Colonos PDF

Colonoscopy
Edited by Paul Miskovitz

COLONOSCOPY
INTECHOPEN.COM
Colonoscopy
http://dx.doi.org/10.5772/806
Contributors
David Weinberg, Minhhuyen Nguyen, Sung Noh Hong, Alberto Vannelli, Luigi Battaglia, Andrzej Skalski, Mirosław
Socha, Tomasz Piotr Zielinski, Mariusz Duplaga, Daniel G. Cimmino, Jose Mella, Fernando Vilarino, Jorge Bernal,
Francisco Javier Sanchez, Najib Haboubi, Emil Salmo, Felice Cosentino, Giovanni Rubis Passoni, Roberta Barbera,
Antonella Rigante, Antonella Tauro, Philipp Cosentino, Thomas Manfred Scholbach, Ulrich Stölzel, Alicja Bartkowska-
Sniatkowska, Malgorzata Grzeskowiak, Jowita Rosada-Kurasinska, Fujimori, Shigeki Tomita, Shigehiko Fujii, Mikihiro
Fujiya, Kentaro Moriichi, Nobuhiro Ueno, Yutaka Kohgo, Yusuke Saitoh, Takashi Shida, Rosalinda Hulse, Fabio Teixeira,
Marco Bustamante, Richard Halberg, Terrah Paul Olson, Vatsala Misra, Kenneth B. Hosie, Anita Balakrishnan, Stephen
Lewis
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Meet the editor
Dr. Paul Miskovitz is Clinical Professor of Medicine

in the Division of Gastroenterology and Hepatology,
Department of Medicine, Weill Cornell Medical College
and Attending Physician at the New York—Presbyterian
Hospital Weill/Cornell Campus in New York. The author
of a variety of articles on gastroenterology, hepatology
and internal medicine topics, co-developer of several
medical computer software programs, the co-author of three books in
the field of gastroenterology, Dr. Miskovitz currently maintains a clinical
consultative practice for gastroenterology, hepatology, gastrointestinal en-
doscopy and gastrointestinal parasitology, and teaches at the Weill Cornell
Medical College in New York City and Doha, Qatar. In the Fall of 2009 Dr.
Miskovitz was the recipient of a CINE Golden Eagle Award in the Pro-
fessional Advertising and Promotion Division, Public Service Announce-
ments, for participation in the CBS Cares Colonoscopy Sweepstakes, a very
successful PSA designed to increased public awareness nationwide with
regard to colorectal cancer screening using colonoscopy.
Contents
Preface XI
A Brief Overview of Selected Aspects

of Colonoscopy: Past, Present and Future XIII
Part 1 The Technique 1
Chapter 1 Preparing for Colonoscopy 3

Rosalinda S. Hulse
Chapter 2 Sedation and General Anaesthesia

for Colonoscopy in Childhood 25
Alicja Bartkowska-Śniatkowska, Jowita Rosada-Kurasińska
and Małgorzata Grześkowiak
Chapter 3 Quality of Screening Colonoscopy:

Learning Technical Skills and Evaluating Competence 47
Marco Bustamante
Chapter 4 Maintaining Quality in Endoscopy 61

Anita Balakrishnan, Stephen Lewis and Kenneth B Hosie
Part 2 Applications 77
Chapter 5 The Impact of Colonoscopy

on Colorectal Cancer Incidence and Mortality 79
Minhhuyen T. Nguyen and David S. Weinberg
Chapter 6 Post-Polypectomy Colonoscopy Surveillance 97

Sung Noh Hong
Chapter 7 Endoscopic Manifestations

and Mucosal Patterns Associated to Collagenous Colitis 121
Daniel Gustavo Cimmino and José Manuel Mella
X Contents
Chapter 8 Endoscopic Approach in Ulcerative Colitis 129

Rogério Saad-Hossne and Fábio V. Teixeira
Chapter 9 Pathological Issues of Ulcerative Colitis/Dysplasia 139

Tomita S., Fujii S. and Fujimori T
Chapter 10 Pathology of Staging of Early Colorectal Lesions

During Surveillance Programmes 153
Emil Salmo and Najib Haboubi
Chapter 11 Endoscopic Submucosal Dissection

for Colorectal Lesions 167
Takashi Shida
Chapter 12 Portal Hypertensive Colopathy 171

Vatsala Misra, Vishal Dhingra, S P Misra and Manisha Dwivedi
Part 3 The Future? 177
Chapter 13 Research and Therapeutic Innovation:

Tissue Resonance InterferoMeter Probe
in Early Detection-Screening for Rectal Cancer 179
Alberto Vannelli and Luigi Battaglia
Chapter 14 Autofluorescence Imaging

for Diagnosing Intestinal Disorders 205
Mikihiro Fujiya, Kentaro Moriichi, Nobuhiro Ueno,
Yusuke Saitoh and Yutaka Kohgo
Chapter 15 Intestinal Dynamic Color Doppler

Sonographic Tissue Perfusion Measurement 221
Thomas Scholbach, Jörg Hofmann and Jakob Scholbach
Chapter 16 Towards Intelligent Systems for Colonoscopy 245

Jorge Bernal, Fernando Vilariño and Javier Sánchez
Chapter 17 Virtual Colonoscopy - Technical Aspects 271

Andrzej Skalski, Mirosław Socha,
Tomasz Zieliński and Mariusz Duplaga
Chapter 18 Robotic Colonoscopy 291

Felice Cosentino, Emanuele Tumino, Giovanni Rubis Passoni,
Antonella Rigante, Roberta Barbera,
Antonella Tauro and Philipp Emanuel Cosentino
Chapter 19 Experimental Small Animal Colonoscopy 309

Terrah J. Paul Olson and Richard B. Halberg
Preface
To publish a book on colonoscopy suitable for an international medical audience,

drawing upon the expertise and talents of many outstanding world-wide clinicians, is
a daunting task. To edit such a book is a comparable challenge. The use of the Internet
for both medical research and communication greatly helps with this international
endeavor.
The field of colonoscopy within the larger realm of gastrointestinal endoscopy is, so to
speak, a moving target. New developments in videocolonoscope instruments and
ancillary equipment, infection risk and control, the use of patient antibiotic
prophylaxis, the doctrine of informed consent, procedural technique, the need for
terminal ileal intubation, documentation including the use of the electronic health
record, patient selection for the procedure, patient preparation, and moderate sedation
and monitoring are being made and reported daily in both the medical and the lay
press. The rigors developed from the discipline of medical outcomes research are
rapidly being applied to the field, hand in hand with questions about procedural
reimbursement issues being raised by government and private insurers as well as by
patients themselves. Just as over the last several decades colonoscopy has largely
supplanted the use of barium enema x-ray study of the colon, new developments in
gastrointestinal imaging such as computerized tomographic colonography (CT
colonography, “virtual” colonoscopy) and video transmitted capsule study of the
colonic lumen and new discoveries in cellular and molecular biology that may
facilitate the early detection of colon cancer, colon polyps and other gastrointestinal
pathology threaten to relegate the role of colonoscopy as a diagnostic screening
technique to the side lines of medical practice.
The field has certainly come a long way since the winter of 1974 when as a fourth year
medical student at Cornell University Medical College doing a gastroenterology
elective rotation at the then New York Hospital in New York City I was given the
opportunity (courtesy of my mentors) to look down the “teaching head” of the
colonoscope and actually see pathology within the lumen of the large bowel of a
patient I was following on the wards! I trust you will find the efforts of the talented
and renowned physicians who have contributed to this endeavor to convey a sense of
X Preface
the history, the present state-of-the art and ongoing confronting issues, and the
predicted future of this discipline both rewarding and worthy of your time and
consideration.
July 2011
Paul Miskovitz MD, AGAF

Clinical Professor of Medicine
Division of Gastroenterology and Hepatology
Department of Medicine
Weill Cornell Medical College
New York, New York, U.S.A.
Faculty Lecturer in Gastroenterology and Hepatology
Weill Cornell Medical College-Qatar
Doha, Qatar
The American Austrian Foundation
Salzburg-Weill Cornell Seminars
Salzburg, Austria
Attending Physician
New York-Presbyterian Hospital
Weill Cornell Campus
Consulting Gastroenterologist
Hospital for Special Surgery
A Brief Overview of Selected Aspects of
Colonoscopy: Past, Present and Future
Paul Miskovitz, MD, AGAF

Clinical Professor of Medicine
Division of Gastroenterology and Hepatology
Department of Medicine
Weill Cornell Medical College
New York, New York USA
Weill Cornell Medical College-Qatar
Doha, Qatar
The American Austrian Foundation
Salzburg-Weill Cornell Seminars
Salzburg, Austria
Attending Physician
New York-Presbyterian Hospital
Weill Cornell Campus
New York, New York, USA
Consulting Gastroenterologist
The Hospital for Special Surgery
New York, New York, USA
1. Introduction
All the organs of the body were having a meeting, trying to decide who should be the one in
charge. "I should be in charge," said the brain, "Because I run all the body's systems, so
without me nothing would happen." "I should be in charge," said the blood, "Because I
circulate oxygen all over so without me you'd all waste away." "I should be in charge," said the
stomach," Because I process food and give all of you energy." "We should be in charge," said
the legs, "because we carry the body wherever it needs to go." "We should be in charge," said
the eyes, "Because we allow the body to see where it goes." "We should be in charge," said the
colon and rectum, "Because we’re responsible for waste removal." All the other body parts
laughed at the colon and rectum and insulted them, so in a huff, they shut down tight. Within a
few days, the brain had a terrible headache, the stomach was bloated, the legs got wobbly, the
eyes got watery, and the blood became toxic. They all decided that the colon and rectum should
XII Preface
be the boss. The moral of the story? The importance of the colon and rectum to patient
well-being has been affirmed and colonoscopy has come of age!
As editor of this book it is my intent in this brief introductory book chapter to provide
a sampling of some of the varied topics related to the discipline of colonoscopy. By
whetting the reader’s appetite for this subject one will better enjoy the many superb
multi-authored chapters written with an international perspective that follow.
2. The historical development of colonoscopy

In the last half century the field of gastroenterology has recruited ever increasing
numbers of well-motivated and capable physician trainees. During the period 1950–70,
investigations of the colon were largely restricted to barium radiographic studies, stool
examinations, and the performance of rigid sigmoidoscopy. [Old habits such as
performing diagnostic contrast enema studies of the colon die hard, however
(Matsukawa et al., 2007).] In contrast, the modern-day gastroenterologist undergoes
advanced training in gastroenterology and hepatology, unlike his predecessors has a
wide armamentarium of services to offer and medications to use in clinical care, and is
expected to develop a high level of skill in performing endoscopic procedures
including colonoscopy and interpreting diagnostic studies such as CT enterography,
magnetic resonance cholangiopancreatography, and capsule endoscopy. Because of
patient demand and the financial considerations inherent in maintaining a clinical
practice, the average practicing gastroenterologist however, may find that he has his
plate full of endoscopic procedures, particularly screening colonoscopy to the possible
detriment of teaching, research and perhaps other aspects of clinical care (Ganz, 2004).
The development that irreversibly altered the field of gastroenterology forever, by

allowing the widespread use of endoscopes to peer into gastrointestinal orifices (and
later, body cavities), occurred in the 1950s and 1960s when Drs. Basil Hirschowitz.
William Wolff, Hiromi Shinya, Bergein Overholt and others used the principles of
fiberoptics to develop and apply to gastroenterology the ‘fiberscope’ (Modlin, 2000,
Wolf, 1989). Fiberoptic colonoscopes arrived on the scene in the 1970’s (Achord, 2005).
At first, the procedure was thought to be technically difficult in a way similar to the
simultaneously developed biliary and pancreatic procedure endoscopic retrograde
cholangiopancreatography (ERCP). Due to a lack of complete understanding of the
intraluminal colonic anatomy, early attempts at using colonoscopy often required the
aid of fluoroscopy. Because of this, the widespread acceptance of colonoscopy as a
diagnostic and later therapeutic procedure was delayed despite the introduction of
colonoscopic polypectomy (Dr. Hiromi Shinya in New York City using a home-made
wire threaded through a thin plastic catheter with an assistant hand-holding the
connection between the active cord of an electrosurgical unit and a hemostat clamped
on the wire after the polyp was ensnared) and the demonstration of superior
diagnostic results for colonoscopy when compared to barium enema studies and rigid
sigmoidoscopy (Wolff & Shinya, 1971). Developments in colonoscopy have continued
at a rapid pace with one major one occurring in 1983 when Welch Allyn® Inc. inserted
Preface XIII
an image sensor or charge-coupled device into the distal tip of an endoscope (Sivak &
Fleischer, 1984). Light was still transmitted down the endoscope through a fiberoptic
bundle but the light falling on the charge-coupled device is converted into an array of
electrical charges that are reconstructed on a video monitor. As electronic solid-state
sensors had only previously been able to produce black and white images, modifications
were required to reproduce the image in color. This was achieved by two techniques:
either the rapid sequential use of the primary colors, red, green and blue, at the light
source or by the use of color-chip imaging where the solid-state sensor has colored
microfilters fixed to its surface. By the 1990’s, videocolonoscopy, through developments
at Olympus®, Pentax® and Fujinon®, had largely replaced fiberoptic colonoscopy with
the video image projected onto monitors and thus facilitating teaching and allowing the
findings to be shared “live” with endoscopy staff and other physicians. It was not long
before the findings of the procedure were able to be “captured” by video recording
devices and entered into the electronic health record. From an international perspective
the development of gastrointestinal endoscopy over the last four decades in Malaysia
has recently been chronicled (Goh, 2011).
As we will see, the future of (particularly therapeutic) colonoscopy seems assured,

with new developments on the horizon.
3. Credentialing of colonoscopists
The provision of high-quality colonoscopy by well trained colonoscopists should be
the goal of any institution whether it be an academic university medical center,
hospital, ambulatory endoscopy center, physician’s office, subspecialty society,
government regulatory agency, or health insurance provider (ASGE, 1998, Parry &
Williams, 1991, Marshall, 1995, Chak et al., 1996, ASGE, 1999, Wexner et al., 2001).
Issues include uniformity of standards, training and determination of competence, the
learning of new procedures, monitoring of colonoscopic performance and the need for
continuing education (Cohen, 2011). This area has come under increased scrutiny in
both training programs (Sedlack, 2010) and for application and re-application for
hospital colonoscopy privileges (Wexner et al., 2002, Obstein et al., 2011). Polypectomy
rate has been proposed as a useful quality measure with a high degree of correlation
with the rate of detection of colorectal adenomas (Williams et al., 2011).
Gastrointestinal procedure oriented meetings and sponsored courses (American
Society of Gastrointestinal Endoscopy meeting held during the annual Digestive
Disease Week and the annual course held in New York City sponsored by the New
York Society for Gastrointestinal Endoscopy to name two of many available in the
United States) are well attended and produce enduring materials that are circulated
well beyond the population of the course attendees. Advanced DVD and Internet
courses are becoming increasingly popular among those performing colonoscopies.
4. Indications for colonoscopy

Colonoscopy has made gains in popularity as a medical diagnostic procedure. It has
been popularized by the publication of a patient-oriented paperback guide book,
XIV Preface
Colonoscopy for Dummies, (Dobie & Burke, 2011) and in a television media public
service announcement campaign to make people aware of the importance of screening
for colorectal cancer in the United States, launched by the Columbia Broadcasting
System’s CBS Cares® Program (http://www.cbs.com/cbs cares/topics/?sec=colorectal
cancer, http://www.cbs.com/cbs cares/video/?cid=822059380)). A colonoscopy has even
become the prize of a popular sweepstakes (http://promotions.mardenkane.com
/cbs/cbscares/rules.cfm). Nevertheless, it is prudent to keep in mind the proven utility
of the procedure.
Colonoscopy is most useful in diagnosing and treating patients with neoplasms,

strictures or colonic mucosal disease previously diagnosed on radiological imaging.
Other uses include the evaluation of patients with gastrointestinal hemorrhage
(hematochezia and occult bleeding) (Davila et al., 2005, Miskovitz & Steinberg, 1982,
Miskovitz et al., 1987, Khalid et al., 2011, Kistler et al., 2011), unexplained iron
deficiency anemia (Goddard et al., 2011), screening and surveillance for colonic
neoplasms (Davila et al., 2006, Denberg et al., 2005, Wilschut et al., 2011, Lasser et
al., 2011)), diagnosis and surveillance of inflammatory bowel disease (Leighton et
al., 2006, Basseri et al., 2011), evaluation of chronic diarrhea (with or without stool
microbiology sampling, intubation of the terminal ileum for Crohn’s disease and
multiple mucosal biopsies to diagnose microscopic colitis) (Eisen et al., 2001,
Miskovitz & Rochwarger, 1993, Jaskiewicz et al., 2006, Misra et al., 2010),
constipation (Qureshi et al., 2005), foreign body removal (Safioleas et al., 2009),
decompression of megacolon and sigmoid volvulus (Eisen et al., 2002), and the
treatment of anorectal disorders (Eisen et al., 2001). “Open access colonoscopy”, a
program designed to make colorectal cancer screening more convenient and
available has been the subject of some debate (Rex, 2010-2011, Feld, 2010-2011). In
this situation, patients without significant gastrointestinal symptoms have a
screening colonoscopy without the inconvenience or cost of a preliminary office
visit. Its purpose is to provide colonoscopy for screening purposes to a wider
audience with less waiting time.
World-wide, colorectal cancer is the third most commonly diagnosed cancer in

males and the second in females, with more than 1.2 million new cases and more
than 600,000 deaths estimated to have occurred from colorectal cancer in 2008 (Jemal
et al., 2011). Despite more than three decades of experience with using colonoscopy
for colorectal cancer screening controversies about the procedure do exist (Smith,
2011a, Helwick, 2011a, Helwick, 2011b, Smith, 2011b). The field of colorectal cancer
screening and prevention in women has recently been reviewed (Krishnan & Wolf,
2011) as has the overuse of screening colonoscopy in the Medicare (federal
government subsidized health insurance for older people) population in the United
States (Goodwin et al., 2011). The upper age limit for colorectal cancer screening by
colonoscopy has recently drawn attention (Habbema et al., 2011, Naravadi et al.,
2011). Recently proposed cascade colorectal screening guidelines from the World
Gastroenterology Organization (Winawer et al., 2011) advocate that each country,
Preface XV
region or healthcare setting needs to determine whether colorectal cancer screening

is a legitimate consideration based upon other healthcare priorities. This group
endorses enhanced colorectal screening worldwide, especially in developing
countries where the colorectal cancer incidence and mortality is rising.
As chapters in this book will illustrate, the indications for colonoscopy are expanding
with advancements in technology.
5. Contraindications to and risks of colonoscopy

Contraindications to performing colonoscopy must take into account that this
procedure represents a somewhat stressful physiological experience for the patient.
Hypotension, cardiac dysrhythmias (including bradyarrhythmias from increased
vagal stimulation), abdominal distention with compromise of diaphragmatic function,
and oxygen desaturation, are a few among the many complications that may occur
during the procedure. For this reason, patient selection for the procedure should take
into account any bleeding diathesis the patient may have, the cardiovascular (recent
myocardial infarction or recent evaluation of the patient’s cardiac status) and
pulmonary status of the patient along with concomitant conditions such as infection
(contraindicated in acute diverticulitis), severe ulcerative, ischemic, infective or
Crohn’s colitis (contraindicated). It has become customary to use the American Society
of Anesthesiologists 1963 derived and subsequently amended preoperative physical
status classification system (ASA IASA VI) (American Society of Anesthesiologists
http://www.asahq.org/clinical/physicalstatus.htm) in classifying patients undergoing
the procedure. The clinician must also exercise judgment in deciding to convert a
planned colonoscopy into a flexible fiberoptic sigmoidoscopy if findings in the
rectosigmoid suggest that the planned procedure be terminated.
Colonoscopy is not without its risks (Miskovitz & Gibofsky, 1995). Perforation is
perhaps the most dreaded, occurring more frequently in therapeutic colonoscopy
than in diagnostic colonoscopy. Statistics from the last two decades of the last
century reveal a perforation rate of approximately 1 in 2,500 procedures (Sieg et al.,
2001) and a mortality rate of 1 in 15,000 procedures (Waye et al., 1996), deaths often
being related to the management of perforations. Immediate laparoscopic surgery is
the best treatment although there may be a role for conservative therapy with
surgical observation, intravenous fluids and the use of antibiotics in select cases
(Kavin et al., 1992). Hemorrhage, related to biopsy, polypectomy or balloon
dilatation is another risk of the procedure occurring on up to 1.5% of cases (often
with a delay up to four weeks). The risk of hemorrhage can be lessened by the sole
use of coagulation current (as opposed to “cutting” current), slow transection of the
polyp stalk, the submucosal injection of saline and or epinephrine at the polyp site,
the use of endoscopically placed clips and loops, and the treatment of bleeding sites
with biopolar electrocautery. A recent outpatient colonoscopy study proposes that
the use of a 14-day time period for reporting would capture all perforations and the
XVI Preface
majority (96%) of post-procedure hemorrhages that required hospital admission

(Rabeneck et al., 2011).
As with many decisions in clinical medicine, the decision to perform colonoscopy on a

patient is a balance between the risks and benefits of the procedure, made easier by a
careful medical history, physical examination and a review of available laboratory
data. These same factors are utilized in obtaining informed consent for the procedure
from the patient and/or the patient’s family.
6. Informed consent for colonoscopy

The concept of informed consent (and its corollary, informed refusal) for colonoscopy
involves an assessment of the competence of the patient, disclosure of, in an
understandable way, the information necessary to allow the patient to make an
informed decision regarding the role of colonoscopy in his care, and the
documentation of these proceedings in the medical record (Stunkel et al., 2010). It is an
intrinsic part of the doctor-patient relationship and an ethical obligation on the part of
the physician in the practice of medicine. In the United States, the doctrine of medical
informed consent is often traced to a 1914 New York court decision centered about the
observation that since most surgical operations involve some use of force, there must
be consent. Because the nature of surgery is outside the experience of most patients,
the consent must be granted only after the patient is properly informed. The most
famous description of informed consent is a quote from Justice Benjamin Cardozo
who, in 1914, stated that: "Every human being of adult years and sound mind has a right to
determine what shall be done with his own body; and a surgeon who performs an operation
without his patient's consent commits an assault for which he is liable in damages"
(Schloendorff v Society of New York Hospital, 1914).
Without going into detail regarding the subsequent legal history of the development of
the doctrine of informed consent and its applications, nor the legal consequences of not
obtaining proper informed consent for colonoscopy, recent international reviews have
concluded there is room for improvement in this area (Banic et al., 2008, Bai et al., 2007).
Novel approaches to facilitating the obtaining of informed consent have even included
the use of video presentations (Agre, 1994) and more recently by referring patients to
peer-reviewed Internet educational websites for information about colonoscopy,
preparation and procedure-associated risk prior to the patient’s arrival in the unit. As
colonoscopy is often performed under intravenous (“conscious”) sedation, the issue of
withdrawal of informed consent by a patient experiencing pain has recently drawn
attention (Ward et al., 1999). Of interest is that patient recall post-procedure of having
given informed consent for colonoscopy appears to be similar whether the consent is
obtained immediately or several days before the procedure. (Elfant et al., 1995).
7. Bowel preparation for colonoscopy

Proper and safe patient bowel preparation for colonoscopy is essential (Beck, 2010). It
is generally accepted that inadequate bowel preparation for colonoscopy can result in
Preface XVII
missed lesions, cancelled procedures, increased procedural time, and a potential

increase in complication rates. Bowel preparation itself may also be associated with
complications (Korkis et al., 1992). An evidence based medicine summary of bowel
preparations for colonoscopy has recently been published by the United States
Department of Health and Human Services, Agency for Healthcare and Quality,
National Guideline Clearinghouse and is accessible through the Internet (Wexner et
al., 2006, http://asge.org/ PublicationsProductsIndex.aspx?id=352). Consideration is
given to the elderly, those with documented or suspected underlying inflammatory
bowel disease, those with diabetes mellitus, the pediatric population and the
admittedly rare pregnant patient who requires colonoscopy. A new trend is to look at
the timing of the bowel preparation with regard to its efficacy (Gurudu et al., 2010,
Eun et al., 2011). Others have recommended a split-dose bowel preparation as effective
and better accepted by patients in terms of tolerance (Huffman et al., 2010). Suffice to
say that “one size does not fit all” in this matter.
8. Antibiotic prophylaxis for selected patients undergoing colonoscopy

The value of antibiotic prophylaxis for patients undergoing colonoscopy has been the
subject of much debate. In the past, the rationale for antibiotic prophylaxis was to
prevent patients with high-risk cardiac conditions from developing infective
endocarditis and from those with prosthetic devices in place (vascular grafts, ventriculo-
peritoneal shunts, prosthetic joints, etc.) from developing infected hardware. Recently,
the practice of antibiotic prophylaxis for colonoscopy has substantially changed due in
part to the low incidence of infective endocarditis following this procedure and the lack
of evidence based medicine data supporting the benefit of antibiotic prophylaxis. It is
also recognized that the widespread use of antibiotics can be associated with the
development of resistant organisms, Clostridium difficile colitis, added expense, and the
risk of drug toxicity. Recent guidelines for the use of antibiotic
Heart Association and the American Society for Gastrointestinal Endoscopy,

respectively (Wilson et al., 2007, ASGE Standards of Practice Committee, 2008).
Although the recommendation in these published guidelines are largely consistent
with one another, they substantially differ from prior guidelines, the largest change
being that both sets of guidelines no longer consider and gastrointestinal procedure
high risk for bacterial endocarditis, thus lifting the recommended routine use of
antibiotics for bacterial endocarditis including for those patients with high risk cardiac
conditions such as prosthetic heart values and prior history of bacterial endocarditis).
Although antibiotics are not recommended for patients receiving peritoneal dialysis
who are undergoing colonoscopy with or without polypectomy, it may be reasonable
to drain the peritoneum before performing the colonoscopy to minimize the risk of
developing bacterial peritonitis.
9. Antithrombotic agents in patients undergoing colonoscopy

P4atients requiring colonoscopy with or without biopsy and/or polypectomy are often
taking antithrombotic agents including anticoagulants such as warfarin, heparin, and
XVIII Preface
low molecular weight heparin, and antiplatelet agents such as aspirin, non-steroidal
anti-inflammatory drugs, thienopyridines such as clopidrogel and ticlopidine, and
glycoprotein IIb/IIIa receptor inhibitors. Indications for the use of these medications
include atrial fibrillation, acute coronary syndrome, deep venous thrombosis
hypercoagulable states and endoprotheses such as coronary artery stents. When
bleeding does occur in patients taking these agents it is most commonly from the
gastrointestinal tract (Choudari et al., 1994). Risk stratification for these patients can be
relegated to two categories. Low risk procedures include diagnostic colonoscopy
including mucosal biopsy (Sieg et al., 2001, Parra-Blanco et al., 2000)) and high-risk
procedures include colonoscopy with polypectomy and the dilatation of colonic
benign or malignant strictures (guidelines extrapolated in part from experience
reported in the upper gastrointestinal endoscopy literature) (Singh et al., 2005, Solt et
al., 2003, DiSario et al., 1994). A comprehensive review of the types of antithrombotic
therapies, their implications for patients undergoing colonoscopy, and
recommendations and a management algorithm for such patients using these agents
has recently been published (ASGE Standards of Practice Committee, 2009). Newer
anticoagulants, for which current guidelines regarding their being held for endoscopic
procedures are lacking, are reaching the market at an increasing rate. These include
danaparoid, a low molecular weight heparinoid consisting of a mixture of heparan
sulfate, dermatan sulfate, and chondroitin sulfate (Danhof et al., 1992, Nurmohamed,
et al., 1991) which was recently removed from the US market due to shortages; the
direct thrombin inhibitors recombinant hirudin (lepirudin), argatroban, desirudin and
bivalirudin (Greinacher & Warkentin, 2008, Clarke, et al., 1991, Warkentin, et al., 2008);
the recently available orally active direct thrombin inhibitor dabigatran etexlate
(Schulman, et al., 2009); and the factor XA inhibitors idraparinux, rivaroxaban, and
apixaban (Turpie, 2008).
10. Sedation for colonoscopy

The use of sedation for colonoscopy is undergoing changes both in the United States
and worldwide (Heuss et al., 2005, Aisenberg et al., 2005, Aisenberg & Cohen, 2006,
Cohen et al., 2006). Driven in part by insurance reimbursement, the desire to improve
efficiency in the procedure facility, the availability of anesthesiologists to sedate and
properly monitor patients for endoscopic procedures and the development of new,
short acting anesthetics, the days of either unsedated colonoscopy and/or endoscopist
administered benzodiazepine and opioid cocktail may well be numbered (Luginbühl
et al., 2009). This topic has been nicely reviewed in a recent Internet-based
international study of endoscopic sedation practices (Benson et al., 2008). The authors
conclude that although benzodiazepine with an opioid is used 56% of the time for
colonoscopy sedation by the 84 endoscopists from 46 countries who participated in the
study, propofol was use 18% of the time (as opposed to an unsedated colonoscopy rate
of 10%). A comparison of sedation practices worldwide showed that sedation is used
for most colonoscopies and sedation practices did not differ significantly between
developing and developed countries. Computer-assisted personalized sedation holds
Preface XIX
the promise of delivering safe and effective minimal to moderate propofol sedation to
ASA class I and II patients undergoing colonoscopy with the medication provided by
health care professionals who are not anesthesiologists (ASGE Technology Committee,
2011, Pambianco, et al., 2011). The effect that the untimely death of superstar Michael
Jackson due to an off-label use of propofol by a non-anesthesiologist has had and will
continue to have on the acceptance of the use of propofol outside of the operating
room (and by those other than credentialed anesthesiologists) by insurance companies
and regulatory agencies has been recently addressed
(http://blogs.wsj.com/health/2009/08/06/ the-other-propofol-issue-when-insurance-
should-pay-for-it/, http://thehappyhospitalist.blogspot.com/2009_08_01_archive.html,
Coté, 2011)). As a counterpoint, the need for conscious sedation in routine adult cases
has recently been challenged (Khalid et al., 2011).
The means for sedation of pediatric patients undergoing colonoscopy has also received
attention (Fredette & Lightdale, 2008). Two general types of sedation are available for
children undergoing colonoscopy: general anesthesia which entails increased costs
and the need for hospital resources and intravenous sedation runs the risk of agitation
(Thakkar et al., 2007). Increasingly, propofol, which can be given alone or in
combination with other sedatives, administered by a dedicated anesthesiologist, is
being used (Elisur et al., 2000). Wider concerns exist about the long-term effects of the
use of anesthetics in infants and children (Rappaport et al., 2011, Blum, 2011))
11. Patient monitoring during colonoscopy

It is difficult to talk about sedation for colonoscopy without considering issues regarding
patient monitoring during colonoscopy. Since the first colonoscopies were performed in
the hospital setting, it has long been recognized that patients (“consciously”) sedated for
colonoscopy required proper peri-procedure monitoring (Bell et al., 1991). The
availability of resuscitation equipment, airway suctioning equipment, EKG cardiac
monitoring, and parenterally administered medications (including sedative reversal
agents) in the procedure and recovery areas, having staff who were properly
credentialed in state-of-the-art resuscitation methods, the presence of a qualified
registered nurse to monitor the patient during the procedure, the obtaining and
documenting of a preoperative history and performance and documenting of a
preoperative physical examination, adequately maintained intravenous access, the use of
oxygen enriched air by nasal cannula or face mask monitored by pulse oximetry, and
more recently capnography monitoring of respiratory depression (Cacho et al., 2010),
and the recording of vital signs from the procedure and in the recovery room became
commonplace and the norm. As colonoscopy moved to the outpatient setting including
ambulatory endoscopy facilities and doctors’ offices, and the duration of the procedure
lengthened due to therapeutic maneuvers, these standards became more formalized,
often involving input from the anesthesiology community (particularly in situations
where moderate or deep sedation were employed) with debate and at times even
controversy as to the best method of sedation patients (from minimal sedation or
XX Preface
anxiolysis through general anesthesia). Much of the impetus for this came from the
simultaneously evolving practice of using anesthesiology services outside of the
operating room such as in the emergency department, the intensive care unit, the
bronchoscopy suite, doctors’ and dentists’ offices and the radiology suite.
Today, many feel that propofol is the agent of choice for sedation for colonoscopy
(Luginbühl et al., 2009). The increasing demand for sedating and properly monitoring
patients may not be met by anesthesiology departments because of staffing reductions,
reimbursement issues which drive up health care costs, and challenges by health
insurance companies (Aisenberg & Cohen, 2006). Currently, the use of propofol in this
setting by non-anesthesiologists (gastroenterologist-directed propofol use) is
controversial (Faigel et al., 2002), monitoring-intensive because of the level of sedation,
and may violate the package insert for the use this drug in some locales. The answer to
this dilemma in the future may be computer-assisted sedation systems that are
currently under development and investigation (Hickle, 2001, Pambianco, 2008,
Caruso et al., 2009, ASGE Technology Committee, 2011).
12. The electronic endoscopic record and colonoscopy

Electronic endoscopic medical record systems with report generating capabilities and
patient flow management modules are increasingly becoming an integral part of the
daily operation of many office, hospital and ambulatory endoscopy center endoscopy
units (Savides et al., 2004, Petersen, 2006). Using pull-down template menus designed
for standardization, data retrieval, and coding for billing purposes, rather than “old-
fashioned” free-text entry, the costs for such programs vary significantly between
vendors and may range between $5,000 and $45,000 (US) per room for software
implementation with an additional requirement for an annual maintenance contract
and telephone support. Besides providing a standardized procedure report these
systems provide for ease of information retrieval particularly when generating
endoscopy unit statistics and maintaining research-related databases (Groenen et al.,
2006, Faigel et al., 2006). They are also of value in providing a means for patient recall
to improve adherence to follow up recommendations after colonoscopic examinations
(Leffler et al., 2011). Issues confronting the colonoscopist contemplating the
implementation of such systems include the multitude of competing systems available
to choose from (some of which are Internet based and others of which require a Virtual
Private Network to access) and the necessity to integrate these systems with pre-
existing electronic health records already in place in doctors’ offices and hospitals.
Although features of these systems may improve patient care and enhance endoscopy
unit efficiency and productivity, further studies to document this are necessary (ASGE
Technology Committee, 2008).
13. The future of colonoscopy

“Perhaps the best thing about the future is that it comes one day at a time”-U.S.
Secretary of State Dean Acheson (1893-971)
Preface XXI
“Prediction is extremely difficult, especially about the future”—Danish physicist Niels

Bohr (1885-1962)
“640 K should be enough for anybody”-CEO of Microsoft® Corporation Bill Gates,

1981
The future of colonoscopy has been the subject of much speculation (Sawhney, 2011,
Marshall, 2011). Before reviewing the future of colonoscopy it would be prudent to
review where we are today. Currently, colonoscopy is useful for diagnosis,
polypectomy and biopsy, hemostasis, endoscopic mucosa resection, endoscopic
submucosal dissection, decompression of the colon, treatment of radiation proctitis,
stenting for malignancy, stenting for benign strictures, the occasional treatment of
hemorrhoids and rarely cecostomy placement. Sometimes advances in colonoscopy
technique are subtle in nature such as the increasingly accepted use of carbon dioxide
over air for colonic insufflation (Church & Delaney, 2002, Uraoka et al., 2009, Yamano
et al., 2010). Other advances are more profound. Future developments in colonoscopy
will likely center about five areas: new methods of imaging, new colonoscopes, new
colonoscopy assisting devices, new therapeutic tools, and new territories to explore.
New imaging techniques to enhance our vision are already upon us and undergoing
refinement. Chromoscopy providing morphological enhancement (Brown & Baraza,
2010, Kahi et al., 2010, Pohl et al., 2011), magnifying endoscopy (Filip et al., 2011), high
definition endoscopy (Singh et al., 2010, Buchner et al., 2010), confocal laser
endomicroscopy (Gheona et al., 2011), endocytoscopy (Singh et al., 2010), narrow band
imaging with enhancement of mucosal fine structure and vasculature (Cash, 2010, Van
den Broek et al., 2011, Chiu et al., 2011, Oka et al., 2011, Wada et al., 2011), multiband
imaging (Fedeli et al., 2011), computed virtual chromoendoscopy (Chung et al., 2010),
optical coherence tomography (Roy et al., 2009, Adler et al., 2009, Consolo et al., 2008),
spectroscopy and fluorescence (Ortner et al., 2010), autofluorescence imaging (ASGE
Technology Committee, 2011a) and molecular endoscopy (Buchner et al., 2010) are but
some of the new imaging techniques being unfurled. Using these techniques the
colonoscopist is deepening the depths of colonic mucosal interrogation to the level of
the submucosa with image resolution approaching that of conventional pathology in
essence becoming an in vivo pathologist! This is not unlike our current use of
visualization over histology for diagnosing duodenal ulceration, gastrointestinal
stromal neoplasms, lipomas and pancreatic rests.
New colonoscopes are under development (Rösch et al., 2007) including the Aer-O-
ScopeTM which is a pneumatic, skill-independent, self-propelling, self-navigating
colonoscope providing an omni-directional view through a conic lens and mirror
system (Pfeffer et al., 2006). The Third Eye® Retroscope® (Waye, 2010, Rex, 2009,
Leufkens et al., 2010) provides a continuous retrograde (backward) view side-by-side
with the usual forward view of the colonoscope. This is particularly useful in locating
polyps hidden behind folds. A novel computer-assisted colonoscope (NeoGuide
Endoscopy System) (Eickhoff et al., 2007) delivers a real-time, three-dimensional map
XXII Preface
of the tip position and insertion tube shape in addition to the video image of the colon
lumen. Three-dimensional map images generated by the NeoGuide endoscopy system
provide accurate information regarding tip position, insertion tube position, and
colonic looping. The Invendoscope™ SC20 (http://www.invendo-medical.com/index
eng.html, Rösch et al., 2008) has several features that are new to the field of
colonoscopy. It is a single-use colonoscope with a working channel that is not pushed
or pulled, but driven in and out of the colon. All endoscopic functions are performed
using a handheld device and most importantly, it reduces potential forces on the colon
wall to enable a gentle colonoscopy lessening the need for patient sedation. A recent
study reports that for patients with a previously incomplete conventional optical
colonoscopy, balloon colonoscopy performed by using the single-balloon enteroscope
with an overtube was superior to a repeat attempt with a standard colonoscope in
completing the examination (Keswani, 2011).
It is likely that current videocolonoscopes with only minor modifications will be

widely used for the next 5-10 years with the ideal colonoscope of the future being a
multi-modal instrument capable of switching from white light colonoscopy to
magnification colonoscopy, multiband imaging and even endoscopic ultrasound. It is
also quite likely that patient preference for capsule colonoscopy over conventional
colonoscopy will drive the development of this modality (Sacher-Huvelin et al., 2010,
Kuramoto et al., 2011).
One of the therapeutic tools that will undergo increased availability and usage in the
future is stenting. This area, shared by both colonoscopists and interventional
radiologists (Katsanos et al., 2010, Bonin & Baron, 2010), uses a minimally invasive
procedure for palliation of inoperable malignant disease and for temporary bowel
decompression, often as a bridge to surgery. Recent technological advances have been
supported by an increasing number of publications detailing clinical experience with
these devices (Farrell, 2007, Farrell & Sack, 2008).
Another therapeutic tool that will undergo refinements and increased availability is
endoscopic mucosal resection, the technique of injecting fluid (saline or
hydroxypropylmethylcellulose [HPMC]) into the submucosal space to create a
submucosal cushion followed by resection of the lesion (De Melo et al., 2011, Moss et
al., 2011). Wider acceptance of this technique will parallel outcomes research data and
complications rates. Colonoscopic closure of colonic perforation with band ligation
after enoclip failure (not for the faint at heart) has recently been reported (Han et al,
2011)!
Despite the lack of Medicare (government subsidized insurance for the elderly in the
United States) coverage for the procedure and questions about its sensitivity and
specificity, the use of CT colonography for colorectal cancer screening in United States
hospitals appears to be on the rise, particularly in medical facilities that do not offer
optical colonoscopy and may not be prepared to provide adequate follow up for
Preface XXIII
patients with failed CT colonography (McHugh et al., 2011). This trend, if sustained,
will undoubtedly impact upon the future of conventional colonoscopy.
The use dogs for colorectal cancer screening not withstanding (Sonoda et al., 2011),
along with avoiding performing the procedure late in the day (Lee et al., 2011),
although others would argue that time-dependent factors such as colonoscopist
fatigue and decreased colon cleanliness can be addressed (Freedman et al., 2011), the
future of colonoscopy seems secure and bright.
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Part 1
The Technique
1
Preparing for Colonoscopy

Rosalinda S. Hulse
Jordan Hospital
Plymouth, MA,
USA
1. Introduction
Colorectal cancer is the third leading cause of cancer-related mortality in the United States
and the fourth most common cancer in men and women. Colonoscopy is the best screening
test done to detect and prevent colorectal cancers. Abnormal growths such as a polyp, a
tumor, or a suspicious-looking lesion in the colon or rectum can be biopsied or removed
preventing the initiation of the carcinogenic process and potential metastases into other
areas of the body, thereby, allowing patients to obtain a more effective treatment (s) with
fewer side effects. Patients whose cancers are found early and treated in a timely manner are
more likely to survive than those whose cancers are not found until symptoms appear
(Atreja, A., Nepal, S. & Lashner, B., 2010; American Cancer Society [ACS], n.d, 2005). Figure
1 shows a picture of a polyp. Figure 1.a shows a picture of a cancerous tumor of the colon.
Fig. 1. Polyp in sigmoid colon Fig. 1.a Cancerous tumor in the colon
The hardest part of the colonoscopy procedure is the preparation. It usually starts one-to-
two weeks prior to the test depending on the recommendation of the physician. Careful
planning and strict adherence to these instructions is crucial to the success of the test. Many
individuals who have undergone this procedure will attest to the difficulty in complying
4 Colonoscopy
with these instructions and the harshness of taking the oral prep. As a result, many are
hesitant to go through with it risking the possibility of missing diagnoses of cancerous or
non-cancerous lesions, tumors or polyps in the colon or rectum.
The key to a successful colonoscopy is good bowel prep, which also depends on the right
choice of bowel cleansing agent. The colon needs to be totally clean for good visualization to
avoid missing any abnormal or suspicious-looking areas. A small polyp or lesion can hide
behind a small piece of stool. Poor or inadequate bowel prep may lead to a prolonged and
costly procedure and a potentially inaccurate exam. It may also increase the chance of being
aborted; to be repeated at another time which may be at an interval sooner than what is
called for or suggested in the standard guidelines. A repeated colonoscopy also increases the
risks and complications, such as perforation and bleeding of the colon, and infection
(Lawrence, E. & Pickhardt, P., 2010; Hendry, P., Jenkins, J. & Diament, R., 2007; Froehlich, F.,
et al, 2005). Preparing for colonoscopy may sound complicated, uncomfortable and time-
consuming, but it doesn’t have to be. Following the instructions carefully and being
prepared ahead of time will help the individual tolerate the procedure with minimal
discomfort.
This chapter will discuss the step-by-step process in preparing for this procedure for the
adult population, explaining the different types of oral preps (including the adjuncts) to take
as well as diet modification that will achieve the best results, taking into consideration any
medical condition the individual might have. Special conditions that might be adversely
affected by the prep, such as diabetes and any heart condition that require taking blood
thinners will also be discussed. Tips to alleviate the discomfort while taking the prep will be
outlined as well. The goal is to explain the process in a simple, non-intimidating fashion to
encourage more individuals to avail of this life-saving screening procedure minimizing any
fear and anxiety they may have. A well-informed individual is better able to follow
directions carefully to ensure good results. Figure 2 shows an adequately clean transverse
colon.
Fig. 2. Transverse Colon

Preparing for Colonoscopy 5
2. Bowel cleansing preps

Some key questions need to be answered prior to selecting an appropriate bowel cleansing
agent for the individual:
1. Does the individual have any condition (s) that is contraindicated to taking a bowel
prep (i.e. bowel obstruction, perforation, and severe ileus)? If the answer is “yes,” then
another alternative diagnostic exam need to be considered.
2. Is the individual at risk for fluid and/or electrolyte imbalances? If the answer is “yes,”
then avoid the sodium phosphate group. Choose the polyethylene glycol.
3. Can the individual tolerate full volume solutions? If not at risk for fluid and electrolyte
imbalance and cannot tolerate large doses, choose low-volume polyethylene glycol or
sodium phosphate. Sodium picosulfate and magnesium citrate can also be another
alternative to sodium phosphate. This is the choice in most European countries and is
currently not available in the United States (Atreja, A., Nepal, S. & Lashner, B., 2010).
Otherwise, a 4-L polyethylene glycol solution is the choice especially if the individual
has a history of poor bowel prep or is worried about cost or insurance coverage.
Compliance to completing a bowel prep is also dependent on a number of factors, namely,
poor palatability of the prep, concomitant medications, comorbitites affecting renal and
hepatic functions, time of test i.e. early morning or late in the afternoon, sex, and cost
(Atreja, A., Nepal, S. & Lashner, B., 2010 & ASGE, 2009). Colonoscopies performed in the
afternoon have shown higher rates of poor bowel prep and lower rates of adenoma
detection (Varughese, S., Kumar,A.,George, A., & Castro, F., 2010; Sanaka,M., Shah,N.,
Mullen,K. et al,2006; Ness,R., Manam, R., Hoen,H. et al, 2001). One study found males to
have poorer preps than females and the authors recommended these individuals schedule
their colonoscopies in the afternoon to take advantage of the split-dosage regimen. The
authors also found that colonoscopies performed within 6-8 hours of the end of the bowel
prep resulted in a better cleansing than those performed more than 8 hours after ingestion of
the last prep dose (Marmo, R., Rotondano, G., Riccio, G. et al. 2010).
The criteria for good bowel prep include:
• Require a short period of ingestion and the ability to empty out the colon in a rapid
fashion without grossly or microscopically altering the lining of the colon
• Will not cause undue shifts in fluid and electrolyte balances
• Are safe to administer in light of existing comorbidities
• Easy to complete regimen
• Reimbursed by health insurance company or is inexpensive
Unfortunately, none of the preparations currently available on the market meet all these
criteria. As a result, several adjunctive methods have been added along with the main prep
and are now available on the market to make it easier and tolerable for the individual to
take (Lawrence, M. & Pickhardt, P., 2010).
Historically, bowel cleansing agents evolved from preparations prior to surgical and
radiologic exams. These included enemas, ingestion of cathartics as well as dietary
restriction of low residue diet for 2-3 days prior to the procedure (Wexner, S., et al. 2006).
These were harsh regimens which were time consuming, uncomfortable and inconvenient
for the patient; hence, compliance was difficult. In addition, the early preparations
contained mannitol, which, when fermented by bacteria in the colon resulted in combustible
methane and hydrogen, which created a high risk for gas explosion when cautery was used.
This was also true for sorbitol preparations (ASGE, 2009). This led to the development of an
6 Colonoscopy
osmotically balanced solution with minimal water absorption or secretion into the colon by
Davis and his colleagues in the 1980s (Davis, 1980). The solution was polyethylene glycol, “a
high-molecular weight, nonabsorbable polymer in a dilute electrolyte solution that has an
osmotic effect on the colon (Atreja, A., Nepal, S. & Lashner, B., 2010).” There are several
commercially prepared bowel cleansers, and the compounds used in these preps generally
fall into three major groups according to their mechanism of action: isosmotic (the
polyethylene glycol group), hyperosmotic (the sodium phosphate group), and bowel
stimulants (Atreja, A., Nepal, S. & Lashner, B., 2010; ASGE, 2009; Barkun, A. et.al, 2006;
Wexner, S., Beck, D., Baron, T., et al., 2006). Other preparations have since been introduced
to improve palatability and compliance, e.g. low volume prep such as PEG and Bisacodyl
(Halflytely) and PEG and ascorbic acid (MoviPrep). The most commonly used bowel
preparations in the United States are the oral sodium phosphate (NaP) solutions and the
polyethylene glycol (PEG) solutions (Atreja, A., Nepal, S. & Lashner, B., 2010 & ASGE, 2009;
Barkun, A., Chiba, N., Enns, R., et al., 2006). A summary is shown on Table 1.
Approved
Approved
Bowel Prep by
Product Active Ingredient Bowel Prep By Amount
FDA for
FDA for Adults
Pediatrics
Isosmotic FV*
Colyte ( Flavored Polyethylene
Yes No 4000 ml (4L)
& Nonflavored) Glycol (PEG)
GoLYTELY
Polyethylene
(Flavored & No 4000 ml (4L)
Glycol (PEG) Yes
Nonflavored)
Sulfate-free
TriLyte
Polyethylene Yes >6 months 4000 ml (4L)
(Flavored)
Glycol
NuLYTELY Sulfate-free
(Flavored & Polyethylene Yes >6 months 4000 ml (4L)
Nonflavored) Glycol
Isosmotic LV**
PEG & Ascorbic
Yes No 2000 ml (2L)
MoviPrep Acid
4 Bisacodyl
Delayed-Release
Halflytely PEG & Bisacodyl Yes No tablets plus
2000 ml (2L)
PEG
PEG-3350 without
Glycolax No No 255 grams
electrolytes
PEG-3350 without
Miralax No No 255 grams
electrolytes
Hyperosmotic
Sodium phosphate
Osmoprep Yes + No 32 tablets
(oral)
Sodium phosphate
Visicol Yes + No 40 tablets
(oral)
Sodium phosphate
Fleet Enema Yes + >12 years 135 ml
(enema)
Magnesium Magnesium citrate
Yes >6 years 300 ml
Citrate (oral)
Available as
Fleet Phospho- Sodium phosphate
prescription No 75 ml
Soda EZ-Prep (oral)
only+
Magnesium citrate
LoSoPrepKit plus Bisacodyl oral Yes No One package
& suppository
Sodium No. Available Two sachets
Picolax picosulfate & only in Europe Yes dissolved in 300
magnesium citrate & UK ml solution
CitraFleet picosulfate & only in Europe No dissolved in 300
Stimulant
laxatives
Picolax # picosulfate & only in Europe Yes dissolved in 300
CitraFleet# picosulfate & only in Europe No dissolved in 300
Senna Senna No No 100 tablets
*Full Volume +Black Box warning included # Classified as osmotic and stimulant laxative
**Low Volume +FDA recommends against over-the-counter use
Table 1. Commonly Used Bowel Preparation Agents
2.1 Isosmotic or the polyethylene glycol group

Polyethylene glycol solutions are nonabsorbable fluids that act as purgatives to evacuate
the colon of stool. These are high volume gut lavage solutions that are osmotically
balanced and do not induce a significant electrolyte and fluid shifts, hence, are more
effective, better tolerated, and safer for individuals who have advanced liver or kidney
disease, poorly compensated congestive heart failure, or have documented electrolyte
imbalances. These also do not cause significant physiologic changes in the individual’s
vital signs, weight, and blood counts. However, some rare adverse events have been
reported in association with polyethylene glycol ingestion. These include Mallory-Weiss
tear, esophageal perforation, colitis, cardiac dysrhythmias, hyponatremia, aspiration,
pancreatitis, and a syndrome of inappropriate antidiuretic hormone secretion
(Lichtenstein, G., Cohen, L. & Uribarri, J., 2007). Commercially prepared polyethylene
glycol solutions come in full volume: flavored and unflavored GoLYTELy, flavored and
unflavored Colyte, NuLytely (sulfate-free), Trilyte flavored (sulfate-free); and low
volume: Halflytely and MoviPrep (ASGE, 2009).
8 Colonoscopy
The standard large volume polyethylene glycol (PEG) solutions, Colyte and GoLYTELY
have been studied extensively and were found to have the most evidence for safety and
effectiveness. The sodium sulfate in PEG allow for a reduction in sodium absorption in the
small intestine. These solutions are also inexpensive and most health insurance companies
reimburse the cost. The conventional adult dose is 4L, given as 240ml of the solution every
10 minutes 12-15 hours prior to the procedure until the 4L is consumed and rectal output is
clear and watery. If given through a nasogastric tube, 20 to 30ml is instilled every minute.
However, because of the large volume required to cleanse the colon and its poor palatability
(salty taste and smell of sulfates), about 15% of individuals do not complete the prep (Atreja,
A., Nepal, S. & Lashner, B., 2010 & Wexner, S., Beck, D., Baron, T., et al., 2006). The main
complaint was nausea, bloating, abdominal cramping, and vomiting. To remedy this,
splitting the dose allowed for better compliance and tolerability by the patients; half the
dose was ingested the night before the procedure and the other half taken 4-5 hours prior to
the procedure (Marmo, R., Rotondano, G., Riccio, G. et al, 2010). This method resulted in a
better cleansing of the colon. With the traditional method of single dosing, the long interval
between the end of the prep and the start of the procedure allowed secretions from the small
intestine to flow into the large intestine, obscuring the view of the cecum and ascending
colon. A study conducted by Varughese and associates found that for colonoscopies
scheduled in the afternoon, ingestion of the one gallon or 4 L solution of polyethylene glycol
resulted in superior cleansing of the colon and was better tolerated by the study
participants. There were fewer side effects, too. This method evacuated the contents of the
large intestine in a timely manner and did not allow time for the contents of the small
intestine to flow to the large intestine thereby obscuring the view (Varughese, S.,
Kumar,A.,George, A., & Castro, F., 2010). Stimulant laxatives or ascorbic acid were also
added to low-volume PEG solutions (e.g. MoviPrep) to improve compliance and palatability
(Atreja, A., Nepal, S. & Lashner, B., 2010).
Other suggestions to make ingestion of PEG solutions more tolerable are:
• Adding flavor enhancers, such as Crystal Light, Gatorade, lemon juice or lemon slices.
• Chilling the solution or adding ice cubes and drinking through a straw.
• Taking metoclopramide (Reglan) 5-10mg tablets prior, to prevent nausea.
• Adding one bottle of magnesium citrate (about 300 ml) or two to four tablets of
bisacodyl 5mg/tab to decrease the volume ingested.
• Stopping ingestion of the prep once the stool is clear and watery on the day of the test.
• Administration of the prep via a nasogastic tube for individuals with altered mental
status or with swallowing disability.
• Ingestion of sulfate-free or flavored PEG solutions, such as NuLytely and TriLyte
(flavors come in cherry, pineapple, orange, lemon-lime, and citrus-berry).
• Ingestion of a low-volume solution (2 liters) plus a stimulant laxative, e.g. HalfLytely
with two bisacodyl tablets and magnesium citrate; MoviPrep which is PEG plus
ascorbic acid.
A sulfate-free PEG solution was developed by Fordtran et al in the 1990s to improve
palatability and smell of PEG solutions. The improved taste is the result of a decreased
amount of potassium, increased amount of chloride and no sodium sulfate. Examples of
these products are NuLYTELY and TriLyte and come in different fruit flavors. Dosing is the
same as the 4L PEG solution. It is comparable in terms of safety, tolerance, and effectiveness
to the conventional PEG solutions (Wexner, S., Beck, D., Baron, T., et al. 2006). Low-volume
Fig. 3. Several commercially prepared polyrethylene glycol solutions:

