. These
devices can track probe’s position and couple real-time ultrasound images to a set
of pre-acquired MR images uploaded in the system, displaying magnetic resonance
multiplanar reconstruction (MPR) images along with real-time ultrasound images
side by side or as overlying (fusion) images. A major limitation of these systems is
that MR images are acquired in a prone position to reduce artifacts from breathing
motion and heart beating, while ultrasound is usually performed in a supine posi-
tion, and breast deformation in each position can lead to misalignment and morpho-
logical differences between the acquired images. Several solutions to reduce
misalignment have been developed, such as performing both examinations in the
same position (prone or supine) and improvements in algorithm to compensate
deformation between the two modalities. These techniques have shown promising
results, with reported rates of successful correlation ranging from 83% to 95.5%
[38–41].
Although lesions that present a sonographic correlate are more likely to be
malignant, malignancy is found in about 12% of cases where no sonographic cor-
relate is found, and the lack of correlation does not obviate the need for histological
analysis [42].
10.23.2 Second-Look Mammography
The rationale behind reviewing mammography images before performing an MRI-

guided biopsy is similar to a second-look ultrasound. Performing a mammography-
guided biopsy is more cost-effective and less time-consuming than performing an
MRI-guided biopsy. The radiologist should look for any abnormalities on mam-
mography that could correlate to the suspicious MRI finding. A careful review of
calcifications is recommended for nonmass enhancements, as calcifications can be
reliable targets and are frequently not seen on ultrasound evaluation.
Recent reports have also shown the value of second-look DBT. Clauser et al.
published a study evaluating the performance of DBT and ultrasound in detecting
84 additional findings in 135 patients with breast cancer who underwent breast
MRI. While ultrasound alone showed a positive correlation in 52% of the cases,
when combined with DBT, the detection rate rose to 75% [43]. These results are in
agreement with a study published by Mariscoti et al. analyzing 164 additional find-
ings in 520 women with breast cancer who underwent breast MRI, showing that
ultrasound alone was able to identify 69.5% of those additional lesions, while DBT
increased the detection success rate by up to 89% [31]. This increase is probably
related to the ability of tomosynthesis to evaluate masses, asymmetries, microcalci-
fications, or architectural distortions that may be subtle or not visible at all on US.
Similar to second-look ultrasound, the rest of the cases that do not have ultra-
sound or mammogram correlate require MRI-guided histological analysis.
10.23.3 The Procedure
MRI-guided biopsy requires a compatible and dedicated breast coil for the proce-
dure, as well as an MRI-compatible vacuum-assisted biopsy device, usually con-
taining an 8–12G needle and an introducer kit. As with stereotactic and DBT-guided
biopsies, the use of VAB is the standard of care, ensuring the procedure is performed
in a timely manner and that adequate samples are retrieved. Before starting the pro-
cedure, MRI safety should be checked, as well as contraindications to intravenous
gadolinium injection. A thorough review of the original diagnostic MR examination
is necessary to be familiar with the lesion’s morphological features and location.
The radiologist uses this information to aid in patient positioning and to select the
best approach to sample the target lesion. Older systems are limited to lateromedial
approach only; however, improvements in design made coils available from multi-
ple vendors that also allow craniocaudal and mediolateral approaches, improving
accessibility to the lesion.
The patient should be positioned in prone position, with the index breast placed
on the breast coil. The breast is compressed between the compression plate and the
biopsy grid, from which the radiologist manipulates the needle during the procedure.
200 V. C. Zanetta
Adequate compression is critical to ensure that the breast is fixed in place while
the procedure is performed; however, care should be taken not to overcompress,
which can interfere with enhancement of the target lesion.
The biopsy grid consists of evenly sized squared holes, one of which will be used
for needle insertion. Some grids have a built-in marker in one of its holes that can
be seen in non-enhanced T1-weighted sequences, while other grids require the
placement of a fiducial marker in one of its holes. Since the marker can be seen on
MR images and its actual location on the grid is known, it is used to identify a par-
ticular hole seen on the MR image and its actual location on the grid plate
(Fig. 10.32).
Pre-contrast images are obtained to check for adequate fat saturation, and the
radiologist attempts to see if the expected lesion location is within the limits of the
grid, using landmarks and the location from the original diagnostic MRI (Fig. 10.33).
Since the grid will be used to locate the needle in the horizontal and vertical planes,
if the expected lesion is not seen within the limits of the grid, the patient can be
repositioned before resuming the procedure.
a b
Fig. 10.32 (a) Breast coil and biopsy grid from Siemens (a) and from General Electric (b). The
fiducial marker is placed in one of the grid holes (arrow) to serve as a landmark for hole identifica-
tion on MR images
a b
Fig. 10.33 (a, b) Non-enhanced sagittal T1 slices showing that the expected location of the lesion
(circle), based on anatomical landmarks, is within the grid boundaries in (b)
Post-contrast dynamic sequences are obtained to accurately identify and target

the lesion. If the enhancing lesion is not seen, the biopsy cannot be performed.
Targeting the lesion can be either done visually or using designed software for this
purpose. The visual method is very straightforward and consists of comparing the
location of the lesion with the fiducial or built-in marker in the biopsy grid. For
instance, when using sagittal sequences to perform the biopsy in a lateral approach,
the radiologist must scroll through the slices until the lesion is clearly depicted.
Once the lesion is found, the radiologist can pinpoint its center with a crosshair and
then scroll back to the slices containing the fiducial marker. By comparing the pin-
pointed location with the fiducial marker, the radiologist chooses the most appropri-
ate grid hole for needle introduction (X-Y coordinates) (Fig. 10.34).
Lesion depth is obtained by multiplying the number of slices between the skin
and the lesion by the slice thickness (Z coordinate). With coordinates in hand, the
patient is removed from the magnet and the biopsy area should be prepared with
aseptic technique. The skin and needle path are anesthetized similarly to other pro-
cedures, and a small incision in the skin with a scalpel is made to facilitate the
introduction of the coaxial device. The introducer kit contains a tunneled needle
guide that is plugged into the grid hole to stabilize the needle and a three-part coax-
ial system, consisting of an outer plastic cannula, an inner metallic stylet, and an
inner plastic obturator (Fig. 10.35).
After placing the needle guide into the chosen grid hole, the coaxial system is
first introduced with the outer plastic cannula and the inner metallic stylet inside.
The inner stylet is responsible for cutting and dissecting through the breast tissues,
while the outer plastic cannula is marked with inches and centimeters that are used
for depth control. Once the target depth is achieved, the inner stylet is removed and
replaced by the inner plastic obturator. The patient reenters the magnet, and new
images are obtained to ensure accurate positioning by comparing the signal from
the obturator, target related landmarks, and slices. The lesion may be displaced by
a b
Fig. 10.34 (a) Crosshair placed in the center of target nonmass enhancement and (b) after scroll-
ing back, the adequate grid hole for needle introduction is selected
202 V. C. Zanetta
a b
c d
Fig. 10.35 Biopsy kit. (a) Suros biopsy kit and (b) Bard biopsy kit. Inner plastic obturator (arrow),
outer plastic cannula (arrowhead) tunneled needle guide (double arrowhead) and inner stylet
(curved arrow); (c) detail of Bard tunneled guide plastic and (d) obturator and inner stylet inserted
into the needle guide
Fig. 10.36 Sampling is

usually performed in a
clockwise 360° fashion if
the sampling chamber is
centered in the lesion
anesthesia or bleeding, and occasionally, the coaxial system pushes and displaces
the tissue instead of cutting, which is known as the “snowplow” effect. If needed,
the inner stylet may be reinserted and necessary adjustments performed.
Once the coaxial system with the outer plastic cannula and the inner plastic obtu-
rator is confirmed in satisfactory position, the patient is again removed from the
magnet, the obturator is removed and replaced by the actual VAB needle, and sam-
ples are obtained, usually in a clockwise fashion or according to suitable tailoring of
the sampling chamber toward the lesion (Fig. 10.36).
Usually from 6 to 12 samples are obtained according to the radiologist’s discre-
tion. The VAB needle is then removed and replaced by the plastic obturator, and a
new set of images are obtained to confirm if the expected lesion location has been
sampled. Once adequate sampling has been confirmed, the obturator is removed and
a clip marker is deployed at the biopsy site through the plastic cannula.
Technical issues with MRI-guided biopsy are usually associated with thin breasts
or posterior lesions. MRI guidance allows a minimum thickness of 30 mm for stan-
dard needles and 18 mm for a petite needle. Most of the techniques previously
described to overcome technical problems with breast thickness in mammography-

guided biopsy can be used in MRI-guided biopsy, such as rolling or taping the
breast or increasing the anesthetic wheal. For posterior lesions, the patient may be
rolled to include more posterior tissue, and the biopsy grid can be raised.
10.23.4 Complications and Post-biopsy Care
MRI-guided biopsy is at risk for complications similar to other VAB procedures,

including bleeding, hematoma formation, skin damage, pneumothorax, and vasova-
gal reaction. In addition, although the risk for contrast reactions with gadolinium is
low, the patient must be kept under surveillance for a certain amount of time. Other
complications and post-procedure care and orientations are identical to other VAB
procedures.
10.24 Imaging-Pathology Correlation
Imaging-pathology correlation consists of evaluation of the suspicious imaging

finding and the final diagnosis provided by the pathology, assessing whether the
histologic report is in agreement with the image and providing an appropriate man-
agement recommendation. This is a mandatory part of the final biopsy report, with
the main purpose of preventing a malignant lesion with a benign pathology report
after breast biopsy from receiving further investigation, delaying cancer treatment.
When establishing imaging-pathology correlation, two aspects have to be con-
sidered: (1) whether the target lesion was accurately sampled and (2) whether the
histologic results can explain the imaging finding.
10.25 Discordant Biopsy
Whenever the lesions were missed during sampling, the results are considered dis-
cordant. A thorough review of all available images is required: the original diagnos-
tic examination and the biopsy and post-biopsy images. Morphological features,
size, and location of the target lesion are compared between the studies to ensure
that the suspicious lesion was indeed targeted during the biopsy. Post-biopsy images
may show reduction in size or complete removal of the lesion, especially when VAB
has been performed. If a biopsy marker has been deployed, the radiologist can com-
pare its location in relation to the target lesion, taking into account that migration
may occur. For all procedures, it is very useful to check the proper positioning of the
needle in relation to the target lesion during the procedure. For lesions with calcifi-
cations, the radiologist should obtain sample radiographs to ensure that the
204 V. C. Zanetta
calcifications have been retrieved, as well as to compare morphological features

between the calcifications within the samples and the target area, to ensure that the
correct group of calcifications has been sampled. Rarely, calcifications may not be
seen in the sample radiographs but can be seen in histopathology. Another aspect to
take into consideration is representativeness. If too few calcifications are present in
the sample, it may be considered not representative of the original group. For heter-
ogenous lesions, it is critical to ensure that the most suspicious part of the lesion has
been sampled. Representativeness is also related to the needle gauge used to obtain
the samples, with FNA at one end of the spectrum and VAB with larger gauge nee-
dles at the other end.
The next step is to establish whether the pathology report is consistent with the
imaging finding. Imaging-pathology concordance is often a multidisciplinary task,
involving the referring physician, the radiologist, and the pathologist. Parikh et al.
described five scenarios of imaging-pathology correlation [44]:
10.25.1 Concordant Malignancy
The radiological features of the lesion are suspicious (BIRADS 4 and 5), and the
pathology report is malignant, for instance, a spiculated mass diagnosed as infiltrat-
ing carcinoma, or a segmental enhancement or calcifications diagnosed as DCIS. The
radiologist should communicate the results to the referring physician, and the
patient contacted and referred for appropriate therapy.
10.25.1.1 Discordant Malignancy
The radiological features of the lesions suggest a benign etiology, but the pathology
report is malignant. This can be either related to an incidental finding, inadequate
prior assessment of image features, or the overlap between malignant and benign
image features of some malignant lesions. Management of such cases is identical to
concordant malignant.
10.25.2 Concordant Benign
The radiological features suggest a benign etiology, and the pathology report is a
benign lesion. A classic example is an oval mass with circumscribed margins clas-
sified as a fibroadenoma. When establishing concordance of benign image features
and a benign histological result, it is important to differentiate benign pathological
entities that are a definitive diagnosis from benign entities that are nonspecific find-
ings. Although the list of definitive and nonspecific diagnosis may be slightly vari-
able within the literature, definitive diagnosis is lesions that have distinct image
features and are easily correlated with the image findings. Definitive diagnosis
includes fibroadenoma, tubular adenoma, hematoma, abscess, hamartoma (fibroad-
enolipoma), fat necrosis, granulomatous disease, lymph node, myofibroma, and
cyst contents.
On the other hand, nonspecific breast benign results on histopathology might be
less reassuring and require a careful imaging-pathology correlation. Nonspecific
benign entities include fibrocystic changes, apocrine metaplasia, duct hyperplasia,
and stromal fibrosis. Although these lesions, alone or in combination, might be
related to the image findings that led to biopsy, such as suspicious calcifications or
an indistinct mass (e.g., fibrosis), these results are often incidental findings. Thus,
establishing concordance for such entities frequently requires communication
between the radiologist and the interpreting pathologist.
Short-term imaging follow-up protocol after a concordant benign finding is not
consensual. The current NCCN guidelines (2020, version 1) support that either a
6- or 12-month follow-up is appropriate. Some authors suggest that for stereotactic
or US-guided core biopsies, a short-term 6-month follow-up should be recom-
mended to avoid delay in diagnosing a falsely negative biopsy [45, 46], while others
suggest that a short-term follow-up may be appropriate for nonspecific diagnosis
[44, 47, 48]. Recent reports have shown little benefit from short-term follow-up and
that 12-month follow-up for benign concordant lesions is ideal [49–51].
Benign and concordant biopsies guided by MRI may benefit from short-term
follow-up given its technical challenges: MRI-guided biopsy is not a real-time pro-
cedure; specimen radiograph to confirm lesion retrieval is not possible; contrast
wash-out during the procedure and bleeding may limit sampling accuracy. A study
by Hayward et al. showed a 2.4% rate of false-negative results after benign concor-
dant assessment [52]. A short-term MRI follow-up may be useful for reassuring
adequacy of tissue sampling and to avoid delays in false-negative results.
10.25.3 Discordant Benign
The radiological features suggest a malignant lesion, while the pathology report is
benign and cannot explain the imaging features that lead to biopsy. For instance, a
spiculated mass with microcalcifications cannot be explained by fibrocystic changes
or a fibroadenoma result. A few benign entities can present findings highly sugges-
tive of malignancy, such as granular cell tumor, fat necrosis, diabetic mastopathy,
and granulomatous mastitis. These diagnoses may be concordant but require a care-
ful correlation.
A discordant result is usually related to suboptimal or sampling error, and a thor-
ough review is required to identify possible flaws during sampling. There are sev-
eral reasons that can be related to a discordant result:
–– Inaccurate targeting – wrong location was sampled, which can be related to sub-
tle findings, patient movement, technical issues with the biopsy equipment, or
206 V. C. Zanetta
even complications during the procedure (such as hematoma and lesion

displacement).
–– The correct lesion may have been sampled, but due to heterogeneity in the lesion,
only a benign portion was taken for histological analysis.
–– Suboptimal quality of the samples.
The radiologist should contact the pathologist and referring physician to discuss
the results and how to proceed with new biopsy. Both image-guided re-biopsy, usu-
ally with VAB, and surgical excision are viable alternatives.
10.25.4 High-Risk and Borderline Lesions
Some nonmalignant histologic results have a potential association with malignancy.

Albeit benign, this diverse group of histologic results can coexist with malignant
lesions, and the lesion itself confers a risk of increased malignancy over time.
Borderline or high-risk lesions include atypical ductal hyperplasia (ADH), lobular
neoplasia, papillary lesions, radial scars and complex sclerosing lesions, fibroepi-
thelial lesions with atypia, atypical lobular hyperplasia (ALH), and lobular carci-
noma in situ (LCIS).
Although atypical ductal hyperplasia has high well-known rates of underestima-
tion from percutaneous biopsy, usually leading to an excision recommendation [53],
the management of other high-risk or borderline lesions found after percutaneous
biopsy is usually less well established and determined in a case-by-case basis due to
the great variability of images, pathology, and clinical features that must be
accounted for.
References
1. Parker SH, Lovin JD, Jobe WE, et al. Stereotactic breast biopsy with a biopsy gun. Radiology.
1990;176(3):741–7. https://doi.org/10.1148/radiology.176.3.2167501.
2. Parker SH, Lovin JD, Jobe WE, Burke BJ, Hopper KD, Yakes WF. Nonpalpable breast lesions:
stereotactic automated large-core biopsies. Radiology. 1991;180(2):403–7. https://doi.
org/10.1148/radiology.180.2.1648757.
3. Parker SH, Jobe WE, Dennis MA, et al. US-guided automated large-core breast biopsy.
Radiology. 1993;187(2):507–11. https://doi.org/10.1148/radiology.187.2.8475299.
4. Liberman L. Percutaneous imaging-guided core breast biopsy. Am J Roentgenol.
2000;174(5):1191–9. https://doi.org/10.2214/ajr.174.5.1741191.
5. Wallis M, Tarvidon A, Helbich T, Schreer I. Guidelines from the European Society of Breast
Imaging for diagnostic interventional breast procedures. Eur Radiol. 2007;17(2):581–8.
https://doi.org/10.1007/s00330-006-0408-x.
6. Chetlen AL, Kasales C, Mack J, Schetter S, Zhu J. Hematoma formation during breast core nee-
dle biopsy in women taking antithrombotic therapy. Am J Roentgenol. 2013;201(1):215–22.
https://doi.org/10.2214/AJR.12.9930.
7. Portnow LH, Thornton CM, Milch HS, Mango VL, Morris EA, Saphier NB. Biopsy marker
standardization: what’s in a name? Am J Roentgenol. 2019;212(6):1400–5. https://doi.
org/10.2214/AJR.18.20577.
8. Durand MA, Haas BM, Yao X, et al. Early clinical experience with digital breast tomosyn-
thesis for screening mammography. Radiology. 2015;274(1):85–92. https://doi.org/10.1148/
radiol.14131319.
9. Sharma B, Jurgensen-Rauch A, Pace E, et al. Breast implant–associated anaplastic large cell lym-
phoma: review and multiparametric imaging paradigms. Radiographics. 2020;40(3):609–28.
10. Wang M, He X, Chang Y, Sun G, Thabane L. A sensitivity and specificity comparison of fine
needle aspiration cytology and core needle biopsy in evaluation of suspicious breast lesions:
a systematic review and meta-analysis. Breast Edinb Scotl. 2017;31:157–66. https://doi.
org/10.1016/j.breast.2016.11.009.
11. Yu Y-H, Wei W, Liu J-L. Diagnostic value of fine-needle aspiration biopsy for breast mass:
a systematic review and meta-analysis. BMC Cancer. 2012;12(1):41. https://doi.org/10.118
6/1471-2407-12-41.
12. Berg WA, Krebs TL, Campassi C, Magder LS, Sun CC. Evaluation of 14- and 11-gauge direc-
tional, vacuum-assisted biopsy probes and 14-gauge biopsy guns in a breast parenchymal
model. Radiology. 1997;205(1):203–8. https://doi.org/10.1148/radiology.205.1.9314986.
13. Nakano S, Imawari Y, Mibu A, Otsuka M, Oinuma T. Differentiating vacuum-assisted breast
biopsy from core needle biopsy: is it necessary? Br J Radiol. 2018;91(1092) https://doi.
org/10.1259/bjr.20180250.
14. Wen X, Cheng W. Nonmalignant breast papillary lesions at core-needle biopsy: a meta-analysis
of underestimation and influencing factors. Ann Surg Oncol. 2013;20(1):94–101. https://doi.
org/10.1245/s10434-012-2590-1.
15. Rageth CJ, O’Flynn EA, Comstock C, et al. First international consensus conference on
lesions of uncertain malignant potential in the breast (B3 lesions). Breast Cancer Res Treat.
2016;159(2):203–13. https://doi.org/10.1007/s10549-016-3935-4.
16. Krishnamurthy S, Bevers T, Kuerer HM, Smith B, Yang WT. Paradigm shifts in breast care
delivery: impact of imaging in a multidisciplinary environment. AJR Am J Roentgenol.
2017;208(2):248–55. https://doi.org/10.2214/AJR.16.17130.
17. Kettritz U, Rotter K, Schreer I, et al. Stereotactic vacuum-assisted breast biopsy in 2874
patients. Cancer. 2004;100(2):245–51. https://doi.org/10.1002/cncr.11887.
18. Philpotts LE, Shaheen NA, Carter D, Lange RC, Lee CH. Comparison of rebiopsy rates
after stereotactic core needle biopsy of the breast with 11-gauge vacuum suction probe ver-
sus 14-gauge needle and automatic gun. Am J Roentgenol. 1999;172(3):683–7. https://doi.
org/10.2214/ajr.172.3.10063860.
19. Huang XC, Hu XH, Wang XR, et al. A comparison of diagnostic performance of vacuum-
assisted biopsy and core needle biopsy for breast microcalcification: a systematic review
and meta-analysis. Ir J Med Sci 1971. 2018;187(4):999–1008. https://doi.org/10.1007/
s11845-018-1781-6.
20. den Dekker BM, van Diest PJ, de Waard SN, Verkooijen HM, Pijnappel RM. Stereotactic
9-gauge vacuum-assisted breast biopsy, how many specimens are needed? Eur J Radiol.
2019;120:108665. https://doi.org/10.1016/j.ejrad.2019.108665.
21. Stereotactic 11-gauge Vacuum-Assisted Breast Biopsy: Influence of Number of Specimens
on Diagnostic Accuracy - PubMed. Accessed June 21, 2020. https://pubmed.ncbi.nlm.nih.
gov/15273332/
22. Durand MA, Wang S, Hooley RJ, Raghu M, Philpotts LE. Tomosynthesis-detected architec-
tural distortion: management algorithm with radiologic-pathologic correlation. Radiographics.
2016;36(2):311–21. https://doi.org/10.1148/rg.2016150093.
23. Conant EF, Barlow WE, Herschorn SD, et al. Association of digital breast tomosynthesis vs
digital mammography with cancer detection and recall rates by age and breast density. JAMA
Oncol. 2019;5(5):635–42. https://doi.org/10.1001/jamaoncol.2018.7078.
208 V. C. Zanetta
24. Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digi-
tal mammography plus tomosynthesis in a population-based screening program. Radiology.
2013;267(1):47–56. https://doi.org/10.1148/radiol.12121373.
25. Health C for D and R. MQSA National Statistics. FDA. Published online January 6, 2020.
Accessed June 13, 2020. https://www.fda.gov/radiation-emitting-products/mqsa-insights/
mqsa-national-statistics
26. Alshafeiy TI, Nguyen JV, Rochman CM, Nicholson BT, Patrie JT, Harvey JA. Outcome
of architectural distortion detected only at breast tomosynthesis versus 2D mammography.
Radiology. 2018;288(1):38–46. https://doi.org/10.1148/radiol.2018171159.
27. Partyka L, Lourenco AP, Mainiero MB. Detection of mammographically occult architec-
tural distortion on digital breast tomosynthesis screening: initial clinical experience. Am J
Roentgenol. 2014;203(1):216–22. https://doi.org/10.2214/AJR.13.11047.
28. Patel BK, Covington M, Pizzitola VJ, et al. Initial experience of tomosynthesis-guided vacuum-
assisted biopsies of tomosynthesis-detected (2D mammography and ultrasound occult)
architectural distortions. Am J Roentgenol. 2018;210(6):1395–400. https://doi.org/10.2214/
AJR.17.18802.
29. Bahl M, Maunglay M, D’Alessandro HA, Lehman CD. Comparison of upright digital breast
tomosynthesis–guided versus prone stereotactic vacuum-assisted breast biopsy. Radiology.
30. Schrading S, Distelmaier M, Dirrichs T, et al. Digital breast tomosynthesis–guided vacuum-
assisted breast biopsy: initial experiences and comparison with prone stereotactic vacuum-
assisted biopsy. Radiology. 2015;274(3):654–62. https://doi.org/10.1148/radiol.14141397.
31. Ariaratnam NS, Little ST, Whitley MA, Ferguson K. Digital breast Tomosynthesis vacuum
assisted biopsy for Tomosynthesis-detected Sonographically occult lesions. Clin Imaging.
2018;47:4–8. https://doi.org/10.1016/j.clinimag.2017.08.002.
32. Chesebro AL, Chikarmane SA, Ritner JA, Birdwell RL, Giess CS. Troubleshooting to over-
come technical challenges in image-guided breast biopsy. Radiographics. 2017;37(3):705–18.
33. Soo MS, Walsh R, Patton J. Prone table stereotactic breast biopsy: facilitating biopsy of poste-
rior lesions using the arm-through-the-hole technique. Am J Roentgenol. 1998;171(3):615–7.
https://doi.org/10.2214/ajr.171.3.9725284.
34. Zhang Y, Ren H. Meta-analysis of diagnostic accuracy of magnetic resonance imaging
and mammography for breast cancer. J Cancer Res Ther. 2017;13(5):862–8. https://doi.
org/10.4103/jcrt.JCRT_678_17.
35. Peters NHGM, Borel Rinkes IHM, Zuithoff NPA, Mali WPTM, Moons KGM, Peeters
PHM. Meta-analysis of MR imaging in the diagnosis of breast lesions. Radiology.
36. Park VY, Kim MJ, Kim E-K, Moon HJ. Second-look US: how to find breast lesions with
a suspicious MR imaging appearance. Radiographics. 2013;33(5):1361–75. https://doi.
org/10.1148/rg.335125109.
37. Nakano S, Yoshida M, Fujii K, et al. Fusion of MRI and sonography image for breast cancer
evaluation using real-time virtual sonography with magnetic navigation: first experience. Jpn J
Clin Oncol. 2009;39(9):552–9. https://doi.org/10.1093/jjco/hyp087.
38. Mazzei MA, Di Giacomo L, Fausto A, Gentili F, Mazzei FG, Volterrani L. Efficacy of second-
look ultrasound with MR coregistration for evaluating additional enhancing lesions of the breast:
review of the literature. Biomed Res Int. 2018;2018 https://doi.org/10.1155/2018/3896946.
39. Nakano S, Kousaka J, Fujii K, et al. Impact of real-time virtual sonography, a coordinated
sonography and MRI system that uses an image fusion technique, on the sonographic evalu-
ation of MRI-detected lesions of the breast in second-look sonography. Breast Cancer Res
Treat. 2012;134(3):1179–88. https://doi.org/10.1007/s10549-012-2163-9.
40. Nakano S, Yoshida M, Fujii K, et al. Real-time virtual sonography, a coordinated sonogra-
phy and MRI system that uses magnetic navigation, improves the sonographic identification
of enhancing lesions on breast MRI. Ultrasound Med Biol. 2012;38(1):42–9. https://doi.

org/10.1016/j.ultrasmedbio.2011.10.005.
41. Park AY, Seo BK, Han H, et al. Clinical value of real-time ultrasonography-MRI fusion imag-
ing for second-look examination in preoperative breast cancer patients: additional lesion detec-
tion and treatment planning. Clin Breast Cancer. 2018;18(4):261–9. https://doi.org/10.1016/j.
clbc.2017.07.007.
42. Spick C, Baltzer PAT. Diagnostic utility of second-look US for breast lesions identified at
MR imaging: systematic review and meta-analysis. Radiology. 2014;273(2):401–9. https://
doi.org/10.1148/radiol.14140474.
43. Clauser P, Carbonaro LA, Pancot M, et al. Additional findings at preoperative breast MRI: the
value of second-look digital breast tomosynthesis. Eur Radiol. 2015;25(10):2830–9. https://
doi.org/10.1007/s00330-015-3720-5.
44. Parikh J, Tickman R. Image-guided tissue sampling: where radiology meets pathology. Breast
J. 2005;11(6):403–9. https://doi.org/10.1111/j.1075-122X.2005.00130.x.
45. Shin S, Schneider HB, Cole FJ, Laronga C. Follow-up recommendations for benign breast
biopsies. Breast J. 2006;12(5):413–7. https://doi.org/10.1111/j.1075-122X.2006.00302.x.
46. Parker SH, Burbank F, Jackman RJ, et al. Percutaneous large-core breast biopsy: a
multi-institutional study. Radiology. 1994;193(2):359–64. https://doi.org/10.1148/
radiology.193.2.7972743.
47. Bassett LW, Mahoney MC, Apple SK. Interventional breast imaging: current procedures and
assessing for concordance with pathology. Radiol Clin N Am. 2007;45(5):881–94. https://doi.
org/10.1016/j.rcl.2007.06.010.
48. Wendie A. Berg JL. Diagnostic imaging: breast. 3rd ed; 2019. Accessed September 21, 2020.
https://www.elsevier.com/books/diagnostic-imaging-breast/berg/978-0-323-54812-0
49. Johnson JM, Johnson AK, O’Meara ES, et al. Breast cancer detection with short-interval
follow-up compared with return to annual screening in patients with benign stereotactic or
US-guided breast biopsy results. Radiology. 2015;275(1):54–60. https://doi.org/10.1148/
radiol.14140036.
50. Moon HJ, Jung I, Youk JH, Kim MJ, Kim E-K. Short-term follow-up in 6 months is unnecessary
for asymptomatic breast lesions with benign concordant results obtained at ultrasonography-
guided 14-gauge core needle biopsy. Am J Surg. 2016;211(1):152–8. https://doi.org/10.1016/j.
amjsurg.2015.03.036.
51. Monticciolo DL, Hajdik RL, Hicks MG, et al. Six-month short-interval imaging follow-up for
benign concordant core needle biopsy of the breast: outcomes in 1444 cases with long-term
follow-up. Am J Roentgenol. 2016;207(4):912–7. https://doi.org/10.2214/AJR.15.15853.
52. Hayward JH, Ray KM, Wisner DJ, Joe BN. Follow-up outcomes after benign concordant
MRI-guided breast biopsy. Clin Imaging. 2016;40(5):1034–9. https://doi.org/10.1016/j.
clinimag.2016.06.005.
53. Kohr JR, Eby PR, Allison KH, et al. Risk of upgrade of atypical ductal hyperplasia after
stereotactic breast biopsy: effects of number of foci and complete removal of calcifications.
Radiology. 2010;255(3):723–30. https://doi.org/10.1148/radiol.09091406.
Chapter 11
Breast Imaging Preoperative Localization
Procedure
Heni Debs Skaf, Juliana Hiraoka Catani,

and Vivian Simone De Medeiros Ogata
Abbreviations
CC Craniocaudal
FDA Food and Drug Administration
LM Lateromedial
MG Mammography
ML Mediolateral
MR Magnetic resonance
MS Magnetic seed
NRW Nonrepositionable wires
NWL Nonwire localization
OR Operation room
PL Preoperative localization
RFID Radiofrequency identification tag
ROLL Radio-guided occult lesion localization
RSL Radioactive seed localization
RW Repositionable wires
SNOLL Sentinel node and occult lesion localization
US Ultrasound
WL Wire localization
H. D. Skaf · J. H. Catani · V. S. D. M. Ogata (*)


Switzerland AG 2022
212 H. D. Skaf et al.
11.1 Introduction
As breast imaging evolves, there is an increase in diagnosis of clinically occult

small cancerous lesions, which represent approximately 25–35% of all breast can-
cers diagnosed in developed countries [1, 2]. In particular, mammographic
screening-detected malignancies are often small and clinically occult, and many of
these patients are candidates for conservative surgery, as it is a safe and effective
method to treat early breast cancer. Additionally, breast conservation therapy may
be indicated to treat larger lesions after neoadjuvant chemotherapy, resulting in sig-
nificant tumor shrinkage.
In order to achieve excision of these lesions with adequate surgical margins in a
conservation surgery, while providing a good cosmetic outcome, an imaging-guided
localization procedure is advised and often performed before operation to guide the
surgeon [3].
Our objective is to provide an overview of preoperative localization indications
and of pre-procedure planning, the process itself guided by different imaging
modalities, reviewing the most recent techniques available, as well as to expose
problems that may arise during or after its execution and possible solutions.
11.2 Indications of Preoperative Localization
Preoperative localization (PL) is in general terms indicated for clinically occult

lesions, hence non-palpable ones, that are detected by conventional breast imaging,
requiring diagnostic or therapeutic surgical removal [4]. Furthermore, PL for diag-
nostic excision is required for some histologic entities resulting from percutaneous
biopsy, which may require complete excision for adequate diagnosis due to the
inherent risk of sample underestimation, for instance, atypical ductal hyperplasia [5,
6]. In addition, cases of radiologic-pathologic discordance or with insufficient sam-
pling after percutaneous biopsy may also require PL for an excisional biopsy [7].
11.3 Pre-procedure Review of Preoperative Localization
Before the procedure, the radiologist reviews relevant imaging findings in order to
become familiar with the target lesion and its topography and proceeds to choose
the best imaging modality for guiding the localization procedure: typically, mam-
mography (MG) or ultrasound (US) and, rarely, magnetic resonance (MR) [8, 9].
Previous discussion with the surgeon to review the PL planning is necessary to
ensure that the chosen procedure will be the most helpful considering the lesion
imaging presentation, its localization in the breast, the technical apparatus available
in the operation room, the surgeon preferences, as well as the radiologist skill and
familiarity with different localization modalities [10].
11 Breast Imaging Preoperative Localization Procedure 213
Informed consent is not routinely obtained by the radiologist performing the PL

[11]. Frequently, consent is obtained by the surgeon and contemplates the localiza-
tion and surgical procedures. Regardless of whether written or verbal consent is
obtained by the radiologist, the procedure should be beforehand clearly explained to
the patient as well as any possible complications exposed.
The patient should also be inquired about previous bleeding disorders in advance.
It is not mandatory to submit a patient with no known coagulation disorders or a
history of taking anticoagulant to blood coagulation tests [12]. However, these
blood tests may be required when the patient is undergoing anticoagulant therapy.
Anticoagulant therapy may increase the risk of bleeding and hematoma forma-
tion during percutaneous procedures; however, there are potential life-threatening
risks to stop such medications, mainly in a context of secondary prevention of
thrombotic events. Current evidence supports that it is safe to perform percutaneous
breast procedures under certain medications like acetylsalicylic acid. However, the
necessity of temporary discontinuation of any anticoagulant therapy should be dis-
cussed in advance with the patient physician and be made on a case-by-case basis
[13–17].
Another preprocedural care that should be discussed in advance with the patient
physician includes the prescription of antibiotic prophylaxis for endocarditis in
selected cases, not routinely. This is a topic of constant debate and evolution, and
the currently adopted stance by most guidelines suggests antibiotic prophylaxis for
patients at highest risk of endocarditis, such as bearers of a damaged heart valve,
submitted for valve replacement; those diagnosed with structural congenital heart
disease; and those with a history of previous infective endocarditis, among oth-
ers [18].
Lastly, the patient should also be inquired about confirmed allergies [12].
Allergies to anesthetics that may eventually be used during PL, to latex, to metal or
other components of the localization wire, and to the adhesive bandage tape are
some examples.
11.4 Wire Localization
When performing wire localization (WL), a wire is introduced into the breast with
the aid of a puncture needle (Fig. 11.1) [10]. The wire is then advanced out of the
puncture needle when in the desired position, exposing its hook and anchoring in
the lesion (Fig. 11.1) [19].
When dealing with small breast lesions, the hookwire should ideally penetrate
the center of the lesion, and the maximum distance between the wire and the lesion
should be 1 cm [20, 21]. Larger breast lesions, usually represented by clustered
calcifications, may be best marked with multiple hookwires in order to achieve an
excision with tumor-free resection margins [22]. The preferred imaging modality
used for imaging-guided WL should be the one in which the target lesion is best
visualized while being tolerated by the patient and at an acceptable cost [10].
a b
Fig. 11.1 WL. A wire is introduced into the breast with the aid of a puncture needle (a). The
hookwire is then advanced out of the puncture needle, exposing the hook and anchoring itself in
the lesion (b)
11.4.1 MG-Guided and Stereotactic-Guided Wire Localization
MG-guided or stereotactic-guided WL is usually performed when the lesions are

conspicuous on MG but are not visualized on US [12]. Developing asymmetries,
architectural distortions and small breast masses that are not visible on US, micro-
calcifications, and marker clips or coils that have been placed during a percutaneous
biopsy or a pre-chemotherapy tissue marker are among examples of such lesions.
11.4.1.1 Technique Using a Perforated or Marked Compression Plate
The approach chosen for the puncture needle insertion when using a perforated or
marked compression plate for WL should, ideally, result in the shortest distance
from the skin surface to the target lesion with the intention of minimizing the dis-
tance that the needle must travel in the breast, decreasing the chance of needle
deviation from the intended target [23]. In some situations, that approach may not
be the most adequate. Inferior approaches, for example, may require uncomfortable
positioning for the patient and for the radiologist performing the procedure, who
must insert the needle from below, often from a kneeling position. Thus, breast
lesions in the inferior quadrants may be more easily localized from either the medial
or lateral side. Another situation when the shortest approach may not be used is
when the lesion is visualized with greater clarity on another particular MG projec-
tion. Taking the surgical approach into consideration when planning the skin punc-
ture site as well as the needle trajectory for PL is no longer mandatory as tumoral
cell displacement or track seeding is no longer considered a relevant factor in the
rate of local recurrence and overall survival in a context of conservative surgery plus
adjuvant radiotherapy, as many studies have demonstrated [10].
WL is usually performed with the patient in a sitting position when a compres-

sion plate is employed. A reclinable chair can be useful for a prompt treatment of a
vasovagal reaction, a common complication [24]. After deciding on the best
approach to be used, based on the principles already emphasized, an initial MG
image with the patient’s breast in compression is acquired in the most adequate
view using a perforated or a fenestrated compression plate with alphanumeric mark-
ings along its edge. Then, oriented by the compression plate markings, the skin
insertion point is chosen according to the coordinates of the intended target. The
skin over the lesion is cleansed, and the needle is inserted perpendicular to the com-
pression plate and parallel to the chest wall; therefore, patients should never develop
a pneumothorax in this context. The needle is inserted beyond a depth calculated on
the second orthogonal view until it passes far enough through the lesion or, in order
to minimize errors, until it touches the opposite skin in contact with the compressor.
Next, a second MG image in the orthogonal plane is obtained. Based on this image,
the depth of needle insertion is adjusted, if necessary, but only by retracting the
needle, as it would deviate from the target if inserted in this plane. Once the needle
is in the correct position, the wire is deployed. Correct needle insertion is then docu-
mented in two planes before the patient is sent to the operating room (Figs. 11.2,
11.3, and 11.4).
a b c d e f
Fig. 11.2 MG-guided WL of a small non-palpable breast lesion using a marked compression
plate. The first CC projection showed a clip marker (dashed circle) within the fenestrated paddle
view (a). The puncture needle was inserted, oriented by the compression plate markings, perpen-
dicularly to the skin, until it touched the opposite skin in contact with the compressor. The new CC
projection showed the hub of the needle obscuring the clip marker (b). The orthogonal MLO pro-
jection obtained by using a nonfenestrated compression paddle showed the needle extending
through and beyond the clip marker (c). Documentation in two planes after insertion of the wire
and removal of the puncture needle showed the clip marker appropriately positioned at the thick-
ened segment of the wire (d, e). The intraoperative specimen radiograph showed the distal portion
of the hookwire and the clip marker (f)
a b c d h
e f g
Fig. 11.3 MG-guided WL using a marked compression plate of a large non-palpable breast lesion.
WL was performed on a cluster of pleomorphic calcifications (dashed circle) (a). The MLO pro-
jection showed the lesion within the fenestrated paddle view (b). In order to achieve complete
excision of the lesion, the area of calcifications was bracketed by placing needles into both ends of
the lesion (c). The needles were inserted perpendicularly to the skin until they touched the oppos-
ing skin in contact with the compressor. The first orthogonal CC projection obtained with a non-
fenestrated compression paddle showed the needles extending through and beyond the lesion
extremities, but further than necessary (d). The depth of the needle insertions was then adjusted by
retracting them, and the new position was confirmed in another CC projection (e). Documentation
in two planes after insertion of the wires and removal of the puncture needles showed the area of
calcifications extending between the thickened segments of the two wires (f, g). The specimen
radiograph obtained after surgery showed the distal portion of the hookwires and the calcifica-
tions (h)
11.4.1.2 Technique Using a Stereotactic Table
The accuracy of WL under stereotactic guidance is comparable to that using a per-

forated or marked compression plate [25]. It may be the method of choice to guide
the localization when the target lesion is much more evident in one mammographic
view than the other, because you do not necessarily need both orthogonal views to
guide localization by this method, just a scout and a stereo pair image [23].
Before the procedure, MG imaging in two orthogonal views (CC and ML or LM)
of the affected breast is required to identify the target position. Stereotactic localiza-
tion is then initiated from the view in which the target is best identified. After posi-
tioning the patient on the stereotactic table, the compression plate’s window is
placed over the breast, and a scout image is acquired, preferably showing the lesion
centered in the window. The x-, y-, and z-coordinates are determined by targeting
the epicenter of the lesion on the unit’s monitor using a stereo pair image (+15° and
−15°) acquired based on the scout, in a similar way to stereotactic guided percuta-
neous biopsy. The puncture needle is placed in the holder, guided to the targeted
a b
c d
Fig. 11.4 CC and MLO projections of the case shown in Fig. 11.3 before (a, b) and after breast
conservation surgery (c, d). By removing the smallest possible amount of healthy tissue with
adequate surgical margins, conservation breast surgery provides optimal therapeutic results with
good cosmetic outcomes
x- and y-coordinates, and advanced to the z-coordinate. The correct needle’s tip
position may be checked using a second stereo pair image, and it should be posi-
tioned within or directly behind the target lesion. The needle is then advanced nearly
1 cm beyond the z-coordinate and the wire is deployed. Lastly, another MG imaging
in two orthogonal views is obtained to document the correct needle positioning.
When performing a stereotactic WL, especially with a hookwire, if the wire is
deployed in the same plane as the initial compression one, for example, a craniocau-
dal compression and a caudal needle insertion, without changing to an orthogonal
plane, it may hook onto tissues deeper ou superficially than the originally intented
targeted point in the z-direction and, consequently, being incorrectly located after
compression release (which is called “the accordion effect”). A positioning error of
a few millimeters in the compressed breast can correspond to a large positioning
error in the non-compressed breast. Some strategies to minimize this effect are to
gently release the breast from compression after deploying the wire [23]. Another is
to obtain a new stereo image in the orthogonal plane, then adjust the depth of needle
insertion based on this image, and then insert the wire. In modern breast biopsy
systems, another possibility is to perform the procedure using lateral needle
approach, in which the needle is inserted orthogonally to the compression plane,
thus eliminating the “accordion effect.”
Additional challenges that may arise during stereotactic WL often are the same
as those encountered during percutaneous biopsy guided by the same method and
will be discussed in more detail in a specific chapter (Fig. 11.5).
11.4.2 US-Guided Wire Localization
US-guided WL is performed when the lesions are visualized on this image modal-
ity, and it should always be considered due to cost-effectiveness and improved
patient comfort, especially when compared to other image modalities like stereotac-
tic guidance.
The procedure starts by positioning the patient similar to that during a percutane-
ous biopsy. The puncture needle should advance through and 1 cm beyond the target
lesion, and then the wire is deployed. Then, distances from lesion to skin and lesion
to wire tip and total inserted wire length should be documented and reported to
guide the surgeon.
Similarly, after MG or stereotactic guided WL and after US-guided procedure,
MG views in two orthogonal planes should be obtained to document the correct
needle insertion (Figs. 11.6, 11.7, and 11.8).
US-guided WL can be adapted for use in the axilla, but it has been infrequently
utilized [26]. WL complications such as pain, hematoma, and adjacent tissue injury
particularly occur in the axilla where sensitive structures (brachial plexus as well as
axillary artery and vein) are nearby [3]. In addition, there is a higher wire migration
and transection risk in the axilla compared to the breast due to arm movement and
ratcheting effect or muscular contraction [27–29].
a b e i
f
c
h
j
Fig. 11.5 WL using a stereotactic table. The MLO MG projection showed a clip marker (dashed
circle) in the right breast (a). Stereo pair (±15°) images obtained based on the scout (0°) image
were used to determine the x-, y-, and z-coordinates by targeting the clip (b). Pre-fire and postfire
stereo pair (±15°) images showed the needle extending through and beyond the clip marker (c, d).
An additional stereotactic image was obtained to confirm the depth of the needle (e). A new stereo
image in the orthogonal plane of this last image was obtained, and the depth of the needle insertion
was adjusted based on this orthogonal image in order to avoid “the accordion effect” (f). After
depth adjustment, the wire was inserted and the puncture needle was carefully removed (g, h). MG
documentation after stereotactic procedure showed the clip marker appropriately positioned at the
thickened segment of the wire (i). The specimen radiograph obtained after surgery showed the
distal portion of the hookwire and the clip marker (j)
11.4.3 MRI-Guided Wire Localization
MRI-guided WL is usually performed when the lesions are detected only on MRI,
without US or MG imaging correlates. The target lesion may be identified using
contrast-enhanced MRI guidance, in a similar way to MRI-guided percutaneous
biopsy. To locate the lesion, an image is acquired in a sagittal plane associated to a
plastic frame with reference markers (Fig. 11.9). A corresponding external location
of the lesion on the patient’s breast is determined relative to the frame and used to
guide the point of needle insertion. The puncture needle is then placed in the holder
and advanced nearly 1 cm beyond the depth estimated by using an axial reconstruc-
tion obtained from the sagittal acquisition or a new axial acquisition with a smaller
field of view in order to decrease sequence duration and reduce the possibility of
non-lesion characterization due to gadolinium washout (Fig. 11.10).
It is recommended to use wires made from MRI-compatible metals, which are
typically alloys with high titanium and nickel content, to avoid imaging artifacts
[10]. Because these special wires only have minor ferromagnetic properties, the
a d e
Fig. 11.6 US-guided WL with a hookwire. US image showing a hypoechoic mass with a clip
marker (dashed circle) (a). The puncture needle was advanced through and 1 cm beyond the lesion,
and then the wire was deployed (b). The distances from lesion to skin and lesion to wire tip are
documented (c). MG documentation in two planes after the procedure showed the lesion appropri-
ately positioned on the thickened segment of the wire (d, e)
a c
d e f
Fig. 11.7 US-guided WL with a hookwire. US performed after chemotherapy showed a non-mass
breast lesion with a clip marker (dashed circle) (a, b). The puncture needle was carefully advanced
through and beyond the lesion, and then the wire was deployed (1: hookwire, 2: thickened segment,
3: wire) (c). MG documentation in two planes obtained after the procedure showed the lesion
appropriately positioned at the distal portion of the thickened segment of the wire (d, e). The speci-
men radiograph obtained after surgery showed the hookwire and the clip marker (f)
a c
Fig. 11.8 US-guided WL with a retractable J-wire. The J-wire (dotted line) was placed adjacent
to a clip marker (arrow) that could be clearly visualized on US (a, b). MG documentation after the
procedure showed the clip marker appropriately positioned at the distal portion of the wire (dashed
circle) (c)
HEAD
PECTORALIS B8 A8
D6 C6 B7 A7
HEAD
FOOT
A1 A2 A3 A4 A5 A6 A7 A8
D5 C5 B6 A6 PECTORALIS
B1 B2 B3 B4 B5 B6 B7 B8
NIPPLE
E2 D4 C4 B5 A5
C1 C2 C3 C4 C5 C6
E1 D3 C3 B4 A4
D1 D2 D3 D4 D5 D6
D2 C2 B3 A3
E1 E2
D1 C1 B2 A2
NEEDLE NEEDLE
NIPPLE
GUIDE GUIDE B1 A1
A B C J F C
D E F I E B FOOT
H I J H D A
Fig. 11.9 To locate a lesion, the breast is imaged on MR while using a frame with reference mark-
ers which show up on the acquired image. The corresponding lesion location, relative to the frame,
is then determined and used to determine the biopsy needle insertion site
a b c
d e
Fig. 11.10 WL under contrast-enhanced MRI guidance. To locate the lesion, the sagittal MRI was
acquired associated with a plastic frame. A vitamin D capsule (arrow) was used as a skin marker
to help determine the corresponding external location of the breast lesion relative to the frame (a,
b). MR images acquired after contrast injection showed the target lesion, a focal non-mass
enhancement (dashed circle) (c, d). MR image acquired after insertion of the coaxial needle
showed its correct positioning within the focal non-mass enhancement (e)
susceptibility artifact caused by them produces a signal extinction that can be dis-
tinctly seen without masking relevant findings and fine structures.
Access to an MRI-guided WL is sometimes poor. It is worth mentioning that a
clip marker placed in the cavity after an MRI-guided vacuum-assisted biopsy not
only enables the radiologist to localize the biopsied area once again but also allows
other imaging methods beyond MRI to be utilized in order to perform PL. Therefore,
an originally MRI-visualized lesion can be preoperatively localized using cheaper
imaging guidance, like mammography or ultrasound, for example, by using an MRI
inserted marker.
11.4.4 Wire Variations
There are various designs of localization wires that influence the tenacity of it stay-
ing in place, which is also determined by the composition of the breast parenchyma
[25]. In this regard, in patients with fatty breasts, the wire may dislocate more easily
because of the limited stroma for anchorage.
In general, wire variations can be classified into nonrepositionable and reposi-
tionable types, and both have advantages and disadvantages (Figs. 11.11 and 11.12).
A nonrepositionable wire (NRW), such as a hookwire, is more stable than a repo-
sitionable one, preventing movement out of the breast. It also optimizes intraopera-
tive identification of the localized lesion, since the NRW frequently presents a
thickened distal segment that provides a tactile guide to the surgeon. However, this
type allows only one-way forward movement, and once the hook is deployed, it can-
not be drawn back into the puncture needle. Thus, if the hook is improperly placed
or pushed into the breast, it can be permanently displaced away from the tar-
geted area.
A repositionable wire (RW), such as a retractable J-wire, can be withdrawn from
the puncture needle and repositioned if necessary, as many times as needed. Besides
being less stable than a nonrepositionable one due to its design, the absence of the
thickened distal segment on RW can also limit intraoperative identification of the
localized lesion.
As both types have been shown to be effective in localizing breast lesions, the
choice of the needle is largely a matter of service material availability and surgeon’s
and radiologist’s preference [23].
a b
Fig. 11.11 WL. After accurate placement of the puncture needle in the breast, either a nonreposi-
tionable hookwire (a) or a repositionable retractable curved-end wire (or J-wire) (b) can be
inserted. Both types have been shown to be effective in localizing breast lesions
a b c d e f g h
Fig. 11.12 Some of the various designs of localization wires. (a–e) represent nonrepositionable
wires, and (f–h) represent repositionable wires
11.5 Nonwire Localization Methods
WL has been the standard for PL in breast imaging for decades due to its simplicity
and low cost. However, the available options for performing it have expanded
greatly and now include the use of substances (such as carbon and radiotracers) or
nonwire localization (NWL) devices (such as radioactive and magnetic seeds, radar
reflectors, and radiofrequency identification tags).
Compared with wires, these NWL alternatives, except for radiotracers, can be
placed prior to the surgery date, at the patient’s convenience, in contrast to the WL
device procedures that are performed on the day of surgery. Radioactive seeds can
be placed up to 5–7 days before, and carbon, radar reflectors, magnetic seeds, and
RFID tags have been approved for long-term placement (more than 30 days), with
no restriction on the length of time that they can remain in the breast tissue, which
can be very useful in patients undergoing neoadjuvant systemic therapy.
Consequently, this decoupling of the radiology and surgery schedules results in
fewer delays, minimizes presurgical fasting as the resection can be the first surgery
of the day, reduces the risk of vasovagal syncope, and overall improves patient
satisfaction.
Another advantage of using NWL methods is the absence of a wire partially
outside the breast, improving patient experience, and removing the possibility of
wire migration.
Additionally, when the surgeon makes use of wire localization techniques, the
wire and the healthy tissue along its course are usually retrieved. In contrast, with
NWL, the surgeon keeps a continuous intraoperative target tracking in order to keep
the lesion in the center of the specimen, retrieving a smaller quantity of nontargeted
healthy tissue and improving cosmesis. Besides, wire placement affects the surgical
planning because it must be fully retrieved, sometimes determining the incision site
and increasing unnecessary healthy tissue removal.
11.5.1 Carbon Marking
There are commercially available carbon suspension products approved by the Food
and Drug Administration (FDA) for tattooing the gastrointestinal tract that can be
used in PL of breast lesions and axillary lymph nodes, although this use is not cur-
rently FDA approved and should be considered off label [30–37].
A sterile solution can be prepared using 4 g of activated charcoal in 100 ml of
0.9% saline solution. And 0.2–0.3 ml of nonionic radiographic contrast medium can
be added when performing MG-guided localization for subsequent image docu-
mentation of correct dispersion, as charcoal is not often identified radiographically
[23]. The charcoal is suspended quickly, so it is important to shake the bottle well
before drawing it into the syringe. Approximately 1–1.5 ml of the solution is injected
into the target lesion or directly proximal to it to achieve sufficient dispersion and
visualization. Then a fine line of the solution extending all the way to the skin is
injected as the needle is withdrawn. Being particulate and not soluble in water, the
carbon solution remains on the path [23, 34–36]. During surgery, the targeted lesion
is localized by visualization of the skin mark and dissection along the carbon track
(Fig. 11.13).
A particular advantage of this PL method is the ease of locating the injection site
during the specimen histopathological examination. However, the coal can render
breast tissues more resistant to microtomy, occulting or distorting the lesion on
microscopy.
There are few reported disadvantages of using carbon for PL. The carbon sus-
pension does not diffuse significantly, but it can rarely spread into the surrounding
tissues, particularly by accidental intraductal injection [23]. In this case, the demar-
cated area can be larger than initially expected, consequently increasing unneces-
sary healthy tissue removal. The surgeon can also remove a larger amount of breast
Fig. 11.13 Several of the methods currently used to localize lesions in the breast may be adapted
for use in the axilla. Axillary lymph node carbon marking permits the surgeon to locate the target
lymph node by visualization of the skin mark and dissection along the carbon trail to the lesion.
(With permissions from Lucas Roskamp Budel, MD)
tissue when it faces difficulty to identify the demarcated area intraoperatively, espe-
cially in deeper tissues, where the carbon track is harder to palpate [30].
Carbon marking may be performed immediately after biopsy, obviating a sepa-
rate PL, which is an advantage cost-wise [38]. However, when resection of the
marked biopsy path is not accomplished in 6 months, local granulomatous reactions
can occur and mimic suspicious lesions [39–41]. There are reported cases of mam-
mographic lesions coinciding with previous coal marking sites, whose further
investigation yielded charcoal granulomas.
11.5.2 Radio-Guided Occult Lesion Localization (ROLL)
Radio-guided occult lesion localization (ROLL) consists of a radiotracer injection

into the target lesion on the same day as the surgery or on the day before, not exceed-
ing 24 h between the injection and the procedure, guided by ultrasonography, ste-
reotactic mammography, or even MRI [38]. This radiotracer is composed of a dose
of human serum albumin macroaggregates, with particle diameter ranging between
80 nm and 150μm, labeled with 7–10 MBq of Tc-99 m (equivalent to 1–2% of the
dose used for a whole-body bone scintigraphy) [42–44].
Scintigraphic images are usually acquired in front and lateral projections about
10 min after radiotracer injection. A cobalt-57 source is applied to outline the
patient’s contour during the acquisition in order to facilitate viewing of the inocula-
tion site. The scanned images must highlight a focal spot of tracer accumulation
with well-defined margins. In case of skin contamination, the acquisition must be
repeated after properly cleaning with a decontaminant substance. If the tracer uptake
spreads to the lesion surrounding tissues on the scanned images, PL must be repeated
using another method, such as WL.
During surgery, the lesion is detected by using a gamma probe. All the tissue area
with a higher radioactivity count compared to the background is removed. The
edges are defined as points where radioactivity count drops sharply. After removing
this area, if the radiotracer is still detected by the gamma probe at the surgical site,
it is necessary to extend the resection until the counting rate disappears.
ROLL is comparable to WL in terms of costs; however, due to radiation con-
cerns, it cannot be realized on an outpatient basis, resulting in scheduling restraints;
additionally, it requires the need for a gamma radiation detector in the operating
room (Figs. 11.14 and 11.15) [45].
11.5.2.1 Sentinel Node and Occult Lesion Localization (SNOLL)
Sentinel lymph node identification using radiotracers and ROLL can be performed
in combination for the same surgical session in a procedure called sentinel node and
occult lesion localization (SNOLL) [42, 46, 47]. It consists of peritumoral injection
a c d e
f
b
Fig. 11.14 MG-guided ROLL using a marked compression plate. The MLO projection showed a
clip marker (dashed circle) while using a fenestrated paddle (a). The puncture needle was inserted,
oriented by the compression plate markings similar to WL (b). The orthogonal CC projection
obtained with a nonfenestrated compression paddle showed the needle extending through and
beyond the clip marker, but further than necessary (c). The depth of the needle insertion was then
adjusted, and the new position was confirmed in another CC projection. Once in the correct posi-
tion, the radiotracer was injected through the puncture needle (d). The scintigraphic image obtained
after the procedure showed the presence of a focal spot of tracer accumulation corresponding to the
breast localized lesion (e). The specimen radiograph obtained after surgery showed the clip
marker (f)
of a supplementary radiotracer carried by micromolecules, with particle sizes rang-

ing between 16 and 100 nm, in addition to the macroaggregates used for ROLL
[48]. Scanned images acquired after radiotracer injection must highlight the pres-
ence of at least two focal spots of the tracer accumulation with well-defined mar-
gins, the breast lesion and the sentinel lymph node (Figs. 11.16, 11.17, and 11.18).
Furthermore, some studies also suggest that SNOLL may be associated with a
higher identification rate of internal mammary chain drainage lymph nodes [49].
11.5.3 Current Lesion Localization Techniques
In order to overcome some of the WL inherent limitations, additional nonwire lesion

localization techniques were more recently developed such as iodine-125 (125I)
radioactive seed (Advantage® I-125, IsoAid, Port Richey, FL), infrared radar reflec-
tors (Savi SCOUT®, Cianna Medical, Aliso Viejo, CA), magnetic seed markers
(Magseed®, Endomagnetics, Cambridge, England), and radiofrequency identifica-
tion (RFID) tags (LOCalizer®, Hologic, Marlborough, MA) (Fig. 11.19).
a b
c d
Fig. 11.15 Stereotactic guided ROLL. The scout (0°) image showed a clip marker (dashed circle)
(a). The stereo pair (±15°) images obtained based on the scout were used to determine the x-, y-,
and z-coordinates by targeting the clip (b). After needle insertion, a new stereo pair (±15°) image
showed the tip of the needle in the correct position; then the radiotracer was injected (c). The scin-
tigraphic image obtained after the procedure showed the presence of a focal spot of tracer accumu-
lation corresponding to the clip (d)
These current nonwire devices may be deployed under mammography, ultra-

sound or stereotactic mammography guidance. Although they cannot be deployed
under MRI guidance, due to the lack of an MRI-compatible introducer needle,
patients with such devices may still undergo MRI under appropriate conditions, and
the subsequently device-related susceptibility artifacts vary according to device and
sequence parameters, as will be further discussed.
They are composed of three parts: a single-use sterilized device loaded in a nee-
dle introducer (12G to 18G), a reusable small console, and a handheld intraopera-
tive probe, which may be available as a single-use sterilized device or a reusable one
requiring an appropriate sterile cover. The intraoperative probe is capable of detect-
ing the device, while the specific console emits numerous forms of feedback in
order to guide the surgeon during the procedure.
Such devices cannot be repositioned once deployed, and multiple devices can be
used to ensure the resection of the full lesion extent, particularly in patients with
extensive microcalcifications, with large masses or with associated satellite nod-
ules. However, superimposed multiple devices positioned in the anteroposterior
plane may be detected as an isolated one in a supine patient, impairing the full
extent disease excision and possibly the prognosis. Additionally, when multiple
devices are deployed, they should approximately be at least 2 cm apart from one
other in order to be detected separately [50, 51].
a c d e
b f
Fig. 11.16 MG-guided SNOLL. The MLO projection showed pleomorphic clustered calcifica-
tions (dashed circle) while using the fenestrated paddle (a). The puncture needle was inserted,
oriented by the compression plate markings similar to WL (b). The orthogonal CC projection
obtained with a nonfenestrated compression paddle showed the needle extending through and
beyond the lesion (c). The depth of the needle insertion was then adjusted by retracting it, and the
new position was confirmed in another CC projection. Once in the correct position, the radiotracer
was injected (d). The scintigraphic image obtained after the procedure showed the presence of two
spots of tracer accumulation corresponding to the lesion and the sentinel lymph node in the ipsilat-
eral axilla (e). The specimen radiograph obtained after surgery successfully showed the presence
of the targeted pleomorphic clustered calcifications in it (f)
Cost-wise, at first glance, these current nonwire localization devices may seem
more expensive than wires. Implementing these systems requires investment in the
reusable console and probe, which are the most expensive components, and the
single-use device itself is costlier than a wire. But they may not be unfavorable on a
cost-benefit analysis, as the elimination of operation room delays as well as
increased schedule flexibility may result in cost savings, particularly in a bundled
payment system [52].
11.5.3.1 Radioactive Nonwire Localization Device
Radioactive Seed Localization
Radioactive seed is a 5-mm titanium-encased implant containing iodine-125