Top left, GoLytely; top right, HalfLytely.
Bottom left, Colyte and bottom right, MoviPrep.
PEG preparations (e.g. PEG + ascorbic acid, PEG + electrolytes) were developed to improve
patient tolerance by reducing the amount of solution required, and thus, reducing volume-
related symptoms such as nausea, bloating, and abdominal cramping. Studies have shown
equal efficacy with full volume PEG solutions but with improved compliance and tolerance
by patients (Ell, C., Fischbach, W., Bronisch, H. et al. 2008; Bitoun, A., Ponchon, T., Barthet,
M. et al., 2006; DiPalma, J., Wolff, B., Meagher, A. & Cleveland, M., 2003).
2.2 Hyperosmotic or the sodium phosphate solutions

Sodium phosphate is widely used worldwide and is an effective bowel cleansing agent. It is
better tolerated than PEG preps due to its smaller volume (1.5 -2 liters compared with
10 Colonoscopy
polyethylene glycol’s 4 liters) and better flavor. Its hyperosmotic property draws water into
the colon stimulating peristalsis and eventually affecting a bowel movement. Unfortunately,
this is the main disadvantage of NaP solutions, because it causes major fluid and electrolyte
shifts in the body, such as hyperphosphatemia, hypocalcemia, hypokalemia, hyponatremia
and/or hypernatremia, hypovolemia and increased plasma osmolality. This may lead to an
acute phosphate nephropathy in patients with renal failure (ASGE, 2009; Balaban, D., 2008;
Khurana, A., McLean,L, Atkinson, S. et al., 2008; Curran, M. & Plosker, G., 2004). Sodium
phosphate solutions are therefore, not recommended in individuals with congestive heart
disease, bowel obstruction, hepatic and renal disease, ascites, and megacolon. The following
may also be at risk of injury to the kidneys if prescribed NaP: individuals over the age of 55,
patients who are already dehydrated, patients with acute colitis, individuals taking
diuretics, ACE (angiotensin converting enzyme) inhibitor drugs, ARB (angiotensin receptor
blockers), and non-steroidal anti-inflammatory drugs (NSAIDS) (Ker, T., 2006; Hookey, L.,
Depew, W. & Vanner, S., 2002). A study done by Yakut and his associates found that in a
selected group of elderly patients without comorbidities such as heart, kidney and liver
failure, and diabetes, the administration of NaP preparation for colonoscopy was safe and
well tolerated, with a low frequency of side effects (Yakut, M., Kubilay, C., Gülseren, S. et
al., 2010). Dong Choon and associates conducted a retrospective study between August of
2005 and May of 2008 in patients with normal kidney function, undergoing colonoscopy at a
health center in Korea using NaP solution as the bowel cleansing agent and found that it
was safe and effective and no untoward renal injury was noted (Dong Choon, S., Sung Noh,
H., Jeong Hwan, K. et al. 2010). Abaskharoun and colleagues also corroborated this findings
with their own retrospective study in a Canadian health center (Abaskharoun, R., Depew,
W. & Vanner, S., 2007). A prospective study by Casais et al. found that hyperphosphatemia
in low-risk individuals was related to low weight and can be minimized with adequate
hydration. It was their recommendation to prescribe an appropriate NaP dose according to
the individual’s weight (Casais, M., Guillermo, R-D., Perez, S, et al., 2009). In December
2008, the Federal Drug Administration (FDA) has recommended NaP preparations be
removed as an over-the-counter bowel prep to avoid inappropriate use or overdosing, and a
black box warning be included in the labels of prescription products warning consumers of
the risk of acute phosphate nephropathy. C.B. Fleet Company voluntarily recalled its oral
NaP products, Fleets Phospho-Soda and Fleet EZ-PREP. Sodium phosphate comes in tablet
form or aqueous solution. The tablet form, Visicol and OsmoPrep, are the only two sodium
phosphate prep available in the United States. The aqueous solution is no longer available
(US FDA, 2008; Ainley, E., Winwood, P. & Begley, J., 2005). Figure 4 shows examples of
sodium phosphate products available in the market.
The differences in efficacy and safety of PEG and NaP solutions in cleansing the bowel prior
to colonoscopy have been studied extensively, and, in general, the histology of the normal
colon has been shown to be preserved with PEG solutions.
Sodium phosphate solutions can alter the macroscopic as well as the microscopic
appearance of the mucosa of the colon mimicking inflammatory bowel diseases. Thus, these
preps are to be avoided in individuals with or suspected with colitis or inflammatory bowel
diseases (Bucher, P., Gervaz, P., Egger, J., et al., 2006; Rejchrt, S., Bures, J., Siroky, M. et al.
2004).
Magnesium Citrate is a saline laxative and also a hyperosmotic, and like sodium phosphate,
acts by drawing water into the colon. Since it contains magnesium, and elimination is
Fig. 4. Sodium phosphate products available in the US: OsmoPrep and Visicol. The aqueous
formula is available only as a prescription.
through the kidneys, administer with extreme caution in individuals with renal
insufficiency or failure (Atreja, A., Nepal, S. & Lashner, B., 2010). Magnesium citrate is often
used as an adjunct to bowel prep. In addition to the PEG solution, adding magnesium
citrate to the prep reduces the amount of PEG solution required to 2L. Taken the night
before the procedure (one 300 ml bottle of magnesium citrate) plus two bisacodyl tablets
and 2L of PEG solution, has shown to be just as effective as taking the full dose of PEG
solution. Used alone, magnesium citrate is not an effective bowel cleansing agent prior to
colonoscopy procedures. Magnesium citrate is often used as an adjunct to bowel prep
(Atreja, A., Nepal, S. & Lashner, B., 2010; Wexner, S., Beck, D., Baron, T., et al., 2006).
Fig. 5. Magnesium Citrate bottle
2.3 Stimulant preparations

Stimulant laxatives such as bisacodyl (Dulcolax) have been added to low volume PEG
solutions and have achieved comparable results to those given the standard dose of PEG
solutions (Atreja, A., Nepal, S. & Lashner, B., 2010). It is poorly absorbed in the small
intestine and its active ingredients stimulate colon motility, with an onset of action between
6-10 hours (ASGE, 2009).
12 Colonoscopy
Fig. 6. Dulcolax tablets

Sodium picosulfate is another cathartic with osmotic action on the bowel similar to NaP. It
is a saline laxative used in combination with magnesium citrate. An observational study
done in Canada by Love and his colleagues found that administration of sodium picosulfate
and magnesium citrate yielded a high percentage positive rate for efficacy (Yakut, M.,
Kubilay, Ç., Gülseren, S. et al., 2010). This preparation is mostly used in Europe and Canada
and is not available in the United States (ASGE, 2009).
Fig. 7. Sodium picosulfate products. Not available in the US

Senna, an anthracene derivative also helps stimulate colon peristalsis by increasing smooth
muscle wall activity. A low dose senna (four 8.6 mg tablets of Sennakot) added to a low-
volume solution of polyethylene glycol have been found to be just as effective as taking the
full-volume PEG solution. It is usually taken within 2 to 6 hours of starting the PEG
solution. A study found that there was better visualization of the right colon when senna
was added to the magnesium citrate prep and was also better tolerated by the subjects
(Vradelis, S., Kalaitzakis, E., Sharifi, Y. et al 2009).
Fig. 8. Senna products
2.4 Adjunct bowel preparation agents

Enemas are useful in cleansing the distal colon in preparation for a sigmoidoscopy, but not
recommended as prep for a full colonoscopy. They are used as adjuncts when patients come
poorly prepped. The common types are: tap water enemas, soap suds enemas, sodium
biphosphate (Fleet), and oil-based enemas such as, cottonseed oil plus docusate (Colace) and
diatrizoate sodium (Hypaque). The last one is an iodinated water-soluble contrast agent
used in radiographic exams that has a cathartic property. It slows absorption of water from
the bowel so that the stool is softer. One study found that combining diatrizoate sodium
with a low-volume saline laxative prep (preferably magnesium citrate) was just as effective
as, if not better, than the other regularly prescribed preps. It consistently outperformed the
standard high-volume PEG solutions in terms of effectiveness as a bowel cleanser and
patient compliance and tolerance (Lawrence, E. & Pickhardt, P., 2010). One disadvantage to
using this prep was that some individuals developed severe allergic reactions such as
anaphylaxis and angioedema. Others have experienced muscle cramps and intermittent
leakage of stool in their undergarments for up to 24 hours after the test (Atreja, A., Nepal, S.
& Lashner, B., 2010; Lawrence, E. & Pickhardt, P., 2010 & Sohn, N. & Weinstein, M., 2008;
Wexner, S., Beck, D., Baron, T., et al., 2006).
Dietary modifications alone are inadequate prep for colonoscopy, but are a beneficial adjunct,
by decreasing the formation of solid residue. Drinking clear liquids is recommended in ALL
bowel preps and helps maintain adequate hydration (Atreja, A., Nepal, S. & Lashner, B., 2010;
ASGE, 2009; Dykes, C. & Cash, B., 2007; National Guideline Clearinghouse, 2006).
Carbohydrate-electrolyte solutions such as Gatorade and E-Lyte have been added to both
PEG and NaP solutions to improve palatability and to avoid severe fluid and electrolyte
shifts (Wexner, S., Beck, D., Baron, T., et al., 2006).
Antiemetic agents such as metoclopramide (Reglan 5-10mg) are commonly used to prevent
nausea and vomiting associated with taking bowel preparations.
Antifoaming agents, such as Simethicone (three 80 mg tablets), an anti-gas, anti-flatulent
agent, has been added to the prep to reduce the bubbles and improve visibility during
colonoscopy (Tongprasert, S., Sobhonslidsuk, A. & Rattansiri, S., 2009).
Nasogastric or orogastric tube installation is usually reserved for inpatients that are unable
to drink the polyethylene glycol solutions, for patients who are unresponsive or those on
mechanical ventilators.
14 Colonoscopy
Rectal Pulsed Irrigation administered immediately prior to the colonoscopy preceded by

intake of magnesium citrate the night before is also another alternative, though this is time
consuming, expensive and requires expert nursing skill to be efficiently performed
(Wexner, S., Beck, D., Baron, T., et al., 2006).
Clebopride is another adjunct that has gained some interest among endoscopists. It is a D-2
dopamine antagonist with antiemetic and prokinetic properties which can improve the
efficacy of bowel cleansing. A study was done to evaluate the efficacy, safety, tolerability,
and acceptance of Clebopride as an adjunct to PEG solution as prep for colonoscopy. The
authors found that Clebopride was better accepted by patients and was better tolerated as
well. It diminished the symptom of nausea, abdominal distention, and borborygmus
(Abdullah, M., Aziz Rani, A., Fauzi, A. et al., 2010).
3. Special considerations
Diabetes Mellitus. Diabetic patients need to follow certain pre- and post- colonoscopy
instructions to prevent hyper- or hypoglycemia episodes. The individual needs to discuss
his/her medications with the physician at least two weeks prior to the test. Individuals
taking insulin may need to have their regular dosages adjusted the day before and the day
of the procedure. See tables 2 and 3 for general guidelines.
Cardiac conditions. Individuals taking blood thinners will need to consult their physician as
to when to stop taking these medications prior to colonoscopy. A blood test to check the
PT/INR will need to be drawn in the morning the day before the exam. He or she should
not stop taking his or her other cardiac medications without consulting his or her physician.
Blood pressure medications are generally allowed to be taken even on the day of the
procedure.
The elderly. The elderly often have poorer bowel preps which may be attributed to a decrease
or alteration in intestinal motility secondary to the aging process or other comorbidities.
Constipation contributes to the poor quality of the colonoscopy which may be associated
with the elderly’s sedentary lifestyle, inadequate intake of fiber, depression, and dementia
(Yakut, M., Kubilay, Ç., Gülseren, S. et al., 2010). They are also at risk for fluid and
electrolyte imbalance, especially phosphate intoxication, due to concomitant medication use,
comorbidities, poor kidney function or other gastrointestinal disorders. Adequate hydration
without compromising cardiac function is of utmost importance with this population.
Pregnancy. The need for colonoscopy during pregnancy is rare, hence the safety and efficacy
of the bowel preps have not been studied. If it is deemed that the potential benefit of
colonoscopy outweigh the small, but possible risks, then the pregnant woman may be
cleansed with PEG solutions. NaP preps may be used with caution in select patients (ASGE,
2009; National Guideline Clearing House, 2006).
The pediatric population will be discussed in another chapter.
4. Colonoscopy bowel preparations: general patient instruction guidelines

Two weeks prior to your procedure:
• You need to speak with or see the physician who will be performing your colonoscopy
to go over your medical and surgical history, medications you take on a regular basis,
allergies, any other pertinent information relevant to your procedure or concerns you
may have. For women, please let the physician know if you are pregnant or maybe
pregnant. If you have kidney or liver disease and are on fluid restriction, your prep and
diet may need to be adjusted.
• Your physician will advise you what medications you need to discontinue and when to
discontinue these prior to the test. These include all types of blood thinners or
antiplatelet medications, anti-inflammatory drugs, multivitamin with iron and any
other medication containing iron preparation, and bulk-forming agents.
• If you have diabetes, it is advisable to schedule an appointment early in the day so that
you can eat after and take your medications as close to your usual time as possible. You
will be asked to bring your blood glucose meter and test strips and any treatment you
use when you experience low blood sugar levels on the day of the exam.
• For asthma sufferers, you need to bring your inhaler (s) the day of the exam.
• For individuals using a CPAP or BiPAP machines, you will be asked to bring these on
the day of the exam as well.
• You will be asked to arrange for a ride to your colonoscopy as you will not be
allowed to drive a car, take the bus or taxi home after the procedure. You will be
given sedation medications for the procedure and the effects usually linger for a few
hours after the test is completed. You will spend about 1-2 hours in the endoscopy
suite, which includes the pre-procedure prep, the colonoscopy itself, and post-
procedure recovery time. You will go home after to rest and allow the rest of the
sedatives to wear off. If you arrive without an escort, your test will be cancelled or
rescheduled.
Seven days prior to your procedure:
• Stop taking the following medications:
• Iron, vitamin E and medications containing either component
• Garlic, Ginko Biloba, ginger
• Blood thinners (anticoagulant) such as warfarin (Coumadin), Fondaparinux
(Arixta), enoxaparin (Lovenox)
• Antiplatelets such as prasugrel (Effient), clopidogrel (Plavix), cilostazol (Pletal),
anagrelide (Agrylin), pentoxifyline (Trental), dipyridamole (Persantine),
dipyridamole with aspirin (Aggrenox), aspirin and any other products containing
aspirin (Anacin, Alka Seltzer, Bufferin).
Note: You must have your PT/INR checked in the morning the day before your test if you
are on Coumadin or Warfarin, Plavix or Jantovan.
Five to three days prior to your test:
• Confirm your ride.
• If you need to cancel or reschedule your appointment, this is the time to do so. Call the
office where you booked your appointment.
• Review the diet you need to follow as well as medication schedule if you are a diabetic.
Most heart medications such as ones for high blood pressure are generally allowed to
be taken even on the day of the exam. Diuretic medications are usually asked to be
taken after the procedure is completed.
• Purchase your prescription bowel prep, but DO NOT MIX or PREPARE the solution
until the day before the exam, if not taking the pill form.
• Stop taking bulk-forming agents such as Metamucil or Citrucel.
16 Colonoscopy
Two days before the procedure:

• Stop taking ALL anti-inflammatory drugs such as ibuprofen and ibuprofen products
(Advil, Motrin, Nuprin), Voltaren, naproxen (Aleve, Anaprox, Midol Extended Relief,
Naprelan, Naprosyn), Indocin, Relafen, Voltaren. Acetaminophen (Tylenol) is okay to
take for any headache or discomfort you might be experiencing.
• Stop eating seeds, nuts, corn, popcorn, whole grains.
• Drink a minimum of eight glasses of water throughout the day.
• Do not eat any solid food after midnight.
Day before the procedure:
• Beginning at breakfast, DO NOT EAT ANY SOLID FOOD. Instead, start a clear liquid
diet which means drinking liquids that you can see through, e.g. apple juice, white
grape juice, ginger ale, lemon-lime soda, Gatorade, Kool-Aid, Jello, coffee (without the
creamer), tea, Seltzer, broth, bouillon or consommé. Do not drink liquid that is red,
blue, or purple (cherry, purple grape, or berry flavors). Also avoid milk, milk
products, non-dairy creamers, or alcohol.
• For diabetics, the following are suggested clear food choices:
• Apple juice (4 oz.) 15 Gm carbohydrate
• Plain Jello without fruit (regular sweetened, ½ C.) 15 Gm carbohydrate
• Grape juice (white, 4 oz.) 20 Gm carbohydrate
• Any sports drink such as Gatorade (8 oz.) 15 GM carbohydrate
• Italian Ice 3 0 Gm carbohydrate
• Ice pops, orange or yellow popsicles 15 Gm carbohydrate
• Coffee or tea with 1 tsp. sugar (one packet) 4 Gm carbohydrate
• Fat-free beef or chicken broth, bouillon or consomme´ no carbohydrate
• Clear diet soda, such as ginger ale no carbohydrate
• Seltzer (flavored or nonflavored) no carbohydrate
• Flavored water no carbohydrate
• Tea with slice of lemon
*Note: Aim for 45 grams of carbohydrate during mealtimes and 15-30 grams for snacks.
Read the label of commercially prepared drink items for carbohydrate measurement per
serving. Refer to Table 2 for diabetic medication guidelines.
• In addition to water, drink a variety of liquid throughout the day (recommended every
hour while awake). Your body needs a combination of water, sugar, and electrolytes. It
will keep you from being dehydrated, weak, and hungry and you will be better able to
tolerate the bowel prep. A new product on the market, called Colonoscopy Prep
Assistant, helps individuals keep track of their hydration status. It is a web application
that tracks the number of glasses of fluid the patient has taken, the time interval
between drinks, and notifies the patient when it’s time to take the next glass of fluid.
This application is available for free in the Android market and iTunes and can also be
downloaded at www.wellapps.com.
• For individuals taking polyethylene glycol (PEG) prep, do the following:
• In the morning, mix the PEG solution as directed and refrigerate.
• Around 1:30 PM, take one tablet of metoclopramide (Reglan), if prescribed, to
prevent or relieve the nausea that accompanies ingestion of the PEG solution.
Medications Morning Lunch Dinner/Supper Bedtime

Actos, Actoplus
Met, Avandamet,
Avandia, Take your usual Take your usual Take your usual
Metformin, dose dose dose
Janumet, and
Januvia
Amaryl,
Avandaryl,
Duetact,
Glipizide,
Glucovance, Do not take Do not take
Glyburide,
Metaglip,
Prandin, and
Starlix
Humalog, Regular If prescribed a If prescribed a
or Novolog fixed dose, take fixed dose, take
Insulin ½ the regular ½ the regular
amount OR amount OR
cover your carbs cover your carbs
with usual carb with usual carb
ratio ratio
Lantus or NPH Take your usual Take your
Insulin dose usual dose
Novolog Mix
Take half the
70/30, Novolin Take half the usual
usual dose at
70/30, Premixed dose at dinner time
breakfast
insulin75/25
Table 2. General guidelines for diabetic medications the day before colonoscopy
Fig. 9. Varieties of clear liquid: broth, Jello, apple juice or white grape juice, Gatorade, and
ginger ale
18 Colonoscopy
• If prescribed the 4-L GoLytely, take one glass (8 oz) every 15-20 minutes half-an-
hour after taking the metoclopramide tablet, until half gallon is gone. Remember to
drink clear liquids or water in between until you go to bed. Be sure to stay close to
the bathroom. The rest of the half gallon will be taken the next day, about 3-4 hours
prior to the scheduled procedure. If you have a morning appointment, you may
need to get up in the middle of the night to complete your prep. If your test is in
the afternoon, you may start taking the rest of the prep at 6 AM, one glassful every
15-20 minutes until the half gallon is consumed.
• If nausea continues, take a second tablet of metoclopramide around 5 or 6 PM. Let
your physician know if you are having difficulty completing the prep or
uncomfortable side effects such as nausea, vomiting continues.
• Another approach would be to take 3L the night before and 1L the day of the
procedure.
• For low-volume PEG preparations plus bisacodyl tablets, the clear liquid diet the day
before is also followed.
• Around noon time, take four (5mg) bisacodyl delayed-release tablets.
• Start taking the PEG solution after a bowel movement occurs following taking the
bisacodyl tablets. Keep drinking a glassful of the prep every 10-15 minutes until the 2
liters is consumed. You may take a break in-between dose if bloating, nausea, or
vomiting ensues. Resume after the symptom (s) subsides.
• For low-volume PEG prep (MoviPrep) with magnesium citrate, do the following:
• Upon waking up the day before the exam, prepare the solution by mixing pouches
1 & 2 into the disposable container provided. Add lukewarm to the top line and mix
until completely dissolved. Refrigerate. At around 5 PM, start drinking a cupful of the
solution (about 8 oz.) down to the first mark on the container. Make sure you follow this
with clear liquid of your choice. Keep drinking the solution down to the next line and so
forth every 15 minutes until the liter is consumed.
• The process will be repeated again for dose #2, but will not be taken until around
7:30 PM the same evening.
• For individuals taking the sodium phosphate (NaP) prep, do the following:
• Only clear liquids are consumed the day before the procedure.
• For the aqueous NaP prep, take a 30 to 45 ml solution with at least 8 oz. of water
(or any other preferred clear liquid) 10-12 hours prior to your scheduled exam. The
second dose will be ingested at least 3-4 hours prior to your test the next day.
• Continue to drink clear fluids until you go to bed.
• Another recommended approach is to take the two doses of NaP, three hours apart
in-between dose, starting at 4 PM or 5 PM for the first dose followed by the second
dose around 9 PM, and supplemented around 10 PM by four bisacodyl (5mg)
tablets.
• For individuals prescribed the pill form (Osmo-Prep or Visicol: The recommended
dose is 3 tablets every 15 minutes for 6 doses and then 2 tablets for a total of 20
tablets, the day before the procedure. This is again repeated the next day, 3 to
5 hours before the scheduled test. Osmo-Prep uses only 32 tablets in divided
doses similar to Visicol. Again, these are taken with water or clear liquid. Dulcolax
or magnesium citrate may also be added as an adjunct to ensure clear bowel
return.
Tips: Do not be surprised if you do not have a bowel movement soon after ingesting your
prep. It usually takes about 2-4 hours before you have your first bowel movement. Stay
close to the bathroom as you will spend most of your day on the toilet. Try to use moistened
wipes or a water spray instead of toilet paper to clean yourself to minimize irritation of the
anal area. If you have a colostomy, be prepared to empty out your pouch often and liquid
stool may leak around your pouch as well. Remember to keep drinking plenty of clear
liquids to prevent dehydration. Follow your instructions for the prep as you do not want to
repeat this procedure all over again because you did not get it right the first time.
Day of the procedure:
• Take your regular medications allowed by the physician with a small sip of water. You
may have clear liquids three hours before your test. Refer to Table 3 for medication
guidelines if you are a diabetic and remember to check your blood sugar in the morning
before coming to the colonoscopy. Also bring your glucometer, extra test strips and
your treatment for any hypoglycemic (low blood sugar) episodes.
• Have your driver drive you to the colonoscopy place half-an-hour before your scheduled
procedure or whatever time you were instructed to arrive. Remember to bring your paper
work, medications, inhalers, CPAP or BiPAP machine, and health insurance card.
• Make sure you wear comfortable clothing and bring extra clothes, underwear or peri-
pads in case you have an accident and soil your clothes or underwear.
Medications Morning Lunch Dinner/Supper Bedtime

Actos, Actoplus
Met, Avandamet,
Avandia, Take your usual Take your usual Take your usual
Metformin, dose dose dose
Janumet, and
Januvia
Amaryl, Avandaryl,
Duetact, Glipizide, Resume
Glucovance, regularly
Do not take
Glyburide, prescribed dose
Metaglip, Prandin, if allowed to eat
Starlix
Humalog, Regular Resume
Resume regularly
or Novolog Insulin regularly
Do not Take prescribed dose if
prescribed dose
allowed to eat
if allowed to eat
Lantus or NPH Take your
Take half of
Insulin regularly
your regularly
prescribed
prescribed dose
dose
Novolog Mix Resume
Resume regularly
70/30, Novolin regularly
Do not Take prescribed dose if
70/30, Premixed prescribed dose
allowed to eat
insulin 75/25 if allowed to eat
Table 3. General guidelines for diabetic medications day of the colonoscopy
20 Colonoscopy
Post procedure recovery:

• You will be cared for by a nurse or a nurse’s aide and your vital signs monitored for
about half-an-hour to an hour immediately after the procedure in the recovery area.
This will also allow for most of the effects of the sedatives to wear off.
• During this time, your doctor will talk to you about the results of your colonoscopy.
If a biopsy was performed, the results are usually not available until a few days later
as the sample (s) will be sent to the lab for analysis. He will also provide you with
any pertinent additional information or instructions for follow-up.
• You will be discharged home with your designated driver once you are feeling okay
and are able to tolerate oral fluids without being nauseous or vomiting. If you are
diabetic, it is a good idea to check your blood sugar before going home.
• Plan to rest for the remainder of the day.
• Eat foods that are easy to digest to minimize or avoid nausea and vomiting which is
mostly due to the lingering side effects of the sedatives received. Examples are, toast,
soup, light sandwich (e.g. grilled cheese), tea, and coffee.
• You may occasionally feel some bloating or be flatulent. This is normal and should
disappear within 24 hours. If you had a biopsy done, it is not uncommon to see some
flecks of blood in your stool for a couple of days following your colonoscopy. This is
usually dark in color. Call your physician if you have bright red blood in your stool,
experiencing persistent nausea, vomiting, and abdominal pain or bloating.
5. Safety and efficacy

All colonoscopy bowel preparations are generally considered safe when properly dosed in
individuals without contraindications to the specific product, but are not completely
immune to the adverse reactions, and on occasion, severe negative outcomes. The safety of
the bowel cleansing agent is related to the safety profile of the base agent, i.e, polyethylene
glycol or sodium phosphate. The most commonly encountered side effects are bloating,
abdominal pain, borborygmus, nausea, vomiting, dizziness, and fluid and electrolyte
imbalance. Often the symptoms of nausea, vomiting and abdominal pain disappear once
bowel movement commences. These symptoms have also been minimized and safety
improved by splitting the dosages, adding adjuncts, administering low-volume preps, and
increasing the interval time in-between dosages to 10-12 hours (ASGE, 2009; NGCH, 2006).
Generally, the administration of isotonic polyethylene glycol solutions do not cause
significant physiologic changes in vital signs, individual’s weight, laboratory results
(complete blood count, blood chemistries, and serum electrolytes). It has been safely
administered in individuals with advanced liver and kidney failure, congestive heart failure,
and fluid and electrolyte imbalances. Some concerns were raised with the use of some PEG
solutions, HalfLytely, in particular, in patients taking angiotensin converting enzyme drugs
(ACE) or potassium-sparing drugs such as aldactone, because of the small amount of
potassium found in the solution. However, there were no clinical reports noted to date
(ASGE, 2009; NGCH, 2006).
Sodium phosphate, on the other hand, has been shown to alter both the macroscopic and
microscopic (aphthoid erosions) mucosal lining of the intestine, which may mimic
inflammatory bowel disease. This prep should then be avoided in individuals with or
suspected to have inflammatory bowel disease. Serum electrolyte and fluid imbalances have
also been reported with sodium phosphate use. Hyperphosphatemia was seen in 40% of
healthy individuals taking NaP. This could be significant for patients with renal failure. About
20% of individuals taking NaP preps have developed hypokalemia, elevated blood urea
nitrogen, increased plasma osmolality, decreased exercise endurance, significant
hyponatremia, hypocalcemia, and seizures. A rare adverse event, nephrocalcinosis, has been
reported in patients with acute renal failure (Balaban, D., 2008; Gonlusen, G., Akgun, H., Ertan,
A., et al., 2006; NGCH, 2006). As a result, the Federal Drug Administration (FDA) has
recommended that over-the-counter use of sodium phosphate solutions be discontinued and a
black box warning be included in prescription products. Manufacturers of sodium phosphate
products were also required to perform a “risk evaluation and mitigation strategy, including a
post marketing trial,” to further assess occurrence of renal injury (ASGE, 2009).
All bowel preps are contraindicated in individuals with known or suspected bowel
obstruction, perforation or ileus. Bowel cleansing agents containing magnesium and
phosphate should be used with caution or avoided in individuals with kidney failure. To
minimize or avoid fluid and electrolyte imbalance, it is necessary to screen patients carefully
and to instruct them to hydrate themselves, pre- and post-procedure. Intravenous fluids are
usually given during the procedure.
6. Conclusion
Colonoscopy remains the gold standard in the screening and evaluation of the colon for
colorectal disorders and diseases. For maximum visualization of the colon, it is imperative that
the bowel is thoroughly cleaned. Several commercially prepared agents are available on the
market, but the most commonly used ones are the polyethylene glycol and sodium phosphate
preps. Adjuncts have also been recommended in addition to the main prep to make it easier to
administer. The choice of an appropriate bowel cleansing agent is influenced by its safety, ease
of administration and completion, cleansing effectiveness, patient tolerance, adverse effects,
palatability, reimbursed by health insurance, will not interact with regularly prescribed
medications, and cost. It should be tailored to every individual based on his or her state of
health, comorbidities, and medications taken on a regular basis. Kidney function should be
evaluated prior to choosing a bowel cleansing agent particularly in the elderly. Thus, careful
screening of the patients prior to colonoscopy, prescribing the appropriate dose and bowel
cleansing agent, patient education and adequate hydration before and after colonoscopy will
help ensure the safety and efficacy of the procedure.
7. Acknowledgement
The author wishes to thank Kira Hulse, BS for her review of the article, Dr. Jonathan Russo,
Chief of Endoscopy, for his expert advice regarding colonoscopy, and to my good friend,
Marian de la Cour, BSN, MLS, for all her efforts in obtaining most of the literature referred
to in this chapter.
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2
Sedation and General Anaesthesia for

Colonoscopy in Childhood
Alicja Bartkowska-Śniatkowska1, Jowita Rosada-Kurasińska1
and Małgorzata Grześkowiak2
University of Medical Sciences,
1Department of Paediatric Anaesthesiology and Intensive Therapy
2Department of Teaching Anaesthesiology and Intensive Therapy
Poznań,
Poland
1. Introduction
Fiberoptic colonoscopy was successfully introduced into paediatric practice several decades
ago and has improved the detection and management of gastrointestinal diseases in
children worldwide (El Mouzan et al, 2005). Since the early 1970’s colonoscopy has become
more useful and more advanced method for diagnosis and treatment in many large-bowel
diseases in paediatric population (Steiner et al, 2006). This expansive development has also
been possible thanks to the rapid development of anaesthetic techniques and new drugs.
There are many indications for colonoscopy in children: diarrhea, hematochezia,
unexplained rectal bleeding, abdominal pain, inflammatory bowel disease, polyposis
syndrome, polypectomy, vascular ablation, dilation of stricture, foreign body removal,
decompression. All reports have shown that this procedure could be safe and useful tool in
children of all age groups only if it is based on good practice standards and experienced
management, provided by both paediatric gastroenterologist and paediatric
anaesthesiologist (Dillon et al, 1998).
Children are often difficult and non-cooperative patients. Due to the anatomical differences,
when compare with adults, they need diagnostic specificity and ability to be examined by
the paediatric endoscopist. His opinion and comfort during the procedure is a key for
effective and satisfactory diagnostic or therapeutic procedure. On the other hand children
are completely different group of patients with the higher risk of unpredictable events
during invasive procedures being associated with the younger child is. Therefore they need
paediatric anaesthesiologist to provide deep sedation or general anaesthesia. In some cases,
conscious sedation should be also provided by anaesthesiologist if the child is extremely ill.
Although paediatric colonoscopy is performed routinely in hospitals still the most
important thing to remember to perform this procedure at least safely, reasonably quickly,
and comfortably for the children (Strauss & Giest, 2003). They feel pain and discomfort
connected with the overinsuflation of the bowel and heavy-handed instrumental technique.
They are more sensitive to dehydration as a consequence of preoperative and preanaesthetic
management and this could be reflected in cardiovascular and respiratory complications.
26 Colonoscopy
Finally, they can present different responses to the administered drugs that could
complicate procedural and post-procedural course (Groot & Mulder, 2010).
Thus, conscious sedation, deep sedation, and general anaesthesia have been widely adopted
in paediatric gastroenterological practice because the number of noninvasive and minimally
invasive procedures performed in pediatric population has grown exponentially.
Evidenced Base Medicine (EBM) does not allow to answer which method is the best and
could be recommended as a standard. To optimize the choice one should be considered
three main aspects:
1. Ideal and excellent conditions for instrumental technique
2. Short recovery time
3. High level of satisfaction
The first point is assessed by the endoscopist and his opinion is the most important.
Reduced total time for sedation and recovery of patients undergoing colonoscopy plays a
special role as large number of procedures are undertaken as day-cases. The last aspect, the
patients’ satisfaction, is the most difficult to assess because of the age of child and the child
is sleeping during the procedure. Additionally discomfort and pain is more with
instrumental procedure than sedation or anaesthesia. When child is not able to give an
answer, parents’ or relatives’ opinion will be important but also somewhat subjective.
2. Preanaesthetic management
Children should be routinely assessed by anaesthesiologist in connection with the plan for
anaesthesia at least one day before sedation or general anaesthesia. In childrens’ hospitals
there should be a special room – a preoperative assessment clinic - where children and
parents can get answers and explanations to their questions and where good conditions
exist for comfortable examination of the child (Cavill & Kerr, 2009a). Equally important is
getting the consent for anesthesia during this visit signed by each patient (in Poland over 16
years old) and/or parents or the legal representatives (Steiner et al, 2006, Malviya S, 2011).
Babies and younger children are not very often interested in this visit. They don’t
understand what happens nor the purpose of this interest. They may be running around the
room, not accepting the examination and sometimes crying upon seeing doctor or nurse
wearing an white. The person responsible for this first contact (in different countries are
different systems e.g. doctors, register nurses) should be strongly experienced in the
paediatric field.
2.1 Assessment of child’s state of health

Children differ significantly from adults depending on their anatomy, physiology and
pathophysiology the greater the difference the smaller child is. Therefore the ratio of
complications in the perioperative period is higher than in adults, especially the risk of
cardiac arrest. In paediatric anaesthetic cases the incidence of cardiac arrest is assessed to be
approximately 1,4 in 10,000. Moreover, an overall mortality of 26% was reported following
cardiac arrest (from current database of Paediatric Perioperative Cardiac Arrest (POCA)
Registry (Bharti et al, 2009). Compared to adults, two predictors of mortality are the same:
ASA physical status 3–5 and emergency surgery. Despite this, 33% of paediatric patients
who suffered a cardiac arrest were ASA physical status 1–2. The most important causes are
cardiovascular (37%), medication related (32%), respiratory (20%), equipment related (7%)
and other (4%).
Sedation and General Anaesthesia for Colonoscopy in Childhood 27
2.1.1 American Society of Anesthesiologists (ASA) scoring system

The ASA scoring system is helpful in the description of physical status of a patient and is
routinely used by the anaesthesiologists all over the world (Saklad, 1941). Even though there
is a correlation between ASA score and perioperative mortality it was never intended for
risk mortality prediction (Table 1).
Code - ASA Description

I A normal healthy patient
II A patient with mild systemic disease
II A patient with severe systemic disease
IV A patient with severe systemic disease that is a constant threat to life
V A moribund patient who is not expected to survive without the operation
VI A declared brain-dead patient whose organs are being removed for donor
purpose
Table 1. ASA classification (modified)
Neonates are classified as ASA III and infants as ASA II due to their immature organs and
significantly unpredictable responses to the drugs. When the endoscopist desires to perform
both the colonoscopy and the sedation only by himself he should remember the statistics
about the high risk found for paediatric patients even though ASA physical status was
assessed for I or II.
2.1.2 Airway associated problems in children

Inadequate ventilation and difficult intubation are everyday hazards in paediatric
anaesthesia and can cause higher morbidity and mortality in this group of patients. During
the preoperative visit the ability to recognize “difficult to ventilate patient” is essential.
Neonates, and smaller children have a unique anatomy of the larynx with the shape of
funnel. Other important differences are a large tongue, a long epiglottis, and short and
narrow trachea and bronchi which result in increased resistance. Intercostal muscles are
very poorly developed and ventilation is therefore diaphragmatic and rate dependent,
abdominal distension may cause splinting of the diaphragm (Berg, 2006). Some congenital
defects of upper airways disturb normal ventilation (e.g. Pierre-Robin syndrome, Marfan’s
syndrome, mucopolysaccharidosis) (Inal, 2010).
Assessment should be based on the search for predictors of the difficult airways. A number
of useful tests are available for clinical practice. The modified Mallampati scoring system
can be applied among older children, who are able to open the mouths and protrude the
tongues (Table 2)
Class Comment
Class 1 Faucial pillars, soft palate, visible uvula
Class 2 Faucial pillars and soft palate visible, uvula masked by base of tongue
Class 3 Only soft palate visible
Class 4 Soft palate not visible
Table 2. Mallampati Scoring Scale
28 Colonoscopy
When the child is classified as class 3 or 4 the child should be assessed further using
laryngoscopy to obtain a better view of things capable of causing higher risk of respiratory
disturbances during deep sedation or general anaesthesia. (Cormack & Lehane, 1984)
Grade Comment
Grade 1 Whole of glottis visible
Grade 2 Glottis incompletely visible
Grade 3 Epiglottis but not glottis visible
Grade 4 Epiglottis not visible
Table 3. Laryngoscopy Scoring
The most important thing to remember is that combination of sedatives and opioid
analgesics decrease the ability to sustain sufficient ventilation, as worse as concomitant
defects.
Airway obstruction (another adverse event) should be distinguished from the respiratory
depression. Upper airway obstruction in paediatric patients arises from both anatomical
structures and laryngospasm. The latter one results from the closure or spasm of the glottic
muscles including the false and true vocal cords. This state could be very dangerous during
procedural and deep sedation in young children when secretions from upper airway and a
impaired cough irritate the larynx and triggered the spasm (Becker & Haas, 2007).
2.2 Requirement laboratory tests

There are many different opinions about the necessity of the laboratory tests among the
children before medical procedures. The range of these tests depends on the invasiveness of
medical or diagnostic procedure on the one hand and comorbidity of chronic diseases on the
other. Healthy children (ASA I and II) should be able to be sedated or receive anaesthesia
without any lab tests if the gastroenterologist doesn’t see any unusual risk factors from the
bowel disease e.g. unexplained bowel bleeding, diarrhea or inflammation. If he does, it is
necessary to collect venous blood and check at least blood type, CBC, electrolytes,
coagulation parameters before the procedure. For those children with congenital defects or
diseases and coexisting severe systemic diseases it is necessary to consider additional
laboratory tests and/or to send the child to proper consultant.
2.3 Exclusion criteria

Contraindications for sedation or anaesthesia for elective procedures include the presence of
or contact with patients with contagious diseases (postpone procedure for the intubation
period, usually 2 to 3 weeks), abnormalities in the physical examination or laboratory tests
e.g. productive cough, purulent chest or nasal secretions, pyrexia or signs of viraemia.
Anaesthesia in the presence of upper respiratory tracts infection is associated with a higher
risk of excess secretions, airway obstruction, laryngospasm and bronchospasm. Children
just inoculated (before 3rd day after vaccination containing killed and 3rd week after
vaccines with live, attenuated microorganisms) should not be electively sedated or
anaesthetized. Vaccines often stimulate the immune system to react as if there were a real
infection. A child found to be post viral infection, afebrile, and with no chest signs is
probably fit for the procedure even if he has a runny nose (Berg, 2006).
2.4 Feeding before the procedure

Before having a colonoscopy, the bowel needs to be completely empty. This requirement is
helpful for anaesthesia because every patient before sedation or general anaesthesia needs to
be fasting to perform anaesthesia safely and comfortably. In the last decade the idea of a
shorter fasting is preferred among the paediatric and adult anaesthesiologist. Prolong
fasting doesn’t decrease the risk of gastric aspiration even though it helps to minimize the
volume of gastric fluid up to 0.4 ml/kg but there is no reduction in gastric pH which is
closed to 2.5 (Royal College of Nursing, 2005 ). In small children the rate of gastric emptying
after feeding breast milk is about 25 minutes while that after the administration of formula
compound is 50 minutes. For this reason minimally safe time from the breast milk feeding is
4 hours and for artificial feeding mixtures and solid foods - 6 hours. If the child needs
hydration, up to 2 hours before procedure is possible to give clear fluids including water,
apple juice, weak tea. Children stratified to a high-risk group of regurgitation are not
allowed to be fed 6 (or even 8 hours) regardless of the type of the food (Table 4).
Children with diagnosed chronic disease could continue the most of their medications as
usual.
No risk of gastric High risk of gastric

aspiration aspiration
Clear fluid 2 hours 6 (8) hours
Breast milk 4 hours 6 (8) hours
Formula/cow’s milk, solid food 6 hours 6 (8) hours
Table 4. Restrictions of feeding before sedation or anaesthesia in children
2.5 Premedication
The aim of premedication is to achieve state of controlled perioperative emotions and
behaviors among the child. For children, any medical procedure can be very distressing and
may lead to a lack of cooperation and refusal (Machotta, 2010). Knowledge about the
reasons of this behavior is important to develop strategies and techniques to minimize
preoperative stress and fear. Another desired effect of premedication is to cause amnesia,
especially in the group of patients undergoing colonoscopic procedure, often repeatedly.
Additionally, premedication could be helpful in inhibiting unwanted vegetative reflexes and
reduction of the secretion of saliva and mucus in the airways, so typical and characteristic
for pediatric population under 5-7 years old. The last indication for specific premedication is
the elimination of pain accompanying the disease to minimize child’s discomfort.
Considering all these aspects, adequate preparation and the use of anxiolytic premedication
are important modalities. Non-pharmacological interventions are interesting and could be
an alternative to the use of sedative drugs in the future (Vagnoli et al, 2010)
In many cases parental presence could be helpful, even during the initiation of sedation or
the induction of general anesthesia. The enthusiasts of the use of psychological methods try
to introduce completely modern methods including even the presence of a clown in the
preoperative room (Vagnoli et al., 2010). They achieved a significantly better effect when
compared to parental presence or the influence of midazolam. In many hospitals this
practice is not common for not only medical but also organizational and administrative
reasons.
30 Colonoscopy
The best-documented practice for premedication of children for minor procedures seems to
be the pharmacological method with midazolam (Kentrup et al, 1994, Isik et al, 2010).
2.5.1 Midazolam
Midazolam (described in 3.1.1) is indicated for premedication because it produces amnesia,
anxiolysis and sedation. Oral administration is a favorite choice for premedication in
children with the dose of 0.5 – 0.75 mg/kg given 30 minutes before the procedure but the
effect is not always predictable (Robinson, 2000). Recently for smaller children (up to 30 kg
of body weight) a syrup can be prepared for use by the hospital pharmacy department to
avoid the use of intravenous route. The total volume of this mixture is limited to the 6 ml.
Older children willingly use tablets. Oral midazolam is useful prior to planned intravenous
sedation and general anaesthesia but does not give the prolonged depression of
consciousness (Baygin et al, 2010, Kazak et al, 2010, Kulikov et al, 2010)
2.5.2 Clonidine
Clonidine is a partial agonist of central and peripheral alfa-2 adrenoreceptors and is a
central imidazole receptor agonist. It also effects alfa-1 receptors (alfa1:alfa2 > 200:1). It is a
known antihypertensive agent but with its sedative and analgesic effects potentiates
volatile anaesthetic agents and decreases intraoperative requiments for propofol, although
recovery time may be prolonged. It has a synergistic analgesic effect with opioids
(Thompson, 2007). Oral clonidine premedication in dose of 4 – 5 mcg/kg has been shown to
reduce the incidence of sevoflurane induced emergence agitation. (Tazeroualti et al, 2007). It
also attenuates reflex sympathetic responses and may improve cardiovascular stability
during anaesthesia (Cao et al, 2011).
2.5.3 Dexmedetomidine
Dexmedetomidine, an imidazole compound, is the pharmacologically active dextroisomer
of medetomidyne and is the most selective central alfa-2 adenoreceptor agonist available
clinically. This agonist has eight times higher affinity for the alfa-2 adenoreceptor than
clonidine. It offers beneficial pharmacological properties, provides dose-dependent
sedation, analgesia, sympatholysis and anxiolysis without significant respiratory depression
(Goksu et al., 2008). Like clonidine, dexmedetomidine reduces occurrence of sevoflurane
emergence agitation in a dose of 2.5 mcg/kg (Ozcengis, 2011). Both agents also can be
administered intranasally for premedication in doses of 0.5-1 mcg/kg for dexmedetomidine
and 2-4 mcg/kg for clonidine(Yuen, 2008; Basker, 2009).
Clonidine and dexmedetomidine preoperatively have similar levels of anxiety and sedation
postoperatively as midazolam. However, children given alpha-2 agonists had less
perioperative sympathetic stimulation and less postoperative pain than those given
midazolam (Ali & El Ghoneimy, 2010, Al-Zaben, 2010, Dere et al, 2010, Schmidt, 2007).
3. Procedural sedation
Procedural sedation and analgesia (PSA) is intended to result in a depressed level of
consciousness that allows the patient to maintain oxygenation and airway control
independently. It is divided into two types: minimal sedation and conscious sedation.
3.1 Minimal sedation (anxiolysis)

Minimal sedation could be accurate and sufficient type of sedation for gastrointestinal
procedures performed in older children. They are able to respond to verbal stimulation
normally, but cognitive function and coordination may be impaired. What is most important
is that ventilatory and cardiovascular functions are unaffected.
3.2 Conscious sedation (moderate sedation)

This type of sedation is usually performed for smaller and for older children and the
depression of consciousness is drug-induced. Conscious sedation also commonly known as
“moderate sedation” means that patient retains the ability to respond to vocal and light
touch commands at any time during the sedation. Usually the circulatory system is not
disturbed. Additionally patients have to be able to breathe spontaneously and protect their
own airway. This last condition is extremely difficult to achieve in babies and smaller
children because of specific anatomy and unpredictable response to drugs. In this group of
patients intravenous administration of hypnotic drugs could provoke depression of
spontaneous breathing and result in the need for manual or automatic ventilation via facial
mask. This type of sedation could very often change from “moderate” to “deep” without
clear symptoms and therefore requires the presence and expertise of an experienced
pediatric anesthesiologist.
Some authors suggest that intravenous procedural sedation can be administered by the
endoscopist, who both administers the sedation drug and performs the procedure. Of
course this can only be done when qualified nurse helps the doctor monitor the patient’s
state of consciousness and vital signs. This method seems to be safe in the endoscopist’s
hands when restricted to ASA I and ASA II patients. Children relegated to ASA III and more
status should have anaesthesia performed by a pediatric anaesthesiologist even if only
minimal procedural sedation is planned (Hansen et al, 2003, Heuss et al, 2003, Lee et al,
2003). Other authors, highly experienced in paediatric anaesthesiology are opposed to idea
“sedationist-operator”. They claim the best and the safest method of sedation for children is
to have it performed by an anesthesiologist who is highly experienced and understands the
differences of paediatric population.
3.3 Drug regimens

Pharmacologic regimens that ensure safe, effective and efficient sedation for all paediatric
patients would be ideal but are not always achievable. Those used should act predictably
and rapidly and allow the anaesthesiologist to induce the desired level of sedation necessary
for the procedure being performed. After the procedure, the drugs should allow the child to
awaken quickly and they should not prolong the recovery time.
Various drugs are available to provide procedural sedation. Midazolam either alone or in
combination with an opioid analgesic is commonly selected for procedural sedation.
Combining use of a benzodiazepine and an opiate may be preferable for longer procedures
but increases the risk respiratory and circulatory depression. Specific reversal agents for
opioids (naloxone) and benzodiazepines (flumazenil) must be available during the
procedure.
3.3.1 Midazolam
The effect of midazolam as a short acting benzodiazepine (in children half-life 2.5-4 hours) is
controlled, reversible and produces light sedation, anxiolysis, and amnesia. Midazolam is
32 Colonoscopy
characterized by a relatively high volume of distribution (Vd) compared with other

benzodiazepines because of its lipophilicity. In obese patients the activity could be increased
from 2.7 hours to 8.4 hours. Midazolam is cleared by hepatic hydroxylation to 1-
hydroxymidazolam (which has about 10% of the pharmacologic activity as parent compound).
Age Administration route Comment

Intravenous Rectal Oral
Up to 6 month 0.04 – 0.1 mg/kg - - -
b.w.
6 month–5 year 0.05 – 0.1 mg/kg 0.35 – 0.45 0.5 mg/kg Total dose 6
mg/kg mg/kg/d
5 – 12 year 0.025 – 0.05 0.35 – 0.45 0.5 mg/kg Total dose 0.4
mg/kg mg/kg mg/kg/d;
max 10 mg/d
5 – 12 year 0.025 – 0.05 0.35 – 0.45 0.5 mg/kg Total dose 0.4
mg/kg mg/kg mg/kg/d;
max 10 mg/d
12 -18 year 2.5 mg 0.35 – 0.45 0.5 mg/kg i.v. bolus 1 mg;
mg/kg Total dose 10 mg
1 – 1.5 mg i.v. bolus 1 mg;
Total dose 3.5 mg
Table 5. Midazolam dosing for procedural sedation in children.
Intravenous administration is the best way in this group of patients but sometimes oral,
rectal and possibly nasal method might be equally as good for colonoscopy as well as other
procedures (Wood, 2011). The most important thing to consider is the route of the
administration of the drug to the child. Dosing of midazolam depends very strictly on the
age and body weight of patient.
Intravenous doses of midazolam should be titrated to effect, especially in neonates and
small babies, to achieve a desirable level of sedation and prevent inadvertent and deeper
sedation (Robinson, 2000).
3.3.2 Other benzodiazepines

Diazepam has an extremely long half-life (0.8-2.25 day) especially in neonates and babies
but also in obese patients (3.9 day and 3.29 day). Additionally, its active metabolites have
long half-lives (N–desmethyldiazepam, nordiazepam). Lorazepam is another
benzodiazepine that may be used for mild-to-moderate sedation; its limitation is onset of
action up to 15-20 minutes after administration. The duration of action of lorazepam is
longer (6-8 hours) than that of midazolam (30-60 min).
3.3.3 Other sedative drugs

In the literature there are also proposals for the use of other sedatives (e.g. etomidate,
propofol or ketamine) for procedural sedation. These drugs are registered as anaesthetic
drugs, not sedative, so according to the strict recommendations of the Food and Drug
Administration (FDA) and The Helsinki Declaration on Patient Safety in Anaesthesiology
2010 are not allowed for procedural “sedation”. (Mellin-Olsen et al, 2010)
Given the above specific conditions midazolam is the only single drug that can be used by
the non-anaesthesiologists for procedural sedation.
3.3.4 Analgesic opioids

Analgesic opioids (described in 4.1.4) should be added when more painful colonoscopy is
planned. Reducing the dose of opioids of about 50% is recommended because of the
accumulation of side effects, especially depression of spontaneous ventilation.
3.4 Indications and contraindications for procedural sedation in children

Children are sometimes a major challenge for doctors and nurses. On the other side is
necessary to understand their immaturity and lack of experience to accept fear, pain or
disconnection from parents.
3.4.1 Indications for conscious sedation in children

Indications in the paediatric population differ from those among adults. They could be
divided into two groups depending on the side of interest: patient and doctor.
Indication of the patient Indication of the doctor

Unexplained fear Babies and small children
Unaccepted discomfort Non-cooperative children
Claustrophobia Diagnostic and therapeutic procedures
Prolonged and repeated procedures associated with pain
Table 6. Indications for conscious sedation during colonoscopy in children
3.4.2 Contraindications for procedural sedation in children

Contraindications for procedural sedation, whether performed by an anaesthesiologist or by
non-anaesthesiologist are following:
• Congenital defects of respiratory system
• Acute respiratory insufficiency
• Persistent respiratory insufficiency
• Congenital Central Hypoventilation Syndrome (CCHS)
• Important circulatory insufficiency
• Neuromuscular diseases
• Impaired or loss of consciousness in the history
• Child too excitable, even after the earlier application sedatives
• Child with behavioral disorders
• Lack of agreement of child and/or parents and/or legal representatives
Additionally special conditions for performing conscious sedation should be met in the
following general situations:
• Neonates, particularly preterm birth neonates, especially with regard to individual
susceptibility to depressive influence of sedatives on respiratory depression
• Children below 1 year and 5 year, with regard to higher risk complications and adverse
events after overdosing of drugs and/or insufficient sedation
• Renal insufficiency
• Liver insufficiency
34 Colonoscopy
3.5 Complications of procedural sedation

Factors that increase the risk of complications during conscious sedation in children are: age
below 12 months and coexisting congenital and/or chronic diseases.
The most important adverse events after conscious sedation among children are:
• Loss of protective reflexes of the upper respiratory tract
• Closure and upper airway obstruction
• Allergic reaction
• Breathing disturbances
• Cardiac arrest
3.6 Equipment and supplies

The place use to perform colonoscopy under procedural sedation should be equipped with
an oxygen supply, a suction system, airway management equipment, resuscitation
medications and equipment, intravenous accesses equipment, cardiac monitor equipment
and a defibrillator.
Monitoring. All the time of performing procedure should be monitored ECG, pulse
oximeter, respiratory rate, systemic blood pressure and other clinical sign such skin color.
The state of unconsciousness should be regularly assessed from the beginning to the end of
sedation and this data be documented in the chart. In paediatric practice the most common
used scale is Ramsay sedation scale.
Score Response
1 Anxious or restless or both
2 Cooperative, orientated and tranquil
3 Responding to commands
4 Brisk response to stimulus
5 Sluggish response to stimulus
6 No response to stimulus
Table 7. Ramsay Sedation Scale
3.7 Recovery of the child after procedural sedation