(Fig. 11.20), first described as an alternative to wire localization in 2001. Since then,
many studies have compared radioactive seed localization (RSL) with WL and have
demonstrated no significant differences in the re-excision rate, ratio of tumor vol-
ume to specimen volume, cosmetic outcome, or the rate of close positive margins,
with rates of clear surgical margins ranging from 75% to 97% [53–57].
a b c f
Fig. 11.17 US-guided SNOLL. MG images (a, b) obtained after chemotherapy showing a focal
asymmetry with a clip marker (dashed circle), more evident with Eklund maneuver (b). US image
showing a hypoechoic mass with a clip marker (arrow) corresponding to the lesion observed on the
mammogram (c). The puncture needle was advanced to the lesion, and the distance from its tip to
skin was documented (d). Once in the correct position, the radiotracer was injected adjacent to the
lesion (e). The scintigraphic image obtained after the procedure showed the presence of two spots
of tracer accumulation corresponding to the localized lesion and the sentinel lymph node in the
ipsilateral axilla (f)
a b c
d e f
Fig. 11.18 Another example of US-guided SNOLL. MG image obtained after chemotherapy
showing a small mass with a clip marker (dashed circle) (a). US image showing a hypoechoic mass
associated with a clip marker (arrow) corresponding to the mammographic lesion (b). The punc-
ture needle (dotted line) was advanced to the lesion, and the distance from its tip to skin was docu-
mented (c, d). Once in the correct position, the radiotracer was injected adjacent to the lesion (e).
The scintigraphic image obtained after the procedure showed the presence of two spots of tracer
accumulation corresponding to the localized lesion and the sentinel lymph node in the ipsilateral
axilla (f)
a b c d
Fig. 11.19 Some schematic examples of current nonwire localization devices, such as iodine
radioactive seed (a), radar reflector (b), magnetic seed (c), and radiofrequency identification tag (d)
Depending on the specific regulatory commission guideline, the seeds can be

placed up to 5–7 days before surgery (they have a half-life of 60 days), and no spe-
cial instructions need to be given to the patient or family after deployment because
radioactivity is low (0.100–0.200 mCi [3.7 to 7.4 MBq]).
The seed is transported to the procedure room in a lead envelope. The presence
of radioactivity in the seed must be confirmed before its placement in the breast with
a Geiger counter. Either loose seed assemblies or preloaded seeds into needles can
be used.
It is deployed into the breast by a technique similar to traditional wire localiza-
tion (Figs. 11.21 and 11.22), within or adjacent to the lesion, and more than one may
be used to bracket a defined area for excision. However, the maximum number of
seeds allowed varies according to the institution due to safety concerns. After
deployment and before anyone exits the room, the patient is assessed for radioactiv-
ity with a Geiger counter to confirm placement of the seed within the breast.
The surgeon then uses an intraoperative gamma probe to identify the target and
excise the area. After surgery, the presence of 125I activity in the resected tissue and
lack of activity in the surgical bed confirm successful removal of the seed and the
target lesion.
a b c
Titanium capsule
Adsorbed I-125
0,8 mm
d 4,5 mm
Fig. 11.20 A digital mammographic craniocaudal view of the right breast containing a post-
biopsy marker alongside a radioactive seed (a). As depicted in the magnified view, despite having
the same radiological density, the seed is thinner and longer than the marker (b). On ultrasound,
the radioactive seed is clearly seen as a linear, echogenic structure, within the targeted breast mass
(c). (With permissions from Fernanda Philadelpho Arantes Pereira, MD, PhD, from Dasa).
Schematic drawing of a radioactive seed example (d)
a b c
Fig. 11.21 Radioactive seed deployment under sonographic guidance of an irregular retroareolar
mass on the left breast (a) as well as an ipsilateral suspicious axillary lymph node (b). Left breast
mediolateral oblique mammographic view showing both lesions associated with correctly posi-
tioned markers (c). (With permissions from Aline Campos, MD, and Carla Tajima, MD, from
BP – A Beneficência Portuguesa de São Paulo)
From the patient’s point of view, those who undergo RSL had fewer vasovagal
reactions at insertion in comparison to those who undergo wire localization, prob-
ably because patients were not fasting for surgery on the day the localization proce-
dure was performed; additionaly, radioactive seeds are usually deployed quicker than
wires are positioned, resulting in less algic stimulus thus decreasing the odds of a
vasovagal reaction [58].
Another benefit of RSL is the possibility to use the same gamma probe, only
adjusting the activity detection setting on the probe, to localize and excise sentinel
a b c d e
Fig. 11.22 Radioactive seed deployment under mammographic guidance using a marked com-
pression plate. Digital mammography mediolateral (a) and craniocaudal (b) views depicting a
post-biopsy marker on the junction of the outer quadrants of the left breast on the site with an
established diagnosis. Digital mammography craniocaudal view using a marked compression plate
showing the radioactive seed insertion needle in a lateral approach with its tip next to post-biopsy
marker (c) and the seed adequate deployment (d, e). (With permissions from Aline Campos, MD,
and Carla Tajima, MD, from BP – A Beneficência Portuguesa de São Paulo)
nodes submitted for technetium 99 m localization, as the 125I seeds emit gamma rays
with a photon energy of 27 keV, while technetium 99 m has a 140-keV activ-
ity signal.
Unlike other nonwire localization techniques, there is no reported depth limita-
tion for detectability when RSL is utilized.
However, any RSL program must follow strict regulations due to the radioactiv-
ity involved and requires massive inter-departmental coordination for its execution.
Therefore, establishing a radioactive seed program can take some time, in contrast
to other nonwire localization programs which can be set up relatively quickly, and
limits the widespread adoption of this localization technique.
Contrary to a migrated biopsy clip, a migrated radioactive seed must be excised
and disposed accordingly due to the radioisotope presence. After the surgery, it is
placed in a lead container and sent back to the nuclear medicine service for safe
disposal. If the seed’s removal takes longer than 5 days, a radiation safety officer
must be notified, and the patient must be monitored until its removal.
Another RSL limitation is that these patients may not undergo MR imaging
while the seed is in place due to the fact that the gamma probe to detect eventually
extruded RSL seeds is not MR compatible (Zone IV), precluding recovering of a
potentially lost seed and limiting long-term RSL use for patients who have MR
follow-up imaging in the neoadjuvant setting.
During radioactive seed localization, it is crucial to not discard any material used
in the procedure until the mammography confirms its placement, which will aid in
the recovery if a seed is lost.
11.5.3.2 Non-radioactive Wireless Localization Devices
In the wake of limitations inherent to RSL, some non-radioactive wireless devices

have recently emerged. Among their advantages, besides being devoid of radioac-
tive emission, they are not constrained by specific regulations and protocols, do not
require special license to be handled or operational adjustments to be made, and can
be implemented quicker as well as inserted in one facility and removed in another.
Radar Reflector Localization
This localization technique uses radar technology and was first introduced in 2014,
being composed of a device detected by a specific intraoperative probe that emits
infrared light to excise the area of interest which can be placed under ultrasound or
mammographic guidance in a similar way as a biopsy marker clip (Fig. 11.23).
One of the first radar reflector devices, the SAVI Scout System® (Merit Medical
Systems, USA), measures 12 mm in length, with a 4-mm body and two 4-mm
antennas on each side, including an infrared light detector. Being FDA approved for
long-term placement, it is biocompatible and inert, responding only to signals emit-
ted from the respective reader, and can be implanted at any time prior to surgery.
The reflector is deployed using a 16G needle by withdrawing a release button,
rather than pushing the reflector, in order to prevent antenna bending. After
a c e
b d f
Fig. 11.23 A 12-mm radar reflector with a 4-mm body and two antennas on either side (a).
Console with an attached handpiece probe (b). Mammographic (c), sonographic (e), surgical spec-
imen (d), and MRI (f) appearance of the radar reflector, (© Merit Medical, reprinted with
permission)
displacement, the radiologist uses a console to make sure that an audible signal can
be obtained from the radar reflector. Researchers have successfully detected reflec-
tors at a depth of up to 8 cm; however, in certain circumstances, a radar placed
deeper than 6 cm may not produce a detectable signal through the skin, unlike radio-
active seeds, and additional compression to tissue with the handpiece may be
required [59, 60].
In the OR, the detector console emits power to the infrared light source through
the hand probe, activating it, which results in the reflection of an electromagnetic
wave signal back to the handpiece. The console then processes these signs and pro-
vides visual and audible feedback to the surgeon.
In contrast to the RFID tag and magnetic seed devices, which can cause MRI
susceptibility signal void artifact, the radar reflector causes minimal artifact, and the
patient with the device in place may safely undergo MRI at 3 T or less. However, the
Scout system is costlier than WL or RSL.
Clear surgical margin rates achieved by using radar reflector-guided excision
have ranged from 85% to 93%, and when compared to wire localization surgical
outcomes, researchers found no substantial differences in margin positivity, close
margin, and re-excision rates [19, 60, 61]. Another study comparing the SAVI Scout
system to WGL and RSL found no difference in margin positivity, specimen vol-
ume, or 30-day complication rate but did find that the SAVI Scout device reduced
the overall operating time [62].
Failures related to radar reflector technique are typically due to a lack of signal
from the device: dense objects such as calcified masses, hematomas or wires, as
well as certain plastics, positioned between the reflector and the handpiece, can
interfere with signal detection [61, 63]. Halogen and some older model OR lights
were shown to affect detection of the reflector as well; however, shielding the breast
from these lights or redirecting them while using the handpiece solved these issues.
Besides, LED lights, which are more prevalent than halogen lights in these settings,
did not interfere with radar detection [60].
On top of it, this system cannot be placed in patients with a nickel allergy, as the
radar reflector antennae are made of nitinol, an alloy of nickel and titanium.
In comparison to RSL, radar reflector localization lacks radioactivity and regula-
tory issues, can be implanted for longer periods and is associated with minimum
susceptibility artifact on MRI. However, it should not be placed within or deep to a
hematoma, there is the possibility of an allergic reaction in some patients due to the
presence of nitinol and the Scout system costs more than WL or RSL.
Magnetic Seed Localization
The Magseed® (Endomagnetics, Cambridge, UK) device was FDA cleared in 2016,
being a stainless-steel marker measuring 5 × 1 mm, the smallest among non-
radioactive localization devices. It is deployed under mammogram or ultrasound
guidance, in a similar way to a biopsy marker or RSL, through a preloaded 18G
needle introducer.
These seeds have a textured surface to optimize their ultrasonographic visibility

and may be placed up to 30 days before surgery. Recently, the FDA granted perma-
nent implant status, so there is no time limit for retrieval and its signal strength does
not decay.
Magseed is not permanently magnetic. It contains iron particles, which are not
themselves magnetic but can be induced to transiently become a magnet under the
influence of a Sentimag® probe (Endomagnetics, Cambridge, UK), creating a mag-
netic field. The probe then provides audible and numeric feedback for the strength
of the magnetic field and consequently estimates the distance from the seed to the
probe. Magseed® is intended to be placed up to a 3 to 4 cm depth, at the risk of not
producing a detectable signal; however, seeds have been detected in locations
deeper than this limit [50].
This same probe can also be used to perform sentinel node biopsy and lymphatic
mapping by using Magtrace®, a liquid containing superparamagnetic iron oxide
nanoparticles with a carboxydextran coating [64].
Magseed® is MRI conditional and has been tested in up to 3 T scanners; how-
ever, it produces a significant 4 cm signal void artifact due to its iron content, bigger
than those associated with other nonwire localization methods, limiting diagnostic
accuracy of breast MRI, and it should be taken into account in a preoperative setting.
Price et al. achieved 83% clear surgical margin by using magnetic seed-guided
excision in a series of 64 patients [50]. Gera et al. reviewed 16 studies in a pooled
analysis, obtaining a successful localization rate of 99.86% with a relatively low
re-excision rate of 11.25% [65].
Some caveats are associated with its use in patients with pacemakers or implanted
chest wall devices as the Sentimag® probe should not be placed within 15 mm from
any part of an operating pacemaker. Non-metallic surgical tools are recommended
while the probe is in use in order to not interfere with the signal, resulting in addi-
tional start-up costs.
Radiofrequency Identification Tag (RFID) Localization
Radiofrequency identification tags are a part of the LOCalizer® (Hologic Inc.,

Santa Clara, CA, USA) localization system introduced in 2017. The RFID tag is a
passive device, measuring 9 × 2 mm, containing a ferrite rod wrapped in copper and
a microprocessor, associated with an anti-migratory sheath. It is deployed through a
preloaded 12G needle similar to a biopsy clip. The current license in the European
Union permits deployment of the RFID tag within 30 days of surgery; however, this
duration has been extended to “long term” in the United States, which permits
deployment at the time of diagnostic core biopsy in patients requiring neoadjuvant
chemotherapy. However, it has not yet been approved for placement in lymph nodes.
In the OR, a battery-powered RFID localizer reader sends a radiofrequency sig-
nal to the tag, which re-emits the signal modified to the portable handheld localizer
device. The reader device operates in two different modes that can be used to reab-
sorb the signal, one with a 6 cm range and another with a 3 cm range. The probe
with the deeper range can be draped for use in a sterile surgical environment and is
reusable, while the one with the smaller range is a pencil-sized, single-use device.
On the reader screen, associated with an audible signal, the distance from the lesion
to the probe can be viewed in millimeters as well as the tag’s unique identifica-
tion number.
There are no clear contraindications to RFID tags nor any adverse effects associ-
ated with their use. The tags have a long history of use similar to those embedded in
livestock, pets, and breast implants as a form of identification.
Maggie et al. found that the clear surgical margin rate associated with RFID tag-
guided excision was 97% in a subset of 33 patients [66].
It is MRI conditional; however, the ferrous and copper material creates a 2.5 cm
susceptibility artifact when imaging is performed using a gradient-echo pulse
sequence in a 3 T MRI unit.
We summarize and compare the main features of the aforementioned localiza-
tion techniques in Table 11.1.
11.6 Post-procedure Complications
Complications of the preoperative imaging-guided localization procedures involve

failure to excise the localized abnormality or procedure-associated complica-
tions [67].
The procedure-related complications include pain, vasovagal reactions, bleed-
ing, hematoma formation, infection, pneumothorax, pseudoaneurysm formation,
implant rupture, and milk fistula in lactating patients [51, 67, 68].
The majority of pain perceived by the patient is felt during insertion of the needle
through the skin itself. Advancing the needle or wire through the breast tissue or
injecting contrast solution (dye or carbon) is generally much less painful.
Bleeding is only a problem when an artery is inadvertently injured during local-
ization. If this occurs, firm compression has to be applied for a sufficient period of
time (approximately 10 minutes).
Vasovagal reactions are biphasic with an initial rise in heart rate, blood pressure,
systemic resistance, and cardiac output. This rapidly reverses as bradycardia associ-
ated with splanchnic and muscle vasodilatation occurs associated with nausea, pal-
lor, lightheadedness and diaphoresis. They are usually treated with simple supportive
measures, including placing the patient in a supine position with legs raised at the
onset of symptoms. The physician must always be prepared for vasovagal reactions
since individual tolerance to the introduction of a needle into the breast varies
greatly [24].
Ecchymoses or hematomas may follow after insertion of the needle into the
breast. Although these most commonly occur in the region of the target lesion, an
occasional more remote one may occur.
Although pneumothorax is probably the most serious potential complication, it
is an extremely rare event, as is migration of wires into remote locations of the body.
Table 11.1 Comparison of different preoperative localization techniques
238
Features of localization Techniques

Wire Carbon ROLL Radioactive Seed Magnetic Seed Radar Reflector RFID Tag
Implantation Hospital Hospital/ Hospital Hospital Hospital/outpatient Hospital/ Hospital/
Facilities outpatient outpatient outpatient
Repositionable Certain types No No No No No No
Device size 3–15 cm – – 5 mm 5 mm 12 mm 9 mm
Device Isolated Low Low Low Low High High High
Cost
Additional None None Console and Console and Probe Console, probe, Non Console and Console and
equipment Probe Ferromagnetic Probe Probe
requirements Surgical instruments
Depth limit for None None None None 3–4 cm 6 cm 3–6 cm
detectability
Maximal duration Same day as No restriction Same day as 5–7 days prior To No restriction No restriction No restriction
of implantation surgery surgery surgery
MRI Deployment MRI-compatible Available Available Not available Not available Not available Not available
Wires are
available
MRI Device MRI-compatible Safe Safe MRI Conditional MRI Conditional (3 T MRI Conditional MRI Conditional
Safety Wires are (3 T or less) or less) (3 T or less) (3 T or less)
available
FDA Approved Not approved for Approved Approved Approved Approved Approved
breast lesion
localization
H. D. Skaf et al.
11
Strengths Cost effective Can be placed No depth No depth limitation Small size Axillary node Pencil size
No depth with MRI limitation Console and probe Axillary node localization surgical probe
limitation guidance Can be placed are the Same used localization available
Can be placed with MRI for sentinel lymph Each tag has a
with MRI guidance node biopsy unique ID
guidance Axillary node number visible
localization on console
Weaknesses Scheduling Potentially Scheduling Radiation safety Requires nonferrous Contains nickel MRI artifact
inflexibility difficult difficulties concerns surgical tools MRI artifact Axillary use is
Presurgical visualization on Radiation Lengthy Process to Largest susceptibility Multiple factors still off label
Patient will be imaging methods safety begin Program artifact on MRI may limit signal
in fasting state Foreign-body concerns Contraindicated in detection on OR
Potential reaction that may Lengthy patients with
discomfort mimic malignancy Process to implanted cardiac
while waiting begin Program devices
for surgery
Breast Imaging Preoperative Localization Procedure
239
WL specifically has a multitude of complications. Because part of the wire is

external, it can dislocate, migrate, bend, fracture, or be transected before or during
surgery [68]. An uncommon event is intramammary dislocation of the hook from its
intended location. Distal migration of the wire within the breast can occur as repo-
sitioning and recompression result in more of the wire being enveloped by the
breast. Respiratory and muscular activity during transportation, prolonged delays,
and transfer from stretcher to operating table may result as well in distal wire dis-
placements, particularly with posterior lesions. These complications are preventable
by bending and securely taping the wire to the skin or, in the case of the curved-end
J-wires, by using the skin clamp provided. In patients with fatty breasts, the wire
may retract toward the skin surface because of limited stroma for hookwire
anchorage.
Broken or transected wires are a problem that will have a variable incidence,
depending on the surgical personnel involved. Failure to excise the localized
mammographic abnormality has been reported in 2.5–6.7% of cases and is more
likely with two lesions, small breast, microcalcifications, small lesions, and
small specimen [21, 69]. Potential reasons for failure to excise include place-
ment of the wire more than 1 cm from the lesion, placing the wire without reach-
ing the lesion, advancing the wire significantly beyond the lesion, wire movement
during patient transfer, and bleeding causing hematoma formation and wire
displacement.
11.7 Post-procedure Assessment
The radiologist estimates the projection of the tumor on the skin surface, positions
a marker in the corresponding spot, and reports the skin-to-lesion as well as skin-
to–localization device depths, as well as the lesion distance from the nipple and
pectoral muscle. After the procedure, the radiologist must summarize it for the sur-
geon and even consider a call to discuss the procedure, particularly if the localiza-
tion device is not in an ideal position.
After the target tissue is excised, the specimen is labeled for orientation, and
radiographs are obtained to confirm the removal of both the lesion and the localiza-
tion device. Surgical specimens, excised under needle localization guidance, should
be radiographed for several reasons. The radiography verifies that the entire lesion
has been removed, serves as a lesion location guide in the specimen to the patholo-
gist, and certifies that the wire has been removed from the breast. This is an absolute
requirement when localization is performed for calcification, architectural distor-
tion, or asymmetries. If the entire length of the wire is not visualized on the speci-
men radiograph, it is imperative to report this information to the surgeon.
Intraoperative radiography or postoperative imaging is appropriate to identify the
retained fragment [67].
References
1. Franceschi D, Crowe J, Zollinger R, Duchesneau R, Shenk R, Stefanek G, et al. Biopsy of the

breast for mammographically detected lesions. Surg Gynecol Obstet. 1990;171(6):449–55.
2. Goedde TA, Frykberg ER, Crump JM, Lay SF, Turetsky DB, Linden SS. The impact of mam-
mography on breast biopsy. Am Surg. 1992;58(11):661–6.
3. Hayes MK. Update on preoperative breast localization. Radiol Clin. 2017;55(3):591–603.
4. Gundry KR, Berg WA. Treatment issues and core needle breast biopsy: clinical context. AJR
Am J Roentgenol. 1998;171(1):41–9.
5. Dershaw DD, Morris EA, Liberman L, Abramson AF. Nondiagnostic stereotaxic core breast
biopsy: results of rebiopsy. Radiology. 1996;198(2):323–5.
6. Philpotts LE, Shaheen NA, Carter D, Lange RC, Lee CH. Comparison of rebiopsy rates after
stereotactic core needle biopsy of the breast with 11-gauge vacuum suction probe versus
14-gauge needle and automatic gun. AJR Am J Roentgenol. 1999;172(3):683–7.
7. Liberman L. Clinical management issues in percutaneous core breast biopsy. Radiol Clin N
Am. 2000;38(4):791–807.
8. Mayo RC III, Kalambo MJ, Parikh JR. Preoperative localization of breast lesions: current
techniques. Clin Imaging. 2019;56:1–8.
9. Spillane RM, Whitman GJ, McCarthy KA, Hulka CA, Hall DA, Kopans DB. Computed
tomography—guided needle localization of nonpalpable breast lesions: review of 24 cases.
Acad Radiol. 1996;3(2):115–20.
10. Fischer U, Baum F, Luftner-Nagel S. Breast cancer: diagnostic imaging and therapeutic guid-
ance. Thieme. 2018;9:166–73.
11. Reynolds HE, Jackson VP, Musick BS. A survey of interventional mammography practices.
Radiology. 1993;187(1):71–3.
12. Fischer U, Baum F. Interventional breast imaging: ultrasound, mammography, and MR guid-
ance techniques. Thieme; 2011.
13. Patel IJ, Davidson JC, Nikolic B, Salazar GM, Schwartzberg MS, Walker TG, et al. Consensus
guidelines for periprocedural management of coagulation status and hemostasis risk in percu-
taneous image-guided interventions. J Vasc Interv Radiol. 2012;23(6):727–36.
14. Patel IJ, Davidson JC, Nikolic B, Salazar GM, Schwartzberg MS, Walker TG, et al.
Addendum of newer anticoagulants to the SIR consensus guideline. J Vasc Interv Radiol.
2013;24(5):641–5.
15. Jaffe TA, Raiff D, Ho LM, Kim CY. Management of anticoagulant and antiplatelet medica-
tions in adults undergoing percutaneous interventions. Am J Roentgenol. 2015;205(2):421–8.
16. Veltri A, Bargellini I, Giorgi L, Almeida PAMS, Akhan O. CIRSE guidelines on percutaneous
needle biopsy (PNB). Cardiovasc Intervent Radiol. 2017;40(10):1501–13.
17. Kaye AD, Kucera I, Sabar R. Perioperative anesthesia clinical considerations of alternative
medicines. Anesthesiol Clin North Am. 2004;22(1):125–39.
18. Thornhill MH, Dayer M, Lockhart PB, Prendergast B. Antibiotic prophylaxis of infective
endocarditis. Curr Infect Dis Rep. 2017;19(2):9.
19. Patel SN, Mango VL, Jadeja P, Friedlander L, Desperito E, Wynn R, et al. Reflector-guided
breast tumor localization versus wire localization for lumpectomies: a comparison of surgical
outcomes. Clin Imaging. 2018;47:14–7.
20. Chadwick D, Shorthouse A. Wire-directed localization biopsy of the breast: an audit of results
and analysis of factors influencing therapeutic value in the treatment of breast cancer. Eur J
Surg Oncol. 1997;23(2):128–33.
21. Jackman RJ, Marzoni FA Jr. Needle-localized breast biopsy: why do we fail? Radiology.
1997;204(3):677–84.
22. Butler R, Berg WA. Preoperative lesion localization, bracketing. Diagnostic imaging: breast.
3rd ed. Philadelphia, PA: Elsevier; 2019.
23. Dershaw DD. Imaging-guided interventional breast techniques. Springer Science & Business
Media; 2002. p. 31–52.
24. Helvie MA, Ikeda DM, Adler DD. Localization and needle aspiration of breast lesions: com-
plications in 370 cases. AJR Am J Roentgenol. 1991;157(4):711–4.
25. Sylvia H, Dershaw D, Schreer I. Diagnostic breast imaging; 2001. p. 152–60.
26. Woods RW, Camp MS, Durr NJ, Harvey SC. A review of options for localization of axillary
lymph nodes in the treatment of invasive breast cancer. Acad Radiol. 2019;26(6):805–19.
27. Homer MJ. Transection of the localization hooked wire during breast biopsy. Am J Roentgenol.
1983;141(5):929–30.
28. Martinez SR, Gelfand M, Hourani HS, Sorrento JJ, Mohan EP. Cardiac injury during needle
localized surgical breast biopsy. J Surg Oncol. 2003;82(4):261–5.
29. Bristol J, Jones P. Transgression of localizing wire into the pleural cavity prior to mammogra-
phy. Br J Radiol. 1981;54(638):139–40.
30. Choy N, Lipson J, Porter C, Ozawa M, Kieryn A, Pal S, et al. Initial results with preoperative
tattooing of biopsied axillary lymph nodes and correlation to sentinel lymph nodes in breast
cancer patients. Ann Surg Oncol. 2015;22(2):377–82.
31. Patel R, MacKerricher W, Tsai J, Wood L, Allison K, Wapnir I. Pathological confirmation of
pre-chemotherapy biopsied and tattooed axillary lymph nodes; 2018. p. 426–7.
32. Rose A, Collins J, Neerhut P, Bishop C, Mann G. Carbon localisation of impalpable breast
lesions. Breast. 2003;12(4):264–9.
33. Ko K, Han B-K, Jang KM, Choe YH, Shin JH, Yang J-H, et al. The value of ultrasound-guided
tattooing localization of nonpalpable breast lesions. Korean J Radiol. 2007;8(4):295–301.
34. Svane G. A stereotaxic technique for preoperative marking of non-palpable breast lesions.
Acta Radiol Diagn. 1983;24(2):145–51.
35. Langlois SLP, Carter ML. Carbon localisation of impalpable mammographic abnormalities.
Australas Radiol. 1991;35(3):237–41.
36. Canavese G, Catturich A, Vecchio C, Tomei D, Estienne M, Moresco L, et al. Pre-operative
localization of non-palpable lesions in breast cancer by charcoal suspension. Eur J Surg Oncol.
1995;21(1):47–9.
37. Mullen DJ, Eisen RN, Newman RD, Perrone PM, Wilsey JC. The use of carbon marking after
stereotactic large-core-needle breast biopsy. Radiology. 2001;218(1):255–60.
38. Franceschini G, Mason EJ, Grippo C, D’Archi S, D’Angelo A, Scardina L, et al. Image-
guided localization techniques for surgical excision of non-palpable breast lesions: an over-
view of current literature and our experience with preoperative skin tattoo. J Personal Med.
2021;11(2):99.
39. Ruiz-Delgado M, López-Ruiz J, Sáiz-López A. Abnormal mammography and sonography
associated with foreign-body giant-cell reaction after stereotactic vacuum-assisted breast
biopsy with carbon marking. Acta Radiol. 2008;49(10):1112–8.
40. Cavalcanti TCS, Malafaia O, Nassif PAN, Skare TL, Ogata DC, Miguel MT, et al. Non-
palpable breast lesions marked with coal suspension: evaluation of anatomopathological
aspects, viability of interpretation and inflammatory response. Revista do Colegio Brasileiro
de Cirurgioes. 2012;39(6):469–75.
41. de O Salvador GL, Barbieri PP, Maschke L, ALA N, Louveira MH, Budel VM. Charcoal
granuloma mimicking breast cancer: an emerging diagnosis. Acta Radiol Open.
2018;7(12):2058460118815726.
42. Veronesi U. Conservative surgery 23. Breast cancer: innovations in research and management;
2017. p. 247–64.
43. Luini A, Zurrida S, Galimberti V, Paganelli G. Radioguided surgery of occult breast lesions.
Eur J Cancer (Oxford, England: 1990). 1998;34(1):204–5.
44. Grüning T, Brogsitter C, Jones IW, Heales JC. Resolution recovery in planar bone scans: diag-
nostic value in metastatic disease. Nucl Med Commun. 2012;33(12):1307–10.
45. Postma EL, Koffijberg H, Verkooijen H, Witkamp A, Van Den Bosch M, Van Hillegersberg
R. Cost-effectiveness of radioguided occult lesion localization (ROLL) versus wire-guided
localization (WGL) in breast conserving surgery for nonpalpable breast cancer: results from a
randomized controlled multicenter trial. Ann Surg Oncol. 2013;20(7):2219–26.
46. Paganelli G, De Cicco C, Luini A, Cassano E, Pizzamiglio M, Fiorenza M, et al. Radioguided
surgery in non-palpable breast lesions. Eur J Nucl Med Mol Imaging. 1997;24:893.
47. De Cicco C, Trifiro G, Intra M, Marotta G, Ciprian A, Frasson A, et al. Optimised nuclear
medicine method for tumour marking and sentinel node detection in occult primary breast
lesions. Eur J Nucl Med Mol Imaging. 2004;31(3):349–54.
48. Ahmed M, Douek M. Sentinel node and occult lesion localization (SNOLL): a systematic
review. Breast. 2013;22(6):1034–40.
49. Krynyckyi BR, Shim J, Kim CK. Internal mammary chain drainage of breast cancer. Ann Surg.
2004;240(3):557.
50. Price ER, Khoury AL, Esserman LJ, Joe BN, Alvarado MD. Initial clinical experience with an
inducible magnetic seed system for preoperative breast lesion localization. Am J Roentgenol.
2018;210(4):913–7.
51. US Nuclear Regulatory Commission. iodine-125 and palladium-103 low dose rate brachy-
therapy seeds used for localization of non-palpable lesions. Washington, DC: US Government
Printing Office; 2015. p. 27. http://www.nrc.gov/materials/miau/med-use-toolkit/seed-
localization.html
52. Loving VA, Edwards DB, Roche KT, Steele JR, Sapareto SA, Byrum SC, et al. Monte Carlo
simulation to analyze the cost-benefit of radioactive seed localization versus wire localization
for breast-conserving surgery in fee-for-service health care systems compared with account-
able care organizations. Am J Roentgenol. 2014;202(6):1383–8.
53. Jakub JW, Gray RJ, Degnim AC, Boughey JC, Gardner M, Cox CE. Current status of radioac-
tive seed for localization of nonpalpable breast lesions. Am J Surg. 2010;199(4):522–8.
54. McGhan LJ, McKeever SC, Pockaj BA, Wasif N, Giurescu ME, Walton HA, et al. Radioactive
seed localization for nonpalpable breast lesions: review of 1,000 consecutive procedures at a
single institution. Ann Surg Oncol. 2011;18(11):3096–101.
55. Hughes JH, Mason MC, Gray RJ, McLaughlin SA, Degnim AC, Fulmer JT, et al. A multi-site
validation trial of radioactive seed localization as an alternative to wire localization. Breast
J. 2008;14(2):153–7.
56. Sharek D, Zuley ML, Zhang JY, Soran A, Ahrendt GM, Ganott MA. Radioactive seed localiza-
tion versus wire localization for lumpectomies: a comparison of outcomes. Am J Roentgenol.
2015;204(4):872–7.
57. Dryden MJ, Dogan BE, Fox P, Wang C, Black DM, Hunt K, et al. Imaging factors that influ-
ence surgical margins after preoperative 125I radioactive seed localization of breast lesions:
comparison with wire localization. Am J Roentgenol. 2016;206(5):1112–8.
58. Zhang Y, Seely J, Cordeiro E, Hefler J, Thavorn K, Mahajan M, et al. Radioactive seed local-
ization versus wire-guided localization for nonpalpable breast cancer: a cost and operating
room efficiency analysis. Ann Surg Oncol. 2017;24(12):3567–73.
59. SAVI SCOUT reflector and delivery system instructions for use. Cianna Medical. 2016;2019.
https://www.ciannamedical.com/wp-content/uploads/2016/11/Instructions-for-Use-Reflector-
Delivery-System.pdf. Published 2016. Accessed 8 May 2019.
60. Cox CE, Russell S, Prowler V, Carter E, Beard A, Mehindru A, et al. A prospective, single arm,
multi-site, clinical evaluation of a nonradioactive surgical guidance technology for the location
of nonpalpable breast lesions during excision. Ann Surg Oncol. 2016;23(10):3168–74.
61. Mango VL, Wynn RT, Feldman S, Friedlander L, Desperito E, Patel SN, et al. Beyond wires and
seeds: reflector-guided breast lesion localization and excision. Radiology. 2017;284(2):365–71.
62. Srour MK, Kim S, Amersi F, Giuliano AE, Chung A. Comparison of wire localization,
radioactive seed, and Savi scout® radar for management of surgical breast disease. Breast
J. 2020;26(3):406–13.
63. Falcon S, Weinfurtner RJ, Mooney B, Niell BL. SAVI SCOUT® localization of breast lesions
as a practical alternative to wires: outcomes and suggestions for trouble-shooting. Clin
Imaging. 2018;52:280–6.
64. Hersi A-F, Eriksson S, Ramos J, Abdsaleh S, Wärnberg F, Karakatsanis A. A combined,

totally magnetic technique with a magnetic marker for non-palpable tumour localization and
superparamagnetic iron oxide nanoparticles for sentinel lymph node detection in breast cancer
surgery. Eur J Surg Oncol. 2019;45(4):544–9.
65. Gera R, Tayeh S, Al-Reefy S, Mokbel K. Evolving role of magseed in wireless localization
of breast lesions: systematic review and pooled analysis of 1,559 procedures. Anticancer Res.
2020;40(4):1809–15.
66. DiNome ML, Kusske AM, Attai DJ, Fischer CP, Hoyt AC. Microchipping the breast: an effec-
tive new technology for localizing non-palpable breast lesions for surgery. Breast Cancer Res
Treat. 2019;175(1):165–70.
67. Kapoor MM, Patel MM, Scoggins ME. The wire and beyond: recent advances in breast imag-
ing preoperative needle localization. Radiographics. 2019;39(7):1886–906.
68. Cheang E, Ha R, Thornton CM, Mango VL. Innovations in image-guided preoperative breast
lesion localization. Br J Radiol. 2018;91(1085):20170740.
69. Shetty MK. Presurgical localization of breast abnormalities: an overview and analysis of 202
cases. Indian J Surg Oncol. 2010;1(4):278–83.
Part III
Different Clinical Scenario: Clinical
Management and Role of Imaging
Modalities
Chapter 12
Screening
Mila Trementosa Garcia, Laura Aguiar Penteado,

Flávia Abranches Corsetti Purcino, and Jose Roberto Filassi
12.1 Introduction
Screening tests are done to detect potential health disorders or diseases in people
who do not have any symptoms of the disease. The goal is early detection to enable
effective treatment or prevention through lifestyle changes. The disease must be
serious and treatable. The exam must be safe, acceptable, and of low cost [1].
For breast cancer, mammography, as a screening test can offer conservative sur-
gery and decrease mortality. Screening mammography detects 2–8 cancers per 1000
mammograms [2], and some guidelines show a 20% of mortality reduction [3].
Periodicity of mammography is controversial, as well as the ideal age to start and
finish scheduled tests. Societies around the world offer different recommendations.
The Brazilian College of Radiology and the Brazilian Society of Breast Cancer
recommends from the age of 40 without a predetermined age for the interruption,
testing women up to the life expectancy of 7 years. The US Preventive Services Task
Force (USPSTF) recommendation (2009 and 2016) is biennial screening mammog-
raphy for women aged 50–74 years. Annual screening mammography of women
aged 40–84 is known to prevent more deaths from breast cancer than biennial
screening of women 50–74 years old. No medical society recommends screening
before 40 years.
On the other hand, mammography is not innocuous. Its main adverse effect is
radiation exposure. Other problems may arise from false-positive results and over-
diagnosis leading to overtreatment.
M. T. Garcia · L. A. Penteado · F. A. C. Purcino · J. R. Filassi (*)


Switzerland AG 2022
248 M. T. Garcia et al.
Overdiagnosis refers to detection in the screening of invasive or noninvasive neo-

plasia that would not cause death or become symptomatic during the patient’s life.
It is a difficult task to state which cases have been overtreated, and literature vary
widely from less than 5% to more than 50%. The greatest challenge for the future is
to find ways to increase the accuracy of the detected cancer and if it threatens the
patient’s health or not [4, 5].
False-positive problems include recalls for further studies, follow-up, and biop-
sies with benign results, which increase the cost of screening and general anxiety. A
good screening test must have high sensitivity so as not to lose cases of the disease
present in the population tested, as well as high specificity, resulting in a few cases
of false positives.
Considering radiation exposure, there are no direct demonstrations that periodic
mammograms induce breast cancer. The glandular dose of two-view mammography
ranges from 2 to 4 mGy. Anyway, it is prudent to avoid unnecessary exposure.
12.2 Screen-Film Mammography
This type of mammography was used in the initial studies that highlighted the
advantage of screening for breast cancer (Table 12.1). The image needs to be devel-
oped and fixed chemically.
12.3 Digital Mammography
Digital mammography was compared with screen-film mammography, and there is

no difference in accuracy for general screening. For women younger than 50 years
old and dense breast tissue, digital mammography is more accurate.
Screen-film mammography has been replaced by digital mammography due to
easier archiving and handling. Although digital mammography has advantages over
Table. 12.1 Reduced mortality in trials

Trial % Mortality decrease 95% Confidence interval
HIP RCT 22 0 –– 39
Malmo RCT 22 5 –– 35
SWEDISH two-county RCT 27 11 –– 41
Edinburgh RCT 21 −2 –– 40
Stockholm RCT 10 −28 –– 37
NBSS1 and 2 RCT 1 −12 –– 12
Gothenburg RCT 23 0 –– 40
Overall RCT 20 14 –– 27
Source: Adapted from Niell et al. [6]
12 Screening 249
screen-film mammography, no medical society recommends the preferred use of

digital mammography in screening the general population.
12.4 Tomosynthesis
In some cases, the fibroglandular tissue can hide lesions or hinder the interpretation
of the exam. With tomosynthesis, a moving x-ray source acquires multiple projec-
tions in each incidence and creates thin sections that could help with the masking
problem.
The combined use with mammography can reduce the rate of recall by 30%, but
it increases exposure to radiation, which generates debate about its routine use in
screening.
12.5 Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging is used regularly to screen for breast cancer in women
at high family risk (>20% lifetime), because MRI has the highest sensitivity for the
detection of invasive as well as of intraductal cancer [7]. On the other hand, MRI
screening has a lower specificity than mammography, and as a result, MRI will
generate more findings judged as uncertain, requiring short-term follow-up or addi-
tional investigations [8].
Kriege et al., in a prospective study, compared the efficacy of mammographic
and MRI screening for breast cancer in women with a positive family history or a
genetic predisposition to breast cancer [9]. Among the women examined by both
methods at the same screening visit, 45 breast cancers were detected (including 6
ductal carcinomas in situ): 32 by MRI (sensitivity, 71.1%) and 18 by mammography
(40%). The sensitivity of MRI was higher than that of mammography, but both the
specificity and positive predictive value of MRI were lower. MRI screening led to
twice as many unnecessary additional examinations as mammography (420 vs. 207)
and three times as many unnecessary biopsies (24 vs. 7) [9].
Despite MRI screening of the breast can detect occult malignancies better than
mammography, several factors must be taken into consideration. MRI is very expen-
sive and is an invasive procedure requiring an intravenous injection of a contrast
agent. It is also contraindicated in women with claustrophobia, pacemakers, or
aneurysm clips. Additionally, low specificity can cause an anxiety regarding the
result of supplemental screening, such as emotional burden, concerns about false-
positive results, or overdiagnosis and aversion to hospitals [10].
Berg et al. observed in the main ACRIN 6666 study that the increase in cancer
detection seen in the MRI sub-study was greater than observed by the addition of
annual ultrasound to mammography [11]. However, given the low rate of 8% of
clinically detected interval cancer rate in the main ACRIN 6666 protocol and given
the fact that all interval cancers remained node-negative at diagnosis, it is unclear
that the added cost and reduced tolerability of MRI screening are justified in women
at intermediate risk for breast cancer in lieu of supplemental screening with ultra-
sound. Despite its higher sensitivity, the addition of MRI screening instead of ultra-
sound to mammography in broader populations of women at intermediate risk with
dense breasts may not be appropriate, particularly when the current high false-
positive rates, cost, and reduced tolerability of MRI are considered [11].
12.6 Ultrasound
Ultrasound (US) traditionally serves as an adjunctive diagnostic modality of mam-

mographic in screening for abnormalities. Where mammography is available, US
should be seen as a supplemental test for women with dense breasts who do not
meet high-risk criteria for screening MRI and for high-risk women with dense
breasts who are unable to tolerate MRI [12].
Dense breast tissue reduces the sensitivity of screening mammography to detect
malignancy and is associated with an increased risk of breast cancer.
It is known that ultrasound is effective for the detection of small, invasive, node-
negative cancers in dense breast tissue, where the sensitivity of mammography
drops from 85% to 47.8–64.4% [13, 14]; therefore, women with mammographically
dense breasts may benefit from supplemental screening with whole breast ultrasound.
Although most of the literature reviews ultrasound as a supplementary detection
technique and its current evidence of effectiveness in the screening scenario is
scarce, there is a growing body of literature describing the capability of ultrasound
to detect breast cancer. Recent systematic review and meta-analysis of 26 studies
with a total of 76,058 patients is the most comprehensive analysis of the sensitivity
of ultrasound as a primary modality for breast cancer detection. The study showed
that ultrasound had an overall pooled sensitivity and specificity (95% CI) of 80.1%
(72.2–86.3%) and 88.4% (79.8–93.6%), respectively, for the detection of breast
cancer. In addition, this high sensitivity and specificity did not differ based on sub-
group analyses [15].
Considering that mammography is not widely available in all countries and
breast cancer incidence is increasing, ultrasound, as a relatively inexpensive and
available tool, can potentially play an important role in screening breast cancer in
these sites. Furthermore, it is used as a primary diagnostic modality to assess focal
breast symptoms in women under 40 years of age. Given that 23% of global breast
cancer cases are seen in women aged 15 to 49 years old in developing countries
[16], the use of ultrasound to screen asymptomatic women is also increasing rapidly.
The automated whole-breast ultrasound (AWBU) is a modality approved for
medical use by the Food and Drug Administration (FDA) and allows the radiologist
to read the images quickly, at a convenient time, while being free from doing
the scan.
12 Screening 251
A blinded study of this system combined with screening mammography has

shown that adding AWBU doubles the overall cancer detection and triples the inva-
sive cancers of 1 cm or less found in women with dense breasts [17]. Training would
be necessary for any facility planning to offer screening US [18].
12.7 Molecular Breast Imaging
Unlike mammography and ultrasound that are based on anatomy, molecular breast
imaging (MBI) is a physiologic approach to breast cancer detection. MBI detects
additional foci of occult breast cancer in 9.0% of women with newly diagnosed
breast cancer, has a high sensitivity for detecting high-risk lesions, and detects 98%
of invasive breast cancer and 91% of ductal carcinoma in situ [19]. Furthermore, in
surveillance of high-risk women, breast-specific gamma imaging (BSGI)/MBI
detects occult cancer in up to 16.5 per 1000 women. This modality is increasingly
being used to assess response to treatment in women undergoing neoadjuvant che-
motherapy and for adjunct screening in women with dense breasts. It has been
shown to influence surgical management in nearly a quarter of women with newly
diagnosed breast cancer. The Society of Nuclear Imaging has established clinical
indications and the American College of Radiology has established appropriateness
criteria as well as an accreditation program for MBI. A BIRADS-like lexicon for
MBI has also been described.
12.8 Clinical Breast Examination
Clinical breast examination is described as the examination of the breasts performed

by a doctor or a nurse. Commonly associated with screening mammography or
executed alone on many low-income areas. Clinically detected cancers are larger,
with a median size of 2.6 cm, compared with those found with screening mammog-
raphy, with a median size of 1.5 cm [20].
Cancers found clinically are more likely to show axillary nodal metastases:
38–45% are node positive compared with 18–25% of cancers detected by mammo-
graphic screening [21, 22]. Even within the same stage of cancer, survival is higher
in screen-detected cancers than in cancers detected clinically [23].
12.9 Breast Self-Examination
Described as an examination of the breasts performed by the patient herself. These

methods do not require any technical equipment and can be performed by the
women themselves if properly trained [24]. Data from two large trials do not
suggest a beneficial effect of screening by breast self-examination whereas there is

evidence for harms. There were no randomized trials of clinical breast examination.
At present, breast self-examination cannot be recommended [25].
The review of data from these trials did not find a beneficial effect of screening
in terms of improvement in breast cancer mortality. This review searched for well-
designed trials that assessed these methods and found two large population-based
studies involving 388,535 women who compared breast self-examination with no
intervention [25].
These meta-analyses also conclude that there is good evidence of harm from
breast self-examination as a result of increased invasive diagnostic procedures
[26, 27].
Other potential harms of screening include emotional distress even after a month
after receiving a clear result after further investigation [28]. A multicenter follow-up
study comparing different breast screening results groups 5 months after their last
breast screening appointment showed that women who go on further investigation
suffer greater adverse psychological consequences than women who do not [28, 29].
12.10 Thermography
A number of new and emerging technologies are being developed for breast cancer
screening and diagnosis internationally. Emerging classes of technology promoted
for breast cancer screening include digital infrared thermal imaging (DITI) – ther-
mography. It is a noninvasive imaging method, which neither emits ionizing radia-
tion nor compresses the breast and operates under differing physiological principles.
DITI aims to detect localized increases in skin temperature, which are thought to
occur as a result of increased vascularization, vasodilation, and recruitment of
inflammatory cells to the site of a developing tumor [30]. Localized differences in
skin temperature are captured by infrared cameras, which produce a heat map of the
breast called a thermogram. Early attempts of thermal imaging technology for
breast cancer detection had poor sensitivity (39%) [31]; however, the recent devel-
opment of high-resolution infrared cameras has generated new interest in the use of
DITI as a tool for breast cancer detection [32].
12.11 Elastography
Elastography incorporates multiple technological approaches. Two subclasses of

elastography – ultrasound elastography (USE) and electronic palpation imaging
(EPI) – will be described. EPI is a technology that generates pressure maps of breast
tissue identifying tumors as more rigid structures than healthy tissue [33]. In con-
trast, USE can be interpreted as a measure of comparative strain between healthy
and cancerous tissue [34], a five-point elasticity score index, or as an automatic
classification of benign or malignant tumors using an artificial neural network [35].
12 Screening 253
12.12 Screening in Special Populations
12.12.1 Increased Breast Density
Screening is one of the main factors that contribute to the reduction of mortality
from breast cancer worldwide. Mammographic screening is a well-known estab-
lished method for all women who are between 50 and 70 years of age and can
reduce mortality from breast cancer by about 25 percent [36]. About the value of
breast cancer screening among women who are under 50 years old, there is no con-
sensus [37]. One of the reasons for the lack of agreement is the difficulty in detect-
ing tumors by mammographic screening in younger women, who have denser
breasts than postmenopausal women [38].
Dense breasts are defined by mammographic appearance. The American College
of Radiology’s (ACR) Breast Imaging Reporting and Data System (BI-RADS) clas-
sifies breasts in four categories based on the fibroglandular breast density [39].
Extremely dense breast tissue is a risk factor for breast cancer and limits the
detection of cancer with mammography. However, there is currently little evidence
that the addition of breast ultrasound or MRI would change the mortality rate.
In J-START (Japan Strategic Anti-cancer Randomized Trial), investigators eval-
uated supplemental ultrasonographic breast screening among Japanese women aged
40–49 years old. 58% of the participants had dense breasts. Cancer-detection rates
were 3.3 per 1000 screenings for mammography alone and 5.0 per 1000 screenings
for mammography plus ultrasonography. The addition of ultrasonographic screen-
ing resulted in an interval-cancer rate of 0.5 per 1000 screenings, as compared with
1.0 per 1000 screenings with mammography alone, and an increase in the false-
positive rate from 8.8% to 12.6% [40].
In a diagnostic setting, magnetic resonance imaging (MRI) is a sensitive method
of breast imaging and is not influenced by breast density. The Dense Tissue and
Early Breast Neoplasm Screening (DENSE) trial is a randomized, controlled trial to
study the effect of supplemental MRI on the incidence of interval cancers in women
with extremely dense breast tissue. The trial assigned 40,373 women between the
ages of 50 and 75 years old with extremely dense breast tissue and randomized to a
group that was invited to undergo supplemental MRI or to a group that received
mammography screening only. The primary outcome was the difference between
groups in the incidence of interval cancers during a 2-year screening period. It was
observed a significantly lower interval-cancer rate in the MRI group (2.5 vs. 5.0 per
1000 screenings). Among the women who were invited to undergo MRI, 59% actu-
ally underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-
invitation group, 4 were diagnosed in the women who had undergone MRI and 16 in
those who had not. A limitation of the trial is that it is not large enough to look at the
effect of MRI screening on breast cancer-specific or overall mortality. This outcome
would require a much larger sample size and longer follow-up [41].
12.12.2 High-Risk of Breast Cancer
A woman is considered at high risk of developing breast cancer if she has a lifetime
risk of more than 20–25% of developing breast cancer based on available risk mod-
els, has a BRCA1 or BRCA2 mutations, or was exposed to therapeutic thoracic
radiation (RT) before age 30. This population needs a special screening due to the
high chances of developing breast cancer.
Kuhl et al. investigated in “the EVA Trial” the contribution of clinical breast
examination (CBE), mammography, ultrasound, and quality-assured breast mag-
netic resonance imaging (MRI), used alone or in different combinations, for screen-
ing women at elevated risk for breast cancer. It was a prospective multicenter
observational cohort study and analyzed 687 asymptomatic women at elevated
familial risk (>20% lifetime). Twenty-seven women were diagnosed with breast
cancer: 11 ductal carcinomas in situ (41%) and 16 invasive cancers (59%). All can-
cers were detected during annual screening; no interval cancer occurred; no cancer
was identified during the half-yearly ultrasound. The cancer yield of ultrasound (6.0
of 1000) and mammography (5.4 of 1000) was equivalent; it increased nonsignifi-
cantly (7.7 of 1000) if both methods were combined. Cancer yield achieved by MRI
alone (14.9 of 1000) was significantly higher; it was not significantly improved by
adding mammography (MRI plus mammography: 16.0 of 1000) and did not change
by adding ultrasound (MRI plus ultrasound: 14.9 of 1000). The positive predictive
value was 39% for mammography, 36% for ultrasound, and 48% for MRI [42].
The National Comprehensive Cancer Network (NCCN) recommends that women
who have a lifetime risk ≥20% should have an annual screening mammography
(begin 10 years prior to when the youngest family member was diagnosed with
breast cancer but not prior to age 30) and also recommends annual breast MRI
(begin 10 years prior to when the youngest family member was diagnosed with
breast cancer, but not prior to age 25) [43].
Special screening has been recommended for women who were exposed to ther-
apeutic thoracic radiation, between the ages of 10 and 30 years. The NCCN recom-
mends an annual screening mammography (begin 8 years after RT but not prior to
age 30) and also recommends an annual breast MRI (begin 8 years after RT but not
prior to age 25) [43].
12.12.3 Elderly Women
The upper age limit at which breast cancer screening should be applied is not estab-
lished by guidelines. The woman’s overall state of health should be considered in
any decision to undertake or forgo screening.
12 Screening 255
References
1. The Johns Hopkins University, The Johns Hopkins Hospital, and The Johns Hopkins Health
System Corporation, Johns Hopkins Medicine. Available at: https://www.hopkinsmedicine.
org/. Accessed 10 Sept 2020.
2. Lee CS, Bhargavan-Chatfield M, Burnside ES, Nagy P, Sickles EA. The national mammog-
raphy database: preliminary data. Am. J. Roentgenol [Internet]. American Roentgen Ray
Society; 2016 ;206(4):883–90. Available at: https://doi.org/10.2214/AJR.15.14312.
3. Oeffinger KC, Fontham ETH, Etzioni R, Herzig A, Michaelson JS, Shih Y-CT, et al. Breast
cancer screening for women at average risk: 2015 guideline update from the american cancer
society. JAMA [Internet]. 2015;314(15):1599–614. Available at: https://doi.org/10.1001/
jama.2015.12783.
4. Olsen AH, Agbaje OF, Myles JP, Lynge E, Duffy SW. Overdiagnosis, sojourn time, and
sensitivity in the Copenhagen mammography screening program. Breast J [Internet].
2006;12(4):338–42. Available at: http://doi.wiley.com/10.1111/j.1075-122X.2006.00272.x.
5. Jorgensen KJ, Gotzsche PC. Overdiagnosis in publicly organised mammography screen-
ing programmes: systematic review of incidence trends. BMJ [Internet]. 2009;339(jul09
1):b2587–b2587. Available at: https://www.bmj.com/lookup/doi/10.1136/bmj.b2587.
6. Niell BL, Freer PE, Weinfurtner RJ, Arleo EK, Drukteinis JS. Screening for breast cancer.
Radiol Clin N Am. 2017;55(6):1145–62. https://doi.org/10.1016/j.rcl.2017.06.004. PMID:
28991557.
7. Kuhl CK, Schrading S, Leutner CC, Morakkabati-Spitz N, Wardelmann E, Fimmers R, et al.
Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women
at high familial risk for breast cancer. J Clin Oncol. 2005;23(33):8469–76.
8. Liberman L, Morris EA, Benton CL, Abramson AF, Dershaw DD. Probably benign lesions
at breast magnetic resonance imaging: preliminary experience in high-risk women. Cancer.
2003;98(2):377–88.
9. Kriege M, Brekelmans CTM, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, et al.
Efficacy of MRI and mammography for breast-cancer screening in women with a familial or
genetic predisposition. N Engl J Med. 2004;351(5):427–37.
10. de Lange SV, Bakker MF, Monninkhof EM, PHM P, de Koekkoek-Doll PK, Mann RM, et al.
Reasons for (non)participation in supplemental population-based MRI breast screening for
women with extremely dense breasts. Clin Radiol. 2018;73(8):759.e1–9.
11. Berg WA, Zhang Z, Lehrer D, Jong RA, Pisano ED, Barr RG, et al. Detection of breast cancer
with addition of annual screening ultrasound or a single screening MRI to mammography in
women with elevated breast cancer risk. JAMA. 2012;307(13):1394–404.
12. Berg WA. Tailored supplemental screening for breast cancer: what now and what next? AJR
Am J Roentgenol. 2009;192(2):390–9.
13. Thigpen D, Kappler A, Brem R. The role of ultrasound in screening dense breasts—a review of
the literature and practical solutions for implementation. Diagnostics [Internet]. 2018;8(1):20.
Available at: http://www.mdpi.com/2075-4418/8/1/20.
14. Rebolj M, Assi V, Brentnall A, Parmar D, Duffy SW. Addition of ultrasound to mammog-
raphy in the case of dense breast tissue: systematic review and meta-analysis. Br J Cancer.
2018;118(12):1559–70.
15. Sood R, Rositch AF, Shakoor D, Ambinder E, Pool K-L, Pollack E, et al. Ultrasound for breast
cancer detection globally: a systematic review and meta-analysis. J Glob Oncol. [Internet].
2019;(5):1–17. Available at: https://ascopubs.org/doi/10.1200/JGO.19.00127.
16. Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJL, et al.
Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis.
Lancet (London, England); 2011;378(9801):1461–84.
17. Kelly KM, Richwald GA. Automated whole-breast ultrasound: advancing the performance of
breast cancer screening. Semin. Ultrasound, CT MRI [Internet]. 2011;32(4):273–80. Available
at: https://linkinghub.elsevier.com/retrieve/pii/S088721711100031X.
18. Mendelson EB, Berg WA. Training and standards for performance, interpretation, and structured
reporting for supplemental breast cancer screening. Am J Roentgenol. 2015;204(2):265–8.
19. Huppe AI, Mehta AK, Brem RF. Molecular breast imaging: a comprehensive review. Semin
Ultrasound, CT MRI [Internet]. 2018;39(1):60–9. Available at: https://linkinghub.elsevier.
com/retrieve/pii/S0887217117301105.
20. Mathis KL, Hoskin TL, Boughey JC, Crownhart BS, Brandt KR, Vachon CM, et al. Palpable
presentation of breast cancer persists in the era of screening mammography. J Am Coll Surg
S1072751509016196.
21. Tabár L, Vitak B, Chen HH, Duffy SW, Yen MF, Chiang CF, et al. The Swedish Two-County
Trial twenty years later. Updated mortality results and new insights from long-term follow-up.
Radiol. Clin. North Am. 2000;38(4):625–51.
22. Vanier A, Leux C, Allioux C, Billon-Delacour S, Lombrail P, Molinié F. Are prognostic fac-
tors more favorable for breast cancer detected by organized screening than by opportunis-
tic screening or clinical diagnosis? A study in Loire-Atlantique (France). Cancer Epidemiol.
S1877782113001070.
23. Moody-Ayers SY, Wells CK, Feinstein AR. Benign tumors and early detection in
mammography-screened patients of a natural cohort with breast cancer. Arch Intern Med.
American Medical Association;. 2000;160(8):1109–15.
24. Baines CJ, Wall C, Risch HA, Kuin JK, Fan IJ. Changes in breast self-examination behav-
ior in a cohort of 8214 women in the Canadian National Breast Screening Study. Cancer.
1986;57(6):1209–16.
25. Kösters JP, Gøtzsche PC. Regular self-examination or clinical examination for early detection
of breast cancer. Cochrane Database Syst Rev. 2003;2003(2):CD003373.
26. Baxter N, Care CTF on PH. Preventive health care, 2001 update: should women be rou-
tinely taught breast self-examination to screen for breast cancer? CMAJ [Internet].
2001;164(13):1837–46. Available at: https://pubmed.ncbi.nlm.nih.gov/11450279.
27. Hackshaw AK, Paul EA. Breast self-examination and death from breast cancer: a meta-
analysis. Br J Cancer. 2003;88(7):1047–53.
28. Brett J, Austoker J, Ong G. Do women who undergo further investigation for breast screening
suffer adverse psychological consequences? A multi-centre follow-up study comparing dif-
ferent breast creening result groups five months after their last breast screening appointment.
J. Public Health (Bangkok) [Internet]. 1998 1;20(4):396–403. Available at: https://academic.
oup.com/jpubhealth/article-lookup/doi/10.1093/oxfordjournals.pubmed.a024793.
29. MacFarlane ME, Sony SD. Women, breast lump discovery, and associated stress. Health Care
Women Int. 1992;13(1):23–32.
30. Anbar M. Clinical thermal imaging today. IEEE Eng Med Biol Mag. 1998;17(4):25–33.
31. Feig SA, Shaber GS, Schwartz GF, Patchefsky A, Libshitz HI, Edeiken J, et al. Thermography,
mammography, and clinical examination in breast cancer screening. Review of 16,000 studies.
Radiology. 1977;122(1):123–7.
32. Jones BF. A reappraisal of the use of infrared thermal image analysis in medicine. IEEE
Trans Med Imaging [Internet]. 1998;17(6):1019–27. Available at: http://ieeexplore.ieee.org/
document/746635/.
33. Egorov V, Kearney T, Pollak SB, Rohatgi C, Sarvazyan N, Airapetian S, et al. Differentiation of
benign and malignant breast lesions by mechanical imaging. Breast Cancer Res Treat [Internet].
2009;118(1):67–80. Available at: http://link.springer.com/10.1007/s10549-009-0369-2.
34. Garra BS. Imaging and estimation of tissue elasticity by ultrasound. Ultrasound Q
LWW. 2007;23(4):255–68.
35. Moon WK, Chang R-F, Chen C-J, Chen D-R, Chen W-L. Solid breast masses: classification
with computer-aided analysis of continuous US images obtained with probe compression.
Radiology. 2005;236(2):458–64.
12 Screening 257
36. Nyström L, Andersson I, Bjurstam N, Frisell J, Nordenskjöld B, Rutqvist LE. Long-term

effects of mammography screening: updated overview of the Swedish randomised trials.
Lancet. 2002;359(9310):909–19.
37. Falun Meeting, Falun, Sweden OC and C. Breast-cancer screening with mammogra-
phy in women aged 40–49 years. Int J Cancer [Internet]. 1996;68(6):693–9. Available at:
https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0215(19961211)68:6%3C693::
AID-IJC1%3E3.0.CO;2-Z.
38. Mandelson MT, Oestreicher N, Porter PL, White D, Finder CA, Taplin SH, et al. Breast den-
sity as a predictor of mammographic detection: comparison of interval- and screen-detected
cancers. J Natl Cancer Inst. 2000;92(13):1081–7.
39. D’Orsi CJ. 2013 ACR BI-RADS atlas: breast imaging reporting and data system [Internet].
5th ed. American College of Radiology; 2014. Available at: https://books.google.com.br/
books?id=nhWSjwEACAAJ.
40. Ohuchi N, Suzuki A, Sobue T, Kawai M, Yamamoto S, Zheng YF, et al. Sensitivity and speci-
ficity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan
Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet.
2016;387(10016):341–8.
41. Bakker MF, de Lange SV, Pijnappel RM, Mann RM, Peeters PHM, Monninkhof EM, et al.
Supplemental MRI screening for women with extremely dense breast tissue. N Engl J Med.
2019;381(22):2091–102.
42. Kuhl C, Weigel S, Schrading S, Arand B, Bieling H, König R, et al. Prospective multicenter
cohort study to refine management recommendations for women at elevated familial risk of
breast cancer: the EVA trial. J Clin Oncol. 2010;28(9):1450–7.
43. NCCN – National Comprehensive Cancer Network. Breast Cancer Screening and Diagnosis.
In: National Comprehensive Cancer Network (NCCN), editor. NCCN Clinical Practice
Guidelines in Oncology. Version 1.2020 ed; 2020.
Chapter 13
Diagnostic
Karina Belickas Carreiro, Juliana Pierobon Gomes da Cunha,

Jose Roberto Filassi, and Caio Dinelli
13.1 Diagnostic Management of Clinical Situations
13.1.1 Palpable Changes of the Breast