Procedural sedation can be successfully performed for many interventional or diagnostic
colonoscopy procedures in children. It should be provided by well-trained and credentialed
professionals at all the times.
After successfully completing procedural sedation the child should breathe spontaneously,
have throat reflexes present, be able to cough, and to adequately maintain an airway.
Depending on the age of the child, child should sit and talk, and in this state may be given
to parents.
4. Deep sedation
Deep sedation is a very good alternative for painful colonoscopy. Depression of
consciousness is drug-induced but much deeper than in procedural sedation. The patient is
not easily arousable but can respond following repeated or painful stimulation.
Spontaneous ventilation may be inadequate and the patient may require assistance in
maintaining a patent airway. Independent ventilatory function is rather impaired while

cardiovascular hemostasis is usually properly maintained.
Deep sedation is indicated for possibly painful colonoscopies, therapeutic examinations and
those more invasive examinations, especially when it is essential to immobilize the patient.
The most discussed dilemma is how to provide deep sedation. The first method is based
rather on deeper sedation rather than analgesia and to limit adverse events by using high
doses of opioid analgesic. The second method involves analgesia even at the expense of less
hypnosis. The truth is that the compilation of sedative and analgesic agents varies slightly
when these agents are used in children, especially younger than 1 year, but much existing
data suggest more variability in choices when the child is older than 7 years (Patel et
al, 2009).
4.1 Drug regimens

Drugs should be administered intravenously. It is important to use small loading doses and
to titrate the dosage because of the narrow margin of their safety. For this reason they
should not be used by the non-anaesthesiologist according to the restrictions imposed by the
FDA and The Helsinki Declaration on Patient Safety. If they are, the provider should be
skilled in airway management and resuscitation, and usage should depend upon regional
statutes. The most important anaesthetic for this type of procedure such colonoscopy is
propofol.
4.1.1 Propofol
Propofol (alkyl phenol) is a short-acting anaesthetic characterized by both rapid onset of
action (within one arm-brain circulation time) and short recovery time. Propofol causes
dose-dependent cortical depression within 30 seconds from the beginning of administration,
mostly without epileptiform activity, although larger doses could provoke excitatory
movements (Eer et al, 2009). The incidence of excitation, cough and hiccup are similar to
those of thiopental. In contrast to barbiturates, propofol attenuates laryngeal reflexes,
facilitating laryngeal mask insertion or intubation. By the way of decreased responsiveness
to CO2, propofol is respiratory depressant, especially when used in conjunction with opioid
analgesics (when more than 50-70% of children will need ventilatory support). Its influence
on the vascular system and heart is variable but often there is a mild cardiodepressant effect.
Propofol is metabolized by the pathway of glucuronidation in the liver and removed by the
kidney (88%) and the digestive system (2%).
Te newest lipid formulations of this agent limit the pain sometimes experienced during
intravenous administration making propofol closed to the “ideal drug” for paediatric
sedation.
One important difference from other intravenous and inhaled anaesthetics is its antiemetic
effect, a desired effect in gastroenterological group of patients (Leon et al, 2011).
Effective deep sedation could be achieved by a single dose method as well as continuous
infusion with recovery time independent to the duration of sedation (10-20 minutes after
discontinuation).
The disadvantage of propofol is its narrow therapeutic range (high rates of hypoxia and
hypotension) and risk of inadvertent general anesthesia and that is the reason why it should
be routinely administered by anesthesiologists. Only this strategy allow to properly control
of the level of sedation and reduced recovery time (Lightdale, 2004).
36 Colonoscopy
The usual standard dose of propofol used for sedation for older children is 0,5-1,5 mg/kg
while children younger than 8 years should be sedated with higher doses e.g. 1,5 – 3,0
mg/kg. The best effect is achieved when continuous infusion is planned, of course keeping
in mind age differences in dosing.
4.1.2 Other anaesthetic drugs

The choice of anaesthetic drug is in the hands of anaesthesiologist based on the status of
patient and predictive duration of and type of colonoscopy.
4.1.2.1 Benzodiazepines
Benzodiazepines are highly lipid-soluble agents and can cross the blood-brain barrier
readily. When used intravenously the onset of their effect usually takes longer than one
arm-brain circulation time. Depending on their lipophilicity they have long a long
persistence. These characteristics limit the usage of this group of drugs for deep sedation.
4.1.2.2 Barbiturates
Sodium thiopental is the most commonly used thiobarbiturate that induces anaesthesia
rapidly within one arm-brain circulation and maintain longer than propofol. Its main
limitation is its cardiodepressant effect with decreased cardiac output and blood pressure.
Respiratory depression as a result of reduced CO2 response is deteriorated by laryngeal
spasm and bronchoconstriction. The other limitation is its prolonged half-life depending on
the total dosage which influences recovery time.
4.1.2.3 Ketamine
Ketamine is a derivative of phencyclidine and cyclohexamine and as a non-competitive
antagonist of the NMDA receptors it is responsible for dissociative anaesthesia and
analgesia. This last advantage allows one to not have to use opioids and in thus decreases
the risk of respiratory depression while maintaining analgesia.
Ketamine is slow-onset anaesthetic with an effect within 1 minute after intravenous
administration and a duration of action much longer than other newer agents. In addition
the dissociative influence of this agent on the brain possibly bringing about hallucinations,
diplopia, and temporary blindness limits its usefulness in short procedures (less than 1
hour) such as colonoscopy even these symptoms are not that prevalent among children
(Gilger et al., 2004)
4.1.2.4 Etomidate
Etomidate is an imidazole characterized by rapid induction with one arm-brain circulation
time and simultaneously long duration of action. In children the main contraindication of
this agent is excitatory phenomenon, epileptic activity, respiratory depression, a relatively
higher risk of emesis and commonly, pain at the injection site (Evered, 2003).
4.1.3 Inhaled anesthetic

Sevoflurane halogenated ether has been available for clinical use since 1990. This volatile
anaesthetic agent remains popular both for induction and maintenance of anaesthesia and
sedation. It has low blood/gas and oil/gas solubility. This produces a more rapid response
to changes in inhaled concentration, and speedier induction and recovery. Intracranial
pressure is increased but minimally at less than 1 MAC (minimal alveolar concentration).
Sevoflurane produces anaesthesia and sedation without analgesia and epileptogenic spikes,
decreases arterial pressure by reducing systemic vascular resistance with little effect on
cardiac output until higher doses are used, and it lowers the heart rate and therefore helps
to reduce myocardial oxygen consumption. This agent reduces tidal volume, respiratory
rate and smooth muscle tone of the bronchi, and it is not irritant to the upper respiratory
tract. Most sevoflurane is eliminated via the lungs, with 5% of the absorbed dose being
metabolized by the liver. It can have toxic effect on the kidneys, liver and brain (Mushambi
& Smith, 2007, Smith, 2008). The use of sevoflurane in paediatric patients which would
enable rapid recovery is complicated by the frequent occurrence of emergence agitation,
particularly with high concentration over 6 vol% with spontaneous breathing and over 5
vol% when ventilated mechanically (Ganzberg et al, 1999, Khattab, 2010)
4.1.4 Opiods
The following opioids (remifentanil, alfentanil and fentanil) are commonly used for
induction and the maintenance of anaesthesia for endoscopic procedures (Colvin, 2007).
Morphine is used additionally to maintain analgesia in the postoperative period.
4.1.4.1 Remifentanil
Remifentanil hydrochloride is a mu-receptor opioid agonist and is currently the shortest-
acting opioid. The onset and peak effect is rapid and the duration of action is short (5 – 10
minutes). Therefore for longer action remifentanil should be administered continuously.
There is a lack of drug accumulation even after prolonged infusions.
Remifentanil is indicated for intravenous administration during induction of anaesthesia
with the infusion rate of 0.5 to 1 mcg/kg/min together with an intravenous or volatile
agent. During the maintenance of anaesthesia the infusion rate may vary in accordance with
the dosing guidelines. For paediatric patients aged 1 to 12 years continuous infusion of 0.25
mcg/kg/min (infusion dose range 0.05 – 1.3 mcg/kg/min) with sevoflurane (0.3 – 1.5 MAC)
or isoflurane (0.4 – 1.5 MAC) is recommended.
Nonspecific blood and tissue esterase metabolizes remifentanil rapidly by hydrolysis.
Pseudocholinesterase plays no special role so if atypical plasma cholinesterase is present
remifentanil’s duration of action remains normal. The effects and side effects are dose
dependent. After administration over 60 seconds a rapid and slower distribution half-life
are 1 and 6 minutes respectively. A terminal elimination half-life lasts 10 - 20 minutes. Renal
and liver insufficiencies do not affect remifentanil’s pharmacokinetics (Toklu et al, 2009).
Side effects, mostly dose-dependent are hypotension and bradycardia, respiratory
depression, and skeletal muscle rigidity (including chest wall rigidity).
4.1.4.2 Alfentanil hydrochloride
Alfentanil hydrochloride is a an OP3 mu-opioid agonist which is ultra-short-acting (5 - 10
minutes). The onset of action is immediate (1 - 2 minutes). Administrated at doses of 8 - 40
mcg/kg it is excellent for procedures lasting up to 30 minutes e.g. colonoscopy. The
recovery time is comparable to that observed with equipotent fentanil dosages. For children
under 12 years of age it is not recommended.
Intravenous administration of a dose of 5 mcg/kg provides analgesia for the conscious but
sedated patient; doses of 105 mcg/kg produce hypnosis; and induction of anesthesia
requires doses 50-150 mcg/kg. Induction with alfentanil should be administered slowly
(over 3 minutes) due to the danger of loss of vascular tone and hypotension. Fluid
replacement prior to induction with this agent is important. Maintenance of anaesthesia (if
38 Colonoscopy
the procedure lasts up to 60 minutes) is carried out with a dose of 50 mcg/kg, but
alternatively, continuous infusion 0.5 – 3 mcg/kg/min is acceptable. The infusion should be
discontinued at least 10-15 minutes prior to the end of the procedure. In obese patients the
dose of alfentanil should be determined on the basis of lean body weight.
After administration a rapid and slower distribution half-life are 1 and 14 minutes
respectively. Terminal elimination half-life lasts 90 - 111 minutes. The volume of distribution
is 0.4-1 L/kg, which is 4 – 10 times smaller than those for fentanil. The liver is responsible
for major biotransformation. Metabolites are eliminated mostly by urinary excretion.
The important side effects consists of hypotension, secondary to vasodilation and
bradycardia, respiratory depression, skeletal muscle rigidity (dose and speed dependent).
4.1.4.3 Fentanil
Fentanil is a strong mu-opioid agonist with a rapid onset (2 – 3 minutes) and short duration of
action (20 – 60 minutes). Fentanil is 100 times more potent than morphine (100 mcg of fentanil
approximately equals 10 mg of morphine). Because of its high lipophilicity it penetrates easily
to the central nervous system causing the rapid onset of action. Due to its high lipophilicity
there is a danger of possible redistribution of fentanil. Hemodynamics are stable after
administration of fentanil, which makes this drug useful in cardiovascular diseases.
Fentanil could be administered orally, subcutaneously, or intravenously. For induction of
anaesthesia doses of 0.5 – 1 mcg/kg (up to 5 mcg/kg) together with a intravenous or volatile
agent are recommended and during maintenance of anaesthesia 1 – 4 mcg/kg according to a
need.
The drug’s large volume of distribution (3.5 – 5.9 L/kg) is responsible for relatively long
half-life. The elimination half-life vary from 3.1 – 7.9 hours. There is a danger of possible
redistribution of fentanil due to its lipophilicity (biphasic depression of ventilation). The
liver is responsible for its metabolism. Side effects are as follows: respiratory depression,
skeletal muscle rigidity (particularly if large doses are administered rapidly), and
stimulation of parasympathetic system.
4.1.4.4. Morphine sulfate
Morphine sulfate is an important alkaloid of opium, a pure opioid agonist. It is mu-opioid
agonist but at higher doses interacts with other opioid receptors. The onset of action after
intravenous administration is 5 – 10 minutes, the duration of action 2 – 4 hours. The lipid
solubility and degree of ionization are crucial in the onset and duration of analgesia as well
as the effects of the central nervous system. The additional hydroxyl group on the molecule
of morphine (pH 7.4) makes the molecule of morphine water soluble, more than other
clinically used opioids. The most therapeutic action of morphine is analgesia but there are
some others like euphoria and anxiolysis.
Administration intravenously requires average doses of 0.1 mg/kg and continuous infusion
20-25 mcg/kg/h, while intramusculary or subcutaneously doses of 0.15-0.2 mg/kg should
be sufficient.
After intravenous administration the volume of distribution ranges from 1.0 to 4.7 L/kg.
The terminal half-life vary from 1.5 – 4.5 hours. Morphine is metabolized to morphine
glucuronide in the liver and eliminated by the kidneys.
Side effects are more extensive than others and include drowsiness, respiratory depression,
peripheral vasodilation, decreased gastrointestinal motility, decreased biliary and pancreatic
secretion, nausea, vomiting, alterations in the endocrine and autonomic nervous system,
and release of histamine.
Analgesic opioid Route of administration Dosing

Morphine i.v. 0.05-0.2 mg/kg b.w.
Fentanil i.v. 0.5-1 mcg/kg b.w.
Alfentanil i.v. 5-20 mcg/kg b.w.
Remifentanil i.v. 0.25-1 mcg/kg b.w.
Table 8. Dosing of analgesic opioids during deep sedation in children
4.2 Advances in patient monitoring during deep sedation

Monitoring during colonoscopy in the paediatric population under deep sedation is
essential for safety and effectiveness. The issue is controlling effects on the cardiovascular,
respiratory and neurological systems particularly in younger children. Recent technologic
advances include electronic vital-sign monitoring systems which should be useful to
maintain physiologic condition in the perioperative time period. The most recent method is
the proposal of advanced capnography as a method of providing early warning for
preventing postoperative respiratory depression (American Society of Anesthesiologists,
1996, Hutchinson & Rodriguez, 2008). Only hospital and/or specially equipped endoscopy
facilities are appropriate setting for colonoscopy under deep sedation among infants, babies
and children.
5. General anesthesia
Colonoscopy under general anaesthesia in children allows endoscopist comfortably prepare
the patient and perform painless procedure. These aspects are important because of the
technical advantages during invasive colonoscopy and higher patient’s satisfaction even the
presence of reported symptoms.
The frequency of the episodes of perforation or bleeding is not described (Steiner et al, 2006).
Similarly postprocedural pain is significantly lower after colonoscopy under general
anesthesia probably because of mild and controlled insufflation resulted in lower gas excess
and abdominal pain.
Complications connected with general anaesthesia are sometimes arguing by the
oppositionists. They emphasize most often sore throat and hoarseness (after endotracheal
intubation), postoperative nausea and vomiting (mainly after inhaled anesthetics) and rarely
irritability and sleep disturbances. The serious adverse events such as respiratory
complications and cardiodepressant effects are statistically comparable to others typical for
paediatric anaesthesia (Samer Ammar et al, 2003, Stringer et al, 1999).
General anaesthesia is defined as reversible, controlled and temporary loss of consciousness,
painless and/or muscle relaxation (anaesthesia & analgesia & muscle relaxation). It needs
the usage of up to date anaesthesia machine and monitoring apparatus what increases
indeed the cost of the colonoscopy and forces to organize the relevant endoscopy room.
5.1 Induction
General anaesthesia is induced by using one of the following techniques: inhalational or
intravenous. Drugs used belong to the three classes according to the tenets of general
anaesthesia: anaesthetics, analgesic opioids and muscle relaxants (the latter more for
endotracheal intubation than colonoscopic technique).
40 Colonoscopy
5.1.1 Inhalational induction

The most common indication for inhalational induction of anaesthesia are following:
• young children
• no accessible veins
• fear of needles by the child
• upper airway obstructions e.g. epiglottis, asthma
• a predictably difficult endotracheal intubation
• acceptance of the use of a child's face mask
Contraindications include in fear of the child regarding the use of a face mask, a higher risk
of aspiration of gastric content and the risk of malignant hyperthermia.
There are three main techniques of induction with inhaled anesthetics:
• single-breathe technique – for cooperative and older children
• normal breathing volumes – for children of all ages, especially infants and babies
• increasing doses of inhaled gases - for children of all ages
After consciousness is lost it is possible to introduce access into a peripheral vein and
continue fluid and drug administration in this way. At the same time depending on the
extent of colonoscopy and the child’s ASA physical state is necessary to consider insertion of
oropharyngeal airway, laryngeal mask airway or endotracheal tube. Laryngeal mask airway
become a major advance in anesthetic airway management, particularly when children
breathe spontaneously during colonoscopy. This method limits the adverse events that
accompany endotracheal intubation.
The most important inhaled anaesthetic in paediatric anaesthesia is sevoflurane (described
in 4.1.3).
5.1.2 Intravenous induction

Intravenously inducted anaesthesia is preferable for most routine procedures, including
colonoscopy because of a less complicated technique used when applying inhaled
anesthetics. Additionally it is very useful for rapid induction in patients with a higher risk
of regurgitation of gastric contents. Many authors report higher comfort and tolerance for
patients. After insertion of a cannula into the peripheral vein administration of the required
drugs is started. In children cannulation is a painful procedure and local anaesthetics should
be used on suitable veins in both forearms (EMLA [Eutectic Mixture of Local Anesthetic],
50% lidocaine and 50% prilocaine).
Currently the most commonly used intravenous hypnotic for colonoscopy is propofol
(described in 4.1.1). Its disadvantage e.g. narrow therapeutic range and risk of hypoxia and
hypotension applies to general anaesthesia as well as deep sedation.
5.2 Maintenance of anaesthesia

For complicated and prolonged colonoscopies in children the preferred method of
maintenance could be Total Intravenous Anaesthesia (TIVA) conducted with a special
infusion pump. After the loading dose continuous infusion is done. The profile of propofol
allows the patient to recover quickly irrespectively of the time of anaesthesia (stop the
infusion 10 minutes before the end of colonoscopy).
In the other cases the maintenance of anaesthesia can be combined with inhalation of
oxygen, air, nitrous oxide, sevoflurane or isoflurane, depending on the available choices. For
colonoscopy in children appropriate level of maintenance of anaesthesia could be achieved
by the method of inhalational anaesthesia with spontaneous ventilation.
Other than the above described intravenous and inhaled anaesthetics there may be some
additional agents which have a role in providing general anaesthesia, decision to use them
belonging to the anaesthesiologist.
5.3 Recovery
After the completion of colonoscopy anaesthetic drugs should be withdrawn and 100%
oxygen delivered. Removal of the endotracheal tube or laryngeal mask airway should be
done when respiratory reflexes are fully returned. This maneuver is challenging in small
children up to 4 year because half of them following laryngeal spasm. After the patient is
ready he should be transported into the recovery area.
5.4 Drug regimens

Anaesthetic drugs (intravenous and inhaled) have to be combined with strong and short
acting analgesic opioids. The introduction of these newer less-toxic, shorter-acting
anaesthetic drugs has reduced the requirement for muscle relaxants not only for diagnostic
procedures like colonoscopy but also for general surgery in the paediatric population.
Moderate anaesthesia conducted with combination of sevoflurane–remifentanil or propofol–
remifentanil can keep children immobile without producing hypotension and facilitate
controlled ventilation once the effects of the intubating dose of a muscle relaxant have worn
off (Meakin, 2007, Liao et al, 2010).
Neuromuscular blocking agents could be selected only for those indications like difficult
airway, higher risk of gastric regurgitation, obesity, and difficulties with patient’s position.
The usage of these agents is limited by prolong muscle blocking and risk of postprocedural
respiratory depression. Thus, only relatively short acting nondepolarizing blocking agents
such mivacurium and rocuronium are recommended for colonoscopy in children
(Eikermann, 2001).
Mivacurium produces onset of maximum block in 1–2 min and 25% recovery in 9–10 min. This
type of action is faster and longer during anesthesia with sevoflurane than with propofol.
Rocuronium retains the characteristics of an intermediate-duration relaxant in the younger
age group of children, longer in infants than in children (42 vs. 27 min).
The introduction of the newest selective relaxant binding agent (SRBA) – sugammadex
(Bridion) - has been an important development in the last few years because of its ability to
provide a rapid reversal from any depth of neuromuscular blockade. Sugammadex is a
modified gamma-cyclodextrin, chemically water-soluble cyclic oligosaccharides with a
lipophilic core, which encapsulates and inactivates rocuronium or vecuronium (Bom, 2007).
Rapid reversal with this agent occurs respectively after less than 4 minutes from deep
neuromuscular blockade (dose 4 mg/kg) and less than 3 minutes from moderate
neuromuscular blockade (dose 2 mg/kg). Any effect on the cholinergic nervous system has
not been observed. Currently there are no recommendations to use sugammadex in full-
term neonates or young infants even though there have been good results off-label but for
older children it is the most desirable (Meretoja, 2010).
6. Conclusion
Recently fiberoptic colonoscopy has become more useful and advanced method for treating
a large number of large-bowel disorders in the paediatric population. All reports have
42 Colonoscopy
shown that this procedure can be a safe and useful tool in children of all age groups only if it
is based on good practice standards and experienced management, provided by both:
paediatric gastroenterologists and paediatric anaesthesiologists. The most important trend
among paediatric gastroenterologists is acceptance of the anaesthesiologist’s performance of
intravenous sedation and/or general anaesthesia based on differences between children and
adults as were presented in this chapter. The choice of sedation or general anaesthesia for
those paediatric gastrointestinal procedures is in the hands of anaesthesiologists who are the
most experienced in this area. Only this pattern of conduct may provide not only optimal
routine sedation or anaesthesia but the most standardized and the safest care for all age
groups of children.
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3
Quality of Screening Colonoscopy: Learning

Technical Skills and Evaluating Competence
Marco Bustamante
Department of Gastroenterology
Dr. Peset University Hospital, Valencia
Spain
1. Introduction
Colonoscopy is an essential part of colorectal cancer (CRC) screening programs since it can
diagnose CRC as well as identify and excise precursor lesions before the carcinoma fully
develops (Winawer et al., 1993). Although colonoscopy has shown to be effective in
decreasing the incidence and mortality of CRC (Kahi et al., 2009), it does not provide total
protection against cancer since, in daily practice, a clinically significant number of CRCs and
adenomas still go undetected. For example, the proportion of undiagnosed CRC in patients
having previously undergone colonoscopy ranges from 2.1%, when the cancer is located in
the left colon and the splenic angle, to 5.9% when located in the right colon (Bressler et al.,
2007). The proportion of undetected adenomas ranges from 2% for polyps ≥10 mm to 26%
for polyps of between 1 and 5 mm (van Rijn, 2006). Consequently, an incidence of interval
cancers has been described which ranges from 1.7 to 2.4/1000 person-years of follow-up in
patients included in a control program following the excision of one or more adenomas
(Pabby et al., 2005).
One of the factors which seem to have the most bearing on the number of lesions diagnosed
by colonoscopy is the endoscopist him/herself. A difference of up to 20% has been
described in the proportion of colonoscopies with at least one adenoma (Chen & Rex, 2007)
and of up to 9 times in the proportion of patients with advanced adenomas (Barclay et al.,
2006). Other studies confirm these results and suggest that some endoscopists could leave
up to half of the adenomas undiagnosed (Rex, 2006b). A number of technical aspects could
be responsible for these differences, in particular the ability to reach the cecum and the
withdrawal technique (longer explorations, better examination of the proximal mucosa in
folds and angles, better management of colon distension and better cleaning of the remains
and fluids in the colon) (Rex, 2000).
Screening colonoscopy is a special situation which involves an invasive exploration of an
asymptomatic subject with the theoretical promise of detecting CRC before it produces
symptoms, or of reducing the individual risk of suffering CRC by detecting and excising
colorectal adenomas. In this context, where the detection of lesions is crucial, it appears to be
essential to have endoscopists with the necessary technical skills. A study carried out
recently in the setting of a CRC screening program based on the detection of fecal occult
blood showed that the endoscopist was an independent predictive factor in the detection of
48 Colonoscopy
adenomas (Bretagne et al., 2010). In fact, the rate of adenoma detection per endoscopist is
the factor most associated with the risk of interval cancer (Karniski et al., 2010).
In conclusion, for a CRC screening program to be truly effective, it must be based on high-
quality colonoscopies in such a way that the protective effect against CRC of this procedure
approaches the theoretical maximum possible. For these programs it would therefore
appear logical to have endoscopists who are experts in colonoscopy in order to reduce to a
minimum the degree of variability in the detection of lesions attributable to the examiner.
However, at the present time, with screening programs still in their infancy, the basic
characteristics of Endoscopy Departments and of those endoscopists who will be in charge
of such programs have yet to be defined. The training of endoscopists to carry out screening
colonoscopies and their evaluation in terms of seeking possible accreditation have not yet
been regulated either. In this review, we will go over the current situation of the training in
colonoscopy for gastroenterology specialists, the possibility of evaluating their skills and we
will make some recommendations for the future.
2. Quality parameters in screening colonoscopies

Over the past few years, much attention has been given to the definition of auditable
parameters to measure the quality of colonoscopies. Systematic monitoring of certain
variables allows for the quality of colonoscopies to be controlled and may be used as a tool
for improvement (Lin et al., 2010; Barclay et al., 2008). This review does not intend to make a
comprehensive review of the parameters used to measure the quality of colonoscopy, for
which there are very recent guides and revisions, including the clinical practice guidelines
on the quality of screening colonoscopies produced by the Spanish Association of
Gastroenterology (Jover, J. ed., 2011). (Table 1).
However, it is worth commenting on the adenoma detection rate (ADR), the variable which
has become the most important, since it is directly related to the preventive capacity of
colonoscopies in terms of CRC. This rate is equal to the proportion of patients undergoing
colonoscopy in which at least one adenoma has been detected. The ADR is associated with a
better technique for carrying out the colonoscopy, for example, a thorough exploration of
folds and angles, adequate management of distension-aspiration, control of the remains of
filth and the time dedicated to the exploration (Rex, 2006b). Since it is necessary to wait for
the pathology result in order to measure this parameter, other authors have suggested using
the number of polypectomies as an auditable parameter, which is associated with the above,
but which is more directly measurable (Williams et al., 2011). Other frequently used quality
parameters are associated with the ADR. Several studies have shown that the time of
withdrawal is associated with the frequency of polyp detection (Barclay et al., 2006; Rex
2000; Imperiale et al., 2009). A recent study found a significant association between the
proportion of adenoma detection and the “cecal intubation time/withdrawal time” ratio < 1
for those endoscopists with higher detection rates (Benson et al., 2010). Almost all
recommendations consider a minimum withdrawal time of 6 minutes for a normal
colonoscopy as the threshold for a quality endoscopy (Rex et al., 2006b). The proportion of
colonoscopies in which the cecum is reached is also associated with the ADR, and is a
parameter which must be controlled, since in several studies, most interval CRCs were
diagnosed in proximal parts of the colon (Pabby et al., 2005; Singh et al., 2006). For example,
the American Society for Gastrointestinal endoscopy (ASGE)/American College of
Gastroenterology (ACG) Task Force on quality in endoscopy recommends that effective
Quality of Screening Colonoscopy: Learning Technical Skills and Evaluating Competence 49
colonoscopists must be able to intubate the cecum in ≥ 90% of cases, and in ≥ 95%, when the
indication for the colonoscopy is screening (Rex et al., 2006b). Other parameters may be the
endoscopic resection of polyps and the control in collecting complications (Rex et al., 2006b;
Romagnuolo et al., 2008; Gonzalez-Huix et al., 2010).
Indicator Advisable level

Adenoma detection rate > 20% (colonoscopy as a primary screening strategy)
> 40% (colonoscopy as a secondary screening
strategy, following a positive FOBT)
Colonoscope withdrawal time > 6 minutes
Number of colonoscopies without 400 before entering the screening program
supervision 200 anually
Cecal intubation rate > 95% colonoscopies
Use of sedation > 90% colonoscopies
Perforation rate < 1/1000 colonoscopies
Post-polypectomy bleeding rate < 1/200 polypectomies
Accurate description of polyp 100%
characteristics
Endoscopic excision of > 95%
pedunculated and sessile/flat
polyps up to 2 cm of diameter
Polyp retrieval rate > 95% for polyps > 10 mm
> 80% for polyps < 10 mm
Table 1. Screening colonoscopy quality indicators
However, the evaluation of these parameters may not be sufficient to increase the frequency
of adenoma detection (Sawhney et al., 2008). For example, a recent study found an inverse
relationship between the total duration of the exploration and the ADR. Furthermore,
control of the ADR by feeding back the results to the endoscopists did not improve the ADR
(Shaukat et al., 2009). This is probably due to the fact that there are other technical aspects
relating to the withdrawal exploration which are essential in order to increase the lesion
detection rate but which are more difficult to evaluate quantitatively. This happens, for
example, with the thorough examination of the colon mucosa, especially the angles and the
proximal parts of the folds, the aspiration of the liquid content and the exploration with
different degrees of insufflation. In a center where a protocol for exploration on withdrawal
was applied, which, in addition to time, included these technical aspects, a 10% increase in
the total number of neoplasms detected was achieved, as well as a 15% increase in the
number of lesions under 10 mm (Barclay et al., 2008).
Therefore, a quality colonoscopy is characterized by the combination of certain measureable
parameters, as well as others which, even though they are not measurable, are essential in
screening colonoscopies. These technical aspects may be responsible for the differences
found between endoscopists in the frequency of lesion detection, in such a way that it seems
to be of the utmost importance to ensure adequate teaching of these technical skills for all
endoscopists, and especially for those who are going to be in charge of a CRC screening
program. Collection and measurement of these parameters must also be the basis for control
and evaluation of the endoscopist competence.
50 Colonoscopy
3. Current situation of learning in colonoscopy: acquisition and evaluation of

competence
Competence in a procedure is the minimum level of skills, knowledge and/or expertise
acquired through training and practice which is required to safely and effectively carry out a
task or procedure without any help or supervision (Faigel et al., 2006). Applied to
colonoscopy, competence entails the ability to confidently carry out the exploration,
interpret the findings, apply the necessary treatments and manage the complications that
may arise.
Clearly, the first step towards achieving competence is adequate training during the
residency period in the specialty of Gastroenterology. However, specialty training programs
are greatly undefined and variable, and they are mostly based on general recommendations
by Scientific Societies and opinions from experts. For example, the training period necessary
to acquire competence has not been clearly defined. In general terms, it appears that the
training period should be no shorter than 6-12 months (Conjoint Committee for the
recognition of training in Gastrointestinal Endoscopy, n.d.). In Spain, a minimum period of 6
months is recommended for basic endoscopy, with an additional 3 months for advanced
endoscopy (Consejo Nacional de Especialidades Médicas, 2009), but training periods vary
greatly from country to country. Generally speaking, there is no structured procedure for
teaching during the residency program either, which would allow all areas of learning to be
managed and for their results to be assessed. Furthermore, trainers in endoscopy are usually
not trained in teaching techniques. In practice, training of endoscopists during the residency
is done in a barely regulated manner, integrating teaching into the normal activities of
attendance in Endoscopy Departments, and by trainers who are not specifically trained to
that effect. All of this may influence the quality of the training and may be responsible for
the poor quality perceived by residents in their learning in endoscopy (Wells et al., 2009).
Traditionally, two supplementary learning methods have been proposed to improve the
results of standard teaching during the residency: short courses and simulators. Short
courses, usually lasting two to three days, are not considered to be enough to acquire the
technical skills or judgment necessary to carry out the colonoscopy, since their short
duration does not allow for adequate training (Romagnuolo, 2008). In a short course, 10
supervised colonoscopies can be done at most, a long way from the Societies’
recommendations and, of course, far short of the minimal number of colonoscopies required
to achieve competence. The ASGE recommends that short courses be considered as training
opportunities or tools for continued education but never as substitutes for a formal training
program of adequate duration (ASGE Taskforce on ensuring competence in endoscopy,
n.d.).
Simulators are computer-based devices which offer different degrees of difficulty, with a
sense of touch through a simulated endoscope and the ability to administer sedation as well
as incorporating systems which simulate pain and discomfort in the virtual patient.
Moreover, data associated with the procedure, such as duration, the ability to visualize the
mucosa and the ability to complete the procedure is collected. The aspect in which they have
been evaluated the most is the resident’s learning, with the aim of shortening the learning
curve and reducing the patient’s discomfort when examined by an inexperienced examiner.
In general terms, it appears that the greatest benefit is obtained in the early stages of
learning, in such a way that experienced endoscopists hardly obtain any benefit (Sedlack &
Kolars, 2002). Moreover, it would appear that even for inexperienced endoscopists, the
learning curve flattens after only 7 simulated explorations (Eversbusch & Grantcharov,
2004). A randomized study compared the skills of two groups of residents, one which had
received simulator training and the other which had not, before starting the traditional
training program. This study showed that if the use of the simulator was extended to 10
sessions in the residents in the first group, a benefit in competence parameters was seen,
which was maintained until real exploration number 80 (Cohen et al., 2006). However, this
device does not seem to be of any use to endoscopists who have already completed the
standard period of practical training. In fact, this type of device is able to distinguish
between the user’s technical capacity and differentiate expert endoscopists from novice ones
(Grantcharov et al., 2005; Koch et al., 2008). In one study, for expert endoscopists, the
learning curve in the device was only two simulated explorations (Eversbusch, 2004).
Residents do, however, perceive this device as being effective as a supplementary learning
system (Lightdale, 2010).
As regards the evaluation of competence, until now, the most usual way has been a
subjective assessment whereby at the end of the residency period the trainer states that the
resident can carry out colonoscopies autonomously. A more objective attempt at evaluation
is the measurement of parameters which support the fact that the individual is competent to
carry out the exploration. The one which has been studied the most, perhaps because it is
the easiest to measure is the minimum number of colonoscopies performed, but this also
involves great variability. In the United States, the ASGE recommends carrying out a
minimum of 140 colonoscopies during the training period, with at least 20 polypectomies.
However, the program for the specialty of surgery is different with only a minimum of 50
explorations being required (Accreditaton Council for Graduate Medical Education, 2006).
The Canadian and Australian Societies of Gastroenterology require 100 complete, totally
unassisted explorations up to the cecum to have been carried out (Romagnuolo, 2006;
Conjoint Committee for the recognition of training in Gastrointestinal Endoscopy, n.d.). In
Spain, the minimum number of colonoscopies which must be carried out is 150 (Consejo
Nacional de Especialidades Médicas, 2009). However, carrying out a specific number of
colonoscopies does not guarantee competence in this exploration since learning varies
greatly from individual to individual. In a recent study, it was determined that the number
of colonoscopies necessary to reach the cecum in 90% of explorations was 150, and 200 in
95% (Lee et al., 2008). However, another study suggested a threshold of 500 colonoscopies
for all residents to have autonomy of ≥ 90% to carry out colonoscopies (Spier et al., 2010).
The first resident to become autonomous did so after carrying out 330 colonoscopies. It
would therefore appear that linking the evaluation of competence to having carried out a
specific number of explorations is not an adequate system. This was demonstrated by Cass
et al., who designed an evaluation system with key points which should be learned in order
to carry out a colonoscopy, which included, for example correct identification of any
anomalies found in the exploration (Cass et al., 1993). Adequate competence in these
variables was not reached with the minimum number of colonoscopies recommended by
the experts (Cass et al., 1996). Another finding of this study was that the subjective
assessment overestimated the resident’s competence compared to objective assessments.
Moreover, nowadays competence assessment cannot focus solely on variables related to
diagnostic colonoscopy, such as the number of procedures carried out or the percentage that
reached the cecum. These days a student cannot be considered competent if he/she is not
capable of carrying out the endoscopic treatment of the lesions found.
52 Colonoscopy
Finally, in addition to the basic training, continued practice is necessary to maintain

competence. The secondary results of a Canadian study showed that endoscopists who
carried out less than 240 colonoscopies per year had significantly more incomplete
colonoscopies than those who carried out 370 per year (Shah et al., 2007). A similar study in
the U.S. showed that endoscopists who carried out less than 100 colonoscopies per year had
a significantly lower proportion of complete colonoscopies (Wexner et al., 2001).
In conclusion, there are still no standardized or universally accepted methods to achieve and
evaluate competence when autonomously carrying out colonoscopies. Carrying out a
certain number of explorations does not guarantee competence, and specific tools must be
developed to assess cognitive aspects and competence skills.
4. Towards a new teaching system: structured learning and training the

trainers
Colonoscopy is a complex procedure at the psychomotor level which also requires a solid
knowledge base allowing for clinical and therapeutic decisions to be made. Traditionally,
however, the learning of endoscopy has been based on passing from watching explorations
to carrying them out outside the context of an organized teaching system which ensures that
learning is carried out correctly. This procedure has several limitations which affect the
quality of the learning, such as the ever greater work load of endoscopy departments which
reduces the time assigned to each exploration, the reduction of the residents’ overall
working hours, who thus have less time to dedicate to practicing colonoscopy, and the fact
that every person learns in a different way and at a different pace. An alternative teaching
system which allows these difficulties to be overcome is therefore necessary. In this system,
the responsibility for learning would no longer lie on the student but would focus on the
trainer, who must follow a structured teaching system based on communication and
feedback with the student, and who must also be responsible of evaluating the student in
each of the phases.
4.1 The teaching process. The role of trainers and endoscopy departments
The trainer must have broad technical knowledge and experience in diagnostic and
therapeutic colonoscopy, and must be able to finalize a procedure when the student fails. This,
however, is not enough. He/she must know what the resident needs to learn, know the basic
concepts of the learning process and apply teaching techniques which ensure the resident’s
training. The learning of colonoscopy includes three areas: i) cognitive skills which include the
indications and contraindications of the test, the identification and classification of lesions and
clinical decision-making based on the findings; ii) technical skills, which include methods for
advancing the endoscope and handling the loops that are formed, the ability to carry out the
test adequately and in a reasonable time, as well as the ability to apply endoscopic treatments,
and iii) procedure-related skills, such as information to the patient, informed consent, risk
assessment, the safe administration of sedation-analgesia and the drafting of an adequate
report of the exploration (Raman & Donnon, 2008).
The colonoscopy teaching process should go through three phases: acquisition of theoretical
knowledge, observation of the procedure with comments by the tutor and tutored practice.
Each of these phases will be planned beforehand and it will be the active responsibility of
the trainer to ensure that the way in which students go through each one of the phases is not
left to chance (Figure 1).
COGNITIVE PREPARATION Reading material, video (before

watching the first colonoscopy)
Testing of knowledge
WATCHING COLONOSCOPIES Technical commentaries,

discussing management of findings
Feed-back
PRACTICE Commenting performance and
findings with the trainer
Help in difficult situations
Simulator Patients Self-assessment
Fig. 1. Teaching phases in colonoscopy

Evaluation of the student by the trainer and the feedback between both is a fundamental
part of this process and is supported by recent evidence. For example, the use of checklists
which ensure the inclusion of key points in colonoscopic technique and the design of a
system for evaluating trainees, with feedback to the trainers on their results, seems to
improve the effectiveness of teaching certain aspects of endoscopy (Alevi, 2010).
As for the role of endoscopy departments, a working group suggested that endoscopy
departments where teaching is carried out must have at least two designated trainers, each
with one or two sessions dedicated to the teaching process. Furthermore, at least 300
colonoscopies should be carried out annually in the department, of which at least 100
should be carried out by the student. It would also be advisable to have audiovisual
teaching material available. The department should have a record of the student’s
colonoscopy activity, including the parameters described above (Teague, 2002). Teaching
should be student oriented (trainer-student), with dedicated time established and separated
from the needs of the department.
4.2 Answer to these demands. Training the trainers and evaluation systems
The main problem behind implementing such a change in the form of teaching is the
trainer’s and institution’s lack of knowledge of learning techniques. The solution would
involve the training of trainers, which has shown to be effective in improving the results of
the teaching process. For example, in the aforementioned study by Alevi et al. (Alevi, 2010),
trainers attended a previous educational module on the effective practice of feedback with
the student. This training is necessary because an analysis of cognitive tasks, in which 3
colonoscopists were asked to explain what they were doing and why, allowed the relevant
steps and important clinical decisions that were omitted during traditional training to be
identified (Sullivan, 2008).
In the United Kingdom, in 2004, a structured training program on endoscopy was put into
practice. This system is based, firstly, on the training of trainers by means of a three-day
course, where they learn teaching techniques. The trained trainers complete 3-day courses
locally, where the technical principles of colonoscopy are taught. Finally, the students must
54 Colonoscopy
continue developing their technical skills in their own centers (Balfour, 2001). This centrally
organized system has been shown to improve the quality of explorations, reduce
complications and increase the students’ satisfaction with their training (Haycock, 2010).
The importance of training the trainers is included in the recent recommendations by the
United European Gastroenterology Federation (UEGF), where it recommends providing
trainers in gastroenterology with a standardized tool for teaching (Berberat, 2010).
As for the evaluation of the student, supervision must be done by the trainer by way of the
systematic collection and evaluation of a series of technical data. In general terms, the
resident should be successful in 80-90% of the technical objectives included in the training
program in order to complete it successfully (ASGE standards of training committees, 1999).
These parameters should coincide with the quality markers for colonoscopy and should,
amongst others, include intubation in the cecum and ileum, adenoma detection rate,
technical ability to carry out standard polypectomies and recover polyps for pathological
analysis, an acceptable rate of complications, the number of colonoscopies carried out and a
correct use of sedation (Romagnuolo, 2008; Joint Advisory Group [JAG] on Gastrointestinal
Endoscopy, n.d.a; JAG, 2010). This evaluation should also include cognitive criteria and
assessment of tasks related to the procedure (table 2).
Cognitive criteria Related tasks

Identification of risk factors Reviewing of patient chart and images
Evaluation of indications and Obtention of informed consent
contraindications
Recognizing and managing complications Preparation of an accurate report
Planning management based on findings Discussion of findings with the patient,
family and other healthcare providers
Table 2.
The development of several tools for objectively measuring competence is currently
underway. For example, the Accreditation Council for Graduate Medical Education
(ACGME) developed a structured tool for evaluating residents (ACGME, 2000) which could
be effective in terms of teaching colonoscopy (Spier, 2010). More recently, authors in the
Mayo Clinic have developed a tool to objectively measure the quality in conducting
colonoscopies longitudinally in time, which also includes parameters of endoscopic
treatment (Sedlack, 2010). Other groups have proposed similar tools (Vassilou, 2008; Tang,
2006). A structured evaluation is also to be found in the English system, in which the latest
component of this system is monitoring and auditing (Balfour, 2001). Although all these
instruments have to be specifically validated in the evaluation of competence, it is clear that
this is the path that must be taken in order to achieve a more objective assessment of the
individual ability to carry out colonoscopies.
5. Credentialing of individuals and units

The final goal of healthcare systems is to provide high quality medical services. In the case
of colonoscopy, local institutions and stakeholders are responsible for designing and
implementing a quality assurance program able to ensure quality and safety of all phases of
the colonoscopy process including pre- and post-procedural aspects. This quality control
program must apply to individuals and endoscopy units in a standarized way.
5.1 Granting privileges to individuals for colonoscopy

A privilege is the authorizacion by a local institution (hospital or endoscopy unit) for a
physician to perform a particular procedure (Faigel, 2009). Granting privileges is the
mainstay of this process as it requires reviewing in a systematic and reproductible manner
the performance of endoscopists and units involved in the colonoscopy process. Privileges
must be granted only to competent individuals, and healthcare providers must stablish
specific policies for granting, complying with local, regional and national regulations (fig. 2).
The process for granting privileges includes a formal review of the applicant´s credentials
by a physician member of the healthcare institution, including documentation of the
accomplished training. The reviewer should also have privileges to perform colonoscopy. If
the applicant´s credential acomplish healthcare institution criteria, a proctoring evaluation
must follow. Proctoring includes direct observation of the applicant performing a pre-
specified number of procedures, with evaluation of a group of criteria that should include
the aforementioned technical and cognitive items (Tables 1 and 2). The proctor must be an
unbiased individual, with expertise in colonoscopy to allow judgement of the applicant
skills but uninvolved in teaching or active patient care (Dominitz, 2008). A written guideline
of the whole competence assessment process must be included in the institution´s bylaws.
Competence must be reassessed periodically through a renewal of privileges process,
performed in a similar way to the initial credentialing process. Again the institution must
have a written guideline for the renewal process, including timing of reevaluation and
recommendations for additional training.
HEALTHCARE INSTITUTIONS
National Scientific Societies

regulations statements
Granting privileges policy
Individuals Endoscopy Units
Renewal policy
- Number of
Credentials Quality improvement policy
procedures
review - Indicators
- Sentinel events
- Compliance rates
- Proctoring
- Evaluation of underperformance
- Endoscopy report
Proctoring
- Monitoring efficiency
Fig. 2. Granting and renewal of privileges for individuals and endoscopy units
5.2 Credentialing for endoscopy units

Units are responsible for maintaining and enhancing the quality of endoscopic procedures,
by means of an institutional policy for quality improvement (Faigel, 2009). Individual
56 Colonoscopy
quality indicators must be assessed periodically and improvement plans must be

implemented if needed. Poor performance must be addressed offering feed-back and plans
for improvement to underperformers. Each institution should have policies for reviewing
and reporting sentinel events. This term is used to describe significant deviations from
optimal patient care, which in the case of colonoscopy, should include adverse outcomes of
sedation, bleeding, perforation and infections. Inappropriate indications, lack of informed
consent and inadequate colonoscopy report should also be included and formally assessed.
All the process of quality control, indicators, feed-back and consequences of repeated
underperformance should be pre-specified and written-down.
Units should be evaluated and subject to a formal credentialing and re-credentialing
process. The ASGE is recognizing units which adhere to ASGE guidelines on privileging
and quality assurance with a Certificate of Recognition award (ASGE, n.d.a). In the UK the
British Global Rating Scale is the standard of accreditation for endoscopy services (JAG,
n.d.b) and in Spain the Spanish Association of Gastroenterology (AEG) has recently
launched a practice guideline for quality in screening colonoscopy aimed to define auditable
quality indicators for endoscopists and units (table 1 ) (AEG & SEED working group, 2011).
6. Conclusions and recommendations

The performance of screening colonoscopy requires high quality standards to guarantee the
efficiency of the CRC screening programs. Since there is a great variability between
endoscopists in the detection of colorectal lesions, only experienced examiners with
adequate technical and cognitive skills should be in charge of those programs. However,
there is a lack of uniformity and standardization in the evaluation of technical skills, and
classical teaching programs may not be enough to meet all the quality requirements.
Recently, much attention has been given to the definition of auditable parameters to
measure the quality of colonoscopies. Systematic monitoring of certain variables allows for
the quality of colonoscopies to be controlled and may be used as a tool for evaluation and
improvement. The identification of these variables may also point out the main issues to be
taught, leading to a more structured way of teaching.
Based on the current evidence the following general recommendations may be stressed:
- The use of auditable parameters to assess quality is of paramount importance in
screening colonoscopy. These parameters will be also useful to evaluate competence.
- The teaching process should be structured in different phases, and monitoring and
evaluation in each phase is advisable. Teaching techniques should be learned by the
trainer, preferably during training the trainers courses. Endoscopy units should be
adapted to teaching activities.
- A structured and reproducible system of evaluating competence, taking into account
cognitive and technical skills, should be designed and validated.
- Local institutions and stakeholders are responsible for designing and implementing a
quality assurance program able to ensure quality and safety of all phases of the
colonoscopy process. Granting privileges for individuals and endoscopy units is advisable.
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4
Maintaining Quality in Endoscopy

Anita Balakrishnan1, Stephen Lewis2 and Kenneth B Hosie1
1Department of Surgery
2Department of Gastroenterology,
Derriford Hospital, Plymouth,
United Kingdom
1. Introduction
If something is worth doing it is worth doing well.
A colonoscopy is only of value if the procedure accurately assesses the whole of the mucosa
with minimal morbidity and distress to the patient. Colonoscopic examination properly
performed is safe, sensitive and well-tolerated by the majority of patients. The benefits of
colonoscopy are within acceptable cost-benefit rates; screening colonoscopies carry a cost of
$20,000 per year of life saved(Pignone, Saha et al. 2002; Smith, Cokkinides et al. 2002;
Winawer, Fletcher et al. 2003). However complications, such as the need for repeat
procedures, and the use of surgical intervention for endoscopically-removable polyps, will
reduce this cost-benefit ratio thereby reducing patient acceptance of this examination.
The inconsistency in the degree of technical expertise of colonoscopists as documented in
the literature suggests the need for standardization of the quality of colonoscopy service
provision nationally and internationally(Marshall and Barthel 1993; Rex, Cutler et al. 1997;
Rex 2000; Postic, Lewin et al. 2002; Gatto, Frucht et al. 2003; Rabeneck, Souchek et al. 2003;
Schoenfeld, Cash et al. 2005; Barclay, Vicari et al. 2006; Rex, Petrini et al. 2006; Simmons,
Harewood et al. 2006; Shah, Paszat et al. 2007; Rabeneck, Paszat et al. 2008; Imperiale,
Glowinski et al. 2009). These studies have contributed to the identification of a number of
parameters that can be analysed to determine the quality of the colonoscopic procedures
performed by an individual endoscopist or within an endoscopy unit(Rex, Petrini et al. 2006;
Lieberman, Nadel et al. 2007) (Table 1). This chapter examines these factors which contribute
to quality outcomes by review of the published evidence and expert opinion.
2. Patient experience
Pre-procedural checks are essential to identify risk factors that may contribute to an adverse
outcome from colonoscopy. Such risk factors include the use of anti-coagulants that may
predispose to bleeding following a therapeutic component of colonoscopy such as biopsy or
polyp removal, or the existence of comorbidities such as heart failure, respiratory problems
or renal failure(Sharma, Nguyen et al. 2007; Ko, Riffle et al. 2010). Indeed the commonest
complications following colonoscopy are respiratory depression due to oversedation and
renal failure induced by dehydration due to the effects of bowel preparation(Sharma,
Nguyen et al. 2007; Ko, Riffle et al. 2010). The American Society of Anesthesiologists (ASA)
score is a crude but effective parameter in the risk assessment for sedation and correlates
62 Colonoscopy
with sedation-related complications of endoscopy(Dominitz, Eisen et al. 2003; Sharma,

Nguyen et al. 2007; Vargo 2007).
Appropriate indication for procedure

Informed consent obtained, including discussion of risks of and alternatives to colonoscopy
Use of recommended post-polypectomy and post-resection surveillance intervals
Documentation of the adequacy of bowel preparation
Caecal intubation rates evidenced by photodocumentation
Adenoma detection rate in asymptomatic (screening) individuals
Withdrawal time (minimum > 6 minutes in individuals with intact anatomy)
Biopsies taken in patients with chronic diarrhoea
Sufficient biopsies obtained in patients with inflammatory bowel disease
Endoscopic resection of polyps where possible or documentation of unresectability
Incidence of perforation or bleeding documented
Post polypectomy bleeding managed endoscopically (nonoperatively)
Adapted from Rex et al, Gastrointestinal Endoscopy 2006; 63 (4):S16-S28
Table 1. Quality indicators for colonoscopy
3. Bowel preparation
Bowel preparation is another important factor in ensuring successful colonoscopic outcomes
as poor bowel preparation has been shown to not only increase procedure time but also to
decrease the adenoma detection rate(Harewood, Sharma et al. 2003; Froehlich, Wietlisbach
et al. 2005; Chiu, Lin et al. 2006). Common bowel preparation regimens include split dose
sodium picosulphate or polyethylene glycol-electrolyte solutions. Patient related factors
such as prior constipation, comorbid status and mobility may affect the regime prescribed as
well as compliance thereby determining the success of bowel preparation(Athreya, Owen et
al. 2011). The quality of bowel preparation and mucosal views should be documented for
every case and is considered adequate if it permits the detection of polyps of 5mm or
greater(Rex, Bond et al. 2002). High rates of inadequate bowel preparation should highlight
the need for investigation into the method of patient information and the sufficiency of the
bowel preparation regimen in use.
4. Patient information
Patients are often anxious about the impending procedure and their reassurance and
subsequent tolerance of the procedure is dependent on the manner and professionalism of
the doctors and nurses as well as the physical environment(Ko, Zhang et al. 2009). The use
of electronic media such as information videos has been found to positively supplement the
written information contained in leaflets by improving patients knowledge of colonoscopy
and decreasing anxiety levels compared to information leaflets alone(Luck, Pearson et al.
1999). A consultation with either a medical professional or a nurse specialist prior to the
procedure is necessary to allow detailed explanation of the procedure prior to obtaining
informed consent. During the consent process, specific risks of colonoscopy should be
explained including bleeding, perforation, infection, sedation adverse events, missed
diagnosis, missed lesions and intravenous site complications(Rex, Petrini et al. 2006).
Maintaining Quality in Endoscopy 63
5. Endoscopy facilities
Appropriate waiting facilities, bathrooms and endoscopy rooms are essential in ensuring a
comfortable patient experience. In addition, endoscopy departments are obliged to adhere
to the published guidelines for endoscope disinfection(Banerjee, Shen et al. 2008; Beilenhoff,
Neumann et al. 2008) and to have full resuscitation facilities including a cardiac defibrillator
and emergency drugs tray(Working Party of the Clinical Services Committee of the British
Society of Gastroenterology 1991). Procedure rooms should be equipped with pulse
oximetry, piped oxygen and suction, electronic blood pressure cuffs and facilities for ECG
monitoring(Working Party of the Clinical Services Committee of the British Society of
Gastroenterology 1991).
6. Ensuring appropriate indications and surveillance intervals

Colonoscopy should be performed in accordance with accepted guidelines (Terraz,
Wietlisbach et al. 2005; Rex, Kahi et al. 2006; Winawer, Zauber et al. 2006; U.S. Preventive
Services Task Force 2008; Cairns, Scholefield et al. 2010) as previous studies have shown a
higher rate of detection of pathology when endoscopies are performed for appropriate
indications(Vader, Pache et al. 2000; de Bosset, Froehlich et al. 2002; Balaguer, Llach et al.
2005). The indications for colonoscopy in symptomatic patients are well described, and
include evaluation of gastrointestinal bleeding of unknown origin, investigation of
unexplained iron deficiency anaemia, evaluation of an abnormality (such as a filling defect,
stricture or wall thickening) on barium enema or CT, assessment of chronic inflammatory
bowel disease of the colon and changes in bowel habit such as diarrhoea(American Society
for Gastrointestinal Endoscopy 2000). In particular, endoscopists should adhere to the
recommended surveillance guidelines post-resection or post-polypectomy as well as the
guidelines for surveillance in patients with Crohn’s or ulcerative colitis, which make the
assumption of caecal intubation, adequate bowel preparation and careful examination(Rex,
Petrini et al. 2006). Overuse of surveillance colonoscopy is not cost-effective and
unnecessarily exposes patients to the discomfort and risks of a colonoscopy.
7. Sedation and analgesia

Ensuring an adequate yet safe degree of sedation is of paramount importance for successful
colonoscopy and increases the likelihood of the patients’ willingness to have a repeat
procedure if necessary. Recent studies have suggested that “moderate” sedation, in which
patients continue to respond purposefully to either verbal commands alone or with light
tactile stimulation without requiring intervention to maintain a patent airway or
spontaneous ventilation, is sufficient for colonoscopy and safer than deep sedation, in which
ventilation may be inadequate and airway protection may be required(Triebwasser and
Browning 2001; American Society of Anesthesiologists 2002; Faigel, Baron et al. 2002; Brisith
Society of Gastroenterology 2003; Waring, Baron et al. 2003; Rex 2006). Agents used for
sedation include benzodiazepines (midazolam, diazepam), narcotics (fentanyl, meperidine),
propofol, neuroleptic tranquilizers (droperidol), antihistamines (diphenhydramine), and
dopaminergic receptor antagonists (promethazine). A meta-analysis showed no difference
in the incidence of hypoxemia, need for supplemental oxygen, physician satisfaction with
the procedure, or rates of patient pain or discomfort when either midazolam or diazepam
was co-administered with a narcotic for colonoscopy (McQuaid and Laine 2008).
64 Colonoscopy
The use of propofol as a sole sedative agent was associated with higher rates of patient
satisfaction and less memory of the procedure compared to midazolam co-administered with a
narcotic, however no significant difference was noted in the incidence of bradycardia,
hypotension, hypoxemia, physician satisfaction, or the number of patients reporting pain or
discomfort(McQuaid and Laine 2008). Rates of propofol use are increasing in the United
States, with >20% of physicians using propofol routinely for endoscopy. The narrow
therapeutic window of propofol and the lack of a reversal agent can contribute to rapid
depression of consciousness and cardiovascular function, necessitating additional training and
monitoring when using this agent(American Society of Anesthesiologists 2002; Faigel, Baron et
al. 2002; Vargo, Cohen et al. 2009). Combining propofol with midazolam and narcotics is
believed to allow lower doses to be used thus improving the safety profile(Cohen, Dubovsky
et al. 2003; Cohen, Hightower et al. 2004). The use of patient controlled analgesia using
narcotics such as alfentanyl and fentanyl has also been associated with high patient satisfaction
and willingness to undergo repeat procedure(Usta, Turkay et al. 2011).
The inhalational agent nitrous oxide is also used for sedation and analgesia in colonoscopy
due to its rapid onset of action and short recovery time. Randomised trials comparing
nitrous oxide to intravenous opiates with or without benzodiazepines failed to show a clear
difference between the two groups in terms of pain relief, reaction times or complex psycho-
motor co-ordination(Lindblom, Jansson et al. 1994; Saunders, Fukumoto et al. 1994; Notini-
Gudmarsson, Dolk et al. 1996; Trojan, Saunders et al. 1997; Forbes and Collins 2000;
Maslekar, Gardiner et al. 2009; Welchman, Cochrane et al. 2010). Patients given intravenous
sedation had worse recall of the procedure and reduced manual dexterity compared to those
given nitrous oxide(Lindblom, Jansson et al. 1994; Saunders, Fukumoto et al. 1994; Notini-
Maslekar, Gardiner et al. 2009; Welchman, Cochrane et al. 2010). All studies showed
reduced post-procedural stay in patients given nitrous oxide compared to intravenous
sedation(Lindblom, Jansson et al. 1994; Saunders, Fukumoto et al. 1994; Notini-
Maslekar, Gardiner et al. 2009; Welchman, Cochrane et al. 2010).
Carbon dioxide insufflation has been recommended during colonoscopy as carbon dioxide is
highly soluble and can thus be passively absorbed by the colon and excreted by the lungs,
thereby minimizing intra-procedural and post-procedural discomfort(Williams 1986). In
addition the rapid absorbance of carbon dioxide allows double contrast CT or barium enema
to be performed on the same day if necessary, while the minimal interference of carbon
dioxide with colonic blood flow reduces the risk of ischaemia(Williams 1986). Studies
comparing the use of carbon dioxide insufflation to the more routinely used air insufflation in
colonoscopy have demonstrated decreased levels of pain and shorter examination times in the
carbon dioxide insufflations group (Bretthauer, Thiis-Evensen et al. 2002; Sumanac, Zealley et
al. 2002; Church and Delaney 2003; Uraoka, Kato et al. 2009; Yamano, Yoshikawa et al. 2010).
8. Measurements of technical expertise

8.1 Caecal intubation rates
Caecal intubation (passage of the colonoscope to a point proximal to the ileocaecal valve) is
necessary to ensure adequate visualisation of the entire colon. A significant fraction of
colonic neoplasms are located in the right colon(Imperiale, Wagner et al. 2000; Rabeneck,
Souchek et al. 2003), hence successful caecal intubation should be specifically noted, ideally
by photo documentation(Rex 2000). Intubation of the terminal ileum or visualization of the

lips of the ileocaecal valve may be further necessary if there is any doubt as to whether the
caecum has been entered. Failure to intubate the caecum is associated with decreased
sensitivity of the examination as well as the need for further radiographic imaging or repeat
colonoscopy, thereby reducing the cost-effectiveness of the procedure. Recommended caecal
intubation rates are >90% for all cases(Marshall and Barthel 1993) and >95% of screening
cases in healthy adults(Rex, Petrini et al. 2006; Rabeneck, Rumble et al. 2007; Levin,
Lieberman et al. 2008; National Health Service Cancer Screening Programmes 2011).
Procedures which have been aborted due to poor bowel preparation, severe colitis,
equipment failure and those performed solely for the treatment of strictures or polyp
removal (where complete colonic imaging has been previously performed) are not included
in calculation of the caecal intubation rate(Rex, Bond et al. 2002; Rex, Petrini et al. 2006).
8.2 Adenoma detection rate in screening

The adenoma detection rate (ADR) in asymptomatic patients undergoing screening
colonoscopy is an important quality indicator in colonoscopy. A recent study by Kaminski et
al demonstrated that the ADR of the endoscopist was an independent risk factor for the
subsequent development of interval cancers (cancers occurring during surveillance
colonoscopy after a previous screening colonoscopy). The number of interval cancers was
significantly higher in patients who had undergone colonoscopy by endoscopists with an
ADR of <20% compared to those who had undergone colonoscopy by endoscopist with an
ADR of >20% (Kaminski, Regula et al. 2010). Studies of different practice groups have
shown large disparities in the rates of adenoma detection between endoscopists within the
same practice for both screening and symptomatic indications(Barclay, Vicari et al. 2006;
Chen and Rex 2007; Imperiale, Glowinski et al. 2009) highlighting the possibility that
suboptimal colonoscopy rather than technological limitations may be a significant
contributing factor to the miss rate of incident cancers(Rex, Hewett et al.; Rex, Petrini et al.
2006). The decrease in sensitivity of colonoscopy associated with missed adenomas also has
implications on surveillance intervals, as guidelines for surveillance interval assume
thorough examination of the colon and cannot compensate for disparities in technical
expertise between colonoscopists. Tandem colonoscopy studies demonstrated adenoma
miss rates ranging from 0-6% for adenomas more than 1cm in size, 12-13% for those
between 6-9mm, and 15-27% for those under 5mm(Hixson, Fennerty et al. 1990; Rex, Cutler
et al. 1997). CT-colonography in turn demonstrated miss rates between 12 and 17% for
adenomas greater than 1cm in size, indicating that tandem colonoscopies may
underestimate the true prevalence of missed lesions (Pickhardt, Nugent et al. 2004; Van
Gelder, Nio et al. 2004). Colonoscopy screening studies have consistently demonstrated
adenoma prevalence rates of >25% in men and >15% in women over 50 years old (Johnson,
Gurney et al. 1990; Lieberman and Smith 1991; Lieberman, Weiss et al. 2000; Schoenfeld,
Cash et al. 2005); hence these form the basis of the current recommended ADRs in the
United States. In the United Kingdom a slightly higher ADR of 35% has been set for
screening colonoscopy (performed following positive faecal occult blood tests)(National
Health Service Cancer Screening Programmes 2011).
While the ADR is considered a good quality indicator for colonoscopy, this parameter
cannot be determined at the time of endoscopy and requires histological confirmation before
66 Colonoscopy
an accurate ADR can be calculated. Polypectomy rates have therefore been postulated as a
suitable surrogate, as this can be calculated at the time of colonoscopy and appear to
correlate with the ADR(Williams, Le et al. 2011). A disadvantage of using polypectomy rates
is the potential for “gaming” –endoscopists artificially increasing their polypectomy rates by
removing benign hyperplastic polyps rather than true adenomas(Rex, Hewett et al. 2010).
A recent randomized study examining the effects of the antispasmodic buscopan on
polyp detection demonstrated increased polyp detection rates in only a subgroup of patients
with significant colonic spasm (Lee, Cheon et al. 2010). In addition, the majority of studies
to date have focused on the use of buscopan for the alleviation of colonic spasm and
attendant discomfort during colonoscopy with inconsistent results (Saunders and Williams
1996; Mui, Ng et al. 2004; Yoong, Perkin et al. 2004), suggesting that further studies are
necessary before buscopan can be routinely recommended for the improvement of polyp
detection.
9. Withdrawal time
Measurement of colonoscope withdrawal time (the time between reaching the caecum and
withdrawing the scope from the anus) has been used as a further quality indicator in units or
endoscopists with low adenoma detection rates. Endoscopists who took longer than 6 minutes
to withdraw the colonoscope were found to have very low miss rates and more than 2-fold
higher rates of detection of both small and large adenomas(Rex 2000; Barclay, Vicari et al. 2006;
Simmons, Harewood et al. 2006). It has therefore been recommended that withdrawal of the
colonoscope in patients without any prior colonic surgery should last at least 6 minutes on
average(Rex, Petrini et al. 2006). Mean withdrawal times are used rather than individual times
as this figure is influenced by the adequacy of colon preparation as well as the length of the
colon and the prominence of haustral markings. In addition a recent study has shown that the
withdrawal time can be reduced safely with the use of wide angle scopes(Deenadayalu,
Chadalawada et al. 2004). Despite the positive correlation between withdrawal time and ADR,
Gellad et al showed that withdrawal times failed to correlate with 5-year interval
neoplasia(Gellad, Weiss et al. 2010). In addition in their study withdrawal times beyond a
threshold of 5.2 to 8.6 minutes no longer correlated with adenoma detection rates. This may be
explained by the possibility that longer withdrawal times were representative of more difficult
rather than more careful examinations. Additionally longer withdrawal times have been found
to correlate with the detection of smaller polyps(Simmons, Harewood et al. 2006), not all of
which might have been removed at colonoscopy.
10. Surrogate markers

Despite the emphasis placed on caecal intubation rates and withdrawal times as a marker of
adequacy of examination, Beckly et al (2007) found no correlation between caecal intubation
rate or withdrawal times and the detection of artificial bowel markers placed within the
colon by a separate intubating colonoscopists (Beckly, Douie et al. 2007). The miss rates of
these markers corroborated the findings of Postic et al identifying synchronous lesions in
specimens of resected colon(Postic, Lewin et al. 2002) as well as the findings of tandem
colonscopy studies which used a second closely sequential colonoscopy to determine the
miss rate of the first colonoscopy(Hixson, Fennerty et al. 1990; Rex, Cutler et al. 1997). The
higher miss rate for markers placed at the flexures highlights the fact due to the high degree
of angulation required to navigate these corners lesions may be missed at these sites even
with good technique. The use of surrogate markers for assessing lesion detection may
therefore represent a useful addition to endoscopy training.
10.1 Colonic biopsy

The sensitivity of colonoscopy for neoplastic and other pathological processes increases
when coupled with endoscopic biopsies. This is particularly relevant in patients undergoing
colonoscopic surveillance for Crohn’s or ulcerative colitis. The sensitivity of the examination
for detecting dysplasia in this patient group is improved by quadrantic biopsies every 10cm
of colon as well as biopsy of any suspicious lesions (Rubin, Haggitt et al. 1992).
Panchromoscopy (dye-spray) of the colon with targeted biopsies has also been shown to
increase sensitivity for dysplasia (Kiesslich, Fritsch et al. 2003; Rutter, Saunders et al. 2004).
In addition to surveillance in inflammatory bowel disease, recent guidelines also
recommend the use of biopsies in patients with chronic diarrhoea(Rex, Petrini et al. 2006).
Serial biopsies of macroscopically normal colon can identify microscopic ( collagenous and
lymphocytic) colitis in patients with normal mucosa at colonoscopy (Zins, Tremaine et al.
1995; Yusoff, Ormonde et al. 2002). Detection of collagenous colitis in particular is improved
when the proximal colon is biopsied (Zins, Tremaine et al. 1995; Yusoff, Ormonde et al.
2002).
10.2 Colonoscopic polypectomy

Routine polypectomy should be performed at diagnostic colonoscopy to minimize the
reduction in cost-effectiveness and increased risk associated with an additional unnecessary
colonoscopy for removal of the polyp. The UK national guidelines recommend that 90% of
screen-detected polyps are removed at the time of detection (National Health Service Cancer
Screening Programmes 2011). Consistent referral of sessile polyps <2cm in size for surgical
resection is discouraged as these polyps are frequently amenable to endoscopic removal. In
cases of technically difficult polyps, referral to an endoscopist experienced in endoscopic
resection may be appropriate. The need for surgical intervention, where unavoidable,
should be substantiated by photo documentation of the polyp and subsequent review of
images with a second endoscopist. Furthermore, correlation of the endoscopic and
pathologic measurements of the polyp should be performed following surgical resection to
confirm the necessity of surgical resection(Rex, Petrini et al. 2006).
11. Post-procedure quality indicators

11.1 Complication rates
All complications such as perforation or bleeding following the procedure should be
monitored and documented to allow identification and correction of any systematic errors
that may be contributing to the incidence of these events.
Perforations can occur during diagnostic colonoscopies, either mechanical in nature (e.g.
rupture of the rectosigmoid by the instrument or perforation through a stricture) or
barotrauma-related due to an excess of pneumatic pressure causing rupture of the caecum
(Woltjen 2005). Therapeutic colonoscopies often run a greater risk of perforation, which can
occur following polypectomy. This is most often associated with electrocautery and most
68 Colonoscopy
frequently occurs following attempts at removal of large polyps from the proximal colon.
Submucosal saline injection prior to polypectomy has been suggested might reduce the risk,
(Norton, Wang et al. 2002; Singh, Harrison et al. 2004) however randomized controlled trial
evidence on this observation is lacking. Current guidelines suggest that perforation rates of
greater than the rate of 1:500 overall or 1:1000 in screening patients as documented in
previous studies should highlight the need for further investigation into any inappropriate
practices that may be a contributory (Silvis, Nebel et al. 1976; Nivatvongs 1986; Gatto, Frucht
et al. 2003; Rabeneck, Paszat et al. 2008; National Health Service Cancer Screening
Programmes 2011).
Bleeding is the most common complication following colonoscopic polypectomy, and is
more frequent in large polyps with a proximal colonic location. Bleeding rates of large
polyps (>2cm) in the proximal colon may exceed 10% however the recommended overall
acceptable rate of bleeding is 1% (National Health Service Cancer Screening Programmes
2011). The risk of bleeding (particularly immediate bleeding) may be reduced by the use of
epinephrine injections (Hsieh, Lin et al. 2001; Di Giorgio, De Luca et al. 2004) or detachable
snares(Iishi, Tatsuta et al. 1996; Di Giorgio, De Luca et al. 2004). Immediate bleeding can
often be managed endoscopically by pressure on the stalk for up to 10-15 minutes or
injection of adrenaline followed by electrocautery (Rex, Lewis et al. 1992). Delayed bleeding
is rarely significant and often stops spontaneously. Exceptions are patients who continue to
pass bright red blood who may be experiencing arterial bleeding; urgent repeat colonoscopy
with clipping or injection and electrocautery of the bleeding site is then necessary (Rex,
Lewis et al. 1992). By these means over 90% of post-polypectomy bleeding can be managed
conservatively without resorting to surgical intervention(Rex, Petrini et al. 2006). Accurate
assessment of the delayed complication rates of individual colonoscopists such as
perforation or bleeding may be difficult as patients may present to different centres, hence
regular feedback and audit systems should be in place to ensure delayed complications are
recorded.
11.2 Standardised reporting

Although standardized reporting and data collection systems are currently in use for many
other large scale tests such as Papanicolaou testing and mammography, these have not
currently been adopted for colonoscopy. Standardization of reporting colonoscopic
procedures would allow improved communication of test results to primary care providers
and patients as well as standardized terms and measurement criteria. In addition this would
allow the development of national databases to be interrogated for audit and research
purposes. In 1997 the Quality Assurance Task Group in the United States developed a
standardized colonoscopy reporting and data system (CO-RADS) in conjunction with the
major national gastroenterological societies, outlining the key components of colonoscopy
that should be closely monitored in every endoscopy unit(Lieberman, Nadel et al. 2007)
(Table 2). The use of and adherence to this standardized reporting has not been audited and
remains to be seen. No standardized national reporting system exists for symptomatic
colonoscopies in many other countries including the United Kingdom. (these are however in
place in the United Kingdom for screening colonoscopies). Most endoscopic units in the
United Kingdom employ commonly used endoscopic data recording software such as
Endosoft® or Endoscribe® which require the documentation of the major quality indicators.
Patient demographics
History of complaint and indications for colonoscopy
Assessment of patient risk and comorbid status
Technical description of procedure
Findings on colonoscopy
Assessment
Any intervention / unplanned events
Follow-up plan
Pathology
Adapted from Lieberman et al, Gastrointestinal Endoscopy 2007; 65(6): 757-766
Table 2. Key subject areas in a standardized colonoscopy report
12. Other factors

12.1 Training and accreditation
As indicated by the studies quoted above, technical competence is of paramount importance
in ensuring the delivery of a high quality endoscopy service. To achieve this particular
attention must be paid to the instruction of medical and surgical trainees in the necessary
skills for competent colonoscopy, and in many countries including the United Kingdom
endoscopists are required to be formally certified to perform independent procedures
(British Society of Gastroenterology 2004). Several studies have attempted to better define
the learning curve that unquestionably accompanies colonoscopic training. Lee et al
demonstrated achievement of the basic competencies (in terms of caecal intubation rate and
polyp detection rate) after 150 colonoscopies(Lee, Chung et al. 2008), however this was
disputed by Spier et al, who showed that over 500 colonoscopies were necessary before their
gastroenterological fellows could perform > 90% of colonoscopies independently(Spier,
Benson et al. 2010; Spier, Durkin et al. 2010). Simulator training has been suggested as an
alternative or adjunct to colonoscopic experience on live patients; Haycock et al
demonstrated no significant difference between the performance novice colonoscopists
trained on a simulator or live patients when assessed on live cases(Haycock, Koch et al.
2010), suggesting that use of the simulator may shorten the learning curve to competency on
live patients.
Once competencies are acquired continued regular colonoscopic experience is necessary to
maintain the skill levels required for this procedure. A recent study from Canada revealed
that patients were more likely to have an incomplete colonoscopy if the procedure was
performed by a low volume endoscopist (<240 colonoscopies per year) compared to a high
volume endoscopist (370 colonoscopies per year)(Shah, Paszat et al. 2007). This was
corroborated by a study from the United States showing no difference in complications but
significant differences in completion rates and time to completion between endoscopists that
performed 100-200 colonoscopies per year and those that only performed less than 10 per
year(Harewood 2005). In keeping with these findings the National Institute for Clinical
Excellence (NICE) in the United Kingdom has recommended that on average colonoscopists
should perform a minimum of 100 procedures per year(National Institute for Clinical
Excellence 2004). while screening colonoscopists should perform at least 150 procedures per
year(National Health Service Cancer Screening Programmes 2011)
70 Colonoscopy
12.2 Nurse endoscopists

In countries such as the United Kingdom the demand for endoscopists is rapidly
outstripping the capacity for medical endoscopists to perform the service within a
reasonable time-frame. This has led to the training of nurse endoscopists to meet this need.
To avoid any compromise in quality, nurse endoscopists are required to train to achieve the
same competencies as medical endoscopists. Two to three sessions a week are mandated to
maintain competencies achieved by a closely supervised period of apprenticeship as well as
attendance of national endoscopy courses(Brisith Society of Gastroenterology 2001). A
recent pilot study from the Netherlands identified no difference in the caecal intubation rate
and caecal intubation time between nurse endoscopists and gastrointestinal fellows in
training, with 150 examinations required before independent procedures could be
performed(Koornstra, Corporaal et al. 2009).
12.3 Cost effectiveness

Provision of a quality colonoscopic service should not only encompass clinical performance
but also cost-effectiveness, which relies on the efficient use of resources as well as successful
team-working. Challand et al found that colonoscopists performing >150 cases per year were
more likely to achieve the recommended workload of 4 colonoscopies per 4 hour session
that would be required to meet session costs, however the volume of cases of each
endoscopist per year had no effect on the caecal intubation rate. In addition, endoscopists
who offered > 15% of their sessions for training were more likely to achieve the work
required to meet session costs, suggesting that the most clinically effective endoscopists also
offered the greatest number of training opportunities(Challand, Bullen et al. 2010).
Cost-effectiveness has also been an important factor in the development of screening and
surveillance guidelines. The majority of gastroenterological societies recommend
surveillance colonoscopy following adenoma detection at ten yearly frequency in low-risk
groups or five yearly in groups where the miss rate for adenomas is suspected to be
high(Saini, Schoenfeld et al. 2010). Three yearly surveillance is not cost-effective and the
inherent risks of colonoscopy may make such frequent surveillance incrementally harmful
(Saini, Schoenfeld et al. 2010). Cost-effectiveness analyses have shown that colonoscopy is
not an appropriate first line screening tool but is instead often used as a further
investigation in patients with positive faecal occult blood tests(Pignone 2005).
13. Conclusion/ summary

The effectiveness and safety of colonoscopy is dependent on the quality of the procedure
performed. The identification of specific quality indicators for colonoscopy as described above
(outlined in Table 3) has contributed to the development of recommendations for improving
the quality of colonoscopy internationally. Adherence to these recommendations will ensure a
thorough examination that achieves the expected sensitivity of the procedure while avoiding
complications that would offset the cost-benefit ratio of the process. Ensuring quality in
colonoscopy is therefore of paramount importance in ensuring the delivery of a safe, accurate,
effective and acceptable service for the diagnosis and management of colonic pathology.
Disclosures: est.
Copyright licence statement:
The authors attest that this manuscript is not currently under consideration by any other
journal or publisher.
Abbreviations:
ADR – adenoma detection rate
ASA – American Society of Anaesthesiologists
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Part 2
Applications
5
The Impact of Colonoscopy on Colorectal

Cancer Incidence and Mortality
Minhhuyen T. Nguyen and David S. Weinberg
Fox Chase Cancer Center
United States of America
1. Introduction
In the United States, periodic colorectal cancer (CRC) screening rates increased from 45% of
the eligible population in 2002 to 63% in 2008 (Richardson et al., 2010). Over a similar time
period, colonoscopy has become the most widely utilized colorectal cancer screening tool in
the United States. In other countries, colonoscopy is the most commonly recommended
screening test, particularly in Europe. However, in many locales in which other screening
tests such as fecal occult blood tests (FOBT) are preferred due to cost or availability,
colonoscopy is used to follow up on patients screening positive (Brenner et al., 2001; Hoff &
Dominitz, 2010; Classen & Lambert, 2008).
The ascendance of colonoscopy in the US corresponds with a significant reduction in
colorectal cancer incidence and mortality. In the Annual Report to the Nation on the Status
of Cancer from 1975-2006, microsimulation modeling demonstrated the relatively large
contributions of screening, along with risk factor modifications and improved cancer
treatments, to this decline (Edwards et al., 2010).
The focus of this chapter is the effectiveness of colonoscopy, as a means to decrease CRC
incidence and mortality. In addition, we identify factors including tumor biology,
instrumental, patient-related issues and endoscopist characteristics that may influence the
impact of colonoscopy on these rates.
2. Randomized controlled trials in CRC screening using endoscopy

Currently, there are no published randomized controlled trials examining the impact of
colonoscopy on CRC incidence and mortality. Before we review the published studies
involving the colonoscopy, we will first examine two randomized, controlled trials of
sufficient size and duration using screening flexible sigmoidoscopy to address the same
questions. The results of these studies are often extrapolated to support the efficacy of
colonoscopy, which is often thought to be an extended sigmoidoscopy. In the first study,
Atkin and colleagues randomized more than 170,000 people in 14 United Kingdom medical
centers to either once-only flexible sigmoidoscopy or no screening, with 71% included in the
exam arm. The median follow-up was 11.2 years. The incidence and mortality of colorectal
cancer were measured in both intention-to-treat and per-protocol analyses. Overall CRC
incidence reduction was 23%-33%. Overall CRC mortality reduction was 31%-43% and distal
CRC mortality reduction was 50% (Atkin et al., 2010). The protective effect appears
80 Colonoscopy
persistent, with reduction of left-sided CRC incidence continuing at the rate of 0.02% to
0.04% per year after year 5.
In the second study with similar design, Hoff and colleagues in the NORCAP trial
randomized more than 55,000 men and women between 55 to 64 years of age in Norway to
once-only screening flexible sigmoidoscopy or no screening. The planned duration of
follow-up was 15 years. The published study reported cumulative incidence after 7 years of
follow-up. Interestingly, by intention-to-treat analysis, there was an insignificant (P= 0.16)
reduction in overall CRC mortality by 27% and in rectosigmoid cancer mortality by 37%.
Per-protocol analysis with its inherent risk of selection bias yielded a significant 59%
reduction in overall CRC incidence and a significant 76% reduction in distal CRC incidence.
The authors suggested that these findings might be the results of a short timeframe for the
follow-up period (Hoff et al., 2009).
Two other randomized controlled trials using screening flexible sigmoidoscopy, namely, the
SCORE trial in Italy and the PLCO trial (US National Cancer Institute-led Prostate, Lung,
Colorectal and Ovarian cancer screening trial) are expected to report on their results within
the next few years (Segnan et al., 2002; PLCO NCI web page).
In addition, researchers in Europe and the US are currently conducting a randomized
controlled trial examining the efficacy of screening colonoscopy on CRC incidence and
mortality. The Northern-European Initiative on Colorectal Cancer (NordICC) trial will
randomly draw 66,000 individuals from population registries to compare screening
colonoscopy with a control group of unscreened individuals for a planned follow-up period
of 15 years. Final data collections and analyses are not expected until 2026 (Baxter &
Rabeneck, 2010).
3. CRC incidence and mortality after colonoscopy with adenomatous

polypectomy
Muto et al first proposed the adenoma-carcinoma sequence of colorectal cancer in 1975 (Muto
et al., 1975). Endoscopic polypectomy interrupts the carcinogenic sequence by preventing the
transformation of adenomas, thereby inhibiting cancer development. The seminal National
Polyp Study (NPS) in 1993 provided primary evidence in support of this theory as well as the
rationale for colonoscopy with polypectomy as the major method to prevent colorectal cancer
(Winawer et al., 1993). In this study, 1418 patients were randomized post-adenoma removal to
frequent (follow-up exams in years 1 and 3) and less frequent (exams in year 3) colonoscopies.
Outcomes in each group were compared with three historical reference groups, two where
polyps were simply observed and one general-population cohort (the Surveillance,
Epidemiology, and End Results or SEER). After an average follow-up of 5.9 years, the
interventional groups showed a 76% to 90% reduction in CRC incidence compared with the
observed incidence in the reference groups (standardized incidence ratios (SIRs), 0.10, 0.12 and
0.24, respectively). The cancer incidence rate was 0.6 cancers per 1000 person-years.
Subsequent studies based on NPS demonstrated the persistent reduction in CRC mortality
associated with the initial polypectomy. Zauber and colleagues used mathematical
modeling to show that at 20 years, the cumulative mortality rate was 2.5% for patients who
had an initial polypectomy, compared to 5.5% for patients who did not (Zauber et al., 2007).
Colonoscopic polypectomy could reduce CRC deaths by about 90% among patients with
adenomas and by about 50% in the general population. Furthermore, these significant
reductions in CRC mortality were mainly associated with the index clearing colonoscopy,
not with the subsequent surveillance examinations.
The Impact of Colonoscopy on Colorectal Cancer Incidence and Mortality 81
Similar strong reduction in CRC incidence was also reported in two other studies involving
patients with adenoma removal. The Italian Multicentre Study Group, a retrospective,
observational study of 1693 men and women who had polypectomy with a mean follow-up
of 10.5 years, reported SIR of 0.34 and cancer incidence rate of 0.4 cancers per 1000 person-
years (Citarda et al., 2001). The Telemark Polyp Study, a prospective cohort study of 799
men and women with a mean follow-up of 10 years, showed SIR of 0.2, and cancer incidence
rate of 0.5 cancers per 1000 person-years, although the trend toward CRC mortality
reduction was not significant (Thiis-Evensen et al., 1999).
However, other studies examining the adenoma cohorts have demonstrated much less
dramatic impact of colonoscopy with polypectomy. The Polyp Prevention Trial, the Wheat
Bran Fiber Trial, the Funen Adenoma Follow-Up Trial, the Australian Polyp Study and the
Combined Chemoprevention Trial have all shown cancer incidence rates 2 to 4 times higher
than that of the NPS, actually approaching or exceeding the expected rate in the SEER data
(1.7 cancers per 1000 person-years).
The Polyp Prevention Trial was a randomized, double blind study of 2079 men and women
with history of adenoma removal examining the effects of a low-fat, high-fiber diet on the
adenoma incidence. Patients had surveillance colonoscopy at years 1 and 4 post-
randomization. The study found no benefits of nutritional intervention on incident
adenomas. In addition, the cancer incidence rate was 2.2 cancers per 1000 person-years and
more than 50% of prevalent cancers could be prevented or detected earlier if the quality of
colonoscopy had been improved (Schatzkin et al., 2000; Pabby et al., 2005).
The Wheat Bran Fiber Trial using a similar design studied the effects of high fiber on
adenoma recurrence in 1429 men and women with adenomas. It found 41-48% recurrent
adenomas located in the proximal colon and cancer incidence rate of 2.4 cancers per 1000
person-years (Alberts et al., 2000).
The Funen Adenoma Follow-Up Trial by Jorgensen et al randomized 1056 men and women
with adenomas to surveillance colonoscopy at varying intervals between 6 and 48 months
after the index colonoscopy with polypectomy. Its cancer incidence rate was 2.2 cancers per
1000 person-years. It found a significant six-fold reduction in CRC incidence in the post-
polypectomy group if all carcinomas were assumed to develop from large (> or = 10 mm)
adenomas or adenomas with severe dysplasia according to the adenoma-carcinoma
sequence (Jorgensen et al., 1993). It also found a significant reduction in CRC mortality
when compared with the normal population.
The Australian Polyp Study by a single surgeon studied 645 patients with adenoma removal
for a mean follow-up period of 4.4 years. The cancer incidence rate was 1.05 cancers per 1000
person-years, which was at first glance indistinguishable from that of the general population.
However, based on analysis of previously published data, the authors found that the risk of
developing colorectal cancer in patients with adenomas was approximately 2.5 times higher
than that of the general population (3.3 cancers per 1000 person-years). Therefore, the authors
concluded that colonoscopy did reduce CRC incidence (Meagher & Stuart, 1994).
The Combined Chemoprevention Trial consisted of 2915 patients drawn from three previous
chemoprevention trials using calcium, aspirin and antioxidant vitamins in an effort to reduce
polyp recurrence. It involved a large number of endoscopists from across North America, in
both university and private practices. Its cancer incidence rate was 1.74 cancers per 1000
person-years, with 84% in the early stage and approximately half found in the proximal colon
(Robertson et al., 2005). The lowered cancer incidence rate, compared with the other studies,
was partially attributed to the chemopreventive properties of aspirin and calcium.
82 Colonoscopy
4. Why these differences?

Although all of these studies include participants who had an adenoma removed,
methodological differences make comparisons of results difficult. First, criteria for patient
enrollment differed in these studies. For instance, the NPS patients underwent rigorous
baseline colonoscopic clearance of adenomas, with some (13%) receiving at least 2
examinations, before randomization. The NPS also excluded patients with polyps larger
than 3 cm in size, or with prior history of adenomas, while other trials included patients
with history of adenomas and any-sized polyps (Rex & Eid, 2008). Second, colonoscopic
follow-up periods varied among the studies (Table 1). The NPS, Italian Multicentre Study
and the Telemark Polyp Study had a mean follow-up of 6 to 13 years, whereas the others
had much shorter follow-up periods, 3-4 years at most. As discussed below, cancers
detected during the shorter follow-up periods were possibly due to lesions missed initially,
not true incident cancers seen in longer follow-up (Robertson et al., 2007). Third, the
expected cancer incidence rates in the various cohorts are difficult to measure due to
differences in the type and size of adenomas removed at study entry (Kahi et al., 2009).
Fourth, differences in the rate and the timing of the follow-up colonoscopy might also lead
to variable outcomes. For example, one-fifth of the NPS and one-fourth of the Italian Trial
subjects did not have follow-up colonoscopic surveillance, while most of the subjects in the
chemoprevention trials did. Fifth, other confounding factors such as the use of
chemopreventive agents such as aspirin, family history of CRC, cigarette smoking history
were not fully accounted for and might not be comparable in these studies.
Cancer Mean
Number Number of
incidence follow-
Study of cancer in SIR
rate (per up
patients follow-up
1000 pr-yrs) (years)
SEER 1.7
NPS--Winawer 1993 1481 0.6 5 5.9 0.1-0.24
Italian Polyp Study--
1693 0.4 6 10.5 0.34
Citarda 2001
Telemark Polyp
Study--Thiis-Evensen 799 0.5 1 10 0.2
1999
Polyp Prevention
2079 2.2 13 3.1
Study--Schatzkin 2000
Wheat Bran Trial
1429 2.4 9 3.0
Alberts 2000
Funen Adenoma
1056 2.2 10 4.3
Trial--Jorgensen 1993
Combined
Chemoprevention 2915 1.74 19 3.7
Trial--Robertson 2005
Australian Polyp
645 1.05 3 4.4
Study—Meagher 1994
Table 1. Adenoma Cohorts and Interval Cancers
5. CRC incidence in screening cohorts

Despite the significant, although variable, reduction in CRC incidence risk for patients with
prior adenoma removal, these higher risk populations may not have direct applicability to
screening settings where only a proportion of participants have adenomas.
The incidence of CRC has been examined in a number of screening cohorts. Lieberman et al
in 2000 studied 3121 individuals, 97% of who were men, for the Veterans Affairs
Cooperative Study 380. They found that 37.5% of patients had neoplastic lesions. The
presence of distal lesions increased the risk of proximal lesions (OR 3.4). However, 52% of
proximal advanced neoplasms had no distal lesions (Lieberman et al., 2000). When 1193
previously screened patients had a follow-up colonoscopy within 5.5 years, 22 cancers and
high-grade dysplastic lesions (1.8%) were identified. Most of these lesions (15/22) were
found within 36 months of the initial colonoscopy and 6 out of 9 cancers were located in the
proximal colon (Lieberman et al., 2007).
In 2005, Schoenfeld et al investigated the prevalence and location of advanced colonic
neoplasia in women of average and high risk (15.7% had a family history of colon cancer).
Among 1463 asymptomatic women who underwent screening colonoscopy, 72 had
advanced neoplasia (4.9%). Had flexible sigmoidoscopy, which visualizes only the distal
colon, been the screening tool, only 35.2% of women with advanced neoplasia would have
been identified, compared to 66.3% of men from the VA Cooperative Study 380 (P<0.001)
(Schoenfeld et al., 2005). The Schoenfeld study provided support for the concept that
screening needs of women may differ from those of men.
In a similar vein, the use of the screening colonoscopy in high-risk families was further
advocated by the prospective, observational study with a long follow-up period of 16 years
by Dove-Edwin et al. In this study, 1678 individuals from high-risk families with hereditary
non-polyposis colorectal cancer (HNPCC) and moderate-risk families with up to 3 affected
first-degree relatives had screening colonoscopy. Significant reduction of CRC incidence in
these screening cohorts were 80% and 43% in the moderate-risk and high-risk groups,
respectively, when compared to the expected incidence in similar families lacking
surveillance (Dove-Edwin et al., 2005).
Brenner and colleagues studied two different patient populations in Germany, one in the
state of Saarland and the other in the Rhine-Neckar region, by two different methods to
assess the question of CRC protection from previous screening colonoscopy. In the study
from Saarland, the prevalence of advanced neoplasms including CRC in 586 participants
following colonoscopy within the previous 10 years was compared to that in 2701
participants with no previous colonoscopy. Adjusted prevalence ratios were 0.52 for overall
CRC, 0.33 for combined left colon and rectum, and 1.05 for right-sided colon (cecum to
transverse colon) (Brenner et al., 2010a). Thus, this study showed that in the community
setting with experienced endoscopists (completing at least 200 colonoscopies and 50
polypectomies), screening colonoscopy reduced the CRC incidence strongly in the distal,
but not in the proximal, colon.
In contrast, a second study by Brenner and colleagues suggested that colonoscopy protected
against proximal CRC in average risk populations. This population-based, case-control
study based in the Rhine-Neckar region of Germany, examined 1688 CRC cases and 1932
controls and their history of previous colonoscopy within 1 to 10 years. The adjusted odds
ratios were 0.23 for overall CRC, 0.16 for left-sided CRC and 0.44 for right-sided CRC.
Significant risk reduction increased over the years in both right and left colon, in both sexes,
84 Colonoscopy
and among those with and without family history of CRC, with the exception of moderate,
non-significant risk reduction for right-sided CRC in persons aged 50-59 years (Brenner et
al., 2011).
Two main factors are likely explanations for the different results in these two studies. The
first report included participants with advanced adenomas and CRC, while the second
included only CRC patients. The development of advanced adenomas may take less time
that that of CRC. In addition, the 10-year cumulative risk of progressing from advanced
adenoma to CRC is estimated to be less than 50% in individuals 55 years or older (Brenner et
al., 2007). Second, the frequency of patients with right-sided CRC in the second study was
much higher compared to the number of patients with right-sided advanced neoplasms in
the first study, resulting in better statistics.
6. CRC mortality associated with colonoscopy

Prospectively demonstrating the beneficial effect of any intervention on CRC mortality is
difficult given the disease’s relatively long latency, and methodological needs for many
participants with long follow-up. Disease latency also contributes to a possible
underestimate of CRC prevalence. In addition, prevalent and incident cancer rates are often
indistinguishable in the reference groups such as SEER data. If colonoscopy reduces the
incidence of CRC in different screening populations, then could we logically deduct that it
has to reduce CRC mortality as well?
In a population-based, observational cohort study, Kahi et al reported on 10,492
asymptomatic average-risk patients with screening colonoscopy in a university hospital
setting. Median post-colonoscopy follow-up was 8 years (range 3-16 years). Compared to
expected rates from the SEER data, the SIR was 0.33 (a relative risk reduction of 67%).
Likewise, the standardized mortality rate was 0.35 (a relative risk reduction of 65%) (Kahi et
al, 2009).
Another study by Singh et al used Manitoba’s billing claims database to follow, until 2008, a
large cohort of 24,342 men and 30,461 women, who had their first colonoscopy between 1987
and 2007. CRC mortality after the index colonoscopy was compared with that of the general
population. Standardized mortality ratios (SMRs) were 0.71 (29% reduction) in overall
mortality, 0.53 (47% reduction) in distal CRC mortality and 0.94 (no reduction) in proximal
CRC mortality (Singh et al., 2010a).
Baxter et al using a different administrative claims database from Ontario selected 719 case
patients with a CRC diagnosis between 1996 and 2001, all of whom died of CRC by 2003.
They were matched against 5031 controls. Colonoscopy was strongly associated with fewer
deaths from left-sided CRC (adjusted OR 0.33 [95% CI, 0.28-0.39]), but not from right-sided
CRC (adjusted OR 0.99 [95% CI, 0.86-1.14]) (Baxter et al., 2009). In this study, screening
colonoscopy could not be differentiated from diagnostic procedures and completeness of
exams could not be verified.
Because of the methodological challenges associated with the studies of CRC mortality,
other investigators have turned to mathematical models in an attempt to answer the same
questions. As mentioned above, Edwards and colleagues have shown by micro-simulation
modeling that declines in CRC mortality rates are consistent with a relatively large
contribution from screening. These declines could be accelerated further with favorable
trends in higher utilization of screening (Edwards et al., 2010). Similar findings were also
found by other studies (Zauber et al., 2007; Vogelaar et al., 2006). Vogelaar et al also applied
a microsimulation model to the 2000 US population to study CRC risk factor prevalence,
screening use and treatment use. They concluded that without many changes to the current
trends (e.g., CRC screening in the eligible population rates are 43% and 47% in women and
men, respectively), CRC mortality would be reduced by 17% by 2020. However, if screening
use were increased to 70% of the target population, in tandem with improvement of CRC
risk factors and chemotherapy effectiveness, then the reduction in CRC mortality could
reach almost 50% by 2020. Screening and surveillance methods in this study included both
sigmoidoscopy and colonoscopy with FOBT.
7. CRC protection in patients after a negative colonoscopy

A number of studies have demonstrated that CRC protection after a negative colonoscopy is
durable, perhaps as long as 10-15 years. In two prospective cohort studies of average-risk
subjects, Rex and Imperiale showed that no CRC was detected at re-screening 5 years after
the negative baseline colonoscopy. In the first, the investigators re-screened 154 persons
with initial negative colonoscopy at a mean of 66 months. None had cancer while 27% had
at least one adenoma, only one of which was advanced. The presence of hyperplastic polyps
in the baseline colonoscopy did not predict incident adenomas at re-screening. However,
confounding factors including the use of non-steroidal anti-inflammatory agents might have
reduced the rate of incident adenomas (Rex et al., 1996). The second study had a larger
number of participants with negative initial colonoscopy (1256 persons, 56.7% of who were
men). Again, baseline hyperplastic polyps did not predict incident advanced adenomas. At
repeat colonoscopy, no participants had cancer and 16% had at least one adenoma. Only
1.3% of participants had advanced adenomas, more than 50% of which were located in the
distal colon. Men were more likely than women to have any adenoma, especially advanced
adenoma (RR 1.88 and 3.31, respectively) (Imperiale et al., 2008).
In 2006, two population-based studies confirmed that CRC risk following a negative
colonoscopy remained low, for as long as 10-20 years. In a case-control study in the Rhine-
Neckar region of Germany, Brenner et al analyzed the records of 380 colonoscopy cases and
485 controls without previous colonoscopy. They found a 74% risk reduction (OR 0.26 [95%
CI, 0.16-0.40]) in subjects with negative colonoscopy compared to those without previous
colonoscopy. This lower risk persisted even when the colonoscopy had been done up to 20
years previously. Interestingly, risk was lower among subjects with multiple colonoscopies,
who more often had a family history of CRC. On the other hand, with less than 20% of
multiple-colonoscopy persons reporting previous polypectomy, the possibility of missed
polyps on repeat colonoscopy would be very low indeed, thus contributing partly to this
particular finding (Brenner et al., 2006). In addition, this study still demonstrated less CRC
protection for the right colon compared to the left (OR 0.39 vs. 0.17, respectively), even when
colonoscopies without documented completeness were excluded from analysis.
Using Manitoba Health’s physician claims database, Singh et al retrospectively analyzed
32,203 individuals with negative colonoscopy. They found that a negative colonoscopy was
associated with 31% reduction in the CRC incidence up to 10 years (SIR of 0.66 at 1 year, 0.55
at 5 years, and 0.28 at 10 years). The proportion of right-sided CRC (defined as cecum to
hepatic flexure in this study) was significantly higher in the colonoscopy cohort compared
to that in the provincial population (47% vs. 28%; P<0.001). Colorectal cancer cases were
more likely to be right-sided if diagnosed within the initial 2 years, compared to those
diagnosed more than 5 years, following the index colonoscopy. There was a non-significant
86 Colonoscopy
trend toward general practitioners performing the index colonoscopy cases with subsequent
CRC detection (Singh et al., 2006).
In yet another population-based retrospective analysis in Saarland, Germany, which
examined a larger number of participants (533 with negative colonoscopy and 2701 without
previous colonoscopy), Brenner et al arrived at similar conclusions. No cancer was detected
in participants within an average of 11.9 years from negative baseline colonoscopy. The
prevalence of advanced neoplasms was more than 60% reduced at 15 years, and
approximately 50% reduced beyond 16 years, compared to those without colonoscopy
(Brenner et al., 2010b).
Certainly, a negative colonoscopy in and of itself is not a tool that can reduce CRC incidence
as a colonoscopy with polypectomy can. Its inherent value exists in its ability to reliably
predict the sustained low risk of CRC in the near and distant future. Consequently, a
negative colonoscopy supports the lengthening of colonoscopic screening intervals up to 10
years or longer, which in turn increases the cost-effectiveness of the CRC screening process
in clinical practice.
8. Gender and location in CRC protection by colonoscopy

The weight of evidence suggests that overall, colonoscopy protects against the development
of CRC. However, the degree of benefit apparently varies by colonic location and by gender.
Studies by Brenner (Brenner et al., 2010a) and Singh (Singh et al., 2010a) demonstrated
reduced incidence and mortality of distal, but not proximal CRC. Even in studies, which
suggest protection against proximal CRC, that effect appears muted (Brenner et al., 2011).
In addition, there are differences in the CRC incidence and protection by colonoscopy in
men and women. In a large meta-analysis consisting of 17 studies involving 924,932 men
and women, Nguyen et al provided strong evidence that men are at greater risk for
advanced colorectal neoplasia across all age groups. The pooled relative risk for advanced
neoplasia for men compared with women was 1.83 (95% CI, 1.69 -1.97) (Nguyen et al., 2009).
Although men in general appear to be more likely to develop incident adenomas of all types
(Imperiale et al., 2008), Schoenfeld and colleagues urged the use of the full colonoscopy in
women for CRC screening in particular due to the increased prevalence of proximal
advanced lesions in women (Schoenfeld et al., 2005).
Why colonoscopy might not protect as well against proximal CRC is not well understood. The
questions are: (1) Are more missed or early cancers located in the proximal colon? (2) Do
cancers arise de novo or from missed or incompletely resected lesions following colonoscopy?
(3) What patient or provider factors might contribute to this clinical observation?
Pohl and Robertson found that a significant number of interval cancers came from missed
lesions, which could be either cancer or adenomas. They estimated the adenoma prevalence in
the screening cohort, adenoma miss rates, cancer prevalence among patients with adenomas
based on size, and rates of adenoma-to-cancer transitions from the literature. They then used a
model to apply these risk estimates to a hypothetical average-risk population that received
screening colonoscopies. They found that the expected rate of persons with CRC from missed
cancer and adenomas was 1.8 per 1000 persons within 5 years (range: 0.5-3.5 per 1000 screened
persons) (Pohl & Robertson, 2010). This rate would more than double (5.1 per 1000 screened
persons) if colonoscopy is applied to an entirely adenoma-bearing population. When this
model was extrapolated to average-risk patient populations (Kahi et al., 2009; Lieberman et al.,
2007), they found that approximately 65% of the interval cancers might have been related to
missed adenomas. When compared against the observed risks in the adenoma-bearing
populations (Alberts et al., 2000; Winawer et al., 1993, Pabby et al. 2005), between 70% and 80%
of interval cancers might be attributed to a missed lesion.
Bressler et al determined that the rates of missed cancer in the proximal colon were more
than twice as high as those in the distal colon. Using the data from Ontario registries, they
calculated the rates of interval colorectal cancers in different locations. The interval cancers
were defined as cancers found within 6 and 36 months following a colonoscopy. The rates of
the right-sided and transverse colon cancers were 5.9% and 5.5%, respectively, while those
of the left-sided colon (distal to the splenic flexure) were halved (2.1%-2.3%) (Bressler et al.,
2007). The independent risk factors for these interval cancers were older age, diverticular
disease, proximal CRC, colonoscopy in an office setting, and colonoscopy by an internist or
family physician.
Although women tend to have fewer adenomas than men, their adenomas tend to occur in
the proximal colon. Therefore, it is not surprising to find that proximal CRC protection is
lower in women than in men.
Additional studies confirm that the issues of gender and CRC location are intertwined.
Singh et al in a population-based study using the Manitoba Cancer Registry examined a
cohort of 4883 patients with CRC. They classified 388 (7.9%) of these as early or missed
cancers, i.e. those that were detected in the time frame of 6-36 months after a colonoscopy,
with a range of 4.5% of distal cancers in men to 14.4% of proximal cancers (cecum to splenic
flexure) in women (Singh et al., 2010b). In another case-control study in the California
Medicaid population with 4458 CRC cases and 43,815 controls, Singh et al again found that
despite the overall CRC risk reduction of 45% (RR 0.55 [95% CI, 0.46-0.65]), CRC protection
for the left colon after negative colonoscopy (0.16) was disproportionately higher than that
for the right side (0.67). The CRC risk reduction for both sexes was equivalent in the left
colon (84%), but that for women in the right colon was only 18%, compared to 62% for men
(Singh et al., 2007).
Even in patients with negative colonoscopy, differential CRC protection by colonic location
was also observed. In a large population-based retrospective analysis, Lakoff et al studied
111,401 patients with negative previous colonoscopy. As in other studies on negative
colonoscopy, they found a significant CRC risk reduction up to 14 years of follow-up,
compared to the Ontario population (RR 0.21 [95%CI, 0.05-0.36]). However, the sustained
reduction in incidence of proximal CRC only started in year 8 (Lakoff et al., 2008).
9. Factors that influence the impact of video colonoscopy

There are several possible explanations for missed or early CRC, particularly in the proximal
colon. We can divide these into two categories, operator-independent and operator-
dependent. The operator-independent category includes tumor biology, patient-related
factors and endoscopic technology. The operator-dependent category includes a set of key
skills required for a successful colonoscopy performance, i.e., high adenoma detection rate
and cecal intubation rate, adequate instrument withdrawal time and adequate training in
both endoscopic techniques and conceptual knowledge of colon cancer.
9.1 Operator-independent factors

The traditional adenoma-to-carcinoma sequence characterized by chromosomal instability
or mismatch repair defects explains most, but apparently not all, CRC. Recently, there is a
88 Colonoscopy
growing body of evidence pointing to other lesions as the precursors in CRC carcinogenesis
(Jass, 2001). In 1990, Longacre and Fenoglio-Preiser first coined the term “serrated
adenoma” as a distinct form of colonic neoplasia, 11% of which contained foci of
intramucosal carcinoma (Longacre & Fenoglio-Preiser, 1990). Mäkinen et al showed that
5.8% of all CRC in their study developed through the sessile serrated adenoma (SSA)
pathway. These lesions have a predilection for the proximal colon (51% in the cecum) and
excessive mucus production (Mäkinen et al., 2001). Sessile serrated adenomas in the
proximal colon tend to be slightly larger, mucus-covered, flatter, and harder to detect than
distal lesions (Spring et al., 2006; Torlakovic et al., 2003). Instead of the progressive
accumulation of APC, K-ras, DCC and p53 gene mutations in the traditional adenoma-to-
cancer sequence (Vogelstein et al., 1988), sessile serrated adenomas are characterized by the
CpG island methylator phenotype (CIMP) and three-fold increase in DNA microsatellite
instability (MSI) as a result of hypermethylation-related gene silencing and BRAF oncogene
mutations (Mäkinen et al., 2001). This carcinogenic pathway may also be associated with
more rapid transformation to cancer (Sawhney et al., 2006; Arain et al., 2008). Other studies
also showed significantly higher MLH1 and MGMT promoter methylation in the normal
proximal colon in older women (Worthley et al., 2010; Menigatti et al., 2009) and K-ras
mutations in 80% of hyperplastic polyps in women, compared to 36% in men (Otori et al.,
1997), suggesting the intriguing possibility that the epigenetic signatures of cancers may
have sex- and segment-specific, early-stage and normal-tissue counterparts.
The failure to detect proximal lesions may also be caused by incomplete colonoscopy, which
in turn is associated with patient-related factors such as prior history of pelvic or abdominal
surgery (i.e., hysterectomy, gastrectomy), old age and inadequate bowel prep (Lee et al.,
2006). For the first two factors, adequate conscious sedation or water immersion technique
has been used to improve the colonoscopy performance (Leung et al., 2010). For the third
factor, poor colon preparation reduces polyp detection, both large and small, especially in
the right colon (Froelich et al., 2005; Harewood et al., 2003). Split-prep protocol has been
used to address this problem (Marmo et al., 2010).
Another way of rendering the colonoscopy safe and painless is the use of computer-assisted
self-propelled colonoscopes and swallowed video capsules for atraumatic locomotion
through the colon. Several different systems have been tested for their feasibility. The
Invendoscope™ (Invendo Medical, Kissing, Germany) is a single-use colonoscope based on
motor driven inverted sleeve technology with a working channel (Rösch et al., 2008). This
system has been shown to nearly painlessly achieve high cecal intubation rate comparable to
that of the video colonoscope (Groth et al., 2011). However, no data are currently available
on its diagnostic accuracy. The Endotics System (ES) is another robotic device composed of a
workstation and a disposable probe, the advancing of which through the colon follows a
cyclic sequence of steps (Cosentino et al., 2009). Although taking longer time to complete
and having lower cecal intubation rate, the ES has been shown to have comparable
sensitivity and specificity for the detection of lesions and require no sedation (Tumino et al.,
2010). The Aeroscope (GI View Ltd, Ramat Gan, Israel), a self-propelled, disposable
endoscope using low-pressure carbon dioxide to propel a balloon device through the colon,
on the other hand, did not reduce abdominal discomfort in healthy volunteers although it
did achieve cecal intubation (Vucelic et al., 2006). The Video Capsule Endoscopy (Given
Imaging Ltd., Yoqneam, Israel), a pill-size capsule activated upon swallowing,
demonstrated lower sensitivity compared to that of standard colonoscopy (Van Gossum et
al., 2009).
Regular white light technology may contribute to the under-recognition of the neoplastic
lesions in the proximal colon. For paler, smaller, flatter adenomas, the use of high-definition
white light and chromoendoscopy with methylene blue or indigo carmine has been shown
to improve adenoma detection rate (Rex, 2010). Electronic highlighting such as narrow band
imaging (NBI), Fuji Intelligent Chromo Endoscopy (FICE), autofluorescence and I-scan have
not consistently proved effective to augment adenoma detection rate.
Another method of increasing the rate of polyp detection is to improve the view through the
colonoscopic lens. Wide-angle-view (> 170 degrees) colonoscopy, hooded colonoscopy and
the Third-Eye Retroscope are several new technologies being developed to expose hidden
mucosa during colonoscopy. They have shown some initial promise in improving adenoma
detection and are under active investigation (Rex, 2010).
9.2 Operator-dependent factors