13.1.1.1 Breast Lump
The clinical complaint referred by the patient can be the first indication of the
appearance of breast cancer and should always be valued. The most common clini-
cal complaint is a palpable lump in the breast, but other complaints such as burning
feeling, pain, and changes in color, texture, and appearance of the skin can also be
mentioned. Despite this fact, it should be emphasized that most palpable complaints
correspond to benign lesions in the breasts.
A breast lump is the most frequent presentation of breast cancer, regardless of the
woman’s age. It can be insidious or fast-growing, depending on the characteristics
of the developing tumor. A breast lump is the second most frequent complaint in the
breast surgeon’s office, after breast pain, and is the most frequent complaint pre-
sented by patients with breast cancer.
A study by Barton et al. showed that 16% of the patients in primary healthcare
offices had breast complaints during a 10-year period, with women under 50 years
old having more complaints (twice as much) when compared to the group of women
K. B. Carreiro · J. P. G. da Cunha · J. R. Filassi (*)

C. Dinelli

Switzerland AG 2022
260 K. B. Carreiro et al.
over 50 years old, and the diagnosis of cancer was made in 23 of the 372 women
who presented symptoms (6.2%) [1].
Another palpable complaint that can be a symptom of cancer is breast thicken-
ing. This one differs from a mass as it does not have a three-dimensional configura-
tion and presents itself differently from surrounding breast tissues on palpation and
does not have a similar area in the contralateral breast, being asymmetrical.
Thickening is associated with breast cancer about 5% of the time.
The masses and thickenings associated with breast cancer are ill-defined, are
hardened, and may be attached to the skin or muscular plane and may be associated
with changes in the skin and papillae, such as retraction.
Because many breast masses may not exhibit distinctive physical findings, imag-
ing evaluation is necessary in almost all cases to characterize the palpable lesion.
Any woman presenting with a palpable lesion should have a thorough clinical breast
examination, usually by the referring clinician or by a clinical breast specialist, but
the radiologist must also be able to establish a concordance between an imaging
finding and a clinically detected mass [2].
When a suspicious finding is identified, an image-guided biopsy is indicated. It
is preferable to do imaging examinations before biopsy, as changes related to the
biopsy may confuse, alter, obscure, and/or limit image interpretation. The negative
predictive value of mammography with ultrasound (US) in the context of a palpable
mass ranges from 97.4% to 100% [2]. Nevertheless, a negative imaging evaluation
should never overrule a strongly suspicious physical examination finding or vice
versa. Any highly suspicious breast mass detected by imaging or palpation should
undergo biopsy unless there are exceptional clinical circumstances such as the sig-
nificant comorbid conditions presented by the patient.
Diagnostic mammography is indicated for women aged 40 years and over who
present a palpable lump. In several series evaluating palpable breast abnormalities,
the sensitivity of mammography alone was 86–91%, depending on the breast den-
sity (Fig. 13.1). If a clearly benign correlate for a palpable finding (oil cyst,
a b c d
Fig. 13.1 Breast composition on mammography – comparison of breast density: (a) Almost
entirely fatty. (b) Scattered areas of fibroglandular density. (c) Heterogeneously dense. (d)
Extremely dense
13 Diagnostic 261
hamartoma, degenerating fibroadenoma, lipoma, benign lymph node) can be identi-

fied on mammography, this modality alone may be sufficient and clinical follow-up
rather than imaging follow-up or tissue sampling is appropriate [3, 4].
The diagnostic mammography technique is similar to screening mammography
and may include complementation with additional views (true lateral view, magni-
fication, and localized spot compression for instance), identification of the palpable
complaint with a radiopaque marker (Fig. 13.2), and complementation with tomo-
synthesis if available [5].
If mammography is negative or an imaging correlate is identified that is not
clearly benign, multimodality imaging is usually indicated, with targeted US
directed toward the palpable finding [6] (Fig. 13.3). In most of these cases, supple-
mental ultrasound is helpful to further characterize the lesion.
In women younger than 40 years old, pregnant or lactating women, ultrasound
should be used as the initial approach to a palpable complaint. Ultrasonography
allows real-time image evaluation, can be correlated with mammography, and can
Fig. 13.2 A 30-year-old

patient with a palpable
lump in the right breast.
Mammography shows the
skin marker (radiopaque
triangular marker) in the
topography of a palpable,
oval, and circumscribed
mass. Histologically
proven fibroadenoma
a b
Fig. 13.3 Mammography and magnetic resonance imaging (MRI). (a) Mammography was nega-
tive for suspicious findings. (b) MRI (T1W post-contrast image) showed an irregular mass with
homogeneous enhancement in the left breast. (c) Second-look ultrasound showed an irregular
hypoechogenic mass with indistinct margins. Histologically proven grade 3 ductal carcinoma in
situ (DCIS)
also assess superficial cutaneous and subcutaneous lesions with the use of high-
frequency transducers and appropriate techniques.
In addition, younger women also tend to have relatively denser breast tissue,
which is associated with decreased mammographic sensitivity [6]. However, in the
event of a suspicious finding, mammography or digital breast tomosynthesis (DBT)
is warranted even in younger women to better delineate disease and identify features
of malignancy that may be seen on mammography or DBT alone.
If a palpable lump can be definitively characterized as benign on US (e.g., simple
cyst, benign lymph node, duct ectasia, lipoma), clinical follow-up is the appropriate
management, and imaging follow-up or tissue sampling is not indicated.
To improve the sensitivity and specificity, the combined use of diagnostic mam-
mography and ultrasonography in palpable lesions has been recommended [2]. The
combination of these two imaging modalities increases true positive rates and
13 Diagnostic 263
allows the detection of masses hidden by dense tissue on mammography. When

both tests are negative or show benign findings when assessing a palpable mass, the
negative predictive value (NPV) is quite high (> 97%).
The presence of palpable masses with a benign feature on ultrasound has been
evaluated in the literature, and it is known that the incidence of cancer in these situ-
ations ranges from 0% to 6% but most recent studies indicate an incidence of less
than 2%, which would justify its semiannual sonographic follow-up, in a population
ideally below 40 years old. In situations of palpable masses in women over 40 years
old, with a high family or personal risk of breast cancer, and male patients, masses
with documented significant growth or suspicious appearance in any of the imaging
exams, a biopsy is always indicated [7].
Breast tomosynthesis added to the mammographic technique appears as an
option for breast imaging that eliminates overlapping tissues [5]. In tomosynthesis,
multiple projections are obtained while the x-rays emitted by the source follow a
pre-defined semicircular angulation; the angle used varies according to the manu-
facturer; the projections obtained (slices) can still be reconstructed in a synthesized
mammographic image, depending on the software model. The radiation dose of the
method associated with digital mammography, both performed in a single time,
does not exceed the average safe glandular dose [5].
A significant number of prospective studies and some retrospective studies com-
pared the total field digital mammography alone with the total field digital mam-
mography associated with tomosynthesis [8–10]; the results obtained show an
increase of about 30% in the breast cancer detection rate, especially in the invasive
form, and a decrease in the false-positive results of mammography, consequently
reducing the recall rates when tomosynthesis is used. The addition of this technique
to mammography shows evidence of increased specificity and sensitivity for inva-
sive tumors. The most evident findings detected by tomosynthesis are architectural
distortions and focal asymmetries. In the case of calcifications, these are better visu-
alized by digital mammography, and tomosynthesis does not add significant benefit.
Digital breast tomosynthesis (DBT) can ease some of the limitations encoun-
tered with standard mammographic views. In addition to planar images, DBT allows
the creation and viewing of thin-section reconstructed images that may decrease the
lesion-masking effect of overlapping normal tissue and reveal the true nature of pos-
sible false-positive findings. DBT was evaluated predominantly in the screening
setting, but it also proved to be useful in the diagnostic setting as well, improving
lesion characterization in noncalcified lesions in comparison with the conventional
mammographic workup [3, 11, 12].
In symptomatic patients setting, DBT demonstrated better diagnostic accuracy
compared to 2D mammography, an improved reader confidence in distinguishing
benign from malignant lesions, and higher accuracy in assessing tumor size and
identifying multifocal diseases [13] (Fig. 13.4). New equipment are also available
for image-guided biopsy using DBT guidance.
Several studies have specifically included women presenting clinical symptoms
as palpable lumps, with promising results [4, 11, 12]. The diagnostic accuracy of
one-view breast tomosynthesis in the diagnostic workup of women with clinical
a b
Fig. 13.4 A 42-year-old patient screening mammography with tomosynthesis. (a) Conventional
2D mammography was negative for suspicious findings. (b) Tomosynthesis showed an area of
architectural distortion in the outer upper quadrant of the left breast (circle). Histologically proven
grade 2 invasive lobular carcinoma
signs and symptoms and in women recalled from screening has also been shown to
be equivalent to or better than supplemental diagnostic mammographic views in
several studies [11, 14]. DBT can be used with or without spot compression views
in the diagnostic context.
Interpretation time for DBT images is greater than for standard mammography
[14, 15]. Additionally, the dose is increased if standard 2D images are obtained in
addition to DBT images. However, synthesized reconstructed images (a virtual pla-
nar image created from the tomographic data set) may replace the need for a 2D
correlate view, and current data suggest that these synthetic images perform as well
as standard full-field digital images [14, 16].
13 Diagnostic 265
In summary, mammography or DBT may be helpful in women between 30 and

39 years old as well as in women younger than 30 years old with palpable masses [5].
Although magnetic resonance imaging (MRI) can be used to assess patients with
a palpable mass, it is not the method of choice to start the investigation, and its indi-
cation is more suitable for cases in which the palpable lesion is already defined as
malignant, in order to assess the extent of disease [2].
In general, it is more cost-effective to use mammography or DBT and US as
initial imaging examinations. There are few studies that evaluate the efficacy of
MRI specifically in the setting of palpable lesions. A recent study from Moy et al.
evaluating MRI workup for conventional imaging BI-RADS 0 cases included 29
palpable masses and found a sensitivity of 100% and specificity of 74% for this
palpable lesion subset [2].
MRI may be of value in the very specific circumstance of distinguishing between
scarring and recurrent disease in the context of a post lumpectomy patient with a
palpable lump at the surgical site and inconclusive conventional imaging findings;
however, the evidence for this indication is not well established. In addition, breast
MRI without intravenous contrast has no role in the evaluation of a woman with a
palpable breast mass.
In patients with a biopsy-proven breast cancer, MRI may be used to assess the
extent of disease and detect additional lesions in the same quadrant (multifocal), in
different quadrants (multicentric) or in the contralateral breast potentially impacting
patient management. In this context, MRI is more useful than mammography and
US in the staging of multifocal and multicentric disease or when DCIS is present. In
addition, numerous studies have shown that MRI is superior to mammography and
US for assessing tumor size, although there are still over- and underestimation in up
to 15% of patients.
Magnetic resonance imaging may also detect cancers that were occult on mam-
mography and/or sonography in the contralateral breast in approximately 3% of
women with unilateral cancer detected by mammography or US. The detection of
these initially unsuspected tumors may have a greater impact on patient outcomes
than the detection of additional ipsilateral tumor foci since they would not be treated
with concomitant radiation therapy [17].
13.1.1.2 Paget Disease
Since 1307 breast lesions have occurred similar to what we now recognize as Paget’s
breast disease, but which were only described as such in 1874 by Sir James Paget.
Clinically, it corresponds to a lesion in the nipple-areola complex (NAC) repre-
sented by eczema, erythema, pruritus, and ulceration. Unlike papillary lesion due to
invasion of the underlying tumor, Paget’s breast disease is characterized by the cell
described as large, pale-staining cells with round or oval nuclei and prominent
nucleoli. It is considered a rare pathology, comprising 1–4% of cases of malignant
breast disease [18].
In a paper published by Fu et al., 41 cases of Paget’s disease treated at Providence

Hospital & Medical Centers from 1980 to 1999 were analyzed. Of these patients, 17
had a palpable mass at diagnosis, which resulted in an invasive lesion in 100% of
cases and positive axillary lymph node in 70%. Among the 24 patients who did not
have a palpable mass, 30% had invasive lesions, 66% only ductal carcinoma in situ,
and only 1 Paget’s disease. The lymph node involvement in these patients reached
30% [19].
Song et al. analyzed 72 cases seen between 1991 and 2010 in their service in
Wuhan, China, among which 60% had palpable masses; 25% suspected axillary
lymph nodes, with the final histologic result of 45 cases associated with invasive
carcinoma; 12 cases of ductal carcinoma in situ; and 9 cases with isolated Paget’s
disease. Of the total number of patients, there were 34 with affected axillary lymph
node, 32 with invasive disease, and 2 with in situ disease. None of the patients with
isolated Paget’s disease had axillary involvement [20].
Although it is a noninvasive disease, about 8% of cases may present invasion of
the basement membrane by Paget cells, being important to differentiate it from inva-
sive diseases with skin involvement, due to the diverse prognosis between strains.
Lee et al. in a retrospective study with 205 cases of breast Paget’s disease identified
16 cases of invasive Paget’s disease, of which 12 had invasive carcinoma and 3
associated ductal carcinomas in situ in another location of the breast. The compari-
son between cases with and without nipple invasion did not show worsening of
prognosis during the follow-up of patients [20].
The evaluation using imaging methods is important for the identification of other
breast lesions that may be associated, without alterations in the clinical examina-
tion, and for assessing the extent of involvement of the nipple-areola complex
(NAC) (Fig. 13.5) [21]. Zakaria et al. published a retrospective study, with data col-
lected between 1975 and 2000, including 86 patients diagnosed with Paget’s disease
of which 82 had data from the preoperative clinical evaluation and mammography.
All patients with suspected mammographic and clinical findings including nipple
complaints had invasive disease confirmed in the final specimen histology. Among
patients without clinical changes, but with suspected mammographic findings, 93%
had an additional malignant lesion in the breast, 45% of which was invasive, and
48% in situ. Even in the group in which neither clinical changes nor suspicious
mammographic alterations were observed, there was an occurrence of 73% of pre-
viously undiagnosed lesions, being 68% in situ and 5% invasive [22].
Morrogh et al. published a series at the Memorial Sloan Kettering Cancer Center
in which 69 patients with NAC-related breast complaints were selected from 2294
patients who sought the service for various breast complaints, without a previous
diagnosis of cancer. Of the 69 patients submitted to NAC biopsy, 34 confirmed a
diagnosis of Paget’s disease. All patients underwent mammography to assess the
extent of disease and to assess additional lesions, yielding 67% lesions character-
ized as BIRADS 3 and 33% lesions characterized as BIRADS 4 or 5. All BIRADS
3 patients underwent surgery (total of 15) or underwent complementary MRI (total
13 Diagnostic 267
a b
Fig. 13.5 A 63-year-old patient with Paget’s disease of the right breast. (a) The mammography
showing a diffuse thickening of the nipple-areola complex and fine pleomorphic calcifications in
segmental distribution in the breast extending to the nipple. Histologically proven grade 3 DCIS.
(b) Mammmographic magnification view showing pleomorphic calcifications in segmental
distribution
of 8), and all patients with suspected lesions had a histological confirmation of an
additional malignancy. Among the patients submitted to MRI, 50% had biopsy-
proven suspicious lesions. The remaining four patients had confirmation of malig-
nancy only in the final histological result from surgical specimen analysis. This
work was able to demonstrate the possibility of an adequate surgical scheduling.
The surgical procedures were divided into 21 mastectomies and 17 conservative
surgeries, of which only 4 were converted to mastectomy after the final result. 59%
of patients had disease only in the central breast sector [23].
Although Paget’s disease affects only NAC and is almost exclusively in situ, it
can present invasion of the basement membrane and lymph node involvement, influ-
encing directly the proposed treatment. In addition, associated malignant lesions are
often associated with Paget’s disease, and proper assessment of the rest of the breast
tissue is essential. Patients with suspected lesions on clinical examination are usu-
ally diagnosed with associated malignancy. Even those patients with no palpable
changes should undergo mammography and eventually MRI, to define the extent of
disease and look for additional lesions that need attention during treatment.
13.1.1.3 Occult Breast Cancer and Axillary Lymphadenopathy
Axillary lymph nodes receive drainage from the arm, chest wall, and breast, that is,
any benign or malignant pathology that occurs in these regions may be associated
with local lymphadenopathy. Some neoplastic diseases may also be associated with
the involvement of axillary lymph nodes, even from distant sites, such as primary
tumors of the pancreas, ovary, and bladder, in addition to lymphoma itself. We call
it occult breast carcinoma when there is a metastatic axillary lesion with immuno-
histochemistry pointing to the breast as the primary tumor, with no changes in clini-
cal or radiological examination (Fig. 13.6). The most commonly used radiological
evaluation is mammography and ultrasound, but nowadays MRI shows better per-
formance in detecting the primary tumor.
The incidence of occult breast carcinoma was around 0.3–1.0% between the
1950s and 1980s, as shown by the survey by Ge et al. in which the main radiological
exam for breast investigation was mammography [24]. However, in a 2017 publica-
tion, Hessler et al. published their own statistics based on the National Cancer
Database (NCDB). The NCDB is a clinical oncology database sponsored by the
a b
Fig. 13.6 Occult breast carcinoma in a 34-year-old patient with BRCA1 mutation presenting with
palpable lumps in the left axilla. (a) Mammogram shows multiple enlarged axillary lymph nodes.
No suspicious findings in the breast. (b) MRI (T1W post-contrast image with subtraction) of the
same patient shows multiple round lymph nodes with obliteration of the fatty hilum and heteroge-
neous enhancement. No suspicious enhancements were found in the breast. Histology of axillary
lymph nodes: metastatic triple-negative breast carcinoma
13 Diagnostic 269
American College of Surgeons and the American Cancer Society. In this study, they
found an incidence of 0.1%, with an analysis carried out between the years 2004
and 2013, with 1853 patients [25]. With the evolution of imaging exams and
improved resolution of the images generated by the mammographic and ultrasound
devices, in addition to the beginning of the MRI exams, it was possible to identify
the primary breast lesions that were not possible before.
Vlastos et al. published a survey carried out at MD Anderson of patients treated
at these sites with a metastatic axillary disease, with no specific primary site. Of the
479 identified patients, 45 were considered to be primarily of breast origin. The
inclusion criteria were lymph node biopsy with histological diagnosis of adenocar-
cinoma or undifferentiated or unclassified carcinoma. All patients underwent surgi-
cal treatment, with 13 having mastectomies and 32 breast-conserving surgeries. The
proposed conservative surgery was the resection of the superolateral quadrant of the
breast, which is a denser region with the highest prevalence of breast tumors, com-
prising about 50%. It was possible to identify among the patients who underwent
mastectomy 1 case of invasive tumor and 1 case of Paget’s disease. Among the
patients who underwent conservative surgery, 10 cases of malignant disease were
identified, not stratified as invasive or in situ [26].
Within breast assessment, one factor that makes it difficult to diagnose breast
lesions is the localization in the axillary tail or accessory mammary gland. However,
MRI sensitivity can reach 95%, after negative mammography, ultrasound, and clini-
cal examination, and 71% specificity, as demonstrated in a 2011 study [27].
Currently there are studies that question the existence of ectopic breast tissue in
axillary lymph nodes, which would characterize occult carcinoma in this way, but
with the possibility of definition only after surgery for histological confirma-
tion [28].
Axillary metastasis can arise from the breast or any other extra-mammary site,
requiring histological and immunohistochemical assessment to define the primary
lesion. When compatible with breast origin without clinical evidence on physical
examination, complementary radiological examinations are essential to search for
the primary lesion. The initial workup consists of conventional imaging evaluation
with mammography and ultrasound, and complementation with MRI when conven-
tional imaging is negative. There are studies that include positron emission tomog-
raphy (PET) scan, but this is not part of the initial recommendation for investigation
yet [29].
13.1.2 Non-palpable Breast Changes
13.1.2.1 Image Screening Findings
The aim of mammographic screening is to reduce mortality rates from breast can-
cer through early detection compared to cancers diagnosed clinically at a later
stage. Despite ongoing controversy, the effectiveness of mammographic screening
and the importance of diagnosing breast cancers at an early stage have been empha-
sized [30]. It is known that current screening with 2D digital mammography
(2DDM) detects some cancers that might not cause symptoms during the woman’s
natural life. This has been termed “overdiagnosis,” and the frequency of detecting
such cases has been discussed in the independent review of breast screening.
Screening with DBT will detect even more breast cancers at an earlier stage in
some cases [5].
The accuracy of 2DDM screening is limited because of the effect of overlapping
of normal breast structures and abnormal features on a two-dimensional image. The
mammographic signs of breast cancer may be partially or completely obscured,
particularly in women with a dense glandular parenchymal pattern on mammogra-
phy, leading to delays in the diagnosis of breast cancer.
DBT demonstrates mammographic characteristics of soft-tissue lesions better
than 2DDM, which leads to improved diagnostic accuracy, more accurate workup
of soft-tissue lesions, and better local staging, with performance shown to be even
more beneficial in women with dense breasts. There is improved interpretive perfor-
mance of DBT in the detectability of invasive lobular cancers that present as distor-
tions and spiculations as these lesions are more conspicuous on DBT.
Conversely, well-defined margins of benign lesions are more clearly demon-
strated, potentially eliminating the need for biopsy and reducing recall rates. The
better visibility of the margins of soft-tissue lesions improves the ability of the radi-
ologist to distinguish between benign and malignant masses [5, 8, 31]. Circumscribed
masses may also show a halo sign on DBT. For soft-tissue lesions, DBT improves
the classification of the mammographic features seen on 2DDM and the accuracy of
predicting malignancy.
In the largest retrospective study involving 7060 subjects, the TOMMY trial, the
addition of DBT improved sensitivity in women with dense breasts (93% versus
86% for DBT versus 2DDM, in women with breast density of 50% or more;
p1/40.03). Specificity was significantly improved in all subgroups (57% for 2DDM,
70% for 2DDM + DBT; p < 0.001 in both cases) [9].
13.1.2.2 Nipple Discharge
Nipple discharge corresponds to the majority of complaints from patients who seek
breast surgeons, with an incidence of 2.5–5% [32–34]. Nipple discharge can be
spontaneous or provoked, uniductal or multiductal, unilateral, or bilateral and can
have several presentations: serous, bloody, milky, greenish, or transparent. The flow
can be secondary to organic or structural causes. Among the organic causes, we can
highlight the postpartum pregnancy cycle, metabolic changes, and the use of medi-
cations. Normally, in these situations, the flow is multiductal and bilateral and with
a dairy aspect. In the case of structural changes, the flow most commonly presents
itself as unilateral, with uni or multiductal secretion output, and can be spontaneous
or provoked [35]. Among the most frequent causes of nipple discharge due to ana-
tomical changes are papilloma (35–48%), carcinoma (5–21%), and ductal ectasia or
13 Diagnostic 271
fibrocystic changes (3–50%), but it varies greatly between studies according to the
type of complaint and clinical and radiological alteration included [32].
The initial assessment of patients with complaints of nipple discharge must con-
tain clinical history and physical examination, in order to better characterize the
flow and identify possible tangible changes. In the case of palpable complaints, it is
possible to perform an examination directed to the site, through ultrasound or mam-
mography. In cases of absence of palpable lesions, there is the benefit of evaluation
by means of MRI [36]. Ductography is an evaluation of the affected duct through
the injection of iodinated contrast and, afterwards, mammography with subareolar
magnification to view possible defects of the ductal tree (Fig. 13.7). It is able to
identify single or multiple lesions, in addition to peripheral lesions when the affected
duct is well identified [33].
Adepoju et al. evaluated 168 cases of patients with spontaneous and uniductal
papillary flow, of which 85% were bloody. Mandatory mammography, physical
examination, and evaluation by complementary ductography and ultrasound, if the
team considered it opportune, were performed before ductal resection to evaluate
the etiology and its imaging correlation. Malignant lesions were diagnosed in 12%
of cases and high-risk lesions in 11%. The mean age of patients with benign changes
was 51 years old, with high-risk lesions 57 years old and malignant lesions 69 years.
The sensitivity and specificity of ultrasound and mammography ranged from 10%
to 35% and 68% to 94%, respectively, in high-risk and malignant lesions.
Ductography, when performed, showed sensitivity and specificity of 75% and
49–53%, respectively, for high-risk and malignant lesions, but showed some limita-
tions as scarcity of places and professionals able to perform the procedure, in
Fig. 13.7 Ductography in a 72-year-old patient with bloody nipple discharge in the left breast
showing a filling defect (circle). Histologically proven intraductal papilloma
addition to anatomical variations that may make it impossible, such as ductal atro-
phy secondary to age [37].
Currently, the use of ductography has been questioned due to the discomfort
potentially caused by duct catheterization and contrast injection, in addition to the
need for a trained staff for the exam. Consequently, Baydoun et al. published an
article evaluating 94 patients retrospectively, who underwent ductography between
January 2005 and October 2010. The indications for the exam consisted of a woman
with a negative image exam but with a persistent or bloody discharge in a 1-month
clinical follow-up, and the biopsy result of an identified lesion was incongruous
with the clinic or in a presurgical evaluation. In case the ductography was not per-
formed properly or if it was negative, the patient was referred for contrast MRI
exam (a total of 12 exams). Seven malignant lesions were identified (5 DCIS and 2
Invasive cancers) and 3 premalignant lesions (atypical hyperplasia). Comparing the
exams, the sensitivity of mammography, ultrasound, and ductography were, respec-
tively, 13%, 73%, and 76%. The low number of MRI performed in this study pre-
cluded the comparison with other modalities, but its sensibility appeared to be
comparable to ductography (Fig. 13.8) [38].
Bahl et al. in a retrospective study evaluated a group of 118 women with papil-
lary flow complaints with at least one of these characteristics: unilateral bloody,
serous, or spontaneous. In these women, an evaluation with contrast MRI was per-
formed after a negative mammography and ultrasound. Four cases of DCIS and two
cases of invasive cancer not previously identified were diagnosed but with two false
negatives cases (two cases of BIRADS 3 biopsied during the follow-up) [39].
Sanders et al. in a retrospective study evaluated 200 women with bloody nipple
discharge with negative mammographic and ultrasound evaluation who would
undergo duct resection. A total of 115 patients were submitted directly to surgery,
and 85 underwent contrast MRI before. In both groups, the incidence of malignant
breast cancer was 7%, and in the MRI group, only one case of false negative was
identified (the final histological result of low-grade ductal carcinoma), but three
malignant lesions were identified in the contralateral breast. The main causes for
a b
Fig. 13.8 A 46-year-old patient with bloody nipple discharge. (a) MRI (post-contrast subtracted
image) shows a linear ductal enhancement in the left breast. (b) Second-look ultrasound depicted
an intraductal mass with vascular flow on Doppler imaging. Biopsy proven Intraductal papilloma
13 Diagnostic 273
papillary flow were papilloma, periductal inflammation, ectasia/ ductal hyperplasia,

and fibrocystic disease [39].
Based on the literature, patients with suspected nipple discharge, which are, uni-
lateral, uni- or multiductal, persistent, or spontaneous, associated with changes in
physical examination, should undergo a targeted imaging examination to assess the
flow etiology. If there is no palpable change, this radiological evaluation is indicated
in order to determine possible non-palpable intraductal changes. Among the exams
that can be performed, mammography and ultrasound can be included, and if these
tests are negative, complementation with MRI is indicated. Ductoscopy can be per-
formed to identify small lesions; however, a trained team is required to perform this
procedure as it can cause discomfort to the patient associated with the exam. It is
important to highlight that even the most complex changes in papillary flow are
commonly associated with benign lesions, such as adenomas and papillomas.
Whenever there is a suspected lesion after radiological evaluation, histological
evaluation of the alteration is necessary. It is possible to choose the evaluation
through biopsies guided by the imaging method responsible for identifying the
alteration or surgical biopsy, when a diagnosis was not possible.
13.1.3 Breast Biopsy in Clinical Scenario
If a suspicious mass has been identified on mammography, DBT, MRI, or US, tissue
sampling is warranted except in rare circumstances (e.g., if the patient has comor-
bidities that would contraindicate biopsy). If a lesion is seen equally well on mam-
mography and US, US guidance is preferred because of patient comfort, efficiency,
economy, absence of ionizing radiation, and sampling accuracy due to real-time
visualization of the needle within the lesion.
13.1.3.1 S and Mammography-Guided Biopsy (Fine-Needle Aspiration

U
(FNA)/Core-Needle Biopsy (CNB)/Vacuum Aspiration
Biopsy (VAB))
Although some practices demonstrate very good results using fine-needle aspiration
(FNA) biopsy as the first means of diagnostic evaluation of a palpable breast mass,
especially if a cytopathologist is available to interpret results in real time [16, 40],
larger series demonstrate that core biopsy is superior to FNA in terms of sensitivity,
specificity, and correct histological grading of palpable masses [41]. Core biopsy is
therefore recommended in most cases. Either stereotactic or DBT (x-ray) or US
guidance can be used for core biopsy, especially if the mass is vaguely palpable,
small, deep, or mobile or if there are multiple lesions [40]. Even when a lesion is
clinically palpable, image-guided biopsy has advantages over tissue sampling by
palpation, allowing confirmation of biopsy accuracy and the possibility to place a
post-biopsy marker clip.
The decision to perform surgical excisional versus percutaneous biopsy should

involve the patient and her healthcare provider. However, image-guided core-needle
biopsy has become the procedure of choice for most image-detected breast lesions
requiring tissue diagnosis. Its advantages over surgical biopsy are well recognized,
including less scarring, fewer complications, faster recovery, lower cost, and similar
accuracy.
The cytological or histological diagnosis of suspected breast lesions by fine-
needle aspiration cytology (FNAC)/core needle biopsy (CNB) has the advantage of
allowing surgical planning or scheduling of neoadjuvant therapies for patients with
malignancies and limiting the number of surgeries for patients who do not have a
malignant disease. Concerning the preoperative assessment of breast cancer, both
CNB and FNA are promising tools for the nonoperative pathological diagnosis of
breast cancer. Nevertheless, FNA and CNB are methodologically different and have
their advantages and disadvantages [16, 41, 42].
FNA is a diagnostic procedure in which a pathologist or radiologist or surgeon
uses a very thin needle (usually 22 to 25 gauge) connected to a vacuumed syringe to
aspirate a small amount of tissue from the suspicious area. FNA was first introduced
by Martin and Ellis in 1930. Its use to detect breast lesion became increasingly
important from the 1980s as a diagnostic adjunct in the population-based screening
setting. FNA is a safe, economical, effective, and accurate technique, but its efficacy
largely depends on the experience of those who perform the procedure and
pathologists.
CNB is a technique that usually performed by a radiologist or surgeon using a
large, hollow needle (a special 8–16 gauge) to withdraw small tissue fragments
from the abnormal area in the breast. CNB was introduced as an assessment tool in
the late 1990s. In addition to its high accuracy, CNB provides more material for
grading tumors and for assessing predictive factors like hormone receptor status and
HER2 (human epidermal growth factor receptor 2) status. On the other hand, it is
more expensive and more invasive than FNA and has a rare but potential risk of
track seeding in the biopsy path.
In most of the varied clinical studies, in general but not invariably, CNB has both
higher sensitivity and specificity than FNA in diagnosing suspicious lesions, e.g.,
sensitivity and specificity values can range from 35% to 95% and 48% to 95% for
FNA and 85% to 100% and 86% to 100% for CNB, respectively [42, 43].
Although thousands of people with suspected breast lesions have been enrolled
in diagnostic studies for breast cancer by using FNA and/or CNB, no formal quan-
titative review of the available evidence has been published to comprehensively
compare the accuracy performance of those two techniques. Nowadays, the use of
FNA is in decline due to its limitations and its replacement by CNB, but it still
remains as an important modality as FNA is fast, convenient, and economical [40].
Wang et al. studied 1802 patients and showed in a pooled analysis that the sensi-
tivity of CNB is better than of FNA [87% (95% CI, 84%e88%, I2 1/4 88.5%) versus
74% (95% CI, 72%e77%, I2 1/4 88.3%)] and the specificity of CNB is similar to
FNA [98% (95% CI, 96% e99%, I2 1/4 76.2%) versus 96% (95% CI, 94%e98%, I2
1/4 39.0%)]. For subgroup analysis, the sensitivities of both tests are better for
13 Diagnostic 275
palpable lesions than for non-palpable lesions. The study suggests that both FNA
and CNB have good clinical performance. In similar circumstances, the sensitivity
of CNB is better than that of FNA, while their specificities are similar. FNA could
be still considered the first choice to evaluate suspicious non-palpable breast
lesions [42].
Under stereotactic guidance, vacuum-assisted biopsy (VAB) has proven to be
more effective than CNB and less invasive than surgical excision of breast lesions.
VAB is being increasingly utilized as an alternative to stereotactic-guided CNB. The
advantages include biopsy of lesions only visible on DBT/2DDM, low-density
lesions or lesions only identifiable on one view, fewer exposures required, better
technical accuracy in localizing masses, distortions, and asymmetrical densities.
Several studies have shown superior accuracy in lesion targeting and a lower com-
plication rate [5, 44].
13.1.3.2 MRI- and DBT-Guided Biopsy
The result of the widespread use of MRI in breast diagnostics is an increase in inci-
dental findings. Because of the high sensitivity and lower specificity of breast MRI,
it is imperative that these findings be histologically assessed before any surgical
intervention [41, 45].
The first step to investigate any MRI abnormalities should be a second-look tar-
geted US. The efficacy of the second-look US is reported between 23% and 71%,
with a malignancy detection rate of 15–56% [44, 45]. Larger enhancing masses and
BIRADS 5 (highly suspicious for malignancy) lesions are more readily identified
on a second-look targeted US, with a detection rate estimated between 25% and
62%; however, certain types of MRI lesions, such as non-mass enhancement or
small foci less than10 mm, are less likely to have a US correlate, with a detection
rate ranging from 11% to 42%. In a positive sonographic correlation, it is better to
perform intervention under US guidance instead of MRI, because it is simpler,
faster, and more cost-effective than MRI.
The possible MRI-guided interventions are wire localization of breast lesions
followed by a surgical biopsy, CNB, and VAB [44].
Wire localization was one of the earliest procedures to be attempted under MR
guidance. The technique has been performed freehand and with guidance systems
in open and closed magnets with patients in supine, prone, and prone oblique posi-
tions. The relatively large surgical specimen reduces the chance of sampling error
and compensates for some inaccuracy of needle placement. In a series of 101
patients, Eby et al. reported placement of the needle tip within 10 mm of the target
in 53% of cases and between 11 and 20 mm in 46% of cases with successful exci-
sion in 100% [45].
CNB under MRI guidance also requires an extremely accurate targeting tech-
nique. Postfire sequences should demonstrate the needle within the target. Therefore,
the patient must be scanned with the device in place. To achieve this goal, MRI-
compatible CNB devices must be composed of nonferrous alloys including various
a b
Fig. 13.9 MRI-guided biopsy in a 39-year-old patient with Li-Fraumeni syndrome. (a) Pre-biopsy
image (T1W post-contrast image) shows an irregular mass with heterogeneous enhancement in the
left breast. (b) Post-biopsy image (T1W post-contrast) shows a dark linear structure extending
from the biopsy site to the lateral skin, corresponding to the artifact of the biopsy needle.
Susceptibility artifacts from gas bubbles and tissue marker are also seen on the biopsy site.
Histologic result: grade 1 tubulo lobular carcinoma
amounts of titanium and nickel. As a result of the advances and refinements, MRI-
guided CNB is considered both safe and accurate with published reports of a high
rate of technical success (95–100%) and cancer yields (20–38%) comparable to the
accepted rates reported in mammographic- and sonographic-guided procedures.
The Mammotome (Ethicon Endo-Surgery) is an 11-gauge MRI-compatible VAB
system. It was the first system to be developed and subsequently proved that VAB is
possible under MRI guidance (Fig. 13.9). Clinical studies in Europe have demon-
strated successful VAB in 98% of 341 lesions and have identified important barriers
to the more widespread use of this technology, including needle artifact, tissue dis-
placement during probe insertion, and washout of contrast enhancement during the
procedure. These challenges limited the application of this early technology to
lesions larger than 10 mm in diameter.
DBT-guided breast biopsy has been developed both for use with standard DBT
mammographic equipment and dedicated prone table apparatus, often combined
with stereotaxis. It is essential for lesions seen only with DBT and may be used as
an alternative to stereotactic-guided VAB for both sonographically occult and soft-
tissue lesions with micro-calcifications [44].
References
1. Barton MB, Elmore JG, Fletcher SW. Breast symptoms among women enrolled in a
health maintenance organization: frequency, evaluation, and outcome. Ann Intern Med.
1999;130(8):651–7. https://doi.org/10.7326/0003-4819-130-8-199904200-00005.
13 Diagnostic 277
2. Moy L, et al. ACR appropriateness criteria® palpable breast masses. J Am Coll Radiol.
2017;(5S):S203–S224. https://doi.org/10.1016/j.jacr.2017.02.033.
3. Ciatto S, Houssami N. Breast imaging and needle biopsy in women with clinically evi-
dent breast cancer: does combined imaging change overall diagnostic sensitivity? Breast.
2007;(4):382–6. https://doi.org/10.1016/j.breast.2007.01.007.
4. Murphy IG, et al. Analysis of patients with false negative mammography and symptomatic
breast carcinoma. J Surg Oncol. 2007;16(4):382–6. https://doi.org/10.1002/jso.20801.
5. Michell MJ, Batohi B. Role of tomosynthesis in breast imaging going forward. Clin Radiol.
2018;73(4):358–71. https://doi.org/10.1016/j.crad.2018.01.001.
6. Durfee SM, et al. Sonographic evaluation of clinically palpable breast cancers invisible on
mammography. Breast Journal. 2000;6(4):247–51. https://doi.org/10.1046/j.1524-4741.2000
.99111.x.
7. Gilbert FJ, Pinker-Domenig K. Diagnosis and staging of breast Cancer: when and how to
use mammography, tomosynthesis, ultrasound, contrast-enhanced mmmography, and
magnetic resonance imaging; 2019 Feb 20. In: Hodler J, Kubik-Huch RA, von Schulthess
GK, editors. Diseases of the Chest, Breast, Heart and Vessels 2019–2022: Diagnostic and
Interventional Imaging [Internet]. Cham (CH): Springer; 2019. Chapter 13. https://doi.
org/10.1007/978-3-030-11149-6_13.
8. Greenberg JS, et al. Clinical performance metrics of 3D digital breast tomosynthesis com-
pared with 2D digital mammography for breast cancer screening in community practice. Am J
9. Gilbert FJ, et al. The TOMMY trial: a comparison of TOMosynthesis with digital mammog-
raphy in the UK NHS breast screening programme – a multicentre retrospective reading study
comparing the diagnostic performance of digital breast tomosynthesis and digital mammogra-
phy with. Health Technol Assess. 2015;19(4):i–xxv, 1–136. https://doi.org/10.3310/hta19040.
10. Vedantham S, et al. Digital breast tomosynthesis: state of the art1. Radiology.
11. Shetty MK, Shah YP, Sharman RS. Prospective evaluation of the value of combined mam-
mographic and sonographic assessment in patients with palpable abnormalities of the breast. J
Ultrasound Med. 2003;22(3):263–8; quiz 269–70. https://doi.org/10.7863/jum.2003.22.3.263.
12. Lehman CD, Lee AY, Lee CI. Imaging management of palpable breast abnormalities. Am J
13. Dennis MA, et al. Breast biopsy avoidance: the value of normal mammograms and normal
sonograms in the setting of a palpable lump. Radiology. 2001;219(1):186–91 https://doi.
org/10.1148/radiology.219.1.r01ap35186.
14. Bernardi D, et al. Application of breast tomosynthesis in screening: incremental effect on
mammography acquisition and reading time. Br J Radiol. 2012;85(1020):e1174–8. https://doi.
org/10.1259/bjr/19385909.
15. Dang PA, et al. Addition of tomosynthesis to conventional digital mammography: effect on
image interpretation time of screening examinations. Radiology. 2014;270:49–56. https://doi.
org/10.1148/radiol.13130765.
16. Liew PL, et al. Rapid staining and immediate interpretation of fine-needle aspiration cytology
for palpable breast lesions: diagnostic accuracy, mammographic, ultrasonographic and histo-
pathologic correlations. Acta Cytol. 2011;55(1):30–7. https://doi.org/10.1159/000320869.
17. Spick C, et al. Breast MRI used as a problem-solving tool reliably excludes malignancy. Eur J
Radiol. 2015;84(1):61–4. https://doi.org/10.1016/j.ejrad.2014.10.005.
18. Sven J, Kister MD, Cushman D, Haagensen M. Paget’s disease of the breast. Am J Surg.
1970;119(5):606–9. https://doi.org/10.1016/S1776-9817(06)73026-7.
19. Fu W, Mittel VK, Young SC. Paget disease of the breast: analysis of 41 patients. Am J Clin
Oncol. 2001;24(4):397–400. https://doi.org/10.1097/00000421-200108000-00019.
20. Lee HW, et al. Invasive Paget disease of the breast: 20 Years of experience at a single
institution. Human Pathol. Elsevier Inc. 2014;45(12):2480–7. https://doi.org/10.1016/j.
humpath.2014.08.015.
21. Lim HS, et al. Paget disease of the breast: mammographic, US, and MR imaging findings
with pathologic corelation. Radiographics. 2011;31(7):1973–88. https://doi.org/10.1148/
rg.317115070.
22. Zakaria S, et al. Paget’s disease of the breast: accuracy of preoperative assessment. Breast
Cancer Res Treat. 2007;102(2):137–42. https://doi.org/10.1007/s10549-006-9329-2.
23. Morrogh M, et al. MRI identifies otherwise occult disease in select patients with Paget
disease of the nipple. J Am Coll Surg. 2008;206(2):316–21. https://doi.org/10.1016/j.
jamcollsurg.2007.07.046.
24. Ge LP, et al. Clinicopathological characteristics and treatment outcomes of occult breast
cancer: a SEER population-based study. Cancer Manag Res. 2018;10:4381–91. https://doi.
org/10.2147/CMAR.S169019.
25. Hessler LK, et al. Factors influencing management and outcome in patients with occult breast
cancer with axillary lymph node involvement: analysis of the national cancer database. Ann
Surg Oncol. Springer International Publishing,. 2017;24(10):2907–14. https://doi.org/10.1245/
s10434-017-5928-x.
26. Vlastos G, et al. Feasibility of breast preservation in the treatment of occult primary carci-
noma presenting with axillary metastases. Ann Surg Oncol. 2001;8(5):425–31. https://doi.
org/10.1007/s10434-001-0425-6.
27. Lu H, et al. Breast magnetic resonance imaging in patients with occult breast carci-
noma: evaluation on feasibility and correlation with histopathological findings. Chin Med
J. 2011;124(12):1790–5. https://doi.org/10.3760/cma.j.issn.0366-6999.
28. Terada M, et al. Occult breast cancer may originate from ectopic breast tissue present in
axillary lymph nodes. Breast Cancer Res Treat. Springer US,. 2018;172(1):1–7. https://doi.
org/10.1007/s10549-018-4898-4.
29. Wong YP, et al. Occult primary breast carcinoma presented as an axillary mass: a diagnostic
challenge. Malays J Pathol. 2020;42(1):151–5.
30. Brandt KR, et al. Can digital breast tomosynthesis replace conventional diagnostic mammog-
raphy views for screening recalls without calcifications? A comparison study in a simulated
clinical setting. Am J Roentgenol. 2013;200(2):291–8. https://doi.org/10.2214/AJR.12.8881.
31. Gilbert FJ, Tucker L, Young KC. Digital breast tomosynthesis (DBT): a review of the e vidence
for use as a screening tool. Clin Radiol. 2016;71(2):141–50. https://doi.org/10.1016/j.
crad.2015.11.008.
32. Murad TM, Contesso G, Mouriesse H. Nipple discharge from the breast. Ann Surg.
1982;195(3):259–64. https://doi.org/10.1097/00000658-198203000-00003.
33. Dawes LG, et al. Ductography for nipple discharge: no replacement for ductal excision.
Surgery. 1998;124(4):685–91. https://doi.org/10.1067/msy.1998.91362.
34. King TA, et al. A simple approach to nipple discharge. Am Surg. 2000;66(10):960–5; discus-
sion 965–6.
35. Montroni I, et al. Nipple discharge: is its significance as a risk factor for breast cancer fully
understood? Observational study including 915 consecutive patients who underwent selec-
tive duct excision. Breast Cancer Res Treat. 2010;123(3):895–900. https://doi.org/10.1007/
s10549-010-0815-1.
36. Morrogh M, et al. Lessons learned from 416 cases of nipple discharge of the breast. Am J Surg.
Elsevier Inc. 2010;200(1):73–80. https://doi.org/10.1016/j.amjsurg.2009.06.021.
37. Adepoju LJ, et al. The value of clinical characteristics and breast-imaging studies in predicting
a histopathologic diagnosis of cancer or high-risk lesion in patients with spontaneous nipple
discharge. Am J Surg. 2005;190(4):644–6. https://doi.org/10.1016/j.amjsurg.2005.06.032.
38. Bahl M, Gadd MA, Lehman CD. Diagnostic utility of MRI after negative or inconclu-
sive mammography for the evaluation of pathologic nipple discharge. Am J Roentgenol.
39. Sanders LM, Daigle M. The rightful role of MRI after negative conventional imaging in the
management of bloody nipple discharge. Breast J. 2016;22(2):209–12. https://doi.org/10.1111/
tbj.12551.
13 Diagnostic 279
40. Rosa M, Mohammadi A, Masood S. The value of fine needle aspiration biopsy in the diagnosis
and prognostic assessment of palpable breast lesions. Diagn Cytopathol. 2012;40(1):26–34.
https://doi.org/10.1002/dc.21497.
41. Garg S, et al. A comparative analysis of core needle biopsy and fine-needle aspiration cytology
in the evaluation of palpable and mammographically detected suspicious breast lesions. Diagn
Cytopathol. 2007;35(11):681–9. https://doi.org/10.1002/dc.20721.
42. Wang M, et al. A sensitivity and specificity comparison of fine needle aspiration cytology and
core needle biopsy in evaluation of suspicious breast lesions: a systematic review and meta-
analysis. Breast. 2017;31:157–66. https://doi.org/10.1016/j.breast.2016.11.009.
43. Homesh NA, Issa MA, El-Sofiani HA. The diagnostic accuracy of fine needle aspiration cytol-
ogy versus core needle biopsy for palpable breast lump(s). Saudi Med J. 2005;26(1):42–6.
44. Imschweiler T, et al. MRI-guided vacuum-assisted breast biopsy: comparison with stereotacti-
cally guided and ultrasoundguided techniques. Eur Radiol. 2014;24(1):128–35. https://doi.
org/10.1007/s00330-013-2989-5.
45. Eby PR, Lehman C. MRI-guided breast interventions. In: Seminars in ultrasound, CT and
MRI; 2006;27(4):339–50. https://doi.org/10.1053/j.sult.2006.05.008.
Chapter 14
Preoperative (Breast)
Jonathan Yugo Maesaka , Yedda Nunes Reis , and Jose Roberto Filassi
14.1 Preoperative Tests for the Breast
Newly diagnosed patients with breast cancer should be evaluated clinically and with
imaging exams to guide locoregional surgical treatment (breast and axilla). In this
context, understanding the locoregional extent of the disease assists the physician to
make the best decision for the treatment and will enable the choice of the most
appropriate surgical option, which can be a breast conservative surgery (quadrantec-
tomy/lumpectomy), or a mastectomy; if there is a need for immediate breast recon-
struction or even if there is an ipsilateral or contralateral synchronic disease that
needs to be treated concomitantly or for contralateral breast symmetrization.
When assessing a patient who is a candidate for conservative surgery, the attending
physician uses clinical and imaging parameters for safe decision-making. Important
considerations are made about the tumor size, as well as the extent of the disease, the
presence of multifocality/multicentricity, and involvement of adjacent structures.
Preoperative imaging exams will assist in understanding the true size of the
tumor, so that adequate resection is programmed. Currently, “no ink on tumor” is
the goal for patients with invasive breast disease undergoing conservative surgery,
and in patients with pure ductal carcinoma in situ (DCIS), the recommended margin
is 2 mm. Thus, the surgical approach must be personalized, and there is no longer
contraindication for conservative surgery for multicentric tumors or with extensive
J. Y. Maesaka (*) · Y. N. Reis · J. R. Filassi


Switzerland AG 2022
282 J. Y. Maesaka et al.
DCIS components. Conservative surgery can be offered as long as the entire tumor
is resected and the aesthetic result is adequate.
Special attention is required for patients with invasive lobular carcinoma (ILC)
subtype. Invasive lobular carcinoma is the second most common histological type of
breast cancer, representing 5–15% of cases, and due to its specific characteristics of
involvement of the breast lobes, without significant inflammatory reaction, it can
bring challenges in the clinical and imaging evaluation. Clinically, in most cases, it
is not possible to identify well-defined palpable masses. This presentation is due to
a slight change in the consistency of the breast. Invasion by malignant cells some-
times occurs insidiously, resulting in little or no desmoplasia. Masses and microcal-
cifications in lobular subtypes are incommon. In addition, lobular carcinoma has a
tendency to multifocal proliferation, with greater challenge in safe delimitation of
the disease. As we will mention further in this chapter, in view of this histological
type, an individualized imaging evaluation must be performed.
14.1.1 Imaging Methods
14.1.1.1 Mammography
Mammography (MG) is the gold standard imaging method for preoperative breast
assessment and should be performed by all patients diagnosed with breast cancer.
As it is the main test used in screening, the diagnosis is often made based on the
findings of this test.
In addition, mammography is widely used in patients scheduled for non-
oncological aesthetic breast surgery. At this point, it is worth mentioning the
Choosing Wisely statement of the American Society of Plastic Surgeons [1] that
recommends avoiding the routine use of mammograms before breast surgery,
reserving its use for patients with indications for screening. A study carried out by
Sears et al. identified that mammography in patients under 40 years of age at preop-
erative mammoplasty (without other clinical indication) increased the rates of more
exams (such as magnetic resonance imaging (MRI)) and more biopsies, without
objective evidence of their benefit [2].
A characteristic to be mentioned in the use of preoperative mammography is the
interobserver reproducibility. A study carried out by Kim et al. showed an almost
perfect agreement of mammography between different observers, compared to oth-
ers methods such as ultrasound (US) and MRI, when looking for prediction charac-
teristics of an extensive intraductal component [3]. As it is a static method and
easier to interpret, mammography is used by surgeons in the operating room to plan
incisions and tumor location and assess the extent of the disease.
Berg et al. carried out in 2004 a study of the accuracy of MG, US, and MRI tech-
niques in 111 patients [4]. MRI showed greater sensitivity when compared to
MG. An interesting fact is that adding MRI led to a 12% increase in the diagnosis
of new lesions, when compared to the use of MG + US. At the same time, in this
same study, MRI showed a tendency to overestimate the final tumor size. In 2009,
14 Preoperative (Breast) 283
Wasif et al. performed a comparative study between MG, US, and MRI [5]. Of the
61 patients evaluated, 52 were invasive ductal carcinomas. When the final size in
pathology was used as a parameter, the correlation was better with MRI, followed
by US and finally MG, identifying MRI as the exam with the best accuracy in rela-
tion to the pathological size of the lesion.
14.1.1.2 Ultrasound
Ultrasonography is the second most used exam, after mammography, for breast
assessment. It is a widely available test, with a lower cost in relation to MRI, but it
is also worth mentioning that this test depends on the operator and the device used.
Preferably, it should be performed in conjunction with mammography, for a more
complete and global assessment. During the exam, the patient is in the supine posi-
tion, a position similar to that of the surgery, and the characterization of the lesions
can assist in surgical planning, such as the skin distance, distance between lesions,
and distance from the nipple.
Like mammography, ultrasonography also has a moderate correlation coefficient
(0.68) with the pathological size of the tumor and is often due to the presence of
uncalcified DCIS, lobular histologies or tumor isoechogenicity in relation to the
breast parenchyma, especially in dense breasts.
14.1.1.3 Tomosynthesis
Tomosynthesis emerged as a new imaging technique that could overcome classic

limitations of mammography, reducing the effect of overlapping breast tissue,
decreasing recalls, and improving the method’s detection capacity. However, stud-
ies showing real superior efficacy in assessing lesion size and multifocality have not
been conclusive. In a patient with dense breasts, the benefit in terms of assessing
tumor size seems to be greater with the use of tomosynthesis [6].
14.1.1.4 Breast Magnetic Resonance Imaging
Despite the increasingly frequent use in surgical programming, the use of MRI in
preoperative locoregional staging is still controversial. Increased rates of mastec-
tomy, high rates of false-positive findings, and absence of evidence that the use of
MRI has an impact on patient survival are the main points of this controversy.
The objective of using MRI in the preoperative scenario should be the same as
for screening: increased sensitivity. The sensitivity of MRI in detecting multicentric
tumors and contralateral disease reaches 93% and 88%, respectively. Some studies
suggest that this increase in sensitivity is particularly valid in patients with dense
breasts and in lobular tumors. In theory, increased sensitivity should reduce positive
margin rates, decrease reoperation rates, and potentially decrease local recurrence.
However, the results of the studies are not consistent for these benefits and
sometimes bring an increase in mastectomy rates, without reducing reoperation

rates or even impacting on survival, as a result of a published meta-analysis [7]. To
date, there is no consensus on the use of preoperative MRI in patients with initial
surgical treatment and it is suggested to use them in lobular tumors, as a consensus,
and to consider it in patients with dense breasts.
Another limiting factor in the use of preoperative MRI is the low availability of
services with the possibility of performing MRI-guided percutaneous biopsy.
Therefore, an additional finding on MRI that cannot be verified by biopsy will end
up being approached surgically, which would lead to more, not less, surgical
procedures.
A situation in which the use of breast MRI is mandatory is in occult breast carci-
noma. For patients who are candidates for neoadjuvant chemotherapy, it is sug-
gested, even with the aforementioned scores and as long as there is no delay in
treatment, to perform MRI before and after chemotherapy (before surgery), for bet-
ter surgical planning [8].
14.1.1.5 ositron Emission Tomography-Computed Tomography

P
(PET-CT)
The use of 18FDG PET-CT for breast is not routinely recommended. The method
has low sensitivity and low specificity in the local assessment of breast cancer. For
example, it has no capacity to detect lesions smaller than 1 cm, nor does it make the
differential diagnosis with inflammatory diseases or even fibroadenoma [9].
14.2 Preoperative Tests for the Axilla
The presence of axillary disease in the context of breast cancer is an important prog-
nostic factor for the disease. Proper assessment of this condition will guide the
proposed therapy for each patient. The purpose of preoperative assessment is to
define whether or not there is axillary involvement and when present, the magnitude
of this involvement, also known as “axillary burden”. For this we can use, in addi-
tion to the physical examination, imaging methods. At the moment, no available
imaging exam has an acceptable negative predictive value to contraindicate surgical
assessment of the axilla when only normal lymph nodes are identified [10].
14.2.1 Indications
The axillary physical examination is always performed before surgery; however, it

is not a good indicator of the presence or absence of lymph node metastases. In situ-
ations of clinically negative axilla, it will depend on the strategy adopted by the
surgeon to request tests directed to the axilla, as we will discuss below and also as
explained in Chap. 4. In patients with clinically positive nodes, a scenario in which
the sentinel lymph node is contraindicated, ultrasound-guided fine-needle aspira-
tion (FNA) can confirm cytologically the presence of metastasis. In scenarios where
the physical examination is inconclusive, additional tests should be ordered, and
ultrasound can be of great use in conducting the case. The fact that ultrasound is an
operator-dependent exam must also be taken into account when ordering and inter-
preting the results of the exam.
14.2.2 Methods
14.2.2.1 Ultrasound
Ultrasonography is the most established exam for axillary evaluation. The suspicion
and diagnosis of axillary metastasis can modify the patient’s therapeutic planning:
negative axillae favors the performance of sentinel lymph node biopsy and, thus,
reduces the morbidity associated with axillary dissection. Positive axillae favors the
adoption of neoadjuvant treatment in order to reduce lymph node involvement by
disease and enable axillary surgical de-escalation. Finally, in some cases, it may be
contraindicated to perform the sentinel lymph node technique and guide the pro-
posal for up-front axillary dissection. Such an approach is detailed in Chap. 4.
In the ultrasound evaluation, morphological criteria (concentric or focal cortical
thickening greater than 3 mm, hilar obliteration, increased peri-hilar vasculariza-
tion, round shape) can be used, as well as the size of the lymph node, to identify
suspicious nodes. According to the criterion used, the specificity and sensitivity of
the method may vary. In a systematic review, which included literature from 1980
to 2004, Alvarez and colleagues found that in patients with palpable lymph nodes,
the sensitivity of the ultrasound was 68% on average when using the lymph node
size criteria, with a specificity of 75.2%, whereas if morphological criteria were
used, the sensitivity increased to 71% with a specificity of 96.1% on average. In the
group of patients without palpable lymph nodes, mean sensitivity and specificity
were 60.9% and 75.2%, respectively. However, when using the morphological cri-
teria in these patients, the average sensitivity was 43.9%, with 92.4% specific-
ity [11].
As we can see, there is a variety in the results found in the literature and in the
accuracy of the ultrasound to identify the lymph nodes, and this can be explained by
the variability of the method and criterion used, as well as whether the reference
used was sentinel lymph node biopsy or axillary dissection.
A cost-effective analysis study was conducted by Boughey et al., for the perfor-
mance of FNA guided by ultrasound in all lymph nodes with at least one altered
morphological criterion and compared with the performance of sentinel lymph node
biopsy intraoperatively, without performing axillary ultrasound (standard treat-
ment). As a result, the strategy proved to be cost-effective with a minimal difference
(US $ 36 dollars) between the strategies, and in 63% of the patients, there were
savings when the ultrasound was performed [12].
In 2017, a study published by Teixeira et al. created a nomogram for predicting
the presence of metastases based on the tumor characteristics and ultrasound image
of the axilla [13]. Using cortical thickening, tumor size, histological type, lesion
location as variables in the breast (quadrant) and the patient’s menopausal status,
the nomogram achieved satisfactory discrimination, with an area under the curve
(AUC) of 0.848.
14.2.2.2 Mammography
Although mammography is the main exam performed for breast assessment, its role
in the preoperative assessment of the axilla is limited [14]. In general, the axilla is
not fully included in the mammographic examination, and the accuracy of its find-
ings is limited. Benign lymph nodes appear on the mammographic exam smaller
than 2 cm in diameter and radiolucent hilar center. Suspicious findings are the
increased size and density of the lymph node.
14.2.2.3 Magnetic Resonance Imaging
Most MRI breast protocols cover the entire axillary field and allow a good evalua-
tion of this field. Suspicious findings in axillary lymph nodes on MRI include corti-
cal thickening, loss of fatty hilum, and rounded shape. The presence of perifocal
edema, defined as T2 hyperintensity in the adjacent fatty tissue (“marked T2 prolon-
gation in the surrounding fat”), demonstrated the greatest accuracy among the
descriptors, with a positive predictive value of 100% [15].
14.2.2.4 PET-CT
Another imaging method is the 18-FDG PET-CT, which has a role as a highly sensi-
tive method for detecting distant metastases, even in early tumors. However, its role
in axillary staging is limited: studies have shown a low to moderate sensitivity, and
therefore, it is not recommended for routine axillary assessment [16]. A prospective
trial involving 312 patients demonstrated that, compared to sentinel lymph node
biopsy, the sensitivity of FDG-PET/CT was 24%, with a specificity of 99% [17].
Another classic study by Veronesi et al. demonstrated a sensitivity of 37% [18], and
in a systematic review including 7 studies and 869 patients, PET-CT showed an
average sensitivity of 56% (95% CI 44 to 67%), with an average specificity of 95%
(95% CI 90 to 99%) [19].
14.3 Case Examples
14.3.1 Case 1
This is a case of invasive ductal carcinoma in the left breast. What is demonstrated
here is the capacity of MRI in demonstrating larger extension of the tumor, includ-
ing involvement of the nipple (Figs. 14.1 and 14.2).
14.3.2 Case 2
In this case, the mammography was unable to identify the index breast cancer lesion
due to an extremely dense breast, but suspicious axillary lymph nodes were partially
seen. The lesion was identified on breast ultrasound as a hypoechogenic mass. With
MRI, we were able to confirm both the breast and the axillary lesions (Figs. 14.3,
14.4, and 14.5).
Fig. 14.1 Invasive ductal

carcinoma in the left breast
Fig. 14.2 Invasive ductal

carcinoma with a greater
extension on MRI than on
mammography (Fig. 14.1).
MRI demonstrates
extension to the nipple
Fig. 14.3 Invasive

carcinoma not identified on
mammography, showing
an extremely dense breast.
Suspicious axillary lymph
nodes are partially seen on
mammography
Fig. 14.4 Invasive

carcinoma identified on
ultrasound as a
hypoechogenic mass (the
same case from Fig. 14.3)
Fig. 14.5 Invasive

carcinoma identified on
MRI as an enhancing mass
(the same case from
Figs. 14.3 and 14.4).
Suspicious axillary lymph
nodes are better
demonstrated on MRI
14.3.3 Case 3
In this case, all methods were able to accurately identify the breast lesion (Figs. 14.6,
14.7, and 14.8).
Fig. 14.6 Invasive

carcinoma seen on
mammography, with
similar dimensions in other
methods
Fig. 14.7 Invasive

carcinoma seen on
ultrasound, with similar
dimensions in other
methods
Fig. 14.8 Invasive

carcinoma seen on MRI,
with similar dimensions in
other methods
14.3.4 Case 4
In this case, suspicions axillary lymph nodes were identified in mammography and
confirmed on ultrasound (Figs. 14.9 and 14.10).
Fig. 14.9 Suspected

axillary lymph nodes seen
on mammography in a
patient with invasive ductal
carcinoma
Fig. 14.10 Suspected

axillary lymph nodes seen
on ultrasound in a patient
with invasive ductal
carcinoma (the same case
from Fig. 14.9)
14.3.5 Case 5
Example of normal lymph nodes identified on mammography and ultrasound