Colonoscopy performance is clearly operator-dependent requiring quality training and
experience. Tandem endoscopic studies showed miss rates of 0-6% for adenomas 1 cm or
larger, and 12-13% for adenomas 6-9 mm in size, and 15-27% for adenomas 5 mm or smaller
(Rex et al., 1997; Hixson et al., 1990). When computed tomography colonography (CTC) was
used in segmental unblinding to assess polyp detection during colonoscopy, the miss rates
increased to 12% for adenomas 1 cm or larger (Pickhardt et al., 2004).
These miss rates varied among endoscopists, suggesting that skillful colonoscopy
performance plays a major role in neoplasia detection and prevention. In a large tandem
endoscopic study, Chen et al demonstrated a wide range of adenoma miss rates from 17% to
48% among 26 colonoscopists (Chen et al., 2007). Rex et al in another large study also
showed cancer miss rates of 3% for gastroenterologists and 13% for non-gastroenterologists
(Rex et al., 1997). Other studies also found that endoscopist quality measures were closely
associated with post-colonoscopy or interval colorectal cancer. Colonoscopy by an internist
or family physician in the office setting was associated with higher CRC incidence following
colonoscopy (Baxter et al., 2011; Bressler et al., 2007). In patients with negative colonoscopy,
those who had their procedures performed by a gastroenterologist were less likely to
develop CRC (Rabeneck et al., 2010). Interestingly, there was no correlation between high
colonoscopy volume and lower CRC incidence, suggesting that ongoing training and
tracking of quality indicators for colonoscopy are crucial.
The optimal measures for “high quality” colonoscopy are under debate. Three frequently
discussed indicators are adenoma detection rate, cecal intubation rate or endoscopy
completion rate, and instrument withdrawal rate. Using the database of the National
Colorectal Cancer Screening Program in Poland from 2000 to 2004, Kaminski et al studied a
large population of 45,026 subjects who underwent colon cancer screening by 186
endoscopists. They suggested that the higher an adenoma detection rate (ADR) (in this case,
20% or higher), the better CRC protection could be obtained from the screening colonoscopy
(Kaminski et al., 2010). The investigators used an ADR of 20% or higher as the gold standard
and this ADR is close to those recommended in the US guidelines (15% among women and
25% among men) (Rex et al., 2002). They found that the relative risks of interval cancer
following colonoscopy were 10-12 folds higher if the ADR was less than 20%. They also
found that the rate of cecal intubation was not significantly associated with the risk of
interval cancer.
The need for high cecal intubation or colonoscopy completion rates (95% or higher for
screening in healthy adults) is based on repeated observations that CRC protection by
90 Colonoscopy
colonoscopy is suboptimal in the proximal colon as discussed above. Documentation of

cecal intubation has been encouraged as part of ongoing quality improvement program (Rex
et al., 2006). However, evidence for a strong association between cecal intubation and
reduction in proximal CRC incidence or mortality has yet to be demonstrated.
Likewise, instrument withdrawal rate emerged as an important quality indicator when
withdrawal time quicker than 6 minutes was shown to be associated with a lower rate of
adenoma detection (Barclay et al., 2006). However, later, in another study, institution-wide
policies to keep the colonoscopic withdrawal time within the recommended limits had no
effect on polyp detection rate (Sawhney et al., 2008).
10. Conclusion
In summary, the emergence of colonoscopy as the preferred screening test for colorectal
cancer by both the public and the medical profession coincides with the substantial decline
in the incidence and mortality related to this disease. The impact of colonoscopy on CRC
incidence can be seen in various patient populations, including the adenoma cohorts and
average-risk cohorts, and this positive protection effect can be long-lasting in individuals
with negative colonoscopy as well. However, colonoscopy is imperfect when it comes to
CRC protection in the proximal colon, especially in women, although men are more likely to
develop incident adenomas. This gender and location disparity can be caused by multiple
factors including tumor biology, technological shortcomings, patient-related issues and
endoscopist skill level. When colonoscopy fails, often it is due to inadequate lesion detection
by the endoscopist. Therefore, the endoscopist can bring about the most significant positive
impact on CRC prevention through continuous quality improvement programs.
11. Acknowledgement
We wish to express our sincere thanks to Ms. Eileen Keenan and Ms. Kathleen Lugas for
their critical help in preparing the manuscript.
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6
Post-Polypectomy Colonoscopy Surveillance

Sung Noh Hong
Department of Internal Medicine, Konkuk University School of Medicine, Seoul
Korea
1. Introduction
Surveillance is becoming common in the practice of colonoscopy because a large number of
patients with colorectal polyps are now being discovered as a result of the increased use of
colorectal cancer screening, and particularly because of the dramatic increase in screening
colonoscopy. Although the term ‘colorectal polyp’ is not synonymous with colorectal
adenoma, two-thirds of colorectal polyps are adenomas and most colorectal cancers arise
from them. Therefore, removal of colorectal polyps using colonoscopic polypectomy has
been shown to reduce the risk of future colorectal cancer (Winawer et al., 1993; Atkin et al.,
2010).
A patient with one colorectal adenoma has a 30 to 50% likelihood of harboring a second
synchronous adenoma elsewhere in the colon and rectum at that time, and they have a 30-
50% likelihood of developing metachronous adenoma sometime in the future (Winawer et
al., 2006; Arditi et al., 2009). Therefore, to minimize the risk for colorectal cancer in the
future, patients with adenomas are usually placed into a post-polypectomy surveillance
program.
Post-polypectomy surveillance refers to periodically examining the colon to detect and
remove missed synchronous and new metachronous adenomas and cancers, by screening or
other means, after the detection and removal of a precancerous lesion. Generally, it does not
refer to the use of colonoscopy or other procedures to monitor for polyp or cancer
recurrence following a diagnosis of colorectal cancer.
This chapter reviews the rationale, the recent literature and the current recommendations
for post-polypectomy surveillance, with emphasizing the need to tailor surveillance
strategies to the carefully considered individualized assessment of the risk factors as related
to the characteristics of the baseline adenoma and those of the individual patient.
2. Risk of colorectal adenoma or cancer following polypectomy

The objective of post-polypectomy surveillance is to reduce the risk of the development of
and death from a colorectal cancer by detecting and removing subsequent adenomas and
cancers. The largest study on the risk of colorectal cancer after removal of adenoma in the
colon or rectum was reported in 2010 from St. Mark’s Hospital, London by Atkin et al. and
the study involved using flexible sigmoidoscopy screening (Atkin et al., 2010). After 113,195
people were assigned to the control group and 57,237 people were assigned to the
intervention group, they were followed for a median of 11.2 years. The incidence of
colorectal cancer in the patients who underwent sigmoidoscopy was reduced by 23%
98 Colonoscopy
(hazard ratio: 0.77, 95% CI: 0.70-0.84) and mortality was reduced by 31% (hazard ratio: 0.69,
CI: 0.59-0.82). On the per-protocol analyses, after adjusting for a self-selection bias for the
patients who underwent sigmoidoscopy, the incidence of colorectal cancer in the people
attending the screening was reduced by 33% (hazard ratio: 0.67, CI: 0.60-0.76) and the
mortality was reduced by 43% (hazard ratio: 0.57, CI: 0.45-0.72). The relative colorectal
cancer risk after polypectomy in all the previously published studies has ranged from 0.2
(range: 0.1–0.6) in the National Polyp Study to 1.3 (range: 0.6–2.3) in the Funen Adenoma
follow-up Study (Winawer et al., 1993; Meagher and Stuart 1994; Citarda et al., 2001; Lund
et al., 2001; Bertario et al., 2003; Loeve et al., 2005; Atkin et al., 2010). The difference can
partially be explained by the inclusion or exclusion of patients with large sessile polyps and
other factors too such as the patient characteristics at baseline, the duration of follow-up, the
patient compliance and the quality of the initial colonoscopy and polypectomy. The risk of
colorectal cancer for patients after polypectomy is lower than that in the general population.
2.1 Concept of the advanced adenoma as a surrogate marker of colorectal cancer

Based on the studies on the prevalence of adenoma from autopsy, the studies on follow-up
colonoscopy after polypectomy and the lifetime cumulative incidence of colorectal cancer, it
appears that only about 5% of colorectal adenomas undergo malignant transformation
(Muto et al., 1975; Stryker et al., 1987; Vogelstein et al., 1988; Center et al., 2009; Hong et al.,
2010). These follow-up experiences as well as the increasing information about the
molecular genetics for the adenoma-carcinoma sequence are increasingly shifting the
emphasis away from simply finding and harvesting large numbers of clinically insignificant
adenomas toward strategies that focus on ways to reliably detect and resect the less
common, but clinically much more dangerous advanced adenoma.
Colorectal carcinogenesis is a multistep process that occurs over many years and it results
from the progressive accumulation of genetic and epigenetic alterations. An adenoma is a
monoclonal derivative of a single epithelial stem cell that either inherits or acquires the first
of these many genetic alterations. Each additional genetic "hit," which is probably caused by
environmental carcinogenic factors, leads to a new clone of daughter cells with a growth
advantage that allows the clone to take over the developing polyp. The reason most small
simple tubular adenomas stay small and clinically benign is because they never develop the
additional genetic alterations needed to make them advance (Vogelstein et al., 1988).
Observational studies also reported the different behavior of small tubular adenomas and
advanced adenomas. Most previous studies of the natural history of small colorectal
adenomas showed no increase in size, no changes that would have necessitated treatment
within a couple of years and that malignant transformation is rare. Hoff et al. reported that
215 polyps less than 5 mm in diameter were left in situ in 112 persons for a 2 year follow-up
period to ascertain their growth rate. At the end of the 2 years, 49% of the adenomas had
increased in size and 14% had regressed. Although the total adenoma mass had increased
by 36%, none had grown to a size greater than 5mm and none had developed high-grade
dysplasia or cancer (Hoff et al., 1986). On the other hand, Eide reported that the risk of
developing cancer in a 1cm sized adenoma was 3% per year in a Norwegian population
(Eide 1986). Stryker et al. showed the considerable malignant potential of large adenomas.
Before the availability of colonoscopy, 226 patients who had large (>l cm) polyps detected
with a barium enema, but who refused their removal by surgery were followed for up to 20
years. Follow-up of these untreated patients showed that 37% of the polyps enlarged, 21
invasive cancers developed at a polyp site and 11 cancers developed at another site. The
Post-Polypectomy Colonoscopy Surveillance 99
cumulative risk of cancer at 5, l0 and 20 years was 2.5, 8 and 24%, respectively (Stryker et al.,
1987).
Based on a large volume of high-quality scientific evidence published during the past
decade, the concept of the advanced adenoma as a surrogate biological indicator of the
cancer risk has been established (Winawer and Zauber 2002). Although colorectal cancer
would be a more ideal outcome measure, the advanced adenoma was adopted as an early
outcome measure of efficacy because a much longer period of time would be required for
conclusions to be drawn if cancer was used as the outcome measure.
The recent guidelines for surveillance after polypectomy have adopted the concept of
advanced adenoma and the guidelines have introduced the concept of risk stratification of
patients at the time of polypectomy into those who are more likely or less likely to develop
subsequent serious neoplasia (Bond 2000; Davila et al., 2006; Winawer et al., 2006; Sung et
al., 2008; Arditi et al., 2009; Schmiegel et al., 2009; Cairns et al., 2010). However, a uniform
definition of an advanced adenoma has not yet been clearly established, but most definitions
include that advanced adenoma is an adenoma with high-grade dysplasia or an adenoma
that is >10 mm in size or it has a villous component (≥25%), and advanced neoplasia is
advanced adenoma and invasive cancer. A synchronous adenoma is an adenoma that is
diagnosed at the same time as that of an index colorectal neoplasm. Thirty to fifty percent of
colons with one adenoma will contain at least one other synchronous adenoma. A
metachronous adenoma is an adenoma that is diagnosed at least 3 to 6 months after the
diagnosis of a previous adenoma.
2.2 Colonoscopy is the procedure of choice for post-polypectomy surveillance

Colonoscopy is the preferred modality for post-polypectomy surveillance. It offers the
advantages of complete visualization of the entire colon, detection and removal of polyps,
and diagnostic sampling of cancers. An early controlled, single-blinded study that
compared the accuracy between colonoscopy and a double contrast barium enema
performed in the same patients demonstrated a sensitivity of double-contrast barium enema
and colonoscopy for detecting polyps of 67% and 94%, respectively (Durdey et al., 1987;
Winawer et al., 2000).
Computed tomography (CT) colonography is now being studied for the surveillance of
patients with colorectal cancer or polyps. CT colonography has already been shown to be
more accurate than a double-contrast barium enema for detecting polyps as well as having
similar or more accuracy than colonoscopy for detecting large (≥ 1cm) polypoid adenomas,
although the accuracy rapidly drops for medium-sized and small polyps (Kim et al. 2007;
Benson et al., 2010). However, a major limitation of CT colonography compared with
conventional colonoscopy is that, as with a barium enema, this modality has only
diagnostically usefulness. Whenever a suspicious lesion or clinically significant neoplasia is
found, the patient must undergo a subsequent colonoscopy to confirm and resect the lesion.
Considering a patient with one colorectal adenoma has a 30-50% likelihood of developing
new metachronous adenoma, the need to do two expensive tests would make such
surveillance costly and inconvenient.
3. Quality of baseline colonoscopy

The quality of the baseline colonoscopy is important to clearly visualize synchronous and to
predict the risk for subsequent neoplasia. To assess the quality of colonoscopy, several direct
100 Colonoscopy
and indirect quality measures have been proposed, including the bowel preparation status
and other parameters for the performance of colonoscopy, and the parameters include the
cecal intubation rate, the withdrawal time and the adenoma detection rate. Until now, there
is a lack of objective data related to any of these measures to assess the most important
outcome of screening colonoscopy, which is the subsequent incidence of advanced adenoma
or colorectal cancer. However, the US Multi-Society Task Force defined a high-quality
colonoscopy as a colonoscopy that reaches the cecum, it has little fecal residue and it has a
minimum time of withdrawal from the cecum of 6–10 minutes (Rex et al., 2002). With the
current recommendations suggesting that the postpolypectomy surveillance colonoscopy
intervals should lengthen to improve the efficacy of the utilization of resources, the need for
high-quality colonoscopy is of paramount importance.
3.1 Bowel preparation

Even small amounts of fecal material can obscure colorectal adenomas, advanced adenoma
and cancers. In a retrospective evaluation of more than 5,000 colonoscopies performed over
a 3.5-year period, Leaper et al. identified 17 patients with a missed colorectal cancer. Poor
bowel preparation was noted in 6 of these patients, which suggested that the cleansing
quality may have an impact on the diagnostic yield during a colonoscopy.(Leaper et al.,
2004) In a larger retrospective study, Harewood et al. analyzed the impact of the adequacy
of bowel-preparation on the detection of polypoid lesions for approximately 93,000
colonoscopies recorded in the Clinical Outcome Research Initiative database. Suspected
neoplasms were identified in 26,490 colonoscopies (29%) overall, with higher detection rates
for those cases with adequate preparation (rated excellent or good by the endoscopist)
versus those cases with inadequate preparation (fair or poor) (29% vs. 26%, respectively,
P<.0001). Although significant lesions (a polyp >9 mm or a mass lesion) were detected in
approximately 7% of the colonoscopies, regardless of preparation quality (P = .82), lesions ≤
9 mm were more likely to be detected when the bowel preparation was adequate versus
inadequate (22% vs. 19%, respectively P<.0001) (Harewood et al., 2003). Although the risk of
advanced neoplasia increases with polyp size, high-grade dysplasia and carcinoma can
occur in adenomas of any size. High-grade dysplasia was reported in 0.9 to 3.4% of the
adenomas ≤5 mm and in 3.6 to 12.5% of the adenomas 5 or 6 mm to 10 mm in size.
In addition, a prospective study by Froehlich et al. reported that the detection of neoplasia,
including polyps of any size as well as large lesions (>10 mm), was associated with the
quality of bowel preparation; polyps were detected in 29% of the patients with high-quality
cleansing versus 24% of the patients with low-quality cleansing (P<.007). Identifying polyps
of any size significantly depended on the cleansing quality (intermediate-quality vs. low-
quality preparation: OR: 1.73, 95% CI: 1.28-2.36; high-quality vs. low-quality preparation:
OR: 1.46, 95% CI: 1.11-1.93). For polyps ≥ 10 mm in size, the OR was 1.83 (95% CI: 1.11-3.05)
for intermediate-quality cleansing and 1.72 (95% CI: 1.11-2.67) for high-quality cleansing,
respectively (Froehlich et al., 2005). Furthermore, flat and depressed lesions are rarer than
protruding lesions, but they more frequently contain advanced neoplasia, including
invasive carcinoma. Parra-Blanco et al. reported that the number of flat lesions detected in
patients with inadequate bowel preparation was significantly lower than that in patients
with adequate bowel preparation (9 vs. 28, respectively, P = .002) (Parra-Blanco et al., 2006).
3.2 Adenoma detection rate

In one of the most important studies of the past year, Kaminski et al. demonstrated that the
adenoma detection rate for individual endoscopists, which is the most commonly proposed
proxy for quality in colorectal cancer screening, is indeed an independent predictor of the
risk for subsequent colorectal cancer after screening colonoscopy. Among 45,026 patients
who were enrolled in a national screening colonoscopy program, 42 interval colorectal
cancers were identified by a search of national and regional cancer registries in Poland. Most
patients with cancer had no family history of colorectal cancer (83.3%) and no polyps
identified on the screening examination (92.9%). Only one cancer (2.4%) was attributed to
incomplete polyp resection at the time of the screening procedure. The 186 contributing
endoscopists had a median adenoma detection rate of 12.2%. The 42 interval cancers
occurred after procedures by 32 endoscopists, with three endoscopists contributing three
cases each and four contributing two cases each. A strong association between the adenoma
detection rates and the subsequent identification of interval cancers was noted (P=0.008),
with significant hazard ratios for those endoscopists with adenoma detection rates of less
than 11%, 11–14.9%, and 15–19.9%, as compared with those endoscopists with adenoma
detection rates over 20% (P = 0.02 for all comparisons). The adenoma detection rate is an
independent predictor of the risk of interval colorectal cancer after screening colonoscopy
(Kaminski et al., 2010).
3.3 Withdrawal time

Numerous published series have assessed correlations between the proportion of patients
with identified polyps or adenomas and the colonoscopic withdrawal time. Barclay et al
compared the rates of detecting neoplastic lesions among 12 gastroenterologists who had
mean colonoscopic withdrawal times of less than 6 minutes with the rates of those
gastroenterologists who had mean withdrawal times of 6 minutes or more. There were large
differences among the gastroenterologists in the adenoma detection rates (9.4% to 32.7%)
and in their withdrawal times of the colonoscope from the cecum to the anus (range: 3.1 to
16.8 minutes). As compared with the colonoscopists with mean withdrawal times of less
than 6 minutes, those colonoscopists with mean withdrawal times of 6 minutes or more had
higher rates of detecting any neoplasia (28.3% vs. 11.8%, respectively P<0.001) and advanced
neoplasia (6.4% vs. 2.6%, respectively, P=0.005) (Barclay et al., 2006). Furthermore, most
series have also shown significant associations between the speed of withdrawal and the
polyp or adenoma detection rates, and some series have shown associations between the
speed of withdrawal and the detection of high-risk lesions, based on size or histology.
3.4 Cecal intubation

Cecal intubation is defined as insertion of the colonoscope tip into the cecal caput so that the
medial wall of the cecum proximal to the ileocecal valve can be fully inspected. The targets
for successful cecal intubation rates are 90% for all colonoscopies and 95% for screening
colonoscopies. However, because almost all the previous studies excluded the colonoscopy
with incomplete cecal intubation from analysis, there is very scare information about the
effect of incomplete colonoscopy on the detection of advanced neoplasia with surveillance
colonoscopy. In the Funen adenoma follow-up study by Jorgensen and colleagues, the 53
patients with incomplete initial colonoscopy had at least 1 complete colonoscopy during
surveillance; advanced neoplasia was detected in 6 of these patients. The area of new
advanced neoplasia had been covered by the initially incomplete colonoscopy in three of the
six patients, and later the area was covered in four of the six, before advanced neoplasia was
detected. Newly detected advanced neoplasia was associated with incomplete colonoscopy
at the initial examination (OR: 2.5; 95% CI: 1.0-6.3) (Jorgensen et al., 1995).
102 Colonoscopy
3.5 Completeness of polypectomy

In the absence of magnifying endoscopy combined with dye spraying, it is often not possible
to determine the histological type of a polyp by endoscopic inspection. Diminutive polyps
(<5 mm) may be indistinguishable from hyperplastic polyp and adenomas. In addition, the
unusual large hyperplastic polyp may mimic an adenoma. For this reason, all polyps should
be considered for removal. Magnifying endoscopy is likely to become increasingly available
and an endoscopic diagnosis may reduce the requirement to remove minute polyps in
patients with multiple lesions. Diminutive polyps may be too numerous to be completely
cleared. In subjects with multiple small polyps, a sample of at least three should be biopsied
for histological study. The cancer risk is related to the number of adenomas, so the
documentation of the polyp type has prognostic value and surveillance implications. Hot
biopsy and electrocoagulation have been used to eradicate diminutive polyps, but
destruction of the specimen makes it difficult to histologically review it, and hot biopsy and
electrocoagulation may leave residual polyp behind. Cold snare polypectomy is an effective
alternative and it does not compromise the histology(Deenadayalu and Rex 2005).
Lesions less than 2 cm in diameter can readily be transected with one application of the
snare with submucosal injection. Inclusion of a small portion of normal mucosal adjacent to
the confines of the polyp does not pose a problem, providing that this portion of normal
mucosa is also resting on the submucosal fluid-filled bleb. However, sessile polyps greater
than 2cm in diameter may require piecemeal removal, but this will make histological
evaluation difficult or it may be impossible to completely remove them in a piecemeal
fashion. Residual neoplastic tissue has been reported in up to one-third of cases after
piecemeal resection of sessile polyps greater than 2cm in diameter. The area may be tattooed
with sterile India ink to facilitate follow-up evaluation. Tattooing will also identify the site
for subsequent surgical resection. A repeat clearing colonoscopy to insure complete
polypectomy is essential after piecemeal resection of large sessile polyps. Such polyps often
contain appreciable amounts of villous tissue with a high malignant potential and they tend
to recur locally after colonosoopic resection even in cases where the initial polypcctomy
appeared to be complete. A repeat clearing colonoscopy should be performed in 3-6 months
to confirm that the resection was complete (Winawer et al., 2006; Cairns et al., 2010). In order
to decrease the incidence of recurrent polyp at the polypectomy site, the base and edges of
the polyp can be treated with a thermal modality. Although many endoscopists treat small
residual fragments of adenoma following removal of large polyps with a thermal modality,
this has not been studied for any device except the argon plasma coagulator (Zlatanic et al.,
1999). If polyp tissue persists after two or three examinations, then patients with low
surgical morbidity should usually be referred for surgical resection. When patients are
found to have these large sessile polyps, they need to be educated at the time of the initial
diagnosis about the importance of complying with the entire course of management and
follow-up. Most experienced colonoscopists have witnessed tragic cases in which a patient
was partially treated by piecemeal snare polypectomy and was then lost to follow-up, and
the patient returned later with an advanced cancer at the polyp site.
4. Predictors of subsequent advanced adenomas

The increased risk of recurrent adenomas after polypectomy is the result of lesions missed
during the initial colonoscopy as well as a true increased risk of developing de-novo
neoplastic lesions due to environmental and genetic risk factors that are particular to the
patient. In other words, the characteristics of initial adenoma and the patient serve as a
marker for an increased risk of colorectal neoplasia. Although multiple studies have tried to
identify the risk factors for metachronous neoplasia at the time of surveillance, the studies
differed with respect to the classification levels of the risk factors and on the definition of
advanced neoplasia. In addition, the studies also covered different periods of follow-up
evaluation and they used different measures of effect such as ORs, relative risks, hazard
ratios and standardized incidence ratios. To clarify these issues, Martinez and colleagues
published the pooled analysis using individual data from 8 prospective studies (The
Antioxidant Polyp Prevention Study, National Polyp Study, Calcium Polyp Prevention
Study, Wheat Bran Fiber study, Veterans Affairs Cooperative Study, Aspirin Folate Trial
and Ursodeoxycholic Acid study) that included 9167 men and women aged 22 to 80 with
previously resected colorectal adenomas to quantify their risk of developing subsequent
advanced adenoma or cancer, as well as to identify factors associated with the development
of advanced colorectal neoplasia during surveillance (Martinez et al., 2009).
4.1 Characteristics of baseline adenomas

4.1.1 Multiplicity
Multiplicity at baseline has been shown to predict subsequent detection of advanced
adenomas. The pooled analysis of prospective studies showed that the number of adenomas
at baseline was related to an increased risk (OR: 1.32, 95% CI: 1.25–1.40) for advanced
adenomas at the time of surveillance. Of the randomized controlled trials, with excluding
the studies included in the pooled analysis, Funen’s adenoma follow-up study and the
European fiber and calcium study showed that multiplicity conferred an increased risk for
advanced neoplasia at the time of surveillance. The Erlangen Registry of Colorectal Polyps
by Nusko and colleagues showed that individuals with 2 or more adenomas at baseline
were more likely than those with 1 adenomas at baseline to have an adenoma detected at the
time of surveillance (OR: 1.54, 95% CI: 1.12–2.12).
The observational prospective cohort studies also showed that multiplicity was a risk factor
for subsequent advanced adenomas and cancer. Noshirwani and colleagues reported that
the number of adenomas at baseline was related to an increased risk (OR: 1.25, 95% CI: 1.13–
1.38) for advanced adenomas at surveillance in a cohort from the Cleveland Clinic.
However, the Study of Colonoscopy Utilization described by Pinsky and Bertario et al.
failed to show a significant association between baseline multiplicity and the detection of
advanced adenoma at the time of follow-up evaluation.
Study Number of Total Patients with Adjusted

index adenoma patients Metachronous OR/RR/HR
(N) Advanced (95% CI)
Neoplasia (N)
Jorgensen (The Funen 1 not mentioned 1
Adenoma Follow-up 2 not mentioned 1.3 (0.6-3.0)
Study) 1995 ≥3 not mentioned 3.0 (1.2-7.1)
Noshirwani per 1 increase 697 63 1.25 (1.13-1.38)
(Cleveland Clinic
Foundation Adenoma
Registry) 2000
104 Colonoscopy
Nusko (Erlangen 1 not mentioned 1

Registry of Colorectal ≥2 not mentioned 1.54 (1.12–2.12)
Polyps) 2002
Bertario 2003 1 736 7 1
≥2 350 7 2.0(0.7–5.8)
Bonithon-Kopp 1 360 18 1
(European Fiber- 2 109 8 1.4 (0.59–3.51)
Calcium Intervention ≥3 83 15 3.6 (1.64–7.89)
trial) 2004
Martinez (Pooled 1 5465 497 1
anaylsis) 2009 2 2054 271 1.39 (1.17–1.66)
3 890 146 1.85 (1.46–2.34)
4 326 68 2.41 (1.71–3.40)
≥5 377 94 3.87 (2.76–5.42)
Pinsky (Study of 1–2 small not mentioned 1
Colonoscopy tubular
Utilization) 2009 adenoma
≥ 3 small not mentioned 1.5 (0.8–2.6)
tubular
adenoma
The below studies were included in the pooled analysis (Martinez et al. 2009)
Winawer (National 1 541 6 1
Polyp Study) 1993 2 200 4 1.5 (0.4-5.6)
≥3 197 18 6.9 (2.6-18.3)
van Stolk (Antixoidant 1 or 2 393 13 1
Polyp Prevention ≥3 84 5 1.13 (0.40–3.18)
Trial) 1998
Martinez (Wheat bran 1 742 86 1
fiber trial) 2001 2 284 28 0.76 (0.43–1.36)
≥3 261 32 1.01 (0.54–2.10)
Table 1. Multiplicity of adenoma as a risk factor for advanced neoplasia at surveillance
4.1.2 Size
An adenoma size larger than 1 cm also was shown to predict metachronous advanced
adenomas in a pooled analysis of prospective studies by Martinez (OR, 1.68; 95% CI, 1.39-
2.02). However, other randomized controlled trials, including Funen’s adenoma follow-up
study and the European fiber and calcium study, did not find adenoma size at baseline to be
an independent predictor of advanced neoplasia at the time of surveillance. Adenoma size
was important in the prospective observational cohort studies that assessed advanced
neoplasia. Noshirwani’s study, the Erlangen Registry of Colorectal Polyps and the Study of
Colonoscopy Utilization showed that a baseline adenoma of 1 cm or larger, as compared
with a baseline adenoma 1cm or smaller, conferred an OR of 3.68 (95% CI: 2.01-6.76), 1.81
(95% CI: 1.42-2.31) and 1.5 (95% CI: 1.03–2.3), respectively, for subsequent advanced
neoplasia. Bertario found that patients with adenomas larger than 2 cm, as compared with
adenomas 2 cm or smaller, at baseline had a hazard ratio of 4.0 (95% CI: 1.1–14.4) for the
development of follow-up advanced adenomas.
Study Size of index Total Patients with Adjusted

adenoma (mm) patients Metachronous OR/RR/HR
Neoplasia (N)
Jorgensen (The Funen ≤5 not mentioned 1
Adenoma Follow-up 6-10 not mentioned 1.2 (0.5-2.9)
Study) 1995 >10 not mentioned 1.2 (0.5-2.9)
Noshirwani < 10 not mentioned 1
(Cleveland Clinic ≥ 10 not mentioned 3.68 (2.01-6.76)
Foundation Adenoma
Registry) 2000
Nusko (Erlangen ≤10 not mentioned 1
Registry of Colorectal > 10 not mentioned 1.81 (1.42–2.31)
Polyps) 2002
Bertario 2003 ≤10 700 6 1
10-20 256 4 1.9 (0.5–6.6)
> 20 107 4 4.0 (1.1–14.4)
Bonithon-Kopp <10 243 19 1
(European Fiber- ≥ 10 309 22 1.06 (0.54–2.06)
Calcium Intervention
trial) 2004
Martinez (Pooled <5 2540 209 1
anaylsis) 2009 5-10 3115 287 1.17 (0.95–1.42)
10-20 2487 415 2.27 (1.84–2.78)
≥ 20 672 138 2.99 (2.24–4.00)
pooled not mentioned 1.56 (1.39-1.74)
Pinsky (Study of <10 not mentioned 1
Colonoscopy ≥10 TA not mentioned 1.5 (1.03–2.3)
Utilization) 2009
Winawer (National ≤5 228 3 1
Polyp Study) 1993 6-10 354 8 1.3 (0.3-5.2)
> 10 356 17 2.2 (0.6-7.8)
van Stolk (Antixoidant < 10 258 11 1
Polyp Prevention ≥ 10 219 7 0.49 (0.16–1.51)
Trial) 1998
Martinez (Wheat bran < 5 395 36 1
fiber trial) 2001 6–10 543 52 0.88 (0.52–2.14)
10 349 58 2.27 (1.25–4.14)
Table 2. Size of adenoma as a risk factor for advanced neoplasia at the time of surveillance
4.1.3 Histology
The histologic type of adenoma at baseline also was shown to predict metachronous
advanced adenomas in a pooled analysis of prospective studies by Martinez (OR: 1.40, 95%
CI: 1.17-1.68). However, in the randomized trials, the histologic type of adenoma at baseline
106 Colonoscopy
was not a significant predictor of advanced neoplasia. In the observational cohorts, villous
or tubulovillous adenoma was a significant predictor of advanced neoplasia in the Study of
Colonoscopy Utilization, but not in the study by Norshirwani.
Study Histology of Total Patients with Adjusted
adenoma at the patients Metachrono OR/RR/HR
index polyp (N) us (95% CI)
Advanced
Neoplasia
(N)
Jorgensen (The Funen Tubular not mentioned 1
Adenoma Follow-up Tubulovillous not mentioned 1.2 (0.6-2.7)
Study) 1995
Noshirwani Tubular not mentioned 1
(Cleveland Clinic Others not mentioned 1.37 (0.72-2.62)
Foundation Adenoma
Registry) 2000
Bertario 2003 Tubular 772 10 1
Tubulovillous 205 3 1.5 (0.4–5.6)
Villous 80 1 1.2 (0.2–10.2)
Bonithon-Kopp Tubular 455 31 1
(European Fiber- Tubulovillous/villo 97 10 1.67 (0.76–3.67)
Calcium Intervention us
trial) 2004
Martinez (Pooled Tubular 7268 749 1
anaylsis) 2009 Tubulovillous/villo 1899 336 1.28 (1.07–1.52)
us
Pinsky (Study of Tubular not mentioned 1
Colonoscopy Tubulovillous/villo not mentioned 2.2 (1.5–3.1)
Utilization) 2009 us
Martinez (Wheat bran Tubular 842 92 1
fiber trial) 2001 Tubulovillous 317 41 1.10 (0.64–1.87)
Villous 59 9 0.41 (0.15–1.13)
Unspecified/incipie 69 4 0.47 (0.09–2.62)
nt
Lieberman (VA No neoplasia 298 7 1
Cooperative Study Villous adenoma 81 13 6.05 (2.48-14.71)
Group 380) 2007
Table 3. Tubulovillous/villous adenoma as a risk factor for advanced neoplasia at the time
of surveillance
4.1.4 Degree of dysplasia

By definition, all adenomas have some level of dysplasia. In the past, dysplasia has been
classified as mild, moderate, severe or carcinoma in situ. Currently, severe dysplasia or
carcinoma in situ is considered the equivalent of high-grade dysplasia and mild or moderate
dysplasia is considered the equivalent of low-grade dysplasia. High-grade dysplasia at

baseline was not a significant predictor of advanced neoplasia in the pooled analysis of
prospective studies (OR: 1.08, 95% CI: 0.82-1.41) and randomized controlled studies.
However, high-grade dysplasia is related to a larger adenoma size and villous component at
baseline. Although the VA Cooperative Study by Lieberman and colleagues was included in
the pooled analysis, the VA Cooperative Study determined that 10.9% of the patients with
high-grade dysplasia in adenomas of any size at baseline had advanced neoplasia over the
5-year surveillance period, as compared with 0.6% in those with tubular adenomas less than
1.0 cm in size and that lacked high-grade dysplasia.
Study Degree of atypia of Total Patients with Adjusted

the index polyp patients Metachrono OR/RR/HR
(N) us (95% CI)
Advanced
Neoplasia
(N)
Jorgensen (The Funen Mild not mentioned 1
Adenoma Follow-up Moderate not mentioned 1.0 (0.4-2.2)
Study) 1995 Severe not mentioned 2.1 (0.6-7.1)
Bertario 2003 Low/moderate 1050 11 1
Severe 36 1 3.3 (0.7–15.5)
Bonithon-Kopp Mild 308 17 1
(European Fiber- Moderate/Severe 244 24 1.86 (0.96–3.64)
trial) 2004
Martinez (Pooled Low grade 6485 719 1
anaylsis) 2009 dysplasia
High grade 683 118 1.05 (0.81–1.35)
dysplasia
Lieberman (VA no neoplasia 298 7 1
Cooperative Study High grade 46 8 6.87 (2.61-18.07)
Group 380) 2007 Dysplasia
CRC 23 8 13.56 (5.54–
33.18)
Table 4. High-grade dysplasia of adenoma as a risk factor for advanced neoplasia at the time
of surveillance
4.1.5 Location
The pooled analysis by Martinez reported that a proximal adenoma at baseline was
associated with an increased risk for subsequent advanced adenomas. The OR was 1.68
(95% CI: 1.39–2.02) for any proximal adenomas at baseline vs distal adenomas only at
baseline. Similarly, Bonithon-Kopp reported an OR of 2.63 (95% CI: 1.31–5.3) for subsequent
advanced neoplasia for patients with a proximal location of baseline adenomas compared
with no proximal location of baseline adenomas. In the observational cohort study of
108 Colonoscopy
Pinsky, the risk of metachronous neoplasia at surveillance was significant higher for
patients with adenomas on the proximal colon only at baseline than for patients with
adenomas on the distal colon only.
Study Location of index Total Patients with Adjusted

adenoma patients Metachronous OR/RR/HR
Neoplasia (N)
Bertario 2003 Right colon 317 2 0.7 (0.1–7.6)
Left colon 641 11 2.0 (0.3–16.1)
Rectum 128 1 1
Bonithon-Kopp No distal location 50 2 1
(European Fiber- Distal location 502 39 3.37 (0.74–15.3)
Calcium Intervention No proximal 438 23 1
trial) 2004 location
Proximal location 114 18 2.63 (1.31–5.3)
Martinez (Pooled Distal 4434 395 1
anaylsis) 2009 Proximal only 2620 330 Any proximal:
Both 1754 325 1.68 (1.43–1.98)
Pinsky (Study of Distal colon only not mentioned 1
Colonoscopy Proximal colon not mentioned 1.8 (1.1–2.7)
Utilization) 2009 only
Martinez (Wheat Distal colon 701 68 1
bran fiber trial) 2001 Proximal colon 349 44 1.65 (1.02–2.67)
Both 234 33 2.69 (1.34–5.42)
Table 5. Location of adenoma as a risk factor for advanced neoplasia at the time of
surveillance
4.1.6 Shape of adenoma

The flat adenoma may be a more aggressive pathway in colorectal carcinogenesis. However,
O’Brien reclassified the histopathologically sessile adenomas from the National Polyp Study
cohort as flat (defined as an adenoma thickness ≤1.3 mm and <2× the normal mucosa
thickness) or polypoid and O’Brien compared between the initial and surveillance
pathology. Flat adenomas identified in the National Polyp Study cohort at baseline were not
associated with a higher risk for advanced adenomas at the time of surveillance.
4.1.7 Serrated polyps

Recent studies have shown that, aside from classic adenomas, serrated polyps (sessile
serrated adenomas, mixed mucosal polyps and traditional serrated adenomas) are of
special significance. These lesions are also associated with an elevated risk of malignant
degeneration via the so called serrated cancer development pathway (Hiraoka et al.,
2010; Leggett et al., 2010; Lu et al., 2011). However, in contrast, after the removal of
singular hyperplastic polyps, no special follow-up examination is required (Imperiale et
al., 2008).
4.2 Patient’s characteristics

4.2.1 Age
Pooled analysis and several prospective observational studies by Bertario and Yamaji
reported an increasing risk for subsequent neoplasia with increasing age. However, age was
frequently used as a control variable in the analyses without an explicit risk factor presented
for the age effect.
Study Age at the time of Total Patients with Adjusted

polypectomy patients Metachronous OR/RR/HR
(years) (N) Advanced (95% CI)
Neoplasia (N)
Jorgensen (The ≤60 not mentioned 1
Funen Adenoma >60 not mentioned 1.5 (0.8-3.0)
Follow-up Study)
1995
Noshirwani per 10-year not mentioned 1.10 (0.82-1.45)
(Cleveland Clinic increase
Foundation
Adenoma Registry)
2000
Bertario 2003 <60 503 5 1
60–69 339 5 2.1 (0.6–7.5)
≥70 244 4 4.1 (1.0–16.0)
Yammaji 2004 < 40 154 6 1
40-49 804 52 2.3 (0.7–7.6)
50-59 2397 213 3.6 (1.1–12)
≥ 60 62 12 5.5 (1.6–19)
Martinez (Pooled < 40 154 6 0.41 (0.18–0.94)
anaylsis) 2009 40-49 804 52 0.67 (0.48–0.93)
50-59 2397 213 1
60-69 3676 460 1.39 (1.16–1.68)
70-79 2074 328 1.72 (1.40–2.11)
≥ 80 62 12 2.70 (1.31–5.57)
< 40 154 6 0.41 (0.18–0.94)
Laiyemo 2009, USA ≤65 not mentioned 1
> 65 not mentioned 1.3 (0.7–2.5)
Table 6. Age at the time of polypectomy as a risk factor for advanced neoplasia at the time of
surveillance
4.2.2 Gender
Gender was also frequently used as a control variable in the analyses without an explicit risk
factor presented for the gender effect. The pooled analysis and the observational study by
Bertario reported an increased risk for males for advanced neoplasia at the time of
surveillance.
110 Colonoscopy
Study Gender Total Patients with Adjusted

patients Metachronous OR/RR/HR
Neoplasia (N)
Jorgensen (The Female not mentioned 1
Funen Adenoma Male not mentioned 1.1 (0.6-2.5)
Follow-up Study)
1995
Noshirwani Female not mentioned 1
(Cleveland Clinic Male not mentioned 1.48 (0.74-2.93)
Foundation
Adenoma Registry)
2000
Bertario 2003, Italy Female 487 2 1
Male 599 12 6.5 (1.4–29.9)
Yammaji 2004, Japan Female not mentioned 1
Male not mentioned 0.9 (0.5–1.5)
Martinez (Pooled Female 2642 267 1
anaylsis) 2009 Male 6525 815 1.40 (1.19–1.65)
Laiyemo (Continued Female not mentioned 1

Follow-Up Study of Male not mentioned 2.0 (0.9–4.6)
the Polyp Prevention
Trial) 2009
Pinsky (Study of Female not mentioned 1
Colonoscopy Male not mentioned 1.2 (0.9–1.8)
Utilization) 2009
Table 7. Gender as a risk factor for advanced neoplasia at the time of surveillance
4.2.3 Family history of colorectal cancer in first degree relatives

A family history of colorectal cancer in first degree relatives is an established risk factor for
the development of colorectal cancer. However, few studies have specifically addressed the
relationship between a family history and metachronous advanced adenomas in
postpolypectomy patients. The Erlangen Registry of Colorectal Polyps reported that a
parental history of colorectal cancer is associated with subsequent advanced neoplasia, but
the pooled analysis, Bertario’s study and the Continued Follow-Up Study of the Polyp
Prevention Trial by Laiyemo did not find a significant association between the subsequent
advanced neoplasia and a family history of colorectal cancer in first degree relatives.
4.2.4 History of previous polyps

Both the pooled analysis and Bonithon-Kopp study noted that a history of polyps before the
baseline adenoma was associated with an increased risk for advanced neoplasia at the time
of surveillance. Although it is not always possible to determine whether prior polyps are
adenomatous polyps, the presence of prior polyps can be considered as an additional risk
factor.
Study Family history of Total Patients with Adjusted

colorectal cancer patients Metachronous OR/RR/HR
Neoplasia (N)
Nusko (Erlangen No not mentioned 1
Registry of Yes not mentioned 2.32 (1.77–3.04)
Colorectal Polyps)
2002
Bertario 2003, Italy No 787 10 1
Yes 299 4 1.3 (0.4–4.1)
Martinez (Pooled No 6547 759 1
anaylsis) 2009 Yes 2089 255 1.17 (0.99–1.38)
Laiyemo (Continued No not mentioned 1
Follow-Up Study of Yes not mentioned 1.0 (0.5–2.0)
the Polyp Prevention
Trial) 2009
Table 8. A family history of colorectal cancer in first degree relatives as a risk factor for
advanced neoplasia at the time of surveillance
Study History of previous Total Patients with Adjusted

polyp patients Metachronous OR/RR/HR
Neoplasia (N)
Bonithon-Kopp No 468 29 not mentioned
(European Fiber- Yes 84 12
trial) 2004
Martinez (Pooled No 6941 722 1
anaylsis) 2009 Yes 2057 329 1.76 (1.48–2.09)
Table 9. A history of previous polyp as a risk factor for advanced neoplasia at the time of
surveillance
4.2.5 Race
The pooled analysis of prospective studies by Martinez reported that the race of patients
with polyp removal was associated with a different risk for subsequent advanced neoplasia.
Compared to the white race, the black race showed an increased risk for subsequent
advanced neoplasia (OR: 1.08, 95% CI: 0.79–1.47), whereas other races showed a tendency
for a decreased risk for subsequent advanced neoplasia (OR: 0.83, 95% CI: 0.60–1.16).
5. Risk stratification for the metachronous advanced adenoma risk

The totality of evidence suggests that multiplicity (3 or more adenomas), size (1 cm or
more), villous features, high-grade dysplasia, a proximal location and a history of previous
polyp are the predictors of future advanced neoplasia. Race, age, gender and a family
112 Colonoscopy
history of colorectal cancer also may predict metachronous advanced neoplasia, but this has
not been well studied. Analysis of the relative importance of each of these predictors is
complicated by their interrelationships.
The current guidelines from the major organizations, including the US Multi-Society Task
Force on Colorectal Cancer (USMTF), the American College of Gastroenterology (ACG), the
American Society of Gastrointestinal Endoscopy (ASGE), and the British Society of
Gastroenterology (BSG), have accepted the risk stratification listed in Table 10 (Bond 2000;
Davila et al., 2006; Winawer et al., 2006; Cairns et al., 2010).
There is a consensus among many of the studies that the group at a lower risk for
subsequent advanced neoplasia has only 1 or 2 tubular adenomas that are less than 1 cm in
size and low-grade dysplasia and they are located only in the distal colon. In the
colonoscopy based studies, the patients have been followed-up for only 5–6 years after
colonoscopic polypectomy to assess their subsequent risk for neoplasia.
Term Definition
All of the following:
1 or 2 adenomas
Low risk group Size < 1 cm
Tubular histology
No high-grade dysplasia
Any of the following:
Multiple adenomas (≥ 3)
Size ≥ 1 cm
High risk group
Villous or tubulovillous histology
High-grade dysplasia
Any of the following:

Higher risk group >10 small adenomas
Piecemeal resection of large sessile adenoma
Table 10. Risk stratification for subsequent advanced neoplasia
6. Post-polypectomy surveillance interval

Based on risk stratification, the major organisations have suggested the post-polypectomy
colonoscopy surveillance interval (Table11). All the guidelines rely on periodic colonoscopy
as the primary method of surveillance. The surveillance interval is based on the risk of
metachronous advanced neoplasia as predicted by the findings on initial colonoscopy. Most
of the guidelines recommend repeat colonoscopy in 5–10 years for low-risk patients (only
one or two small adenomas, <1 cm in size); for such patients, the BSG advises either repeat
colonoscopy in 5 years or no surveillance at all (the patients can continue average-risk
screening). For the patients at high risk (advanced neoplasm or 3–10 small adenomas),
colonoscopy should be repeated in 3 years, with subsequent colonoscopies every 5 years if
the preceding colonoscopy was negative. In most of the guidelines, an advanced neoplasm
is defined as a villous or tubulovillous adenoma, an adenoma with intermediate-grade or
high-grade dysplasia, or a tubular adenoma 1 cm in size or larger. The USMTF guidelines
specify that the colonoscopy intervals can be extended to 10 years if the preceding
colonoscopy did not show adenomas. In patients with numerous (>10) adenomas but there
was no overt adenomatous polyposis syndrome, colonoscopy should be repeated in less

than 3 years, with the exact interval to be determined by the endoscopist. For patients with
large sessile adenomas that are difficult to completely remove in one session, a repeat
colonoscopy after a short interval (2–6 months) is recommended. Subsequent intervals are
customized according to the level of suspicion for residual adenomatous tissue at the
polypectomy site. If a sessile polyp is very extensive or it has high-grade dysplastic features,
then surgical resection should be considered. After it is certain that all adenomatous tissue
has been removed, surveillance with 3–5 year intervals can be resumed.
Organization First Second surveillance

surveillance interval if surveillance
interval colonoscopy shows no
adenomas
Low risk group
1–2 tubular USMTF 5–10 years -
adenomas, <1cm and ACG 5 years* 5 years
lowe-grade dysplasia ASGE No earlier than 5 No earlier than 5 years
years
BSG 5 years or no No surveillance
surveillance
High risk group
3-10 adenomas, ≥ 1 USMTF 3 years 5 years
cm, tubulovillous ACG 3 years† 5 years
/villous adenoma or ASGE 3 years No earlier than 5 years
High-grade dysplasia BSG 3 years‡ 3 years§
Higher risk group
>10 small adenomas USMTF <3 years
ACG - -
ASGE <3 years 5 years
BSG 1 year¶ 3 years‡
Large sessile USMTF 2–6 months Customised
adenoma ACG 3–6 months -
ASGE 2–6 months Customised
BSG 3 month 1 year||
Abbreviation: US Multi-Society Task Force on Colorectal Cancer, USMTF; American College of
Gastroenterology, ACG; American Society of Gastrointestinal Endoscopy, ASGE; British Society of
Gastroenterology, BSG.
*The ACG guidelines note that selected low-risk patients might not need surveillance at all, but they do
not further elaborate. †The ACG guidelines consider patients with 1–2 small adenomas and a positive
family history in a first-degree relative to be at intermediate risk. ‡The BSG guidelines define
intermediate-risk patients as those with 3–4 small adenomas or at least one adenoma ≥1 cm in size. §The
BSG guidelines recommend ceasing surveillance if two consecutive follow-up colonoscopies are
negative. ¶The BSG guidelines define high risk patients as those with ≥5 adenomas or ≥3 adenomas with
at least one of which is ≥1 cm in size. ||The BSG guidelines recommend repeating colonoscopy in 1 year
after confirmation of complete removal, and then every 3 years.
Table 11. Summary of the post-polypectomy guidelines

114 Colonoscopy
Over the past few decades, the recommended intervals between surveillance colonoscopies
have been extended, on the basis of accumulating data that showed longer surveillance
intervals are safe. For example, the National Polyp Study showed no difference in the
adenoma risk between patients who had repeat colonoscopy at 1 year versus those who had
colonoscopy at 3 years, while the Funen Adenoma Study showed no statistically significant
difference in the adenoma recurrence rates at 4 years colonoscopy compared with 2 years
colonoscopy. Depending on the patient’s and physician’s preference, surveillance may be
discontinued if the life expectancy is under 10 years (USMTF) or if the patient is over 75
years old (BSG). For most guidelines, the surveillance recommendations are relaxed after
one or two negative follow-up colonoscopies. However, the ACG considers those patients
with a history of adenomas to be at a lifelong risk for metachronous lesions and the ACG
recommends colonoscopies at least every 5 years indefinitely. It is important to note that
these surveillance interval recommendations are based on the assumption that the baseline
colonoscopy is of high quality with good bowel preparation, thorough removal of polyps
has been done, there is an adequate examination time and complete visualization of all
colonic mucosa up to and including the caecum.
Surveys have shown that the patients’ compliance with physicians’ recommendations for
surveillance is high (up to 85%), and particularly in the presence of multiple or larger polyps
(Klabunde et al., 2003; Mysliwiec et al., 2004; Kang et al., 2006). Also, patients are often
interested in chemopreventive measures such as antioxidants, fiber, and calcium or other
dietary supplements, although the efficacy of all these agents has not been unequivocally
shown. The effect of surveillance colonoscopy on the quality of life has not been directly
studied, although patients probably derive benefit if we extrapolate the results from quality-
of-life studies on screening colonoscopy. Unfortunately, many clinicians do not adhere to
the surveillance guidelines and they often do colonoscopies more frequently than is
recommended. This over-surveillance is probably due to concerns about missed lesions or
interval cancers, which can occur even in patients who are under close surveillance.
Improved adherence to guidelines could be achieved by the use of reminder devices and
algorithms for continuous improvement. Other screening measures, such as the use of
interval testing of faecal occult blood, might also allow practitioners to feel more
comfortable with longer surveillance intervals (Bampton et al., 2005).
7. Conclusion
Identifying the high risk subjects is important, as is ensuring that the subjects accept and
comply with the recommended surveillance program. Two important factors, in addition to
the individual patient factors, have a profound effect on the cancer risk: these are the quality
of performing the examination, and ensuring complete removal of large sessile lesions. In
addition to the potentially therapeutic value of polyp removal, colonoscopy is an
opportunity to identify a small, high risk group of patients who require careful surveillance
to prevent the development of cancer. It is also an opportunity to identify a much larger
group of patients who can be informed with some confidence that their cancer risk is low.
The overall effectiveness of an adenoma surveillance program for preventing colorectal
cancer depends on each colonoscopy being undertaken slowly, carefully and thoroughly
with a fail-safe system in place for recalling the higher risk patients
Further research will help define the best surveillance intervals, as well as the role of
technical innovations such as CT colonography, chromoendoscopy and narrow-band
imaging.
8. Acknowledgment
I would like to express sincere thanks to Ewe Chung Chung, who has given me the most
support and encouragement.
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7
Endoscopic Manifestations and Mucosal

Patterns Associated to Collagenous Colitis
Daniel Gustavo Cimmino and José Manuel Mella
Endoscopy Unit and Gastroenterology Unit, Hospital Alemán, Buenos Aires,
Argentina
1. Introduction
Microscopic colitis (MC) are clinical pathologic entities characterized by secretory-like
aqueous chronic diarrhea, in its large majority without hematochezia. From the first
descriptions of MC1, normal endoscopic and radiological findings have been a
pathognomonic feature. It is thought that up to 20% of adults with chronic diarrhea who
have an endoscopically normal colonoscopy may have MC.
Most common MC are collagenous colitis and lymphocytic colitis. They are two
morphologically distinct entities of MC. They are similar in presentation but differ
histologically. Endoscopic biopsy is required for the diagnosis of MC2. As there are usually
no mucosal abnormalities, the biopsies taken must be random. However, several authors
have described different mucosal abnormalities related to the MC, most of them related to
collagenous colitis.
Our aims were to review the medical literature and to describe the mucosal patterns and
mucosal abnormalities that have been associated with the microscopic colitis, especially
those related to the collagenous colitis.
1.1 Search
A MEDLINE search (1966-December 2010), was done using the terms "Colitis,
Microscopic"[Mesh] or "Colitis, Collagenous"[Mesh] or "Colitis, Lymphocytic"[Mesh] and
"Endoscopy, Digestive System"[Mesh] or "Endoscopy, Gastrointestinal"[Mesh] or
"Colonoscopy"[Mesh] to find relevant articles. The search was carried out without
restrictions or limits. The selection process of the articles was done independently by both
authors. Agreement was measured using kappa coefficient (k). First, relevant studies were
selected by the title (k 0.80, CI95% 0.63-0.97) and differences were resolved by consensus.
Then, the fulltexts of selected articles were read.
2. Role of endoscopy in microscopic colitis

Endoscopy is essential for the diagnosis of microscopic colitis2. The diagnosis of microscopic
colitis is based on mucosal biopsies taken during colonoscopy at the appropriate sites. It is
essential to take colonic biopsies when endoscopic examinations are carried out in the
clinical context of chronic diarrhea, even if the functional nature of the diarrhea is suspected.
122 Colonoscopy
By definition, the colonic mucosa has an endoscopically normal appearance in microscopic

colitis. However, some authors have reported endoscopic abnormalities and mucosal
patterns in patients with MC (see below).
2.1 Colorectal biopsy samples: where and how much?

Histological abnormalities in MC are generally pancolonic as they can be distributed
throughout the colon as well as limited to the right colon3. In collagenous colitis, thickening
of the subepitelial collagen band is in some cases more marked in the proximal colon than in
the distal colon. The two endoscopically normal sites in which biopsies should be taken for
optimal diagnosis of MC are the ascending colon and the sigmoid colon. Three to four
biopsies should be taken per site.
3. Mucosal patterns and mucosal lesions associated to microscopic colitis

In the colonoscopy, the colonic mucosa has usually a normal aspect or it can present
minimum and unspecific abnormalities such as erythema patches, edema or alterations in
the vascular pattern.
In our search, we found several case reports and case series of endoscopic findings that
would suggest the presence of this type of colitis, most of the findings related to collagenous
colitis. In Table 1 there is a summary of the different endoscopic manifestations of the
collagenous colitis and the authors of these findings.
Author Colorectal findings in collagenous colitis

Richieri et al 4 (1993) mucosal tears
Katsinelos et al 16(1997) multiple red spots
Sato et al 17 (1998) spindle network pattern
Cruz−Correa et al 5 (2002) mucosal tears
Buchman et al 18 (2004) pseudomembranous collagenous colitis
Koulaouzidis et al 6 (2006) mucosal tears and scars
Tysk et al 7 (2006) mucosal tears, longitudinal mucosal lacerations
Smith et al 13 (2007) mucosal tears on insufflattion, colonic perforation
Allende et al 14 (2008) bleeding linear ulcers, colonic perforations
Hashimoto et al 8 (2008) linear ulcers, scar−like areas; crowded vascularity of
the colonic mucosa and dilated, circling or winding
blood capillaries
Dunzendorfer et al 21 (2008) mucosal tears
Umeno et al 10 (2008) linear mucosal defects
Couto et al 9 (2009) scars; mucosal tears, superficial lacerations or ‘‘cat
scratches’’ enhanced with air insufflation during
colonoscopy
Hashimoto et al 19 (2009) mucosa similar to ischemic colitis
Cimmino et al 20 (2010) colorectal mosaic pattern
Nomura et al 11 (2010) linear mucosal defects
Table 1. Summary of the mucosal abnormalities associated with collagenous colitis.
Endoscopic Manifestations and Mucosal Patterns Associated to Collagenous Colitis 123
3.1 Mucosal tears

Mucosal tears were the most frequent endoscopic findings in our search. The terms “linear
mucosal defects” have been used by several authors to describe mucosal tears and sharp
longitudinal ulcers (characteristic colonoscopic findings in patients with collagenous colitis).
One of the first descriptions of mucosal tears that we found data were from 1993 (Richieri et
al.4) and 2002 (Cruz−Correa et al.5).
In 2006, Koulaouzidis et al.6 described discrete linear mucosal breaks in the caecum after
gentle insufflation, suggesting that this mucosal tears in the colon could occur
spontaneously in patients with collagenous colitis.
In the same year, Curl Tysk et al.7 reviewed the medical literature and reported longitudinal
mucosal lacerations in the colon of patients with collagenous colitis (Figure 1 and 2),
emphasizing that these lesions may be a sign of underlying collagenous colitis, and that
mucosal biopsies should be obtained to confirm the diagnosis. Based on the previous reports
that they had found, they advised that these lesions might be associated with an increased
risk of colonic perforation, and that the colonoscopist should be aware that the risk of
perforation is likely to be increased.
Fig. 1. Mucosal tears in patients with collagenous colitis (Courtesy of Dr Curt Tysk 7)
In 2008, Hashimoto et al 8 described a surprising finding in a patient with chronic diarrhea: a
20 cm long linear ulcer or scar like area of mucosal damage without bleeding in the
descending colon. The biopsies taken revealed that it was a collagenous colitis.
In 2009, Couto et al 9 suggested that the scars found in the colonic mucosa were signs of
scaring of previous spontaneous mucosal tears, superficial lacerations or ‘‘cat scratches’’
enhanced with air insufflation during colonoscopy in patients with collagenous colitis.
3.1.1 Drugs associated with mucosal tears

Umeno et al 10 and Nomura et al 11 have associated the presence of these linear mucosal
defects to the drug lansoprazole, a proton bomb inhibitor. They found that linear mucosal
defects and friable mucosa may be characteristic colonoscopic findings in cases of
lanzoprale-associated collagenous colitis (Figure 2).
124 Colonoscopy
Fig. 2. Mucosal tears in patients with lansoprazole associated-collagenous colitis (Courtesy

of Dr Eiki Nomura11)
3.1.2 Risk of colonic perforation in patients with collagenous colitis

Several authors have suggested that patients with collagenous colitis have an increased risk
of colonic perforation during the colonoscopy procedure. Most of them agree that the
mucosal tears might be the initial lesion of the perforations.
Sherman et al 12 and Smith et al 13 found mucosal tears (linear “fractures” of the colon)
following diagnostic colonoscopies in patients with severe collagenous colitis. They
theorized that the stiffness of the colon in areas of collagenous colitis with submucosal
fibrosis could made it susceptible to linear "fractures" during colonoscopic air insufflation
with subsequent transmural air dissection. They urged extreme caution if these lesions were
recognized at colonoscopy and recommended aborting the examination and obtaining plain
radiographs to detect free intraperitoneal air.
Allende et al 14 published the largest series up to date about 12 patients with collagenous
colitis complicated with colonic perforations. In their series the most outstanding
colonoscopic findings were bleeding linear ulcers. They observed that the colon in
collagenous colitis perforates not only with colonoscopy, but also with barium enema.
Colonoscopic perforations were more common than barium enema, probably due to its
higher intraluminal pressures. They thought that marked collagenous colitis severity was
implicated as a risk factor for perforation. They found that the right colon was the most
common perforation site, corresponding to its preferential involvement by collagenous

colitis and predisposing physical properties of the right colonic wall.
In 2010, Hussain et al 15 published a systematic review about the colonic perforations in
patients with collagenous colitis. They did an exhaustive and systematic search and found
21 case reports of colonic perforation, mainly following colonoscopy. The site of colonic
perforations and mucosal tears were predominantly in the right colon.
3.2 Other mucosal abnormalities

In 1997, Katsinelos et al 16 reported the presence of multiple red spots in the lower part of the
ascending colon in a patient with chronic diarrhea. The histological examinations of the
biopsies taken from this pathological area showed it was a collagenous colitis.
In 1998, Sato et al 17 reported a spindle network pattern after indigo carmine dye-spraying, in
association with collagenous colitis.
In 2004, Alan Lewis Buchman et al 18 described an interesting endoscopic manifestation of
collagenous colitis in two patients with chronic diarrhea: pseudomembrane formations
(Figure 3) in the absence of Clostridium difficile infection. They used the term of
“pseudomembranous collagenous colitis”.
Fig. 3. Pseudomembranes in a patient with collagenous colitis (Courtesy of Dr Alan

Buchman 18)
In 2008, Hashimoto et al 8 reported numerous crowded, small, dilated, circling or winding
blood vessels on the mucosal surface of the entire colon, especially the transverse colon
(appearing like a spider web) in association with this type of colitis.
In 2009, Hashimoto et al 19 found an actively hemorrhagic linear ulcer and a linear ulcer scar
in a woman with abrupt onset of lower abdominal pain and heavy blood in her stool.
Histopathological examination of biopsy samples taken showed subepithelial collagen
bands and the diagnosis of collagenous colitis was made. They thought it was a case of
lansoprazole-associated collagenous colitis with a unique presentation similar to an
ischemic colitis.
126 Colonoscopy
In 2010, Cimmino et al 20 described a mosaic pattern as an endoscopic finding in the

collagenous colitis (Figure 4). They compared the presence of this mosaic pattern in patients
with chronic diarrhea, and they found that the presence of this colorectal mosaic pattern
would have a high specificity (99%) and a high positive likelihood ratio (LR+ 17) for the
diagnosis of collagenous colitis in patients with chronic diarrhea who undergo a
colonoscopy.
Fig. 4. Colorectal mosaic pattern in patients with collagenous colitis (Courtesy of Dr

Cimmino 20)
4. The future of endoscopy in microscopic colitis

Endomicroscopy is a newly developed endoscopic modality, which allows in vivo
microscopy of the mucosal layer in about 1000-times magnification with subcellular
resolution during ongoing gastrointestinal endoscopy. This technique enables subsurface
imaging of living tissue during ongoing endoscopy and allows confocal microscopy in
addition to standard video endoscopy.
Kiesslich et al 22 showed that endomicroscopy allows localization and measurement of the
amount of collagenous bands in the mucosal layer, offering the possibility of targeted
biopsies, which would be a new approach in collagenous colitis.
5. Summary
The term microscopic colitis includes the collagenous colitis and the lymphocitic colitis, both
entities are characterized by chronic diarrhea and normal colonoscopy, and the diagnosis is
confirmed by biopsies taken at random. In recent years, abnormalities in the mucosa, mainly
related with collagenous colitis, have been described. In Table 1 we summaries the mucosal
patterns and the endoscopic manifestations which have been associated with collagenous
colitis. Most of the reports mentioned the mucosal tears as the most frequent abnormality.
Scars following mucosal lacerations were also a frequent finding. The risk of colonic
perforations seems to be slightly higher in patients with collagenous colitis during
colonoscopy. The main reason appears to be the lacerations done during air insufflations in
the procedure. Other endoscopics findings were blood vessels alterations,
pseudomembranes and mosaic pattern.
6. Conclusion
Several mucosal patterns and mucosal abnormalities have been reported in association with
collagenous colitis. Knowledge of these endoscopic manifestations of the collagenous colitis
could help to a better understanding of this disease and to target the colonic biopsies.
7. Acknowledgment
We want to thank Dr. Curl Tysk, Dr. Eiki Nomura and Dr. Alan Lewis Buchman for
providing us the pictures and photos of their endoscopic findings. They have been very
kind.
8. References
[1] Lindstrom CG. “Collagenous colitis” with watery diarrhoea — a new entity? Pathol Eur
1976;11:87.
[2] Beaugerie L, Napoleon B, Ponchon T, Boyer J, Canard JM, Dalbies P, Escourrou J, Greff
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[4] Richieri JP, Bonneau HP, Cano N, Di Costanzo J, Martin J. Collagenous colitis: an
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[5] Cruz−Correa M, Milligan F, Giardiello FM. Collagenous colitis with mucosal tear on
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128 Colonoscopy
[8] Hashimoto Y, Endo Y, Kuroki Y, Yoshikumi H, Yoshiba M. Collagenous colitis with

unique colonoscopic findings. Endoscopy. 2008 Sep;40 Suppl 2:E162.
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[10] Umeno J, Matsumoto T, Nakamura S, Jo Y, Yada S, Hirakawa K, Yoshimura R,
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H. Linear mucosal defects: a characteristic endoscopic finding of lansoprazole-
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[16] Katsinelos P, Katsos I, Patsiaoura K, Xiarchos P, Goulis I, Eugenidis N. A new
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8
Endoscopic Approach in Ulcerative Colitis

Rogério Saad-Hossne1 and Fábio V. Teixeira2
1Medical
School - UNESP Botucatu, São Paulo,
2Medical School - UNESP Botucatu and GI Surgeon and consultant of UNIGASTRO
e Clínica GASTROSAUDE, Marília, São Paulo,
Brazil
1. Introduction
The term inflammatory bowel disease (IBD) is frequently used in the medical literature to
define a set of diseases involving the digestive tract, particularly the small and the large
intestine. The major IBDs are Crohn’s Disease (CD) and ulcerative colitis (UC).
Ulcerative colitis is a chronic inflammatory disease characterized by diffuse mucosal
inflammation limited to the colon. UC affects 500,000 individuals in the United States with
an incidence of 12 per 100,000 per year. The lifetime risk of a severe exacerbation of UC
requiring hospitalization is 15%. Patients with extensive disease (macroscopic disease
proximal to the splenic flexure) are more likely to develop acute severe colitis.
Approximately 4% to 9% of UC patients will require colectomy within the first year of
diagnosis; the risk of colectomy following that is 1% per year. The vast majority of UC
patients will require medical therapy throughout their lifetime.
Ulcerative colitis, usually, involves the rectum at presentation and may extend proximally in
a symmetrical, circumferential, and continuous pattern to involve parts or all of the large
intestine. The disease course of UC is characterized by exacerbations and remissions, which
may occur spontaneously or in response to treatment changes, superimposed infection. The
diagnosis of inflammatory bowel disease is based on clinical history in combination with the
results of various tests, once a single pathognomonic test allowing for a diagnostic definition
is not available. Hence, the following can be cited: radiology, laboratory and hematological
tests, and endoscopy combined with histology in particular.1-3
With this respect, endoscopy has revolutionized the management of patients with IBD by
increasingly enabling the identification and study of lesions. Some more recent advances in
endoscopic techniques can be cited, such as double-balloon enteroscopy and the capsule
endoscopy, which allow for evaluating areas of the small intestine that have not been
thoroughly studied to this date, in addition to digital chromoendoscopy.
Improvement in IBD diagnostic capacity has direct implications in the diagnosis and follow-
up of patients that have or are suspected to have IBD as well as in better understanding their
pathogenesis, which consequently influences treatment.
Great changes have occurred in IBD treatment and management in the last few decades due
to the introduction of biological agents in its therapeutic arsenal. Biological therapy,
represented by its major drugs – anti-TNF antibodies – has rapidly become the top of a
mountain whose base is represented by other drugs that have been used in the treatment of
inflammatory bowel disease for several decades.
130 Colonoscopy
These new drugs directly interfere with the individual’s immune response by decreasing the
activation of T cells and inducing apoptosis of defense cells, thus controlling this complex
mechanism which is still not fully known and triggers diseases such as ulcerative colitis and
Crohn’s Disease.
Some time ago, it was believed that the most important objective in treatment would be the
patient’s clinical remission, normally based on symptom and sign scores, in CD (CDAI –
Crohn’s disease activity index < 150 points), and in UC (Mayo Score < 5 points). However,
after the advent of biological therapy, which induces healing of the inflamed intestinal
mucosa, such objectives have changed, that is, in addition to seeking sustained clinical
remission, mucosal healing should also be sought.
Due to these characteristics and to the fact that such healing can be maintained for long
periods, it is believed that the development and prognosis of IBD will also change.
As previously pointed out, mucosal healing is one of the objectives of clinical trials and of
daily clinical practice. For this reason, endoscopy, and colonoscopy in particular, assumes a
major role in these patients’ follow-up by enabling the direct visualization of the mucosa as
well as the removal of fragments for histological analysis.
2. Indications
The diagnosis of UC can be suggested initially by sigmoidoscopy in great number of cases
during first attack of UC, fewest biopsies usually are sufficient to confirm the diagnosis and
indicate the initial therapy. In patients with diarrhea, mucus, active and flares, this exam can
be performed in unprepared bowel so the earliest signs of UC can be detected; other reason
to do the sigmoidoscopy without bowel prep is to decrease the hyperemia that is often
present after enemas.
In this active fase, colonoscopy is not recommended for fear of perforation and the risk of
cause great distention in colon. Only after this acute and active fase the colonoscopy can be
performed to establish the extent of the disease and to exclude other disease and Crohn's
disease.
The initial aim points in colonoscopy are to evaluate both the extension and intensity of UC.
In a second moment, to evaluate the response to the treatment. Thus, the colonoscopy is
useful to make the diagnosis, to follow the evolution and response and finally prevent
colorectal cancer (displasia).
The most recent studies confirm that the mucosal healing is the end point of treatment, so
the indications of colonoscopy do not resume in diagnostic only. In TABLE 1, are the most
important indications of colonoscopy in UC.
Acute Sub acute chronic

Diagnosis Extension Treatment response
Biopsy Intensity Displasia surveillance
Differential diagnosis Biopsy Cancer surveillance
Treatment response
Table 1. Indications of colonoscopy in ulcerative colitis
Endoscopic Approach in Ulcerative Colitis 131
3. Bowel preparation
Correct diagnostic of colonoscopy depends on the quality of the colonic preparation or
cleansing. The ideal preparation should reliably empty the colon of fecal material in a rapid
fashion and do not cause histological alteration or gross of the rectal and colonic mucosa.
For patients, the preparation should not cause discomfort and shifts in electrolytes and
fluids; those are the ideal bowel preparation, unfortunately none of the preparations
available meet them.
Recently, the American Society of Colon and Rectal Surgeons (ASCRS), the American
Society for Gastrointestinal Endoscopy (ASGE), and the Society of American
Gastrointestinal and Endoscopic Surgeons (SAGES) made a document: “A Consensus
Document on Bowel Preparation Before Colonoscopy”. 4 Based on this document the
recommendations are (grade of recommendation supported by evidence-based medicine):
1. Diet- Dietary modifications, such as a clear liquid diet, alone are inadequate for
colonoscopy. However, they have proven to be a beneficial adjunct to other mechanical
cleansing methods (Grade IIB).
2. Enemas - Use enemas in patients who present to endoscopy with a poor distal colon
preparation and in patients with a defunctionalized distal colon.
3. High-Volume Gut Lavage - Neither high-volume nor unbalanced solutions, such as
mannitol, should be used for colonic preparation (Grade IA). In addition, caution
should be exercised when using nasogastric tubes for the administration of any bowel
preparation infusion (Grade VD).
4. Rectal Pulsed Irrigation - administered immediately before the procedure combined
with magnesium citrate given the evening before the procedure is a reasonable
alternative to full-volume (4-liters) PEG in those individuals who cannot tolerate per
oral administration of PEG (Grade IIB).
5. PEG - Faster, more effective, and better-tolerated method for cleansing the colon than a
restricted diet combined with cathartics, high-volume gut lavage, or mannitol/NaP
(Grade IA). PEG is safer than osmotic laxatives/NaP for patients with electrolyte or
fluid imbalances, such as renal or liver insufficiency, congestive heart failure, or liver
failure and is, therefore, preferable in these patient groups (Grade IA). Divided-dose
PEG regimens (2–3 liters given the night before the colonoscopy and 1–2 liters on the
morning of procedure) are acceptable alternative regimens that enhance patient
tolerance (Grade IIB). Cleansing preparations for colonoscopies performed in the
afternoon should instruct that at least part of the PEG solution be given the morning
before the procedure (Grade IIB). Enemas, bisacodyl, and metaclopramide as adjuncts
to the full volume of PEG have not been demonstrated to improve colonic cleansing or
patient tolerance and are, therefore, unnecessary (Grade IIB).
6. NaP - Aqueous NaP colonic preparation is an equal alternative to PEG solutions except
for pediatric and elderly patients, patients with bowel obstruction, and other structural
intestinal disorders, gut dysmotility, renal or failure, congestive heart failure, or liver
failure (Grade IA). Dosing of aqueous NaP should be 45 ml in divided doses, 10 to 12
hours apart with one of the doses taken on the morning of the procedure (Grade IIB).
Aqueous NaP is the preferable form of NaP at this time (Grade IIB). Apart from
anecdotal reports, the addition of adjuncts to the standard NaP regimen has not
demonstrated any dramatic effect on colonic cleansing preparation. Carbohydrate-
electrolyte solutions such as E-Lyte\ may improve safety and tolerability.
132 Colonoscopy
In those patients with possible underlying IBD, NaP preparations may cause mucosal
abnormalities that mimic Crohn’s disease 5-7. However, the frequency of this problem is rare
and may not mitigate against using NaP. This caveat is most important in the initial
colonoscopic evaluation of patients with symptoms suspect for colitis.
We may conclued that bowel preparation is safe for patients with UC and must be avoid in
acute phases.
4. Macroscopic characteristics of ulcerative colitis

The macroscopic characteristic of UC is symmetrical and continuous inflammation, which
begins in the rectum and extends proximally without interruption during the whole
extension of the disease. When present, this aspect is easily made visible by colonoscopy.
The figure 1 shows the initial endoscopic signs of UC:
1. Reduction or loss of normal vascular patterns.
2. Loss or distortion of vascular markings and relief, and, many times, this aspect may be
the only endoscopic alteration in patients with UC in its quiescent phase
3. Mucosal erythema and edema
Fig. 1. Mucosal friability, loss of vascular pattern, eythema and edema

As the disease progresses, the mucosal pattern changes, becomes extremely friable, and
shows a granular aspect. The disease, then, enters the most severe phase, when the mucosa
is covered with yellowish and sometimes mucopurulent exudate, with intense ulceration of
the adjacent mucosa. (FIGURE 2) Such exulceration and ulceration pattern is mainly
characterized by a serpiginous, linear, dotted or annular aspect, or even an association of
such aspects. As to size, they may vary from millimeters to centimeters, and may, at times,
be deep, depending on the phase and inflammation intensity.
Fig. 2. Colonic mucosa with intense ulceration covered with yellowish and mucopurulent
exudates
In the active and acute phase of the disease, a simple touch to these lesions by the
instrument may cause bleeding due to mucosal friability. Another important aspect is that
when such edema is intense and diffuse, it may lead to lumen narrowing. The differential
diagnosis is made by adenomatous polyps, which can only be differentiated under
microscopy. Another important differential diagnosis is made by CD. Crohn´s colitis
endoscopic features includes: skip lesions(pathchy inflammation adjacent to normal
mucosa), rectal sparing, aphtous ulcerations and cobblestone appearance of the mucosa due
to the presence of deep linear ulcers.
The inflammation/cicatrization process may lead to the onset of pseudopolyp images,
which, in reality, are healthy mucosal areas amidst areas of an intense inflammatory
process. (FIGURE 3) They can be characterized by endoscopy with small, bright and soft
lesions that may develop to large pedunculated or sessile lesions. Also, they may be
detected both in the acute and chronic phases of the disease and are largely suggestive of
UC, showing the appearance of cobble-like shapes both by colonoscopy and opaque enema.
134 Colonoscopy
Other endoscopic aspects that can be made visible in patients with a chronic form of the
disease are:
1. Loss of normal haustration patterns
2. Loss of normal colon architecture, with muscle hypertrophy
3. Colon shortening
4. Luminal diameter reduction
5. Stenosis. In this case, the differential diagnosis is made from cancer.
With this regard, some UC endoscopic activity scales have been developed with the purpose
to classify and quantify such inflammatory activity in the colonic mucosa. The scale
proposed and used by the Mayo Clinic is noteworthy.
Table 2. Mayo score for ulcerative colitis *

* from: Cima RR, Pemberton JH. Medical and surgical management of chronic ulcerative colitis. Arch
Surg. 2005;140(3):300-10
Fig. 3. Pseudopolyps and colonic mucosal healing after infliximab treatment
5. Histology
The histological analysis of biopsy has the following aims: confirm the UC diagnosis,
graduate the inflammatory response and third, confirm the presence of displasia or cancer.
An early and accurate diagnosis is necessary. It is important to distinguish between IBD and
acute self-limited colitis and a differential diagnosis between UC and CD. The
histopathological diagnosis of UC should, therefore, be based on discriminating histological
features which are sufficiently reproducible and suitable in routinely processed biopsy
specimens.
In cases where the clinical picture is unclear, the histomorphologic analysis often plays a
pivotal role in determining the diagnosis and thus the management. By contrast, a biopsy
analysis may be indeterminate, and thus the clinical progression of the disease must inform
its treatment.
Great changes have occurred in IBD treatment and management in the last few decades
due to the introduction of biological agents in its therapeutic arsenal. Thus, mucosal
healing is one of the objectives of clinical trials and of daily clinical practice. FIGURE 3 For
this reason, colonoscopy assumes a major role in these patients’ follow-up by enabling the
direct visualization of the mucosa as well as the removal of fragments for histological
analysis.11-19
136 Colonoscopy
Fig. 4. Photomicrography of a colectomy specimen (pancolitis): we observe distortion of

crypt architecture, inflammation of crypts (cryptitis) and crypt abcess (arrow) Courtesy of
Prof. Dr. Marcus M. Matsushita, professor of the Pathology Department of the Hospital
Universitário - ABHU, Medical School of the University of Marilia, São Paulo, Brazil.
www.unimar.br
6. Dysplasia and Colorectal Cancer (CRC) surveillance

Dysplasia is considered the best marker of cancer risk in UC. The clinical management
depends on the endoscopic and histological identification of dysplasia in mucosal biopsy
specimens of the colon by pathologists with particular expertise in gastrointestinal
disorders. The dysplasia can be divided in two groups: low-grade dysplasia (LGD) and
high-grade dysplasia (HGD), not all patients with LGD will progress through detectable
HGD. Patients with HGD have higher risk of progression to colorectal cancer.19
Rubin and colleagues in Seattle showed that among a group of colectomy specimens
obtained from UC patients, 33 biopsies per examination was the number of nontargeted
biopsies required to exclude dysplasia with 90% confidence. 19 It has being reported that
80% to 90% of UC patients with cancer have dysplasia when analyzed the colectomy
specimen. However, colorectal cancer can develop in patients without a prior history of
dysplasia. 14-15,19
In a meta-analysis with 116 published studies, Eaden and colleagues found that the
overall prevalence of CRC in any patient with UC is 3.7% which increases to 5.4% for
those with pancolitis. 18 The cumulative risk for CRC of any patient with UC is 2% at 10
years, 8% at 20 years, and 18% at 30 years. Increasing duration of disease is as one of the
most important risk factors for the development of cancer in UC, which is significant after
9 years of disease and increases in subsequent years.13-19 The extension of the disease is
also a risk factor for cancer. Most cancers arise in patients when the whole colon is
affected (pancolitis). Patients with UC beyond the distal sigmoid and rectum are at
increase risk of CRC and risk is intermediate in patients with left-sided disease and lower
in patients with proctitis.14-19
Recently, we have published the Brazilian consensus for management of IBD. Supported
by evidence-based medicine, we recommend that the screening should be performed
using colonoscopy every 3 years in the 2nd decade, every 2 years in the 3rd decade and
yearly in the 4th decade of illness together with 4-quadrant biopsies of non-inflamed
mucosal at every 10 cm of colon, in the whole colon in association with biopsies of
suspected areas. 14
7. Chromoendoscopy
Because of the limitations of what could be seen with traditional colonoscopies emitting
white light, adjunct techniques have been investigated in colitis and sporadic polyp
surveillance practices that have the potential to enable endoscopists to better visualize the
colorectal mucosa. It has being demonstrated a higher diagnostic accuracy for dysplasia
diagnosis in biopsies targeted by chromoendoscopy when compared to biopsies obtained
with standard colonoscopy.17 Chromo colonoscopy with biopsy of suspected area is a valid
alternative to multiple biopsies.14 There are a stronger correlation between the endoscopic
assessment of colonic inflammation and histopathologic findings. In this scenario,
chromoendoscopy allow for the differentiation between nonneoplastic and neoplastic
lesions with a sensitivity and specificity of 93%.
It became apparent that adding an adjunct technique would enable us to identify more
patients with dysplasia. Unfortunately, however, there are no longitudinal data showing
that chromoendoscopy actually lessens either the incidence of dysplasia on follow-up
colonoscopy or cancer-related morbidity or mortality. On the other hand, once this
technique are inexpensive, safe, and relatively easy to perform, it should be have an
important role in surveillance of dysplasia and cancer in UC patients.
8. Narrow Band Imaging (NBI)

Narrow band imaging (NBI) and Multi-Band Imaging (MBI)* are real-time, on-demand
endoscopic imaging techniques designed to enhance visualization of the vascular network
and surface texture of the mucosa in an effort to improve tissue characterization,
differentiation, and diagnosis. 17 NBI and MBI were developed to be an alternative to
chromoendoscopy. The techniques may allow contrast enhancement of tissue surface
structures helping in the endoscopic diagnosis. In contrast, neither NBI nor MBI have being
studied extensively as chromoendoscopy.17
It has being reported in the literature that, in ulcerative colitis, the role of NBI is not as
promising as observed in other scenarios. 8-10 On the other hand, in an uncontrolled study
consisting of 46 patients with ulcerative colitis, the relative frequency of dysplasia was
higher in areas of tortuous pattern (8%) than in those of honeycomb-like or villous pattern
(0.4%), as seen under NBI with magnication. The tortuous pattern determined by NBI may
be a clue for the identication of dysplasia during surveillance of UC. 9,16
138 Colonoscopy
9. References
[1] Meyers S, Janowitz HD. The ‘‘natural history’’ of ulcerative colitis: an analysis of the
placebo response. J Clin Gastro- enterol 1989;11(1):33–37
[2] Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR.
Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence,
and survival. Gut 2000;46(3):336–343
[3] Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic
distribution of Crohn’s disease and ulcerative colitis in the United States. Clin
Gastroenterol Hepatol 2007;5(12):1424–1429
[4] Rejchrt S, Bures J, Siroky M, Kopacova M, Slezak L, Langr F. A prospective,
observational study of colonic mucosal abnormalities associated with orally ad-
ministered sodium phosphate for colon cleansing before colonoscopy. Gastrointest
Endosc 2004;59: 651 – 654.
[5] Zwas FR, Cirillo NW, el-Serag HB, Eisen RN. Colonic mucosal abnormalities associated
with oral sodium phosphate solution. Gastrointest Endosc 1996;43:463 – 6
[6] Wong NA, Penman ID, Campbell S, Lessells AM. Microscopic focal cryptitis associated
with sodium phosphate bowel preparation. Histopathology 2000; 36:476 – 8
[7] Matsumoto T, Esaki M, Fujisawa R, Nakamura S, Yao T, Iida M. Chromoendoscopy,
narrow-band imaging colonoscopy, and autofluorescence colonoscopy for
detection of diminutive colorectal neoplasia in familial adenomatous polyposis. Dis
Colon Rectum 2009;52(6):1160–1165
[8] Tung SY, Wu CS, Su MY. Magnifying colonoscopy in differentiating neoplastic from
nonneoplastic colorectal lesions. Am J Gastroenterol 2001;96(9):2628–2632
[9] Song LM, Adler DG, Conway JD, et al; ASGE TECH-NOLOGY COMMITTEE. Narrow
band imaging and multiband imaging. Gastrointest Endosc 2008;67(4):581– 589
[10] Cima RR, Pemberton JH. Medical and surgical management of chronic ulcerative
colitis. Arch Surg. 2005 Mar;140(3):300-10
[11] Lichtenstein GR, Rutgeerts P. Importance of mucosal healing in ulcerative colitis.
Inflamm Bowel Dis. 2010;16(2):338-46.
[12] Frøslie KF, Jahnsen J, Moum BA, Vatn MH; IBSEN Group. Mucosal healing in
inflammatory bowel disease: results from a Norwegian population-based cohort.
Gastroenterology. 2007;133(2):412-22.
[13] Fratila OC, Craciun C. Ultrastructural evidence of mucosal healing after infliximab in
patients with ulcerative colitis. J Gastrointestin Liver Dis. 2010;19(2):147-53.
[14] Consensus guidelines for the management of inflammatory bowel disease. Brazilian
Study Group of Inflammatory Bowel Diseases. Arq Gastroenterol. 2010;47(3):313-25.
[15] Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A
population-based study. N Engl J Med. 1990;323(18):1228-33.
[16] Lukas M. Inflammatory bowel disease as a risk factor for colorectal cancer. Dig Dis.
2010;28(4-5):619-24.
[17] Matsumoto T, Kudo T, Jo Y, et al. Magnifying colonoscopy with narrow band imaging
system for the diagnosis of dysplasia in ulcerative colitis: a pilot study. Gastrointest
Endosc 2007;66:957-65.
[18] Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a
meta-analysis. Gut. 2001;48(4):526-35.
[19] Rubin DT, Rothe JA, Hetzel JT, Cohen RD, Hanauer SB. Are dysplasia and colorectal
cancer endoscopically visible in patients with ulcerative colitis? Gastrointest
Endosc. 2007 Jun;65(7):998-1004.
9
Pathological Issues of
Ulcerative Colitis/Dysplasia
Tomita S.1, Fujii S.2 and Fujimori T1
1Department of Surgical and Molecular Pathology,
DOKKYO Medical University School of Medicine
2Center for Gastrointestinal Endoscopy, Kyoto-Katsura Hospital
Japan
1. Introduction
The first ulcerative colitis (UC)-associated carcinoma (colitic cancer) appears to have been 14-
year history of UC (Fujii et al., 2002, as cited in Crohn & Rosenberg, 1925). It is widely accepted
that inflammation plays important roles in the development of various cancers, and indeed,
patients with UC show an increased incidence of colorectal neoplasia, and UC-associate
dysplasia/neoplasia represents a major cause of increased mortality in such patients. In order
to improve the prognosis of patients with UC-associated dysplasia/neoplasia, diagnosis at an
early or precancerous stage is crucial. Predisposition to colorectal dysplasia/neoplasia in UC is
generally considered to depend on 2 risk factors, namely the presence of long-standing disease
and extensive colitis (Fujii et al., 2008, as cited in Ekbom, et al., 1990, and Eaden et al., 2001).
Thus, colitic cancers are believed to arise through a chronic inflammation-dysplasia-carcinoma
sequence, and therefore early detection of precancerous dysplasia is very important for
optimizing the prognosis of patients with long-standing UC. In a clinical setting, UC patients
are monitored for dysplasia endoscopically on a regular basis, but it is difficult to discriminate
UC-associated dysplasia/neoplasia from inflamed regenerating epithelium even by
pathological examination. Therefore, surveillance colonoscopy with multiple random biopsies
has been widely recommended for patients with long-standing and extensive UC. However,
because UC-associated dysplasia/neoplasia is often difficult to detect endoscopically and to
discriminate from inflammatory regenerative epithelium histologically, it remains a matter of
contention whether conventional surveillance colonoscopy is effective for the early detection
of UC-associated dysplasia/neoplasia. Here we describe the ulcerative colitis/dysplasia based
on pathology and discuss relevant issues in arriving at the correct differential diagnosis based
on morphological, immunohistochemical and molecular findings.
2. Risk factor and clinicopathological characteristics of dysplasia/neoplasia

development in the patients with ulcerative colitis
The reported prevalence rates of colitic cancer range from 1 to 10% of all patients with UC.
This increased risk, above that of the general population, appears approximately 8–10 years
after the onset of the disease. The risk increases with the duration of disease and is greater in
persons with extensive colitis (Fujii et al., 2002, as cited in Dobbins, 1984). A cumulative
140 Colonoscopy
incidence of colorectal cancer was 5–10% with UC of 20 years duration and 12–20% with UC
of 30 years duration (Fujii et al., 2002, as cited in Levin, 1995). The risk of colorectal cancer in
patients with left-sided colitis was considered to increase 20 years after the onset of UC.
Moreover incidence of colitic cancer in patients with left-sided disease did not differ from
that in patients with pancolitis. In order to detect UC-associated dysplasia/neoplasia and
the early stages of cancer, surveillance colonoscopy has been recommended for patients
with long-standing and extensive UC. In Japan, possibly because the number of UC patients
with dysplasia/neoplasia is smaller than that in Western countries. We reviewed Japanese
case reports of UC-associated dysplasia/neoplasia published between 1990 and 2002 (Fujii
et al., 2003b). Of 118 patients with UC-associated neoplasia, 41 underwent surveillance
colonoscopy (surveillance group), 64 did not (nonsurveillance group), and the remaining 13
cases were unknown as to surveillance status. The 64 UC associated neoplasias including
colitic cancer (UC associated carcinoma) in the nonsurveillance group were found by
colonoscopy that was undertaken because of developing symptomatic episode, or for the
evaluation of inammation activities. The depth of tumor invasion, incidence of lymph node
metastasis, incidence of liver metastasis, and stage in the two groups are shown in Table 1.
Surveillance (41) Nonsurveillance (64)

Depth of neoplastic invasion
Tis 11 11
T1 12 5
T2 5 6
T3 10 30
T4 0 6
Unknown 3 6
Lymph node metastasis
Positive 4 25
Negative 25 23
Unknown 12 16
Liver metastasis, positive 1 4
Peritoneal dissemination, positive 0 7
Dukes’ stage
A 22 15
B 2 8
C 4 25
Unknown 13 16
Table 1. Clinicopathological features of neoplasias in the surveillance and nonsurveillance
groups (adapted from Fujii et al., 2003b)
Regarding depth of tumor invasion, early colorectal cancer, dened as tumor invading the
lamina propria and/or muscularis mucosae and/or submucosa, was more frequent in the
surveillance group than in the nonsurveillance group (60.5% vs. 27.6%). The incidence of
lymph node metastasis was lower in the surveillance group than in the nonsurveillance group
(13.8% vs. 52.1%). Four out of the ve tumors associated with liver metastasis and, all seven
tumors associated with peritoneal dissemination were in the nonsurveillance group. The
distribution of Dukes’ stages in the two groups was: A/B/C, 78.6%/7.1%/14.3% in the
Pathological Issues of Ulcerative Colitis/Dysplasia 141
surveillance group, compared with 31.2%/16.7%/52.1% in the nonsurveillance group. Similar

to Western countries, surveillance colonoscopy in Japan contributes to the early detection of
UC-associated dysplasia/neoplasia. The surveillance colonoscopy appears to contribute to the
early detection and excellent prognosis of UC-associated dysplasia/neoplasia. But it still
remains questionable whether surveillance colonoscopy with multiple-step biopsy effectively
enables the early detection of UC-associated dysplasia/neoplasia.
3. The morphological, immunohistochemical and molecular finding of

ulcerative colitis/dysplasia
Morphological futures of macroscopic and endoscopic images, UC-associated
dysplasia/neoplasias in the precancerous and early stages show various changes. Such
dysplasia/neoplasias are often at, plaque-like, and supercially elevated or even
depressed, and frequently appear as faintly red, mildly discoloured, nely villous, and
granular (Fig.1).
Fig. 1. Morphological classication of dysplastic epithelium in ulcerative colitis. (adapted

from Fujii et al., 2002)
Macroscopic and endoscopic changes are not clear, and are sometimes missed in chronically
inamed epithelium. Detecting UC-associated dysplasia/neoplasias in the precancerous and
early stages is difcult by macroscopy (Fig.2), endoscopy (Fig.3a), and stereomicroscopic
finding (Fig.3b). We retrospectively verified the percentage of UC-associated
dysplasia/neoplasias that was detectable endoscopically before surgical resection
（Yamagishi et al., 2009）. When classified UC-associated dysplastic/neoplastic lesions
according to macroscopic appearance, 79.1% lesions were of flat-type. In detail, 92.5%
dysplasias, 80.9% Tis carcinomas, 60% T1 carcinomas were of flat (flat and superficial
elevated type), whereas 6 of 7 (85.7%) T2-4 carcinomas were protruding (polypoid type). In
each T category, the detection rare of lesions tends to be high in the protruding appearance
(Table 2). Most of the undetectable lesions were the flat or flat-elevated type
macroscopically. Thus, endoscopic detection of UC-associated dysplasia/neoplasias at the
precancerous and early stage appears to be difficult. Therefore, improvements to the current
methods of colonoscopy are needed in order to detect UC-associated dysplasia/neoplasias
more effectively and accurately. On the other hand, several Japanese investigators reported
that observation of the configuration of the outlet of the colorectal surface lesion using high-
resolution endoscopy, chromoendoscopy (Fujii et al., 2008, as cited in Rembacken, et al.,
2000, and Kudo et al., 1994), increasingly useful for diagnosing and treating colorectal
neoplasia. Recent reported the usefulness of high-resolution endoscopy, chromoendoscopy,
142 Colonoscopy
and new endoscopic system (NBI, FICE, i-scan) for detecting UC associated dysplasia
・neoplasia (East et al., 2006).
Fig. 2. Macroscopic appearance of ulcerative colitis/dysplasia, post formalin-fixed. Most of

the endoscopic undetectable lesions were the flat and superficial elevated type
macroscopically. (Red bar: UC-IV, Yellow bar: UC-III, Blue bar: UC-IIb)
(a) Endoscopic nding (b) Stereomicroscopic nding
Fig. 3. Endoscopic nding of the UC-III lesion. In non-dysplastic epithelium, circle and/or
oval pits were scattered in the area (a). Stereomicroscopic nding of the UC-III lesion. The
mucosal surface shows packed distribution of oval and/or club-like shape and/or branch-
like shaped pit (b).
T grade P value Protruding Flat *P value

Dysplasia(n=40)
Detectable 19 3 16 0.058
Undetectable 21 0 21
Tis(n=15
Detectable 10 0.205a 3 7 0.171
Undetectable 5 0 5
T1(n=5)
Detectable 2 0.751a 2 0 <0.05
Undetectable 3 0.292b 0 3
Advanced (n=7)
Detectable 7
<0.05 a 6 1 ND
0.082 b
Undetectable 0 <0.05 c 0 0
a Compared with dysplasia, b Compared with Tis, c Compared with T1.
* Relationship between detection and macroscopic appearance. NF: not determined

Table 2. Relationship between detection and macroscopic appearance of UC-associated
lesions (adapted from Yamagishi et al., 2009)
3.1 Histological diagnosis of ulcerative colitis/dysplasia

UC associated dysplasia was a precursor of colitic cancer in UC, several studies have shown
that UC-associated dysplasia correlates with the presence of colitic cancer. The existence of
carcinoma at the time of colectomy in UC patients with high-grade dysplasia, as determined
by a preoperative rectal biopsy. A presence of dysplasia could identify patients likely either
to have or to develop colitic cancer. Thus, dysplasia is not only a precursor of colitic cancer,
but may also be a marker for the existence of colitic cancer in other areas of the colorectum.
Gastrointestinal surgical pathologist have been diagnosis inflammatory grade and epithelial
injury on UC patient using by Matts grading system (Table 3) , The Inammatory Bowel
Disease Morphology Study Group in Western countries attempted to verify a standardized
terminology and classication for the assessment of dysplasia in UC (Table 4). However, in
Japan, the interpretation of‘dysplasia’ in UC varies from one pathologist to another.
Therefore, the Research Committee on Inammatory Bowel Disease of the Ministry of
Health and Welfare of Japan proposed a new classication for UC associated
dysplasia/neoplasia in 1993 (Table 5).
Grade 1 Normal appearance.

Grade 2 Some infiltration of the mucosa or lamina propria with either round cells or
polymorphs.
Grade 3 Much cellular of the mucosa or lamina propria and submucosa.
Grade 4 Presence of crypt abscess, with much infiltration of all layers of the mucosa.
Grade 5 Ulceration, erosion, or necrosis of the mucosa, with cellular infiltration of
some or all its layer.
Table 3. The value of rectal biopsy in the diagnosis of ulcerative colitis (adapted from Matts ,
1961).
144 Colonoscopy
Negative
Normal mucosa
Inactive (quiescent) colitis
Active colitis
Indenite
Probably negative (probably inammatory)
Unknown
Probably positive (probably dysplasia)
Positive
Low-grade dysplasia
High-grade dysplasia
Table 4. Biopsy classication of dysplasia in inammatory bowel disease (adapted from
Riddle et al., 1983).
Category Description
UC-I Inammatory change
UC-II Indenite
UC-IIa Probably inammatory
UC-IIb Probably neoplastic
UC-III Neoplastic but not carcinoma
UC-IV Carcinoma
UC: ulcerative colitis.
Table 5. Histological classication of the neoplasia epithelium arising in ulcerative colitis
(adapted from Konishi et al., 1993).
Matts grading system (Table 3) and UC associated dysplasia/neoplastic classication (Table
4 & 5) are used for clinical and research purposes and applies to both colectomy and biopsy
specimens. The histological characteristics of each stage of UC-associated dysplasia/
neoplasia with inflammatory lesion (Fig 4). However, it is difficult and sensitive to
discriminate between UC-associated dysplasia and regenerative epithelium by the
conventional Hematoxylin and Eosin staining section. Histological diagnosis of UC-
associated dysplasia/neoplasia is based on a combination of architectural and cytological
alterations. The architectural alterations often result in glandular arrangements, e.g., club-
shaped villi, crawling glands or bifid formation at the base of the crypts. The cytological
alterations comprise cellular and nuclear pleomorphism, nuclear hyperchromatism, loss of
nuclear polarity, marked nuclear stratification, dystrophic goble cells and failure of
maturation from the crypt base to the surface.
3.2 Immunohistochemical finding of ulcerative colitis/dysplasia

Pathologically, it is not rare those surgical pathologists are unable to distinguish between
from UC-associated dysplasia/neoplasia and inflammatory regenerative epithelium using
by hematoxylin and eosin staining. Furthermore, there are differences in the diagnostic
criteria that different surgical pathologist use for dysplasia/neoplasia. In order to improve
the accuracy of pathological diagnosis, it will be necessary to use ordinary method for
immunohistochemical technique.
(a) Crawling crypts. (b) Dystrophic goblet cell
(c) Distorted crypts with cellular atypia (d) Invasive crypt and crypt abscess
Fig. 4. Histological appearance of UC-associated dysplasia/neoplasia on Hematoxylin and

Eosin staining section. There are marked distorted and crawling crypts. This epithelium could
be interpreted as UC-IIb with Matts grade 3 (a). There are a lot of goblet cells, so-called
dystrophic goblet cell. This epithelium could be interpreted as UC-IIb with Matts grade 3 (b).
There are marked distorted crypts with cellular atypia. This epithelium could be interpreted as
UC-III with Matts grade 3 (c). Neoplastic crypts with submucosal invasion. This epithelium
could be interpreted as UC-IV with Matts grade 4 including crypt abscess. (d).
3.2.1 P53 protein nuclear accumulation

Several reports have shown that the rate of the tumor suppressor p53 gene alteration is high
in UC-associated dysplasia/neoplasia (Lashner et al., 1999). Immunohistochemical analysis
of P53 protein is a useful and easy method for detecting p53 gene alterations. In our study,
59.5% of neoplastic lesions (UC-III and IV) and 40.0% of lesions that were probably
neoplastic (UC-IIb) displayed nuclear accumulation of P53 protein (Fujii et al., 2003a). Thus,
immunohistochemical analysis of P53 could be a useful marker of UC associated
dysplasia/neoplasia in cases where discriminating between neoplasia and regenerative
epithelium is difcult (Fig 5) (Table 6).
3.2.2 Increased expression of DNA Methyltransferase -1

Neoplastic progression in UC occurs in a histologically stepwise manner, from chronic
epithelial inflammation to dysplasia/neoplasia, and the process of neoplastic progression
involves accumulation of genetic and epigenetic alterations. Some of these alterations are
146 Colonoscopy
(a) Hematoxylin and Eosin (b) P53 protein
Fig. 5. Mucin droplets are well preserved but have lost their normal polarity, being present
apically or basally or lateral to the nucleus (a). This epithelium could be interpreted as UC-
IIb. Immunohistochemistry analysis revealed normal accumulated P53 protein in the
nucleus (b).
Histological diagnosis n Positive staining(%)

Inflammatory change (UC-I) 5 0(0)
Indefinite, probably inflammatory (UC-IIa) 38 0(0)
Indefinite, probably neoplastic (UC-IIb) 35 14(40.0)
Neoplastic but not carcinoma (UC-III) 24 14(58.3)
Carcinoma (UC-IV) 18 11(61.1)
Table 6. Relation between nuclear accumulations of P53 protein and histological diagnosis
(adapted from Fujii et al., 2003a)
known to occur in both the neoplastic and nonneoplastic epithelium of UC patients with
neoplasia, and are considered to be widespread and to occur early in the process of
neoplastic progression. In several types of neoplasia, aberrant methylation of promoter-
region CpG islands, as an epigenetic modification of DNA, is associated with transcriptional
inactivation of tumor suppressor genes and plays a crucial role in the development and
progression of neoplasia (Hsieh et al., 1998). DNA methylation results from a methyl
transfer reaction performed by the three active DNA methyltransferases (DNMTs): DNMT1,
DNMT3a and DNMT3b (Okano et al., 1999). Of these, DNMT1 is the most abundant DNMT
targeted to replication foci and has a preference for hemimethylated DNA substrates.
Recent investigations have shown that DNMT1 is overexpressed in tumorigenic cells and
several types of human tumors, and that increased expression of DNMT1 is dependent on
cell proliferation. We reported that the immunoreactive DNMT1 expression gradually
increased from rectal epithelium of UC patients without neoplasia to nonneoplastic rectal
epithelium of UC patients with neoplasia (p <0.001), and to colorectal neoplasia (p <0.001)
(Fujii et al., 2010). Among 31 neoplasias, there was no difference in the immunoreactive
DNMT1 expressions between dysplasia and invasive cancer. Expression of DNMT1 in
non-neoplastic epithelium may precede or be a relatively early event in UC-associated

carcinogenesis (Fig. 6).
(a) Non-neoplastic epithelium without colitic cancer
(b) Non-neoplastic epithelium with colitic cancer
(c) Colitic cancer.

Fig. 6. Immunohistochemical staining for DNMT1 protein in non-neoplastic rectal
epithelium from UC patients without neoplasia (a), non-neoplastic rectal epithelium from
UC patients with neoplasia (b) and colorectal neoplasia (c).
148 Colonoscopy
3.3 Molecular alterations of ulcerative colitis/dysplasia

Numerous reports have revealed molecular alterations (e.g., K-Ras gene mutation, p16 gene
hypermethylation, p14 gene hypermethylation, p53 gene mutation, DNA aneuploidy,
chromosomal instability, microsatellite instability, age-related methylation, telomere length
shortening) of nonneoplastic epithelium in UC patients with neoplasia (Brentnail et al., 1994,
Holzmann et al., 2001, Fujii et al., 2005). Several of these reports have indicated higher
frequencies of molecular alterations to nonneoplastic epithelium in UC patients with
dysplasia/neoplasia than in nonneoplastic epithelium in UC patients without neoplasia,
suggesting that these molecular alterations may be applicable as new markers for
identifying individuals with UC at increased risk of neoplasia.
3.3.1 P53 gene abnormalities

In the p53 gene, point mutations have been reported in 40–50% and LOH in 80% of sporadic
colorectal cancers (Baker et al., 1990). However, these genetic alterations of the p53 gene
have only been found in approximately 10% of sporadic adenomas. These data suggest that
genetic alterations in the p53 gene are involved in the progression from adenoma to cancer.
Alterations in p53 gene were reported in both UC-associated dysplasia and colitic cancer at
an incidence of about 50–80%.The point mutations in p53 gene were detected in 48% of case
of UC-associated dysplasia, and that both point mutation and allelic loss were found in
more than 80% of cases of colitic cancer (Brentnail et al., 1994. When the p53 gene has a
nonsense mutation or frameshift, the P53 protein does not accumulate in the nucleus despite
the alteration. In fact, 92.9% of the neoplastic lesions that displayed negative
immunohistochemical staining for P53 protein demonstrated a p53 gene mutation within
exons 5–8 under PCR singlestranded conformation polymorphism (Fujii et al., 2003a). This
suggests that screening for p53 gene mutation using PCR single-stranded conformation
polymorphism is more accurate than immunohistochemistry for discriminating between
UC-associated neoplasia and regenerative epithelium.
3.3.2 Age-related methylation and methylation analysis of ER Gene

In several neoplasias, aberrant methylation of promoter region Chg. islands, as an epigenetic
modification of DNA, is associated with transcriptional inactivation of tumor suppressor
genes and plays a crucial role in the development and progression of neoplasia (Hsieh et al.,
1998). In normal colorectal epithelium, some genes are methylated with aging, and this
alteration is known as age-related methylation. A methylation of the estrogenic receptor
(ER) Chg. Island increased with age in no neoplastic colorectal epithelium and that the same
methylation occurred in most sporadic colorectal neoplasias (Isa et al. 1994). They concluded
that methylation of the ER gene in aging colorectal epithelium could represent one of the
earliest events predisposing to sporadic colorectal carcinogenesis. Therefore, in our recent
study (Fujii et al., 2005 and Tominaga et al., 2005), we analysed ER gene methylation in
multiple samples taken from 6 regions throughout the colorectum: the rectum, sigmoid
colon, descending colon, transverse colon, ascending colon and cecum (Fig. 7). Non-
neoplastic colorectal epithelia from patients with longstanding and extensive UC, including
8 UC patients with neoplasia and 10 patients without, were evaluated. The combined
bisulfite restriction analysis method (COBRA) was used to determine the methylation status
of the ER gene. The mean methylation level of the ER gene was 25.4% in the nonneoplastic
epithelia from UC patients with neoplasia, whereas it was only4.0 % in those without
neoplasia (P < 0.001). The methylation level of the ER gene in UC patients with neoplasia
was significantly higher than in UC patients without neoplasia throughout the colorectum
except for the cecum. In UC patients with neoplasia, the mean ER methylation level in the
distal colon was significantly higher than in the proximal colon (P < 0.001) Analysis of ER
gene methylation may have potential as a useful marker for identifying individuals at
increased risk of neoplasia among those with longstanding and extensive UC.
(a) Non-neoplastic colon epithelium with colitic cancer
(b) Non-neoplastic colon epithelium without colitic cancer

Fig. 7. COBRA for the ER gene in each region of the non-neoplastic epithelium of the
colorectum from patient with UC-associated neoplasia (a) and without UC-associated
neoplasia (b). UM, the unmethylated breast cancer cell line MCF-7; M, the methylated colon
cancer cell line DLD-1; R, rectum; S, sigmoidcolon; D, descending colon; T, transverse colon;
A, ascending colon; C, cecum. A, representative samples
4. Conclusion
In this issue, we have discussed the efficacy of surveillance colonoscopy for UC associated
dysplasia/neoplasia, several problems related to the diagnosis of UC–associated
dysplasia/neoplasia and molecular markers that can be used to identify individuals with
UC at increased risk of dysplasia/neoplasia. Current surveillance colonoscopy remains
unsatisfactory, due to difficulties with endoscopic and histological diagnosis of UC-
associated dysplasia/neoplasia. These difficulties may be overcome by introducing
adjunctive techniques for diagnosing UC-associated dysplasia/neoplasia, analysis of p53
gene alteration and/or new endoscopic system. However, it seems impartial for all UC
patients with conventional risk factors, long-standing disease and extensive colitis to
undergo close surveillance colonoscopy using such techniques. In order to realize the full
potential of close surveillance colonoscopy, higher-risk groups selecting from patients with
long – standing and extensive UC. Analyses of age-related methylation and expression of
DNMT1 in nonneoplastic epithelium may allow identification of such higher-risk patients.
150 Colonoscopy
5. Acknowledgment
The authors thank Dr. S. Kameok a and Dr. M. Itabashi (Department of Surgery II, Tokyo
Women’s Medical College), Dr. B. Iizuka (Institute of Gastroenterology, Tokyo Women’s
Medical College), Dr. H. Mitooka (Division of Gastroenterology, Kobe Kaisei Hospital), Dr.
T. Tanaka (Division of Gastroenterology, Shizuoka City Shizuoka Hospital) and Dr. N.
Kitajima (Division of Gastroenterology, Kasai City Hospital) for kindly supplying the tissue
materials. We would like to thank Dr. K. Ichikawa, Dr. J, Imura (Department of Surgical and
Molecular Pathology, DOKKYO Medical University School of Medicine), Dr. H. Yamagishi
(Department of Pathology, DOKKYO Medical University Koshigaya Hospital), and Dr. H.
Fukui (Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo
College of Medicine) for their insightful comments. The authors greatly thank Ms C. Sato -
Matsuyama, A. Shimizu, T. Ono, M. Katayama, N. Nagashima, (Department of Surgical and
Molecular Pathology, DOKKYO Medical University School of Medicine) for technical
assistance and to Ms. A. Kikuchi (Department of Surgical and Molecular Pathology,
DOKKYO Medical University School of Medicine) for secretarial assistance in preparing the
manuscript.
This work was partially supported by the Grant-in-Aid for Young Scientists (B: No
16790390), Grant-in-Aid for Scientific Research (C: No 18659101, 23590410) from the
Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan and
Dokkyo Medical University Young Investigator Award (2009 for graduate student Dr. H.
Tanaka and 2011-03-2 for graduate student Dr. K. Oono).
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10
Pathology of Staging of Early Colorectal

Lesions During Surveillance Programmes
Emil Salmo1 and Najib Haboubi2
1Department of Histopathology, Royal Bolton NHS Foundation Trust, Bolton,
2Department of Histopathology, Clinical Sciences Building,
University Hospital of South Manchester,

United Kingdom
1. Introduction
Colorectal carcinoma (CRC) is the second most common cancer in women after carcinoma of
the breast and the third most common cancer in men after carcinoma of the prostate and
lung with a lifetime risk in the UK of one in 16 for men and one in 20 for women (C-R-UK,
2011). In 2008, around 40,000 people in the UK were diagnosed with bowel cancer and
approximately 16,000 died from the disease. In the same year, there were an approximately
334,000 new cases of CRC in the European Union (GLOBOCAN, 2008). The lowest rates for
both men and women were in Greece and the highest rates for men were in Hungary and
for women in Denmark. Rates for the UK for men and women were below the EU27 average
(C-R-UK, 2011). Worldwide, every year, more than 1 million will develop CRC (Parkin et al.,
2005).
Over 90% of CRC is sporadic in nature and affects 25 per 100 000 per year of individuals
aged 45–55, but over 300 per 100 000 per year in individuals aged 75 and over (West et al.,
2008). Internationally, the UK has an incidence of CRC close to the average for all EU
countries, which is slightly lower than that for Australia, New Zealand and North America
(Halloran, 2009).
Survival rates in individuals with CRC have increased substantially in the past few years,
possibly as a result of early diagnosis and improved treatment. Although substantial
information about risk factors exists, about 75% of diagnoses are in patients with no
apparent risk factors other than old age (ACS, 2011), however, the 5-year survival is still less
than 60% in most European countries (Verdecchia et al., 2007).
2. Why screen for bowel cancer?