(Figs. 14.11 and 14.12).
Fig. 14.11 Lymph nodes

with usual features on
mammography
Fig. 14.12 Lymph nodes

with usual features on
ultrasound. Thin cortical
and presence of a fatty
hilum
References
1. Gutowski K, Gray D. The ASPS choosing wisely list for plastic surgery. Plast Reconstr Surg.
2014;134(4):853–5.
2. Sears ED, Lu YT, Swiatek PR, Chung TT, Kerr EA, Chung KC. Use of preoperative mam-
mography during evaluation for nononcologic breast reduction surgery. JAMA Surg.
2019;154(4):356–8. https://doi.org/10.1001/jamasurg.2018.4875.
3. Kim HR, Jung HK, Ko KH, Kim SJ, Lee KS. Mammography, US, and MRI for preoperative
prediction of extensive intraductal component of invasive breast cancer: interobserver vari-
ability and performances. Clin Breast Cancer. 2016;16(4):305–11. https://doi.org/10.1016/j.
clbc.2016.02.005.
4. Berg WA, Gutierrez L, MS NA, Carter WB, Bhargavan M, Lewis RS, et al. Diagnostic accu-
racy of mammography, clinical examination, US, and MR imaging in preoperative assessment
of breast cancer. Radiology. 2004;233(3):830–49. https://doi.org/10.1148/radiol.2333031484.
5. Wasif N, Garreau J, Terando A, Kirsch D, Mund DF, Giuliano AE. MRI versus ultrasonography
and mammography for preoperative assessment of breast cancer. Am Surg. 2009;75(10):970–5.
6. Eghtedari M, Tsai C, Robles J, Blair SL, Ojeda-Fournier H. Tomosynthesis in breast cancer
imaging: how does it fit into preoperative evaluation and surveillance? Surg Oncol Clin North
Am. 2018;27:33–49. http://dx.doi.org/10.1016/j.soc.2017.07.004.
7. Houssami N, Turner R, Macaskill P, Turnbull LW, McCready DR, Tuttle TM, et al. An individ-
ual person data meta-analysis of preoperative magnetic resonance imaging and breast cancer
recurrence. J Clin Oncol. 2014;32(5):392–401.
8. Sardanelli F, Boetes C, Borisch B, Decker T, Federico M, Gilbert FJ, et al. Magnetic resonance
imaging of the breast: recommendations from the EUSOMA working group. Eur J Cancer.
2010;46(8):1296–316. https://doi.org/10.1016/j.ejca.2010.02.015.
9. Ulaner GA. PET/CT for patients with breast cancer: where is the clinical impact? Am J
Roentgenol. 2019;213:254–65.
10. Rahbar H, Partridge SC, Javid SH, Lehman CD. Imaging axillary lymph nodes in patients with
newly diagnosed breast cancer. Curr Probl in Diagn Radiol. 2012;41:149–58.
11. Alvarez S, Añorbe E, Alcorta P, López F, Alonso I, Cortés J. Role of sonography in the diagno-
sis of axillary lymph node metastases in breast cancer: a systematic review. Am J Roentgenol.
2006;186:1342–8.
12. Boughey JC, Moriarty JP, Degnim AC, Gregg MS, Egginton JS, Long KH. Cost modeling of
preoperative axillary ultrasound and fine-needle aspiration to guide surgery for invasive breast
cancer. Ann Surg Oncol. 2010;17(4):953–8.
13. Akissue de Camargo Teixeira P, Chala LF, Shimizu C, Filassi JR, Maesaka JY, de Barros
N. Axillary lymph node sonographic features and breast tumor characteristics as predictors
of malignancy: a nomogram to predict risk. Ultrasound Med Biol. 2017;43(9):1837–45.
https://doi.org/10.1016/j.ultrasmedbio.2017.05.003.
14. Dialani V, James DF, Slanetz PJ. A practical approach to imaging the axilla. Insights Imaging.
2015;6:217–29.
15. Baltzer PAT, Dietzel M, Burmeister HP, Zoubi R, Gajda M, Camara O, et al. Application
of MR mammography beyond local staging: is there a potential to accurately assess axil-
lary lymph nodes? Evaluation of an extended protocol in an initial prospective study. Am J
Roentgenol. 2011:196–5.
16. Liu Y. Role of FDG PET-CT in evaluation of locoregional nodal disease for initial staging of
breast cancer. World J Clin Oncol. 2014;5:982–9.
17. Pritchard KI, Julian JA, Holloway CMB, McCready D, Gulenchyn KY, George R, et al.
Prospective Study of 2-[ 18F]fluorodeoxyglucose positron emission tomography in the assess-
ment of regional nodal spread of disease in patients with breast cancer: an Ontario Clinical
Oncology Group study. J Clin Oncol. 2012;30(12):1274–9.
18. Veronesi U, De Cicco C, Galimberti VE, Fernandez JR, Rotmensz N, Viale G, et al. A com-
parative study on the value of FDG-PET and sentinel node biopsy to identify occult axillary
metastases. Ann Oncol. 2007;18(3):473–8.
19. Cooper KL, Meng Y, Harnan S, Ward SE, Fitzgerald P, Papaioannou D, et al. Positron emis-
sion tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary
lymph node metastases in early breast cancer: Systematic review and economic evaluation.
Health Technol Assess. 2011;15(4):iii–iv, 1–134. https://doi.org/10.3310/hta15040.
Chapter 15
Systemic Staging (Total Body – When,
How)
Fabiano de Almeida Costa and Rudinei Diogo Marques Linck
15.1 Introduction
The staging of a neoplasm is an important step for the management of cancer

patients and must be established as soon as cancer diagnosis occurs. Systematic
staging allows the choice of the most appropriate treatments (local and systemic)
and adequate comparison of results between institutions and clinical studies and
provides initial prognostic information [1].
The initial evaluation of a patient with breast cancer should include anamnesis
with special attention to menopausal status and familial history of breast or ovarian
cancer, physical examination including bimanual breasts and regional lymph nodes
palpation, as well as search for signs and symptoms that may indicate potential sites
of metastasis. Initial laboratory evaluation with complete blood count, liver and
kidney function tests, and assessment of serum alkaline phosphatase and calcium
can alert about the possibility of systemic metastatic dissemination [2]. Despite the
importance of anamnesis and physical examination and precise determination of
tumor involvement extension with complementary exams, evaluating locoregional
involvement and eventual systemic involvement is a fundamental step for initial
therapeutic planning in breast cancer patients.
The decision to use imaging exams to assess possible systemic metastatic lesions
must be made rationally since these exams led to increased financial costs and are
associated with potential risks to patients’ health. On the other hand, the failure to
identify a metastatic lesion may lead to a futile indication of locoregional treatments
or adjuvant therapies. Thus, this chapter will address the appropriate selection of
F. de Almeida Costa · R. D. M. Linck (*)

Departamento de Oncologia, Instituto do Cancer do Estado de São Paulo ICESP,

Switzerland AG 2022
298 F. de Almeida Costa and R. D. M. Linck
patients who are candidates for systemic staging by imaging, as well as the choice
of the most appropriate complementary exams to be requested.
15.2 TNM Staging System
The TNM system was proposed by the American Joint Committee on Cancer
(AJCC) and the Union for International Cancer Control (UICC) and is currently
considered the standard staging system. For a most accurate prognostic information,
the eighth edition of the TNM breast cancer classification in use since 2018 includes
histological and molecular characteristics to the anatomical staging previously
used [3].
Currently, it has been frequent the use of anatomical TNM classification criteria,
especially important for the definition of cancer treatments and the use of the prog-
nostic TNM classification (including histological and molecular information) for an
improved definition of the survival impact of these treatments.
15.2.1 Anatomic Staging
The tumor size statement, either through physical examination and complementary
evaluation using imaging methods (cT) or by the anatomopathological measure of
the surgical specimen (pT), is a fundamental step of the TNM classification. The
lymph node involvement of the ipsilateral regional chains of the compromised
breast, either by clinical/imaging (cN) or anatomopathological (pN) evaluation,
associated with the tumor size, make up the main prognostic factors in nonmeta-
static breast cancer and are determinants in the therapeutic choice of this disease
regardless of the tumor subtype [3].
Determining the metastasis existence or absence (M), on the other hand, clarifies
about the virtual incurability of the disease when M1, although great advances have
emerged in the last years as options for palliative therapies which brought signifi-
cant improvements in survival and quality of life. Thus, the accurate recognition of
the systemic metastatic disease is essential to define at the initial diagnosis the pos-
sibility of a treatment strategy with curative potential (definitive local treatment
accompanied by neo/adjuvant systemic therapies) or the need for systemic palliative
treatment to control the metastatic disease [4].
15.2.2 Biomarkers and Prognostic Staging
Biomarkers in breast cancer are important because they are able to establish the
prognosis of the disease or, even, to predict the benefit of a specific treatment.
Associated with tumor size and lymph node involvement, the histological grade
15 Systemic Staging (Total Body – When, How) 299
determination is the most important risk factor for disease recurrence after the initial
treatment of a locoregional breast cancer [5]. The main factors that predict the ben-
efit of antihormonal treatment are the positive expression of estrogen or progester-
one receptors (HR-positive), as well as HER2 hyperexpression or amplification
(HER2-positive) which are directly associated with the benefit with anti-HER2
therapies [6, 7]. Nowadays, tests for the tumor gene expression analysis have been
able to refine the prognosis of the initial HR-positive, HER2-negative tumors, and
even helping to select the patient who needs adjuvant chemotherapy [8].
The changes in AJCC staging proposed in its eighth edition included the infor-
mation of histological grade, status of hormone receptors, HER2, and score of the
oncotype DX gene expression test as components of its classification. These changes
are taking into account the advances in the breast cancer treatment that occurred in
the past years and the consequent improvement in the prognosis of certain tumor
subtypes. With this new classification, the ability to predict the survival of breast
cancer patients undergoing conventional treatments has been significantly improved
[3]. However, the prognostic staging is less relevant for choosing which adjuvant
treatment should or should not be indicated.
15.2.3 Therapeutic Decisions According to Staging
The TNM classification of locoregional breast cancer (stages I, II, and III) helps to
determine the strategy of local and systemic treatment, since the more extensive the
locoregional disease, the greater the risks of future recurrence and, therefore, the
greater the absolute benefit of a more aggressive and extensive treatment. On the
other hand, the definition of metastatic disease at the initial diagnosis (de novo met-
astatic cancer/stage IV) establishes a virtual incurability and indicates palliative
strategies for its treatment. The failure to identify a metastatic lesion, with the con-
sequent under-staging of the neoplasia, may result in unnecessary treatments, such
as surgical or radiotherapy treatment of locoregional disease or even the indication
of futile neo−/adjuvant treatments for this scenario. In addition, understaging can
also represent inadequate choices for the treatment of metastatic disease [9].
15.3 Systemic Staging – When
Today, breast cancer represents the malignancy with the highest incidence in the
world, with an estimated 2.3 million people having this diagnosis in 2020 [10]. Of
these, approximately 90–95% are diagnosed as locoregional breast cancer, without
systemic metastases [11]. The chances of systemic involvement are directly associ-
ated with the locoregional involvement extension. It is more likely to identify sys-
temic metastases in more extensive locoregional disease or the more aggressive the
characteristics of this tumor are [9]. Therefore, it is possible to define the need for
investigation of systemic metastases with complementary exams according to the

chance of detecting disseminated neoplasia.
The initial assessment of any patient with breast cancer should include anamne-
sis and physical examination looking for signs and symptoms that may indicate
potential sites of metastasis. In addition, the initial laboratory evaluation should
include complete blood count, liver and kidney function tests, and serum alkaline
phosphatase and calcium tests, since changes in these tests may suggest a possible
systemic neoplastic dissemination [2]. Every patient who presents any signs or
symptoms suggestive of systemic metastatic dissemination should be properly
investigated with imaging exams. For instance, the presence of dyspnea, cough, or
hemoptysis should trigger a further investigation in search of lung metastases; the
presence of elevated alkaline phosphatase, abnormal liver marker tests, abdominal
symptoms, or findings of abdominal changes on physical examination indicates the
need for investigation for abdominal metastases; as well as bone pain or elevated
alkaline phosphatase suggest the possibility of bone metastases.
In view of early diagnosis with small neoplasia and limited or absent lymph node
involvement (staging up to T2N0 or T1N1) assessed as anatomical stage I or IIA,
there is no need for routine imaging exams, unless with signs or symptoms sugges-
tive of metastatic involvement [1, 2, 12]. However, retrospective studies suggest that
early tumors, when they involve lymph node or aggressive tumor subtypes (espe-
cially HER2-positive or triple-negative), are more likely to have systemic metas-
tasis [9].
15.4 Systemic Staging – How
Unlike initial tumors, those that present with extensive loco-regionally neoplasms
may benefit from the systematic investigation of distant metastases. The incidence
of metastatic lesions to other organs and systems, when asymptomatic, is low even
in these cases. According to Ravaioli et al. [13], in a retrospective evaluation of
1218 cases of breast cancer in clinical stage (CS) III, the prevalence of abnormal
abdominal ultrasound and chest radiography was 6% and 7%, respectively. Myers
et al. [14] presented a meta-analysis of 11 studies, in which 8.3% of the CS III par-
ticipants had bone scintigraphy suggestive of bone metastasis, 2.0% had an abdomi-
nal ultrasound with suspected liver metastasis. and 1.7% had chest x-ray with
lesions suspected for metastasis.
In cases of locally advanced tumors, patients with T3 (≥5 cm) or N positive
(CS ≥ IIB) must undergo a systemic assessment that includes chest computerized
tomography (CT), CT or magnetic resonance imaging (MRI) of the abdomen, and
bone scintigraphy [1, 2, 12]. Exams with less sensitivity for the detection of sys-
temic metastases, such as abdominal ultrasound (US) and chest radiography, are
generally not useful in clinical practice because they have high rates of false nega-
tive [9]. Assessment of central nervous system (CNS) metastasis should be per-
formed exclusively when the patient has suggestive neurological symptoms and
preferably with MRI [4].
The positron emission tomography with 18F-fluorodeoxyglucose (PET-CT

FDG) is not routinely indicated [2, 12], but it can be useful when CT and bone scans
are doubtful [1, 3]. Trials that demonstrate the superiority of PET-CT FDG over
anatomical exams are already well established, but clinical benefits, which lead to
recurrence-free survival and overall survival improvement, are less discussed and
not defined. When PET-CT FDG is requested, it replaces chest and abdomen CT,
abdominal MRI, and bone scintigraphy.
A prospective study conducted in Barcelona, Spain, evaluated 60 patients with
tumors larger than 3 cm with chest CT, liver US, bone scintigraphy, and PET-CT
FDG and compared the methods for at least one of year follow-up [15]. The sensi-
tivity and specificity of PET-CT FDG to detect axillary lymph nodes were 70% and
100%, respectively. The overall sensitivity and specificity of PET-CT FDG to detect
distant metastases were 100% and 98%, while the sensitivity and specificity of con-
ventional exams were 60% and 83%, respectively. The most important finding in
this study was that PET-CT FDG led to a change in initial staging in 42% of patients.
Unfortunately, this study did not discuss clinical outcomes.
Another prospective study, conducted in Paris, France, evaluated 131 breast can-
cer patients with tumors larger than 2 cm [16]. In this study, PET-CT FDG was
responsible for modifying the staging of 5.6% of patients previously diagnosed as
stage IIA, 14.6% of previously diagnosed as stage IIB, and 27.6% of previously
diagnosed as stage IIIA.
The PET-CT FDG is not routinely recommended in the first approach to sys-
temic staging due to several issues: the high rate of false-negative for lesions smaller
than 1 cm or low-grade tumors, the low sensitivity to detect axillary involvement,
the low initial likelihood of these patients having measurable metastases, and the
high rate of false positives [16]. We add the absence of evidence on most important
clinical outcomes and the lack of cost-effectiveness studies suggesting that replace-
ment of conventional investigation methods does not allow us to recommend rou-
tinely PET-CT FDG to initiate a systemic evaluation. However, there is limited
evidence suggesting that PET-CT FDG may be a useful adjunct to standard imaging
for systemic staging in high-risk patients (such as stage T4 or N2-3) due to its
greater sensitivity to identify a more disseminated disease [1, 16, 17].
Complete blood count and liver function tests are recommended for all patients
who are candidates for systemic neoadjuvant or adjuvant treatment. Other labora-
tory tests are indicated only if there are signs or symptoms [1, 3]. There is no recom-
mendation for tumor markers such as CEA and Ca 15–3 in the initial evaluation [2,
12]. PET-CT with fluoroestradiol F-18 is a new methodology capable of identifying
lesions with hormone receptors expression in patients with metastatic disease; how-
ever, there are no studies evaluating clinical utility [18, 19].
15.5 Biopsy or Rebiopsy
Patients who were suspected of having metastatic lesion on initial exams, whenever
possible, must undergo a biopsy of the metastatic site, since the metastatic diagnosis
is associated with a major impact on therapeutic planning. In addition to confirming
the diagnosis of systemic metastasis against alternative hypotheses such as an even-

tual benign condition or even a second primary tumor, access to the new immuno-
histochemical evaluation is highly recommended in breast cancer. Since breast
cancer treatment is dictated by the result of hormone receptor expression and/or
HER2 positivity, a different status of these markers at the metastasis site (becoming
present when they were initially absent) could lead to a significant change in the
treatment strategy [20].
At the neo/adjuvant and local treatment conclusion, the patient must start a
planned medical follow-up for the possibility of tumor recurrence. Rebiopsy is of
special value when a lesion suspected of recurrence is identified. Anatomopathological
analysis can confirm the diagnosis of recurrent metastatic disease and also allows
for new immunohistochemistry. It is possible to identify a discrepancy in the immu-
nohistochemical profile between the primary tumor and metastasis, which can vary
between 5% and 30% over the course of cancer treatment [1, 21, 22].
15.6 Follow-Up Patients
The follow-up of the patient with breast cancer begins after the conclusion of
locoregional treatment and neo/adjuvant treatments and should be oriented towards
the monitoring of any side effects associated with the treatment employed, as well
as for the identification of any eventual neoplastic recurrence. Tumor relapse can be
divided into two distinct conditions: when locoregional relapse occurs in the breast
or in regional lymph nodes, which must be promptly identified as it is a potential
curable situation, the reason why it is important to have routine follow-up by imag-
ing exams, usually annual mammography, associated with physical exam [23], and
when systemic relapse occurs, which are virtually incurable. Thus, early identifica-
tion of systemic recurrence will not necessarily be able to change the natural history
of the disease, and early palliative treatments will not be able to translate into
increased chances of a cure or improved survival [24].
The main recommendation for the adequate breast cancer patients’ follow-up is
to carry out regular medical consultations for the active search for signs and symp-
toms suggestive of treatment toxicities and also the possibility of tumor recurrence
[25]. There is no recommendation for routine exams to identify asymptomatic sys-
temic metastases. However, any clinical suspicion should be promptly investigated.
15.7 Conclusion
Evaluation by imaging exams to investigate possible systemic metastatic disease

should not be requested indiscriminately to all patients diagnosed with breast can-
cer. Most patients are diagnosed with locoregional tumors, and complementary
exams are not free from risk, besides increasing financial costs for health systems.
On the other hand, failure to adequately identify metastatic disease can also lead to
inappropriate choices in the therapeutic planning of these patients. Thus, comple-
mentary exams must be carefully considered.
Patients should always be assessed by anamnesis and physical examination,
looking for signs and symptoms suggestive of metastatic spread, and any evidence
or suspicion of abnormality should be promptly investigated with appropriate exam-
inations. The main sites of metastasis in breast cancer are bones, lymph nodes,
lungs, liver, and central nervous system (the latter especially important in neoplasms
subtype HER2-positive or triple negative). Patients with loco-regionally advanced
tumors, especially those with anatomical staging IIB or more, should undergo rou-
tine imaging assessment when the initial diagnosis is made. The exams indicated for
this evaluation are chest CT, abdominal CT or MRI, and bone scintigraphy. PET-CT
FDG evaluation may be an alternative, especially when the initial exams are
not clear.
Biopsy for histological confirmation of systemic metastasis should be requested
whenever possible, since there is a great impact on therapeutic definitions. The
importance of biopsy of systemic metastases goes beyond the differential diagnosis
between benign conditions or eventually a second primary tumor. In breast cancer,
there is a great impact of immunohistochemical evaluation (related to the expres-
sion of hormone receptors and also of HER2) in the choice between different treat-
ment alternatives. The immunohistochemical profile may, in some cases, differ
between the primary and the metastatic tumor; also, there may be a change in the
immunohistochemical profile after long periods of exposure to cancer treatments.
Patients who are on follow-up after the end of treatment or in adjuvant endocrine
therapy need to be evaluated by trained medical staff in search of signs and symp-
toms suggestive of systemic neoplastic recurrence. When there is a clinical suspi-
cion of systemic metastasis, it necessarily needs to be promptly investigated with
correct and accurate propaedeutics. However, asymptomatic patients with no suspi-
cion of metastatic spread should not be subjected to indiscriminate routine imaging
exams for systemic evaluation.
References
1. National Comprehensive Cancer Network. Breast Cancer (Version 8.2021). https://www.nccn.

org/professionals/physician_gls/pdf/breast.pdf. Accessed September 14, 2021.
2. Barrios CH, Bedin SR, Reinert T, Tavares M, Sahade M, Cruz M, et al. Mama: Estadiamento.
Diretrizes Trat Oncológicos da SBOC. 2020.
3. Amin MB, Edge SB, Greene FL. AJCC Cancer Staging Manual. 8th ed. Springer; 2017.
4. Cardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro MS, André F, et al. 5th ESO-
ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol
[Internet]. 2020;31(12):1623–49. Available from: https://linkinghub.elsevier.com/retrieve/pii/
S0923753420424603
5. Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-year risks of breast-
cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med [Internet].
2017;377(19):1836–46. Available at: http://www.nejm.org/doi/10.1056/NEJMoa1701830.
6. Breast E, Trialists C; Group C. Relevance of breast cancer hormone receptors and other
factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised
trials. Lancet [Internet]. 2011;378(9793):771–84. Available at: https://doi.org/10.1016/
S0140-6736(11)60993-8.
7. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et
al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl
J Med [Internet]. 2005;353(16):1659–72. Available at: http://www.ncbi.nlm.nih.gov/
pubmed/16236737.
8. Andre F, Ismaila N, Stearns V. Use of biomarkers to guide decisions on adjuvant systemic
therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline
update summary. J Oncol Pract [Internet]. 2019;15(9):495–7. Available at: http://ascopubs.org/
doi/10.1200/JOP.19.00264.
9. Soares G, Pereira A, Vilas Boas M, Vaisberg V, Magalhães M, Linck R, et al. Value of sys-
temic staging in asymptomatic early breast cancer. Rev Bras Ginecol e Obs/RBGO Gynecol
Obstet [Internet]. 2018;40(07):403–9. Available at: http://www.thieme-connect.de/DOI/
DOI?10.1055/s-0038-1666997.
10. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer
statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers
in 185 countries. CA Cancer J Clin [Internet]. 2021:caac.21660. Available at: https://onlineli-
brary.wiley.com/doi/10.3322/caac.21660.
11. Cardoso F, Spence D, Mertz S, Corneliussen-James D, Sabelko K, Gralow J, et al.
Global analysis of advanced/metastatic breast cancer: decade report (2005–2015). Breast
[Internet]. 2018;39:131–8. Available at: https://linkinghub.elsevier.com/retrieve/pii/
S096097761830050X.
12. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast
cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann
Oncol. 2019;30(8):1194–220.
13. Ravaioli A, Pasini G, Polselli A, Papi M, Tassinari D, Arcangeli V, et al. Staging of breast
cancer: new recommended standard procedure. Breast Cancer Res Treat. 2002;72(1):53–60.
14. Myers RE, Johnston M, Pritchard K, Levine M, Oliver T, Crump RM, et al. Baseline staging
tests in primary breast cancer: a practice guideline. CMAJ. 2001;164(10):1439–44.
15. Fuster D, Duch J, Paredes P, Velasco M, Muñoz M, Santamaría G, et al. Preoperative stag-
ing of large primary breast cancer with [ 18F]fluorodeoxyglucose positron emission tomog-
raphy/computed tomography compared with conventional imaging procedures. J Clin Oncol.
2008;26(29):4746–51.
16. Groheux D, Giacchetti S, Espié M, Vercellino L, Hamy AS, Delord M, et al. The yield of 18F-
FDG PET/CT in patients with clinical stage IIA, IIB, or IIIA breast cancer: a prospective study.
J Nucl Med. 2011;52(10):1526–34.
17. Carkaci S, Macapinlac HA, Cristofanilli M, Mawlawi O, Rohren E, Gonzalez Angulo AM, et
al. Retrospective study of 18FFDG PET/CT in the diagnosis of inflammatory breast cancer:
preliminary data. J Nucl Med. 2009;50(2):231–8. https://doi.org/10.2967/jnumed.108.056010.
18. Linden HM, Peterson LM, Fowler AM. Clinical potential of estrogen and progesterone recep-
tor imaging. PET Clin [Internet]. 2018;13(3):415–22. Available at: http://www.ncbi.nlm.nih.
gov/pubmed/30100079.
19. Jones EF, Ray KM, Li W, Chien AJ, Mukhtar RA, Esserman LJ, et al. Initial experience of
dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol. NPJ Breast
Cancer [Internet]. 2019;5:12. Available at: http://www.ncbi.nlm.nih.gov/pubmed/31016232.
20. Van Poznak C, Somerfield MR, Bast RC, Cristofanilli M, Goetz MP, Gonzalez-Angulo
AM, et al. Use of biomarkers to guide decisions on systemic therapy for women with meta-
static breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J
Clin Oncol [Internet]. 2015;33(24):2695–704. Available at: http://www.ncbi.nlm.nih.gov/
pubmed/26195705.
21. Aurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano G, et al. A meta-anal-

ysis of oestrogen receptor, progesterone receptor and human epidermal growth factor recep-
tor 2 discordance between primary breast cancer and metastases. Eur J Cancer [Internet].
2014;50(2):277–89. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24269135.
22. Pusztai L, Viale G, Kelly CM, Hudis CA. Estrogen and HER-2 receptor discordance between
primary breast cancer and metastasis. Oncologist [Internet]. 2010;15(11):1164–8. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21041379.
23. Schootman M, Jeffe DB, Lian M, Aft R, Gillanders WE. Surveillance mammography and
the risk of death among elderly breast cancer patients. Breast Cancer Res Treat [Internet].
2008;111(3):489–96. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17957465.
24. Rojas MP, Telaro E, Russo A, Moschetti I, Coe L, Fossati R, et al. Follow-up strategies for women
treated for early breast cancer. Cochrane database Syst Rev [Internet]. 2005;25(1):CD001768.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/15674884.
25. Khatcheressian JL, Hurley P, Bantug E, Esserman LJ, Grunfeld E, Halberg F, et al. Breast
cancer follow-up and management after primary treatment: American Society of Clinical
Oncology clinical practice guideline update. J Clin Oncol [Internet]. 2013;31(7):961–5.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/23129741.
Chapter 16
Neoadjuvant Systemic Therapy
Ana Carolina de Ataíde Góes, Heni Debs Skaf, and Laura Testa
Abbreviations
ADC Apparent diffusion coefficient map

AI Artificial intelligence
BCS Breast-conserving surgery
CEM Contrast-enhanced mammography
DCE-MRI Dynamic contrast-enhanced MRI
DCIS Ductal carcinoma in situ
DWI Diffusion-weighted imaging
HER2 Human epidermal growth factor receptor 2
HR Hormone receptor
IBC Inflammatory breast cancer
LN Lymph nodes
MRI Magnetic resonance imaging
NCT Neoadjuvant chemotherapy
NET Neoadjuvant endocrine therapy
NST Neoadjuvant systemic therapy
pCR Pathological complete response to therapy
PPV Positive predictive value
RECIST Response Evaluation Criteria in Solid Tumors
A. C. de Ataíde Góes (*) · H. D. Skaf

L. Testa

Switzerland AG 2022
308 A. C. de Ataíde Góes et al.
SLNB Sentinel lymph node biopsy

TN Triple negative
US Ultrasound
16.1 Indications
Neoadjuvant systemic therapy (NST) was first introduced in breast cancer treatment
to make surgery possible for inoperable tumors.
As systemic treatment evolved and survival benefits were shown for adjuvant
treatment, the scenario changed, and once a patient has a clear indication of chemo-
therapy, for example, it could be used upfront, making breast conservation possible.
More recently, residual disease in pathological surgical specimens after neoadju-
vant chemotherapy (NCT) is a marker for the need to escalate treatment, both for
HER2 and triple-negative (TN) breast cancer.
The current understanding of the breast medical oncology community is that for
TN disease we should offer NCT for patients with tumor size over 2 cm (some
would say even 1 cm) irrespectively of nodal involvement. For HER2-positive dis-
ease, this is also the case, with some debate on the agents and regimens.
Patients that present with HR-positive breast cancer are usually referred to NCT
when they have locally advanced disease or any node-positive patients who have
other markers of better response to treatment such as Grade 3 or high Ki67
(Table 16.1).
Neoadjuvant endocrine therapy (NET) development followed a different path.
Patients who had postmenopausal locally advanced disease but were not fit for che-
motherapy were offered first tamoxifen with 50% of patients achieving clinical
responses. When aromatase inhibitors became available, they showed improved
rates of response and chances for BCS (breast-conserving surgery).
PCR is not as prognostic for HR (hormone receptor)-positive breast cancer as it
is for TN- or HER2-positive disease, but patients who achieve low Ki67, tumor
staging pT2 or less, and pN0 after 24 weeks of NET have excellent disease-free and
overall survival. These tumor characteristics are evaluated with PEPI (preoperative
endocrine prognostic index) score, and it has been useful. NET was better studied in
postmenopausal patients, so it’s not routinely recommended for premenopausal
HR-positive breast cancer.
Table 16.1 Indications of neoadjuvant chemotherapy for breast cancer

Triple-negative disease Tumor size over 2 cm (or 1 cm for some)
HER2-positive disease Tumor size over 2 cm
HR-positive disease Locally advanced breast cancer (clinical stage T3 N1–N3 M0)
Or
Any node positive + markers of response (e.g., grade 3 or high Ki67)
Inflammatory breast cancer
16 Neoadjuvant Systemic Therapy 309
16.2 Introduction to Multimodality Response Assessment
Presently there are no established guidelines to best evaluate tumoral response dur-
ing or after NST. However, prior to initiation of chemotherapy, diagnostic imaging
should be performed for both breasts, and, depending on the disease stage and the
presence of symptoms, whole-body imaging should be conducted as well.
Historically, this first evaluation consists of conventional breast imaging (mammog-
raphy and ultrasound), besides physical examination.
Imaging monitoring during NST may help anticipate which patients aren’t expe-
riencing a response in cases of uncertain clinical progression, avoiding unnecessary
chemotherapeutic toxicity. It also permits the oncologist to tailor specific therapy
regimens to be used before or after surgery.
The same imaging modality and protocol should be executed after NST in order
to assist to predict which patients will achieve pCR, as well as estimate residual
tumoral size for the purpose of planning a BCS.
Breast tumor should be clipped with image-detectable marker prior to neoadju-
vant therapy for future preoperative localization and identification of tumor bed.
Similarly, it’s important to clip metastatic axillary lymph node(s). Preferable to use
clip that can be well seen on US for future localization (Fig. 16.1).
However, the surgical planning may dictate the decision whether or not to obtain
posttreatment imaging studies: repeating breast imaging after neoadjuvant therapy
may not be necessary for patients with multicentric disease, extensive lesions, or
another clear contraindication to BCS.
Physical examination is subjective and relies on the physician’s experience, and
its accuracy to determine pCR is inferior to the usual breast imaging methods [1].
Besides, the presence of fibrosis and firm fibroglandular tissue may overestimate the
amount of residual disease, and the absence of a palpable lesion does not exclude
the presence of a remaining tumor, being notably inaccurate for small early-stage
cancers, particularly smaller than 2 cm [2].
a b c
Fig. 16.1 Marker clip (arrows) within breast lesion on different imaging modalities. (a)
Mammography shows a metallic clip. (b) The tissue marker is visible on ultrasound as hyperecho-
genic spots. (c) T1-weighted MR image shows local signal intensity void caused by marker clip
a b c d
e f
Fig. 16.2 CLM, 58-year-old female. MLO mammography before and after neoadjuvant systemic
therapy shows two partially obscured masses (a), with signs of partial response to therapy charac-
terized by reduced size associated to morphological changes of the lesions, now irregular and
spiculated (b). However, despite the reduction in size after neoadjuvant systemic therapy (c, e), the
cutaneous involvement became more pronounced on post-contrast MR subtracted images (d, f),
emphasizing the intrinsic limitation of mammography in the skin evaluation
In the following sections, we will discuss each imaging modality, its advantages
and limitations, as well as pitfalls and pearls in response evaluation. DCE-MRI
offers the highest diagnostic accuracy in primary tumor therapy response assess-
ment among the currently established imaging methods (mammography and ultra-
sound) [1], and its usage for response evaluation to NST is recommended by the
American College of Radiology and European Society of Breast Imaging
(Fig. 16.2) [3, 4].
Mammography and ultrasound (US) provide suboptimal evaluations in the accu-
rate assessment of response to NST, and such limitations will be further discussed
in this chapter. Predicting pCR is not highly accurate with US or mammography,
correlating with these methods in only 13–25% of cases [5–7].
Despite DCE-MRI more accurately reflects true pathologic tumor size, it is more
expensive, time-consuming, and less widely available and may still overestimate or
underestimate residual disease but only within 1 cm of the final tumor size when
compared to anatomopathological examination of the surgical specimen [8, 9]. The
largest diameter of the lesion in the DCE-MRI showed the highest correlation with
pathology in the evaluation of residual invasive disease after NST [10].
16.3 Mammography Interpretation
Mammography has a variable accuracy to assess residual tumor after neoadjuvant

chemotherapy partly because of posttreatment image changes, such as the develop-
ment of fibrosis or lesion fragmentation.
Furthermore, the pretreatment tumor mammographic presentation impacts the

accuracy on assessment of the response to therapy, for example, lesions with cir-
cumscribed margins are better evaluated later, while indistinct or spiculated lesions
negatively impact the method’s accuracy [11]. This is partly due to the inherent
method limitation in evaluating lesions with superimposed breast tissue, particu-
larly in dense breasts, and may be alleviated by using digital breast tomosynthe-
sis [12].
Some changes in mammographic images are more reliable response indicators
than others, as the decrease in density and size is more common and trustworthy of
response than changes in clustered calcifications, for instance.
Calcifications are often misleading, as they may remain stable, decrease, or
increase after neoadjuvant chemotherapy (Fig. 16.3). A study analyzed 494 patients
who underwent NST due to locally advanced breast cancer. There was no correla-
tion between changes in clustered calcifications extent after pathologic complete
response. In fact, they were associated at surgery with benign findings in 41% of
patients. Regarding biological markers, positive estrogen receptor tumors were
associated with a higher proportion of residual calcifications correlated with malig-
nant findings at surgery when compared to negative estrogen receptor tumors, which
a b c d
e f
Fig. 16.3 GALO, 32-year-old female. MLO mammography before neoadjuvant systemic therapy
shows an indistinct lesion occupying almost the entire left breast, diagnosed as invasive ductal
carcinoma, associated with pleomorphic clustered calcifications (a). After the systemic therapy,
there was partial regression of the lesion; nevertheless, we observed an increase in the extent and
density of the calcifications (b). Post-contrast MRI before treatment characterizes an irregular
mass with heterogeneous enhancement associated with non-mass diffuse enhancement of the left
breast (c, d). After neoadjuvant systemic therapy, there were signs of a partial response character-
ized by a complete regression of the mass lesion with residual non-mass enhancement in multiple
areas (e, f)
attained lower rates of pCR. Consequently, concerns about incomplete excision in

this cancer subtype may be less of an issue [13].
Even though calcifications lacking enhancement more commonly represent
benign findings, they can be malignant, as neoangiogenesis is not the same for all
malignant breast lesions, not being always present in ductal carcinoma in situ or in
lobular carcinomas. So regardless of enhancement dynamics, calcifications with
malignant morphologic findings on mammography, without enhancement on MRI,
which have not yet been histologically evaluated, should undergo biopsy [14].
According to some studies, mammography is more sensitive than physical exam-
ination for detecting residual tumor after neoadjuvant chemotherapy, especially in
inflammatory carcinoma; however, it comes at the expense of decreased specificity
and underestimation of the degree of response, with more false positives when com-
pared to physical examination. False-positive mammographic assessments were
mainly due to residual microcalcifications, benign at surgical specimen evaluation,
and fibrosis [15, 16].
Contrast-enhanced mammography (CEM) is emerging as a feasible method
capable of associating image features such as density and morphology with physi-
ologic information due to tumoral neoangiogenesis.
CEM employs a dual-energy technique in order to highlight areas of contrast
uptake in breast tissue by subtracting low-energy images from high-energy ones,
canceling the enhancement of the background breast tissue. It uses standard mam-
mography equipment upgraded to include copper filtration; the additional software
needed for dual energy-imaging and a low-osmolar iodinated contrast material are
also used.
Several studies have demonstrated CEM as an alternative to MRI to detect resid-
ual disease after NST. Patel et al. in 2018 retrospectively compared both methods in
patients with invasive breast cancer after NST and both methods yielded compara-
ble sensitivity and PPV in this matter [17]. Iotti and colleagues in 2017 made a
prospectively evaluation of CEM and MRI in 54 patients and CEM demonstrated
pCR better than MRI; nevertheless, both methods led to an underestimation of the
extent of the residual tumor [18].
16.4 Ultrasound Interpretation
Breast and axillary US should be performed for malignant breast masses for clinical
staging if neoadjuvant therapy is planned, being widely available and
cost-effective.
There are some limitations though, as in physical examination and mammogra-
phy, chemotherapy-induced fibrosis can be difficult to differentiate from residual
disease by US and lesion fragmentation may underestimate its therapeutic response
evaluation (Fig. 16.4).
Keune and colleagues retrospectively evaluated 196 patients diagnosed with
invasive breast carcinoma and concluded that ultrasound was more accurate than
a b c
d e f
Fig. 16.4 BGK, 53-year-old female. Ultrasound of the left breast shows a hypoechoic irregular
mass with angulated margins in the retroareolar region diagnosed as invasive ductal carcinoma (a,
b), characterized on MRI as an irregular mass with heterogeneous enhancement (c). The lesion
was marked with a clip (arrow) before systemic therapy and later characterized on ultrasound as a
smaller hypoechoic irregular lesion (d, e) without corresponding enhancement on MRI (f). The
final surgical specimen yielded a small ductal carcinoma in situ, without invasive component, with
extensive regression signs
mammography in predicting residual tumor size after NST, demonstrating that

59.6% of residual tumors were accurately sized within 1 cm, when compared to
surgical measurement, while mammography accurately sized 31.7% of the tumors
[2]. Chagpar et al. corroborated these findings evaluating 189 patients, showing that
US correlated with the size of the residual pathologic tumor (within an accuracy of
1 cm) in 75% of patients, mammography in 70%, and physical examination in
66% [19].
However, there was little difference in the ability of each method to predict pCR
and the likelihood of a complete pathologic response was 80% when both imaging
modalities did not demonstrate residual disease [2]. Peintinger et al. concluded that
the combination of both methods, ultrasound and mammography, improves even
more the accuracy of predicting a pCR to neoadjuvant chemotherapy to a greater
degree than using either method isolated [20].
Ultrasound is listed on ACR Appropriateness Criteria® with a better rating than
mammography to evaluate NST response, being a reliable modality to determine
residual tumor size, particularly if it measures more than 7 mm and has been previ-
ously documented by the same method before NST [21, 22].
Regarding contrast-enhanced US, there is still not sufficient data to support its
routine use in this setting, even though some studies suggest that change in time-
intensity curves, representing quantitatively the tumoral perfusional changes after
NST, may reliably predict response to therapy [23].
US also plays an important role in the management of the axilla due to its moder-
ate sensibility and great specificity in the diagnosis of metastatic axillary involve-
ment (Fig. 16.5) [24]. For those in whom axillary lymph nodes are palpated on
physical exam, US is the first step in radiological investigation. If a suspicious
a b c e
Fig. 16.5 MAS, 50-year-old female. MLO and CC mammography show an indistinct irregular
mass at the junction of the inner quadrants on the right breast, diagnosed as invasive ductal carci-
noma, as well as two smaller lesions at the upper outer quadrant and round enlarged axillary lymph
nodes (a, b). These lymph nodes were better evaluated by ultrasound, both with thickened cortex
and no visible hilum (c, d). Ultrasound better characterized both lesions in the upper outer quad-
rant which were diagnosed as compromised lymph nodes after core needle biopsy (e). All the
breast lesions were marked with a clip before neoadjuvant systemic therapy for better surgical
planning (f)
lymph node is found, ultrasound-guided needle biopsy should be performed to con-

firm pathologic involvement, and a marker can be placed in case a complete imag-
ing response is obtained (see Lymph Node Evaluation).
This method is the most accurate predictor of NST response in axillary lymph
nodes, when compared to physical examination and mammography [5], being the
modality of choice according to the ACR Appropriateness Criteria®, as it permits
the visualization of lymph nodes level I and II routinely, with a higher spatial resolu-
tion to evaluate these structures, better depicting cortical thickening or lobulations,
absent hilum, and abnormal cortical vascularization by Doppler imaging, among
other alterations.
16.5 MRI Interpretation
Magnetic resonance imaging (MRI) is the most accurate and reproducible method
available to monitor breast cancer response to NST, being an excellent modality to
define the extent of the disease and assist the surgeon in determining the optimal
surgical approach. However, like any method, it has its advantages and limitations,
and in this scenario, it can both overestimate and underestimate the tumor response.
According to the different aims for which NST is applied, MRI can be used for
different purposes. From an oncologist’s perspective, assessing the response to a
specific regimen and measuring changes in the size of the invasive tumor as early as
possible helps to adapt the regimen in case of failure to respond [25, 26]. MRI has
also been used to monitor the degree of response to induction chemotherapy as a
surrogate marker for pCR, that is, to guide further systemic treatment [27]. For a
surgeon, assessing the extent of possible residual disease, including DCIS, is impor-
tant to guide subsequent surgery [28, 29]. Thus, separate strategies might be needed
to determine response to a specific chemotherapy regimen and to determine residual
tumor size after NST.
MRI Technique MRI is often acquired on a scanner of at least 1.5-T using a
dedicated breast coil in the prone position. The imaging protocol usually consists
of fat-suppressed axial T2-weighted images, diffusion-weighted imaging (DWI),
and dynamic contrast-enhanced fat-suppressed T1-weighted images, besides stan-
dard subtraction images [30]. For further improvement of therapy response predic-
tion and monitoring, other advanced imaging approaches are being evaluated.
These include the quantitative dynamic contrast-enhanced imaging, advanced
DWI techniques, and spectroscopic imaging, which are under investigation for the
prediction of neoadjuvant therapy effects [31]. With the advent of artificial intel-
ligence (AI) and machine learning, the large data sets provided by and potentially
extractable from breast MRI make it suitable for AI applications. Recent develop-
ments in predicting the tumor response to the NST show promising results in
objective interpretation of MR images using AI methods in personalized care for
breast cancer patients [32]. However, there still no consensus on its broad
application.
16.5.1 When to Assess Tumor Response
Imaging evaluation should be started prior to treatment, to identify the extent of

disease. The ideal time for response analysis depends on the treatment, which can
be performed in 6–9 weeks, and some authors suggest immediately after the first
cycle of neoadjuvant therapy. Assessing the response at the beginning of treatment
expands the clinical applications, detecting resistant tumor and avoiding the unnec-
essary toxicity of chemotherapeutic agents. Furthermore, previous studies suggest
that MRI at the beginning of neoadjuvant treatment is more accurate and a stronger
predictor of pCR than MRI after NST [33, 34]; however, it is currently mostly
restricted to adaptive clinical trials. Early evaluation of tumor response could also
allow to anticipate the timing of surgery if the tumor is found to be refractory to
neoadjuvant therapy. Lastly, imaging after the completion of NST is important, as it
evaluates residual disease to allow preoperative planning. However, with or without
preceding NAC, preoperative MRI has not been proven to be associated with
improved surgical outcomes or recurrence rates [35].
16.5.2 How to Assess Residual Tumor with MRI
The first step for suitable evaluation is cognizing the factors that affect the accuracy
of MRI in demonstrating residual disease after NST, in order to adopt a tailored
interpretation strategy. These factors include image acquisition parameters, meth-
ods of administration of contrast material, the histologic type of the tumor (ductal
vs lobular), and the status of the tumor’s HR and HER2 receptors. The size of lobu-
lar or HR-positive/ HER2-negative cancers tended to be underestimated on MRI
compared to ductal or other subtypes, respectively (Fig. 16.6) [36]. In cases of
HR-positive cancers, late phases of postcontrast MRI are better to evaluate response.
In addition, factors such as therapy agents and baseline tumor morphology may
modulate the MRI accuracy in identifying residual disease (see below).
To assess response to NST, changes in maximum tumor size, tumor volume, and
enhancement kinetics have been used, as well as functional techniques, including
various DWI, and molecular imaging techniques are being investigated [30]. The
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines are stan-
dardized criteria widely used for response assessment [37]. Based upon measure-
ment of a solid tumor in at least the longest diameter, four response categories are
recognized: complete response, partial response, stable disease, and progressive
disease (Table 16.2). Due to its emphasis on changes in lesion size and the unique
a b c
Fig. 16.6 A 50-year-old woman with invasive ductal carcinoma (estrogen receptor-positive and
HER2-negative). (a) Prechemotherapy MRI shows a 6.0 cm irregular enhancing mass (arrows). (b)
MRI obtained after completion of four cycles of doxorubicin/cyclophosphamide followed by four
cycles of docetaxel in the early post-contrast phase (90 seconds) shows an 0.3 cm enhancing lesion
(arrow). (c) An image obtained in the delayed phase (360 seconds) shows the lesion measuring
0.5 cm (arrow). Surgical histopathology revealed a 4.8 cm invasive ductal carcinoma and 5.0 cm
total tumor size (including both invasive tumor and ductal carcinoma in situ). (Reprinted with
permission from Reig et al. [47]. https://doi.org/10.1002/jmri.27145)
Table 16.2 Evaluation of target and nontarget lesions according to Response Evaluation Criteria
in Solid Tumors (RECIST), version 1.1
Type of lesion and response Criteria
Target lesion
Complete response (CR) Disappearance of all target lesions
Partial response (PR) Decrease in the sum of the diameters of the target lesions ≥30%
Progressive disease (PD) Increase in the sum of the diameters of the target lesions ≥20%
Appearance of new lesions
Stable disease Does not meet criteria for CR, PR, or PD
Non-target lesion
Complete response (CR) Disappearance of all non-target lesions
Non-CR/non-PD Persistence of non-target lesions
Progressive disease (PD) Appearance of new lesions
Unequivocal progression of the non-target lesions
features of breast cancer, RECIST may not be reliable in this setting, being criti-
cized for failing to capture meaningful changes in tumor biology [38].
The measurement of the functional tumor volume was a better predictor of
response than the change in the longest diameter, as shown in the American College
of Radiology Imaging Network (ACRIN) 6657 trial [34]. Furthermore, tumor vol-
ume change was found to be a predictor of recurrence-free survival even as early as
after one cycle of chemotherapy (Fig. 16.7) [27].
Changes in time-signal intensity curve analysis or pharmacokinetic parameters
may also be helpful in predicting response [39], with an early decrease in enhance-
ment as an important predictor of response [40, 41].
Likewise, the apparent diffusion coefficient (ADC) has shown promise for
detecting early response to therapy, with an increase in ADC after treatment as a
predictor of response (Fig. 16.8). Although it sounds appealing, the use of DWI as
an exclusive method to visualize residual disease is limited by its lower spatial reso-
lution compared with DCE-MR imaging [42, 43].
The combination of changes in volumetric and functional assessment of the
tumor may improve the specificity of the diagnosis; however, large-scale studies
with standardized image acquisition are needed to implement these parameters as
alternatives to conventional size measurements.
Still, to date there is no uniformly accepted method to obtain response assess-
ment. In order to lead to a more standardized and less subjective evaluation of breast
MRI acquisitions, a proposal for response types follows:
–– Complete response: defined as total disappearance of the lesion (Fig. 16.9),

being more unusual in separated or replaced lesions. The absence of enhance-
ment in the tumor bed at visual assessment is the most commonly used imaging
criterion for pCR, correlating well for HER2-positive and triple-negative sub-
types, whereas this correlation is substantially weaker in HR-positive breast can-
cers [44, 45]. Note that complete radiologic response is different from the
complete pathological response, which is most commonly defined as no residual
a b
c d
Fig.16.7 A 57-year-old woman with invasive ductal carcinoma. (a) Prechemotherapy maximal
intensity projection (MIP) image of contrast-enhanced MRI shows a 4.5 cm irregular mass (arrow).
(b) Post chemotherapy MIP image of contrast-enhanced MRI shows a 1.7 cm irregular mass
(arrow) [(4.5–1.7)/4.5] × 100 = 62% reduction of the initial tumor diameter, suggestive of partial
response. Computer-aided volumetry (red and yellow color) shows a 95% volume reduction from
27.4 cc (c) to 1.5 cc (d). (Reprinted with permission from Reig et al. [47]. https://doi.org/10.1002/
jmri.27145)
a b c
d e f
Fig. 16.8 A 44-year-old woman with invasive ductal carcinoma. (a) Prechemotherapy contrast-
enhanced subtraction T1-weighted MRI shows an enhancing mass in the left breast (arrow). The
maximal diameter of the mass was measured up to 7.4 cm. (b) After the first cycle of chemother-
apy, the mass was measured up to 5.7 cm (arrow). (c) After the eight cycle of chemotherapy, the
mass is not seen. ADC maps using b = 0 and 750 s/mm2 at baseline (d), post-first cycle (e), and
post-eight cycle chemotherapy timepoints (f) show the signal intensity increases after chemother-
apy. The ADC value for the lowest signal intensity of the tumor was 1.103 × 10−3 mm2/sec,
1.463 × 10−3 mm2/sec, and 2.162 × 10−3 mm2/sec, respectively. %ΔADC was 32.6% at post-first
cycle chemotherapy. The patient underwent surgery, and surgical histopathology revealed no resid-
ual invasive ductal carcinoma. (Reprinted with permission from Reig et al. [47]. https://doi.
org/10.1002/jmri.27145)
invasive disease or no residual invasive and in situ disease in the breast and axilla
[46]. As MRI cannot reliably distinguish between invasive disease and ductal
carcinoma in situ (DCIS), defining pCR as no residual invasive disease will
increase MRI overestimation rates, as MRI identifies residual DCIS that is not
counted in final pathology [47]. It is important to evaluate MRI enhancement in
both early and delayed phases in any patient after NST to reduce underestimation
of risk of residual disease, mainly in patients undergoing antiangiogenic thera-
pies [48]. Although some groups have found that late enhancement may be seen
in HER2+ cancers without residual disease [49], studies evaluating MRI param-
eters by breast cancer subtype are needed to further elucidate these findings.
Lastly, remember that BI-RADS category 6 must be used even in cases of com-
plete response.
–– Partial response: tumor assessment on MRI might be challenging, as NST
causes various histopathological changes in tumor cellularity, causing some
tumors to show concentric shrinkage pattern (usually single mass) [50], while
others may crumble (“fragmentation”) into scattered islands of tumor cells
(Fig. 16.10). In the latter case, a response is present, but the area of residual dis-
ease may remain similar to that prior to treatment. In addition, it is difficult to
determine whether the multinodular enhancing lesions are residual invasive can-
cer, DCIS, or a reactive change after therapy [36]. A shrinkage pattern has also
been found to be associated with tumor molecular subtype [51], with HER2+
tumors more likely to demonstrate concentric shrinkage, and HR-tumors are
a b
c d
Fig. 16.9 A 38-year-old woman with triple-negative invasive ductal carcinoma of the right breast.
Axial subtraction MRI: Image acquired before the NST demonstrates (a) a right breast mass
(arrow) and (b) pathological lymph nodes (arrow). (c, d) Images after neoadjuvant chemotherapy
show resolution of all lesions characterizing complete response. PCR confirmed after breast-
conserving surgery
more likely to demonstrate a mixed pattern of concentric and crumbling

shrinkage.
–– Stable disease: unchanged compared with the baseline study, with unchanged
defined as an enhancement rate of +/− 20% of baseline. It is usually related with
tumor chemoresistance and strongly predictive of nonresponse by the end of
therapy [47].
TYPES OF PARTIAL RESPONSE
CONCENTRIC SHRINKAGE FRAGMENTATION
Fig. 16.10 Shrinkage patterns after neoadjuvant therapy includes concentric shrinkage and reduc-
tion into residual nodular lesions (fragmentation)
–– Progressive disease: it represents the minority of cases and occurs with an

increase in the size of lesion or appearance of new lesions. As breast cancer is a
complex heterogeneous disease, primary tumor and micro metastases don’t nec-
essarily respond to the same therapy; thus, radiologists should be aware of pro-
gressive disease outside the primary tumor (Fig. 16.11) [38].
16.5.3 Pearls and Pitfalls in the Assessment of Response
Although MRI performs better than conventional modalities overall, it does have
limits due to false-positive and false-negative results. Studies have found that MRI
underestimated residual disease in 10% of cases and overestimated in 33% of cases
by up to 1.0 cm [52, 53]. The potential clinical impact of overestimation of residual
tumor is the resection of a larger amount of tissue during breast conservation sur-
gery, which may negatively alter cosmetic outcome or influence a decision for
mastectomy. The impact of underestimation of residual tumor is the potential for
an incomplete resection with positive margins and the need for surgical
re-excision.
Thus, it is important to be aware of the following factors [36, 47, 54–56]:
a b c
d e f
Fig. 16.11 A 31-year-old female with invasive breast carcinoma (not otherwise specified). Pre- (a)
and post-therapy (d) MIP image shows an irregular and indistinct mass that decreased into a frag-
mented pattern after NST. Despite a partial response from the index lesion, new lesions have
appeared on the lower outer quadrant of the right breast (e – circle) and left breast (f - circle), not
shown on prechemotherapy images (b, c), characterizing progressive disease
16.5.3.1 Causes of Underestimation of Residual Disease
–– Invasive cancer cells without mass formation may be underestimated due to

their nonconcentric shrinkage pattern.
–– Residual disease may only enhance in late phases of postcontrast MRI, particu-
larly for HR-positive breast cancer.
–– Invasive lobular carcinoma tends to be underestimated on MRI due to its
growth pattern, subtle enhancement, distribution that mimics the normal breast
parenchyma, and higher HR positivity.
–– The anti-vascular effect of taxane-containing neoadjuvant chemotherapy
may result in the decrease or resolution of enhancement despite residual disease.
16.5.3.2 Causes of Overestimation of Residual Disease
–– Fibrosis or posttreatment changes (inflammation and granulation tissue) in

the original tumor bed may contribute to the remaining contrast enhancement
despite the treatment response, mimicking residual cancer.
–– Mucinous or necrotic tumor may leave residual masses even without residual
cancer. On mucinous carcinoma, persistent pools of mucin result in a continuous
mass effect, so subsequent images may suggest a minimal response or even pro-
gressive disease despite an excellent pathological response (Fig. 16.12).
a b
Fig. 16.12 A 40-year-old female with left invasive mucinous carcinoma (luminal B). (a) MIP
image shows diffuse non-mass enhancement in the left breast that persists after NST (b). Despite
the extent of enhancement in MRI, postoperative histopathologic findings showed an excellent
pathological response (low cellularity)
–– Fibroadenomas and other benign lesions may be stable after therapy, and biopsy
may be required to differentiate them from residual disease.
16.5.4 Challenging Lesions for Assessment of Response
MRI has a significant role in some lesions that are difficult to assess by other modal-
ities, especially in response to nonmeasurable lesions. In addition to non-mass
enhancement, MRI is also useful in evaluating inflammatory breast cancer and com-
plex cystic lesion.
The diagnosis of IBC is clinical, with a combination of skin changes and breast
enlargement presenting rapidly (few weeks or few months), with or without an
underlying palpable mass. MRI can detect a primary breast lesion in 98% of the
cases, and the most common finding is an index mass or multiple small masses.
Skin abnormalities, such as thickening, edema, and cutaneous masses or enhancing
foci, are also better detected with MRI than other modalities. As the disease is best
seen with MRI, response prediction and residual tumor size correlation with final
pathology are also better with MRI than ultrasound or mammography [57]. Note
that the assessment of the post-therapy response of the skin and nipple-areola com-
plex thickening is limited and should be valued when these structures enhance,
especially in a nodular and irregular pattern (Fig. 16.13).
Furthermore, the exact extent of the tumor in complex solid-cystic lesions may
be difficult to delineate. MRI allows the identification of intratumoral necrosis when
there is a very high signal intensity (similar to water) within the tumor in the fat-
suppressed T2-weighted MRI scans [58]. In these cases, it is important to measure
and follow the entire lesion and also the solid component, as necrotic tumors may
leave residual acellular masses.
a b
c d
COMPLETE RESIDUAL
PATHOLOGICAL DISEASE
RESPONSE
Fig. 16.13 Skin and nipple assessment of two different patients with inflammatory breast cancer
(MRI T1W CE with subtraction). Images on the left from the same patient who presented global
skin thickening of the right breast (a – arrowhead) that decreased after NST (c). Final pathologic
findings after mastectomy surgery showed complete pathologic response. On the other hand,
images on the right from another patient show diffuse non-mass enhancement with retraction and
enhancement of nipple-areola complex (b – circle) in addition to skin enhancement that persists
after NST (d – arrow), characterizing residual disease
16.6 Lymph Node Evaluation
NST can be used to reduce tumor burden and downstage the axilla, with pCR rates
of 50–60% in the axillary lymph nodes (LN) [59]. In patients who are expected to
achieve axillary pCR, omission of axillary LN dissection could prevent morbidity
and complications such as lymphedema; therefore, sentinel LN biopsy (SLNB)
could be an alternative surgical method [60]. Regarding axillary management after
NST, two prospective observational trials – the Alliance Z1071 and SENTINA
Fig. 16.14 Illustration of

suspicious axillary lymph
(ALN) node on ultrasound.
Ultrasound image of
metastatic ALN showing
irregular shape, thickened
hypoechoic cortex (>
3 mm), and deformity or
absence of hyperechoic
fatty hilum by compression
(white arrows)
trials – suggested that if at least three sentinel LNs were obtained; then SLNB could
be sufficient in patients who become clinically node-negative after NST [59, 61].
However, the overall false-negative rates of the two aforementioned studies were
13–14%, which is above the accepted cutoff value of 10%. Thus, axillary LN dis-
section has been the standard treatment in clinically node-positive breast cancer
after NST due to the lack of consensus in the selection of proper candidates for
SLNB [62] (see Chap. 4).
According to the American College of Radiology (ACR) Appropriateness
Criteria, the most accurate imaging modality in the assessment of residual disease
after NST is MRI for primary breast cancer and US for axillary LN [63].
Although some controversies remain with unsatisfactory false-negative rates, US
is still known to be the most accurate modality in the evaluation of the axillary LN
in NST setting [64, 65].
MRI may also play a role in evaluating LN; however, the sensitivity of post neo-
adjuvant MRI in the detection of persistent LN metastasis is only moderate, ranging
from 61% to 72% [66, 67]. Likewise, axillary regions may be insufficiently included
in MR images.
Suspicious features of axillary LNs include cortical thickening of more than
3 mm, round or irregular shape, or loss of fatty hilum [68] (Fig. 16.14). While a cut
of a value of 3 mm of cortical thickness is used, a small residual metastatic focus
can be missed, or fibrosis and reactive enlargement of 3 mm may be misinterpreted
as residual disease [69].
Note that radiological and pathological response to NST in the breast and axilla
are often correlated, but a proportion of patients (14.4%) have different responses in
the two sites [69] (Fig. 16.15). Therefore, it is recommended that the axilla and the
breast should be viewed and assessed as two separate entities for treatment planning.
a b
c d
Fig. 16.15 T1W CE MRI in a 60-year-old female with triple-negative invasive ductal carcinoma
in the right breast. Upper images demonstrate baseline MRI: (a) irregular mass in the right breast;
(b) pathologic axillary lymph node (arrow). Bottom images: post-NST MRI shows an increase in
the diameter of the breast mass and evidence of muscular and skin invasion (c), characterizing
progressive breast disease. Even so, there was a reduced lymph node as shown in (d) (arrowheads),
and no axillary metastasis was found at surgery, which impacted the management of the axilla. The
response to NST in the breast and axilla is not always similar, so it is important to evaluate them
separately
References
1. Croshaw R, Shapiro-Wright H, Svensson E, Erb K, Julian T. Accuracy of clinical examination,