In 1998 the NHS started to develop the Bowel Cancer Screening Programme (Hardcastle et
al., 1996) and in 2006, the English CRC screening programme started a 2-yearly screening for
individuals between the ages of 60 and 69 (extended to 74 years in 2010) (Halloran, 2009).
The decision was based on the results of four large randomized controlled trials, including
one in Nottingham (Hardcastle et al., 1996), where a 16% reduction in mortality was
associated with the implementation of bowel screening. These trials showed that population
screening with the faecal occult blood test (FOBT) every two years has the potential to
154 Colonoscopy
reduce colorectal mortality between 15% to 18% in people aged 45-74 (Hardcastle et al.,
1996; Kronborg et al., 1996; Lindholm et al., 2008; Mandel et al., 1993). Individuals who
attend screening have a 25% reduction in their risk of dying from CRC. These studies
supported similar results from trials in Nottingham (Hardcastle et al., 1996; Steele et al.,
2009; UK-Colorectal-Cancer-Screening-Pilot-Group, 2004).
The use of flexible sigmoidoscopy has also been investigated as a screening tool (Atkin et al.,
1993; UK-Flexible-Sigmoidoscopy-Screening-Trial-Investigators, 2002) which showed that a
once-only flexible sigmoidoscopy between the ages of 55 and 64 could reduce CRC
incidence by 33% and mortality from CRC by 43% (Atkin et al., 2010). The test was also
found to be safe and acceptable (Atkin et al., 1993). Several randomised trials and Cochrane
reviews have provided high-quality evidence that this test, if offered every 2 years, has the
potential to reduce mortality rates associated with CRC by 16% (Towler et al., 1998) and
reduces incidence and mortality rates of distal CRC by 60–80% (Newcomb et al., 2003; Selby
et al., 1992).
In general, the NHS Bowel Cancer Screening Programme (NHS BCSP) commenced in April
2006 and invites men and women aged 60–69 to participate via submission of faecal occult
blood test every 2 years; those with a positive result will be offered colonoscopy (West et al.,
2008).
As a marker of the success of the programme, at colonoscopy, the proportion of Duke’s
stage A and B lesions is markedly higher than that diagnosed amongst the symptomatic
population (Goodyear et al., 2008; Halloran, 2009).
3. Principles of screening
The aim of screening for CRC is to prevent the development of advanced disease through
detection of early and premalignant adenomas, from which at least 80% of cancers are
thought to arise (Cunningham et al., 2010). As outlined by Wilson and Jungner, (1968) the
criteria for screening (Table 1), which have been adopted by the WHO, demonstrates that
CRC is an ideal disease for screening. Population screening therefore continues to offer the
best prospects for reduction in mortality rates (Cunningham et al., 2010).
WHO screening principles:
1. The condition sought should be an important health problem for the individual and
community.
2. There should be an acceptable treatment or useful intervention for patients with the
disease.
3. Facilities for diagnosis and treatment should be available.
4. There should be a recognizable latent or early symptomatic stage.
5. There should be a suitable screening test or examination.
6. The test should be acceptable for the population.
7. The natural history of the disease should be adequately understood.
8. There should be an agreed policy for referral for further examination and for whom to
treat as patients.
9. The cost should be economically balanced in relation to possible expenditure on
medical care as a whole.
10. Case finding should be a continuing process and not a once-only project.
Table 1. (Wilson and Jungner, 1968)
Pathology of Staging of Early Colorectal Lesions During Surveillance Programmes 155
The programme uses faecal occult blood testing (FOBt) as the primary screening modality to
select patients for colonoscopy (BCSP, 2011). Colonoscopy is the best means we have to
detect CRC and it provides an opportunity for therapeutic intervention, which is not
possible with virtual colonoscopy (computerized tomography colonography). CT
colonography (virtual colonoscopy) is as sensitive as colonoscopy for the detection of
cancers and large adenomas, but includes exposure to radiation, requires full bowel
preparation, and, at the end, colonoscopy is necessary for definite treatment (Halligan et al.,
2005; Whitlock et al., 2008). Whilst the morbidity and mortality associated with colonoscopy
might be considered acceptable for patients with signs and symptoms of the disease, they
are unacceptable as a first line population screening. Perforation and clinically significant
bleeding occur after colonoscopic polypectomy in about 0.2% and 1% of cases, respectively
(Bond, 2000).
Flexible sigmoidoscopy carries significantly lower risk but will miss some 30 to 40% of
proximal lesions (Halloran, 2009). As a screening test, the guaiac FOBT (gFOBT) has
significant limitations as it cannot detect low concentrations of blood and has a poor
analytical specificity. Any blood that reaches the stool may give a positive test result such as
in cases of ulcerative colitis, Crohn’s disease, haemorrhoids, major dental surgery or upper
gastrointestinal bleeds, as does a diet of large raw steaks and black pudding (Halloran,
2009). Evidence from randomized controlled trials designed to assess the impact of FOBt-
based screening on mortality in the screened population have suggested that FOBt is more
likely to detect distal colonic and sigmoid lesions rather than right-sided tumours (Thomas
et al., 1992).
The sensitivity of FOBt varies but has been quoted as between 6.2% and 83.3% in a recent
systematic review when considering all neoplasms (Burch et al., 2007).
Harmston et al. (2010) showed that the location of screen-detected cancers does not differ from
that seen in the unscreened population which suggests that faecal occult blood test screening
detects cancer irrespective of location within the colon. It should be stressed that patients with
negative FOB negative should not be given the impression of being cancer free.
Hol et al. (2010) recently showed in a population-based CRC screening trial using
immunochemical FOB (IFOB) randomized against guaiac-based FOB that the detection rate
was far better in the former. The authors strongly suggest using the IFOB in screening
programmes, however, these findings need to be validated before changing practice of
screening.
As a result of bowel screening, there will be more cases of malignant polyps detected in the
screening programme than in symptomatic patients. Furthermore, how should patients with
positive FOB and negative colonoscopy be managed?
One review from Canada (McLoughlin and Telford, 2007) addressed the issue and showed
that when there is positive FOB and the patient undergoes both upper and lower
gastrointestinal endoscopy, the yield for upper tract pathology is significant. These authors,
however, argue that in those patients with a positive FOB test and negative colonoscopy, it
is not cost effective to perform routine upper endoscopy unless the patient is anaemic,
symptomatic or has risk factors for gastric cancer.
What happens to the population outside the screening age group?
In an important study, Shellnut et al. (2010) looked at the appropriateness of restricting the
screened age group and found that not screening individuals under 50 and over 75 years
would miss around 49 to 50% of patients in their study. Harmston et al. (2010) looked at 100
patients with CRC in the NHSBCSP and analysed their symptoms. They found that 70% had
156 Colonoscopy
significant symptoms such as rectal bleeding, tenesmus, change in bowel habit and
abdominal pain and they argued that with proper public awareness, these symptoms would
have triggered referral. The study also showed that there was a significant increase in
detecting Dukes A lesions in 28.5% of cases.
Ellul et al. (2010) again showed that with screening there is earlier detection of Dukes A over
a non screened population of 45.3% compared with 10.1%. This is good evidence for the
benefit of screening. It is remarkable, however, that the proportion of Dukes A stage
tumours varied widely from 45.3% in the study of Ellul et al. to 28.5% in that of Harmston et
al. with no apparent explanation for this variation. The screening programme is likely to be
an effective and practical way of reducing CRC, but it does have its limitations, which can
only be reduced by further research to maximize overall patient care (Haboubi, 2010).
4. Pathology and management of early (pT1) colorectal lesions in the

NHSBCSP
Colorectal polyps are extremely common in Western countries and are found in up to 30%
of autopsies performed in people aged more than 60 years (Williams et al., 1982).
Histologically, colorectal polyps are divided into neoplastic or nonneoplastic and it is well
known that more than 95% of CRC arise from neoplastic adenomatous polyps (adenomas)
(Bond, 2000; Morson, 1966) through the well documented adenoma–carcinoma sequence
(Muto et al., 1975).
By definition, all adenomas show dysplasia and is divided into either low or high grade
(Quirke et al., 2007; Riddell et al., 1983) and architecturally into either tubular, tubulovillous
or villous types according to the WHO classification (Hamilton and Aaltonen, 2000). High
grade dysplasia shows complex glandular crowding and irregularity, prominent budding,
cribriform architecture with ‘back to back’ glands and prominent cellular atypia (Quirke et
al., 2007; Riddell et al., 1983). The latter includes loss of cell polarity or nuclear stratification,
markedly enlarged nuclei with a dispersed chromatin pattern and a prominent nucleolus,
abundant mitotic figures with atypical mitoses and prominent apoptosis.
A malignant colorectal polyp is a lesion in which cancer has invaded through the muscularis
mucosae and into the submucosa (Cooper, 1983; Cooper et al., 1995; Lipper et al., 1983;
Morson et al., 1984; Volk et al., 1995) and T1 adenocarcinoma is defined as invasion into the
submucosa and not into the muscularis propria (Edge et al., 2010). The incidence of
malignant colonic polyps amongst all removed colonic adenomas varies between 2.6% and
9.7%, with an average incidence of 4.7% (Coverlizza et al., 1989).
Increasing dysplasia and, presumably, malignant potential correlate with increasing
adenoma size, villous component, and patient age (Konishi and Morson, 1982). The
likelihood of invasive carcinoma also increases with increasing polyp size (Fenoglio and
Pascal, 1982). Size is perceived to be one of the most important risk factor which put an
adenoma into high risk category of malignant transformation. Amongst 5137 adenomas of
diameter of less than 5 mm, none demonstrated malignant transformation (Nusko et al.,
1997).
Generally, malignant colorectal polyps are divided into high and low risk lesions. High risk
malignant polyps were defined as having one of the following: incomplete polypectomy, an
involved resection margin, lymphatic or venous invasion, or are poorly differentiated
histologically (Netzer et al., 1997). Adverse outcome in a malignant colorectal polyp was
defined as residual cancer in a resection specimen and local or metastatic recurrence in the
follow up period (Netzer et al., 1998). In the high risk group, surgery is recommended when
either of the two independent risk factors, such as incomplete polypectomy or a positive
margin is present or if there is a combination of other risk factors. As lymphovascular invasion
or poorly differentiated cancer did not have an adverse outcome when studied alone,
operations in such cases should be individually assessed taking the risk of surgery into
consideration (Netzer et al., 1998) as the risk for death from elective colonic resection averages
about 2% (from 0.2% in the young to more than 5% in the elderly) (Greenburg et al., 1981).
An analysis of published series of malignant polyps estimated that the risk of residual
cancer or nodal metastases from endoscopically resected pedunculated and sessile
malignant polyps with favourable criteria was 0.3% and 1.5%, respectively (Cranley et al.,
1986). Another review of endoscopically resected polyps with poor prognostic factors
(poorly differentiated cancer, margin involvement, or presence of lymphatic or vascular
invasion) reported residual cancer in 8.5% and 14.4%, for patients with pedunculated and
sessile malignant polyps, respectively (Coverlizza et al., 1989). The American College of
Gastroenterologist recommends no further treatment if the polyp is considered to be
completely excised by the endoscopist, the cancer is not poorly differentiated and there is no
vascular or lymphatic permeation and the margin of excision is free (Bond, 2000). Invasion
of the stalk of a pedunculated polyp, by itself, is not an unfavorable prognostic finding, as
long as the cancer does not extend to the margin of resection (Bond, 2000). In large sessile
polyps which are not resectable endoscopically or that might contain invasive carcinoma
with unfavorable prognostic features, it is useful to mark the polypectomy site (Shatz et al.,
1997) to aid future identification of the site if necessary.
If the polyp is removed in one piece, the area of diathermy can be used as the histological
landmark for the true transected margin of resection. If the polypectomy has been performed
in piecemeal, it may be impossible to determine the true margin of resection, therefore
precluding an accurate reporting on the status of completeness of excision (Cooper, 2007).
The presence of multiple adenomas in the same segment as the malignant polyp might be an
argument for resection, particularly if the other polyps subsequently show high grade
dysplasia (Haboubi and Scott, 2000). Similarly, the presence of a malignant adenoma in
association with a strong family history of large bowel cancer would also be in favour of
resection (Haboubi and Scott, 2000).
4.1 Factors against resection

Surgical resection is associated with a significant risk of mortality and morbidity with the risk
of diarrhea after extensive colonic resection, particularly in the elderly (Haboubi and Scott,
2000) with an overall mortality of 5% (Scott et al., 1995). In practice, any individual patient
with a histologically unfavourable malignant polyp has either a 10% chance of cancer-specific
treatment failure or a 3-5% risk of postoperative death (Haboubi and Scott, 2000).
4.2 Margins of excision

Cancer at or near the resection margin is a histological finding that signifies the potential for
an adverse outcome (Hackelsberger et al., 1995; Hassan et al., 2005; Ueno et al., 2004a). In
one study, 21.4% of cases with cancer at or near the resection margin had an adverse
outcome (Cooper et al., 1995). It is also important to record completeness of excision of the
deep and mucosal margins as surgery is usually an indication when the former is involved
and further local excision may be tempted if the mucosal margin is believed to be involved
(Quirke et al., 2007).
158 Colonoscopy
An involved margin has many definitions in the literature. Cancer near the margin has been
variously defined as cancer cells 1mm or less from the transacted margin, (Cooper et al.,
1995) cancer cells 2mm or less from the transacted margin, (Netzer et al., 1997; Volk et al.,
1995) and cancer within the diathermy and/or within one high-power field of the diathermy
(Morson et al., 1984; Ueno et al., 2004b). However, most studies showed that the presence of
cancer near the transected margin has the same clinical significance as cancer at the actual
margin (Cooper et al., 1995; Hackelsberger et al., 1995; Netzer et al., 1997).
Presently, there is no consensus on what represents a ‘negative margin’. A negative margin
has been defined as one in which cancer is not within the actual diathermy, (Morson et al.,
1984) more than one high-power field from the diathermy, greater than 1mm from the
margin (Cooper et al., 1995) and more than 2mm from the margin (Netzer et al., 1997; Seitz
et al., 2004). Incomplete local excision is not a judgement based on histology alone but a
decision made jointly by the endoscopist and pathologist (Cooper, 2007).
4.3 Histological grade

Poorly differentiated (grade III) cancer, which has been classified as a poor risk factor in a
malignant polyp, comprise 5–10% of cases and are associated with a significantly greater
incidence of poor outcome than for better differentiated tumours (Kyzer et al., 1992;
Nivatvongs et al., 1991).
4.4 Vascular invasion

Many studies showed that vascular invasion has been associated with an adverse outcome
(Hassan et al., 2005; Ueno et al., 2004b). Muller et al. (Muller et al., 1989) demonstrated that
vascular invasion on its own predicted an adverse outcome, but other studies have not
supported these findings (Cooper et al., 1995; Volk et al., 1995):
4.5 Haggitt levels

Haggitt level of invasion in a pedunculated polyp is an important risk factor. In the Haggitt
system (Haggitt et al., 1985) the level of invasion in a malignant pedunculated polyp is
defined as follows:
Level 1: Carcinoma invading into the submucosa, but limited to the head of the polyp.
Level 2: Carcinoma invading to the level of the neck (the junction of the head and stalk) of
the adenoma.
Level 3: Carcinoma invading any part of the stalk.
Level 4: Carcinoma invading into the submucosa of the bowel wall below the level of the
stalk but above the muscularis propria.
According to these criteria, invasive cancer arising in a pedunculated adenoma could be
classified as level 1 to level 4, but invasive cancer arising in a sessile adenoma is by
definition a level 4 lesion. Studies have shown that level 4 invasion correlates with an
adverse outcome and that patients with level 1–3 cancers and grade I or II cancers, and no
lymphatic or venous invasion, can be successfully treated by polypectomy alone (Haggitt et
al., 1985; Pollard et al., 1992).
Follow-up surgical resection has been recommended following polypectomy showing
Haggitt level 4 invasion (Haggitt et al., 1985; Kyzer et al., 1992; Nivatvongs et al., 1991) or
with any level polyp with grade III cancer, (Pollard et al., 1992) and/or lymphatic invasion
(Haggitt et al., 1985).
4.6 Kikuchi’s levels

In pT1 tumours, the frequency of lymph node metastasis in sessile tumours that involve the
superficial, middle and deep thirds of the submucosa (so-called Kikuchi levels sm1, sm2 and
sm3 respectively) (Kikuchi et al., 1995) has been reported to be 2%, 8% and 23% respectively
(Nascimbeni et al., 2002). Invasion to level SM1 has been reported to have a significantly lower
incidence of lymph node metastasis than level SM2 or SM3 invasion (Nascimbeni et al., 2002).
However, neither the Kikuchi (for sessile tumours) nor the Haggitt (for polypoid tumours)
system is easy to interpret, especially if there is fragmentation or suboptimal orientation of
the polyp.
More recently, Ueno et al. (Ueno et al., 2004b) proposed that the depth of invasion measured
in microns beyond the muscularis mucosae provides a more objective measure, and this
system has been adopted in Japan. However, again this system is difficult to use in routine
practice.
It has to be highlighted that each classification has advantages and disadvantages. The
Kikuchi system cannot be used if there is no muscularis mucosa in the biopsy and the
Haggitt system is of no value in sessile lesions and measurement depends on a recognisable
submucosa and good orientation of the polyp (Quirke et al., 2007).
In an extensive review of the literature (31 studies involving 1900 patients), Hassan et al.
(2005) reported god outcome in polyps showing favourable histological features (e.g.
negative margin, grade I or II and absence of lymphovascular invasion), supporting the
suggestion that endoscopic polypectomy alone is adequate treatment in these patients.
The treatment of patient with an endoscopically removed malignant colorectal polyp must
be individualized for each patient, taking all factors into consideration. Guidelines endorsed
by the American Gastroenterological Association (Bond, 2000) recommend no further
treatment is indicated after colonoscopic resection of a malignant colorectal polyp if the
following criteria are fulfilled:
• The polyp is considered by the endoscopist to have been completely excised
• The cancer is not poorly differentiated
• There is no vascular or lymphatic permeation
• The margin of excision is not involved.
The guidelines also comment that when a patient’s malignant polyp has poor prognostic
features, the relative risks of surgical resection should be weighed against the risk of death
from metastatic cancer.
4.7 Tumour budding

Tumour budding is defined as isolated single cancer cells or small clusters (fewer than five
cells) of cancer cells at the advancing edge of the tumour. Several studies have defined a
tumour as positive for budding when there are five or more buds per 20 power field
(Kaneko et al., 2007; Ueno et al., 2004b). Studies of T1 cancers have shown that the presence
of tumour budding is significantly associated with lymph node metastasis and other
adverse outcomes (Kaneko et al., 2007; Masaki et al., 2001a; Ueno et al., 2004b).
4.8 Cribriform histology

T1 CRC with a cribriform histology showed a high rate of lymph node metastasis when
analyzed with multivariate analysis. In one of the studies, all the cases were all initially
treated by surgical resection (Egashira et al., 2004).
160 Colonoscopy
4.9 Potential ‘molecular’ markers

Masaki et al. (Masaki et al., 2001b) showed that expression of MMP-7 (a matrix
metalloproteinase) at the invasive margin of T1 cancers was significantly associated with
other poor histological features and unfavourable outcome. Hirano and Minimoto (2000)
reported that a high expression of p53 and a low expression of p27 were significantly
associated with metastasis in cases of T1 CRC.
4.10 Pseudoinvasion/misplaced mucosa

Pseudoinvasion is misplacement of the whole mucosa into the submucosa and this
herniated mucosa often mimics invasive cancer causing a diagnostic difficulty for
pathologists. Even among experienced gastrointestinal pathologists, there is a lack of
unanimity in differentiating invasive carcinoma from pseudoinvasion (Cooper et al., 1995;
Muto et al., 1973). It is commonly seen in prolapsed polyps in the sigmoid colon and is
perceived to be one of the most difficult areas in the interpretation of polyp and in the
context of the bowel screening programme (Quirke et al., 2007).
In cases of pseudoinvasion, the rounded contour of the neoplastic glands and the cytological
similarity of the herniated epithelium to the surface adenoma, continuity of the surface
epithelium with the ‘deep’ epithelium and the presence of lamina propria around the
submucosal are all indications of pseudoinvasion rather than invasive cancer (Cooper, 2007).
The presence of haemosiderin deposits provides a clue to the presence of misplaced
epithelium. The distinction between invasion and pseudoinvasion is made more difficult
when the herniated epithelium is severely dysplastic (Pascal et al., 1990) and there are
instances where the differentiation is difficult with 100% certainty and the pathology report
should indicate this uncertainty.
4.11 Serrated lesions of the colorectum

Serrated lesions have only recently been highlighted as having distinct genetic features and
a different architecture from classical adenomas. The family of serrated polyps comprises
sessile serrated adenomas, also called sessile serrated polyps (SSA/Ps), traditional serrated
adenomas, hyperplastic polyps, and mixed hyperplastic/adenomatous polyps or admixed
polyps (Ensari et al., 2010).
It is estimated that SSA/Ps represent 8-20% of serrated polyps with a predilection for the
right colon. The diagnosis is mainly based on architectural features and are usually larger
than hyperplastic polyps, measuring from 5 mm to more than 10 mm. They are flat to
sessile. The crypts are elongated and epithelial serration and dilatation are usually more
prominent in the basal part of the crypts in a ‘crescendo’ fashion.
Traditional hyperplastic polyps that are large (>1 cm) and/or multiple and/or located in the
proximal colon are associated with an increased risk for CRC, notably in the hyperplastic
polyposis syndrome where they occur throughout the colon with a 50% risk of CRC (Leggett
et al., 2001). From the management point of view they should be treated similar to
conventional adenomas.
5. Conclusion
The histopathology reports on malignant colorectal specimens are of major importance
regarding patient management, prognostic assessment, audit and research. It has been
shown that use of proforma greatly improves the quality of such reports (Quirke et al., 2007;
Quirke and Morris, 2007).
The bowel cancer screening programme will generate many early cancers (pT1) for which
there is poor management protocols as opposed to pT2 tumours which they need a definite
surgical excision (Haboubi, 2010; Quirke et al., 2007).
The preferred care for patients with polypectomy specimens which contain invasive
carcinoma is controversial (Haboubi and Scott, 2000). Taking into considerations all factors
involved, the issue of polypectomy for malignant polyps versus surgical resection is best
resolved by a multidisciplinary team involving the surgeon, pathologist and endoscopist,
taking the patient's condition and wishes into account (Mitchell and Haboubi, 2008).
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11
Endoscopic Submucosal Dissection

for Colorectal Lesions
Takashi Shida
Department of Surgery,
Funabashi Central Social
Insurance Hospital, Funabashi, Chiba,
Japan
1. Introduction
Recently in Japan, Endoscopic submucosal dissection (ESD) is beginning to become widely
performed for the treatment of colorectal lesions. However, ESD is a very difficult technique
which may lead to perforation of the colonic wall and also time consuming compared to
Endoscopic mucosal resection (EMR). In this article, I would like to introduce the indications
and the practical procedure of colorectal ESD.
Since Endoscopic mucosal resection (EMR) is widely and safely performed throughout the
world, the indications for colorectal ESD are as follows: 1) lesions which are difficult to
remove en block with a snare EMR due to size, such as those in the LST-NG category,
lesions exhibiting VI pit patterns, shallow submucosal invasive carcinoma, large depressed
type tumors and large protruded type lesions suspected to be carcinoma. 2) lesions with
fibrosis due to biopsy or peristalsis. 3) sporadic localized lesions in chronic inflammation,
such as ulcerative colitis. 4) local residual carcinoma after EMR. This indication was
proposed by Tanaka S et al and is widely applied in Japan.1) Since, most early colorectal
lesions can be treated by EMR or Endoscopic piecemeal mucosal resection (EPMR),
indications for ESD is relatively limited. The most beneficial point of ESD is the accuracy of
en block resection of the lesion without regard to the specimen size.
Needle knife, IT (Insulated Tipped) knife, Hook knife, Flex knife and Dual knife are
representative knives for ESD.1) For colorectal ESD, Flex knife, Dual knife and Hook knife
are mainly used. Also transparent hood is essential for colorectal ESD. Glycerol or sodium
hyaluronate solution is necessary for submucosal injection. 2) A good quality high-frequency
power supplies like VIO300D, ICC200 (ERBE, Germany), or ESG-100 (Olympus, Japan) is
also required. To decrease patient’s discomfort, the Carbon dioxide insulation system (UCR
system, Olympus, Japan) is useful. Carbon dioxide can be absorbed into the human tissue
more than 100 times faster than room air. The use of this system can decrease the distention
of the colon. 3)
In order to perform colorectal ESD, the most important point is to place the lesion opposite
toward the gravity. You have to change the patient’s position to check this point before
starting ESD. General anesthesia is not necessary because it becomes difficult to change the
168 Colonoscopy
patient’s position during the ESD procedure. In Japan, colorectal ESD is mainly performed
under conscious sedation.
After locating the lesion in the appropriate position, submucosal injection is performed. You
have to inject enough amount of solution to elevate the lesion completely (Glycerol or
sodium hyaluronate solution). ESD requires larger volume of submucosal injection
compared to EMR. Usually, we dilute the sodium hyaluronate solution by glycerol 4 ~5
folds containing a small amount of indigo carmine and epinephrine hydrochloride. Indigo
carmine is useful for a better visualization of the submucosal layer.
After submucosal injection, mucosal incision is performed. For mucosal incision, Flex knife
or Dual knife is used. It is important to fix the knife gently to the colonic wall and not to
press it strongly. Colonic wall is very thin, and there is no need to press the knife strongly
towards the wall. When using the Flex knife, appropriate length of the knife may be about
2mm or less. If the lesion is larger than 40mm, it is important not to complete the circular
mucosal incision before the submucosal dissection. This is because the submucosal solution
leaks out from the mucosal incision space, and the observation of the submucosal space
becomes poor. For submucosal dissection, the important point is to slide into the
submucosal space by using the transparent hood as soon as possible. Flex knife or Dual
knife is mainly used, but in difficult situation, Hook knife is useful. Hook knife is safe
because it allows submucosal dissection by hooking and pulling the tissue towards the
luminal side.4) During this procedure, vessels are usually seen and sometimes it requires
hemostasis. Since the colonic wall is extremely thin, a special hemostatic forceps with a
small cup is used (50~60W, soft coagulation). To prevent delayed perforation, excess
coagulation must be avoided. Post ESD bleeding is a rare event in colorectal ESD, so there is
no need for excess coagulation.
Figure 1 shows a case treated by ESD. This is a granular-type laterally spreading tumor
(LST-G) with a scar, 35mm in diameter in the sigmoid colon. As shown in figure1, you can
see that the lesion is positive for non-lifting sign. It is impossible to perform en-block
resection by conventional EMR method in a case like this. The lesion had severe fibrosis in
the center but it was successfully removed by ESD. The procedure time was 70 minutes.
The most hazardous and dangerous complication in colorectal ESD is the perforation of the
bowel wall. This must be managed with extreme caution because it will easily lead to
peritonitis and may sometimes be life threatening. When the perforation is admitted during
the ESD procedure, the perforation site must be closed by an endoscopic clip immediately.5)
To continue the ESD procedure or not depends on the condition of the patient. In my
opinion, you should stop the ESD and manage the lesion later (ie; laparoscopic operation).
Leading the patient to a life threatening situation should be avoided as much as possible.
The most important point is that colorectal ESD is a very difficult technique and is still a
clinical research procedure. Colorectal ESD should be performed only by a well experienced
colonoscopist.
Colorectal ESD is now beginning to be performed in many hospitals in Japan, but is still at a
clinical research level. More devices and safe procedures are warranted for
the establishment of standard safe colorectal ESD. I hope that all colorectal lesions will
be properly treated by a treatment method appropriately selected from among EMR, ESD
and surgical resection (including laparoscopic operation) after precise preoperative
diagnosis.
Endoscopic Submucosal Dissection for Colorectal Lesions 169
Fig. 1.
170 Colonoscopy
2. Reference
[1] Tanaka S, Oka S, Chayama K: Colorectal endoscopic submucosal dissection: present
status and future perspective, including its differentiation from endoscopic
mucosal resection. J Gastroenterol 2008;43:641-651
[2] Fujishiro M, Yahagi N, Nakamura M, et al. Successful outcomes of a novel endoscopic
treatment for GI tumors: endoscopic submucosal dissection with a mixture of high-
molecular-weight hyaluronic acid, glycerin, and sugar. Gastrointest Endosc
2006;63:243-249
[3] Saito Y, Uraoka T, Matsuda T, et al. A pilot study to assess the safety and efficacy of
carbon dioxide insufflation during colorectal endoscopic submucosal dissection
with the patient under conscious sedation. Gastrointest Endosc 2007;65:537-542
[4] Tamegai Y, Saito Y, Masaki N, et al. Endoscopic submucosal dissection: a safe technique
for colorectal tumors. Endoscopy 2007;39:418-422
[5] Tanaka S, Oka S, Kaneko I, et al. Endoscopic submucosal dissection for colorectal
neoplasia: possibility of standardization. Gastrointest Endosc 2007;66:100-107
12
Portal Hypertensive Colopathy

Vatsala Misra, Vishal Dhingra, S P Misra and Manisha Dwivedi
MLN Medical College, Allahabad,
India
1. Introduction
The portal vein drains blood from the small and large intestines, stomach, spleen, pancreas,
and gallbladder. The superior mesenteric vein and the splenic vein unite behind the neck of
the pancreas to form the portal vein. Normal portal pressure is generally defined between 5
and 10 mm Hg. An increase in the blood pressure to 12 mm Hg or greater, within a system
of veins is called portal hypertension (PHT). The most common cause of portal hypertension
is cirrhosis of the liver. Other causes include portal vein thrombosis and a parasitic infection
by Schistosomiasis. Sometimes the cause is unknown.
Portal hypertension leads to hemodynamic disturbances throughout the gastrointestinal
tract. McCormack et al (1985) coined the term congestive gastropathy to represent the
mucosal changes in gastric mucosa of patients with portal hypertension and distinguished it
histologically from inflammatory gastritis. (McCormack et al., 1985) The entity was
attributed to alteration in gastric microcirculation.( Sarfeh et al., 1987 & Tarnawaski et al.,
1988).Initial reports mainly focused on portal hypertensive gastropathy which demonstrated
endoscopic and histologic changes seen in the gastric mucosa.(Baxter & Dobbs, 1988;
Corbishley et al.,1988; Foster et al.,1989; SP Misra et al., 1990; Papazian et al., 1986 & Triger
& Hosking,1989)The entity was renamed as ‘portal hypertensive intestinal vasculopathy’
with the evidence of small intestinal and colonic involvement. (Kozarek et al., 1991;
Thiruvengadam & Gostout, 1989 & Viggiano & Gostout, 1992). The term portal hypertensive
colopathy was initially described in the 1990, as a poorly defined entity by Naveau et al.
(1991)
In patients with liver cirrhosis and portal hypertension, vascular changes in upper
gastrointestinal tract in the form of varices of the esophagus, stomach and portal
hypertensive gastropathy and enteropathy are well described. (V Misra et al., 1997, 1998 &
SP Misra et al., 1990). In present chapter various aspects of changes in colonic mucosa of the
patients with portal hypertension are described in detail.
2. Colonoscopy
Initially some authors have described hemorrhoids and colorectal hypervascularity in
patients with portal hypertension (Britton,1963; Hosking et al., 1989 & Jacobs, 1980) followed
by hemorrhage from lower G.I. tract (Herman et al., 1993;Izsak & Finlay,1980; Weinshel et
al., 1986 ). The reported prevalence of hemorrhoid and anorectal varices varied from 25.2%
to 63 %(Britton, 1963;Hosking et al., 1989 & Jacobs, 1980) and 0% to 89.3%(Chawala &
Dilawari, 1991 & Rabinovitz et al., 1990).
172 Colonoscopy
None of these studies were planned or had control population. We planned a study (SP
Misra et al., 1996) to find out the prevalence and factor influencing hemorrhoid, anorectal
varices and colopathy. The study included 70 patients with cirrhosis and portal
hypertension and 70 controls. A full length colonoscopy was carried out in all cases and
presence of hemorrhoids, anorectal varices and colopathy was noted. Hemorrhoids and
anorectal varices were noted in 36% and 40% patients as compared to 40% and 0% in
controls respectively. The difference was statistically significant for anorectal varices( P
<0.001). No correlation to severity of cirrhosis (Child’s grade), oesophageal varices, presence
or absence of gastric varices, gastropathy or sclerotherapy treatment was observed.
Colopathy was seen in 48.5% and 3% of patients and controls respectively and it was seen
more frequently in patients with large oesophageal varices as compared to smaller
varices(87% vs 28.5%, P<0.001) and more often in those with gastric varices than without it
(71%vs28.5%, P< 0.001).
Ghoshal et al.( 2001) reported haemorrhoids in 21.9% patients with PHT and 16% controls
(p = ns). Colorectal varices were seen in 31.7% patients with PHT and none of the controls
(p = 0.005). Portal colopathy was present in 36.6% patients with PHT and none of the
controls (p = 0.0005). None of the parameters (e.g. aetiology of PHT, Child's class,
oesophageal variceal eradication by Endoscopic Sclerotherapy with or without Endoscopic
variceal ligation, history of variceal bleeding, grade of oesophageal varices, presence of
portal hypertensive gastropathy or gastric varices) predicted the occurrence of colorectal
varices and portal hypertensive colopathy. Detection of colorectal varices but not portal
hypertensive colopathy was associated with occurrence of hematochezia.
Assuming that PHT may cause the changes all over the gastrointestinal (GI) tract, a number
of colonoscopic studies were performed. (Chen et al., 1996; Scandalis et al., 1994 & Sharma et
al., 1995).The colonoscopy revealed vascular ectasias, vascular irregularity, vascular
dilatation, solitary red spots, diffuse red spots and hemorrhoids. Portal hypertension
produces changes in the colorectal mucosa similar to those seen in the mucosa of upper
gastrointestinal tract. Other endoscopic abnormalities mentioned in this setting are anorectal
and recto-sigmoid varices, hemorrhoids, multiple vascular ectasia like lesions, and
nonspecific inflammatory changes. These changes were classified into four types. Solitary
vascular ectasias were found predominantly in the transverse and ascending colon (55%).
Diffuse vascular ectasias were found predominantly in the right side colon (45%). Redness
was found in the overall colon and blue vein in the rectum. (Ito et al., 2005). They observed
portal hypertensive colopathy in 23% of patients in rectosigmoid colon, 11% in the
descending colon, 24%in the transverse colon, 23% in the ascending colon and16% in the
cecum. These complications are a common cause of lower gastrointestinal hemorrhage.
Bresci et al(2006). also studied the colonoscopic changes in patients with portal
hypertension. They found colonic varices in 31 % of the patients, portal hypertensive
colopathy (PHC; defined as diffuse hyperemia, edema, spider angiomas, and spontaneous
bleeding of the colonic mucosa) in 54 %, and normal colonic findings in 18 %. Colonic
varices and PHC were present simultaneously in 27 % of the patients. They concluded that
colonic lesions are frequent in cirrhotic patients, but statistical analysis showed that these
lesions are not specific for the disease and do not correlate with the etiology and degree of
cirrhosis, with the endoscopic treatment of esophageal varices, or with the risk of bleeding
from the lower gastrointestinal tract.
Portal Hypertensive Colopathy 173
3. Histopathological changes
Portal hypertension leads to hemodynamic disturbances throughout the GI tract. Despite
several studies describing endoscopic changes, histological changes in gastric mucosa were
not studied in detail. In earlier studies the congestion of the mucosal capillaries was
described as the common change seen in gastric mucosa of the patients with portal
hypertension. (Corbishley et al., 1988; Foster et al., 1989 & SP Misra et al, 1990). Studies of
biopsies from the upper GI tract (stomach, duodenum and jejunum) have recorded
predominant changes in the mucosal vessels (venules and capillaries). (Kozarek et al., 1991;
Thiruvengadam & Gostout, 1989 & Viggiano & Gostout, 1992). Later on a detailed
histomorphometric study of mucosal vascular changes seen in gastric, duodenal and jejunal
mucosa showed that irregularity and thickening of the mucosal capillary wall is more
specific than only congestion(V Misra et al., 1997, 1998) that can be seen due to artifactual
factors also. (Corbishley et al.,1988).Despite well documented colonoscopic features very
few studies were there describing histopathological changes, that too in brief.( Eleftheriadis
et al., 1993;Naveau et al., 1991 & Scandalis et al 1994). S P Misra et al (1996) found dilated
and congested mucosal capillaries in 42% of colonic biopsies whereas dilated and thick
walled capillaries were seen in 49%.
We did a detailed histomorphometric study of changes in mucosal capillaries in colonic
biopsies from 55 patients with portal hypertension and 25 controls. (Misra V et al., 2003).
After full length colonoscopy biopsies were taken from caecum, ascending colon, transverse
colon, descending colon and rectum. Morphometric assessment of diameter of the capillaries
and thickness of the capillary wall was done. Presence and absence of the congestion was
also noted. Dilated and congested capillaries, as well as, capillaries with irregular thickening
of the wall were seen in significantly higher number of sections from patients than controls.
Morphometric assessment also showed a significantly higher diameter and thickness of the
capillary wall in sections from patients with portal hypertension than controls. A peculiar
feature observed was thick walled dilated capillaries without red blood cells in the lumen
that were seen in 46.5% biopsies (irrespective of site) from patients with portal hypertension
as compared to 12% in controls (P< 0.025). The histological changes had no correlation with
the clinical or endoscopic findings except that the thickness of the capillary wall was higher
in patients who had undergone endoscopic sclerotherapy as opposed to those who had not
received sclerotherapy. Besides vascular changes, other important histological features seen
in the biopsies are edema, increased mononuclear cell infiltration and fibromuscular
proliferation in lamina propria.
It is very important to differentiate the vascular changes of colopathy with angiodysplasia of
the colon which may sometimes lead to massive lower GI bleeding. (Sharma et al., 1995)
Lesions of angiodysplasia are fewer, smaller, and less widely distributed as compared to
those of portal hypertension, (Naveau et al., 1995) because they are usually formed due to
degenerative changes (V Misra et al., 2003) in contrast to PHT where increased venous
pressure seems to be the main cause. Besides, the age of the patient (angiodysplasia usually
occurs in the elderly), association with cirrhosis and endoscopic appearance may also help
in differentiation. Histopathology examination of rectal mucosal lesions in patients with
portal hypertension shows dilatation of blood vessels in the mucosa, increased lymphocytes
and plasma cells in the lamina propria and edema of the mucosa.
174 Colonoscopy
4. Prognosis and treatment

Lower gastrointestinal bleeding, is the major complication of portal hypertensive colopathy.
These patients may have occult blood loss or overt hematochezia. In patients with liver
cirrhosis as the Child-Pugh class worsens and platelet count decreases, the prevalence of
portal hypertensive colopathy increases. A colonoscopic examination in patients with liver
cirrhosis is indicated, especially those with worsening Child-Pugh class and/or decreasing
platelet count, to prevent complications such as lower gastrointestinal bleeding (Ito et al.,
2005). Octreotide is a safe and effective treatment for severe acute bleeding from PHC,
especially if the patient is not a candidate for transjugular intrahepatic portosystemic shunt
(TIPS) or treatment with a beta-blocker due to the severity of liver disease or haemodynamic
instability. Aydede H et al (2003) studied the effects of octreotide and propranolol on colonic
mucosa in rats with portal hypertensive colopathy and showed that the mucosal changes in
portal hypertensive colopathy could be corrected by drugs modifying portal blood
flow.However, a sufficient reduction of portal pressure by propranolol or other medical
treatment may be needed in order to discontinue octreotide infusion without the recurrence
of bleeding. (Yoshie et al., 2001) Significant relationship between colorectal varices and liver
disease has been reported and colorectal varices is highly appeared in patients with
extrahepatic portal obstruction. Such patients have revealed arteriovenous communications
at angiogram. In general, colonic resection or transanal ligation should be the first option for
treatment of bleeding colonic varices and colonic mucosal lesions. Oesophageal variceal
band ligation (SP Misra et al., 2002) or sclerotherapy (SP Misra et al., 1999) does not affect
the anorectal varices or portal hypertensive colopathy.
5. Conclusion
Thus, portal hypertension is an important factor in the etiology of a relatively new entity
portal hypertensive colopathy, and these need to be evaluated as they can be the cause of
lower gastrointestinal bleeding, in these patients. Major histopathological changes seen in
colonic biopsies of patients with PHT are dilated tortuous mucosal capillaries with irregular
wall-thickening, edema of lamina propria and mild chronic inflammatory infiltrate, which
does not show any association with clinical and endoscopic features. However, these
mucosal changes, if present, should not be overlooked and a report on colonic biopsies from
patients with PHT should include comments on these parameters.
6. References
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Portal Hypertensive Colopathy 175
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Part 3
The Future?
13
Research and Therapeutic Innovation: Tissue

Resonance InterferoMeter Probe in Early
Detection-Screening for Rectal Cancer
Alberto Vannelli and Luigi Battaglia
Fondazione IRCCS “Istituto Nazionale Tumori”, Milan,
Italy
1. Introduction
Clarke's Second Law is: “The only way of discovering the limits of the possible is to venture
a little way past them into the impossible” (Clarke, 1962). Tissue Resonance InterferoMeter
Probe (trimprob) issues this challenge.
Cancer is a major health problem in developed countries, in many of which it is the second
most common cause of death for all ages combined. At the beginning of the 21st century 10
million people in the world develop cancer each year (Blackledge, 2003).
In the Globocan 2002 database of the International Agency for Research on Cancer (IARC),
the worldwide burden of colorectal cancer (CRC) is estimated as 550,000 incident new cases
and 278,000 deaths for men, and 473,000 incident new cases and 255,000 deaths for women.
In 2002, CRC comprised 9.4% of the global cancer burden in both sexes and was most
frequent in North America, Australia, New Zealand, and parts of Europe. This has led to
colorectal cancer being considered as a disease of the Western lifestyle (Winawer, 2007). The
advent of molecularly targeted drugs promised to change survival. Within 20 years CRC
will be considered a chronic disease, joining conditions such as diabetes, heart disease and
asthma. Although very successfully used in combination, chemotherapy results in
metastatic CRC have been disappointing with little more than palliative benefit. For
example chemotherapy for advanced CRC cured with a low complete response and most
patients relapsed with resistant disease (Vincenzi et al., 2004). These conditions impact on
the way people live but will not inexorably lead to death. Individual cancer risk assessment
will lead to tailored prevention messages and a specific screening programme to pick up
early cancer and have far reaching public health consequences. Therefore, improving
screening shows the challenges that need to be addressed in order to deliver most health
benefit. But cancer prevention absorbs only 2 per cent of the total funding of cancer care and
research in the world. Information regarding resources allocated to cancer is particularly
scarce, even more so for CRC (Kanavos et al., 2008). CRC is rapidly increasing in Asia, but
screening guidelines are lacking (Sung et al., 2005). Data regarding resources allocated to
CRC in Latin America or Africa are absent. CRC expenditure adjusted for cancer population
burden in the few countries collecting cancer expenditure, found large variations between
countries (high of €85,116 per total cancer death in Sweden to a low of €9,528 in Russia). This
continued with CRC expenditure, where the range was from €10,288 per CRC mortality
180 Colonoscopy
(Hungary) to €122,828 (France). Approximately half of surveyed countries had formal

resource allocation mechanisms; fewer had disease-specific resource allocation, and only
Australia reported cancer-specific resource allocation. The majority of countries perceived
insufficient resources were allocated to cancer care and CRC care. Eastern European
countries reported significant problems with cancer-specific funds, with persistent
shortcomings and insufficient funding. Many of the countries that have formal screening
activities, be it for CRC or other cancers, have formal screening resource allocation.
Australia, some European countries and the USA all have governmental funding for their
CRC screening programmes, ranging from €8-25 million. These values are half of what these
countries allocate to their breast cancer screening programmes. It appears that cancer
spending displays significant variation between countries, along with the majority of
countries not accounting for cancer in its resource allocation mechanisms. As cancer
accounts for significant morbidity and mortality after cardiovascular disease, this seems to
be an important omission. Cancer care is a significant part of health care expenditure, and
should be accounted and planned for appropriately.
All these data reinforce the opinion on which the CRC is one on the most important problem
in Healthcare. What’s the solution? The current opinion suggests to spread screening
programmes.
But what is a screening? Screening programmes would be developed on a national basis if
they are simple, robust and cheap. Patients would expect the screening to take place at a
convenient venue for them — in shopping malls and not be painful or overly time-
consuming. Health professionals would demand that any programme is accurate and does
not give misleading results, and governments would demand that its costs would lead to
more effective use of other resources. Novel providers of risk assessment services are likely
to emerge. (Sikora, 2007). According to Mayo Clinic staff: “Colon cancer is cancer of the
large intestine (colon), the lower part of your digestive system. Rectal cancer is cancer of the
last several inches of the colon. Together, they're often referred to as colorectal cancers. Most
cases of colon cancer begin as small, noncancerous (benign) clumps of cells called
adenomatous polyps. Over time some of these polyps become colon cancers. Polyps may be
small and produce few, if any, symptoms”. For this reason, doctors recommend regular
screening tests to help prevent colon cancer by identifying polyps before they become colon
cancer.
Therefore it’s correct to assume that most CRCs arise from sporadic adenomas, and a few
from genetic polyposis syndromes or inflammatory bowel disease (IBD). Because of high
prevalence, as well as a long asymptomatic phase and treatability of precancerous lesions,
colorectal cancer is an ideal target for screening. But these axioms cast doubts about the
efficacy of CRC screening.
The term “polyp” refers to a discrete mass that protrudes into the intestinal lumen, but the
reported prevalence of adenomatous polyps, on the basis of screening colonoscopy data, is
only in the range of 18–36%. Moreover the risk for CRC varies from country to country and
even within countries. The risk also varies among individual people based on diet, lifestyle,
and hereditary factors. Current guidelines are directed to test asymptomatic men and
women who are likely to have adenomatous polyps or cancer but current CRC screening are
efficacy only on symptomatic population. This screening always needs to be applied within
the framework of a program that includes: primary prevention (diet, lifestyle), timely
diagnostic work-up with colonoscopy (where available and consistent with the cascade)
Research and Therapeutic Innovation:
Tissue Resonance InterferoMeter Probe in Early Detection-Screening for Rectal Cancer 181
overall in those screened positive, and timely treatment (polypectomy, surgery). CRC
screening is particularly challenging, as reflected in current low screening rates in most
countries where there is a high risk for CRC. CRC screening is complex, as there are
multiple options, it requires considerable patient effort (fecal occult blood test slides,
colonoscopy preparation, etc.), and it requires sedation and a health-care partner for some
tests (colonoscopy). For a screening program to be successful, multiple events have to occur,
beginning with awareness and recommendation from the primary-care physician, patient
acceptance, financial coverage, risk stratification, screening test, timely diagnosis, timely
treatment, and appropriate follow-up. If any one of these steps is faulty or is not of high
quality, the screening will fail.
Previous studies have investigated the cost-effectiveness of colonoscopy, flexible
sigmoidoscopy, and fecal occult blood testing as screening alternatives (Sonnemberg et al,
2000). Flexible sigmoidoscopy was less cost-effective than fecal occult blood testing and
colonoscopy. Fecal occult blood testing is a simple, low-cost screening method, but
colonoscopy was more effective in saving lives. All standard options for CRC screening are
not convincing because are cost-effective only in average-risk individuals. They are more
cost-effective than other forms of medical screening: cholesterol in hypertension.
Screening tests Evidence

Sensitivity Specificity
Occult blood tests 50-60% 95.2% Fecal occult blood testing using the
guaiac smear is currently being
replaced in many countries by fecal
immunochemical tests.
Fecal DNA tests 52% 94.4% the optimal set of molecular markers
remains to be determined, and the
feasibility of such tests when applied
to the general population is as yet
unknown.
Flexible 35-70%, 98–100% the sensitivity is low due to the
sigmoidoscopy significant number of right-sided
adenomas that occur in the absence of
distal tumors and are therefore missed
on flexible sigmoidoscopy.
Colonoscopy at least 95% at least 95% There are no prospective randomized
for large for large studies that have examined the impact
polyps polyps of colonoscopy on incidence or
mortality.
Double-contrast 48% 50% It’s more likely than colonoscopy to
barium enema yield false-positives.
Computed- 93% for 97% for When polyps of all sizes were
tomographic polyps 10 polyps 10 included, the studies were too
colonography mm or mm or heterogeneous in sensitivity (range
larger larger 45–97%) and specificity (range 26–
97%).
Table 1. Screening tests and evidence.
182 Colonoscopy
Systematic screening colonoscopy in first-degree relatives of patients with CRC, starting at

the age of 40, demonstrates an economic benefit only in comparison with multiple-drug
intensive chemotherapy for advanced cancer, screening is cost-saving (Table 1). However,
high costs and low compliance rates for colonoscopy have encouraged a search for different
methods. It has been proposed that cancer exposed to a low level of electromagnetic
incident waves may behave differently than healthy tissue. The phenomenon of ‘‘nonlinear
resonance interaction,’’ which is produced when the oscillations of an electromagnetic probe
are coupled with those from biological tissue, can be used to test for differences between
healthy and cancerous tissues (Vedruccio et al., 2004).
2. Electro-medical device for non invasive diagnostics

2.1.1 Historical background
Diagnosis of cancer in humans is mainly based on microscopic observation of morphological
changes in cells and irregularities in tissues through the use of cytological and histological
methods (Bibbo, 1997). All these processes are the manifestation of hidden processes of
biochemical as well as physical nature. One of the most important as well as misleading
effect is the Mitochondrial Warburg Effect. For a long time, disturbances in physical
processes in cancer development were not adequately taken into consideration. To
understand what does it mean, it’s necessary to start by the end of this process. Therapeutic
selectivity, or preferential killing of cancer cells without significant toxicity to normal cells,
is one of the most important considerations in cancer chemotherapy (Pelicano et al., 2006).
Understanding the biological differences between normal and cancer cells is essential for the
design and development of anticancer drugs with selective anticancer activity. Cancer is a
family of diseases that involve uncontrolled cell division and tissue invasiveness
(metastasis). In the recent years, tremendous progress has been made in our understanding
of the molecular mechanisms of cancer, in identification of specific genes and signalling
pathways involved in carcinogenesis and cancer progression, and in developing chemical
compounds or specific antibodies that specifically target the oncogenic molecules.
Cancers result from a series (progression) of gene mutations that typically involve two
categories of function: promotion of cell division and inactivation of cell cycle suppression.
Proto-oncogenes are normal genes that promote cell growth and mitosis, whereas tumor
suppressor genes discourage cell growth. Proto-oncogenes can be mutated by carcinogenic
agents to become oncogenes. Oncogenes produce excessive levels of growth promoting
proteins. Tumor suppressor gene products typified by p53 are frequently transcription
factors that suppress mitosis and cell growth to allow for DNA repair. Nearly half of all
cancers involve altered p53 genes. Other suppressor genes include Rb (retinoblastoma
family), APC (adenomatous polyposis coli), SMAD4, TP53, p16/CDKN2A and BRCA
(breast cancer susceptibility protein) types 1 and 2. Cancer results from cumulative
mutations of proto-oncogenes and suppressor genes which together allow the unregulated
growth of cells. Oncogenes are typically dominant because they provide gain-of-function,
whereas suppressor genes are recessive. They contain loss-of function mutations. Both
copies of a suppressor gene need to mutate to cause loss-of-suppressor function. Only one
copy of a proto-oncogene needs to mutate for gain-of-function. Mutations of tumor
suppressor genes can be inherited. Over time malignant cells can self-select for
characteristics that make them more malignant: ability to avoid apoptosis; immortalization
due to over expression of telomerase; growth-factor self-sufficiency and resistance to anti-

growth factors; increased cell division; altered differentiation; loss of contact inhibition,
become metastatic; and able to promote angiogenesis. The target-specific agents have major
advantages over the traditional chemotherapeutic compounds in that the targeting agents
specifically interact with the key molecular players in cancer cells and have low toxicity to
the normal cells. In the past researchers assumed that cancer cells and normal cells had
much in common in terms of the internal machinery that allows them to carryout the many
activities necessary to stay alive. Chemotherapy drugs effectively target processes that
cancer cells need to grow and divide, such as the ability of the cancer cells to replicate their
DNA. However, many normal cells, like the cells that line the digestive tract, also need to
replicate. In short, though chemotherapy drugs are particularly toxic to cancer cells, they
also damage healthy cells. The use of standard chemotherapy therefore produces many, and
often severe, side effects. Furthermore, these side effects sometimes prevent patients from
being able to take high enough doses to fight the cancer most effectively. While
chemotherapy drugs are quite effective treatments for many forms of cancer, researchers
have been working diligently to produce drugs that target the processes of cancer cells
specifically so as to leave healthy cells unharmed. The accumulation of knowledge about the
specific differences between normal and cancerous cells has allowed for the development of
treatments targeted at cancer-specific activities.
One of the most fundamental changes found in cancer cells is the presence of mutations in
the genes that are responsible for causing cell growth (oncogenes). The defective proteins
produced by these altered genes are prime candidates for targeted therapy. As an example,
some cancers are caused in part by mutant proteins that send constant signals into the cell
causing cell division. Drugs that block only the mutant form of the protein but do not
interfere with the activity of the normal version would only affect cancer cells, and would
leave healthy cells untouched. Alternatively, many cancers result when genes that normally
prevent cell growth (tumor suppressors) are inactivated or turned off. Drugs that "fix" the
activity of these proteins would repair the damaged cancer cells, but theoretically have no
effect on normal cells.
New agents with a high degree of target specificity and clinical therapeutic activity,
exemplified by Gleevec (imatinib), Iressa (gefitinib), herceptin (trastuzumab), and rituximab,
represent an exciting direction for cancer drug development. However, the mechanisms
underlying cancer development and the disease progression are extremely complex, and it
is now recognized that in many types of cancers there are multiple genetic and epigenetic
alterations. Even within a specific cancer type, the malignant cell populations are
heterogeneous and contain diverse genetic changes, which further alter over time because of
genetic instability as the disease progresses. As such, it would be difficult to specifically kill
these cancer cells by targeting a single gene. Proper combination of multiple target-specific
agents may be required to effectively eliminate the entire cancer cell population.
An alternative strategy to achieve both therapeutic selectivity and efficiency is to take
advantage of the fundamental difference between cancer cells and normal cells in their
biochemical metabolism. Cell proliferation requires the conversion of nutrients into biomass.
One of the first differences noted between cancer cells and normal cells was a difference in
metabolism (Vander Heiden et al., 2009). One of the most prominent metabolic alterations in
cancer cells is the increase in aerobic glycolysis and the dependency on glycolytic pathway
for ATP generation as showed in Figure 1 (Erickson & Cerione , 2010).
184 Colonoscopy
Fig. 1. Different metabolic pathway