digital mammogram, ultrasound, and MRI in determining postneoadjuvant pathologic tumor
response in operable breast cancer patients. Ann Surg Oncol. 2011;18(11):3160–3. https://doi.
org/10.1245/s10434-011-1919-5.
2. Keune JD, Jeffe DB, Schootman M, Hoffman A, Gillanders WE, Aft RL. Accuracy of ultra-
sonography and mammography in predicting pathologic response after neoadjuvant che-
motherapy for breast cancer. Am J Surg. 2010;199(4):477–84. https://doi.org/10.1016/j.
amjsurg.2009.03.012.
3. Lehman C. ACR practice parameter for the performance of contrast-enhanced magnetic reso-
nance imaging (MRI) of the breast. Am Coll Radiol. 2013. Available at: https://www.acr.org/-/
media/ACR/Files/Practice-Parameters/mr-contrast-breast.pdf
4. Mann RM, Kuhl CK, Kinkel K, Boetes C. Breast MRI: guidelines from the European Society of
Breast Imaging. Eur Radiol. 2008;18(7):1307–18. https://doi.org/10.1007/s00330-008-0863-7.
5. Herrada J, Iyer RB, Atkinson EN, Sneige N, Buzdar AU, Hortobagyi GN. Relative value of
physical examination, mammography, and breast sonography in evaluating the size of the pri-
mary tumor and regional lymph node metastases in women receiving neoadjuvant chemo-
therapy for locally advanced breast carcinoma. Clin Cancer Res. 1997;3(9):1565–9.
6. Vinnicombe SJ, MacVicar AD, Guy RL, Sloane JP, Powles TJ, Knee G, Husband JE. Primary
breast cancer: mammographic changes after neoadjuvant chemotherapy, with pathologic cor-
relation. Radiology. 1996;198(2):333–40. https://doi.org/10.1148/radiology.198.2.8596827.
7. von Minckwitz G, Dan Costa S, Eiermann W, Blohmer JU, Tulusan AH, Jackisch C, Kaufmann
M. Maximized reduction of primary breast tumor size using preoperative chemotherapy with
doxorubicin and docetaxel. J Clin Oncol. 1999;17(7):1999–2005. https://doi.org/10.1200/
jco.1999.17.7.1999.
8. Yeh E, Slanetz P, Kopans DB, Rafferty E, Georgian-Smith D, Moy L, Halpern E, Moore
R, Kuter I, Taghian A. Prospective comparison of mammography, sonography, and MRI in
patients undergoing neoadjuvant chemotherapy for palpable breast cancer. Am J Roentgenol.
2005;184(3):868–77. https://doi.org/10.2214/ajr.184.3.01840868.
9. Rosen EL, Blackwell KL, Baker JA, Soo MS, Bentley RC, Yu D, Samulski TV, Dewhirst
MW. Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemo-
therapy. Am J Roentgenol. 2003;181(5):1275–82. https://doi.org/10.2214/ajr.181.5.1811275.
10. Scheel JR, Kim E, Partridge SC, et al. MRI, clinical examination, and mammography for pre-
operative assessment of residual disease and pathologic complete response after neoadjuvant
chemotherapy for breast cancer: ACRIN 6657 trial. Am J Roentgenol. 2018;210(6):1376–85.
https://doi.org/10.2214/AJR.17.18323.
11. Huber S, Wagner M, Zuna I, Medl M, Czembirek H, Delorme S. Locally advanced breast
carcinoma: evaluation of mammography in the prediction of residual disease after induction
chemotherapy. Anticancer Res. 2000;20(1B):553–8.
12. Förnvik D, Zackrisson S, Ljungberg O, Svahn T, Timberg P, Tingberg A, Andersson I. Breast
tomosynthesis: accuracy of tumor measurement compared with digital mammography and ultra-
sonography. Acta Radiol. 2010;51(3):240–7. https://doi.org/10.3109/02841850903524447.
13. Adrada BE, Huo L, Lane DL, Arribas EM, Resetkova E, Yang W. Histopathologic correla-
tion of residual mammographic microcalcifications after neoadjuvant chemotherapy for
locally advanced breast cancer. Ann Surg Oncol. 2015;22(4):1111–7. https://doi.org/10.1245/
s10434-014-4113-8.
14. Kuhl CK. MRI of breast tumors. Eur Radiol. 2000;10(1):46–58. https://doi.org/10.1007/
s003300050006.
15. Helvie MA, Joynt LK, Cody RL, Pierce LJ, Adler DD, Merajver SD. Locally advanced
breast carcinoma: accuracy of mammography versus clinical examination in the prediction of
residual disease after chemotherapy. Radiology. 1996;198(2):327–32. https://doi.org/10.1148/
radiology.198.2.8596826.
16. Moskovic EC, Mansi JL, King DM, Murch CR, Smith IE. Mammography in the assessment of
response to medical treatment of large primary breast cancer. Clin Radiol. 1993;47(5):339–44.
https://doi.org/10.1016/S0009-9260(05)81451-5.
17. Patel BK, Hilal T, Covington M, Zhang N, Kosiorek HE, Lobbes M, Northfelt DW, Pockaj
BA. Contrast-enhanced spectral mammography is comparable to MRI in the assess-
ment of residual breast cancer following neoadjuvant systemic therapy. Ann Surg Oncol.
2018;25(5):1350–56. https://doi.org/10.1245/s10434-018-6413-x.
18. Iotti V, Ravaioli S, Vacondio R, Coriani C, Caffarri S, Sghedoni R, et al. Contrast-enhanced
spectral mammography in neoadjuvant chemotherapy monitoring: a comparison with breast
magnetic resonance imaging. Breast Cancer Res. 2017;19(1):106. https://doi.org/10.1186/
s13058-017-0899-1.
19. Chagpar AB, Middleton LP, Sahin AA, et al. Accuracy of physical examination, ultrasonog-
raphy, and mammography in predicting residual pathologic tumor size in patients treated
with neoadjuvant chemotherapy. Ann Surg. 2006;243(2):257–64. https://doi.org/10.1097/01.
sla.0000197714.14318.6f.
20. Peintinger F, Kuerer HM, Anderson K, et al. Accuracy of the combination of mammography
and sonography in predicting tumor response in breast cancer patients after neoadjuvant chemo-
therapy. Ann Surg Oncol. 2006;13(11):1443–9. https://doi.org/10.1245/s10434-006-9086-9.
21. Ollivier L, Balu-Maestro C, Leclére J. Imaging in evaluation of response to neo-
adjuvant breast cancer treatment. Cancer Imaging. 2005;5(1):27–31. https://doi.
org/10.1102/1470-7330.2005.0009.
22. Roubidoux MA, LeCarpentier GL, Fowlkes JB, Bartz B, Pai D, Gordon SP, Schott AF,
Johnson TD, Carson PL. Sonographic evaluation of early-stage breast cancers that undergo
neoadjuvant chemotherapy. J Ultrasound Med. 2005;24(7):885–95. https://doi.org/10.7863/
jum.2005.24.7.885.
23. Cao X, Xue J, Zhao B. Potential application value of contrast-enhanced ultrasound in neoadju-
vant chemotherapy of breast cancer. Ultrasound Med Biol. 2012;38(12):2065–71. https://doi.
org/10.1016/j.ultrasmedbio.2012.07.027.
24. Alvarez S, Añorbe E, Alcorta P, López F, Alonso I, Cortés J. Role of sonography in the diagno-
sis of axillary lymph node metastases in breast cancer: a systematic review. Am J Roentgenol.
25. Mano MS, Awada A. Primary chemotherapy for breast cancer: the evidence and the future.
Ann Oncol. 2004;15:1161–71.
26. Maur M, Guarneri V, Frassoldati A, Conte PF. Primary systemic therapy in operable breast
cancer: clinical data and biological fall-out. Ann Oncol. 2006;17 Suppl 5:158–64.
27. Hylton NM, Blume JD, Bernreuter WK, et al. Locally advanced breast cancer: MR imaging
for prediction of response to neoadjuvant chemotherapy—results from ACRIN 6657/I-SPY
TRIAL. Radiology. 2012;263(3):663–72.
28. Pediconi F, Miglio E, Telesca M, et al. Effect of preoperative breast magnetic resonance imaging
on surgical decision making and cancer recurrence rates. Investig Radiol. 2012;47(2):128–35.
29. Pettit K, Swatske ME, Gao F, et al. The impact of breast MRI on surgical decision-making: are
patients at risk for mastectomy? J Surg Oncol. 2009;100(7):553–8.
30. Le-Petross HT, Lim B. Role of MR imaging in neoadjuvant therapy monitoring. Magn Reson
Imaging Clin N Am. 2018;26:207–20.
31. Mann RM, Cho N, Moy L. Breast MRI: state of the art. Radiology. 2019;292:520–36.
32. Codari M, Schiaffino S, Sardanelli F, Trimboli RM. Artificial intelligence for breast MRI in
2008–2018: a systematic mapping review. AJR. 2019;212:280–92.
33. Goorts B, Dreuning KMA, Houwers JB, Kooreman LFS, Boerma EG, Mann RM, et al. MRI-
based response patterns during neoadjuvant chemotherapy can predict pathological (complete)
response in patients with breast cancer. Breast Cancer Res. 2018:20–34.
34. Hylton NM, Gatsonis CA, Rosen MA, Lehman CD, Newitt DC, Partridge SC, et al. Neoadjuvant
chemotherapy for breast cancer: functional tumor volume by MR imaging predicts recurrence-
free survival—results from the ACRIN 6657/CALGB 150007 I-SPY 1 TRIAL. Radiology.
2016;279(1):44–55.
35. Hylton NM. Residual disease after neoadjuvant therapy for breast cancer: can MRI help?
Radiology. 2018;289(2):335–6.
36. Kim TH, Kang DK, Yim H, Jung YS, Kim KS, Kang SY. Magnetic resonance imaging patterns
of tumor regression after neoadjuvant chemotherapy in breast cancer patients: correlation with
pathological response grading system based on tumor cellularity. J Comput Assist Tomogr.
2012;36:200–6.
37. Watanabe H, Okada M, Kaji Y, Satouchi M, Sato Y, Yamabe Y, et al. New response evaluation
criteria in solid tumours – revised RECIST guideline (version 1.1). JPN J Cancer Chemother.
2009;36(13):2495–501.
38. Kuhl CK, Alparslan Y, Schmoee J, Sequeira B, Keulers A, Brümmendorf TH, Keil S. Validity
of RECIST version 1.1 for response assessment in metastatic cancer: a prospective, multi-
reader study. Radiology. 2019;290(3):349–56.
39. Martincich L, Montemurro F, De Rosa G, et al. Monitoring response to primary chemotherapy
in breast cancer using dynamic contrast-enhanced magnetic resonance imaging. Breast Cancer
Res Treat. 2004;83(1):67–76.
40. Ah-See ML, Makris A, Taylor NJ, et al. Early changes in functional dynamics magnetic reso-
nance imaging predict for pathologic response to neoadjuvant chemotherapy in primary breast
cancer. Clin Cancer Res. 2008;14(20):6580–9.
41. Dogan BE, Yuan Q, Bassett R, et al. Comparing the performances of magnetic resonance
imaging size vs pharmacokinetic parameters to predict response to neoadjuvant chemotherapy
and survival in patients with breast cancer. Curr Probl Diagn Radiol. 2019;48(3):235–40.
42. Partridge SC, Zhang Z, Newitt DC, et al. Diffusion-weighted MRI findings predict patho-
logic response in neoadjuvant treatment of breast cancer: the ACRIN 6698 multicenter trial.
Radiology. 2018;289(3):618–27.
43. Chu W, Jin W, Liu D, et al. Diffusion-weighted imaging in identifying breast cancer pathologi-
cal response to neoadjuvant chemotherapy: a meta-analysis. Oncotarget. 2017;9(6):7088–100.
44. Chen CA, Hayward JH, Woodard GA, Ray KM, Starr CJ, Hylton NM, et al. Complete breast
MRI response to neoadjuvant chemotherapy and prediction of pathologic complete response.
J Breast Imaging. 2019;1(3):217–22.
45. Santamaría G, Bargalló X, Fernández PL, Farrús B, Caparrós X, Velasco M. Neoadjuvant systemic
therapy in breast cancer: association of contrast-enhanced MR imaging findings, diffusion-weighted
imaging findings, and tumor subtype with tumor response. Radiology. 2017;283(3):663–72.
46. US Department of Health and Human Services Food and Drug Administration Center for Drug
Evaluation and Research. Guidance for industry: Pathological complete response in neoad-
juvant treatment of highrisk early-stage breast cancer (version 2020). Accessed October 1,
2020. Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/default.htm
47. Reig B, Heacock L, Lewin A, Cho N, Moy L. Role of MRI to assess response to neoadju-
vant therapy for breast cancer. J Magn Reson Imaging. 2020;52(6). https://doi.org/10.1002/
jmri.27145.
48. Kim SY, Cho N, Park IA, et al. Dynamic contrast-enhanced breast MRI for evaluating residual
tumor size after neoadjuvant chemotherapy. Radiology. 2018;289(2):327–34.
49. Kim Y, Sim SH, Park B, et al. Magnetic resonance imaging (MRI) assessment of residual
breast cancer after neoadjuvant chemotherapy: relevance to tumor subtypes and MRI interpre-
tation threshold. Clin Breast Cancer. 2018;18(6):459–67. e451
50. Negrão EMS, Souza JA, Marques EF, Bitencourt AGV. Breast cancer phenotype influences
MRI response evaluation after neoadjuvant chemotherapy. Eur J Radiol. 2019;120:108701.
51. Ballesio L, Gigli S, Di Pastena F, et al. Magnetic resonance imaging tumor regression shrink-
age patterns after neoadjuvant chemotherapy in patients with locally advanced breast cancer:
correlation with tumor biological subtypes and pathological response after therapy. Tumour
Biol. 2017;39(3):1010428317694540. https://doi.org/10.1177/1010428317694540.
52. Rosen EL, Blackwell KL, Baker JA, et al. Accuracy of MRI in the detection of residual breast
cancer after neoadjuvant chemotherapy. AJR Am J Roentgenol. 2003;181(5):1275–82.
53. Lorenzon M, Zuiani C, Londero V, et al. Assessment of breast cancer response to neoadjuvant
chemotherapy: is volumetric MRI a reliable tool? Eur J Radiol. 2009;71(1):82–8.
54. Schrading S, Kuhl CK. Breast cancer: influence of Taxanes on response assessment with
dynamic contrast-enhanced MR imaging. Radiology. 2015;277(3):687–96.
55. Chen JH, Bahri S, Mehta RS, et al. Impact of factors affecting the residual tumor size diag-
nosed by MRI following neoadjuvant chemotherapy in comparison to pathology. J Surg Oncol.
2014;109(2):158–67.
56. Kopans DB. Breast imaging. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
57. Shin HJ, Kim HH, Ahn JH, et al. Comparison of mammography, sonography, MRI and clinical
examination in patients with locally advanced or inflammatory breast cancer who underwent
neoadjuvant chemotherapy. Br J Radiol. 2011;84(1003):612–20.
58. Kawashima H, Inokuchi M, Furukawa H, Kitamura S. Triple-negative breast cancer: are the
imaging findings different between responders and nonresponders to neoadjuvant chemother-
apy? Acad Radiol. 2011;18(8):963–9.
59. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant
chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance)
clinical trial. JAMA. 2013;310(14):1455–61.
60. Pilewskie M, Morrow M. Axillary nodal management following neoadjuvant chemotherapy: a

review. JAMA Oncol. 2017;3(4):549–55.
61. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast can-
cer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort
study. Lancet Oncol. 2013;14:609–18.
62. Hennessy BT, Hortobagyi GN, Rouzier R, et al. Outcome after pathologic complete eradica-
tion of cytologically proven breast cancer axillary node metastases following primary chemo-
therapy. J Clin Oncol. 2005;23(36):9304–11.
63. Expert Panel on Breast Imaging; Slanetz PJ, Moy L, et al. ACR appropriateness criteria®
monitoring response to neoadjuvant systemic therapy for breast cancer. J Am Coll Radiol.
2017;14(11S):S462–75.
64. Boughey JC, Ballman KV, Hunt KK, et al. Axillary ultrasound after neoadjuvant chemother-
apy and its impact on sentinel lymph node surgery: results from the american college of sur-
geons oncology group Z1071 trial (Alliance). J Clin Oncol. 2015;33(30):3386–93.
65. Le-Petross HT, McCall LM, Hunt KK, et al. Axillary ultrasound identifies residual nodal dis-
ease after chemotherapy: results from the american college of surgeons oncology group Z1071
trial (Alliance). AJR Am J Roentgenol. 2018;210(3):669–76.
66. Hieken TJ, Boughey JC, Jones KN, Shah SS, Glazebrook KN. Imaging response and residual
metastatic axillary lymph node disease after neoadjuvant chemotherapy for primary breast
cancer. Ann Surg Oncol. 2013;20(10):3199–204.
67. You S, Kang DK, Jung YS, An YS, Jeon GS, Kim TH. Evaluation of lymph node status after
neoadjuvant chemotherapy in breast cancer patients: comparison of diagnostic performance
of ultrasound, MRI and 18F-FDG PET/CT. Br J Radiol. 2015;88(1052):20150143. https://doi.
org/10.1259/bjr.20150143.
68. Saffar B, Bennett M, Metcalf C, Burrows S. Retrospective preoperative assessment of
the axillary lymph nodes in patients with breast cancer and literature review. Clin Radiol.
2015;70:954–9.
69. Morgan C, Stringfellow TD, Rolph R, Kovacs T, Kothari A, Pinder SE, Hamed H, Sever
AR. Neoadjuvant chemotherapy in patients with breast cancer: does response in the breast
predict axillary node response? Eur J Surg Oncol. 2020;46(4 Pt A):522–6.
Chapter 17
Postoperative Breast
Larissa Muramoto Yano and Monica Akahoshi Rudner
17.1 Normal Postoperative Changes (for Benign Disease)
For the proper examination to be performed, the radiologist and technologist must be
aware of pertinent aspects of the patient’s history, such as signs and symptoms, locations
of masses, pain, and prior surgeries that the patient must indicate in a diagram. Extensive
surgical procedures, such as mammoplasty, must be shown diagrammatically only,
without the use of skin markers. Smaller scars are marked with pieces of thin wire that
are taped to the skin to correlate with possible mammographic findings (Fig. 17.1), but
it may not always correlate with the surgical excision site located deeper in the breast.
The entire surgical area must be included on at least one mammographic view and, if
necessary, additional views, such as spot compression, magnification, and tangential
and various angulations, may be useful and should be performed in the projection where
the area is better and more completely seen. Diagnostic accuracy increases with aware-
ness of how procedures were performed, knowledge of time since surgery, and breast
density (detection and interpretation are more difficult in dense breasts).
Normal postoperative imaging findings include architectural distortion, increased
density and parenchymal scarring, and decrease in severity over time, more rapidly
L. M. Yano
Hospital Albert Einstein, São Paulo, SP, Brazil
M. A. Rudner (*)

Switzerland AG 2022
332 L. M. Yano and M. A. Rudner
a b c
Fig. 17.1 Postoperative scarring. Mammography shows thin wire taped to the skin marking the
cutaneous scar to correlate with possible mammographic findings (a, b). Ultrasound depicted a
hypoechoic irregular area with architectural distortion, with different morphologic aspects in dif-
ferent planes, representing a scar (c, d)
and completely in benign biopsies (Fig. 17.2) or aesthetic procedures (Fig. 17.3).
Immediately after the procedure, mammography will show a round/oval mass or
asymmetric soft-tissue density in the postoperative site representing seroma or
hematoma, with or without air in the biopsy cavity. The incidence of postsurgical
fluid collections reflects the surgical technique. Breast edema usually occurs close
to the incision area and may last for the first 1 or 2 months. Outlined by subcutane-
ous fat, linear parenchymal trabeculations extend toward the skin, representing
engorged lymphatics and interstitial fluid. Depending on the extension of the sur-
gery, the breast enlarges, and mammographic compression is more difficult. As the
edema recedes, the breast size also normalizes. Skin thickening and breast edema
are usually seen together and have similar time courses and resolution. Contralateral
asymmetries may be explained by the absence of equivalent tissue on the operative
side and can be mistaken as an abnormality. If there is doubt, sonography can iden-
tify the fluid-filled nature of the mass (Fig. 17.4). Initially, some hematomas show
internal echoes but most soon become anechoic with posterior acoustic enhance-
ment and may present septa (which do not mean complications). The incision can
occasionally be traced from the biopsy cavity to the skin, which is thickened
(Fig. 17.2). Management of a complex mass requires knowledge of the clinical con-
text. If an abscess is not suspected, observation may be preferred [1].
17 Postoperative Breast 333
a b d e
Fig. 17.2 Normal postoperative aspect. Mammogram 1 month after benign biopsy depicts skin
thickening, architectural distortion, increased density, and parenchymal scarring (a, b). Ultrasound
of the same date shows architectural distortion and scarring of the incision from the biopsy cavity
to the skin, which is thickened (c). Late control shows that these findings had diminished over
time (d, e)
In very rare cases, seroma cavities persist 1 year after a benign biopsy [1].
Generally, after a few weeks to 18 months, the fluid collection is gradually reab-
sorbed; the lesion decreases in size and becomes poorly defined. Areas of radiolu-
cency representing fat entrapped by the developing scar are seen interspersed with
soft-tissue density [1]. Scars change appearance in different projections: a spicu-
lated mass like soft tissue in one view may elongate in other projections. After 1 or
2 years, an evolving scar contracts and shrinks as it matures, and architectural dis-
tortion or a spiculated density may be seen. On sequential mammograms, decrease
in size may be barely perceptible or seen in only one projection. It is important to
note that the linear metallic scar marker on the skin will not always be immediately
adjacent to the surgical bed because the skin is pressed away from the underlying
parenchyma. Preoperative mammograms should always be reviewed, fundamen-
tally if a spiculated mass is found far from the marker, and biopsy may be necessary
to eliminate the possibility of cancer. Ultrasound reveals a hypoechoic spiculated
Fig. 17.3 Increased density and parenchymal scarring after liposuction on the axilla (normal
findings)
a b
Fig. 17.4 Postsurgical seroma/hematoma. Ultrasound depicts the fluid-filled nature of the mass
with the surgical path through the breast tissue up to the skin and hyper-echogenicity of the sur-
rounding parenchyma (a). A 1-year control (b) depicts complete resolution of the fluid collection
with architectural distortion and parenchymal scarring, as well as skin thickening and retraction
mass, and, occasionally, retraction of the scar skin is noted (Figs. 17.1 and 17.5).
History and physical findings in the skin can help distinguish this normal postopera-
tive finding from cancer. Scarring not complicated by fat necrosis is perceived as
induration rather than a mass. The period of change is variable and does not depend
on the type of breast parenchyma, but some aspects can induce the rate of scar for-
mation, such as resection size, postsurgical fluid collection volume, and whether or
Fig. 17.5 Postoperative

scarring. Ultrasound shows
a hypoechoic spiculated
mass in the surgical bed
with posterior shadowing
not it was drained. After 3 to 5 years, between 50 and 55% of cases show complete
resolution of the biopsy cavity, leaving no scar or distortion in the underlying breast
parenchyma [2]. The findings should be stable on subsequent mammograms.
To evaluate calcifications at the surgical site, the same morphological and distri-
butional features used in the preoperative period should be applied to classify the
probability of malignancy. In early stages, they may be quite fine, faint, and difficult
to characterize, usually becoming coarser later on. Dystrophic calcifications may
have similar pathogenesis of secretory disease or ductal ectasia, associated with
areas of necrotic tissue, sloughed cells, and cellular detritus, evolving into scars and
in the subcutaneous tissue under surgical incisions. Tangential mammographic
views to the skin can demonstrate their superficial locations. Calcified remnants of
suture material can also be seen, with several millimeters long and quite wide, pre-
senting as knots, branching linear and double tracking calcifications. If the benign
nature of these calcifications cannot be determined, biopsy is indicated [1].
The thickened skin in the incision may be superimposed on the surgical area
causing a mass-like increased density, particularly when a keloid has formed. A
complementary tangential view to the scar permits separation of the skin and paren-
chymal elements, so the surgical bed can be better accessed. Sonographically, a
band of thickened skin will be seen in the incision [1].
Fat necrosis originates from aseptic fat saponification and is associated with all
types of surgical procedures in the breast. It usually appears as a radiolucent lipid-
filled mass. When symptomatic, fat necrosis may present as a lump. In earlier
phases, a hematoma may be present. In all types of imaging methods, it is a com-
mon finding and sometimes a challenging pitfall, manifesting different presenta-
tions that may be indistinguishable from cancer, depending on the stage of the
process (Fig. 17.6). Mammography is pathognomonic if it shows oily cysts or typi-
cal eggshell rim calcifications around a mass with radiolucent center. There is a
wide range of sonographic presentations that include solid mass, complex mass
with mural masses, complex mass with echogenic bands, anechoic mass with pos-
terior acoustic enhancement, anechoic mass with shadowing, or an isoechoic mass.
The margins of the mass vary from well circumscribed to indistinct or spiculated.
a b c
d e
Fig. 17.6 Fat necrosis. MRI shows an irregular mass, hypointense on axial T1-weighted image
without fat saturation (a) and hyperintense on axial fat-saturated T2-weighted image (b). Axial
contrast-enhanced fat-suppressed T1-weighted MR subtraction image (c) and sagittal contrast-
enhanced fat-suppressed T1-weighted image (d) show homogeneous enhancement. Ultrasound
depicts an irregular, ill-defined, heterogeneous mass (e). Core needle biopsy was consistent with
fat necrosis
On magnetic resonance imaging (MRI), fat necrosis usually presents as a round or

oval mass showing high signal intensity on T1-weighted images without fat satura-
tion, high signal intensity on T2-weighted images without fat saturation, and low
signal intensity on fat-saturated images. T1-weighted fat-suppressed sequences are
helpful in differentiating fat from blood (Figs. 17.7 and 17.8). A fat-fluid level may
be present. Fibrosis may appear as high, intermediate, or low signal on T1-weighted
images. Degree of enhancement depends on the stage of the inflammatory process:
recent lesions may have variable enhancement surrounding them, whereas chronic
lesions show marked irregularity and retraction (scar), generally without enhance-
ment. Needle biopsy may be indicated if the diagnosis of fat necrosis is not certain.
MRI can be very useful in evaluation of the postoperative breast, since it shows
high sensitivity and specificity in differentiation between benign postoperative
changes and malignant tumors, eventually minimizing unnecessary intervention.
The most important factor is the correlation of lesion morphology and enhancement
kinetics following administration of gadolinium contrast material. Skin thickening,
architectural distortion (Fig. 17.9), resolving edema, fat necrosis, signal voids or
signal flare from prior bleeding (hemosiderin), a small focal area of non-mass like
a b c
d e
Fig. 17.7 Fat necrosis. Ultrasound shows an oval, circumscribed, and heterogeneous mass (a).
Axial non-fat-saturated T1-weighted (b), axial fat-saturated T2-weighted (c), sagittal contrast-
enhanced fat-suppressed T1-weighted (d), and axial contrast-enhanced fat-suppressed T1-weighted
MR subtraction images (e) show a T1-hyperintense mass with signal loss on the fat-saturated
images and thin discrete peripheral enhancement
a b c
Fig. 17.8 Fat necrosis. Axial T1-weighted image without fat saturation (a), axial fat-saturated
T2- weighted (b), and axial contrast-enhanced fat-suppressed T1-weighted MR subtraction images
(c) show a T1-hyperintense mass with signal loss on the fat-saturated images and thin discrete
peripheral enhancement
Fig. 17.9 T1-weighted MR images without fat suppression show architectural distortion and scar-
ring on mammoplasty bed (arrows)
enhancement, and thin linear non-mass-like enhancement at the surgical area can all
be expected findings. Non-enhancing areas have a high negative predictive value for
malignancy (88–96%). Postoperative seromas have high signal intensity (fluid-
filled structure signal) on T2-weighted images and smooth, thin rim enhancement.
Benign postoperative changes generally demonstrate more gradual uptake of con-
trast material. Breast hematomas show a varying signal according to the hemoglo-
bin degradation status (high signal on T1-weighted at subacute stage, low signal on
T1/T2-weighted at chronic stage). As they dissipate, fibrous tissue in the site of the
fluid collection can appear as an architectural distortion. Scarring enhancement (a
minimal or small focal area of enhancement or thin linear enhancement) can be seen
for up to 18 months or even longer. At follow-up imaging, the enhancement should
demonstrate stability or progressive decrease [2].
17.2 Aesthetic Breast Surgery
17.2.1 Reduction Mammoplasty and Mastopexy
Mammoplasty and mastopexy are different procedures; the central focus of mam-
moplasty is breast volume reduction (most often performed for macromastia) and
for mastopexy is breast shape. Nevertheless, there are many similarities regarding
the techniques used and also postoperative imaging aspects. The multiplicity of
surgical techniques, with different accesses (inframammary and peri-areolar fold
access; peri-areolar, vertical, and horizontal (inverted T); peri-areolar and vertical;
peri-areolar, vertical and lateral horizontal; isolated peri-areolar), evidence the chal-
lenge to achieve a harmonious and symmetrical aesthetic result, with minimal scar-
ring. The resulting surgery leaves a smaller breast with normal skin visible in the
region of the cleavage. Both surgical procedures may be performed concurrently
with breast conservation therapy. Awareness of normal postoperative imaging fea-
tures of these oncoplastic procedures is important to avoid false-positive results.
The most common surgical procedure involves a circumareolar incision, an
inframammary incision, and a vertical incision between the two (traditional inverted-
T scar, or Wise pattern), with removal of the skin, breast parenchyma, and fat, pre-
dominantly from the lower portion, followed by superior relocation of the nipple
(Fig. 17.9). This will result in elevation of the nipple-areolar complex (NAC) and
reduction of the cutaneous envelope of the breast. With the advent of smaller skin-
incision techniques, new vertical scar techniques feature only one vertical incision
leaving a lollipop-shaped scar, compared with the anchor-shaped appearance of the
inverted-T scar. These smaller skin-incision techniques decrease scarring and dis-
tortion of the inframammary fold, allowing parenchymal rearrangement and pedicle
creation, which maintains blood supply to the NAC [3].
Usually, the nipple is kept attached to the breast ducts, but in very ptotic or very
large breasts, the surgeon may choose to remove the nipple and then graft it back
into the breast, which may increase the risk of nipple necrosis and difficulty breast-
feeding. The new nipple site may have little parenchyma behind it and may result in
a relative shift, resulting in transposition of parenchyma to the dependent portion of
the breast, with nonanatomic distribution, linear strands, parenchymal bands, and
calcifications. Depending on the amount of tissue removed from different areas of
the breast, redistribution of glandular tissue occurs, and breast parenchymal pattern
can be patchy [4]. This fact, associated with scarring, makes comparison with previ-
ous images difficult.
Postoperative mammograms show characteristic skin thickening in the region of
the scars, generally over the lower breast, which is most evident on the mediolateral
oblique or mediolateral view. The lower breast shows architectural distortion, and
its general pattern is distorted from the scar (Fig. 17.10). Fibrous bands can be seen
extending to the repositioned NAC in 20% of the patients, representing scarring
associated with the vascular pedicle (Fig. 17.11) [3]. Fat necrosis or oil cysts are
common findings and may have a characteristic appearance or may be atypical,
forming a palpable mass when symptomatic. Epidermal inclusion cysts can also
form in scars and produce a smooth dense round or oval mass close to the skin sur-
face but not connected to it. They represent epidermal cells displaced into breast
tissue during surgery. Skin calcifications along incisions can be distinguished from
intraparenchymal calcifications or cancer because of their typical skin location.
Periareolar dermal calcifications and thickening related to the repositioned NAC
can be seen; therefore, imaging of the nipple in profile is critical (Fig. 17.12) [3].
Recalls may be higher in this group of patients due to surgical architectural distor-
tions and possible areas of fat necrosis with atypical presentations, but tomosynthe-
sis can resolve some doubts and reduce recall rates.
Fig. 17.10 Mammoplasty. Mammography shows architectural distortion in the lower quadrants,
and breast overall pattern is distorted from the scar
Fig. 17.11 Mastopexy. Fibrous bands extending to the repositioned NAC, representing scarring
associated with the vascular pedicle
17.2.2 Breast Implants
Aesthetic surgery rates are raising worldwide, and the use of silicone breast implants
is the main procedure used in breast augmentation. They were introduced in 1962
by Cronin and Gerow, presenting several modifications in the design, texturing, and
gel cohesiveness over subsequent generations [5]. Approximately 80% is placed for
cosmetic reasons and the other 20% for breast reconstruction after mastectomy [6].
The silicone implants can be positioned via periareolar, axillary, transpapillae, or
inframammary incisions. All implants are placed behind the breast tissue, and sur-
geons will choose the ideal place regarding the pectoralis muscle, which may be
subglandular, subfascial, submuscular, or double plane (Figs. 17.13 and 17.14).
Fig. 17.12 Periareolar

dermal calcifications and
thickening related to the
repositioned NAC can be
seen on mammogram.
Dermal calcifications over
the vertical incision are
also present
Breast implants are not lifetime devices [7, 8]. The older the implants, the more
likely they will require removal or substitution [9, 10]. There is no current evidence
that breast augmentation with silicone implants may present increased risk for
developing connective disorders, breast cancer, no proven delay in breast cancer
detection, and no difference in survival or recurrence rates compared with women
with no augmentation [11–18].
17.2.2.1 Implant Types
Breast implants are classified according to its material, shape, surface texturing, and
number of chambers.
Saline implants are composed of an outer silicone shell and an inner envelope
filled with saline solution. Some are pre-filled, and others can be filled during the
surgical procedure. Single-lumen silicone implants are the most common type and
consist in a silicone elastomer shell filled with silicone made from a synthetic poly-
mer of cross-linked chains of dimethyl siloxane. The inner silicone can have a liq-
uid, gel, or solid consistency depending on the length of the individual chains and
the degree to which these chains are cross-linked.
a b c
d e f
Fig. 17.13 Submuscular implant. Mammogram (a, b), ultrasound (c, d), and MRI (e, f) show the
pectoralis muscle (arrows) over the implant
Saline and silicone implants are either round or anatomic (teardrop) in shape,
and the outer envelope can be textured or smooth (uncoated). Textured coating sta-
bilizes the implant within the breast pocket, reducing the risk of rotation and result-
ing in lower rates of capsular contraction, decreasing the risk of a secondary
procedure. Early texturized implants were coated with polyurethane foam, but they
were withdrawn from the market due to concerns about in vivo degradation to car-
cinogenic compounds [5]. Therefore, implant shells started to be texturized mechan-
ically, creating pores of different sizes [19].
Double-lumen implants/expanders have two envelopes inside one another, and
each can contain saline or silicone gel. It is common to find saline filling the inner
lumen and silicone in the outer lumen, but the opposite can also occur (Fig. 17.15).
Tissue expanders present different sizes and shapes and may have a smooth or tex-
tured outer surface. They are inserted under the breast skin, autologous tissue, or
pectoralis muscle, immediately following mastectomy reconstruction or in subse-
quent surgery months or years later. As soon as possible, the tissue expander is
slowly inflated through a series of saline solution injections or through a patient-
controlled device, which releases carbon dioxide gas into the expander. The objec-
tive is to stretch the patient’s tissue for insertion of an implant or the patient’s own
tissue as part of the reconstruction process (after mastectomy, to reconstruct injured
or congenitally deformed breasts, or as part of gender reassignment surgery).
a b c
d e
Fig. 17.14 Subglandular implant. Mammogram (a, b), ultrasound (c), and MRI (d, e) show the
pectoralis muscle (arrows) behind the implant
Stretching may result in breast tissue damage, skin thinning, pain (especially during
saline filling), rupture, and infection.
Motiva implants present a 3D imprinted surface texturing. Radiofrequency iden-
tification transponders are attached to it and can transmit data about the implant
wirelessly. They have a linear radiopaque appearance on mammography and CT
(Figs. 17.16 and 17.17) and produce an important magnetic susceptibility artefact
on MRI (Fig. 17.17).
Stacked implants are two single-lumen, smooth-surface silicone gel-filled
implants placed one on top of the other, firmly joined in the middle. Both have dif-
ferent volumes, the smaller representing 20% of the entire volume and positioned
anteriorly. Each one has its own separate shell so the filling of each portion is
not shared.
a b c d
e f g h
Fig. 17.15 Double-lumen implants/expander. The inner lumen is filled with saline surrounded by
a smaller outer lumen that contains silicone. Mammogram shows a double contour with a low-
density inner lumen and a high-density outer lumen (a, b). Ultrasound depicts the inner envelope
with undulations that may be mistaken for the stepladder sign (c, d). Axial T1-weighted without fat
suppression (e), axial fat- suppressed T2-weighted (f), axial short T1 inversion-recovery silicone-
excited image (g), and sagittal contrast-enhanced fat-suppressed T1-weighted MR images (h)
demonstrate the inner and outer lumens with different signal intensities, depending on the pulse
sequence
Fig. 17.16 Motiva

implant. Radiofrequency
identification transponder
presents a linear
radiopaque appearance on
mammography
a b c
d e f
Fig. 17.17 Motiva implant. Important magnetic susceptibility artefact on T1-weighted image
without fat suppression (a), short T1 inversion-recovery silicone-excited image (b), fat-suppressed
T2-weighted (c), and contrast-enhanced fat-suppressed T1-weighted MR images (d) related to
Motiva’s transponder. Radiofrequency identification transponder presents a linear radiopaque
appearance on CT (e, f)
17.2.2.2 Mammographic Technique, Normal Aspects,

and Screening Considerations
Although breast implants withstand some degree of compression, some situations

can subject them to so much pressure that the implants may rupture (e.g., during
mammography or closed capsulotomy) [20]. Nevertheless, mammographic views
without the necessary compression decreases the sensitivity of the exam in detect-
ing cancer.
Thus, to potentialize mammography detection rate and minimalize the risk of
implant rupture, the recommendation for each implanted breast is two views that
include the implant and surrounding tissue with limited compression, in addition to
two implant displaced views in which the implant is pushed posteriorly against the
chest wall while the breast tissue is pulled over in front of the implant and strongly
compressed (Eklund Maneuver) (Fig. 17.18). The compression paddle avoids the
implant from reentering the field, reducing implant overlap on breast tissue, improv-
ing image resolution and diagnosis of breast pathologies. This technique may
increase 2–5 cm of additional breast compression, and no ruptures were reported.
However, some breast tissue will always be hidden by the implant even with the
a b c d
e f g h
Fig. 17.18 Modified views for implants (Eklund maneuver). Projections of each breast obtained
with routine positioning show the implants contours and only a small amount of breast tissue (a–
d). Projections of each breast after the implant has been displaced posteriorly and the anterior
breast tissue pulled into the compression plates demonstrate more parenchyma (e–h)
implant-displaced views, and only about 80% of the breast tissue is seen, raising the
concern of a possible reduction in detectability of breast (Fig. 17.19) [21–25].
The recommendation for breast cancer screening is the same as that for patients
with no implants. Presurgical and postsurgical mammograms are useful in distin-
guishing benign postoperative changes from other breast pathologies [25]. Limited-
compression views may display a lesion near the implant not evidenced on
implant-displaced views, because masses on the fibrous capsule can be pushed
away from the field of view after Eklund maneuver [22]. Additional views or tomo-
synthesis may be useful for evaluating abnormalities in patients with implants. All
types of percutaneous biopsies and presurgical localization can be performed in the
presence of implants as well, but an informed consent should be obtained, including
implant rupture as a possible complication [24].
To evaluate intracapsular rupture of implants and to detect other complications
such as hematomas and seromas, ultrasound is an important tool. With the exception
a b c d e f
Fig. 17.19 Reduction in detectability of breast carcinoma in augmentation. Spiculated mass hid-
den by the implant (a, b), the saline filler diminished the risk of overlooking this lesion, but it is
important to note that on the implant-displaced views (c, d), it was very difficult to diagnose the
mass. Tomosynthesis (e) shows the irregular spiculated mass in a very posterior area that could
easily have been lost with a bad positioning. Ultrasound (f) confirmed the irregular mass
of cases with dense breast tissue, in which ultrasound may increase detection of
masses obscured by implants, there is no specific screening protocol that includes
this imaging test. Ultrasound is also helpful as an adjunct to mammography in eval-
uating detected breast masses or palpable findings, as it can evaluate the entire depth
of the breast tissue down to the implant, and it may distinguish breast masses from
silicone granulomas caused by ruptured implants. Ultrasound-guided procedures
also reduce the chance of implant perforation.
The US Food and Drug Administration (FDA) recommends evaluating implant
integrity with magnetic resonance imaging (MRI) 3 years after surgery and every 2
years thereafter to depict silent ruptures (asymptomatic) [3, 26]. MRI is considered
the gold standard in evaluating implant integrity and should be performed whenever
mammography and ultrasound detect any abnormality. Regarding screening, MRI
has the same recommendations according to age and risk factors. A dedicated breast
coil obtains high-resolution images, and it is possible to suppress or emphasize the
signal from water, fat, or silicone [27]. Saline implants follow fluid signal on all
sequences. Silicone appears hypointense on T1-weighted image and hyperintense
on T2-weighted image (Fig. 17.20). The envelope and fibrous capsule have low
signal on all sequences. Like other imaging methods, radial folds and periprosthetic
fluid are normal findings and should not be mistaken for rupture (Fig. 17.21).
On mammography, silicone implant appears near the chest wall and behind the
breast tissue as a dense, smooth, oval, and completely opaque image that partially
obscures the surrounding breast tissue. On the other hand, saline implants are radio-
lucent in the center, surrounded by a dense silicone outer envelope, which makes
wrinkles easily detected, unlike on opaque silicone implants. Wrinkles are normal
findings, accentuated by compression because the envelope is easily folded but are
sometimes related to capsular contraction (Fig. 17.22). Double-lumen implants are
a common type of implant, usually filled with saline in the inner lumen and silicone
in the outer lumen. The subglandular position consists in the implant behind the
a d
Fig. 17.20 Normal aspects of silicone implants on MRI. Silicone appears hypointense on
T1-weighted image without fat suppression (a) and on short T1 inversion-recovery silicone-excited
images (b) and hyperintense sign on fat-suppressed T2-weighted MR images (c, d)
a b
Fig. 17.21 Fluid inside a radial fold (normal aspect). Axial short T1 inversion-recovery silicone-
excited image (a) and axial fat-suppressed T2-weighted MR image (b)
a b
Fig. 17.22 Wrinkles on the surface of the implant on mammogram (normal finding)
glandular tissue, overlapping the pectoralis muscle, whose anterior contour will be
underneath the implant on mammography, mostly on the mediolateral oblique view.
On the other hand, in the subpectoral position, the implant is behind the breast tissue
and the pectoralis muscle, which covers the implant [23].
A fibrous capsule is always formed around the implant, usually soft and unde-
tectable by physical examination or mammography, unless it hardens or calcifies
[28]. Dystrophic sheetlike calcifications appear dense, thin, and irregular next to the
implant (Figs. 17.23 and 17.24) [29]. Polyurethane-covered implants are covered
with a spongelike material and, when calcified, produce a typical fine mesh-like
calcification. Implant-displaced views displace the capsular calcifications away
from the implant (Fig. 17.25) [22]. Spot magnification can help differentiate if the
calcifications are in the parenchyma (which may represent postoperative fibrosis or
a more worrisome diagnosis) or in the implant capsule. Sometimes this
a b
Fig. 17.23 Calcified fibrous capsule of a saline implant after 22 years of placement
differentiation is not possible, and capsular calcifications can be mistaken for malig-
nancy, leading to a false-positive examination [29].
Ultrasound cannot differentiate between silicone or saline implant types, but in
double-lumen implants, it is possible to characterize the inner and outer envelopes
as two distinct chambers. The normal implant (Fig. 17.26) is an anechoic mass with
an echogenic shell, a three-layered appearance, two thin echogenic lines, and an
anechoic line between them (“Oreo cookie sign”) [30]. Reverberation artifacts can
be identified as multiple bands of noise caused by repeat reflections of the beam
between the skin surface and the anterior wall of the implant, characteristically seen
in the near field, parallel to the anterior implant wall, showing the same width as the
a b
Fig. 17.24 Calcified fibrous capsule of a silicone implant. Dystrophic sheetlike calcifications
appears dense, thin, and irregular next to the implant
a b c d
Fig. 17.25 Capsular calcifications (c, d) displaced away from the implant after Eklund maneuver
Fig. 17.26 Normal implant on ultrasound. Anechoic mass with an echogenic shell with a three-
layered appearance with two thin echogenic lines (thin arrows) and an anechoic line between them
(“Oreo cookie sign”). Reverberation artifacts (star) and the posterior localization of the seal
(thicker arrow) are also characterized
Fig. 17.27 Reverberation

artifacts (normal findings).
Multiple bands of noise
caused by repeat
reflections of the beam
between the skin surface
and the anterior wall of the
implant, characteristically
seen in the near field,
parallel to the anterior
implant wall, showing the
same width as the breast
tissue anterior to the
implant
breast tissue anterior to the implant (Fig. 17.27) [23, 28]. Radial folds are common
findings and represent infoldings of the intact envelope that look like echogenic
lines extending to the periphery of the envelope [30]. The fibrous capsule may be
seen as another echogenic line superficial to the implant shell separated by a small
anechoic line. Implants that have a sponge structure of the outer shell present the
fibrous capsule growth into this coverage; therefore, it cannot be seen. The clue that
helps to evidence the fibrous capsule is the search for a small radial fold, in which
the fibrous capsule is usually lifted from the implant and easy to measure (Fig. 17.28).
Fig. 17.28 Fibrous capsule. Ultrasound shows small radial folds filled with fluid. In these spots,
fibrous capsule is usually lifted from the implant and easy to measure
Fig. 17.29 Small amount

of periprosthetic fluid
(normal finding) on
ultrasound
Small radial folds and a small amount of periprosthetic fluid are also considered
normal findings (Fig. 17.29) [31].
17.2.2.3 Imaging Findings After Implant Removal (Explantation)
The main reasons patients decide to remove their implants are suspected silicone-
related health problems; suspected rupture; breast firmness; breast and musculo-
skeletal pain; or other complications. Mammography, ultrasound, and magnetic
resonance imaging after explantation are broad and may simulate malignant tumors.
In this context, the comparison with previous exams and a detailed surgical history
are crucial. The imaging findings range from a nearly normal appearance to
architectural distortion (Fig. 17.30), focal asymmetry, residual fibrous capsules or

spiculated silicone granulomas, residual free silicon, or collections [4, 32, 33].
After the removal of the implants, the fibrous capsule often remains totally or
partially in the breasts, which may be seen on subsequent imaging studies
(Fig. 17.31) [32]. The implant cavity may resolve completely but, in some cases
may scar, causing architectural distortion (Fig. 17.32) or may fill with fluid in the
non-collapsed fibrous capsule (seroma), which may simulate an abscess (Fig. 17.33).
Mammogram may show dystrophic calcifications if the fibrous capsule calcifies,
Fig. 17.30 Explantation. There are no signs of the implant removal, except for the discrete archi-
tectural distortion
a b c e
Fig. 17.31 Explantation. Mammogram (a, b) and CT (d, e) show coarse calcifications in the
residual fibrous capsule after implants removal. On ultrasound (c), the fibrous capsule presents as
a hypoechoic mass next to the thoracic wall with a hyperechoic image in the center that represents
the calcification
a b c d e
Fig. 17.32 Explantation. Mammogram performed 1 month after explantation depicts architectural
distortion associated with a spiculated mass and calcifications (a, b). Ultrasound of the same date
shows the distortion as a hypoechoic path from the fluid filled implant cavity up to the NAC (c).
Late control mammogram shows an almost completely resolved cavity with a discrete architectural
distortion (d, e)
typically presenting as a sheetlike curvilinear pattern at the chest wall (Fig. 17.34)
but occasionally can show an undetermined pattern, which can be hard to distin-
guish from other breast pathologies (Fig. 17.35) [4, 29, 33].
It is usually difficult to remove all the extracapsular free silicone from a ruptured
implant, without removing too much of the breast [28]. In this case, some free sili-
cone images, infiltrated lymph nodes (Fig. 17.34), or silicone in the residual fibrous
capsule (Fig. 17.36) can be seen [4]. Ultrasound shows the typical snowstorm sign,
and the free silicone signal on MRI should not be misinterpreted as an acute rupture
of new implants [32].
17.2.2.4 Implant Complications
Complications associated with silicone implants are categorized as early or late

changes. They include contracture of the fibrous capsule, calcification of the fibrous
capsule, implant rippling, seroma, implant displacement, malposition, extrusion,
breastfeeding difficulties, hematoma, infection (Figs. 17.37 and 17.38), breast pain,
scarring, implant rupture, rotation, herniation, and silicone gel “bleed” [34].
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare
clinicopathologic entity associated with implants. Multimodality imaging examina-
tions are useful in investigating a possible complication, fundamentally ultrasonog-
raphy (US) and MR imaging. Mammography with special views and sonography
can frequently delineate a locule within the implant that mimics a parenchymal
breast mass.
Breast implant illness (BII) is a clinical condition in which some patients report
a variety of systemic symptoms, such as chronic fatigue, brain fog, and joint and
muscle pain. There are no typical imaging finding, and radiologic examinations are
useful to exclude other pathologies that could be related to these symptoms. The
a b
c d
Fig. 17.33 Explantation. Axial T1-weighted without fat suppression (a), axial fat- suppressed
T2-weighted (b), and axial contrast-enhanced fat-suppressed T1-weighted MR images (c) depict
the implant cavity after 2 months of implant removal filled with fluid in a non-collapsed fibrous
capsule, mimicking an abscess. Ultrasound shows a seroma with thin septa (d)
removal of breast implants without replacement sometimes appears to reverse their

symptoms.
Systemic autoimmune adverse reactions related to silicone have rarely been
reported. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) syn-
drome was first described in 2011 by Shoenfeld and Agmon-Levin and incorporates
several conditions linked to previous exposure to an adjuvant substance, including
silicone. Clinical manifestations are highly heterogeneous, with development of
both nonspecific and specific manifestations of autoimmune diseases, which cannot
be classified as classic connective tissue disorders. It is currently still being investi-
gated whether silicone implants increase the risk of autoimmunity [35].
a b c e
d f
Fig. 17.34 Explantation. Late postoperative mages of an explantation of 45-year-old implants.

Mammogram shows silicone within intramammary lymph node in the upper quadrants of the right
breast (a) and residual fibrous capsule with calcifications and silicone on the left breast (b).
Corresponding ultrasound images depict a spiculated mass with snowstorm sign (c) and a linear
posterior image with residual silicone (d). CT shows an oval, circumscribed mass corresponding
to the lymph node with silicone (e) and a posterior calcified linear image representing the fibrous
capsule (f)
a b
Fig. 17.35 Explantation. Amorphous calcifications (arrow) after explantation of an 18-year-old

implants (a). Vacuum-assisted needle biopsy (b) was indicated, and the histological result was
calcifications in the fibrous capsule
a b c d f
Fig. 17.36 Explantation. Mammogram (a–c) shows a dense residual fibrous capsule with an asso-
ciated small spiculated density (arrow). An irregular linear image with posterior shadowing is seen
anteriorly to the implant on ultrasound (d). On axial fat- suppressed T2-weighted (e) and axial
short T1 inversion-recovery silicone-excited MR images (f), this image shows signal compatible
with silicone from previous ruptured implant
a c d
e
b
Fig. 17.37 Infection. Axial fat-suppressed T2-weighted (a) and axial contrast-enhanced fat-
suppressed T1-weighted subtraction image (b) and sagittal contrast-enhanced fat-suppressed
T1-weighted MR images (c) show fibrous capsule thickening with enhancement. Patient had
inflammatory signs with fistulization of purulent content in the upper quadrants which resulted in
skin retraction. Ultrasound depicts a small collection with anfractuous contours next to the implant
and hyper echogenicity of the nearby tissue (d, e)
a b
c d
Fig. 17.38 Infection. Axial T1-weighted without fat suppression (a), axial fat-suppressed
T2-weighted (b), axial short T1 inversion-recovery silicone-excited (c), and sagittal contrast-
enhanced fat-suppressed T1-weighted MR images (d) show periprosthetic effusion and fibrous
capsule thickening with enhancement
Rotation
Implant rotation may be clinically suspected from a new asymmetry or deviation

from normal breast contours. Rotation rates vary in the literature and can be related
to lack of development of a connective tissue adhesion layer between the implant
and the capsule, a surgical pocket that is too large for the implant of the patient,
capsular fluid, anatomical shape (asymmetry of anatomical implants can act as the
geometric base for their rotation), double capsules, periprosthetic mesh, and pros-
thetic massage. Texturized surfaces are supposed to have an adhesive effect with the
surrounding tissue after surgical implantation to reduce incorrect positioning. In
most cases, rotation is asymptomatic and does not imply any clinical issue.
Imaging diagnosis can be made by searching for the raised silicone ridge/projec-
tions (Fig. 17.39) used for intraoperative orientation of the implant that usually are
placed between 5 and 7 o’clock, easily visualized on ultrasound. In implants that do
not have an orientation marker, we must look for the posterior seal (Fig. 17.40). If it
is visible on the anterior part of the envelope, it is compatible with rotation
(Fig. 17.41). MRI is a useful tool since it can demonstrate any localization of the
seal, not only anterior or posterior (Fig. 17.42).
Capsular Contraction
Capsular contraction is the most common implant complication [36], with a reported
incidence of more than 70% in older series and about 20% in more recent literature
(lower rates of capsular contracture have been observed with later-generation,
a b
Fig. 17.39 Raised silicone ridge. Ultrasound shows the orientation marker on longitudinal (a) and
transversal position (b) as a hypoechoic periprosthetic layer (arrows)
Fig. 17.40 Posterior seal. Normal positioning of the implant can be confirmed by the posterior
location of the seal that is characterized by its echogenic linear appearance (arrows) separated from
the envelope by a thicker anechoic line
Fig. 17.41 Rotation. Ultrasound of different implants show the posterior seal with an anterior
location
a b c
Fig. 17.42 Rotation. Non-fat-suppressed T1-weighted (a) and short T1 inversion-recovery

silicone-excited MR images (b, c) show the seal as a linear thickening with a little oval projection
into the lumen in an anterior position (arrows). Other types of implants may have different seal
presentations
cohesive-gel, form-stable implants than with those of earlier generations), usually

starting within the first year of implantation and an increasing risk over time [5, 23].
The physiopathology is not well established and is presumed to be multifactorial,
with proposed mechanisms that include bacterial contamination, surface texturing,
selection of implant pocket, the incision type, drain placement, antibiotic use, and
smoking [19]. It may be in part related to a subclinical implant infection caused by
Staphylococcus epidermidis from the breast ducts. The incidence of capsular con-
tracture is higher with transaxillary and periareolar incisions and lower with infra-
mammary incisions.
Implants become hard and resistant, presenting a round morphology, with or
without prominent wrinkles. The diagnosis is based on clinical examination, but
imaging can suggest capsular contraction in some cases and discard other complica-
tions [23, 36]. Baker classification describes increasing levels of capsular contrac-
ture and hardening of breast implants on physical inspection and examination
(Table 17.1).
Table 17.1 Baker classification for capsular contraction

Grade Breast firmness Implant visibility
I Soft Nonpalpable; nonvisible
II Minimal Palpable; nonvisible
III Moderate Easily palpable; distortion
visible
IV Severe Hard, tender, cold; distortion
may be marked
Fig. 17.43 Bilateral capsular contraction. Increased anteroposterior diameter due to the spherical
shape. It is very difficult to suggest a bilateral diagnosis only with mammogram. Clinical history
is critical in these cases
Typical imaging findings are increased anteroposterior diameter due to the

spherical shape (deformation of the implant) (Fig. 17.43), capsular wrinkles and
folds that often mimic breaks especially on ultrasound, and thickening and enhance-
ment of the fibrous capsule on MRI (called capsulitis that may represent an active
stage of capsular contracture) [23]. The diagnosis may be easier if these findings are
unilateral (Fig. 17.44). There are reports showing high correlation between the clin-
ical Baker score and elastography measurements. Contrast-enhanced ultrasound
could be an alternative due to its higher accessibility when compared to MRI to
study the possible changes in enhancement of the capsule (Fig. 17.45) [36].
Treatments for capsular contracture include open surgical capsulotomy (make
incisions in the scar capsule encasing the implant to release and relax it), capsulec-
tomy (excision of portions or the entire capsule), and replacing the implant to
another location. Another option is the closed capsulotomy, which consists of
squeezing the implant manually trying to break the hardened fibrous capsule to
allow the implant to soften again, but this technique can result in implant rupture
and moderate breast pain [28]. Contractures that fail to respond to these treatments
may ultimately benefit from implant removal and autologous reconstruction (auto
augmentation) rather than implant replacement [23].
a b
Fig. 17.44 Unilateral capsular contraction on ultrasound. Increased anteroposterior diameter due
to the spherical shape (a) is better seen when compared to the other side (b)
a d
Fig. 17.45 Unilateral capsular contraction on MRI. Patient with induration of the right breast.
Axial T1-weighted without fat suppression (a), axial short T1 inversion-recovery silicone-excited
image (b), axial contrast-enhanced fat-suppressed T1-weighted subtraction (c), and sagittal
contrast-enhanced fat-suppressed T1-weighted MR images (d) show bilateral rotation with
increased anteroposterior diameter due to the spherical shape and enhancement of the fibrous cap-
sule of the right implant
Subglandular implants have the highest incidence of capsular contracture, unlike

textured submuscular implants that present the lowest incidence. In theory, the over-
lying muscular tissue compresses and massages the implant between the muscle
fibers and the chest wall, inhibiting the development of capsular contracture and
minimizing the unnatural firmness of the implant. Trilucent implants were removed
from the market with a subsequent recommendation that the implants be removed
from patients due to their association with rippling, breast pain, contracture, and
deflation. There are some reports of implants that contain carboxymethylcellulose
(hydrogel), which presented low rates of capsular contracture.
Implant Rupture
Breast implant ruptures consists in partial or total collapse of the envelope, mostly
associated with trauma, closed capsulotomy, and older generation implants [20, 37,
38]. Newer generations of silicone implants are more stable and have rupture rates
estimated in 2.0–3.8% in 6-year follow-up (fifth-generation implants) [3, 5, 8, 38–
41]. Implant type (ruptures in double-lumen and polyurethane-covered implants are
less frequent than in smooth implants) and manufacturers also have influence in risk
factors [5, 36]. Poly Implant Prothèse (PIP) silicone implants have been responsible
for a crisis in this growing aesthetic field, by containing nonmedical industrial sili-
cone and a higher reported rupture rate.
When a saline implant ruptures, the envelope retracts, and deflation is usually
noticeable as the breast becomes smaller [23, 37]. The breast tissue absorbs the
saline solution with no major complications.
The silicone implant usually keeps the original shape and volume if the fibrous
capsule is intact and continues to contain the free silicone (intracapsular rupture).
Intracapsular ruptures account for 77–89% of ruptures, and the patient is usually
asymptomatic. These are also called silent ruptures and occurs in 5% of screening
patients [21].
The collapse of the silicone implant envelope may be associated with a rupture
of the fibrous capsule, with the extrusion of the silicone gel into the breast tissue,
which are not absorbed by the body (extracapsular rupture).
Gel bleed is a situation in which silicone gel leakage is observed through an
apparent intact implant envelope (the existence of undetectable ruptures remains
controversial).
Diagnosis of silicone implant rupture is often difficult based only on clinical
manifestations because they are frequently nonspecific [5, 42]. Reported symptoms
include palpable masses in the axilla, breast, or chest wall (older generations); pain;
or changes in the size, shape, or texture of the breast [3, 28, 43, 44]. Imaging assess-
ment plays a main role in the detection of implant ruptures because physical exami-
nation misses approximately 50% of them [6, 42].
Mammography
Intracapsular ruptures in implants filled with silicone gel are almost undetectable in
mammograms because the silicone gel is still contained within an intact fibrous
capsule [28, 45]. A flared contour may be related to intracapsular rupture (Fig. 17.46)
but also to capsular contracture or herniation of an intact implant envelope through
a rupture in the surrounding fibrous capsule [44].
Silicone beyond the fibrous capsule is a typical and specific finding of an extra-
capsular rupture (Fig. 17.47) [45, 46]. However, mammograms may show only con-
tour abnormality of the ruptured implant when the extruded silicone is not far
enough from the implant to be seen as a separate finding (Fig. 17.48). Eventually
extracapsular rupture may have no apparent abnormality on mammograms, and the
diagnosis must be confirmed by either ultrasound or MRI [44, 47].
Dense axillary lymph nodes are rare and represent silicone infiltration in the
lymphatics, highly suggestive of an extracapsular rupture [23, 28, 48].
It is impossible to remove all of the free silicone without removing too much of
the breast tissue after removal of an implant with extracapsular rupture. The residual
gel stays within the breast tissue without absorption, making it difficult to correctly
assess a new implant. Radiolucent centered coarse eggshell calcifications of silicone
granulomas may be seen after implant rupture.
In ruptured saline implants, mammography usually shows only a slightly dense
collapsed envelope near the chest wall because the saline fluid is absorbed by
breast tissue.
a b c
Fig. 17.46 Intracapsular silicone implant rupture. The silicone gel is still contained within an
intact fibrous capsule. A flared lobulated contour may be seen on mammogram (a, b). Ultrasound
depicts the stepladder sign (c)
a b
Fig. 17.47 Extracapsular rupture. Mammogram (a) shows silicone beyond the fibrous capsule
(arrow). Ultrasound depicts the snowstorm sign (echogenic noise), a typical intense echogenic
artifact caused by the slow velocity of sound in the silicone as compared to the surrounding paren-
chyma, obscuring all findings below it (b, c)
Ultrasound
Ultrasound is a useful tool in screening for ruptured breast implants, less expensive
and more cost-effective than MRI, with sensitivity of 25–65%, specificity of
57–98%, and a negative predictive value of 85% [45].
The classic finding in extracapsular rupture of a silicone implant is the snow-
storm sign (echogenic noise), which is a typical intense echogenic artifact caused by
the slow velocity of sound in silicone when compared to the surrounding paren-
chyma that obscures all findings below it (Figs. 17.47 and 17.48) [43, 45, 49, 50].
The snowstorm sign is present when scanned from all angles, whereas edge artifact
may change or disappear. Echogenic noise may also be seen in lymph nodes with
silicone infiltration (Fig. 17.49), gel bleed, and direct silicone or paraffin injections,
which can be so intense that ultrasound is nondiagnostic (Figs. 17.64 and 17.65) [28].
a b c d g
e f
Fig. 17.48 Extracapsular rupture. Mammogram (a, b) shows contour abnormality due to extruded
silicone that is not far enough from the implant to be seen as a separate finding. It may be difficult
to differentiate from a double contour of periprosthetic effusion. Ultrasound depicts the snowstorm
sign on this topography (c). Axial T1-weighted without fat suppression (d), axial fat-suppressed
T2-weighted (e), and axial short T1 inversion-recovery silicone-excited images (f) demonstrate the
outer silicone next to the implant, and the reconstructed sagittal short T1 inversion-recovery
silicone-excited image (g) shows the discontinuous envelope (arrow)
a b
Fig. 17.49 Snowstorm sign in an intramammary lymph node with silicone infiltration (a), corre-
sponding to the finding with high uptake on PET-CT (b)
The intact fibrous capsule in intracapsular rupture ensures that the silicone is
isolated from the breast parenchyma, so there will be no snowstorm sign, unless
when associated with extracapsular rupture. Instead, stepladder sign may be pres-
ent, which is characterized by multiple thin echogenic lines within the silicone gel
that looks like the steps of a stepladder (Figs. 17.46 and 17.50) [14, 30, 46, 49, 50].
This sign represents the collapsed envelope from ruptured implant contained by the
intact fibrous capsule. False-positive stepladder signs can be caused by radial folds
(which always extend to the implant periphery) (Fig. 17.60) and intact multilumen
implants producing multiple linear echoes [45, 52]. Less specific signs of intracap-
sular rupture are discontinuous envelope lines (Figs. 17.51 and 17.54), diffuse linear
echoes, debris, or diffuse low-level echoes within the implant [50, 53]. When these
signs a re dubious, MRI can confirm the diagnosis [47].
Fig. 17.50 Stepladder sign. The collapsed envelope from ruptured implant contained by the intact
fibrous capsule, characterized by multiple thin echogenic lines within the silicone gel
Fig. 17.51 Intracapsular rupture. Ultrasound shows discontinuous envelope lines
Magnetic Resonance Imaging

MRI remains the most sensitive and specific modality to detect silicone implant
rupture. The Food and Drug Administration’s recommendation for MRI screening
for “silent” rupture is 3 years after implantation and every 2 years thereafter, raising
diagnostic rates of ruptures still in the intracapsular phase, making surgery less
traumatic and shorter [3, 54, 55]. There is no proven systemic health impact with
rupture and extravasation of silicone to adjacent tissues.
It is possible to differentiate silicone gel from fat, water, glandular tissue, and
any other tissues based on their unique relaxation properties using specific pulse
sequences. Silicone and water have high signals on T2-weighted images and com-
bined silicone and water images, but signal suppression of either one makes it pos-
sible to distinguish these components [3, 43, 56, 57]. Intravenous contrast is not
necessary for the detection of implant ruptures but may be useful for evaluating
BIA-ALCL, implant-associated infections, and breast cancer in a patient with
implants (known or suspected).
Normal saline implant shows the intact envelope filled with water, which has
high signal on water-specific images but dark on silicone-specific images. MRI is
usually not used to assess integrity of a saline implant because its rupture is clini-
cally diagnosed by an acute reduction in breast size (Fig. 17.52). Normal single-
lumen silicone implant shows high signal from the silicone gel with a smooth oval
border on silicone-specific images. Radial folds in the envelope are dark lines in all
sequences that extend to the periphery of the implant (Fig. 17.53). Multiplanar
acquisitions enable to look at all implant contours and to differentiate them from
ruptured envelopes [57]. Reactive fluid around the implant and water droplets in a
radial fold topographically outside the envelope are common and nonspecific find-
ings [46].
Intracapsular rupture can be characterized by the keyhole or teardrop sign, the
subcapsular line, or the linguine sign [3, 26, 43, 49, 56, 58–60]. The keyhole or
inverted teardrop sign represents silicone outside the implant envelope within a
short radial fold, characterized with hyperintensity on silicone-specific images
(Fig. 17.54). A subcapsular line is a dark line parallel to the implant shell that does
not reach the implant periphery, representing incomplete shell collapse (Fig. 17.55).
The linguine sign is the collapsed shell represented as curvy noodle-shaped dark
lines inside the implant that do not extend to the periphery and is reported as the
a b
c d
Fig. 17.52 Ruptured saline implant. Ultrasound shows a smaller implant when compared to the
other side, with a normal appearance of the reduced implant (a) and only with a small amount of
periprosthetic fluid (b). Axial T1-weighted MR image without fat suppression (c) shows symmet-
ric hypointense signal inside the fibrous capsule. Axial fat-suppressed T2-weighted MR image (d)
presents a reduced implant with a small amount of periprosthetic fluid (arrow)
a b
Fig. 17.53 Normal radial folds in the envelope on short T1 inversion-recovery silicone-excited
image (a) and fat-suppressed T2-weighted MR images (b), with a small amount of fluid inside the
last one
most sensitive (93%) and specific (65%) finding for rupture (Figs. 17.56 and 17.57)
[26, 28, 47, 58]. Extracapsular rupture is characterized by silicone outside the
fibrous capsule (Fig. 17.48), within the breast parenchyma or axilla, almost always
associated with signs of intracapsular rupture [28, 56]. Severe gel bleed can present
as a thin layer of silicone around the periphery of the implant but with an apparently
intact envelope and fibrous capsule.
Multilumen or multiple implants (Fig. 17.58), stacked implants or implants made
of rare materials, poor positioning of the breast, and a “redo” from a prior rupture
(implant replacement after removal of ruptured implants) are causes of false-
positives when screening for silicone implants rupture [49, 52]. Wrong positioning
may produce artificial bulges by squeezing a part of implant between the coil and
the chest wall. Silicon material extruded from previous rupture may not be com-
pletely removed during an implant replacement surgery and the residual silicone
droplets near the new intact implant may result in misinterpretation as a new extra-
capsular rupture.
Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-LCL)
The World Health Organization (WHO) recognized in 2016, BIA-ALCL, an

extremely rare lymphoma reported in patients with implants, as a rare type of non-
Hodgkin’s lymphoma that accounts for only 3% of this pathology [60–62]. A major
increase in incidence was noted over the last few years, but it may be due to increased
awareness and earlier diagnosis of BIA-ALCL [61, 63]. The absolute risk estimated
in the literature should be considered approximate and potentially biased estimates,
since it has not been based on large population-based studies and there is a lack of
reliable information on the prevalence of women with breast implants over time [60].
The physiopathology is unclear but is probably based on a chronic local inflam-
mation due to the presence of implants and the degradation products derived from
a b
c d
Fig. 17.54 Intracapsular rupture. Axial fat-suppressed T2-weighted MR image (a) shows the
absence of periprosthetic fluid. Silicone-specific images (b, c) show silicone outside the implant
envelope within a short radial fold (keyhole sign) and discontinuity of the envelope (arrows).
Ultrasound was only capable to demonstrate the latter finding (d)
them, which can be retained by trauma, genetic predisposition, immunological

alterations, or bacterial infections (specific bacterial species adherent to the prosthe-
sis surface (biofilm) may play a role, possibly via an auto-immune response) [61–
65]. It does not seem to correlate significantly with the type of implant material
(silicone, hydrogel, saline), surgery (oncological or aesthetic), or position of the
prosthesis (subglandular or submuscular). An important association that has been
noticed worldwide is with macro textured implants [62–64].
ALCL is a T-cell lymphoma emerging within the fibrous capsule that surrounds
the implant and not from the breast tissue. The median reported time interval
between surgery and lymphoma diagnosis is 8 years [62]. The most common
Fig. 17.55 Subcapsular line. Silicone-specific images demonstrate dark lines parallel to the
implant shell that do not reach the periphery of the implant, representing incomplete shell collapse
clinical presentation is an abundant and persistent late seroma around the implant
(more than 70%), which presents more than 1 year after implantation [61]. Other
clinical presentations include a solid mass (20%), distant metastases, asymmetry
and breast pain (21%), aggressive capsular contracture (7%), axillary lymphade-
nopathy, skin lesions (7%), fever (7%), and B-type symptoms (5%) [65]. Two-thirds
of the cases are restricted to the fibrous capsule, and in the remaining cases, it pres-
ents as an infiltrative form associated with nodal and systemic extension. These
forms could represent different stages of the same disease with a very different
prognosis: a favorable outcome in cases of disease limited to the fibrous capsule
(>90% remission following capsulectomy) and a more aggressive outcome in
advanced stages [64]. Limited observations suggest that BIA-ALCL is a clinically
indolent disease, but fatal outcomes have revealed the importance of early diagnosis
and treatment, which can be delayed by lack of knowledge and the absence of
unequivocal signs of disease, which often do not allow the identification of early
pathognomonic radiological signs [65].
Radiological signs are often dubious, highlighting either the periprosthetic effu-
sion or breast masses with varying sensitivity and specificity (Table 17.2) [60].
Periprosthetic effusion presents as a “double contour” in a mammogram, indistin-
guishable between seroma, or a mass (Fig. 17.59). Other mammographic findings
are capsular thickening (Fig. 17.60), irregular contours of implants, and masses
emerging from the fibrous capsule to the breast parenchyma (Fig. 17.61). In some
cases, even when the patient has an abnormality in other tests, mammogram can be
normal. Ultrasound can detect effusion and masses that can be complex solid cystic
or even circumscribed and hypoechoic, not necessarily hyper vascularized.
a b
Fig. 17.56 Linguine sign. The collapsed shell is represented as curvy noodle-shaped dark lines
inside the implant that do not extend to the periphery, better seen on axial T1-weighted MR image
without fat suppression (a) and axial short T1 inversion-recovery silicone-excited image (b).
Computed tomography (CT) also displays the collapsed envelope (c)
Computed tomography (CT) can show masses, lymphadenopathy, capsular thicken-

ing, and irregularity of implant contours, mainly in the contrast phases. MRI show
the same abnormalities in addition to capsule enhancement and can be used in cases
of ambiguous US exams, accurately evaluating other implant complications, such as
ruptures as a cause of periprosthetic collection. Peri-implant seroma typically
appears as a hyperintense fluid collection around the implant on T2-weighted
sequences that can assess and quantify the amount of effusion more accurately than
US, probably due to the different positioning of the breast. PET-CT shows diffuse
or focal uptake surrounding the implants as well as in the lymph nodes (axillary,
supra-, or infraclavicular and internal mammary chains). Hybrid PET/MRI is new
promising imaging technique, especially for oncological workup, and BIA-ALCL
cases could benefit for the high contrast resolution of MRI and for quantitative data
derived from PET.
a b c d h
e f g
Fig. 17.57 Intracapsular rupture of a double lumen implant. Mammogram shows hypodense
images inside the implant (a, b). Ultrasound depicts a heterogeneous outer lumen and the snow-
storm sign which make impossible to evaluate the inner envelope completely (c, d). Axial
T1-weighted image without fat suppression (e), axial fat- suppressed T2-weighted (f), and axial
and sagittal short T1 inversion-recovery silicone-excited MR images (g, h) show the intact inner
saline lumen and a collapsed outer silicone lumen but with no signs of extracapsular rupture
a b c f g
d e
Fig. 17.58 False-positive rupture. Mammogram show the implant with irregular contour in its
upper aspect (a, b), being very difficult to exclude a diagnosis of rupture. Ultrasound (c) depicts
undulated contours of the implant with a regular thin echogenic line inside the implant that reaches
the periphery of the envelope, but with an angulation and a convexity posterior in its trajectory
(arrows). Axial short T1 inversion-recovery silicone-excited image (d) and axial fat-suppressed
T2-weighted MR image (e) show silicone covering the implant that presents regular contours, with
no signs of rupture. Sagittal short T1 inversion-recovery silicone-excited reconstructed image (f)
and sagittal contrast-enhanced fat-suppressed T1-weighted MR image (g) delimits better the nor-
mal aspect of the implant and depicts another image similar to it, inside the fibrous capsule (arrow).
This patient corrected an aesthetic defect with another silicone implant, placed over the first one.
Knowledge about patient’s medical history is the key to avoid misdiagnosis
Table 17.2 Sensitivity and specificity for effusion and a detection rate for masses for each
imaging test
Sensitivity for Specificity for detection rate for
Imaging test effusion effusion masses
Mammography 73% 50% ***
Ultrasound 84% 75% 46%
MRI 82% 33% 50%
Computed tomography 55% 83% 50%
Positron emission tomography 38% 83% 64%
(PET-CT)
***Mammogram is unable to distinguish between effusion and masses
It is important to remember that nonspecific seromas around implants are usual

postoperative findings and that late effusions beyond 1 year after surgery are much
less common, so cytology should be considered. BIA-ALCL peri-implant effusion
does not correspond actually to a seroma, since it is composed of dense liquid from
necrotic tumoral cells. US-guided FNA is performed to sample the peri-prosthetic
collection, and the maximum amount of fluid possible should be collected (mini-
mum 50 ml) to provide sufficient material for cytological examination. The correct
position of the patient allows locating the fluid collection in its most dependent
position, and applying light pressure to expand the target window for aspiration can
help in cases with small effusions. BIA-ALCL is characterized by “hallmark cells,”
large lymphoid cells with abundant cytoplasm, and horseshoe-shaped nuclei.
Immunophenotypically, all tumors’ cells are positive for CD30 and negative for
ALK, with variable expression of one or more T-cell markers, such as CD3 and CD4
[61, 62]. Still, available data are limited for screening implant-associated
ALCL. Awareness of the spectrum of imaging findings may improve early detection
and proper management of ALCL in the future.
Gossypibomas
Gossypibomas are retained surgical material that remains inside the body after sur-
gery, extremely rare in superficial sites (there are few locations of difficult access
that can impair the visibility of a gauze or sponge). Radiologic presentation is broad
and reflects the type of response presented. Acute responses may be exudative, lead-
ing to infection, abscess, and even fistula formation. Chronic responses may present
as aseptic fibrinous, with adhesion/encapsulation, clinically silent or appear within
years after surgery [66].
Mammography pathognomonic finding is the characterization of a radio-opaque
marker (Fig. 17.62). Sponges without radio-opaque markers or markers that are
fragmented or disintegrated may present as a mass with mottled radiolucency, due
to air trapping. Ultrasound may show sponges as a highly echogenic anterior band
a b
Fig. 17.59 Seroma. Mammography (a, b) shows a “double contour” around the implant consis-
tent with periprosthetic effusion on ultrasound (c)
a b c e g
d f h
Fig. 17.60 False-positive exam. Mammogram (a, b) shows a discrete double-contour and capsu-
lar thickening (arrow). Ultrasound (c, d) depicts a false-positive stepladder sign caused by radial
folds and a heterogeneous intracapsular mass (star) above them making really hard to characterize
the envelope margin. Axial T1-weighted MR image without fat suppression (e) and axial short T1
inversion-recovery silicone-excited image (f) show the intact envelope being deformed by a intra-
capsular mass. Axial fat- suppressed T2-weighted MR image (g) demonstrates a heterogeneous
mass with enhancement on contrast-enhanced fat-suppressed T1-weighted MR subtraction image
(h). Explantation was performed and the diagnosis was an organized bruise
a b c h
d e f g
Fig. 17.61 Breast implant-associated anaplastic large cell lymphoma. Mammogram shows a dou-
ble contour implant and an irregular density on the lower part of the implant, next to the fibrous
capsule (a–c). Ultrasound depicts an echogenic periprosthetic effusion (f, g) and an irregular ill-
defined mass next to the fibrous capsule (d, e). CT demonstrates irregular margins of the implant
and the periprosthetic effusion (h). CT sagittal reconstruction (i) shows a discrete irregular density
on the lower part of the implant, next to the fibrous capsule. This patient was submitted to a surgi-
cal explantation and the histological result was BIA-ALCL
with posterior acoustic shadowing that may be associated with fluid collections. On
MRI, a mass with low-signal intensity stripes seen on T2-weighted images is highly
suggestive. In addition, breast augmentation with implants presents diagnostic dif-
ficulties in the evaluation of structures posterior to the implant, both on ultrasound
and on mammography, and MRI is more sensitive in these cases. Strong enhance-
ment on contrast-enhanced sequences is rare and may mimic neoplasm, prompting
biopsy (Fig. 17.63) [66, 67].
a b
Fig. 17.62 Gossypiboma. Mammography (a) shows a circumscribed mass, with typical radio-
opaque marker inside, adjacent to the upper contour of the implant. Ultrasound (b) depicted an
intracapsular complex mass with posterior acoustic shadowing. These findings were consistent
with surgical gauze
a b c
Fig. 17.63 Gossypiboma. MRI shows a circumscribed intracapsular mass, with heterogeneous
signal intensity on axial fat-suppressed T2-weighted image (a) and homogeneous signal intensity
on T1 (b). Sagittal contrast-enhanced fat-suppressed T1-weighted MR image (c) revealed internal
heterogeneous and persistent enhancement, with a small non-enhancing central zone. Surgical
removal of the retained gauze was performed
17.3 Other Aesthetic Procedures
17.3.1 Direct Synthetic Substance Injection (Fillers)
Noninvasive cosmetic surgery is a growing market with a crescent demand, some-

times performed by untrained and unlicensed personnel. Many countries do not
have laws that regulate the performance of cosmetic procedures by properly trained
physicians, and most of the materials used are not approved for medical use.
Injections of non-resorbable synthetic biomaterials for large volume breast aug-
mentation are limited as they usually present a high cost and risk to patient safety,
causing irreversible damage, requiring debridement procedures and breast recon-
structions. Patients who underwent breast injections with permanent biomaterials,
whether symptomatic or not, should avoid breastfeeding as there is a risk of material
displacement in the breast tissue and rupture of the capsule that surrounds it, caus-
ing material leakage and inflammation.
17.3.1.1 Paraffin Injection
Paraffin is a group of hydrocarbons relatively inert. To facilitate injection, the paraf-

fin is heated to form a semiliquid material prior to injection. The early cosmetic
results were often quite acceptable, and the complications related to the injection
frequently did not show up until 5 or 10 years later.
Complications are broad and range from aesthetic failure to death. They include
pulmonary embolism, migration, ulceration, fistulae, infection, and necrosis, most
of which often lead to mastectomy.
Radiologically, it does not form an isolated mass, usually consisting of many
droplets, widely dispersed in the tissues. On mammography, early paraffin injec-
tions appear as multiple, circumscribed, noncalcified masses in the retroglandular
and subpectoral regions. Late-stage paraffin injections demonstrate paraffinomas
that are chronic inflammatory granulomatous reactions, involving skin and underly-
ing soft tissues, not restricted to the injection area. Clinical presentation is charac-
terized by the development of indurated masses, pain, ulceration, fistulae, and
necrosis. Mammograms show numerous multiple dense masses with arc and ring
calcifications.
17.3.1.2 Silicone Injection
Injectable silicones are extensively cross-linked polymers of dimethyl siloxane,

some of them include impurities and additives in the preparation, purposely added
to cause a sclerotic reaction in the breasts, intended to contain the liquid silicone and
prevent migration to other sites.
Many of the complications of paraffin injections were repeated a half-century

later, including migration of silicone to other parts of the body, inflammation, dis-
coloration, formation of granulomas masses (siliconomas), ulceration, fistulae,
fibrosis, chronic sinus tracts, lymphadenopathy, infection, and necrosis. Systemic
complications include hypersensitivity pneumonitis, silicone embolism syndrome,
pulmonary edema, and sepsis.
Clinical manifestations of liquid silicone injected into the breasts vary consider-
ably, reflecting different susceptibility to the deleterious effects of silicone. Some
patients do not develop significant symptoms. There are two main types of clinical
presentations. The first type of patient usually presents with multiple and/or painful
lumps in their breasts. These may occur within 2–3 years until 15 years after injec-
tion. In attempt to decrease the inflammatory reaction, some patients also received
multiple injections of cortisone, which can complicate the clinical picture. The sec-
ond type of patient presents impending breakdown with skin inflammation. The
breasts may show increased capillary filling time and various stages of skin circula-
tory difficulties, from fine telangiectasia to necrosis, as silicone invades the dermis
and epidermis of the overlying skin. Migration of the silicone is common.
Mammography shows silicone globules as multiple radiopaque masses with or
without rim calcifications (former eggshell-type) that obscure the underlying breast
tissue, reducing the accuracy of screening mammograms (Figs. 17.64 and 17.65)
[23]. It also demonstrates two patterns: multiple high-density round and circum-
scribed masses ranging from 0.2 up to 2.0 cm in diameter, often with peripheral
calcifications, or large areas of opacity if larger volumes have been injected into
areas of the breast. Spiculated or ill-defined margins may be present on siliconomas
and lead to biopsy even with the history of silicone injection. Extremely dense axil-
lary lymph nodes may be present. Ultrasound of silicone granulomas shows the
snowstorm sign (echogenic noise), which obscures all findings below it, also associ-
ated with hypoechoic or anechoic masses representing large silicone globules. At
CT, scattered nodular soft-tissue foci is seen, calcified or noncalcified, and discrete
or confluent (Fig. 17.66). At MRI, these nodular foci tend to demonstrate
a b c
Fig. 17.64 Liquid silicone injection. Mammogram views (a, b) show diffuse multiple radiopaque
masses in different patterns. Ultrasound (c, d) shows the snowstorm sign diffusively, which
obscures all findings below it
a b c d e
Fig. 17.65 Liquid silicone injection. Patient underwent a second surgery to remove the previously
injected liquid silicone and repair breasts aesthetically with implants placement. Mammogram
(a–d) shows radiopaque irregular densities with tiny punctate images that resemble calcifications,
representing the residual injected silicone. Ultrasound (e) shows the snowstorm sign, adjacent to
the implant contour, which can make it difficult to diagnose a possible rupture
intermediate signal intensity on T1-weighted images and variable intensity on

T2-weighted images, because high-viscosity silicone is usually more hypointense
on T2-weighted images. Chemical shift artifact and fat suppression may also be
present. Silicone granulomas may enhance suspiciously, mimicking cancer.
Because granulomas may become clinically quite hard and reduce the character-
ization of the underlying breast tissue, the assessment for breast cancer with physi-
cal examination, mammography, and ultrasound can be quite challenging. MRI may
be needed for further assessment.
17.3.1.3 Acrylate Injection
Some nonabsorbable materials contain a family of polymers made from acrylate

monomers, including acrylamide (in the form of polyacrylamide hydrogel PAAG)
or methacrylate (in the form of polymethyl-methacrylate PMMA, ethyl-methacrylate
EMA or hydroxyethyl-methacrylate HEMA). Their use has been banned due to its
myriad complications.
The semisolid consistence of acrylates is a challenge to the complete removal of
the injected material because of its extensive displacement (involving the back,
lower abdomen, upper arm, and sternum), extensive infiltration, dispersive indura-
tion, and confusing injection level. Residual material can be left behind after can-
nula aspiration; therefore, an open procedure with surgical debridement is
recommended, but several complications create unsuitable conditions for immedi-
ate implant reconstruction [68].
PMMA is a polymer with irregular surface particles that cannot be phagocytized,
leading to formation of granulomas. Its low cost resulted in indiscriminate use with
a b
Fig. 17.66 Liquid silicone injection. Mammogram (a, b) shows diffuse multiple radiopaque
masses in different patterns. On CT (c), scattered noncalcified nodular soft-tissue foci is seen
unpredictable cosmetic results due to serious immunologic and inflammatory reac-

tions that may lead to deformities. CT findings include fluid attenuation masses,
with surrounding subcutaneous infiltration. On MRI, PMMA is T1 hypointense and
T2 hyperintense and shows mild peripheral enhancement up to 2 months after pro-
cedure (Fig. 17.67) [69].
a b
Fig. 17.67 PMMA injection. MRI shows multiple confluents, oval, circumscribed masses,
hypointense on axial fat-suppressed T1-weighted MR image (a) and hyperintense on axial fat- sup-
pressed T2-weighted MR image (b)
PAAG is a polymer synthesized from 2.5% acrylamide and 97.5% water highly
exchangeable with the water molecules of tissue fluids. Thereby a 10% reduction
in volume occurs during the first days, as a consequence of osmotic exchange.
Once considered a nonbiodegradable hydrogel that was nontoxic, non-sensitizing,
and non-teratogenic, with long-term clinical application, many complications
began to be reported, such as pain, induration, displacement, deformation, milk
deposition/galactocele formation, and psychological fear. Some studies suggested
that PAAG may decompose acrylamide monomers under multiple factors, with
carcinogenic and toxic effects on the nervous and reproductive systems. Injection
of approximately 150–200 mL of polyacrylamide gel is made into the retroglandu-
lar space of each breast at the inframammary fold or at the upper region of the
breast. At MRI, PAAG presents hypointense to isointense signal on T1-weighted
images; hyperintense with hypointense peripheral rim on T2-weighted images; and
T2-weighted fat-saturated images are useful because of high water content
(Fig. 17.68) [68, 70].
Mammography may show multiple randomly distributed bizarre densities of
varying shapes and sizes, indistinguishable from the adjacent breast tissues or with
a well-defined oval density (generally on single injection). On sonography, PAAG
injection may be seen as a single collection of globular fluid in a retroglandular pre
pectoral location with variable internal echogenicity similar to the asymptomatic
patients. Other manifestation of acrylate injection is the same of mammogram, mul-
tiple bizarre, and randomly distributed masses. The infected breast may show
marked increase in the size of collection as well as a diffuse increase in its internal
echogenicity to midlevel echoes. The position of the acrylate collections is well
depicted on MRI. Superimposed inflammatory changes increase the intermediate
heterogeneous T1 signal and decrease heterogeneous T2 signal, along with irregular
and thickened rim enhancement. A thin regular rim of delayed enhancement can
also be seen around PAAG collection in asymptomatic patient, similar to the rim
enhancement of breast cysts [68, 70].
a d
Fig. 17.68 PAAG injection. MRI presents large lobulated masses, with hypointense signal on
axial T1-weighted image without fat suppression (a), hyperintense with hypointense peripheral
rim on fat-suppressed T2-weighted image (b) and a thin peripheral enhancement on contrast-
enhanced fat-suppressed T1-weighted subtraction image (c). Ultrasound (d, e) shows circum-
scribed and heterogeneous masses
17.3.1.4 Hyaluronic Acid
Hyaluronic acid (HA) is an absorbable filler, and its aesthetic effects are considered
transitory for its natural and progressive degradability. Despite this significant reab-
sorption, there are some reports of absence of radiological signs of reabsorption
even 24 months after the procedure. Some adverse effects related to the product are
development of masses and breast pain. Infection and abscesses formation are also
described. In spite the potential for additional applications in the future, it increases
the total cost and the risk for development of granulomas.
HA injection determines an increase in breast parenchyma radiodensity on mam-
mography, either diffuse or as multiple radiodense lesions. This finding corresponds
to multiple predominantly anechoic collections with internal echoes of variable
sizes and echogenicity on ultrasound (Figs. 17.69 and 17.70). On MRI, HA collec-
tions appear as well delimited areas with hyperintensity on T2-weighted and hypo-
intensity on T1-weighted images. They may be involved by fibrotic capsules,
assuming suspect appearance.
a b c
Fig. 17.69 Hyaluronic acid injection. Mammogram (a, b) and tomosynthesis (c) show a slightly
dense asymmetry on superficial planes of the upper quadrants. Ultrasound depicts elongated cystic
images on the subcutaneous fat (d)
Fig. 17.70 Hyaluronic acid injection. Ultrasound shows multiple cystic images of different sizes,
some of them with thin septa and internal echoes
17.3.2 Lipofilling (Fat Grafting)
Autologous fat grafting (FG) is a reconstructive and aesthetic technique increas-

ingly used in breast surgery, consisting in harvesting fat from one site, preferably
where removal is aesthetically desired and possible, and transferring the fat to other
areas for augmentation in the same patient, also called autologous fat transfer, lipo-
grafting, lipotransfer, liposculpting, and lipofilling. There are various harvesting
methods from the donor site, including vacuum aspiration, syringe suction, and
cutting. The reason why so many techniques exist is to yield viable and functional
adipocytes. Liposuction should be gentle, involving the use of syringes or a low-
pressure apparatus, and avoid exposure to ambient air (closed technique) to handle
the fatty material as little as possible. It should then be purified using low-speed
centrifugation. FG is performed using small cannulas in small quantities to ensure
that the grafted tissue is in full contact with the vascularized tissue of the receptor
region to ensure appropriate nutrition in the first days after surgery. Graft survival
percentage depends on the methods used to aspirate, prepare, and transplant the fat
and the destination of the graft (in well-vascularized muscles, the survival rate is
higher than in a relatively oxygen-poor environment such as scar tissue from previ-
ous breast surgery) [71]. Most studies estimate that 30–40% of the volume is lost
after the first procedure, which might require subsequent procedures or graft over-
correction [72]. There is no significant difference in the volume or viability of the
fat grafted from different donor sources. FG is considered a safe procedure with a
low number of major complications [73].
Fat grafting is a more targeted augmentation technique than implants, but the two
methods combined are increasingly common. It does not cause hypersensitivity or
foreign-body reactions. The complications related to FG are seroma, under correc-
tion, infection, asymmetry, fat necrosis, and fat embolism [72]. The main diagnostic
difficulties are related to fat necrosis [3, 73]. Patients may be symptomatic, and the
mammographic and US images may be misleading. In such cases, MRI may be
helpful to differentiate between cancer recurrence and liponecrosis, due to fat-
suppressed and post-contrast sequences that demonstrate an unenhanced fat-
containing mass on T1-weighted images [3, 74]. Fat necrosis rate is directly
proportional to the amount of fat injected into the same breast, particularly if per-
formed in a single procedure. It can be prevented by injecting small quantities of fat
in different directions and layers [73].
A wide spectrum of mammographic changes after fat grafting have been reported
in the literature, ranging from benign looking lipid cysts (Fig. 17.71) and architec-
tural distortion of normal breast tissue, to findings suspicious for malignancy such
as clustered microcalcifications, spiculated areas of increased opacity, and focal
masses [3, 75]. Pectoral muscle may appear heterogeneous in density and also pres-
ent low-density strips. On CT or MR images, linear subcutaneous fat stranding can
be seen in the harvesting area. At the site of fat transfer, nonspecific subcutaneous
fat stranding may be seen on CT images, because the injected fat can be difficult to
discern from the native subcutaneous fat layer. If intramuscular injections are per-
formed, lobular foci of fat can be identified. Literature reports no statistically
a b c d
Fig. 17.71 Lipofilling. Mammogram shows a lipid cyst in the palpable area after a fat grafting
procedure to reshape the skin depression from previous oncologic surgery (a–c). On ultrasound,
this area was a subcutaneous complex mass with little shadowing (d)
significant difference between breast density findings before and after fat injection
and no interference in cancer detection after breast fat grafting [3, 72, 73, 75, 76].
17.3.3 Biological and Synthetic Mesh
Matrices have been inserted successfully and safely in breast reconstruction and in
cosmetic procedures, with biological or synthetic matrices. Mesh support is used to
restore the lost strength, improving the longevity of ptosis correction in mastopex-
ies. The main objective is to achieve the right balance between persistence, inflam-
mation, biocompatibility, and incorporation without interfering with mammography
or presenting a long-term infection risk. Another advantage is the direct-to-implant
breast reconstruction technique that does not require tissue expansion before implant
insertion, avoids donor site morbidity and lengthy recovery time associated with
autologous flap reconstruction, and substantially reduces operating time, compared
to autologous flap and expander-based breast reconstruction. The high cost of
meshes is a factor to be added when choosing a reconstructive technique, but con-
sidering its good cosmetic outcomes and lower rate of surgical revisions, it can be a
low-cost alternative. The proper selection of patients, considering possible comor-
bidities and risk factors, helps to choose the best reconstructive options for each
one. A low rate of inflammation may not generate the fibrous tissue reaction neces-
sary to prevent recurrent breast ptosis, while higher rates may lead to matrix non-
incorporation and loss.
A biological mesh (acellular dermal matrix – ADM) is a scaffold of dermis pro-
duced from cadaveric human, porcine (Figs. 17.72 and 17.73), bovine, or bovine
pericardium tissue that is stripped of its antigenic cells. It allows rapid host revascu-
larization and cell repopulation, which may favor a better outcome, with statistically
reduced bottoming-out, rippling, capsular contracture of the implant, and
a b c
Fig. 17.72 Porcine biological mesh. Axial T1-weighted without fat suppression (a), fat- sup-
pressed T2-weighted (b) and contrast-enhanced fat-suppressed T1-weighted MR subtraction
images (c) demonstrate a thin intracapsular linear image with hypointense signal in all sequences,
without significant enhancement, which does not cover the entire implant surface, easier to see
because the patient developed a seroma
Fig. 17.73 Porcine biological mesh. Ultrasound shows a hypoechoic periprosthetic layer repre-
senting the biological membrane (arrows). Usually few months after surgery, it is not still identifi-
able. This is probably due to the high biocompatibility of the biological membrane, causing a mild
fibroblastic reaction with focal tissue integration of the matrix and, thus, appearing less visible
during follow-up
mechanical shift when compared to the absence of matrix reconstruction. ADM

might be attached to the inferior-lateral pole of the pectoralis major muscle, expand-
ing the space available for the insertion of an implant, filling the void left between
the muscle and fascia, thereby creating a natural inframammary fold, providing
additional cover and support inferiorly, with faster tissue expansion, larger implant
volumes, and improvement of lower pole projection. Complications include infec-
tion, seroma, hematoma, skin flap necrosis, capsular contracture, implant extrusion/
exposure with explantation/implant loss, besides that ADM may present adverse
effects associated with radiotherapy [77]. Other disadvantages include increased
incidence of seroma; lack of sterility (they are aseptic rather than sterile); and expo-
sure to antibiotics, which may result in allergic reaction, increased incidence of
infection, and high cost [78].
Synthetic matrices are made of absorbable (Vicryl), long-term absorbable, or
nonabsorbable (titanium-coated polypropylene mesh) plastic-like material. Mesh
induces only a thin layer of collagenous tissue, which enhances the overall strength,
acting as a composite material, so strong that rupture or failure is extremely unlikely,
with high flexibility and not palpable under the skin. Synthetic meshes can be
inserted between subcutaneous fat and the glandular tissue and be fixed on thoracic
wall, sometimes with metallic clips. It remains unclear whether the complication
rates between synthetic and biological matrices differ. The surgical outcomes from
both types are similar, and synthetic meshes are cheaper than ADM [78].
Combination of absorbable and nonabsorbable synthetic meshes have been found to
work, despite inflammation and non-incorporation. Infection of a nonabsorbable
mesh remains a persistent risk factor. Single-stage direct-to-implant breast recon-
struction demonstrated a low complication rate, excellent cosmetic outcome, and
significant cost savings in comparison to the use of ADM. On mammography, it
may be possible to see the fixation clips (Fig. 17.74) and the mesh, but radiological
aspects will vary depending on the material. On subsequent exams, it can be reab-
sorbed or calcify partially or totally (Figs. 17.75 and 17.76). Ultrasound can depict
a superficial irregular linear echogenic image, with varying posterior acoustic shad-
owing, representing the mesh (Fig. 17.77). Both methods have limitations in detect-
ing breast lesions with mesh implantation. MRI can be helpful in cases of doubt.
Fig. 17.74 Fixation clips of a synthetic mesh
17.4 Breast Cancer Treatment
Breast cancer treatment depends on the tumor size and stage (TNM) to establish the
surgical management (lumpectomy or mastectomy) and the need for adjuvant ther-
apy (radiotherapy and/ or systemic therapy). The goals are removing all the cancer
from the breast (tumor-free margins), locoregional control, and eradicate occult
a b c g
d
f
Fig. 17.75 Synthetic mesh. Mammogram shows meshes almost totally calcified with coarse and
linear patterns (a, b). Ultrasound (c) shows an irregular linear echogenic image, with posterior
acoustic shadow (arrows). Axial T1-weighted without fat suppression (d) axial fat-suppressed
T2-weighted (e), sagittal contrast-enhanced fat-suppressed T1-weighted MR images (f), and 3D
reconstruction (g) depict the mesh as a linear coarse image usually in the interface between the
subcutaneous fat and the fibroglandular tissue, with hypointense signal on T1 sequences and
hyperintense signal on T2 sequences
a b c g
e f
Fig. 17.76 Synthetic mesh. Mammogram (a, b), ultrasound (c) and MRI axial T1-weighted with-
out fat suppression (d), axial fat-suppressed T2-weighted (e), and axial contrast-enhanced fat-
suppressed T1-weighted subtraction images (f) show similar aspects of Fig. 17.75. Sagittal
contrast-enhanced fat-suppressed T1-weighted MR images (g) demonstrate the same aspect shown
on mammogram
Fig. 17.77 Synthetic

mesh. Ultrasound shows a
superficial irregular linear
echogenic image, next to
the anterior contour of the
implant (arrows)
metastatic disease. The treatment plan is based on the tumor TNM classification,
imaging, physical findings, and the patient’s wishes, involving breast radiologists,
breast surgeons, medical oncologists, radiation oncologists, pathologists, and plas-
tic surgeons [79].
Breast-conserving surgery (also known as lumpectomy, setorectomy, partial
mastectomy, or quadrantectomy) is used when the entire tumor can be removed with
a good cosmetic result. These patients usually undergo postsurgical whole-breast
irradiation to control residual microscopic disease.
Mastectomy is chosen when the entire tumor cannot be excised with a good cos-
metic result, for women with contraindications to radiation therapy (i.e., pregnancy,
previous breast radiation therapy, multicentric or diffuse disease, collagen vascular
disease) or if it is the patient’s preference [80].
Both approaches offer equivalent local control disease and identical survival
rates in women with tumors 4 cm or less in diameter and positive or negative axil-
lary lymph nodes, as shown by Protocol B-06 conducted by National Surgical
Adjuvant Breast and Bowel Project (NSABP). Currently, available data suggest that
local recurrence is more related to tumor biology than to surgical technique.
The definition of tumor-free margin has varied among institutions. A recent con-
sensus guideline from the Society of Surgical Oncology (SSO) and the American
Society of Radiation Oncology (ASTRO) has recommended that a negative margin
be defined as “no tumor on ink” based on a review of multiple studies [81].
17.5 Breast-Conserving Surgery (BCS)
Breast-conserving surgery (also known as lumpectomy, setorectomy, partial mas-

tectomy, or quadrantectomy) consists of surgical removal of the primary tumor,
with negative margins. It is the ideal treatment for most cases of breast cancer, and
the conditions for performing it are the following: the patient’s desire, possibility of
oncological control, and preservation of breast aesthetics [82].
The addition of whole breast external beam radiotherapy (WB-XRT) to conser-
vative surgery reduces the rate of local recurrence by 50%, with an impact on
15-year mortality, according to a meta-analysis by the Early Breast Cancer Trialists
Collaborative Group (EBCTCG); therefore, omission of radiotherapy in BCS is not
recommended.
To perform a local excision for diagnostic or therapeutic purposes, the surgeon

makes an incision in the skin, usually periareolar or in the inframammary fold (more
cosmetic), and removes the tumor with macroscopic margins and appropriate guid-
ance for histological analysis. The adjacent breast tissue, the subcutaneous tissue,
and the skin are then closed. The surgical cavity can be filled with fluid and granula-
tion tissue.
Mammography is rarely obtained immediately after surgery. But if performed,
the image would show a round or oval mass in the postoperative site representing a
seroma or hematoma, with or without air, which should resolve over time.
Thickening of the skin at the incision is usually present, and adjacent breast tissue
shows thickening of trabeculae in subcutaneous fat and increased density caused by
local edema or hemorrhage. On MRI the postoperative site is filled with blood or
seroma, with high signal intensity on T2-weighted images without contrast or fat
suppression. On ultrasound, the early postoperative findings are seroma or hema-
toma, breast edema, and focal skin thickening. Postoperative seroma or hematoma
is normal and is gradually absorbed. However, if the fluid collection persists or there
is a clinical sign of infection (fever, erythema, swelling and pain), drainage with
subsequent culture of fluid can be performed under US guidance to exclude the pos-
sibility of abscess formation.
After subsequent weeks, the postoperative site resorbs the air and fluid collec-
tion, which is replaced by fibrosis and scarring, with residual focal skin thickening
and breast edema.
On MRI, enhancement of the surrounding normal healing tissue is possible for
up to 18 months after the surgery (regular rim enhancement). There is also architec-
tural distortion and sometimes a scar that can simulate cancer with rapid uptake and
washout kinetics and is a common cause for false-positive reading, resulting in
biopsy unless the radiologist investigates the patient’s history. Recurrent invasive
cancers usually appear as a mass at or near the biopsy site in the first few years. It is
important to know that chemotherapy changes the enhancement pattern of the breast
by diminishing the enhancement of normal breast parenchyma and tumor, due to
loss of abnormal tumor vascularity. Thus, enhancement at the site of prior cancer
should be considered residual tumor even if the kinetic curves are benign. In the
ipsilateral axilla, reactive lymph nodes that cannot be distinguished from metastatic
disease may develop.
On mammography the findings include architectural distortion, increased den-
sity, and parenchymal scarring. These findings diminish in severity over time and
should be stable after 3–5 years. Almost 50% of patients continue to have variable
mammographic findings ranging from spiculated mass like scars to slight architec-
tural distortion. As these findings can simulate cancer, it is important to document
the date and location of the surgical procedure, use skin markers (usually linear
metallic marker placed on the scar before the mammogram), and compare with
previous exams. The other half has no scar or distortion in the underlying breast
parenchyma, and only comparison with preoperative images can indicate that breast
tissue has been removed. Fat necrosis is another common finding and usually
appears as a radiolucent lipid-filled mass or a typically calcified eggshell-type rim

around a radiolucent center, pathognomonic in mammography [83].
On ultrasound, the incision can usually be traced from the biopsy cavity to the
skin and appears as a linear scar that disturbs the normal breast architecture. The
seroma or hematoma is gradually absorbed, and only fibrotic scar remains, as a
hypoechoic spiculated mass with acoustic shadowing that simulates breast cancer.
So, the comparison with previous images and the correlation with physical finding
of a scar on the skin can distinguish normal postoperative scarring from cancer.
The whole breast, external beam radiotherapy (WB-XRT) usually is performed
after lumpectomy to eliminate microscopic residual disease and to suppress tumor
recurrence both in the remaining breast parenchyma and in the tissue around the
lumpectomy cavity. During WB-XRT the breast skin becomes erythematous, and
the breast may become edematous, particularly in those patients with larger breasts.
After completion of radiotherapy, the breast edema slowly subsides, and the skin
becomes less edematous and more normal in appearance as the breast heals. Some
options as accelerated partial breast irradiation (APBI) that delivers radiotherapy
only to the lumpectomy cavity plus margins have also emerged as a potential option
for selected patients. Various APBI techniques include intraoperative radiotherapy
(IORT), interstitial brachytherapy, intracavitary brachytherapy, or three-dimensional
(3D) conformal external beam radiation. All types of APBI use a higher dose per
fraction to achieve an effective total dose. Given the higher fractionated dose, post-
treatment changes in the breast after APBI may be different from that seen after
WB-XRT. The shortened time course of radiotherapy increases accessibility of
breast conservation treatment and may increase the proportion of women who
receive appropriate adjuvant radiotherapy after breast-conserving surgery. In addi-
tion, limiting the field of treatment to the local tumor bed should, in theory, reduce
treatment-related morbidities such as radiation pneumonitis, breast lymphedema,
and radiation-induced sarcoma [84].
Normal changes after radiation therapy include the usual post-biopsy changes at
the surgical site plus diffuse skin thickening and whole breast edema from
WB-XRT. Skin thickening in the immediate postradiation therapy period is caused
by breast edema due to small-vessel damage, and in the later period, it is caused by
fibrotic changes. These findings are most obvious compared with the contralateral
side or older mammograms. On mammography, the edema is seen as stromal thick-
ening, diffuse increased breast density and trabecular thickening in subcutaneous
fat. These changes usually decrease after 2.5–3 years or may remain stable.
Progression of breast edema is abnormal and should be investigated to exclude
inflammatory breast cancer, mastitis, trauma, and obstructed breast lymphatic or
venous drainage. Obtaining a mammogram relatively early (6–12 months) after
completion of radiation therapy establishes a baseline for future reference. After
completion of whole-breast irradiation, many facilities use a lumpectomy cavity
boost to sterilize the operative site that is marked with radiopaque clips. In about a
quarter of women, calcifications develop in the treated breast at the biopsy site.
Although most of these calcifications will be caused by benign dystrophic calcifica-
tion, fat necrosis, or calcified suture material, magnification views of the
calcifications at the biopsy site are required to distinguish them from cancer recur-
rence pleomorphic calcifications. When there are no distinguishing features to diag-
nose dystrophic or fat necrosis calcifications, a biopsy should be performed.
Nonspecific microcalcifications that form at or near the biopsy site are a problem.
Unchanged nonspecific calcifications should be monitored because they may repre-
sent either benign findings or incompletely resected tumor. Increasing microcalcifi-
cations are suggestive of breast cancer recurrence and should prompt biopsy unless
they are specific for dystrophic calcifications or fat necrosis [51, 85] (Fig. 17.78).
On MRI, the APBI results in characteristic posttreatment changes, which extend
from the skin to the chest wall. Typically, there is only localized skin thickening in
the APBI area and the absence of the diffuse skin thickening seen with WB-XRT. In
addition, signal voids are common in the postoperative breast after APBI and may
persist up to 25 months after treatment [3].
17.6 Ipsilateral Breast Tumor Recurrence (IBTR)
The incidence of treatment failure is approximately 1% per year. Women who are at
greatest risk for failure include those under age 35 (especially younger than 30) and
treated for invasive cancer with an extensive intraductal component or infiltrating
ductal carcinoma with a large intraductal component; with intraductal carcinoma of
comedo type, intraductal cancer measuring 2.5 cm or greater in diameter, and mul-
ticentric lesions; treated for more than one synchronous cancer in the same breast;
and with angiolymphatic invasion. Microscopic residual disease may not imply a
greater risk of IBTR, but gross residual tumor also has a poor prognosis. Despite the
slightly greater tendency for recurrence in these groups, no risk factor is an absolute
contraindication for breast conservation.
For women who choose lumpectomy, IBTR rates are approximately 5% at 5
years and between 10 and 15% at 10 years after therapy. Invasive IBTR is most
common between 18 months and 7 years after treatment. During this period IBTR
is more common in or around the lumpectomy cavity. After 7 years, IBTR is most
often a random event in any quadrant of the affected breast, not necessarily at the
original site, and is usually unrelated to the original lesion in the breast [86].
Recurrences at the original tumor site are usually caused by original failure to eradi-
cate the cancer and represent true treatment failures and occur earlier than the devel-
opment of a tumor elsewhere in the breast (Fig. 17.79).
On mammography, treatment failures manifest as new pleomorphic calcifica-
tions, scar edges becoming rounder or larger, or masses developing in or around the
lumpectomy cavity [13]. On ultrasound, an IBTR shows a mass with or without
continuity with the surgical scar if it occurs near the original lumpectomy site.
Radiologists must investigate any new mass, because even benign-appearing new
solid masses may represent a new cancer. On MRI, clumped enhancement or an
eccentric residual mass can be seen around the lumpectomy cavity (Fig. 17.80).
Fig. 17.78 Breast-conserving treatment. Imaging findings of a 54-year-old woman with personal
history of Invasive ductal carcinoma (IDC) in the left breast, treated with breast conserving surgery
7 months ago and radiotherapy. (a) Mammogram shows architectural distortion and cutaneous and
trabecular thickening due to radiation therapy on the left breast. (b) US images show the incision
from the surgical cavity to the skin and cutaneous thickening
Fig. 17.79 Recurrence after breast-conserving treatment. Imaging findings of a 48-year-old

woman with personal history of IDC in the right breast 4 years ago, treated with breast conserving
surgery, and familial history of breast cancer. (a) Mammography (with and without Eklund’s
maneuver) showing heterogeneously dense tissue, architectural distortion on the right breast, a
marker clip on the left breast (benign calcifications), and subglandular implants. (b) Ultrasound
images showing a hyperechoic non-mass lesion on the upper inner quadrant of the right breast. (c)
Axial post-contrast fat-suppressed T1-weighted MR images show heterogeneous non-mass
enhancement with segmental distribution on the right breast. DCIS confirmed in US-guided
core biopsy
a b
Fig. 17.80 Infraclavicular recurrence after breast-conserving treatment. Imaging findings of a

58-year-old woman with personal history of IDC in the right breast 13 years ago, treated with
breast-conserving surgery. (a) Mammography showing scattered areas of fibroglandular density,
bilateral surgical architectural distortion, and a benign mass on the left breast. (b) Ultrasound
images show an irregular spiculated mass in the subclavicular chain. There was correspondence on
PET-CT images (not shown), and metastatic breast carcinoma was confirmed on core biopsy
Treatment failures after lumpectomy and WB-XRT are usually treated by sal-
vage mastectomy with or without reconstruction. The choice of repeating lumpec-
tomy without additional radiotherapy or repeating lumpectomy with additional
APBI has little long-term data to conclude on safety and effectiveness [87, 88].
17.7 Mastectomy
Mastectomy is the surgical removal of the mammary gland and is chosen when the
entire tumor cannot be excised with a good cosmetic result, for the women with
contraindications to radiation therapy (i.e., pregnancy, previous breast radiation
therapy, multicentric or diffuse disease, collagen vascular disease), for disease
involving the skin or if preferred by the patient. Even large lesions (more than 5 cm)
or multifocal disease can be treated with breast-conserving surgery if a neoadjuvant
chemotherapy is offered before surgery, and there is a decrease in tumor size
[89–91].
There are various types of mastectomies, and they can be associated or not with
axillary lymph node dissection. In simple mastectomy, the nipple-areolar complex
(NAC) is removed with an ellipse of skin with underlying breast tissue. In the con-
servative mastectomies (skin-sparing mastectomy and nipple-sparing mastectomy),
the aim is to save as much tissue as possible to provide better aesthetic results in
breast reconstruction. Insufficient removal of the breast tissue may increase the risk
of cancer, and the excessive removal impairs the outcome of the reconstruction.
Residual breast parenchymal tissue should be reported by the radiologist as long-
term surveillance imaging may be indicated. A skin-sparing mastectomy (SSM)
suggests that some of the skin on the breast that would normally have been removed
may remain. It involves complete removal of all breast tissue and the NAC while
preserving the skin envelope and is followed by immediate breast reconstruction.
The postoperative appearance of a skin-sparing mastectomy is variable in terms of
the amount of skin remaining, and imaging will demonstrate a skin flap from the
native skin and subcutaneous fat and either autologous or implant augmentation in
place of the glandular tissue [92]. In case of nipple-sparing mastectomy (NSM,
adeno-mastectomy or subcutaneous mastectomy), the breast tissue is removed as it
is done in a simple mastectomy but with preservation of the nipple-areolar complex.
Some ductal tissue may remain within the nipple itself, as well as in the underlying
tissue, which ensures adequate nipple vascularization. This is usually requested by
patients who are having mastectomy for prophylactic reasons. When this technique
is performed in a cancer treatment setting, tumors should be smaller than <3 cm in
size and more than 2 cm away from the NAC, with negative lymph nodes. There are
no randomized studies comparing the effectiveness of these techniques; however,
retrospective studies have shown an acceptable rate of local recurrence. Typically,
radiotherapy is not routinely performed after a nipple-sparing mastectomy unless
there are pathological indications such as involvement of multiple nodes or a large
tumor. The surgical complication rate of conservative mastectomies is higher when
compared to conventional mastectomies. The main complications are the skin flap
and nipple-areolar complex necrosis, which occur in 3–9% of cases (Fig. 17.81).
Unless there is a medical contraindication to breast reconstruction, patients who
choose mastectomy are always offered breast reconstruction with a tissue expander,
implant, or autologous tissue flap. The breast reconstruction options include an
implant, a latissimus dorsi flap with an implant when significant breast skin has
been lost, or a transverse rectus abdominis myocutaneous (TRAM) flap or one of its
derivative procedures, such as a deep inferior epigastric perforator flap (DIEP).
Imaging of the reconstructed breast is not normally performed after placement of an
expander, implant, or after autologous tissue reconstruction [3].
Reduction mammoplasty may be required in the unaffected contralateral breast
to achieve symmetry with the treated breast. The appearance of breasts recon-
structed with autologous tissue and contralateral normal breasts submitted to reduc-
tion mammoplasty are characteristic and should not be mistaken for cancer.
Recurrence of breast cancer in the mastectomy site without reconstruction is
usually detected by physical examination. Due to the low yield of breast cancer
detection from the small amount of remaining breast tissue, surveillance mammog-
raphy of the mastectomy site is not usually performed. Ultrasound can evaluate
Fig. 17.81 Prophylactic nipple-sparing mastectomy. Imaging findings of a 47-year-old woman

after prophylactic nipple-sparing mastectomy. (a) Mammography showing retropectoral implants,
minimal subareolar fibroglandular parenchyma, and preserved NAC. (b) Ultrasound showing
residual parenchyma also in the junction of upper quadrants of the right breast and in the upper
outer quadrant of the left breast
Fig. 17.82 Recurrence after mastectomy without reconstruction. Imaging findings of a 41-year-
old woman before and after mastectomy. (a) Preoperative CT and US show a solid spiculated mass
involving the skin, confirmed IDC. (b) Postoperative routine CT shows the right mastectomy site
without reconstruction after 10 months and a mass in the axillary tail. (c) US shows a solid spicu-
lated mass and some atypical axillary lymph nodes, core biopsy confirmed new IDC, and meta-
static lymph nodes
seroma, lymphadenopathy, and cancer recurrence in the chest wall, subcutaneous

fat, and skin (Fig. 17.82).
17.8 Breast Reconstruction
After mastectomy, the breast may be reconstructed with autologous tissue, implant,
or a combination of both. The aim of breast reconstruction is to create a new breast
and restore chest symmetry, reducing the psychosocial consequences related to the
mastectomy. There is no ideal technique. It is expected to be effective, fast-
performed, with few complications. The choice of breast reconstruction depends on
the patient’s goals, medical history, physical examination, and potential need for
adjuvant therapy [93].
Regardless of the chosen technique, cancer may recur in the reconstructed breast.
To detect breast cancer recurrences at a smaller size, radiologists must be familiar
with the range of normal and abnormal imaging appearances of reconstructed
breasts that occur in different surgical techniques.
Implant reconstruction is the most used technique (80% of cases) and requires
placement of a tissue expander in a retropectoral position at the time of mastectomy
(skin-sparing mastectomy) for expansion of the skin. Usually, a saline expander is
used that is gradually filled until the skin is sufficiently stretched and the space is
adequate to hold an appropriately sized implant. Subsequent surgery is done to
replace the tissue expander with a permanent implant behind the pectoral muscle
(Fig. 17.83). Patients with small breasts and little ptosis present more favorable
results since the skin flap completely accommodates the volume of the implant. For
the other hand, women with large and ptotic breasts present less satisfactory results,
often requiring skin reduction, which increases the risk of skin and the nipple-areola
complex necrosis. The need for radiotherapy after mastectomy is not an absolute
contraindication for this type of reconstruction, but it can be associated with poor
outcome, capsular contracture, and even loss of the implant.
The most common form of autologous tissue reconstruction is made with the
transverse rectus abdominis myocutaneous (TRAM) flap (Fig. 17.84). It can be per-
formed as a pedicle (pedicled TRAM) or free flap (muscle-sparing TRAM flap,
DIEP flap, SIEA flap). Another option used when an additional skin is needed to
close the wound or additional soft tissue is required in an implant-based reconstruc-
tion is a latissimus dorsi myocutaneous flap (Fig. 17.85). In all these cases, skin, fat,
and muscle are transferred to the mastectomy site with attachments to vascular
structures and are shaped to form a breast. The choice of flap relies on the tissue
abundance at the donor site and the viability of the vascular pedicle. The method of
choice for vascular mapping (before TRAM and DIEP flaps) is computed tomo-
graphic (CT) angiography. It has an excellent sensitivity (99.6%) and a high positive
predictive value (99.6%) for identifying clinically relevant perforating branches,
allowing a better assessment of perforating vessel size, hemodynamics (maximal
enhancement quantification), and location within the muscle [94]. In recent years,
MR angiography has gained in popularity with similar results to those obtained with
CT angiography [95, 96]. Complications may be related to the donor area or the flap
itself. The most feared flap-related complication is necrosis, in addition to dehis-
cence and hematoma, which are more frequent.
Another form of breast reconstruction involves autologous fat graft injection
(also known as lipofilling) to augment the volume of the reconstructed breast, usu-
ally in combination to other reconstruction form. This procedure transfers mature
adipocytes and adipocyte-derived stem cells (ADSCs) to the defective breast region.
These ADSCs have the ability to stimulate local neoangiogenesis and stimulate
fibroblasts locally, allowing these mature adipocytes to survive and integrate into
the graft-receiving mammary environment. The main disadvantage of this technique
is the impossibility of predicting how much fat will be reabsorbed, often requiring
Fig. 17.83 Breast reconstruction with double-lumen implant. Imaging findings of a 51-year-old
woman with personal history of IDC in the left breast 4 years ago, treated with nipple-sparing
mastectomy. (a) Mammography showing retropectoral implants, minimal subareolar fibroglandu-
lar parenchyma, and preserved NAC in the left breast. (b) Ultrasound shows the differences
between the single-lumen implant in the right breast (first image) and the expander or double-
lumen implant in the left breast. (c) Axial MR images showing single-lumen silicone implant in the
right breast and double-lumen implant (inner saline compartment; outer silicone gel compartment)
in the left breast
a e
c f h
Fig. 17.84 Tram-flap reconstruction. Imaging findings of a 41-year-old woman who presented
amorphous clustered calcifications in the screening mammogram, confirmed histologically as
DCIS. (a) Preoperative contrast-enhanced MIP reconstruction image shows two irregular masses
(arrow) and large clumped non-mass enhancement (arrowhead). Mastectomy with a pedicled
TRAM flap reconstruction was performed. Biopsy confirmed IDC, ILC, and DCIS*. (b, c)
Postoperative CT and coronal T1-weighted MR image show the contralateral rectus abdominis
muscle tunneled through the inframammary fold to the mastectomy pocket (arrow). Imaging find-
ings 1 year after mastectomy, chemotherapy, and radiation therapy. (d) Sagittal and axial
T1-weighted MR images show cutaneous thickening and steatonecrosis (arrow) due to radiation
therapy and a thin line separating the fat from the skin of the TRAM flap (arrowhead). Imaging
findings 4 year after treatment. (e) Sagittal and axial T1-weighted MR images show decrease of the
postoperative findings. (f) Mammogram shows autologous flap appearing as fat centrally and cal-
cifications from fat necrosis in the left breast and findings of reduction mammoplasty in the right
breast (made for symmetry). (g) Ultrasound shows the differences between the fat distribution of
the TRAM flap in the left breast and the usual breast parenchyma of the right breast. *IDC invasive
ductal carcinoma, ILC invasive lobular carcinoma, DCIS ductal carcinoma in situ
more than one procedure to obtain the expected result. The main complication is fat
necrosis and cellulitis. The imaging studies show oil cysts and fat necrosis that are
easily identified on mammography, ultrasound, and MRI. The interaction between
mature adipocytes, ADSC, and the normal mammary cell, as well as the carcinogen
cell, is still unclear [95].
Also, the nipple can be reconstructed out of the skin and tattooed to provide color
similar to the contralateral side.
Mammography is indicated if any breast tissue has been left at the mastectomy
site (with or without implants). Breast cancer recurrences can appear as masses or
suspicious calcifications. The mammographic evaluation is useful in the autologous
tissue reconstruction, especially when there are suspicious physical findings.
Autologous flaps appear radiographically as fat centrally, with or without muscle
fibers around the edges of the flaps. Common findings are calcifications from fat
necrosis, benign dermal calcifications, and calcified hematoma. In patients undergo-
ing radiotherapy after reconstruction, diffuse thickening of the skin and trabeculae
may be seen, usually within the first 6 months after completion of radiotherapy.
Suspicious findings are masses and clusters of microcalcifications. Recurrence is
more likely to occur if the margins were closer to less than 1 cm or if there was prior
lymphovascular invasion. But some studies have shown that mammographic screen-
ing of asymptomatic women does not increase life expectancy and there is no reason
to do so [96].
MR images may be helpful in showing postoperative findings in autologous
reconstructions and to find cancer in the opposite breast. They show that the flap has
fat signal intensity and the pedicle is isointense to pectoralis muscle, with easily
visible fat necrosis, skin thickening, edema, fluid collection, hematoma, or lipofill-
ing changes. The postoperative findings decrease on subsequent MRI studies [3].
Fig. 17.85 Dorsal-flap reconstruction. Imaging findings of a 53-year-old woman with personal
history of IDC in the left breast 6 years ago with recurrence after 4 years, treated with mastectomy
and latissimus dorsi flap with implant reconstruction and prophylactic nipple-sparing mastectomy
in the contralateral breast. (a) Mammography showing retromuscular implants, autologous flap
appearing as fat centrally in the left breast and minimal subareolar fibroglandular parenchyma, and
preserved NAC in the right breast. (b) Ultrasound shows the differences between the fat distribu-
tion of the TRAM flap in the left breast (arrows) and the usual breast parenchyma of the right
breast (first image). (c) Axial T2-weighted MR image shows major pectoral muscle (arrowhead)
and latissimus dorsi muscle tunneled in the left breast (arrows). (d) Sagittal and axial post-contrast
fat-suppressed T1-weighted MR image show the major pectoral muscle (arrowhead) and a thin line
separating the fat autologous flap (arrow)
17.9 Breast Cancer Recurrence
Although the risk for breast cancer is reduced by more than 90% after mastectomy,
it is not eliminated, because the breast tissue is incompletely excised (usually
remaining in the anterolateral aspect of the chest wall and in the axilla). The reported
breast cancer recurrence rate after TRAM flap reconstruction ranges between 4.2%
and 11.7%, (depending on the primary tumor stage, histology and patient’s genetic
risk). Early detection of recurrent tumors in reconstructed breasts may have bene-
fits, but any benefit would come at the cost of many false-positive findings, and a
benefit in terms of patient survival has yet to be proven [97].
The most common finding of recurrent cancer in the reconstructed breast is a
palpable mass and occurs in the skin envelope superficially to the autologous flap
reconstruction. Other signs and symptoms include local pain and tenderness, irregu-
larity of the flap surface, erythematous rash, as well as nodal metastasis. Local
recurrences arise mostly at the medial aspect of the flap because of lymphatic drain-
age to the internal mammary nodes, which are not dissected during mastectomy and
reconstruction. A recurrence can also arise from the chest wall (this one with the
worst prognosis).
The mammographic and sonographic findings may resemble those of the pri-
mary tumor and may include a solid irregular and spiculated mass, distortion,
microcalcifications, and skin thickening. Ultrasound is more sensitive than mam-
mography for detecting occult recurrences [98], especially smaller ones and those
in peripherical location (not included in the mammographic field of view).
MR images show an irregular mass with avid early enhancement and delayed
washout. Nodal recurrence manifests as an increase in the number and size of axil-
lary or internal mammary lymph nodes [99, 100] (Fig. 17.86).
There is not a consensus on the methods for patient follow-up after mastectomy
and breast reconstruction. Many authors recommend performing a physical exami-
nation to detect subcutaneous recurrences and mammography to detect recurrent
tumors in the chest wall. Follow-up with breast MRI may benefit women at high risk
for breast cancer recurrence (histologically aggressive type or genetic susceptibil-
ity). Early detection of recurrence has not been shown to decrease mortality, as most
patients with recurrent breast cancer have metastases when recurrence is diagnosed
[101, 102].
b c
Fig. 17.86 Recurrence after skin sparing mastectomy (SSM). Imaging findings of a 33-year-old
woman with personal history of DCIS in the right breast 7 years ago, treated with skin sparing
mastectomy. After 5 years she underwent a prophylactic SSM on the left breast. (a) Axial
T1-weighted MR image (anatomical features) and US images show retropectoral implants, absence
of the NAC on the right breast (SSM), and minimal subareolar fibroglandular parenchyma and
preserved NAC on the left breast (NSM). (b) Axial post-contrast fat-suppressed T1-weighted MR
image shows no intramammary suspicious enhancement. (c, d) Axial and sagittal post-contrast
fat-suppressed T1-weighted MR images show an oval, circumscribed axillary mass. (e, f)
Corresponding PET-CT and US images, 7 years after the first treatment. (g) Core biopsy proven
IDC luminal B
e f

17.10 Conclusion
Patients have a wide range of surgical options and adjuvant therapies. Radiologists
should be familiar with them, including normal and abnormal imaging appearances
from surgical procedures, reconstructed breasts, and radiation therapy changes, as
posttreatment changes can sometimes mimic malignancy or obscure locally recur-
rent breast cancer.
References
1. Mendelson EB. Evaluation of the postoperative breast. Breast Imaging: Curr Status Future
Dir. 1992;30:107–38.
2. Drukteinis JS, Gombos EC, Raza S, et al. MR imaging assessment of the breast after
breast conservation therapy: distinguishing benign from malignant lesions. Radiographics.
2012;32:219–34.
3. Margolis NE, Morley C, Lotfi P, et al. Update on imaging of the postsurgical breast.
Radiographics. 2014;34:642–60.
4. Hayes MK, Gold RH, Bassett LW. Mammographic findings after the removal of breast
implants. AJR Am J Roentgenol. 1993;160:487–90.
5. Collis N, Sharpe DT. Silicone gel-filled breast implant integrity: a retrospective review of 478
consecutively explanted implants. Plast Reconstr Surg. 2000;105:1979–85.
6. Ikeda DM, Borofsky HB, Herfkens RJ, et al. Silicone breast implant rupture: pitfalls of mag-
netic resonance imaging and relative efficacies of magnetic resonance, mammography, and
ultrasound. Plast Reconstr Surg. 1999;104:2054–62.
7. Cicchetti S, Leone MS, Franchelli S, Santi PL. Evaluation of the tolerability of hydrogel
breast implants: a pilot study. Minerva Chir. 2002;57:53–7.
8. Collis N, Litherland J, Enion D, Sharpe DT. Magnetic resonance imaging and explan-
tation investigation of long-term silicone gel implant integrity. Plast Reconstr Surg.
2007;120:1401–6.
9. Kreymerman P, Patrick RJ, Rim A, et al. Guidelines for using breast magnetic resonance
imaging to evaluate implant integrity. Ann Plast Surg. 2009;62:355–7.
10. Marotta JS, Widenhouse CW, Habal MB, Goldberg EP. Silicone gel breast implant failure
and frequency of additional surgeries: analysis of 35 studies reporting examination of more
than 8,000 explants. J Biomed Mater Res. 1999;48:354–64.
11. Janowsky EC, Kupper LL, Hulka BS. Meta-analyses of the relation between silicone breast
implants and the risk of connective-tissue diseases. N Engl J Med. 2000;342:781–90.
12. Kessler DA. The basis of the FDA’s decision on breast implants. N Engl J Med.
1992;326:1713–5.
13. Lipworth L, Holmich LR, McLaughlin JK. Silicone breast implants and connective tissue
disease: no association. Semin Immunopathol. 2011;33:287–94.
14. McLaughlin JK, Lipworth L, Murphy DK, Walker PS. The safety of silicone gel-filled breast
implants: a review of the epidemiologic evidence. Ann Plast Surg. 2007;59:569–80.
15. Muzaffar AR, Rohrich RJ. The silicone gel-filled breast implant controversy: an update. Plast
Reconstr Surg. 2002;109:742–8.
16. Noels EC, Lapid O, Lideman JH, Bastiaanner E. Breast implants and the risk of breast can-
cer: a meta-analysis of cohort studies. Aesthet Surg J. 2015;35:55–62.
17. Spear SL, Mardini S. Alternative filler materials and new implant designs: what’s available
and what’s on the horizon? Clin Plast Surg. 2001;28:435–43.
18. Tugwell P, Wells G, Peterson J, et al. Do silicone breast implants cause rheumatologic dis-
orders? A systematic review for a court-appointed national science panel. Arthritis Rheum.
2001;44:2477–84.
19. Derby BM, Codner MA. Textured silicone breast implant use in primary augmentation: core
data update and review. Plast Reconstr Surg. 2015;135:113–24.
20. Handel N, Garcia ME, Wixtrom R. Breast implant rupture: causes, incidence, clinical impact,
and management. Plast Reconstr Surg. 2013;132:1128–37.
21. Destouet JM, Monsees BS, Oser RF, et al. Screening mammography in 350 women with
breast implants: prevalence and findings of implant complications. AJR Am J Roentgenol.
1992;159:973–81.
22. Eklund GW, Busby RC, Miller SH, Job JS. Improved imaging of the augmented breast. AJR
Am J Roentgenol. 1988;151:469–73.
23. Ganott MA, Harris KM, Ilkhanipour ZS, Costa-Greco MA. Augmentation mammoplasty:
normal and abnormal findings with mammography and US. Radiographics. 1992;12:281–95.
24. Silverstein MJ, Handel N, Gamagami P. The effect of silicone-gel-filled implants on mam-
mography. Cancer. 1991;68(Suppl):1159–63.
25. Silverstein MJ, Handel N, Gamagami P, et al. Mammographic measurements before and after
augmentation mammaplasty. Plast Reconstr Surg. 1990;86:1126–30.
26. Shah M, Tanna N, Margolies L. Magnetic resonance imaging of breast implants. Top Magn
Reson Imaging. 2014;23:345–53.
27. Monticciolo DL, Nelson RC, Dixon WT, et al. MR detection of leakage from silicone breast
implants: value of a silicone-selective pulse sequence. AJR Am J Roentgenol. 1994;163:51–6.
28. Berg WA, Caskey CI, Hamper UM, et al. Diagnosing breast implant rupture with MR imag-
ing, US, and mammography. Radiographics. 1993;13:1323–36.
29. Young VL, Bartell T, Destouet JM, et al. Calcification of breast implant capsule. South Med
J. 1989;82:1171–3.
30. DeBruhl ND, Gorczyca DP, Ahn CY, Shaw WW, Bassett LW. Silicone breast implants: US
evaluation. Radiology. 1993;189:95–8.
31. Gossner J. Sonography in capsular contracture after breast augmentation: value of estab-
lished criteria, new techniques and directions for research. J Ultrasound. 2017;20:87–9.
32. Ahn CY, Shaw WW, Narayanan K, et al. Residual silicone detection using MRI following
previous breast implant removal: case reports. Aesthet Plast Surg. 1995;19:361–7.
33. Stewart NR, Monsees BS, Destouet JM, Rudloff MA. Mammographic appearance following
implant removal. Radiology. 1992;185:83–5.
34. Henriksen TF, Holmich LR, Fryzek JP, et al. Incidence and severity of short-term complica-
tions after breast augmentation: results from a nationwide breast implant registry. Ann Plast
Surg. 2003;51:531–9.
35. Cortes MIC, Valadez ER, Martinez RDZ, et al. Breast prosthesis syndrome: pathophysiology
and management algorithm. Aesth Plast Surg. 2020;44:1423–37.
36. Feng LJ, Amini SB. Analysis of risk factors associated with rupture of silicone gel breast
implants. Plast Reconstr Surg. 1999;104:955–63.
37. Holmich LR, Friis S, Fryzek JP, Vejborg IM, et al. Incidence of silicone breast implant rup-
ture. Arch Surg. 2003;138:801–6.
38. Bengtson BP, Eaves FF 3rd. High-resolution ultrasound in the detection of silicone gel breast
implant shell failure: background, in vitro studies, and early clinical results. Aesthet Surg
J. 2012;32:157–74.
39. Heden P, Bone B, Murphy DK, et al. Style 410 cohesive silicone breast implants: safety and
effectiveness at 5 to 9 years after implantation. Plast Reconstr Surg. 2006;118:1281–7.
40. Heden P, Bronz G, Elberg JJ, et al. Long-term safety and effectiveness of style 410 highly
cohesive silicone breast implants. Aesthet Plast Surg. 2009;33:430–6.
41. Heden P, Nava MB, van Tetering JP, et al. Prevalence of rupture in Inamed silicone breast
42. Holmich LR, Fryzek JP, Kjoller K, et al. The diagnosis of silicone breast-implant rupture:
clinical findings compared with findings at magnetic resonance imaging. Ann Plast Surg.
2005;54:583–9.
43. Beekman WH, Hage JJ, Taets van Amerongen AH, Mulder JW. Accuracy of ultrasonography
and magnetic resonance imaging in detecting failure of breast implants filled with silicone
gel. Scand J Plast Reconstr Surg Hand Surg. 1999;33:415–8.
44. Rosculet KA, Ikeda DM, Forrest ME, et al. Ruptured gel-filled silicone breast implants:
sonographic findings in 19 cases. AJR Am J Roentgenol. 1992;159:711–6.
45. Chung KC, Wilkins EG, Beil RJ Jr, et al. Diagnosis of silicone gel breast implant rupture by
ultrasonography. Plast Reconstr Surg. 1996;97:104–9.
46. Di Benedetto G, Cecchini S, Grassetti L, et al. Comparative study of breast implant rupture
using mammography, sonography, and magnetic resonance imaging: correlation with surgi-
cal findings. Breast J. 2008;14:532–7.
47. Ahn CY, DeBruhl ND, Gorczyca DP, et al. Comparative silicone breast implant evaluation
using mammography, sonography, and magnetic resonance imaging: experience with 59
48. Rivero MA, Schwartz DS, Mies C. Silicone lymphadenopathy involving intramam-
mary lymph nodes: a new complication of silicone mammaplasty. AJR Am J Roentgenol.
1994;162:1089–90.
49. Berg WA, Caskey CI, Hamper UM, et al. Single- and double-lumen silicone breast implant
integrity: prospective evaluation of MR and US criteria. Radiology. 1995;197:45–52.
50. Harris KM, Ganott MA, Shestak KC, et al. Silicone implant rupture: detection with
US. Radiology. 1993;187:761–8.
51. Kuzmiak CM, et al. Mammographic findings of partial breast irradiation. Acad Radiol.
2009;16(7):819–25.
52. Kwek JW, Choi H, Ma J, Miller MJ. Gel-gel double-lumen silicone breast implant: mimic of
intracapsular implant rupture. AJR Am J Roentgenol. 2006;187:W436–7.
53. Palmon LU, Foshager MC, Parantainen H, et al. Ruptured or intact: what can linear echoes
within silicone breast implants tell us? AJR Am J Roentgenol. 1997;168:1595–8.
54. Cher DJ, Conwell JA, Mandel JS. MRI for detecting silicone breast implant rupture: meta-
analysis and implications. Ann Plast Surg. 2001;47:367–80.
55. Holmich LR, Vejborg I, Conrad C, et al. The diagnosis of breast implant rupture: MRI find-
ings compared with findings at explantation. Eur J Radiol. 2005;53:213–25.
56. Gorczyca DP. MR imaging of breast implants. Magn Reson Imaging Clin N Am.
1994;2:659–72.
57. Kim SH, Lipson JA, Moran CJ, et al. Image quality and diagnostic performance of silicone-
specific breast MRI. Magn Reson Imaging. 2013;31:1472–8.
58. Herborn CU, Marincek B, Erfmann D, et al. Breast augmentation and reconstructive surgery:
MR imaging of implant rupture and malignancy. Eur Radiol. 2002;12:2198–206.
59. Soo MS, Kornguth PJ, Walsh R, et al. Intracapsular implant rupture: MR findings of incom-
plete shell collapse. J Magn Reson Imaging. 1997;7:724–30.
60. Adrada BE, Miranda RN, Rauch GM, et al. Breast implant-associated anaplastic large cell
lymphoma: sensitivity, specificity, and findings of imaging studies in 44 patients. Breast
Cancer Res Treat. 2014;147:1–14.
61. Chacko A, Lloyd T. Breast implant-associated anaplastic large cell lymphoma: a pictorial
review. Insights Imaging. 2018;9:683–6.
62. Xu J, Wei S. Breast implant-associated anaplastic large cell lymphoma: review of a distinct
clinicopathologic entity. Arch Pathol Lab Med. 2014;138:842–6.
63. Boer M, Leeuwen FE, Hauptmann M, et al. Breast implants and the risk of anaplastic large-
cell lymphoma in the breast. JAMA Oncol. 2018;4(3):335–41.
64. Forgia DL, Catino A, Fausto A, et al. Diagnostic challenges and potential early indicators of
breast periprosthetic anaplastic large cell lymphoma A case report. Medicine. 2020;99:30.
65. Miranda RN, Aladily TN, Prince HM, et al. Breast implant-associated anaplastic largecell
lymphoma: long-term follow-up of 60 patients. J Clin Oncol. 2014;32:114–20.
66. Zanetta VC, Rudner MA, et al. Gossypibomas after breast augmentation: an almost-forgotten
diagnosis. Breast J. 2020;26:2125–8.
67. Morris EA, Comstock CE, Lee CH, et al. ACR BI-RADS® magnetic resonance imaging.
ACR BI-RADS® atlas, breast imaging reporting and data system. Reston: American College
of Radiology; 2013.
68. Qian B, Xiong L, Guo K, et al. Comprehensive management of breast augmentation with
polyacrylamide hydrogel injection based on 15 years of experience: a report on 325 cases.
Ann Transl Med. 2020;8(7):475.
69. Grella R, Almadori A, D’Ari A, et al. Management of complication after breast augmentation
with methacrylate. Int J Surg Case Rep. 2015;15:17–20.
70. Teo SY, Wang SC. Radiologic features of polyacrylamide gel mammoplasty.
AJR. 2008;191:W89–95.
71. Khouri RK, Eisenmann-Klein M, Cardoso E, et al. Brava and autologous fat transfer is a
safe and effective breast augmentation alternative: results of a 6-year, 81-patient, prospective
multicenter study. Plast Reconstr Surg. 2012;129:1173–87.
72. Blumenschein AR, Freitas-Junior R, Tuffanin AT, et al. Breast fat grafting: experimental or
established procedure? Rev Bras Cir Plást. 2012;27(4):616–22.
73. Atia AA, Ghareeb FM, Ellabban MG, et al. Clinical and radiological assessment of autolo-
gous fat transfer to the breast. Eur J Plast Surg. 2020;43:139–46.
74. Gigli S, Amabile MI, Pastena FD, et al. Magnetic resonance imaging after breast oncoplastic
surgery: an update. Breast Care. 2017;12:260–5.
75. Veber M, Tourasse C, Toussoun G, et al. Radiographic findings after breast augmentation by
autologous fat transfer. Plast Reconstr Surg. 2011;127(3):1289–99.
76. Rubin JP, Coon D, Zuley M, et al. Mammographic changes after fat transfer to the breast
compared with changes after breast reduction: a blinded study. Plast Reconstr Surg.
2012;129:1029–38.
77. Loo YL, Haider S. The use of porcine acellular dermal matrix in single-stage, implant-based
immediate breast reconstruction: a 2-center retrospective outcome study. Plast Reconstr Surg
Glob Open. 2018;6(8):e1895.
78. Faulkner HR, Shikowitz-Behr L, McLeod M, et al. The use of absorbable mesh in implant-
based breast reconstruction: a 7-year review. Plast Reconstr Surg. 2020;146(6):731e–6e.
79. Bedrosian I, et al. Changes in the surgical management of patients with breast carcinoma
based on preoperative magnetic resonance imaging. Cancer. 2003;98:468–73.
80. Bleicher RJ, et al. Association of routine pretreatment magnetic resonance imaging with time
to surgery, mastectomy rate, and margin status. J Am Coll Surg. 2009;209:180–7.
81. Bleicher RJ, Morrow M. MRI and breast cancer: role in detection, diagnosis, and staging.
Oncology. 2007;21:1521–33.
82. Morrow M. Should routine breast cancer staging include MRI? Nat Clin Pract Oncol.
2009;6:72–3.
83. Sickles EA, Herzog KA. Mammography of the postsurgical breast. AJR Am J Roentgenol.
1981;136:585–8.
84. Godinez J, et al. Breast MRI in the evaluation of eligibility for accelerated partial breast irra-
diation. AJR Am J Roentgenol. 2008;191:272–7.
85. Liberman L, et al. Mammographic features of local recurrence in women who have under-
gone breast-conserving therapy for ductal carcinoma in situ. AJR Am J Roentgenol.
1997;168:489–93.
86. Tuli R, et al. Prognostic indicators following ipsilateral tumor recurrence in patients treated
with breast-conserving therapy. Am J Surg. 2009;198:557–61.
87. Gorechlad JW, et al. Screening for recurrences in patients treated with breast-conserving
surgery: is there a role for MRI? Ann Surg Oncol. 2008;15:1703–9.
88. Houssami N, Hayes DF. Review of preoperative magnetic resonance imaging (MRI) in breast
cancer: should MRI be performed on all women with newly diagnosed, early stage breast
cancer? CA Cancer J Clin. 2009;59:290–302.
89. Brennan ME, et al. Magnetic resonance imaging screening of the contralateral breast in
women with newly diagnosed breast cancer: systematic review and meta-analysis of incre-
mental cancer detection and impact on surgical management. J Clin Oncol. 2009;27:5640–9.
90. Chen JH, et al. MRI evaluation of pathologically complete response and residual tumors in
breast cancer after neoadjuvant chemotherapy. Cancer. 2008;112:17–26.
91. Dang CM, et al. Increased use of MRI for breast cancer surveillance and staging is not associ-
ated with increased rate of mastectomy. Am Surg. 2009;75:937–40.
92. Pinel-Giroux FM, et al. Breast reconstruction: review of surgical methods and spectrum of
imaging findings. Radiographics. 2013;33:435–53.
93. Clavero JA, et al. MDCT in the preoperative planning of abdominal perforator surgery for
postmastectomy breast reconstruction. AJR Am J Roentgenol. 2008;191(3):670–6.
94. Phillips TJ, et al. Abdominal wall CT angiography: a detailed account of a newly established
preoperative imaging technique. Radiology. 2008;249(1):32–44.
95. Özalp B, Aydinol M. Breast augmentation combining fat injection and breast implants in
patients with atrophied breasts. Ann Plast Surg. 2017;78:623–8.
96. Helvie MA, et al. Mammographic screening of TRAM flap breast reconstructions for detec-
tion of nonpalpable recurrent cancer. Radiology. 2002;224(1):211–6.
97. Medina-Franco H, et al. Factors associated with local recurrence after skin-sparing mas-
tectomy and immediate breast reconstruction for invasive breast cancer. Ann Surg.
2002;235(6):814–9.
98. Edeiken BS, et al. Recurrence in autogenous myocutaneous flap reconstruction after mastec-
tomy for primary breast cancer: US diagnosis. Radiology. 2003;227(2):542–8.
99. Shaikh N, et al. Detection of recurrent breast cancer after TRAM flap reconstruction. Ann
Plast Surg. 2001;47(6):602–7.
100. Vaughan A, et al. Patterns of local breast cancer recurrence after skin-sparing mastectomy
and immediate breast reconstruction. Am J Surg. 2007;194(4):438–43.
101. Lu WL, et al. Impact on survival of early detection of isolated breast recurrences after the pri-
mary treatment for breast cancer: a meta-analysis. Breast Cancer Res Treat. 2009;114:403–12.
102. Seely JM, et al. Breast MRI in the evaluation of locally recurrent or new breast cancer in
the postoperative patient: correlation of morphology and enhancement features with the
BI-RADS category. Acta Radiol. 2007;8:838–45.
Chapter 18
Radiation Therapy
Paula de Camargo Moraes
18.1 Introduction
It has been long established that postsurgical radiotherapy reduces the risk of locore-
gional failure. A survival advantage, however, has recently also been demonstrated
[1, 2]. Therefore, some women with breast cancer will need radiation therapy, in
addition to other treatments, as summarized below:
• After breast-conserving surgery (BCS) to reduce locoregional failure in the same
breast or nearby lymph nodes. Breast radiotherapy is recommended in patients
with invasive breast cancer treated with breast-conserving surgery where com-
plete microscopic excision has been achieved, unless life expectancy is less than
3 years due to comorbidities.
• This approach has enormously improved the quality of life and cosmetic out-
come for appropriately selected and treated patients while achieving excellent
long-term survival rates.
• After a mastectomy, especially if the cancer was large (T3/T4), if cancer is found
in many lymph nodes, or if certain surgical margins have cancer such as the skin
or muscle.
• The need for radiotherapy in patients with ductal carcinoma in situ (CDIS) can
be guided by use of the Van Nuys Prognostic Index (VNPI) score that accounts
for tumor size, grade, margin, presence of necrosis, and patient age.
• If cancer has spread to other parts of the body, such as the bones or brain.
P. de Camargo Moraes (*)

CDB (Centro Diagnóstico Brasil) – Grupo Alliar, São Paulo, SP, Brazil
Alta Medicina Diagnóstica – Grupo DASA, São Paulo, SP, Brazil

Switzerland AG 2022
416 P. de Camargo Moraes
18.2 Imaging Findings
Before addressing the findings expected after radiotherapy, it is important to rein-

force that since radiotherapy generally follows surgical treatment, the findings of
these two procedures often overlap. Besides that, imaging the treated breast presents
challenges due to its limited compressibility and the overlapping features of benign
posttreatment alterations and tumor recurrence, as described below.
18.2.1 Mastectomy
After any type of mastectomy procedure, most of the breast cells are removed.
However, there is a chance of a small amount of breast tissue remaining, and there-
fore the chance of recurrence exists. The rate of recurrence at the chest wall follow-
ing mastectomy is between 5% and 27%.
Recurrence involving the chest wall or skin can frequently be detected on clinical
or breast self-exam, as they are often obvious changes such as palpable masses, skin
thickening, retraction, edema, and redness. The addition of US to clinical exams
may prove to be more accurate than mammography when evaluating a palpable or
visible abnormality, as recurrence tends to be small and close to the skin surface.
Magnetic resonance imaging (MRI) is another imaging tool that can be used to
evaluate the mastectomy site and plays an important role in detecting recurrent
lesions.
For the asymptomatic patients, there is a continuing debate concerning imaging
following mastectomy, because it is said that imaging modalities may not be helpful
after this kind of surgery. So the findings commonly associated with this type of
surgical procedure, followed or not by radiation therapy, will not be addressed in
this chapter.
18.2.2 Breast Conservation Surgery
Breast conservation treatment achieves local tumor control by the surgical removal
of the cancer with margins and is usually followed by radiation therapy. The combi-
nation of conservative surgery and radiation therapy offers the advantage of preserv-
ing the breast, usually with a satisfactory cosmetic result. Given equivalent survival
rates for breast conservation therapy and mastectomy, breast conservation therapy
has become the treatment of choice for early-stage breast cancer.
However, radiologists are faced with increased imaging and diagnostic chal-
lenges when dealing with the conservative treated breast. The treated breasts may be
difficult to position adequately and to compress sufficiently due to surgical
18 Radiation Therapy 417
deformities, pain, or radiation changes. Also, the interpretation of imaging findings

can be difficult because imaging features after treatment may mimic or hide tumor
recurrence [3, 4].
The findings after lumpectomy and radiation therapy often overlap, and it is
important to recognize that radiation therapy often intensifies and delays resolution
of postsurgical changes [3, 4].
Although certain posttreatment alterations may persist, most changes after breast
conservation therapy diminish and regress over time and then remain stable.
Stability, defined as the lack of interval change on two successive studies, usually
occurs at 2–3 years after the completion of radiation therapy, which is around the
same time tumor recurrences typically begin to appear [5]. After stability has been
achieved, any increase in the changes, development of new asymmetries, or calcifi-
cations should raise suspicion for tumor recurrence [4].
It is important to acknowledge that both surgery and radiotherapy alter the
appearance of the breasts and sometimes distinguishing between recurrence and
benign postsurgical changes can be challenging due to overlapping features. Despite
this, differentiation between these two entities is usually possible by recognizing
characteristic features of posttreatment sequelae and the evolution of the appear-
ance of the conservatively treated breast by comparing interval findings on serial
studies. There is an expected chronological appearance for these findings on the
conservatively treated breast, as described below (Fig. 18.1).
The most common posttreatment findings that include breast edema, skin thick-
ening, fluid collections, fat necrosis, architectural distortion, and calcifications [3,
6] will be revised and illustrated.
80,0
70,0
60,0
50,0 Edema
40,0 Skin Thickening
30,0 Fluid collections
Surgical
20,0
associated
enhancement on
10,0
MRI
0,0 years
0,5 1 2 3 4 5 6
Fig. 18.1 Expected chronological appearance of the surgical findings on the conservatively
treated breast
18.2.2.1 Fluid Collections
A common finding on posttreatment mammography is fluid collections at the

lumpectomy site. Dead space is often intentionally left at surgery of a malignant
breast neoplasm to allow fluid to fill in the space and, in this way, achieve better
cosmesis [3].
Fluid with or without blood which collects in the postoperative cavity appears on
mammography as an oval or round circumscribed or obscured mass that is most
commonly seen within the surgical bed and should not be confused with recurrent
tumor (Figs. 18.2 and 18.3).
Sonography of these collections often reveals a complex cystic mass with septa-
tions, loculations, thick walls, or a combination of these findings (Figs. 18.2
and 18.3).
Approximately half of breast cancer patients have fluid collections at the surgical
site at 4 weeks after surgery and about 25% at 6 months. Over subsequent months,
postoperative seromas, and hematomas are gradually resorbed and are replaced by
scarring and fibrosis.
Fluid collections generally diminish in size over time and resolve completely by
12–18 months after surgery, although they may persist in a minority of patients. Any
increase in the size of a fluid collection over time should alert the radiologist to a
possible recurrence.
18.2.2.2 Breast Edema and Skin Thickening
Breast edema and skin thickening are posttreatment findings with similar time
courses for appearance and regression. Typically, post-lumpectomy edema is local-
ized to the area of the incision, and breast edema from radiation therapy usually
encompasses the entire breast.
Breast edema may present as more of an accentuated trabecular pattern or as
overall increased breast density depending on the degree of the edema (Figs. 18.4
and 18.5). The perceived increased density in the irradiated breast may also be
explained by suboptimal exposure because the treated breast often is swollen and
less compressible.
Skin thickening during the period after radiation is secondary to breast edema
from the damage of small vessels. Skin thickening is the most common finding after
breast-conserving therapy, reported in up to 90% of patients. Normal skin thickness
of the breast as seen on mammograms is 2 mm. The skin thickness after radiation
therapy may reach 1 cm or more (Figs. 18.4 and 18.5).
Breast edema and skin thickening are best appreciated when compared with the
contralateral breast or with pretreatment mammograms (Figs. 18.4 and 18.5).
At mammography, maximal breast edema and skin thickening are usually seen
during the first 6 months after completion of radiation therapy. These alterations
then diminish and attain stability within 2–3 years.
Fig. 18.2 Postoperative seroma in a 62-year-old woman with history of invasive left breast carci-
noma. Mediolateral oblique (a) and craniocaudal (b) mammograms obtained 6 months after radia-
tion therapy show an ill-defined mass in upper outer left breast consistent with postoperative
seroma (arrows). The ultrasound image (c) shows a complex solid-cystic mass. These findings are
consistent with postoperative seroma given history of breast conservation therapy in this area
a b c
Fig. 18.3 Postoperative seroma in a 44-year-old woman with history of in situ right breast carci-
noma. Mediolateral (a) and craniocaudal (b) mammograms obtained 6 months after radiation
therapy show an obscured oval mass in upper outer right breast consistent with postoperative
seroma (arrows). Increased breast density and skin thickening can also be seen. The ultrasound
image (c) shows a complex solid-cystic mass with thick walls. These findings are consistent with
postoperative seroma given history of breast conservation therapy in this area
a b
Fig. 18.4 Breast edema and skin thickening due to radiation therapy in a 74-year-old woman with
history of invasive left breast carcinoma. Mediolateral oblique (a) and craniocaudal (b) mammo-
grams of the right and left breasts obtained 1 year after radiation therapy show increased breast
density and skin thickening of the left breast
Edema or skin thickening that increases after stability has been achieved should
alert radiologists to the need for further investigation. The differential diagnoses of
recurrent or worsening breast edema include lymphatic spread of cancer, obstructed
venous drainage, congestive heart failure, and infection.
a b
Fig. 18.5 Breast edema and skin thickening due to radiation therapy in an 80-year-old woman
with history of invasive left breast carcinoma. Mediolateral oblique (a) and craniocaudal (b) mam-
mograms of right and left breasts obtained 3 years after radiation therapy show increased breast
density and skin thickening of the left breast, which is most prominent in the periareolar area
18.2.2.3 Fat Necrosis
Fat necrosis of the breast is a benign entity which may be seen after trauma, surgery,
and radiotherapy, among other conditions [6–8]. Clinically, the patients may be
asymptomatic or may present with a palpable lump, skin tethering, and induration.
In imaging studies, the appearance of fat necrosis ranges from typically benign
to worrisome for malignancy, depending on the time at which diagnostic imaging is
performed. This is directly related to whether inflammation or fibrosis is predomi-
nating within the lesion, and correlation with clinical history is very important for
the correct evaluation of these lesions [6].
The classically benign appearing mammographic findings for fat necrosis are the
oil cysts, which are masses with central lucency. These oil cysts may be accompa-
nied by peripheral rim or “eggshell” calcifications (Fig. 18.6).
The presence of calcifications on mammography suggests that most of the calci-
fications will evolve to a dystrophic morphology as the lesions become older. At the
beginning of the calcification process, sometimes we can intercept pleomorphic or
amorphous appearing calcifications on mammography.
Fat necrosis appearing as suspicious noncalcified masses may demonstrate
increased density due to progressive parenchymal fibrosis resulting in an ill-defined,
spiculated mass on mammography, and biopsy may be warranted for the adequate
diagnosis.
Fat necrosis ranges from simple cyst to complex cystic or solid masses on
sonography (Fig. 18.7). As the appearance of fat necrosis can be undetermined
Fig. 18.6 Different examples of fat necrosis on mammography
Fig. 18.7 Different examples of fat necrosis on ultrasound
on ultrasound, whenever we are faced with complex or inconclusive masses in a

posttreated breast, mammographic correlation is essential for their proper
evaluation.
The amount of inflammatory reaction, presence of liquefied fat, and the degree
of fibrosis determine the varying findings of fat necrosis on MRI (Fig. 18.8).
Administration of contrast may result in enhancement, particularly during the early
stages of the inflammatory process. The presence of fat signal on MRI findings usu-
ally suggests its benignity.
Nonfatty signal intensity irregular masses with variable enhancement patterns
are likely a reflection of the later stages of fat necrosis, when the fibrotic chances are
more prominent.
In summary, mammography is more specific than sonography, and emphasis
should be placed on mammography in making the diagnosis of fat necrosis. In
selected cases, MRI may be helpful in showing findings consistent with fat necrosis,
especially when fat signal can be detected inside the imaging findings.
Fig. 18.8 Fat necrosis on MRI. T1-weighted nonfat-saturated image (NFS) shows a hyperintense
circumscribed mass with a hypointense rim (arrow). The mass signal is similar to the adjacent fat,
characteristic of fat necrosis. Sagittal T1-enhanced and fat-suppressed and subtraction images
show the fat-containing mass with a non-enhancing thin fibrous rim (arrow)
18.2.2.4 Architectural Distortion
Architectural distortion in the treated breast develops secondary to scar formation

and fat necrosis. Architectural distortion is commonly seen in the lumpectomy bed
and within the lower axilla if sentinel node biopsy or axillary node dissection was
performed (Fig. 18.9).
Parenchymal scarring and fat necrosis can cause an irregular spiculated or indis-
tinct mass, associated with skin retraction that mimics recurrent malignancy.
However, the presence of the following mammographic features is more likely to
suggest benign architectural distortion rather than tumor recurrence: the presence of
Fig. 18.9 Mediolateral

oblique mammogram of
the left breast shows post
lumpectomy site as an area
of architectural distortion
in the upper quadrant.
Surgical clips delineate site
of tumor removal
central lucencies; a changing appearance on different projections; and thick, curvi-

linear spiculations [3] (Fig. 18.10).
Central lucencies suggest scarring because they represent fat trapped by fibrous
stranding in the scar. These differentiating features can often be helpful, although
they are not always reliable. For instance, some breast carcinomas, notably, infiltrat-
ing lobular, may contain central lucencies and may not have a central mass.
Architectural distortion usually diminishes in conspicuity and stabilizes over a
2-year period. In evaluating suspicious lesions, spot compression, magnification,
and tomosynthesis views are helpful in showing the features of scarring and in
excluding recurrent tumors.
Annual follow-up mammograms are necessary to show the sequential decrease
in the size and prominence of the density to ensure its benignity. If the scar grows in
size or if it becomes denser or more mass like, recurrent tumor should be suspected
and should prompt biopsy [4, 9].
Fig. 18.10 Mediolateral oblique and craniocaudal mammogram of the right breast shows post-
lumpectomy site as an area of architectural distortion in the upper outer quadrant (arrows). Note
the presence of central lucency and thick, curvilinear spiculations suggestive of surgical scar
18.2.2.5 Benign Calcifications
Benign calcifications may develop at the postoperative site, with a reported inci-
dence of 28% within the first 6–12 months after radiation therapy.
Dystrophic calcifications generally develop in areas of fat necrosis and are usu-
ally round and coarse and typically large and often have lucent centers (Fig. 18.11).
Suture material left in the breast may also calcify, forming distinctive shapes such
as knot like, rod-shaped, and curvilinear (Fig. 18.12).
On magnification views, these benign forms of calcifications can often be recog-
nized and differentiated from pleomorphic or other suspicious calcifications associ-
ated with malignancy (Fig. 18.13).
At times, however, dystrophic calcifications may simulate malignancy. As previ-
ously described, early calcification of evolving fat necrosis may produce an appear-
ance that is mammographically inconclusive. In such cases, careful inspection of
the previous mammograms may help by showing regression of the calcifications
over time or formation of the calcifications around a radiolucent center of fat, sug-
gesting the benign nature (Fig. 18.14). If calcifications cannot be distinguished from
a possible malignant process radiographically, biopsy should be considered.
Fig. 18.11 Dystrophic calcifications in 72-year-old woman with history of right breast carcinoma.
Mediolateral oblique and craniocaudal mammograms of right breast obtained 12 years after
lumpectomy and radiation therapy. Large coarse calcifications (arrows), representing dystrophic
calcifications, are seen within tumor excision site
18.3 Imaging Methods
18.3.1 Mammography
There is currently no universal guideline for posttreatment imaging surveillance.

There are multiple proposed guidelines, and they recommend mammography as
part of routine follow-up after BCT [10].
Fig. 18.12 Sutural calcifications in a 91-year-old woman with a history of left breast cancer that
was treated with lumpectomy and radiation therapy. Mediolateral oblique and craniocaudal mam-
mograms of post-lumpectomy and radiation of the left breast show curvilinear and knot-shaped
calcifications. These findings are characteristic of sutural calcifications, which are most commonly
seen in the irradiated breast and are rarely observed after benign breast surgery
Postsurgical mammograms can be obtained before the initiation of radiation

therapy on selected cases to determine the completeness of tumor excision by iden-
tifying residual calcifications within the breast.
In most cases, however, mammograms of both breasts are obtained 6 months
after the completion of radiation therapy. Images obtained at that time include
craniocaudal and mediolateral oblique views. Magnification views of the
lumpectomy bed are also routinely obtained even though there is no evidence
to support improved outcome. Subsequently, annual mammography is nor-
mally performed [3, 5].
Mammographic imaging in patients after breast conservation surgery is chal-
lenging because surgery alters the normal breast architecture. The distinction of
normal postoperative changes from true findings of recurrence becomes demanding
making it essential to know what are the expected posttreatment findings.
Fig. 18.13 Dystrophic calcifications in a 65-year-old woman with history of right breast carci-
noma. Mediolateral oblique and craniocaudal mammograms of right breast obtained 5 years after
lumpectomy and radiation therapy. Coarse calcifications (arrows), representing dystrophic calcifi-
cations, are seen within tumor excision site
Fig. 18.14 Follow-up mammograms help showing the formation of the calcifications around the
area of fat necrosis, suggesting the benign nature
18.3.2 Tomosynthesis
Digital breast tomosynthesis (DBT) is a mammographic technique that entails

imaging of the breast tissue in multiple sections at varied angles. The overlap
of parenchymal tissues is largely resolved, reducing the false positives as well
as adequately identifying true lesions, increasing the sensitivity of a mammo-
gram [7, 11].
DBT not only helps in triangulation of a lesion but also reduces the requirement
for additional views and lowers the patient call-back rate.
Similar to screening mammography, DBT also helps resolve post conservation
changes such as a scar or other asymmetries due to parenchymal edema from a true
recurrence. The fat density within the scar and that associated with benign calcifica-
tion may also be better appreciated on DBT whereas a true recurrence would dem-
onstrate a mass.
A study by Sia et al. [11] also reported that DBT decreases the rate of indetermi-
nate findings in surveillance imaging of conservatively treated breasts.
18.3.3 Ultrasound
Breast ultrasound is a widely used method adjuvant to mammography for the fur-
ther characterization of lesions identified on mammography. It provides additional
information on lesions’ margin, shape, internal echotexture, vascularity, and elastic-
ity [7, 12].
Ultrasonography is also useful in demonstrating the origin of a palpable mass
either within the breast parenchyma or the implant, in cases of breast
reconstruction.
If a lesion has suspicious morphology on any breast imaging method and is vis-
ible on ultrasound, ultrasound-guided biopsy is the procedure of choice. When per-
formed correctly, this procedure is safe and minimally invasive and has a high
diagnostic accuracy, comparable to surgical biopsy.
18.3.4 Magnetic Resonance
An important component in evaluating the role of MRI following BCS is to com-

pare to the current standard of mammography. Whereas data support the concept
that MRI is more sensitive than mammography as part of high-risk screening, less
data are available in the post-BCT setting. Robertson et al. [10] performed a system-
atic review of nine studies and found that for ipsilateral breast tumor recurrences,
the sensitivity/specificity of MRI was 86–100%/93% as compared with

64–67%/85–97% for mammography with MRI also having higher sensitivity for
nonroutine ipsilateral breast recurrences.
Another potential role for MRI in patients following BCS is to evaluate findings
identified on surveillance mammography. Differentiating benign and malignant
lesions on MRI were summarized by Drukteinis et al. [13] who concluded that MRI
is useful in evaluating posttreatment changes. Breast MR imaging is especially use-
ful in differentiating scar tissue from tumor recurrence, as non-enhancing areas have
a high negative predictive value for malignancy (88–96%).
Another challenging finding is fat necrosis, which can mimic tumor recurrence
on mammography and ultrasonography and lead to increased numbers of biopsies/
interventions. As described above, MRI can help identify fat signals within lesions
and characterize these areas as benign.
Skin thickening, architectural distortion, resolving edema, and signal voids from
surgical or biopsy clips or from prior bleeding (hemosiderin) are frequent findings
in the post-BCT breast [4, 12–14].
The majority of these findings progressively decrease over time. Stability or less
prominent findings are expected and typically occur within 3 years. Edema in the
post-BCS breast may never resolve entirely, but increasing edema may be a sign of
recurrent cancer.
The normal appearance of a post-lumpectomy breast often includes a fluid cavity
filled with blood or serum (seroma) at the surgical site. Smooth, thin (≤5 mm) rim
enhancement around a seroma should be considered benign (Fig. 18.15). Most sero-
mas slowly diminish in size and evolve into scars (architectural distortion) by 1 year
after surgery.
A minimal or small focal area of enhancement or thin linear non-mass-like
enhancement (NME) without an associated mass can be seen for up to 18 months at
the lumpectomy site. This enhancement likely represents the healing process after
surgery and radiation therapy and can be considered appropriate for 6-month fol-
low-up (BI-RADS 3 category) if no previous study is available for comparison, and
no clinical or worrisome mammographic findings are present.
Fig. 18.15 MRI of post-lumpectomy and radiation therapy of the right breast shows fluid cavity
at the surgical site with smooth, thin rim enhancement (arrows)
Fig. 18.16 Post-lumpectomy with positive margins MRI was performed before the radiation ther-
apy of the right breast. Fluid cavity at the surgical site with smooth, thin rim enhancement (thin
arrows). Anterior to the seroma, it is possible to identify a suspicious non-mass-like segmental
enhancement (large arrows)
In contrast, mass-like enhancement or NME of ductal or segmental distribution

can indicate recurrence (Fig. 18.16). Therefore, at MR imaging of the post-BCS
breast, it is important to identify lesions that are benign or appropriate for short-
interval imaging surveillance to minimize unnecessary intervention, as well as to
discern suspicious lesions and optimize the diagnosis of recurrence.
Although there is no randomized evidence supporting the routine use of MRI in
surveillance post-BCS, a review of the literature by Fisher et al. [2] demonstrates
that MRI has increased sensitivity compared to mammography to detect recurrences
and can help evaluate inconclusive mammographic abnormalities before biopsy
(Fig. 18.17).
In patients with higher risk of local recurrence, surveillance with MRI may rep-
resent an effective surveillance strategy although no subgroups have been identified
that could benefit from its use and neither has the impact on cost and quality of life
been evaluated.
18.4 Conclusion
After breast-conserving surgery and radiation therapy, several alterations of the

breast occur and evolve over time.
As surgery and radiotherapy alter the appearance of the breasts, distinguishing
between recurrence and benign postsurgical changes can be challenging due to
overlapping features. Despite this, differentiation between these two entities is usu-
ally possible by recognizing characteristic features of posttreatment sequelae and
the evolution of the appearance of the conservatively treated breast by comparing
interval findings on serial studies. However, certain features of these benign changes
may simulate patterns of tumor recurrence and biopsy may be warranted.
a b
Fig. 18.17 Mediolateral oblique and craniocaudal mammogram (a) of the left breast after lumpec-
tomy and radiation therapy shows area of architectural distortion at the lumpectomy site in the
retroareolar region, with associated increased density (arrows). Target ultrasound (b) shows irregu-
lar mass with angulated margins. MRI (c) was performed to better access this finding and demon-
strated segmentar enhancement of the area and biopsy was recommended. Histologic result was
steatonecrosis associated with chronic granulomatous inflammatory process with multinucleated
giant foreign body cells
18.5 Summary
The posttreatment alterations include fluid collections, breast edema, skin thicken-
ing, fat necrosis, architectural distortion, and calcifications. There is an expected
chronological appearance for these findings on the conservatively treated breast,
and this is important to know for the correct diagnosis and conduct.
Mammograms and other imaging modalities should be evaluated and compared
with earlier studies to maximize detection of recurrent breast carcinoma while mini-
mizing unnecessary recalls and biopsies.
References
1. Joshi SC, Khan FA, Pant I, Shukla A. Role of radiotherapy in early breast cancer: an overview.
Int J Health Sci (Qassim). 2007;1(2):259.
2. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year fol-
low-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus
irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233–41.
3. Chansakul T, Lai KC, Slanetz PJ. The postconservation breast: part 1, expected imaging find-
ings. Am J Roentgenol. 2012;198:321–30.
4. Chansakul T, Lai KC, Slanetz PJ. The postconservation breast: part 2, imaging findings of
tumor recurrence and other long-term sequelae. Am J Roentgenol. 2012;198(2):331–43.
5. Krishnamurthy R, Whitman GJ, Stelling CB, Kushwaha AC. Mammographic findings after
breast conservation therapy. Radiographics. 1999;19(suppl_1):S53–62.
6. Fernandes Chala L, de Barros N, de Camargo Moraes P, Endo É, Kim SJ, Maciel Pincerato
K, et al. Fat necrosis of the breast: mammographic, sonographic, computed tomography, and
magnetic resonance imaging findings. Curr Probl Diagn Radiol. 2004;33(3):106–26.
7. Tayyab SJ, Adrada BE, Rauch GM, Yang WT. A pictorial review: multimodality imaging of
benign and suspicious features of fat necrosis in the breast. Br J Radiol. 2018;91(1092):2018021.
8. Kerridge WD, Kryvenko ON, Thompson A, Shah BA. Fat necrosis of the breast: a pictorial
review of the mammographic, ultrasound, CT, and MRI findings with histopathologic correla-
tion. Radiol Res Pract. 2015;2015:613139.
9. Günhan-Bilgen I, Oktay A. Mammographic features of local recurrence after conserva-
tive surgery and radiation therapy: comparison with that of the primary tumor. Acta radiol.
2007;48(4):390–7.
10. Robertson C, Ragupathy SKA, Boachie C, Fraser C, Heys SD, MacLennan G, et al. Surveillance
mammography for detecting ipsilateral breast tumour recurrence and metachronous contralat-
eral breast cancer: a systematic review. Eur Radiol. 2011;21(12):2484–91.
11. Sia J, Moodie K, Bressel M, Lau E, Gyorki D, Skandarajah A, et al. A prospective study
comparing digital breast tomosynthesis with digital mammography in surveillance after breast
cancer treatment. Eur J Cancer. 2016;61:122–7.
12. Ramli Hamid MT, Rahmat K, Hamid SA, Kirat Singh SK, Hooi TG. Spectrum of multimo-
dality findings in post-surgical breast cancer imaging. Curr Med Imaging Former Curr Med
Imaging Rev. 2018;15(9):866–72.
13. Drukteinis JS, Gombos EC, Raza S, Chikarmane SA, Swami A, Birdwell RL. MR imaging
assessment of the breast after breast conservation therapy: distinguishing benign from malig-
nant lesions. Radiographics. 2012;32(1):219–34.
14. Margolis NE, Morley C, Lotfi P, Shaylor SD, Palestrant S, Moy L, et al. Update on imaging of
the postsurgical breast. Radiographics. 2014;34(3):642–60.
Chapter 19
Adjuvant Therapy
19.1 Indications
Adjuvant systemic treatment improved the outcomes of patients with localized

breast cancer significantly, impacting the reduction of breast cancer mortality.
Nevertheless, appropriate selection of candidates is crucial, since it may be associ-
ated with severe side effects, including late toxicities from chemotherapy such as
secondary myelodysplasia and leukemia. Moreover, some patients have a high
chance of cure without requiring systemic therapy.
For localized disease treated with curative intent, the addition of systemic ther-
apy aims to control microscopic cancer cells, decreasing the risk of recurrence. The
systemic therapy can be used before or after surgery (neoadjuvant or adjuvant,
respectively). Here, we discuss indications of systemic therapy for patients already
submitted to surgery. Indications of neoadjuvant therapy are discussed in a separate
chapter.
The indication of adjuvant chemotherapy will depend on tumor characteristics
such as size, grade, lymph node status, and expression of hormone receptor (estro-
gen receptor (ER) and progesterone receptor (PR)) and HER2. Patient characteris-
tics, including age, performance status, and comorbidities, are also important for the
decision-making process.
For hormone receptor (ER or PR)-positive breast cancer, adjuvant endocrine
therapy should be considered for all patients [1]. Otherwise, the use of adjuvant
chemotherapy in this group is more complex, with diverse factors influencing the
decision. Adjuvant chemotherapy is usually recommended for those with more than
L. Testa (*) · R. C. Bonadio


Switzerland AG 2022
four positive lymph nodes. For patients with negative or less than four positive
lymph nodes, clinical characteristics and tumor pathology need to be evaluated to
assess patients’ risk of recurrence and the benefit of chemotherapy. Features associ-
ated with a higher risk of recurrence include younger age, premenopausal status,
grade 3, positive lymph nodes, presence of angiolymphatic invasion, and low
expression of ER/ PR.
More recently, a helpful tool that can be considered is the use of assays that
evaluate recurrence risk based on gene expression profiles from tumor samples. The
oncotype DX recurrence score (RS) is the most well-validated assay to predict adju-
vant chemotherapy benefit. Oncotype DX RS provided a score based on gene
expression that allows a classification of the risk of recurrence in low (RS < 11),
intermediate (RS 11–25), or high (RS > 25). The TAILORx trial, a phase III trial,
evaluated the use of oncotype DX to predict the benefit of chemotherapy for hor-
mone receptor-positive node-negative breast cancer. Patients with low-risk received
endocrine therapy alone, those with high risk received endocrine therapy plus che-
motherapy, and those with intermediate risk were randomized to endocrine therapy
alone or endocrine therapy plus chemotherapy. Results showed that patients in the
intermediate group can be treated with endocrine therapy alone with satisfactory
outcomes [2]. However, subgroup analysis suggested that women younger than
50 years with a RS of 16–25 might benefit from the addition of chemotherapy [3].
Based on these results, patients with node-negative disease may be spared from
adjuvant chemotherapy if they present a RS less than 16 for women with any age or
less than 26 for those older than 50 years.
HER2 amplification is an important driver of HER2-positive breast cancer.
Adjuvant anti-HER2 therapy is indicated in addition to chemotherapy for HER2-
positive tumors greater than 1 cm or node-positive [1, 4]. Pivotal trials of anti-HER2
therapy did not have a representative population of node-negative tumors smaller
than 1 cm. Nevertheless, anti-HER2 therapy may also be considered for this group
based on a significant risk of relapse described in some studies, especially when
high-risk features are present [5, 6].
Finally, neoadjuvant or adjuvant chemotherapy has a major role for triple-
negative (TN) breast cancer, usually characterized by aggressive behavior and high
recurrence risk. For these patients, chemotherapy should be considered for any
tumor greater than 0.5 cm or with positive lymph node (regardless of primary tumor
size) [1].
19.2 Treatment Options
Treatment regimens based on anthracyclines and taxanes are standard regimens for
breast cancer patients with an indication of adjuvant chemotherapy. These drugs
may be combined in different ways, depending on local expertise and preference. A
largely used regimen is AC-T, based on doxorubicin and cyclophosphamide,
19 Adjuvant Therapy 437
sequential with paclitaxel [7]. AC is done for four cycles (every 3 weeks or every
2 weeks in the dense dose regimen), followed by weekly paclitaxel for 12 weeks.
However, anthracyclines may lead to some concerning adverse events such as
cardiotoxicity and secondary leukemia. Regimens without anthracyclines constitute
an alternative, especially for patients with contraindications to anthracyclines. In
this way, TC (docetaxel and cyclophosphamide, every 3 weeks, for four to six
cycles) and CMF (cyclophosphamide, methotrexate, 5-fluorouracil, every 4 weeks,
for six cycles) regimens are also common options of adjuvant chemotherapy [7, 8].
In recent years, relevant studies suggested that patients who received neoadju-
vant systemic therapy may have their adjuvant treatment modulated by the response
to neoadjuvant therapy. For patients with triple-negative breast cancer, those who
present residual disease in the surgical specimen after neoadjuvant therapy benefit
from additional adjuvant therapy with capecitabine for 6 months [9].
As anti-HER2 adjuvant therapy, the monoclonal antibody trastuzumab remains
the cornerstone [10]. Adjuvant trastuzumab is used for a year and is started concur-
rently with a taxane. For locally advanced tumors, AC-TH (doxorubicin and cyclo-
phosphamide, followed by paclitaxel and trastuzumab) and TCH (docetaxel,
carboplatin, and trastuzumab) are preferred regimens [11, 12]. Recent studies have
favored non-anthracycline regimens due to a similar efficacy and lower rate of late
toxicities than anthracycline-based regimens in HER2-positive breast cancer [13].
Finally, for early HER2-positive breast cancer, TH (taxane and trastuzumab) regi-
men is an option, which is preferred, especially for node-negative tumors smaller
than 2 cm [14]. An intensification of adjuvant anti-HER2 therapy, with the addition
of pertuzumab to trastuzumab, has a small benefit in disease-free survival and may
be considered for selected high-risk patients [15].
For HER-2 positive breast cancer patients who received neoadjuvant treatment,
the anti-HER2 therapy is continued after surgery for a total duration of 1 year. When
a complete pathological response is observed, the same anti-HER2 therapy is con-
tinued as adjuvant therapy. Otherwise, patients with residual disease have a relevant
disease-free survival gain with the modification of the adjuvant therapy to T-DM1,
an antibody-drug conjugate of trastuzumab and emtansine [16].
As adjuvant endocrine therapy, tamoxifen or an aromatase inhibitor is usually
indicated. Treatment with an aromatase inhibitor is preferred for postmenopausal
women, as the single endocrine therapy or with a switch to tamoxifen [17].
Tamoxifen is the treatment of choice for premenopausal women who will not
receive ovarian suppression. As an alternative, premenopausal women, especially
high-risk patients, may be treated with the addition of ovarian suppression to endo-
crine therapy (tamoxifen or an aromatase inhibitor) [18].
After treatment of localized disease, patients are followed with periodic consult
and physical examination (every 3–6 months). Mammography should be done
annually to detect local recurrence and second primary breast cancer that are ame-
nable to potentially curative treatment. Other routine image tests are not indicated
during follow-up and should be performed in case of suspicion of metastatic disease
based on patients’ signs and symptoms.
References
1. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast
cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol.
2019;30(10):1674.
2. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant
chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med.
2018;379(2):111–21.
3. Sparano JA, Gray RJ, Ravdin PM, Makower DF, Pritchard KI, Albain KS, et al. Clinical
and genomic risk to guide the use of adjuvant therapy for breast cancer. N Engl J Med.
2019;380(25):2395–405.
4. Denduluri N, Somerfield MR, Giordano SH. Selection of optimal adjuvant chemotherapy and
targeted therapy for early breast Cancer: ASCO clinical practice guideline focused update
summary. J Oncol Pract. 2018;14(8):508–10.
5. Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F, et al.
High risk of recurrence for patients with breast cancer who have human epidermal growth factor
receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009;27(34):5700–6.
6. Livi L, Meattini I, Saieva C, Franzese C, Di Cataldo V, Greto D, et al. Prognostic value of posi-
tive human epidermal growth factor receptor 2 status and negative hormone status in patients
with T1a/T1b, lymph node-negative breast cancer. Cancer. 2012;118(13):3236–43.
7. Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Comparisons between differ-
ent polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome
among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432–44.
8. Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE, Jacobs SA, et al. Anthracyclines in Early
Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP
B-49 (NRG Oncology). J Clin Oncol. 2017;35(23):2647–55.
9. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast
cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–59.
10. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab con-
taining regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4:CD006243.
11. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, et al. Trastuzumab
plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med.
2005;353(16):1673–84.
12. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastu-
zumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.
13. van der Voort A, van Ramshorst M, van Werkhoven E, et al. Three-year follow-up of neoad-
juvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade
for HER2-positive breast cancer (TRAIN-2): a randomized phase III trial. J Clin Oncol.
2020;15_suppl:501.
14. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant pacli-
taxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med.
2015;372(2):134–41.
15. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in
early HER2-positive breast cancer. N Engl J Med. 2017;377(7):122.
16. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al.
Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med.
2019;380(7):617–28.
17. (EBCTCG) EBCTCG. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-
level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–52.
18. Francis PA, Pagani O, Fleming GF, Walley BA, Colleoni M, Láng I, et al. Tailoring adjuvant
endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122–37.
Chapter 20
Follow-Up After Treatment
Bruno Salvador Sobreira Lima, Fernanda Barbosa,

Maria Carolina Formigoni, Sergio Masili-Oku, and Jose Roberto Filassi
20.1 Introduction
According to statistics from the International Agency for Research on Cancer

(IARC), 44 million people live with the disease worldwide. With the establishment
of effective screening policies and improvement of diagnostic and therapeutic meth-
ods, the number of patients who survive the disease is considerable. Specifically, for
breast cancer, the 5-year survival rate in countries like the United States is around
90% [1].
For those patients who survived the primary neoplasia, the follow-up will have to
consider specific issues of the natural aging process, in addition to the particularities
related to the cancer therapy received. Some aspects, such as the risk of late recur-
rence, the occurrence of a new primary tumor of the mammary site or not, and
sequelae of short- and long-term treatment are added to psychological, genetic,
reproductive, and social issues. All of these aspects must be involved in the follow-
up after cancer treatment.
We can didactically divide the follow-up into some items:
1. Follow-up appointments (anamnesis and physical examination).
2. Imaging exams.
3. Laboratory tests.
4. Genetic counseling.
5. Quality of life and lifestyle change.
6. Sexual and reproductive aspects.
B. S. S. Lima · F. Barbosa · M. C. Formigoni · S. Masili-Oku (*) · J. R. Filassi


Switzerland AG 2022
440 B. S. S. Lima et al.
20.1.1 Follow-Up Appointments (Anamnesis

and Physical Examination)
The most important ways to detect recurrences are still considered [2–4].
Consultations should be held every 3–6 months in the first 3 years, semiannually for
another 2 years, and annually after the fifth year [5].
In anamnesis, one should ask about symptoms of local recurrence or metastasis,
ask about symptoms side by side with the therapy, in addition to reinforcing adher-
ence to it:
Some important topics to be covered include [6, 7]:
• Constitutional symptoms - anorexia, weight loss, fatigue, insomnia.
• Bone health – bone pain, location and characteristic, associated symptoms,
improvement, and worsening factors.
• Pulmonary symptoms – persistent cough, dyspnea.
• Neurological symptoms – headache, nausea, vomiting, visual changes.
• Gastrointestinal symptoms – abdominal pain, change in bowel habits, and char-
acteristics of the stool.
• Genito-urinary symptoms – vaginal bleeding, difficulty urinating.
• Psychological symptoms – depression and anxiety.
• Endocrine/reproductive symptoms – hot flashes, dyspareunia, vaginal dryness,
preservation of fertility.
The physical examination should include a general exam with an assessment of
vital data, cardiac and pulmonary auscultation, and skeletal muscle, abdominal, and
neurological examination. The importance of gynecological follow-up must be rein-
forced, especially for tamoxifen users [6]. Physical analysis of the breasts and arm-
pit must be carried out rigorously, looking for local and lymph node recurrence signs.
In mastectomy cases with reconstruction, special attention should be given to
implants and possible complications related to contractures and or ruptures. In cases
of reconstruction using flaps such as transverse rectus abdominis (TRAM) or great
dorsal attention to steatonecrosis, which, due to its characteristics, can simulate a
recurrence, mammography has typical features that exclude a possible recurrence,
without the need for biopsy.
20.1.2 Imaging Exams
Mammography should be performed on the contralateral breast or after conserva-

tive surgery. It should be performed annually, with the first control exam conducted
6 months after radiotherapy in conservative surgery [8, 9].
Magnetic resonance imaging is not routinely indicated, and such data was dem-
onstrated by a systematic review carried out in 2012 [10]. It can be crucial in cases
20 Follow-Up After Treatment 441
where mammography is not conclusive and formally indicated in patients with

BRCA mutations and patients with a family history of breast cancer [11].
Ultrasound is also not routinely indicated. It should be performed to complement
possible mammographic changes or clinical examination findings without corre-
spondence to the mammogram.
For older patients or those with comorbidities that limit life expectancy to less
than 5–10 years, one can consider not having a mammographic follow-up [12].
In addition to the breast image assessment, we must emphasize the importance
of bone health assessment. It is known that breast cancer treatment increases the risk
of osteoporosis, especially in users of aromatase inhibitors [13]. Therefore,
American Society of Clinical Oncology (ASCO) recommends bone densitometry in
the following cases:
• Women over 65 years old.
• Women aged 60–64 years in the presence of one of the following factors: family
history of osteoporosis, weight <70 kg, history of fracture unrelated to trauma or
other risk factors (smoking, physical inactivity, alcoholism).
• Premenopausal women with indication and/ or use of an aromatase inhibitor.
• Premenopausal women who developed early menopause secondary to cancer
treatment.
20.1.3 Laboratory Tests
Intensive surveillance with laboratory and imaging (systemic) examinations is not

recommended for asymptomatic patients, as this strategy has not shown an increase
in disease-free survival or overall survival [14].
The early diagnosis of metastases provided by these tests increases the number
of interventions with a consequent increase in toxicity, increased cost, with no evi-
dent benefit in survival or quality of life [15].
The guideline for follow-up after breast cancer treatment by ASCO (2012) rein-
forces not performing these exams in asymptomatic patients, among them it is
worth mentioning:
• Tumor markers.
• Liver function tests.
• Bone scintigraphy.
• Alkaline phosphatase.
• Chest imaging exams (x-ray and tomography).
• Abdominal imaging and PET-CT.
Exception made only in those cases in which recurrence is suspected [5].
20.1.4 Genetic Counseling
In the follow-up, evaluate those patients who indicate the need for genetic research
and who may not have been tested during the initial investigation and evalua-
tion phase.
The patients with family cancer history (breast, ovary, colon) and at high risk of
hereditary tumors, such as breast cancer patients before age 50, patients with triple-
negative tumors before age 60, families descended from Jewish Ashkenazis, and
male patients [16].
The BRCA mutation is the most frequent, although other rarer mutations should
be investigated depending on the personal and family history of several types of
cancer, such as Li-Fraumeni and Cowden syndromes.
The performance of these tests and genetic counseling (with a geneticist or
another trained professional) is essential for evaluating other family members. In
this case, with the identification of high-risk individuals, it is possible to establish
risk-reducing measures.
Although it is possible to perform genetic tests on patients not affected by cancer,
these results can often be inconclusive. The ideal is to conduct genetic testing on the
affected individual, and if a particular mutation is identified, it should be investi-
gated on their descendants.
20.1.5 Quality of Life and Lifestyle Change
Several observational studies suggest that physical exercise, avoiding obesity, ade-
quate diet, and low alcohol intake decrease breast cancer recurrence risk [17, 18].
High doses of vitamin D at diagnosis, especially in premenopausal patients, have
been associated with a better prognosis; however, no randomized clinical data asso-
ciate vitamin D supplementation with a lower risk of recurrence.
Complementary therapies, such as acupuncture, mindfulness, music therapy, and
yoga, have been studied in breast cancer survivors. Although there is no evidence of
the relationship between these therapies and a lowest recurrence rate, there is a sig-
nificant improvement in the patients’ quality of life [19]. Some studies suggest that
these practices can improve joint pain in patients using aromatase inhibitors and
physical and psychological pain from breast cancer diagnosis and treatment [20].
20.1.6 Sexual and Reproductive Aspects
Symptoms of menopause, such as hot flushes and vaginal dryness, can be due to
age, chemotherapy treatment (in premenopausal patients), and hormone therapy.
Hormone therapy at menopause should be avoided in patients with a previous

history of breast cancer. Symptom management should be done with nonhormonal
drugs, such as gabapentin or serotonin reuptake inhibitors. Particular attention
should be given to serotonin reuptake inhibitors in patients using tamoxifen, with
venlafaxine and desvenlafaxine being preferred [21].
Acupuncture is a non-pharmacological therapy that has shown promising results
in clinical studies. Cognitive-behavioral therapy also improved hot flushes, night
sweats, and sleep quality [22, 23].
Sexual activity may become less pleasurable in patients with breast cancer.
Psychological sequelae can affect body image and affect relationships, with
impaired sexual function. Sexual dysfunction is associated with depression in breast
cancer survivors [24]. The treatment of vaginal atrophy includes nonhormonal
options such as lubricants.
Although some experts recommend waiting 2 years to conceive, some studies
suggest that pregnancy is safe, even in the first 2 years, the time of the most signifi-
cant risk of early recurrence [25].
The World Health Organization (WHO) suggests using nonhormonal contracep-
tion in patients with a history of breast cancer, as a copper or silver intrauterine
device (nonhormonal IUD), condom, and diaphragm.
20.2 Summary and Recommendations
• Recommend adherence to treatment and healthy lifestyle habits.

• Follow-up should include medical history, complete clinical examination, and
mammography.
• Follow-up should not focus only on cancer recurrence but also on treatment com-
plications and psychological aspects.
• Evaluate the need for genetic counseling.
• Do not perform laboratory or imaging exams in asymptomatic patients.
• Recommend adoption of a healthy lifestyle: adequate diet, regular physical activ-
ity, low alcohol intake, and smoking cessation.
• Assess possible sexual dysfunctions.
• Assess and treat menopausal symptoms.
• Pregnancy does not worsen breast cancer prognosis.
• Give preference to nonhormonal contraception.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7.
2. de Bock GH, Bonnema J, van der Hage J, et al. Effectiveness of routine visits and routine tests
in detecting isolated locoregional recurrences after treatment for early-stage invasive breast
cancer: a meta-analysis and systematic review. J Clin Oncol. 2004;22:4010.
3. Montgomery DA, Krupa K, Cooke TG. Follow-up in breast cancer: does routine clinical exam-
ination improve outcome? A systematic review of the literature. Br J Cancer. 2007;97:1632.
4. Lu W, de Bock GH, Schaapveld M, et al. The value of routine physical examination in the fol-
low up of women with a history of early breast cancer. Eur J Cancer. 2011;47:676.
5. Runowicz CD, Leach CR, Henry NL, et al. American Cancer Society/American Society of
Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol. 2016;34:611.
6. Loomer L, Brockschmidt JK, Muss HB, Saylor G. Postoperative follow-up of patients with
early breast cancer. Patterns of care among clinical oncologists and a review of the literature.
Cancer. 1991;67:55.
7. Pace BW, Tinker MA. Follow-up of patients with breast cancer. Clin Obstet Gynecol.
1994;37:998.
8. Grunfeld E, Noorani H, McGahan L, et al. Surveillance mammography after treatment of
primary breast cancer: a systematic review. Breast. 2002;11:228.
9. Lash TL, Fox MP, Buist DS, et al. Mammography surveillance and mortality in older breast
cancer survivors. J Clin Oncol. 2007;25:3001.
10. Quinn EM, Coveney AP, Redmond HP. Use of magnetic resonance imaging in detection of
breast cancer recurrence: a systematic review. Ann Surg Oncol. 2012;19:3035.
11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology.
Genetic/familial high-risk assessment: breast and ovarian. https://www.nccn.org/profession-
als/physician_gls/pdf/genetics_bop.pdf. Accessed on 04 Feb 2020.
12. Freedman RA, Keating NL, Partridge AH, et al. Surveillance mammography in older patients
with breast cancer-can we ever stop?: a review. JAMA Oncol. 2017;3:402.
13. Pant S, Shapiro CL. Aromatase inhibitor-associated bone loss: clinical considerations. Drugs.
2008;68:2591.
14. Rojas MP, Telaro E, Russo A, et al. Follow-up strategies for women treated for early breast
cancer. Cochrane Database Syst Rev. 2005:CD001768.
15. Henry NL, Hayes DF, Ramsey SD, et al. Promoting quality and evidence-based care in early-
stage breast cancer follow-up. J Natl Cancer Inst. 2014;106:dju034.
16. National Comprehensive Cancer Network. www.nccn.org
17. Friedenreich CM, Gregory J, Kopciuk KA, et al. Prospective cohort study of lifetime physical
activity and breast cancer survival. Int J Cancer. 2009;124:1954.
18. Kwan ML, Kushi LH, Weltzien E, et al. Alcohol consumption and breast cancer recurrence
and survival among women with early-stage breast cancer: the life after cancer epidemiology
study. J Clin Oncol. 2010;28:4410.
19. Lyman GH, Greenlee H, Bohlke K, et al. Integrative Therapies During and After Breast
Cancer Treatment: ASCO Endorsement of the SIO Clinical Practice Guideline. J Clin Oncol.
2018;36:2647.
20. Park S, Sato Y, Takita Y, et al. Mindfulness-based cognitive therapy for psychological distress,
fear of cancer recurrence, fatigue, spiritual well-being, and quality of life in patients with
breast cancer-a randomized controlled trial. J Pain Symptom Manag. 2020;60:381.
21. Barnabei VM, Cochrane BB, Aragaki AK, et al. Menopausal symptoms and treatment-
related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gynecol.
2005;105:1063.
22. Lesi G, Razzini G, Musti MA, et al. Acupuncture as an integrative approach for the treatment
of hot flashes in women with breast cancer: a prospective multicenter randomized controlled
trial (AcCliMaT). J Clin Oncol. 2016;34:1795.
23. Atema V, van Leeuwen M, Kieffer JM, et al. Efficacy of internet-based cognitive behavioral
therapy for treatment-induced menopausal symptoms in breast cancer survivors: results of a
randomized controlled trial. J Clin Oncol. 2019;37:809.
24. Avis NE, Crawford S, Manuel J. Psychosocial problems among younger women with breast
cancer. Psychooncology. 2004;13:295.
25. Azim H Jr, Kroman N, Ameye L, et al. Pregnancy following estrogen receptor-positive breast
cancer is safe – results from a large multi-center case-control study. Eur J Cancer. 2012;48S:
European Breast Cancer Conference #21.
Chapter 21
Breast Cancer During Pregnancy
and Lactation
Yoon Seung Chang and Monica Akahoshi Rudner
21.1 Introduction
Breast diseases associated with pregnancy are those diagnosed during pregnancy
and 1 year after delivery.
During pregnancy and lactation, complete development of the mammary glands
occurs due to increase in hormone levels (estrogen and progesterone) and is pro-
moted by the placenta. Glandular proliferation, ductal distension, and stromal invo-
lution occur. Such structural changes are manifested clinically by progressive
increase in the volume, firmness, and nodularity of the breasts, making physical
examination difficult. Therefore, imaging evaluation is necessary.
During these periods, the breasts can be affected by diseases directly related to
physiological changes, inflammatory and infectious diseases, juvenile papillomato-
sis, and benign and malignant tumors.
Palpable changes are responsible for initiating investigation in these patients. All
masses found during pregnancy and lactation must be carefully evaluated, as the
diagnosis of injuries or physiological changes secondary to hormonal stimulation
can only be established after a thorough radiological evaluation.
Y. S. Chang
Breast Imaging Section, Centro de Diagnósticos Brasil (CDB – Alliar), São Paulo, SP, Brazil
M. A. Rudner (*)

Switzerland AG 2022
448 Y. S. Chang and M. A. Rudner
The ideal protocol for radiological evaluation of the breasts of symptomatic

pregnant or lactating women is controversial. Physiological changes that occur dur-
ing pregnancy and lactation lead to a diffuse and pronounced increase in the density
of the breast parenchyma. On mammography, the gland appears very dense, hetero-
geneous, nodular, and with a sharp decrease in adipose tissue and a prominent duc-
tal pattern. These characteristics, associated with the high density that is generally
observed in young women, reduce the sensitivity of mammography, which usually
ranges from 70% to 90% [1]. In lactating women, mammography should be per-
formed immediately after breastfeeding, when breast density decreases.
Although some researchers suggest that mammography should be reserved for
pregnant and lactating women with proven malignancy [2], others argue that mam-
mography is a useful diagnostic tool during these periods [3, 4].
In contrast to the controversy regarding the use of mammography, there is a con-
sensus on the application of ultrasound (US) when evaluating a pregnant or lactating
woman with breast diseases [1, 5]. During pregnancy, the breast parenchyma is
characterized by the proliferation of the fibroglandular component with slight dif-
fuse heterogeneous hypoechogenicity. In contrast, during lactation the parenchyma
is diffusely hyperechogenic, with a prominent ductal system and increased vascu-
larity (Fig. 21.1).
a b
Fig. 21.1 Lactational breast parenchyma. Imaging findings of a 35-year-old lactating woman with
family history of breast cancer. Medio lateral (a) and craniocaudal (b) views of screening mam-
mogram show pronounced increase in density of breast parenchyma, which is very dense, hetero-
geneous, nodular, and confluent. US image (c) shows diffusely hyperechoic breast parenchyma
with prominent ducts
21 Breast Cancer During Pregnancy and Lactation 449
Ultrasonography is more sensitive (almost 100%) compared to mammography in

the evaluation of patients with carcinoma during these periods. In addition, ultra-
sound helps to differentiate whether the palpable change represents a mass or nor-
mal parenchyma [3].
A recent retrospective review evaluated the accuracy of mammography and
ultrasonography in 155 pregnant, lactating, or postpartum women. Among pregnant
and lactating women, mammography and ultrasound had a negative predictive value
of 100% and identified few cases of cancer [6].
The mammographic and ultrasound characteristics of breast lesions in pregnant
and lactating patients do not differ from nonpregnant patients. However, some
benign lesions may have suspicious characteristics for malignancy during these
periods.
The routine use of magnetic resonance imaging (MRI) in the breast evaluation of
pregnant women is a topic that raises debate. MRI evaluation of malignant neo-
plasms during lactation is controversial and difficult, because during this period the
parenchyma has avid contrast impregnation, which can hide or mimic malignant
lesions [7]. However, some studies have shown that MRI can differentiate malig-
nant masses from background parenchyma enhancement by evaluating the mor-
phology and kinetics of the enhancement [8]. Three months after the end of lactation,
the background enhancement tends to return to the usual pattern. However, if the
patient plans to breastfeed for a long period or is at high risk for breast cancer, MRI
during lactation should be considered.
In summary, ultrasound should be considered as the initial image exam for the
assessment of symptomatic pregnant and lactating women. Although the use of
mammography is controversial, this modality should be performed if malignancy is
suspected, as it is particularly effective in detecting calcifications and subtle archi-
tectural distortions, which are not commonly identified on ultrasound [5].
21.2 Ethical and Legal Aspects
21.2.1 Mammography
The impact of prenatal exposure to ionizing radiation is influenced by three factors:

radiation dose, anatomical distribution of radiation, and fetal developmental stage at
the time of exposure. During the first 2 months of pregnancy (organogenesis), the
fetus is more susceptible to malformations induced by radiation exposure, which
include congenital lesions, growth retardation, perinatal death, and risk of develop-
ing neoplasms after birth.
Such malformations are more frequent with exposure greater than 0.05 Gy of
radiation [9]. Standard mammography exposes the fetus to 0.004 Gy of radiation.
Thus, mammography with the use of abdominal protection can be performed during
pregnancy to stage breast cancer with minimal risk to the fetus [6]. However, it is
recommended to avoid having a mammogram during the first trimester of preg-
nancy, proceeding with the evaluation of breast diseases through ultrasound [5].
21.2.2 Cytological Analysis
Several cellular changes occur in the epithelium of the breasts of pregnant or lactat-
ing women. Most of these changes are so pronounced that they can lead to a false
positive diagnosis of carcinoma. Therefore, the cytological diagnosis of breast
lesions during pregnancy and lactation should be done with caution. An experienced
cytopathologist, with knowledge of pregnancy-specific changes, is needed to avoid
false-positive diagnoses.
21.2.3 Percutaneous Biopsy
Percutaneous biopsy (core biopsy or vacuum-assisted biopsy) is the standard proce-

dure for assessing breast masses during pregnancy and lactation. It is a safe, effec-
tive, and easy method for accurate diagnosis, avoiding surgical biopsy.
However, caution is recommended, as the risk of bleeding is relatively high due
to increased vascularization during these periods. Other complications include for-
mation of milk fistulae and increased risk of infection due to ductal dilation and
trauma-related to breastfeeding [10].
Although these complications are more likely to occur with core biopsy than
with fine needle aspiration (FNA) biopsy, they occur with low frequency [5].
21.2.4 Magnetic Resonance Imaging (MRI)
The American College of Radiology (ACR) recommends the use of MRI only in
situations where the risk-benefit ratio is well established and specifically states that
contrast agents should not be used routinely in pregnant patients, as they cross the
placental barrier and enter fetal circulation [11, 12]. Although there are no reports
of adverse effects on the fetus due to gadolinium, there are few data available that
corroborate the use or not of contrast.
The use of gadolinium does not contraindicate breastfeeding, so interruption is
not recommended. In the first 24 hours, only 0.04% of the injected contrast is pres-
ent in breast milk. Of this amount that is in milk, only 1% is absorbed in the baby’s
gastrointestinal tract [13].
21.3 enign Diseases Closely Related

B
to Physiological Changes
21.3.1 Gestational and Secretory Hyperplasia
Calcifications secondary to gestational or secretory hyperplasia can be identified on

mammography. Calcifications are most commonly punctate and round, with diffuse
or focal distribution. Less commonly, they have an irregular appearance, linear dis-
tribution, and a branching pattern similar to those with malignant characteristics.
The two manifestations can coexist, as punctate calcifications represent hyperplasia
in the lobular acini, while linear calcifications correspond to ductal hyperplasia
[14]. Nodular presentation is rare (Fig. 21.2).
21.3.2 Spontaneous Papillary Discharge
Bloody spontaneous papillary discharge is a condition that can occur in up to 20%

of pregnant women. It most often occurs in the third trimester of pregnancy when
the vascularization of the breast is significantly increased. It is usually self-limited.
In cases of persistence, infection, papilloma and, more rarely, breast cancer should
be suspected.
In the event of suspected secretion, US and/or mammography should be per-
formed to exclude intraductal proliferations, such as intraductal papilloma or carci-
noma. MRI eventually can be considered.
21.3.3 Galactocele
Galactoceles are the most common benign breast lesions in breastfeeding women.
They occur more frequently after the interruption of breastfeeding when the milk is
contained in the breast [15]. They are cysts formed by cuboidal or flattened
a b
Fig. 21.2 Gestational and secretory hyperplasia. Imaging findings of a 33-year-old pregnant
woman (16 weeks) with a palpable mass in the left breast. US images (a, b) show an oval,
hypoechoic with indistinct margin mass). Core biopsy confirmed secretory hyperplasia
epithelium containing fluid similar to milk. The cysts result from ductal dilation and
are often enclosed by a fibrous wall of different thicknesses that can be associated
with an inflammatory component. Clinically, it presents as a softened mass that is
painless on palpation, which can often present as a result of complications such as
infection.
In ultrasonography it presents itself in several ways, including simple cysts, cysts
with posterior acoustic shadow, and debris inside (fat particles in suspension, masses
with liquid-fat level (pathognomonic), among other presentations. Due to the vari-
able amount of fat, protein, and water, echogenicity can be heterogeneous and have
suspicious characteristics, such as irregular shape and non-circumscribed margin.
The most important differential diagnosis includes intracystic carcinomas [16, 17]
(Fig. 21.3).
The mammographic aspect of the galactocele depends on its composition, den-
sity, and viscosity of the fluid [16].
Aspiration puncture is a diagnostic and therapeutic procedure, extracting fluid
milk when performed during lactation and thickened milk when obtained from
older lesions after the end of lactation [15].
21.4 Inflammatory and Infectious Diseases
21.4.1 Puerperal Mastitis
Infectious diseases of the breast are uncommon during pregnancy, but they occur
relatively frequently during breastfeeding, with an estimated incidence of 6.6–31%
[18]. The most common agent that causes infection is S. aureus, followed by
Streptococcus. The source is the infant’s nose or oropharynx. The infection occurs
due to fissures in the epithelium of the papilla and areola with retrograde dissemina-
tion of the organisms. Milk stasis is an important risk factor, as it represents an
excellent culture medium [15].
Mammography is generally not necessary to investigate mastitis in lactating
women, unless malignancy is suspected. On the other hand, US plays an important
role in the diagnosis and treatment of mastitis, especially in the face of suspected
abscess formation.
Abscesses develop in 5–11% of lactating women with mastitis and usually mani-
fest as complex hypoechogenic masses or irregular anechoic masses, sometimes
with fluid levels, debris, posterior acoustic reinforcement, and increased vascular-
ization. The inflammatory tissue manifests itself as a poorly defined, hypoechogenic
region around the lesion [19] (Fig. 21.4).
Abscesses are usually treated with antibiotic therapy and surgical incision and
drainage, but they can also be treated with needle aspiration or catheter drainage,
especially when smaller than 2.5 cm. US-guided drainage has the advantage of
identifying the necrotic cavity, distinguishing it from inflammatory tissue. The high
rate of recurrence is the most common complication related to abscesses.
Fig. 21.3 Galactocele. Imaging findings of a 37-year-old, 4 months after delivery with a palpable
mass in the left breast. (a) US images show an oval, circumscribed complex solid and cystic mass,
not seen in mammogram (not shown). FNA suggested galactocele. (b) US image of another patient
with a palpable oval, circumscribed, isoechoic heterogeneous mass. (c) Mammogram shows a fat
containing mass (galactocele, marked with a BB)
a b
Fig. 21.4 Acute mastitis (puerperal mastitis). Imaging findings of a 33-year-old woman, 6 months
after stop breastfeeding, with erythematous and swollen right breast. US images (a) show an oval
hypoechoic mass, with indistinct margin and internal vascularity at color Doppler (b) in the right
breast (2.7 cm). Core biopsy confirmed acute mastitis (puerperal mastitis)
21.4.2 Increased Intramammary and Axillary Lymph Nodes
During lactation, enlarged lymph nodes may appear, both intramammary and axil-
lary, being related to bacterial propagation from the nipple during breastfeeding.
On ultrasound, these lymph nodes have thickened cortical and globular morphol-
ogy in a symmetrical distribution.
21.4.3 Granulomatous Mastitis
Granulomatous mastitis is a rare chronic inflammatory disease of unknown cause,

which has been closely linked to pregnancy and lactation. It affects young women
usually up to 5 years after a pregnancy.
It often manifests with clinical and radiological changes suggestive of inflamma-
tory carcinoma and breast abscess. For this reason and also due to the tendency of
recurrence, the anatomopathological study is indispensable.
Mammographic characteristics vary from the normal presentation in patients
with dense breast tissue to focal asymmetries, architectural distortion, and masses
with benign or malignant aspects.
Ultrasonography shows hypoechogenic, tubular, and contiguous lesions, some-
times associated with a large hypoechogenic mass (Fig. 21.5).
21.4.4 Juvenile Papillomatosis of the Breast
It is a rare disease during pregnancy and lactation, whose manifestation involves a

tumor consisting of multiple cysts separated by fibrous septa and relatively well
demarcated regarding the surrounding normal parenchyma.
Fig. 21.5 Granulomatous mastitis. Imaging findings of a 31-year-old woman, 4 months after
delivery and 2 months after stop breastfeeding, with a palpable mass in the left breast. US images
show a complex solid and cystic mass with indistinct margin (2.6 cm). Core biopsy confirmed
granulomatous mastitis
On ultrasound, juvenile papillomatosis manifests itself as poorly defined

hypoechogenic masses that are demarcated from the normal parenchyma and com-
posed of multiple cysts of varying sizes.
Mammography is usually negative or may show focal asymmetry and
calcifications.
The diagnosis of juvenile papillomatosis is made only with histopathological
evaluation [5].
21.5 Benign Tumors
21.5.1 Lactational Adenoma
Lactational adenoma is a benign lesion of the breast in response to the physiological

changes that characterize pregnancy and lactation (increased estrogen levels) but with
controversial etiology. It is sometimes interpreted as a variant of fibroadenoma, tubu-
lar adenoma, and lobular hyperplasia, which are also caused by physiological changes.
a b
Fig. 21.6 Lactational adenoma 1 – pregnant. Imaging findings of a 32-year-old pregnant woman
(38 weeks) with a palpable mass in the left breast. (a, b) US shows a solid, oval, circumscribed
mass, parallel, hypoechoic with 3.2 cm. Core biopsy confirmed lactational adenoma
a b
Fig. 21.7 Lactational adenoma 2 – lactating. Imaging findings of a 38-year-old lactating woman
with a palpable mass in the right breast. US image (a) show a solid, irregular, hyperechoic mass
with indistinct margin, parallel, with 3.7 cm, hypervascularized on color doppler (b). Core biopsy
confirmed lactational adenoma
Lactational adenomas manifest radiologically as benign masses that are indistin-

guishable from fibroadenomas. However, some of them, especially when suffering
infarction, have characteristics that can be confused with malignant lesions, such as
irregular shape, microlobulated contours, and posterior and intense acoustic shadow
[20] (Figs. 21.6, 21.7, and 21.8).
The natural course of these lesions is regression after breastfeeding cessation.
21.6 orphological and Physiological Changes

M
in Fibroadenomas Secondary to Pregnancy
and Lactation
Fibroadenoma is the most common tumor found during pregnancy and lactation,
due to the increase in hormone levels that can induce their growth. For this reason,
preexisting or undiagnosed fibroadenomas can be identified during pregnancy. The
radiological aspects do not differ from the nonpregnant state.
a b
Fig. 21.8 Lactational adenoma 3 – lactating. Imaging findings of a 35-year-old lactating woman
with a palpable mass in the left breast and family history of breast cancer (mother). US images
(a–c) show a solid, oval, circumscribed hypoechoic mass, parallel, with 1.0cm (arrows) associated
with a non-mass heterogeneous lesion (arrowheads). Core biopsy confirmed lactational adenoma.
Control exam 10-months after biopsy didn’t show any lesion
a b
Fig. 21.9 Fibroadenoma (pregnant). Imaging findings of a 35-year-old pregnant woman

(16 weeks) with a palpable mass in the right breast. US images (a, b) show a solid, oval, circum-
scribed, hypoechoic mass (increased compared to the last exam). Core biopsy confirmed
fibroadenoma
A relevant aspect is that fibroadenomas, and lactational adenomas can develop

foci of infarction during the third trimester of pregnancy or after childbirth, mani-
festing clinically as sudden pain in a previously painless fibroadenoma.
On ultrasound, it has an oval shape, homogeneous texture, circumscribed mar-
gin, and normal adjacent tissue. However, during pregnancy, it may have an atypical
presentation, with cystic component increased vascularity, and heterogeneous tex-
ture [19] (Fig. 21.9).
21.7 Malignant Tumors
21.7.1 Pregnancy-Associated Breast Carcinoma (PABC)
PABC is defined as breast cancer that occurs during pregnancy or within 1 year after
delivery. PABC affects 1 in every 3000–10,000 pregnancies and represents up to 3%
of all malignant breast tumors. In general, it is biologically aggressive, with nega-
tive hormone receptors (estrogen and progesterone) and positive for type 2 recep-
tors for human epidermal growth factor (Her2-neu).
Currently, women have chosen to become pregnant later, after 30 years of age,
which may contribute to an increase in the incidence of PABC [10].
Patients with a palpable lesion complaint are investigated, so it is important that
the clinical examination of the breasts be performed at the beginning of pregnancy
before breast engorgement occurs, which makes its assessment difficult.
PABC patients tend to have larger tumors and are diagnosed at more advanced
stages, which reflects worse prognosis compared to nonpregnant women of the
same age with breast carcinoma.
The sensitivity of mammography to PABC is lower in pregnant or lactating
women due to increased glandular density. As mentioned earlier, US is the most
appropriate radiological method for assessing PABC. More than 90% of women
with PABC present with masses that are easily assessed using US. In addition, it is
useful in assessing lymph node involvement and monitoring the response to neoad-
juvant chemotherapy. However, mammography plays a complementary role and
should always be performed if cancer is suspected, since it is essential for the
assessment of calcifications. The imaging aspects are the same as for nonpregnant
patients [21, 22].
The diagnosis is made preferably by percutaneous biopsy (core), as it is the saf-
est and most accurate method.
Treatment for patients diagnosed with PABC in the first trimester of pregnancy
consists of modified radical mastectomy with adjuvant chemotherapy after the sec-
ond trimester. For patients with a diagnosis established after the second trimester,
neoadjuvant chemotherapy and conservative surgery with radiotherapy after deliv-
ery can be considered (Figs. 21.10 and 21.11).
After making the diagnosis of PABC, one should assess the risk-benefit of the
mother and fetus before the start of treatment. Therapeutic abortion does not
increase patient survival and should not be indicated.
Survival and recurrence of patients with a previous diagnosis of breast cancer do
not appear to be affected by posttreatment pregnancy.
21.8 Conclusions
The diseases that affect the breasts during pregnancy and lactation have similar
aspects to those observed in nonpregnant women. However, the peculiarities in the
presentation of the lesions together with the physiological changes typical of these
a b
c d
Fig. 21.10 PABC lactating. Imaging findings of a 34-year-old lactating woman (left breast prefer-
ential breastfeeding) with a palpable mass in the left breast. Mediolateral (a), craniocaudal (b), and
magnifications views (c) mammography shows fine pleomorphic segmental calcifications in the
left breast, fine pleomorphic segmental calcifications, and skin thickening in the right breast
(arrows in c), atypical right axillary lymph nodes (arrowheads in a). US images (d, e) show diffuse
hyperechoic parenchyma with prominent ductal system, skin thickening, and an extensive non-
mass hypoechoic lesion that occupies the entire right breast and atypical right axillary lymph nodes
(I, II and III levels in c). Core biopsy (right breast) confirmed invasive carcinoma and ductal carci-
noma in situ. Patient has axillary and hepatic metastasis. Vacuum-assisted biopsy of the left breast
confirmed secretory hyperplasia
c
a
Fig. 21.11 PABC pregnant. Imaging findings of a 41-year-old pregnant woman (12 weeks twin
pregnancy) with personal history of surgical excision of Phyllodes tumor in the left breast. US
routine images (a, b) show new solid, irregular mass, with angular margin in the right breast. Core
biopsy confirmed invasive carcinoma and ductal carcinoma in situ. Preoperative needle localiza-
tion mammogram (c) shows coarse heterogeneous grouped calcifications (circles in c). Patient
underwent conservative surgery 1 week after the diagnosis with radiation therapy and chemother-
apy after childbirth. No suspicious lesions were seen after 4 years of follow-up
periods must be considered for the correct diagnosis. Delayed diagnosis is the main
cause of worse prognosis commonly found in pregnant or lactating patients with
breast carcinoma.
References
1. Obenauer S, Dammert S. Palpable masses in breast during lactation. Clin Imaging. 2007;31:1–5.
2. Hogge JP, De Paredes ES, Magnant CM, Lage J. Imaging and management of breast masses
during pregnancy and lactation. Breast J. 1999;5:272–83.
3. Ahn BY, Kim HH, Moon WK. Pregnancy and lactation-associated breast cancer: mammo-
graphic and sonographic findings. J Ultrasound Med. 2003;22:491–7.
4. Yang WT, Dryden MJ, Gwyn K, Whitman GJ, Theriault R. Imaging of breast cancer diagnosed
and treated with chemotherapy during pregnancy. Radiology. 2006;239:52–60.
5. Sabate JM, Clotet M, Torrubia S, Gomez A, Guerrero R, de las Heras P, Lerma E. Radiologic
evaluation of breast disorders related to pregnancy and lactation. Radiographics. 2007;27
Suppl 1:S101–24.
6. Robbins J, et al. Accuracy of diagnostic mammography and breast ultrasound during preg-
nancy and lactation. AJR. 2011;196:716–22.
7. Talele AC, Slanetz PJ, Edmister WB, Yeh ED, Kopans DB. The lactating breast: MRI findings
and literature review. Breast J. 2003;9(3):237–40.
8. diFlorio-Alexander, et al. Breast imaging of pregnant and lactating women. J Am Coll Radiol.
2018;15:11S.
9. Greskovich JF Jr, Macklis RM. Radiation therapy in pregnancy: risk calculation and risk mini-
mization. Semin Oncol. 2000;27:633–45.
10. Ayyappan AP, Kulkarni S, Crystal P. Pregnancy-associated breast cancer: spectrum of imaging
appearances. Br J Radiol. 2010;83(990):529–34.
11. Amant F, Deckers S, Van Calsteren K, Loibl S, Halaska M, Brepoels L, Beijnen J, Cardoso F,
Gentilini O, Lagae L, Mir O, Neven P, Ottevanger N, Pans S, Peccatori F, Rouzier R, Senn HJ,
Struikmans H, Christiaens MR, Cameron D, Du Bois A. Breast cancer in pregnancy: recom-
mendations of an international consensus meeting. Eur J Cancer. 2010;46(18):3158–68.
12. Kanal E, Borgstede JP, Barkovich AJ, et al. American College of radiology white paper on MR
safety. AJR Am J Roentgenol. 2002;178:1335–47.
13. Committee opinion – diagnostic imaging during pregnancy and lactation. Obstet Gynecol.
2017;130:4.
14. Mercado CL, Koenigsberg TC, Hamele-Bena D, Smith SJ. Calcifications associated with lac-
tational changes of the breast: mammographic findings with histologic correlation. AJR Am J
Roentgenol. 2002;179:685–9.
15. Scott-Conner CEH. Diagnosing and managing breast disease during pregnancy and lacta-
tion. Medscape Womens Health eJournal. 1997;2(3). Available at: http://www.medscape.com/
viewarticle/408859.
16. Son EJ, Oh KK, Kim EK. Pregnancy-associated breast disease: radiologic features and diag-
nostic dilemmas. Yonsei Med J. 2006;47(1):34–46.
17. Stevens K, Burrell HC, Evans AJ, Sibbering DM. The ultrasound appearances of galactoceles.
Br J Radiol. 1997;70:239–41.
18. Holanda AAR, Gonçalves AKS, Medeiros RD, Oliveira AMG, Maranhão TMO. Ultrasound
findings of the physiological changes and most common breast diseases during pregnancy and
lactation. Radiol Bras. 2016;49(6):389–96.
19. Yu Q, Chang C, Zhang H. Ultrasound imaging characteristics of breast lesions diagnosed dur-
ing pregnancy and lactation. Breastfeed Med. 2019;14(10):712–7.
20. Sumkin JH, Perrone AM, Harris KM, Nath ME, Amortegui AJ, Weinstein BJ. Lactating ade-
noma: US features and literature review. Radiology. 1998;206:271–4.
21. Espinosa LA, Daniel BL, Vidarsson L, Zakhour M, Ikeda DM, Herfkens RJ. The lactating breast:
contrast-enhanced MR imaging of normal tissue and cancer. Radiology. 2005;237:429–36.
22. Taylor D, Lazberger J, Ives A, Wylie E, Saunders C. Reducing delay in the diagnosis of
pregnancy-associated breast cancer: how imaging can help us. J Med Imaging Radiat Oncol.
2011;55(1):33–42.
Index
A Anthracyclines, 436, 437

Abnormal lymph node, 128 Anti-HER2 adjuvant therapy, 437
Accelerated partial breast irradiation Apparent diffusion coefficient (ADC), 317
(APBI), 394 Architectural distortion, 331
Acrylate injection, 381–383 Aspiration puncture, 452
Acupuncture, 442, 443 Associated findings, 126
Acute mastitis, 454 Atypical hyperplasia, 22
Adipocyte-derived stem cells (ADSCs), 402 Atypical lobular hyperplasia (ALH), 206
Adjuvant anti-HER2 therapy, 436 Autoimmune/inflammatory syndrome induced
Adjuvant chemotherapy, 435–437 by adjuvants (ASIA) syndrome, 356
Aesthetic breast surgery Autologous fat grafting (FG), 386
acrylate injection, 381, 383 Autologous fat graft injection, 402
breast implants (see Silicone breast Automated breast ultrasound (ABUS),
implants) 107, 109
direct synthetic substances injection Axillary disease, 284
(fillers), 379 indications, 284–285
hyaluronic acid injection, 384–386 mammography, 286
lipofilling (fat grafting), 386 MRI, 286
mammoplasty, 338–340 PET-CT, 286
mastopexy, 338, 340 ultrasonography, 285
paraffin injection, 379 Axillary lymph node dissection (ALND), 39
periareolar dermal calcifications, 341 Axillary management
porcine biological mesh, 388, 389 in clinically node-negative patients, 40–42
silicone injection, 379–381 in clinically node-positive patients, 42–44
synthetic mesh, 390–392 in micro metastases (N1m1), 40
Alliance A11202 study, 44 Axillary surgery, 39
American college of radiology (ACR), 450
American College of Surgeons Oncology
Group (ACOSOG) Z1071 trial, 43 B
American society of clinical oncology Baker classification, 361, 362
(ASCO), 10, 441 Benign calcifications, 425
American society of radiation oncology Bilateral capsular contraction, 362
(ASTRO), 392 Biological mesh, 388
Anamnesis, 440 BI-RADS® Categories, 127–129
© The Editor(s) (if applicable) and The Author(s), under exclusive license to 463
Springer Nature Switzerland AG 2022
https://doi.org/10.1007/978-3-030-84546-9
464 Index
BI-RADS® Lexicon, 114, 115, 117, 118, 120 C

Bone health, 440 Calcifications, 120, 123
BRCA mutation, 26, 442 Calcified fibrous capsule, 351
Breast biopsy, 273 Canadian Sentinel Node Biopsy Following
core needle biopsy (CNB), 274 Neoadjuvant Chemotherapy (SN
DBT-guided breast biopsy, 276 FNAC) trials, 43
fine needle aspiration (FNA) biopsy, 273 Cancer recurrence, 407, 408
MRI-guided biopsy, 275, 276 Capsular calcifications, 351
vacuum-assisted biopsy (VAB), 275 Capsular contraction, 360
wire localization, 275 Capsulitis, 362
Breast cancer Carboxymethylcellulose (hydrogel), 364
basal carcinomas and triple negative Chromogenic in situ hybridization (CISH), 10
carcinomas, 4 Chromosome enumeration probe (CEP17), 10
BRCA1 mutation, 3 Clinical breast examination, 251
genes and associated syndromes, 24–26 Clip placement, 165, 166
genome analysis technologies, 3 Closed capsulotomy, 362
HER2-enriched carcinomas, 9–12 Clustered microcysts, 125, 126
hereditary syndromes, 23, 24 Complementary therapies, 442
heterogeneity of, 3 Complicated cyst, 127
incidence of, 17 Constitutional symptoms, 440
luminal carcinomas, 6, 8, 9 Cytological analysis, 450
neoadjuvant chemotherapy, 151
non-FDG tracers for, 155, 156
recurrence, 150 D
risk factors Deep inferior epigastric perforator flap
alcohol consumption and smoking, 21 (DIEP), 399
contraception and hormone Diffusion-weighted images (DWI), 135
replacement therapy, 19, 20 Digital breast tomosynthesis (DBT), 190,
gender and age, 17 263, 429
gestation and lactation, 18, 19 Digital breast tomosynthesis vacuum-assisted
obesity, 20, 21 biopsy (DBTVAB), 191
precursor injuries, 22 Digital mammography, 248
reproductive factors, 18 Direct synthetic substances injection
thoracic radiation therapy, 21, 22 (Fillers), 379
Breast Cancer Index (BCI) assay, 34 Discordant biopsy, 203–206
Breast cancer treatment, 390, 392 concordant benign, 204–205
Breast conservation therapy, 339 concordant malignancy, 204
Breast-conserving surgery (BCS), 392–394, discordant benign, 205–206
396, 415 discordant malignancy, 204
Breast edema, 332, 393, 394 high-risk and borderline lesions, 206
Breast imaging, 71 DNA microarrays, 6
Breast implant-associated anaplastic large cell Doppler evaluation, 102–104
lymphoma (BIA-ALCL), 170, 355, Dorsal-flap reconstruction, 406
370, 372, 373, 375, 377 Double-lumen implants/expanders, 342,
Breast implant illness (BII), 355 344, 347
Breast implant rupture, 128 Ductal carcinoma in situ (DCIS), 23, 415
Breast implants, 136 Ductography, 271
Breast reconstruction Dystrophic calcifications, 335, 425, 426, 428
autologous fat graft injection, 402
DIEP flap, 402
dorsal-flap reconstruction, 406 E
double-lumen implant, 402, 403 Early breast cancer trialists collaborative
TRAM flap, 402, 404 group (EBCTCG), 392
Breast self-examination, 251 18F-FDG-PET
Index 465
diffuse intense activity, 143 Gene expression assays

histologic subtypes and receptor status, concordance of expression assays, 34
144, 145 genomic tests for, 35
indications in breast cancer, 144 MammaPrint assay, 33
metastatic staging, 147, 149 Oncotype DX assay, 32
nodal metastases, 147 Genetic counseling, 442
physiological uptake, 143 Genito-urinary symptoms, 440
primary breast tumor detection and Genomic tests, 31
staging, 146 Gestational and secretory hyperplasia, 451
prognostic value, 153 Gossypibomas, 375, 378
Eklund maneuver, 345, 346 Granulomatous mastitis, 454, 455
Elastography, 252
automated breast ultrasound, 107, 109
shear wave elastography, 106, 108 H
strain elastography, 105 Hematoma, 332, 334, 335, 338, 346, 389, 393,
Endocrine/reproductive symptoms, 440 394, 402, 405
Endocrine therapy, 435–437 HER2 amplification, 436
EndoPredict assay, 33 HER2 gene-protein assay (GPA)
Epidermal inclusion cysts, 339 technique, 12
Ethyl-methacrylate (EMA), 381 Hereditary syndromes, 23, 24
European SENTinel NeoAdjuvant (SENTINA) Hormone therapy, 443
trial, 43 Hyaluronic acid injection, 385, 386
Exam documentation, 111–114 Hydroxyethyl-methacrylate (HEMA), 381
Expression of epidermal growth factor Hypoechoic spiculated mass, 333–335, 394
(EGFR), 4
Extracapsular rupture, 366, 370
I
Image acquisition, 141
F Imaging-guided percutaneous biopsy
False-positive rupture, 374 complications, 164
Fat grafting, 386, 387 historical perspective, 161
Fat necrosis, 125, 334–337, 339, 387, 393, percutaneous breast biopsy, 164
395, 404, 405 post-biopsy marker, 165
Fibroadenoma, 456, 457 pre-biopsy assessment, 163, 164
Fibrous capsule, 353 purpose of the procedure, 164
Fine needle aspiration (FNA), 42, 285 surgical biopsy, 164
Fixation clips, synthetic mesh, 390 Imaging methods, 109, 111
Flat epithelial atypia (FEA), 22 Imaging pathology correlation, see
Fluorescence in situ hybridization (FISH), 10 Discordant biopsy
Follow-up after treatment Immunohistochemical reaction, 11, 61
appointments, 440 Infraclavicular recurrence, 398
genetic counseling, 442 Injections of non-resorbable synthetic
imaging examination, 440, 441 biomaterials, 379
laboratory tests, 441 In situ hybridization (ISH), 10
lifestyle changes, 442 International agency for research on cancer
quality of life, 442 (IARC), 439
International Breast Cancer Study Group
(IBCSG) 23-01 trial, 41
G Interstitial brachytherapy, 394
Galactocele, 451, 453 Intracapsular rupture, 368
Gamma rays, 142 Intracapsular silicone implant rupture, 365
Gastrointestinal symptoms, 440 Intracavitary brachytherapy, 394
Gel bleed, 364 Intraoperative radiotherapy (IORT), 394
466 Index
Invasive carcinoma, 55, 56 irregular mass with microlobulated

mammography, 288, 290 margins, 74
MRI, 289, 291 large rod-like calcifications, 74
ultrasound, 289, 291 lesions location, 90
Invasive ductal carcinoma magnification view, 74
mammography, 288 masses, 81
MRI, 287 PET/MR mammography, 153
Ipsilateral breast tumor recurrence (IBTR), pregnancy and lactation, 449
395, 397, 398 recommendation, 93
regular and exaggerated CC view, 76
regular and rolled CC view, 75
J single dilated duct, 90
Juvenile papillomatosis, 454 skin breast lesions, 89
spot compression view on, 74
true lateral view on, 73
L Mammography-guided biopsy, 183
Lactational adenoma, 455–457 biopsy probe, 189
Lactational breast parenchyma, 448 CC and ML views, 186
Lesion morphology, 131 DBT biopsy, 190
Linguine sign, 373 DBT vs. stereotactic biopsy, 190
Lipofilling (fat grafting), 386–388, 402 far posterior lesions, 195
Liquid silicone injection, 380–382 field of view (FOV), 191
Lobular carcinoma in situ (LCIS), 23, 206 hologic affirm® prone biopsy system, 193
Loco regional recurrence (LRR) rates, 44 post-fire tomosynthesis, 192
Luminal androgenic subtype (LAR), 5 pre- and post-biopsy images, 194
Luminal carcinomas, 6, 8, 9 subtle findings, 192
Lymph nodes, 293 superficial lesions, 196
mammography, 293 thin breasts, 195–196
ultrasound, 294 field of view (FOV), 186
prone table biopsy systems, 185, 186
six to 12 tissue fragments, 188
M stereopair view, 187
Magnetic resonance imaging, 249, 250 stereotactic biopsy, 184, 189
breast implants, 136 Mammoplasty, postoperative breast, 340
diffusion-weighted images Mammotome (ethicon endo-surgery), 276
(DWI), 135 Mastectomy, 392, 398, 399
imaging acquisition, 131 Mastopexy, postoperative breast, 340
PET/MR mammography, 154 Menopause, 443
signal intensity, 133 Metastatic disease, 152
standard MRI examination, 132 Metastatic staging, 147, 149
3D MIP images, 135 Mindfulness, 442
T1-weighted images, 134 Molecular breast imaging, 251
T2-weighted images, 133 Motiva implants, 343, 345
Malignant tumors, 458, 459 MRI-guided biopsy, 197
MammaPrint assay, 33 adequate compression, 200
Mammography biopsy kit, 202
ACR-BIRADS® final assessment, 91 coaxial system, 202
advantages, 71 complications, 203
architectural distortion, 85 lesion depth, 201
associated findings, 90 non-enhanced sagittal T1 slices, 200
asymmetries, 85 post procedure care, 203
beast composition, 80 pre-contrast images, 200
calcifications, 82 second-look mammography, 199
cleavage view on, 77 second-look ultrasound, 198
indications, 77, 80 visual method, 201
intramammary lymph node, 86 Music therapy, 442
Index 467
N O
National comprehensive cancer network Obesity, 20, 21
(NCCN) guidelines, 27, 42, 144 Oil cysts, 339
National surgical adjuvant breast and bowel Oncotype DX assay, 32
project (NSABP), 392 Oncotype DX recurrence score (RS), 436
National Surgical Adjuvant Breast and Bowel Open surgical capsulotomy, 362
Project (NSABP) B-32 trial, 40 Oreo cookie sign, 350
Neoadjuvant chemotherapy (NAC), 151
Neoadjuvant systemic therapy (NST), 308
lymph node evaluation, 324–326 P
mammography interpretation, 310, 312 Palpable changes
MRI interpretation, 314 axillary lymph nodes, 268
assess response, 316 axillary metastasis, 269
challenging lesions, 323, 324 breast lump, 259
complete response, 317 biopsy-proven breast cancer, 265
DCE-MR imaging, 317 breast tomosynthesis, 263
DCIS, 315 DBT, 263
DWI techniques, 315 diagnostic mammography
functional tumor volume, 317 technique, 260
overestimation of residual ductal carcinoma in situ, 262
disease, 322–323 fibroadenoma, 261
partial response, 319 magnetic resonance imaging, 262, 265
progressive disease, 321 negative predictive value, 263
residual tumor, 316 occult breast carcinoma, 268
stable disease, 320 Paget's disease
time-signal intensity curve BIRADS 3 patients, 266
analysis, 317 imaging methods, 266
underestimation of residual nipple areola complex, 265, 266
disease, 322 noninvasive disease, 266
using AI methods, 315 right breast, 267
multimodality response Papillary neoplasms, 49, 50
assessment, 309–310 Parenchymal scarring, 331
NCT indications, 308 Pathologic complete response (pCR), 5
neoadjuvant endocrine therapy (NET), 308 Pathology, breast cancer of
PCR, 308 atypical ductal hyperplasia and low-grade
ultrasound interpretation, 312, 314 carcinoma in situ, 51
Neurological symptoms, 440 benign high-risk lesions and precursors, 50
Next generation sequencing, 62 biomarkers in ductal carcinoma in situ, 53
Nipple-areolar complex (NAC), 265, 266, fibroepithelial lesions, 48, 49
339, 398–399 immunohistochemistry, 61
Nipple-sparing mastectomy (NSM), 399 in situ hybridization, 61
Noninvasive cosmetic surgery, 379 intermediate and high-grade ductal
Non-mass-like enhancement (NME), 430 carcinoma in situ, 51, 52
Non-palpable breast changes, 269–273 invasive carcinoma, 55, 56
image screening, 269–270 macroscopic evaluation, 57, 58
nipple discharge, 270 next generation sequencing, 62
BIRADS 3 biopsied, 272 papillary neoplasms, 49, 50
ductography, 271 pleomorphic lobular carcinoma in situ
ductoscopy, 273 (PLCIS), 52, 53
initial assessment, 271 pre-analytical procedures, 47
MRI, 272 radiological-pathological
Non-radioactive wireless devices correlation, 47, 48
magseed localization, 236 special subtype, 59
radar reflector localization, 234 Percutaneous biopsy, 450
RFID localizer, 236 Periareolar dermal calcifications, 339
468 Index
Periprosthetic fluid, 347, 353, 369, 371 PET-CT, 284

Phyllodes tumor, 49 tomosynthesis, 283
Polyacrylamide hydrogel (PAAG), 383, 384 ultrasonography, 283
Polymethyl-methacrylate (PMMA), 381 Preoperative localization (PL)
Porcine biological mesh, 388, 389 complications, 237
Positron emission tomography-computed bleeding, 237
tomography (PET-CT), 284 broken/transected wires, 240
Postoperative breast ecchymoses, 237
aesthetic breast surgery (see Aesthetic pneumothorax, 237
breast surgery) vasovagal reactions, 237
architectural distortion and scarring, indications, 212
336, 338 post-procedure assessment, 240
breast-conserving surgery, 392, 394, 396 pre-procedure review, 212
calcifications at surgical site, 335 wire localization (WL) (see Wire
fat necrosis, 336, 337 localization (WL))
increased density and parenchymal Prone stereotactic vacuum-assisted biopsy
scarring, 334 (PSVAB), 191
ipsilateral breast tumor recurrence, Prophylactic nipple-sparing mastectomy, 400
395, 398 Prosigna assay, 34
mammogram one month after benign Protocol B-06, 392
biopsy, 333 Psychological symptoms, 440
mastectomy, 398, 401 Puerperal mastitis, 452, 454
periareolar dermal calcifications, 339 Pulmonary symptoms, 440
scarring, 331, 332, 335
seroma/hematoma, 334
Post-processed images, 135 R
Postsurgical fluid collection, 125, 129 Radial and anti-radial scanning, 99
Pregnancy and lactation Radiation therapy
benign diseases breast-conserving surgery, 415
galactocele, 451, 453 architectural distortion, 423, 424
gestational/secretory hyperplasia, 451 benign calcifications, 425
spontaneous papillary discharge, 451 breast edema and skin thickening, 418,
benign tumors, lactational 420, 421
adenoma, 455–457 expected chronological appearance,
cytological analysis, 450 416, 417
fibroadenoma, 456, 457 fat necrosis, 421, 422
inflammatory and infectious diseases fluid collections, 418
granulomatous mastitis, 454, 455 CDIS, 415
increased intramammary and axillary digital breast tomosynthesis, 429
lymph nodes, 454 magnetic resonance, 429–431
juvenile papillomatosis, 454 mammography, 426
puerperal mastitis, 452 mastectomy, 415, 416
lactational breast parenchyma, 448 ultrasound, 429
magnetic resonance imaging, 449, 450 Radioactive seed localization (RSL), 229,
mammography, 449, 450 232, 233
percutaneous biopsy, 450 Radiofrequency identification tag (RFID)
physiological changes, 448 localization, 236
pregnancy-associated breast Radio-guided occult lesion localization
carcinoma, 458–460 (ROLL), 226
ultrasonography, 449 gamma probe, 226
Pregnancy-associated breast carcinoma MG-guided ROLL, 227
(PABC), 458, 459 scintigraphic images, 226
Preoperative imaging, 281 stereotactic guided ROLL, 228
breast magnetic resonance imaging, 283–284 Raised silicone ridge, 360
mammography, 282 Recurrence, 397, 399, 401, 407, 408
Index 469
Reduction mammoplasty, 399, 404 implant removal

Response evaluation criteria in solid tumors abscess, 356
(RECIST), 316, 317 amorphous calcifications, 357
Retraction, of scar, 334, 336 architectural distortion, 355
Reverberation artifacts, 350, 352 dystrophic calcifications, 354, 357
Ruptured saline implant, 369 fibrous capsule, 354
residual fibrous capsule, 355, 358
magnetic resonance imaging, 347, 348
S motiva implants, 343–345
Saline implants, 341, 347 periprosthetic fluid, 347, 348, 353
Scanning technique radial folds, 347, 348, 352
anatomy, 100 reduction in detectability of breast
compound imaging, 102 carcinoma, 346, 347
doppler evaluation, 102–104 reverberation artifacts, 350, 352
harmonic image, 101 saline implants, 341, 342
longitudinal and transverse scan, 99 stacked implants, 343
Screen-film mammography, 248 subglandular implant, 343
Screening submuscular implant, 342
breast self-examination, 251 ultrasound, 347, 350, 352
clinical breast examination, 251 wrinkles, 347
digital mammography, 248 Silicone implant rupture
elastography, 252 gel bleed, 364
magnetic resonance imaging, 249, 250 magnetic resonance imaging
molecular breast imaging, 251 false-positive rupture, 374
screen-film mammography, 248 intracapsular rupture, 369, 371, 374
in special populations, 253, 254 linguine sign, 373
thermography, 252 normal radial folds, 370
tomosynthesis, 249 ruptured saline implant, 369
ultrasound (US), 250 subcapsular line, 372
Sentinel lymph node biopsy (SLNB), 39 mammography
Sentinel node and occult lesion localization extracapsular rupture, 366, 367
(SNOLL), 226 intracapsular silicone implant
MG-guided SNOLL, 229 rupture, 365
US-guided SNOLL, 230 rates, 364
Seroma, 332–334, 338, 346, 354–356, 372, ultrasound
373, 375, 376, 389, 393, 394, 401 intracapsular rupture, 368
Sexual activity, 443 snowstorm sign, 367
Shear wave elastography, 106, 108 stepladder sign, 368
Silicone breast implants Silver-enhanced in situ hybridization
capsular calcifications, 349, 351 (SISH), 10
complications Skin lesion, 127
ASIA syndrome, 356 Skin sparing mastectomy (SSM), 399, 408
BIA-LCL, 370, 371, 373, 375 Skin thickening, 332–334, 336, 339, 393–395,
breast implant illness, 355 405, 407
capsular contraction, 360, 362–364 Snowstorm sign, 366, 367
gossypibomas, 375, 378 Society of surgical oncology (SSO), 392
infection, 358, 359 Sonographic based imaging, 97, 98
posterior seal, 360 Spontaneous papillary discharge, 451
raised silicone ridge, 360 Stacked implants, 343
rotation, 359, 361 Standard mammography, 72
rupture (see Silicone implant rupture) Stepladder sign, 368
double-lumen implants/expanders, Strain elastography, 105
342, 344 Subcapsular line, 372
Eklund Maneuver, 346 Subglandular implant, 343, 364
fibrous capsule, 349–351, 353 Submuscular implant, 342, 364
470 Index
Suspicions axillary lymph nodes, 292 lymph node, 176

Sutural calcifications, 427 semiautomatic devices, 174, 175
Synthetic matrices, 388, 389 spring-loaded mechanism, 173
Synthetic mesh, 389–392 complications, 172
Systematic staging, 297 cysts, 168
biopsy/rebiopsy, 301 fine-needle aspiration (FNA), 167
early diagnosis, 300 lesion location, 170
follow-up patients, 302 on-site cytotechnologist
initial assessment, 300 or pathologist, 172
metastatic lesion, 297 optimal needle visualization, 181
PET-CT FDG, 301 pistol-grip mechanic syringe holder, 171
systemic assessment, 300 quantity and quality, 178–179
TNM system, 298 scalpel incision, 182
anatomic staging, 298 skin entry point anesthesia, 182
biomarkers, 298 supine oblique position, 170
prognostic staging, 298–299 unwarranted trauma, 171
therapeutic decisions, 299 VAB, 173, 177, 178
Systemic autoimmune adverse reactions, 356 advantages, 179
de-escalate treatment, 180
diagnostic and therapeutic, 181
T papillary lesions, 180
T1-weighted images, 134 stereotactic biopsy, 179
T2-weighted images, 133 surgical excision, 180
TAILORx trial, 436 US-guided, 180
Taxanes, 436 Unilateral capsular contraction, 363
Thermography, 252
Thoracic radiation therapy, 21, 22
Three-dimensional (3D) conformal external V
beam radiation, 394 Vacuum-assisted biopsy (VAB), 459
Tomosynthesis, 249 Vacuum-assisted breast biopsy, 177
Tram-flap reconstruction, 404 Vacuum-assisted needle biopsy, 357
Transverse rectus abdominis myocutaneous Vascular abnormalities, 125
(TRAM) flap, 399, 402, 440 Vitamin D, 442
Trilucent implants, 364
Triple-negative (TN) breast cancer, 436
Tsukuba scoring system, 106 W
Tumor-free margin, 392 Whole breast external beam radiotherapy
Tumor mutational burden (TMB), 6 (WB-XRT), 392, 394
2D digital mammography (2DDM), 270 Wire localization (WL)
hookwire, 213
MRI-guided, 214, 219
U marked compression plate, 214, 217
Ultrasound-guided biopsy, 167 sagittal-MRI, 222
accuracy and availability, 170 stereotactic guidance, 216, 219
adequate sampling, 178 vacuum-assisted biopsy, 222
adequate targeting, 179 nonwire localization methods, 224
axillary management, 168 advantages, 224
BIA-ALCL, 170 carbon marking, 225
CNB, 173 current lesion localization techniques,
automatic core biopsy, 174 227, 231
irregular mass, 176
Index 471
non-radioactive wireless devices hypoechoic mass, 220

(see Non-radioactive wireless mass breast lesion, 220
devices) retractable J-wire, 221
radioactive seed localization, 229, wire variations, 223
232, 233 Wrinkles, 349
ROLL, 226
SNOLL, 227, 230
puncture needle, 214 Y
US-guided, 218 Yoga, 442

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Modern Breast

Modern Breast Cancer

ISBN 978-3-030-84545-2 ISBN 978-3-030-84546-9 (eBook)

era of personalized medicine, in which there is no single-treatment disease. There is

Linei Augusta Brolini Dellê Urban

São Paulo, Brazil Su Jin Kim Hsieh

Part I Updates in Clinical and Pathological Aspects for Breast Cancer

Part II Update in Imaging Method

10 Image-Guided Percutaneous Biopsies���������������������������������������������������� 161

Part III Different Clinical Scenario: Clinical Management

Fernando Nalesso Aguiar, MD Departamento de Patologia, Instituto do Cancer

Yoon Seung Chang, MD Breast Imaging Section, Centro de Diagnósticos Brasil

Bruna Salani Mota, MD Departamento de Mastologia, Instituto do Cancer do

Raquel Civolani Marques Fernandes

© The Author(s), under exclusive license to Springer Nature 3

1.2  C (Basal Carcinomas) and TNC (Triple

BC is characterized by the high expression of several genes that characterize the

eosinophilic or clear cytoplasm, geographic tumor necrosis, central scar, expansive

1.3 Luminal Carcinomas (LC)

Luminal carcinomas represent a group of tumors that corresponds to approximately

characterized by a lower expression of luminal-specific genes, a higher expression

to achieve full inhibition. Thus, ESR1 mutations have emerged as predictors of

1.4 HER2-Enriched Carcinomas

HER2 belongs to the family of four transmembrane receptors (HER1 or EGFR,

Table 1.1 Reporting results of HER2 testing by immunohistochemistry

The heterogeneity of HER2 breast cancer is a complex phenomenon. Before

subtype HER2 enriched determined by PAM-50, tumors with intense immune

37. Godoy-Ortiz A, Sanchez-Munoz A, Parrado MRC, Alvarez M, Ribelles N, et al. Deciphering

Sergio Masili-Oku , Angela Trinconi , Gabriela Boufelli ,

2.2 Gender and Age

S. Masili-Oku (*) · A. Trinconi · G. Boufelli · J. R. Filassi

© The Author(s), under exclusive license to Springer Nature 17

2.3 Reproductive Factors

2.4 Gestation and Lactation

2.5 Contraception and Hormone Replacement Therapy

Regarding hormone replacement therapy, the Women’s Health Initiative (WHI)

unhealthy/overweight (MUOW), metabolically healthy/ obese (MHO), and meta-

2.7 Alcohol and Smoking

2.8 Thoracic Radiation Therapy

Wolden and collaborators [26] evaluated 71 cases of breast cancer in 65 women

2.9 Precursor Injuries

2.10 Hereditary Syndromes and Breast Cancer

2.11 Genes and Associated Syndromes

2.11.1 Genes Associated with High Penetrance

2.11.2 Genes Associated with Moderate Penetrance

2.12 Quantification of Mutation Risk

2.13 Genetic Testing for High-Risk Patients

According to genetic diagnoses, the National Comprehensive Cancer Network

1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating

4. Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for

Laura Testa and Renata Colombo Bonadio

Localized hormonal receptor (HR)-positive breast cancer has a broad spectrum of

L. Testa (*) · R. C. Bonadio

© The Author(s), under exclusive license to Springer Nature 31

3.2 Gene Expression Assays

3.2.3 Other Assays

generated by incorporating clinical factors (tumor size and nodal status).

3.3 Concordance of Expression Assays

Bruna Salani Mota, Rodrigo Goncalves, and Jose Roberto Filassi

São Paulo, Brazil Su Jin Kim Hsieh

Part I Updates in Clinical and Pathological Aspects for Breast Cancer

Part II Update in Imaging Method

10 Image-Guided Percutaneous Biopsies�� 161

Part III Different Clinical Scenario: Clinical Management

1.2 C (Basal Carcinomas) and TNC (Triple

1.3 Luminal Carcinomas (LC)

1.4 HER2-Enriched Carcinomas

2.2 Gender and Age

2.3 Reproductive Factors

2.4 Gestation and Lactation

2.5 Contraception and Hormone Replacement Therapy

2.7 Alcohol and Smoking

2.8 Thoracic Radiation Therapy

2.9 Precursor Injuries

2.10 Hereditary Syndromes and Breast Cancer

2.11 Genes and Associated Syndromes

2.11.1 Genes Associated with High Penetrance

2.11.2 Genes Associated with Moderate Penetrance

2.12 Quantification of Mutation Risk

2.13 Genetic Testing for High-Risk Patients

3.2 Gene Expression Assays

3.2.3 Other Assays

3.3 Concordance of Expression Assays

4.2 xillary Management in Clinically Node-Negative

4.3 xillary Management in Micrometastases (N1m1) or

4.4 xillary Management in Clinically Node-Negative

4.5 xillary Management in Clinically Node-Positive Patients

5.1 Pre-analytical Procedures

5.2 Radiological-Pathological Correlation

5.3 Fibroepithelial Lesions

5.4 Papillary Neoplasms

5.5 enign High-Risk Lesions and Precursors, Including

5.6 typical Ductal Hyperplasia and Low-Grade

5.7 Intermediate and High-Grade Ductal Carcinoma In Situ

5.8 Pleomorphic Lobular Carcinoma In Situ (PLCIS)

5.9 Biomarkers in Ductal Carcinoma In Situ

5.10 Invasive Carcinoma of No Special Type

5.11 acroscopic Evaluation of the Breast Specimen,

5.12 Special Subtypes

5.13 Special Methods

5.13.2 In Situ Hybridization

5.14 Next-Generation Sequencing (NGS)

6.4.1 Breast Composition