This is the Warburg effect (Warburg et al., 1924; Warburg, 1930, 1956). As this metabolic
alteration is frequently seen in cancer cells of various tissue origins, targeting the glycolytic
pathway may preferentially kill the malignant cells and therefore have broad therapeutic
implications. Although cancer cell energy generation is mainly dependent on reactive
anaerobic glycolysis, most malignant tumors still breathe, in part by an uncoupling protein-
mediated mitochondrial pathway. Uncoupling proteins help import fatty acids and are over
expressed in various types of chemo-resistant cancer cells (Mayevsky, 2009). New
technologies will help accomplish this systematic work.
2.1.2 Warburg effect

Otto Heinrich Warburg (October 8th, 1883, Freiburg im Breisgau – August 1st, 1970, Berlin),
was a German physiologist, medical doctor and Nobel laureate. "Warburg effect" is used for
two unrelated observations in biochemical, one in plant physiology and the other in
oncology, As early as 1924 he demonstrated that tumor cells exhibit an altered sugar
metabolism as they are metabolizing up to 20 times more glucose compared to healthy cells
(Warburg et al., 1924). These cancer cells produce lactate in large amounts not only under
anaerobic conditions (like their healthy counterparts) but also in the presence of oxygen.
This so called “Warburg effect” or “aerobic glycolysis”. This is remarkable, since glucose
metabolism under aerobic conditions via Embden-Meyerhof pathway (EMP), citrate cycle
and respiratory chain yields 38 ATP per molecule glucose, while glycolysis to lactate leads
to only 2 ATP. In the presence of oxygen and glucose, healthy cells generate a vast majority
of energy in form of ATP by complete combustion of glucose to CO2, while tumor cells
metabolize the majority of glucose via pentose phosphate pathway (PPP) to lactate.
According to standard textbooks the PPP provides cells with reduction equivalents in form
of NADPH and moreover with ribose- 5-P, a key metabolite for DNA/RNA biosynthesis.
The non-oxidative part of PPP is controlled by transketolase. Ever since the pioneering
observation that aerobic glycolysis in cancer is preferred over oxidative phosphorylation as
a mechanism to generate ATP from glucose, numerous experiments have supported and
extended the significant role that metabolisms have on transformation, proliferation,
angiogenesis and metastasis in cancer. Thus, scanning human tumors with positron
emission tomography (PET) has verified that a high uptake rate of glucose constitutes a
hallmark in cancer cells, presumably required to confer adaptive advantages when facing
acidic and hypoxic environments.
Normal cells use glycolysis prior to respiration in the mitochondria and complete
breakdown of glucose by the tricarboxylic acid (TCA) cycle (Figure 1). In cancer cells,
glycolysis becomes the primary mode of glucose metabolism resulting in lactate and its
secretion. The M2 isoform of pyruvate kinase (PKM2) becomes tyrosine phosphorylated and
attenuates pyruvate acetyl-CoA conversion while glutaminolysis provides the cancer cell
with an alternate source of biosynthetic precursors, fueling the TCA cycle with glutamine-
derived α-keto-glutarate. The anti-tumor drug 968 inhibits glutamine metabolism by
inhibiting the enzyme glutaminase (GLS).
Cancer cells have a high glycolysis rate even in the presence of oxygen (Figure 1). Otto
Warburg, assumed that because of mitochondrial malfunction, cancer cells had to depend
on anaerobic glycolysis to generate ATP (Warburg, 1956). This hypothesis was later
disproved. It was demonstrated, however, that cancer cells with intact mitochondria also
showed evidence of the Warburg effect. This effect provides a marker for detecting tumor
cells. With positron emission tomography using a glucose radioisotope
(18fluorodeoxyglucose), cancer cells can be visualized owing to their significantly higher
than normal glucose uptake.
Thus, an alternative explanation was proposed: the Warburg effect helps cancer cells
harness additional ATP to meet the high energy demand required for their extraordinary
growth while providing a basic building block of metabolites for their proliferation. A third
view suggests that the Warburg effect is a defense mechanism, protecting cancer cells from
the higher than usual oxidative environment in which they survive. Interestingly, the latter
view does not conflict with the high-energy production view, as increased glucose
metabolism enables cancer cells to produce larger amounts of both antioxidants to fight
oxidative stress and ATP and metabolites for growth. It may be related to the surprising fact
that although aerobic respiration produces 18 times the ATP per mole of glucose compared
with anaerobic glycolysis, the rate of anaerobic glycolysis is 100 times that of aerobic
respiration. According to a population biology model developed at the Max Delbrück
Center for Molecular Medicine in Germany, ATP production at a higher rate but lower yield
may confer a selective advantage in competing for shared energy resources. Lactate, also a
product of glycolysis, induces several oncogenes. In addition, lactate surrounds cancer cells,
providing an acidic environment that protects cancer cells from the immune system. A key
enzyme of the pentose phosphate pathway, transketolase, was shown to play an important
role in cancer proliferation and malignancy. Among colon and uroepithelial cancer patients,
the expression level of transketolase-like gene 1 (one of the transketolase genes) was
strongly related to the patients’ survival rate. Autopsy results confirmed the correlation
186 Colonoscopy
between increased expression of transketolase-like gene 1 and a higher mortality rate

(Langbein et al, 2006). Several factors contribute to cellular oxidative stress, which occurs
when the balance between oxidants and antioxidants is disrupted, resulting in an overall
increase in reactive oxygen species (ROS). ROS are produced as a result of various metabolic
events; for example, in the formation of water molecules during mitochondrial respiration.
Molecular oxygen (O2) is the terminal electron acceptor in the electron transport system of
mitochondria and is converted to water (H2O). In some cases, O2 receives just one electron,
becoming a superoxide anion. It is estimated that 4-5% of O2 molecules are normally
converted to superoxide anions (Spitz et al, 2000). Superoxides are then converted to
peroxides by an enzyme called superoxide dismutase. Subesquent, pyruvate scavenges the
peroxides and converts them into water. Thus, an increased glycolysis rate that leads to
increased pyruvate production may reduce oxidative stress.
There are two more ways in which the Warburg effect may reduce oxidative stress.
Mitochondrial dysfunction may result in reduced oxidative stress, given that mitochondria
are a main source of ROS generation (Orrenius, 2007). Alternatively, the antioxidant
production associated with the Warburg effect may protect cancer cells from the negative
effects of their explosive glycolysis.
Network modeling of the interconnections among the crucial factors involved in metabolic
flow and signaling pathways is a necessary future undertaking. In addition, the
mitochondrial uncoupling effect should not be overlooked. Although cancer cell energy
generation is mainly dependent on reactive anaerobic glycolysis, most malignant tumors
still breathe, in part by an uncoupling protein-mediated mitochondrial pathway (Samudio et
al., 2007). Uncoupling proteins help import fatty acids and are over expressed in various
types of chemo-resistant cancer cells. This may increase an apoptotic threshold level. On the
one hand a better understanding of metabolism in cancer cells may lead to the development
of novel therapeutic strategies exploiting their uniqueness.
On the other current technologies may help accomplish this systematic work. In addition to
PET and magnetic resonance, the next-generation scans is needed to precisely study cancer
cell biochemical. As evidenced by current proteomics and biomarker studies, detection
limits should be less than femto- to ato- mole levels, considering that significant proteins or
small peptides secreted from a tiny tumor cell may represent only 1% of the total protein
and are extensively diluted throughout the human body.
2.1.3 Metabolomics
After the pioneered study of Warburg, current research findings confirm that a major
difference between healthy and malignant cells is the supply of energy within the cell by
oxidative phosphorylation in the mitochondria and glycolysis in the cytoplasm. This
biochemical assumption let to develop another innovative consideration in oncology.
Traditional Chinese Medicine, Ayuvedic Medicine and the Ancient Greek and Roman
Doctors all incorporated 'types' into their healing methods the idea that biological fluids
reflect the health of an individual; with the introduction of Warburg effect it has been
possible to think a further step: metabolic effect. During the 1940's and 50's Dr. Roger
Williams developed the concept of 'biochemical individuality' and determined that
"metabolic profiles" were needed to effectively evaluate and treat patients with nutrition.
First time was born the concept that individuals might have a “metabolic profile” that could
be reflected in the makeup of their biological fluids. The work of Williams and his group,
however, was apparently not duplicated by others, to whom his task must have seem rather
herculean, with but few promises of tangible results. Hence, his ideas about the utility of
metabolic pattern analysis remained essentially dormant until the late 1960s, when gas
chromatography and liquid chromatography was advanced sufficiently to permit such
studies to be carried out with considerably less effort. In this way it became feasible to
quantitatively (as opposed to qualitatively) measure metabolic profiles. The term “metabolic
profile” was introduced at the beginning 1970s after they demonstrated that gas
chromatography, especially when interfaced with mass spectrometry could be used to
measure compounds present in human urine and tissue extracts, defining the patterns of
biochemically related metabolites (Horning, et. al. 1971). Moreover it demonstrated the
utility of using nuclear magnetic resonance spectroscopy to detect metabolites in
unmodified biological samples.
In general terms the systematic study of the unique chemical fingerprints that specific
cellular processes leave behind - specifically, the study of their small-molecule metabolite
profiles is metabolomics. Such approach has found applications in many topics: for example
oncology. Metabolomics have led to several successes in the field of cancer biology, such as
the identification of new tumour subtypes, as well as transcriptional and protein biomarkers
for certain types of cancer. Metabolic activity can also be quantified, as various analytical
tools have been developed to measure concentrations of low-molecular-weight metabolites.
This is a particularly challenging task as low-molecular-weight metabolites represent a
diverse range of chemicals.
Metabolomics has also been used to differentiate between different cancer cell lines and to
monitor metabolic processes that occur in cancer cells during events such as apoptosis.
Despite the successful use of metabolomics to investigate phenotypes of transgenic animals
and plants, and its use in the pharmaceutical industry, most functional genomic studies of
cancer have focused on transcriptomics and proteomics. Global metabolic prowling analysis
holds the promise to permit simultaneous monitoring of precursors, intermediates and
products of metabolic pathways. It is a research tool that can detect and monitor
unidentified compounds as well as identified metabolites that play important roles in
metabolism and physiology (Kaplan et al., 2004). For example metabolite profiling was used
to characterize stress responses of potato tissue subjected to reversible electroporation,
providing insights on how potato tissue responds to a physical stimulus such as pulsed
electric fields (PEF), which is an artificial stress (Galindo et al, 2009).
2.1.4 Vedruccio theory

Today the study of biochemical interactions becomes the prevailing paradigm used to
explain cellular functions and disease progression in oncology. Yet many biological
questions cannot be answered with biochemical explanations alone such as the role of
endogenously created electromagnetic fields and electrical currents in the body. In the past
century, a great number of researchers have given their contribution to the study of the
interactions between biological matter and electromagnetic fields. Electromagnetic fields are
waves that transport energy through space. They are characterized by wavelength and
frequency, the two of which are inversely correlated. Electromagnetic fields include the
following (in order of decreasing wavelength and increasing frequency): electromagnetic
fields of extremely low frequency (from electric sources), electromagnetic fields of low
frequency, electromagnetic fields of radiofrequency and microwaves (from mobile
telephones, television antennas etc), ultrasounds, infrared rays, ultraviolet rays, X rays and
gamma rays. Since the 1970s the non thermal effects of electromagnetic fields on living
188 Colonoscopy
organisms have been well known and also the non thermal mechanisms have been
investigated. In the case of a biochemical system we assume that each molecule can be
labelled with a mean velocity energy which, in turn, defines an average energy associated
with each degree of freedom of the molecule itself. In such a picture a perturbation is termed
“thermal” if it is able to change the average kinetic energy associated to each degree of
freedom, in such a way that the average of the energies on the ensemble is changed. The
rotating motion of water molecules induced by microwaves is the most evident achievement
of such a thermal effect. Electromagnetic fields and life identified several significant effects
of the interaction of electromagnetic fields with living organisms. If living organisms
possess the ability to utilize electromagnetic fields and electricity there must exist physical
structures within the cells that facilitate the sensing, transducing, storing and transmitting of
this form of energy.
Normal cells possess the ability to communicate information inside themselves and between
other cells. The coordination of information by the cells of the body is involved in the
regulation and integration of cellular functions and cell growth. When cancer arises cancer
cells are no longer regulated by the normal control mechanisms. Measurements on
biological materials were based on resistivity or impedance and instruments such as the
Wheatstone bridge (Presman, 1970). After the second world conflict, investigations on
biological materials were extended into the microwave bands (Messen, 2000). In the 1920s
Some authors discovered that both proliferating cells and cancer cells had cell membrane
potentials that have been lower than the cell membrane potential of healthy adult cells
(Fricke, 1926). They reported that “malignant tumors have a greater polarizability than
normal breast tissues or benign tumors”. They carried out their experiments at low
frequencies around 20 kHz. In cancerous tissue the electrical potential of cell membranes is
maintained at a lower level than that of healthy cells and electrical connections are
disrupted (Cone, 1975).
Electric fields induce or a cause alignment in dipole movements. Most of the molecules in
the body are electrical dipoles (Beal, 1996). These dipoles electronically function like
transducers in that they are able to turn acoustic waves into electrical waves and electrical
waves into acoustic waves. The natural properties of biomolecular structures enables cell
components and whole cells to oscillate and interact resonantly with other cells. According
to Smith and Best, the cells of the body and cellular components possess the ability to
function as electrical resonators. A dipole movement is a function of polarization processes
and the strength of the electric field. When biological tissue is exposed to an electric field in
the right frequency and amplitude windows a preferential alignment of dipoles becomes
established. Since the cell membrane contains many dipole molecules, an electric field will
cause preferential alignment of the dipoles. This may be one mechanism that electrical fields
alter membrane permeability and membrane functions.
Theoretically we assume two type of electric capacity, the first is the “static capacity” that is
independent to the frequency of the alternating current, the second is the “polarization”
type that depends upon the interphases in the tissues and suggest that capacity might have
a considerable biologic significance. The “polarization” capacity is related to the alternating
current applied or irradiated to the tissue under test. Activation of cell membrane receptors
that act as antennas for certain windows of frequency and amplitude leading to the concepts
of electromagnetic reception, transduction. Biological organisms use weak electromagnetic
fields (electric and photonic) to communicate with all parts of themselves. The major charge
carriers of biological organisms are negatively charged electrons, positively charged
hydrogen protons, positively charged sodium, potassium, calcium and magnesium ions and
negatively charged anions particularly phosphate ions.
For a long time, disturbances in physical processes in cancer development were not
adequately taken into consideration despite Warburg’s experimental discovery of
deteriorated oxygen metabolism. Renewed interest in the Warburg effect has led to research
on physical mechanisms in living cells. The role of mitochondrial dysfunction and
cytoskeleton disintegration in cancer diagnostics has been recently restyling with the
metabolic effect in metabolomics.
There is no doubt that the pathological physical alterations express essential changes in
cancer development. Any diagnostic method has to detect important parameters disturbed
by cancer process. A new diagnostic method developed by Vedruccio utilizes frequency
selective (resonant) absorption of electromagnetic waves in malignant tumors (Bellorofonte
et al. 2005). In malignant tumors, therefore, we should expect to find structures oscillating at
the frequencies of the emitted signals, whose dissipation is different from that of healthy
tissue. As the measurement results do not depend on the tumor size, the electromagnetic
resonant interactions might be assumed to take place in cancer cells. The damping of
oscillations is significantly It has been proposed that cancer exposed to a low level of
electromagnetic incident waves may behave differently than healthy tissue (Vedruccio et al.,
2004). The phenomenon of ‘‘nonlinear resonance interaction,’’ which is produced when the
oscillations of an electromagnetic probe are coupled with those from biological tissue, can be
used to test for differences between healthy and cancerous tissues. increased during cancer
development.
2.2 Tissue resonance interferoMeter probe

In the 1920s the pioneers in the field of radio frequency reported that “malignant tumours
have a greater polarizability than normal breast tissues or benign tumours”. The authors
moreover declared that “It seems probable that the measurement of the capacity may
provide a very practical method for diagnosing the malignancy of a tumor”. In the 1930s,
some authors extended the frequency range of the dielectric properties of biological
materials up to 600 MHz, by exploring the propagation of the electromagnetic waves on
Lecher wires of variable length and which were terminated by a wire surrounding the
biological material. The technological advances in electronic engineering following the
second world war made possible the first work on complex permittivity measurements on
blood cells and other biological tissues up to 30 GHz. Several years after a method which
allowed dielectric measurements on living tissue (‘in vivo’ measurements) has been
presented. The real time determination of complex permittivity is possible over a large
frequency band (100 MHz – 10 GHz) by a rapid and continuous frequency scan. One such
method is based on an antenna modeling theorem and on the application of microprocessor
controlled microwave measurement instrumentation. A short monopole antenna is used as
the in vivo probe. A network analyzer combined with error-correction routines and a semi-
automated data acquisition/processing system (microcomputer) is used to determine the
real part aof the permittivity and the conductivity s of the biological tissue being analyzed.
A non-destructive method for measuring the dielectric properties of materials by means of
an open transmission line resonator was developed in last 1970s. In the 1980s an open-ended
coaxial probe used to measure and compare the fractional power absorption for malignant
tumors relative to normal adjacent tissue in rats between 30 MHz and 2 GHz. It found that
“tumors have a greater absorption, with a broad peak, centered in the 300 – 400 MHz region”.
190 Colonoscopy
The majority of the studies cited herein refer to measurements and assessments of passive
biophysical parameters of the tissues investigated. Measurements were of capacitance,
resistance, complex dielectric constant.
In 1992, while conducting research on the back coupling effects of the damping of the near
zone electromagnetic fields on transmitter-tuned circuits, Vedruccio discovered the
possibility of noninvasive cancer detection. The author analyzed the perturbation of the
electromagnetic field at the open end of a transmission line due to the dielectric material of
unknown properties.
In the practical application of this effect, the author first constructed some prototype pieces
of apparatus then, proceeded to the international patent application n. WO 01/07909A1 and
the licensing of this technology to Galileo Avionica1. The final stage is an apparatus devoted
to medical diagnostic analysis which is CE certified with the commercial name of Trimprob .
This method is fast and accurate up to 4 GHz. The open end of the coaxial line must be in
direct contact with the surface of the dielectric material being investigated which has to be
smooth and flat.
To avoid any air gap effect, and it is necessary to apply a pressure to the material under test.
Measurements on the human skin were given as an example because of the low penetration
depth but, the aim was primarily therapeutic.
Preliminary results confirmed that it was possible to observe a stimulated response in
altered agglomerates of cells (Vedruccio, 2004). Furthermore, it offered the possibility of
detecting responses from biological tissues. When stimulated by the particular pattern of
electromagnetic oscillations these tissues responded in a very selective way and quite
distinct from the previously investigated Debye and Maxwell-Wagner resonances which
extend over decades of frequency. The principle of detection lies in the resonance between
the coupled active nonlinear oscillator (the probe) and the passive oscillator (the tissue) in
the radiofrequency range of the electromagnetic spectrum. The fundamental frequency of
emitted waves is about 465 MHz. The first (930 MHz) and the second (1,395 MHz)
harmonics are transmitted too. The probe consists of a linear oscillator fed from the
nonlinear element T (Figure 2), together forming a nonlinear active oscillator.
In the equivalent circuit, the oscillator is capacitively coupled to the passive one, the tissue,
via the near field of the antenna. The tumor tissue represents a dissipative medium for the
energy stored in the field near to source. The near field energy periodically flows out of the
probe (the source) and returns to it.
The frequency of the emitted signal is adjusted and locked at the point of the highest
absorption. The receiver antenna is located beyond the immediate neighborhood of the
source (Figure 3). In comparison with electromagnetic wave propagation without
interaction with a tumor, the received signal at the fundamental frequency decreases about
fivefold due to damping effects of the cancerous tissue.
The transmitter probe with a resonant cavity incorporates a transmission line tuned to the
frequency of oscillation, which is in the 65 cm wavelength band (465 MHz). At the open end
1 Galileo Avionica S.p.A., a Finmeccanica Company, is the Italian avionics leader. It focuses on the
design, development and production of avionics and electro-optical equipment, space equipment for
platform and payloads. through its Company FIAR it is a national leader in airborne radars, with
METEOR company in tactical and training UAVs, training simulator. Galileo Avionica offers
cooperative programs (Eurofighter, NH-90, EH-101). in 2001 Galileo Avionica had registred a revenue
of more than Euro millions 452.
Fig. 2. Hand-held, battery-operated detection probe.
Fig. 3. Receiver, and computer display.

192 Colonoscopy
of this line, there is a semiconductor element with nonlinear characteristics that is activated
by a nanosecond electromagnetic pulse.
This transient provides an injection of electromagnetic energy into the tuned line, which
performs a damped oscillation. This particular tunable amplifier-oscillator represents the
core of the Bioscanner trimprob diagnostic device.
It possesses lock-in or synchronization characteristics, and because of its particular
construction, it produces a harmonically related group of coherent electromagnetic waves.
These oscillations are radiated as a beam through the beam window of the oscillator dome
at the end of the probe. After geometrical focusing, the beam is used to irradiate the
investigated tissues. The probe is brought close to the investigated region. Nonlinear
resonance interaction between the nonlinear oscillator and the tissue reduces the energy of
the emitted wave at distinct frequencies depending on the pathological state of the tested
tissue. This energy is measured by the spectrum analyzer, which is fed by an antenna
situated about 2 m away from the probe.
2.3 Clinical application

The device is user friendly and analyses the patient fully dressed and with no discomfort.
Diagnostic accuracy of the Bioscanner was evaluated in several clinical studies. (Bellorofonte
et al., 2005; Da Pozzo et al., 2007; Tubaro et al., 2008; and Gokce et al., 2009) performed
studies focused on the diagnosis of prostate cancer at 465 MHz. Trimprob diagnostic
findings were compared to those resulting from the standard prostate cancer diagnostic
methods including digital rectal examination, biopsy, and prostate-specific antigen (PSA)
level. Resulting values are shown in Table 2. Data presented are consistent across studies.
Diagnostic methods are classified by the proportion of positives and negatives correctly
identified, i.e., by sensitivity and specificity, respectively. Prostate cancer diagnosis using
trimprob is characterized by high sensitivity; however, the specificity is rather low.
Bellorofonte moreover reported a significant difference between patients with benign
Organ Sensibility Specificity V.P.P. V.P.N. Accuracy

Prostate
Tubaro (2008)
86 63 60 88 72
Trimp
Tubaro (2008)
96 57 59 95 72
Trimp+DRE
Bellorofonte (2005) 95 43 94 90 --
Bladder
Leucci (2007) 87,5 90,5 83,3 91,1 89,5
Breast
Paganelli-De Cicco (2006) 84 75 -- 80 72
Thyroid
Sacco (2007) 100 100 -- -- 100
Stomach-duodenum
Mascia (2005) 93 93 95 92 --
Sacco (2007) 100 100 -- -- --
Table 2. Clinical application
prostatic hyperplasia and patients with prostate cancer (Bellorofonte et al., 2005). Trimprob
was also tested for detection of breast cancer (De Cicco et al. 2006), bladder cancer (Gervino
et al. 2007), rectal malignant lesions (Vannelli et al. 2009), carcinomas in patients with
multinodular goiter (Sacco et al. 2007a), and gastric cancer (Sacco et al. 2007b). According to
the clinical experience, the trimprob seems to be a simple and reliable investigation method
with good diagnostic results.
The first experiments, carried out by the author in the early days of the Bioscanner invention
and development, as well as several clinical trials during the last years, have scientifically
validated the efficacy of the described low level e.m.f. cancer detector in several body organs
like breast, prostate, bladder, stomach-duodenum, thyroid (Vedruccio, 2010).
3. TRIMprob and rectal cancer

3.1 Test principle
The device is made of a thin probe about 30 cm long, powered by batteries and of a receiver.
A specific software entirely elaborated by Galileo Avionica acquires, reads and manages the
diagnostic data. The TRIMprob emits a beam of coherent electromagnetic waves at very low
power which tunes on the specific frequencies of the examined structures. When the
electromagnetic field hits a biologically altered tissue, a phenomenon of interference with
the analysed structure takes place. The trimprob system (Galileo Avionica, Turin, Italy), also
called a Tissue Resonance InterferoMeter Probe, consists of a hand-held, battery-operated
detection probe, a receiver, and a computer display. The probe, which is about 30 cm long,
contains a nonlinear oscillator that generates a complex electromagnetic wave of low
intensity with three frequency components (465, 930, and 1395 MHz) and a high degree of
spatial and temporal coherence. Malignant and normal tissues may differ in the way they
interact with such electromagnetic waves because proteins acquire more surface charges in
malignant tumours, and the attraction of these charges for water molecules results in the
presence of more ‘‘bound water’’ (Bellerofonte et al., 2005) Furthermore, dramatic changes
in metabolism, intercellular communication, and adhesion properties of cancer cells result in
modification of the number and nature of membrane proteins. The dipolar parts of the
membrane proteins, which protrude from the membrane, can be reoriented by an oscillating
electric field. The electromagnetic field produced by the nonlinear oscillator of the trimprob
stimulates oscillations inside the tissue. When these oscillations begin to resonate, an energy
transfer can be detected in the wave emitted by the probe. The receiver situated a short
distance from the probe detects the change and acts as a spectrum analyzer. When the probe
is brought near cancerous tissue, interaction with the oscillating electric field causes a
negative amplitude change in one or more of the spectral lines. The reduction in signal
amplitude indicates the presence of abnormal tissues and structures. The frequencies 465,
930, and 1395 MHz were previously determined to be optimal because they appeared to
respond in the appropriate way to the resonances of the system.
3.2 Test procedure

The test was performed for each individual patient according to the procedure shown in
Figure 4. The patient stood between the operator and the receiver, at a distance of 120 cm
from the receiver. There was a single operator, who was not blinded to the results of the
colonoscopy, because the endpoint was the feasibility of this device. The patient was
dressed normally, but no metallic objects were allowed on his or her person, and no
194 Colonoscopy
electronic devices were admitted in the test area. The pelvic area was scanned by moving
the detector at close contact over the pelvic surface through six planes, first in three
directions (axial, left, and right) with the patient facing the receiver and then repeating the
process with the patient turned to face the operator. The test was performed for each
individual patient according to the procedure. The detector was kept in close contact with
the pelvic surface and was moved through six planes: A1, posterior right lateral; A2,
posterior median; A3, posterior left lateral; B1, anterior right lateral; B2, anterior median; B3,
anterior left lateral. There was a single operator, who was not blinded to the results of the
colonoscopy, because the endpoint was the feasibility of this device. The patient was
dressed normally, but no metallic objects were allowed on his or her person, and no
electronic devices were admitted in the test area. In this way, a scan of the whole pelvis
volume was obtained with signal acquisition at six positions: posterior median, left lateral,
and right lateral; and anterior median, left lateral, and right lateral. Each change in
amplitude of the emitted signals at the established frequencies was recorded and stored in
an electronic file as a value of the corresponding spectral line expressed in arbitrary units
between 255 and 0. Thus, three numeric values, corresponding to the signal amplitude of the
spectral lines for the frequencies 465, 930, and 1395 MHz, were obtained for each position.
Fig. 4. Trimprob procedures. The detector was kept in close contact with the pelvic surface
and was moved through six planes: A1, posterior right lateral; A2, posterior median; A3,
posterior left lateral; B1, anterior right lateral; B2, anterior median; B3, anterior left lateral.
The test was performed for each individual patient according to the procedure. The detector
was kept in close contact with the pelvic surface and was moved through six planes: A1,
posterior right lateral; A2, posterior median; A3, posterior left lateral; B1, anterior right
lateral; B2, anterior median; B3, anterior left lateral. The patient stood between the operator
and the receiver, at a distance of 120 cm from the receiver. There was a single operator, who
was not blinded to the results of the colonoscopy, because the endpoint was the feasibility of
this device.
The patient was dressed normally, but no metallic objects were allowed on his or her
person, and no electronic devices were admitted in the test area.
4. Remarkable experiments
4.1 Introduction
Population screening programs for the early diagnosis of CRC have the potential to reduce
the incidence and mortality from this disease. Most of these programs are based on stool
tests or structural exams (Vannelli et al., 2010). The main purpose of the screening should be
to detect 90% of the sporadic cases of CRC. In a health care system with unlimited financial
resources the choice of the type of screening and the suitable population for this
examination does not represent a problem. Everywhere, even though there are different
health care systems, financial resources are limited and the rectal screening with the current
methods could be applied only to a selected population. On the other hand, the majority of
adults are not receiving regular age- and risk-appropriate screenings or have never been
screened at all (Zampino et al., 2009). Despite the fact that the primary barriers to screening
are lack of health insurance, lack of physician recommendation, and lack of awareness of the
importance of RC screening, the historical evidence shows that adults have different
preferences and patterns of use among the available CRC screening tests. Thus, a less
expensive, faster, and less invasive RC screening procedure with a similar or better efficacy,
as compared to available methods, would provide a significant advantage for RC prevention
in the general population. We recently carried out a pilot study for the identification of RC
by electromagnetic detection, a method that is rapid, non-invasive, and inexpensive. As
compared to the results of colonoscopy, electromagnetic detection of rectal cancer was
highly specific (85%) and highly sensitive (94%) (Vannelli et al., 2009). Herein, by a
prospective study we evaluated the prediction accuracy of CRC by electromagnetic
detection. A pilot study has been carried out for the identification of CRC by
electromagnetic detection, a method that is rapid, non-invasive, and inexpensive (Vannelli
et al., 2009). A subesquent study protocol was approved by the Institutional Review Board
and Ethics Committee of the Fondazione IRCCS “Istituto Nazionale Tumori” Milano. The
ClinicalTtrials.gov ID of the study is: NCT00963794. This study was carried out using a
blind and a prospective design, with patients undergoing electromagnetic detection
followed by colonoscopy.
4.2 Preliminary results

We hypothesized to adapt trimprobe in early detection-screening for rectal cancer. Of 1,792
patients admitted to our outpatient clinic from March to September 2006 because of
gastrointestinal disease, 756 patients underwent colonoscopy and were evaluated for
possible participation in the Trimprob study. Exclusion criteria consisted of age younger
than 18 years, history of psychiatric illness, and preoperative radiotherapy. To rule out
196 Colonoscopy
possible interference with the electromagnetic field, we also excluded patients with active
phlogistic processes, such as inflammatory bowel disease, anal abscess, or fistulas. To rule out
possible interference from other types of altered tissues, we included only the rectum, with a
cut-off 15 centimetres from the anal verge. A total of 228 patients (113 females and 115 males)
were selected for participation in the study: 114 patients with negative colonoscopy results and
114 patients with colonoscopy positive for rectal cancer. Written informed consent was
obtained from all subjects. The study protocol was approved by the Institutional Review Board
of the Fondazione IRCCS “Istituto Nazionale dei Tumori” Milano.
4.3 Clinical trials

After the encouraging results we decide to prepare a prospective randomized clinical trial.
442 patients have been admitted to our outpatient's Department from January to August
2008 because of gastrointestinal disease or clinical symptoms related to colorectal risk.
Exclusion criteria consisted of age younger than 18 years, history of psychiatric illness, and
preoperative radiotherapy: 27 patients. Under written informed consent, 415 subjects were
recruited consecutively (10 patients refused the protocol). All subjects underwent
electromagnetic detection of RC, followed by colonoscopy. The patients completed the
examination with computed tomography (positive colonoscopy) or abdominal sonography
(negative colonoscopy). The device lets the examination limited to the pelvis and we
regarded the rectum cutoff within 15 cm from the anal verge. Biopsy of suspected neoplastic
lesions and histopathological exam of the eventual lesions were performed (209 patients),
showing that 108 patients carried a rectal cancer whereas 101 patients carried a cancer in the
upper gastrointestinal tract (right or left colon); these latter patients were excluded from this
study (Table 1). The study protocol was approved by the Institutional Review Board and
Ethics Committee of the Fondazione IRCCS “Istituto Nazionale dei Tumori” Milano. The
ClinicalTtrials.gov ID of the study is: NCT00963794.
5. Phenomenon interpretation
No adverse effects of the Trimprob procedure were observed in the two trials. The
procedure was performed in a short time (approximately 10 minutes) and was well accepted
by all patients. In first trial, only the first spectral line, at the 465-MHz frequency,
differentiated the group with positive colonoscopy from that with negative colonoscopy in
all six probe positions (P < 0.001). At 930 MHz, the two groups differed significantly only in
the posterior right, posterior median, posterior left, and anterior left positions; no significant
differences were seen at 1395 MHz. To evaluate the applicability of trimprob
electromagnetic signal as a marker for distinguishing between CRC and non-CRC disease
groups, we performed Receiver Operating Characteristic (ROC) curve analysis. Figure 5
shows the curves ROC calculated for each frequency. Only the 465-MHz frequency had an
AUC-ROC value close to 1 (0.94), indicating good discrimination between positive and
negative colonoscopy at this frequency. In contrast, 930 MHz and 1395 MHz had AUC-ROC
values close to 0.5, indicating poor discrimination. ROC curve showed the diagnostic ability
of trimprob electromagnetic signal in the differentiation of RC patients versus non-cancer
subjects (AUC = 0.96, 95% confidence interval (CI) 0.94 - 0.98; P < 2.2e-16). In our cohort, the
sensitivity of the trimprob device for RC was 0.94, specificity was 0.84, negative predictive
value was 0.88, positive predictive value was 0.92, and accuracy was 0.90 for the
electromagnetic signal cut-off value of 50 U. Indeed, an electromagnetic signal < 50 arbitrary
units (U) was significantly associated with detection of RC by colonoscopy (p < 2.2e-16).
Analysis of accuracy by cut-off value indicated that ~50-55 U represent the best cut-off
values for detection of RC. Second trial of 442 subjects enrolled at our Institute due to signs
of CRC risk was carried out using a blind and a prospective design, with patients
undergoing electromagnetic detection followed by colonoscopy. Histopathologic analysis of
biopsies revealed that all CRC cases were of the adenocarcinoma histotype. Data from 196
patients with negative colonoscopy results and 108 patients with rectal cancer by
colonoscopy were available for analysis. The median patient age was 65 (range, 24-84) years
for the negative colonoscopy group and 65 (range, 22-85) years for the positive colonoscopy
group. All patients with a CRC diagnosis have been subjected to computed tomography,
which revealed 9 liver metastasis and no other primitive cancer types. All patients with
positive colonoscopy were admitted to the hospital with a diagnosis of rectal
adenocarcinoma and submitted to surgery. Patients not carrying a CRC, (exception of 13
subjects), have been subjected to abdominal sonography, which revealed no cancer
pathology. However, 10 patients revealed active phlogistic processes: 6 inflammatory bowel
disease, 1 anal abscess and 3 fistulas. Since PSA levels were not measured as a screening for
prostate cancer, this may be a possible limitation to the study results.
Fig. 5. ROC curve

CRC patients classified by colonoscopy showed a significantly lower electromagnetic signal
than did non-CRC subjects, i.e., 40.9 ± 0.9 U (mean ± S.E.) versus 79.2 ± 1.4 U (Figure 6). To
evaluate the applicability of Trimprob electromagnetic signal as a marker for distinguishing
between RC and non-RC disease groups, we performed ROC (Receiver Operating
198 Colonoscopy
Characteristic) curve analysis. ROC curve showed the diagnostic ability of trimprob
electromagnetic signal in the differentiation of RC patients versus non-cancer subjects (AUC
= 0.96, 95% confidence interval (CI) 0.94 - 0.98; P < 2.2e-16). In our cohort, the sensitivity of
the trimprob device for RC was 0.94, specificity was 0.84, negative predictive value was 0.88,
positive predictive value was 0.92, and accuracy was 0.90 for the electromagnetic signal cut-
off value of 50 U. Indeed, an electromagnetic signal < 50 U was significantly associated with
detection of RC by colonoscopy (p< 2.2e-16, Table 3). Analysis of accuracy by cut-off value
Fig. 6. Lower electromagnetic signal associated with rectal cancer carrier status. P < 2.2e-16,
Kruskal-Wallis test.
Electromagnetic signal score Number of subjects with

Pb
Non-CRC a CRC a
≥50 184 17
<50 12 91 <1.0e-16
≥70 134 0
<70 62 108 <1.0e-16
a By colonoscopy analysis. b Fisher’s exact test.

Table 3. Association between electromagnetic score settled out at different thresholds and
the CRC disease status defined by colonoscopy.
indicated that 50-55 U represent the best cut-off values for detection of RC. Since a major
goal in screening tests is the minimization of false-negative rates, we identified an
electromagnetic threshold, i.e., < 70 U, at which no RC was missed (Table 3). However, at
this threshold, 62 (31.6%) of the non-RC subjects were false-positive (Table 3), whose disease
or healthy status would have required clarification by colonoscopy. No association between
nodal involvement (N0 versus N ≥ 1) and the value of the electromagnetic signal was
observed. A significant inverse correlation was observed between the size of the neoplastic
lesions and the value of the electromagnetic signal (Spearman's rho = -0.290, P = 0.002),
whereas a significant positive correlation was found between increasing distance from anal
verge and the value of the electromagnetic signal (Spearman's rho = 0.362, P = 0.0001).
6. Discussion
Since up to 10% of the general population might carry a RC, depending on the age of the
population undergoing screening, new easy and non-expensive methods for population
screening for RC may be helpful for early detection of such disease. The most frequently
used screening methods for RC include two general categories: stool tests (tests for occult
blood or exfoliated DNA) and structural exams [endoscopy, double-contrast barium enema
and computed tomographic colonography (CTC)]. The popular occult blood test is
characterized by simplicity, non-invasiveness, and demonstrated mortality benefit but
suffers from poor sensitivity, low population compliance, and high costs of follow-up for
false-positives. Indeed, in a large study of asymptomatic patients who underwent occult
blood testing followed by endoscopy, the sensitivity of the occult blood test for identifying
advanced neoplasia was only 24% . Compared to the occult blood test, CTC is much more
expensive, whereas this technique has some clear advantages when compared to endoscopy
since it is non-invasive, less time-intensive and is associated with a lower risk of
complications. However, CTC requires the use of ionizing radiations, a high level of
expertise in reading, and has shown wide variations in sensitivity in the various clinical
trials (Vannelli et al., 2010). Endoscopy is an invasive, lengthy and expensive procedure
requiring adequate clinical infrastructure and medical expertise, and is not without
complications. Thus, it represents even a relatively "poor screening" method for RC at the
general population level, especially as compared with screening methods, such as the PAP
test, for other types of cancer. The ageing of the general population in the Western world,
with the consequent increase of people at risk of RC, further makes large screening
programs based on colonoscopy unfeasible. Still, early detection of RC can save lives and
can also decrease the cost of the patient's clinical management, since patients with early
neoplastic lesions require simpler surgical resections and treatments than those with
advanced disease. Although endoscopy is generally safe, it is still an invasive procedure
with several-fold higher rates of serious complications than for any other commonly used
cancer screening test. Repeated examinations over time may incur a substantial cumulative
rate of complications. In addition, a relatively small risk (2 to 6%) of RC remains 6 to 36
months after negative colonoscopy, especially when internists and family practice
physicians rather than gastroenterologists perform endoscopies. However, in the near term,
even greater incidence and mortality reductions could be achieved if a greater proportion of
adults received regular screening. Although prospective randomized trials and
observational studies have demonstrated mortality reductions associated with early
200 Colonoscopy
detection of invasive disease, as well as removal of adenomatous polyps, a majority of

adults are not receiving regular age and risk-appropriate screening or have never been
screened at all. Recent interest has focused on use of trimprob for diagnosis of disease as
new screening strategy. This technique is characterized by simplicity, efficacy, and good
patient compliance. In the present prospective study, patients with CRC diagnosed by
colonoscopy and histopathologic analysis showed significantly lower values of the
electromagnetic signal as compared to non-CRC patients. At a signal threshold of 50 U,
defined by our previous study as the optimal threshold in discriminating CRC from non-
CRC patients, the electromagnetic detection showed a highly significant association with the
CRC status, thus confirming in an independent cohort our previous findings. This
technology has also been investigated on other cancers, in particular prostate cancers with
favourable outcomes. The observed inverse correlation between the size of the neoplastic
lesions and the value of the electromagnetic signal is consistent with the association between
low electromagnetic signal values and high probability of CRC, and raises the possibility
that CRC size represents a factor affecting the sensitivity of CRC electromagnetic detection.
The positive correlation observed between increasing distance from anal verge and the
value of the electromagnetic signal may reflect a decreasing detection power of the device
with distance of the lesion or, alternatively, with interference of anatomical structures in the
anal region. Further studies are needed to clarify the existence of a dimensional threshold or
of a minimal distance from anal verge of CRC to be detected by electromagnetic signal.
Notwithstanding the highly significant association between electromagnetic detection and
CRC status observed using the 50 U signal threshold, the frequency of false-negative results
at this threshold was relatively high (15.7%,) and, although much less than the frequency of
missing CRCs by the fecal occult blood test, too high for population-based CRC screening.
By increasing the signal threshold value to 70 U, we can avoid all false-negative findings in
our cohort, thus we can correctly identified all CRC cases but increased the frequency of
false-positives to about 30% of the non-CRC subjects. Thus, follow-up colonoscopy in real-
and false positive subjects would be necessary to characterize the subject's disease status.
We are aware of the limitations of our study, since the relatively small size of our series and
the consequent low detection power. Also, trimprob was never tested in a multicentric
study for the detection of CRC and control subjects from general population, without any
gastrointestinal symptoms related to CRC risk, have not been tested. Other possible
limitations that have not been addressed in the present study include operator dependence
and the effects of other gastrointestinal diseases.
7. Conclusion
Our present findings point to the promise of electromagnetic detection as a simple, accurate,
and inexpensive tool for early detection of CRC in cancer prevention programs at the
general population level. However, the present results represent only a first step and studies
in large cohorts and in different populations are needed to further compare the usefulness of
this method with other CRC screening methods, especially colonoscopy. In addition, the
description of benefits is complicated by different performance characteristics of the variants
tests. Moreover, test performances in research settings and in clinical practice may vary.
Therefore, we can imagine in the future the possibility to support the common screening
tests with electromagnetic detection.
8. Acknowledgments
The authors thank Mrs. Roberta Aceto for her assistance with data collection and MD.
Patrizia Gasparini for scientific consulting.
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14
Autofluorescence Imaging for

Diagnosing Intestinal Disorders
Mikihiro Fujiya1, Kentaro Moriichi1, Nobuhiro Ueno1,
Yusuke Saitoh2 and Yutaka Kohgo1
1Division of Gastroenterology and Hematology/Oncology, Department of Medicine,
Asahikawa Medical University, Asahikawa,
2Digestive Disease Center, Asahikawa City Hospital, Asahikawa
Japan
1. Introduction
Image enhanced endoscopies, such as narrow band imaging (NBI) and autofluorescence
imaging (AFI), were recently developed and clinically applied for the diagnosis of
gastrointestinal diseases. From the results of recent clinical studies, these novel technologies
appear to be useful for detecting, as well as evaluating, gastrointestinal disorders. While NBI
can emboss the vessel structure, AFI can capture fluorescence emitted from intestinal tissues
and also describe the area in which the fluorescence intensity is reduced as a magenta color on
the monitor. This device produces an excitation light source of 390-470 nm and delivers it to
the tissue surface through an endoscope. The low light level autofluorescence emitted from the
tissue and white light reflection are detected and amplified by two high sensitivity CCDs. The
fluorescence image is then transformed into a green hue, while the reflection image is
transformed into red and blue hues. Thereafter, the images are displayed on a monitor as color
images in real-time (Figure 1) (Nakashima A, et al. 2001).
(A) (B)
Fig. 1. High resolution endoscopy (HRE) (A) and AFI (B) in the normal colon.
206 Colonoscopy
AFI is characterized as a tool for simply describing the abnormal findings as color changes,
whereas the diagnosis of conventional endoscopy, NBI and other technologies are based on
the empirical judgment of morphological features. Moreover, the characteristics that AFI
provides are based on the strength of fluorescence, so the quantification of the fluorescence
intensity (proposed as the “F index”) using an analytical image software program can
provide an objective diagnosis for intestinal disorders (Figure 2).
This chapter focuses on the efficacy of AFI for the detection and differentiation of colon
neoplasms, as well as the evaluation and surveillance of ulcerative colitis, and reviews the
likely future progression of this technology in the diagnosis of intestinal disorders.
Fig. 2. Lesions are traced and measured to determine the strength of the red and green areas.
The ratio of the reverse gamma value of green (fluorescence) divided by that of red (reflex)
is defined as the fluorescence index (F index).
2. Endoscopic features of colonic lesions obtained by AFI

The typical images of intestinal disorders including neoplasms, inflammatory bowel disease,
other types of colitis, Behcet disease, amyloidosis and other diseases are described in this section.
2.1 Colon cancer and adenoma

Almost all colon cancers and adenomas are described as magenta in AFI (Figure 3). The
invasion depth of the cancer does not appear to influence the intensity of the fluorescence
captured by AFI (Figure 4). The margin of the tumor is clear in AFI, even for flat and depressed
types of tumors (Figure 5). Interestingly, AFI can detect only the tumor area, but not the reactive
changes surrounding the tumor (Figure 6). This suggests that AFI detects some histological
component of the tumor. The intensity of the fluorescence captured by AFI appears to be
inversely proportional to the dysplastic grade of adenoma (Moriichi, et al. in submission).
Autofluorescence Imaging for Diagnosing Intestinal Disorders 207
(A) (B)
(C) (D)
Fig. 3. HRE (A), indigocarmine-spraying image (B), narrow band imaging (C) and AFI (B) of
the colon cancer with submucosal invasion.
(A) (B)
Fig. 4. HRE (A) and AFI (B) of colon cancer limited to the mucosal layer.
208 Colonoscopy
(A) (B)
Fig. 5. HRE (A) and AFI (B) of a flat and depressed type of colon cancer with submucosal
invasion.
(A) (B)
Fig. 6. HRE revealed a flat and depressed type of tumor (A). AFI detected only the
depressed area as magenta (B), thus suggesting that the tumor cells are limited to the
depression area.
(A) (B)
Fig. 7. HRE reveals a smooth yellowish elevation (A). AFI describes the tumor as a slight
magenta area. Sometimes, the surface of a carcinoid shows heterogenous magenta and
green (B).
2.2 Carcinoid tumors

Carcinoid tumors form in the neuroendocrine system. This type of tumor is thought to
initiate from the deep portion of the intestinal epithelia (Modlin IM, et al. 2003). The tumor
is therefore likely to be a submucosal tumor in the early stage. A typical finding of carcinoid
tumors by white light endoscopy is a yellowish elevation with a smooth surface. AFI detects
the tumor as a slight magenta area, but not strong magenta as is seen for typical colon
cancer (Figure 7).
2.3 Lymphoma
The intestinal tract is a major organ presenting with extranodal lymphoma lesions (Groves
FD, et al. 2000)(Gurney KA, et al. 2002)(Morton LM, et al. 2006). The most frequently
observed types of lymphoma are non-Hodgkin’s, B cell lymphomas including diffuse large
B cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue (MALT)
lymphoma. Diffuse large B cell lymphoma frequently forms a submucosal tumor which is
detected as a magenta area by AFI (Figure 8). Conversely, Follicular, MALT and T cell
lymphomas are sometimes detected as diffusely spread magenta spots or areas by AFI
(Figures 9, 10 and 11).
2.4 Ulcerative colitis

Ulcerative colitis is a chronic refractory colitis. While clinical symptoms are essential to
assess the activity of ulcerative colitis, endoscopic assessment helps to predict the relapse or
evaluate the grade of mucosal healing (Fujiya M, et al. 2002). Typical endoscopic features of
ulcerative colitis are an absence of vessel permeation, multiple erosions and ulcers, and
hemorrhage which diffusely appears from the rectum to the oral side of colon. We
previously reported that the activity of ulcerative colitis is inversely proportional to the
intensity of fluorescence captured by AFI (Figures 12 and 13) (Fujiya M, et al., 2007).
(A) (B)
Fig. 8. HRE (A) and an AFI image (B) of a diffuse large B cell lymphoma at the ileocecal
valve.
210 Colonoscopy
(A) (B)
Fig. 9. HRE describes many abnormal vessels in the rectum (A). AFI can detect mosaic
magenta spots which correspond to the invasion of follicular lymphoma (B).
(A) (B)
Fig. 10. HRE describes a mosaic of red and white mucosa in the rectum (A). AFI detects
diffusely spread magenta spots which correspond to the invasion of MALT lymphoma (B).
(A) (B)
Fig. 11. HRE describes an edematous mucosa with no vessel permeation (A). AFI detects a
diffuse and strong magenta area which corresponds to the invasion of T cell lymphoma
originating from the tonsil (B).
(A) (B)
Fig. 12. HRE indicates the presence of an edematous mucosa with small ulcers and bleeding
in a patient with active ulcerative colitis (A). AFI demonstrated diffuse strong magenta
areas with some deep green spots, which reflect the presence of histologically active
inflammation (B).
(A) (B)
Fig. 13. HRE describes the edematous mucosa and an area with vessel permeation (A). AFI
demonstrated a slight magenta area and a green area with vessel permeation, which
corresponds to an active lesion and a quiescent area, respectively (B).
2.5 Enterocolitis
Enterocolitis is an inflammatory disease of the digestive tract caused by various microbes,
parasites and chemicals. While most cases can be diagnosed without the need for
endoscopy, some enteritis that persists in spite of antibiotic treatments require endoscopic
evaluation. The presence of edematous mucosa with multiple erosions, ulcers and bleeding
are typically observed. These findings are enhanced as magenta areas by AFI (Figure 14).
212 Colonoscopy
(A) (B)
Fig. 14. HRE shows the edematous mucosa with minute erosions (A). AFI enhanced the
lesions as magenta areas (B).
2.6 Aphthoid colitis

Aphthoid colitis is a form of intestinal inflammation which cannot be categorized into any
other category of intestinal diseases. Sometimes, aphtoid colitis is an early step in the
process of developing Crohn’s disease, Behcet disease or other inflammatory disorders. In
AFI, aphtoid ulcers exhibit a clear magenta area surrounded by a blurred magenta area that
reflects edema and the infiltration of immune cells (Figure 15).
(A) (B)
Fig. 15. Aphthoid ulcers surrounded by edematous mucosa are observed by HRE (A). AFI
reveals the ulcer bed as a strong magenta area with surrounding edema presented as a faint
magenta area (B).
2.7 Behcet disease

Behcet disease is a systemic vasculitis that frequently presents with mucosal injury and
ocular involvement (International Study Group for Behçet's Disease, 1990). The small
intestine, particularly the ileocecal valve, is a frequently involved site. Punched-out ulcers
and aphtha are typical lesions in the intestinal tract (Figure 16).
(A) (B)
Fig. 16. HRE reveals a large ulcer on the ileocecal valve with an edematous mucosa and
another large ulcer on the opposite site (A). AFI describes both ulcers as slight magenta
areas, and the edematous mucosa surrounding the ulcers as faint magenta areas (B).
2.8 Amyloidosis
Amyloidosis is defined as an extracellular deposit of fibril proteins, P-components, or other
glycoproteins in organs and tissues, causing mild to severe pathophysiological changes
(Westermark P. 2005). The intestinal tract is a frequently involved site of amyloid deposition
(Koppelman RN, et al. 2000). The endoscopic features of intestinal amyloidosis include
elevated lesions, ulcerations, nodules, petechial mucosal hemorrhage. AFI enhances these
changes as magenta areas (Figure 17).
(A) (B)
Fig. 17. HRE reveals a diffuse edematous mucosa with dilated vessels (A). AFI describes the
edematous mucosa as a magenta area and the dilated vessels as deep green (B).
2.9 Phlebosclerotic colitis

Phelebosclerotic colitis is characterized as the presence of sclerosis with calcification in the
tributaries of the superior mesenteric vein (Arimura Y, et al. 1998). This leads to chronic
214 Colonoscopy
venous insufficiency and congestion, causing abdominal pain, diarrhea and intestinal
obstruction. The endoscopic feature of phelebosclerotic colitis is a dark purple mucosa with
a marked thickness and absence of the haustra at the right side colon. AFI typically reveals a
strong green area with magenta spots at the corresponding site (Figure 18).
(A) (B)
Fig. 18. HRE reveals a dark purple mucosa with edematous changes and an absence of the
haustra. (A). AFI exhibits a strong green area with magenta spots (B).
2.10 Disuse atrophy

When the intestinal tract does not function for a long time due to a bowel rest or an
intestinal operation with a stoma, disuse atrophy of the intestine develops. The typical
endoscopic features are an edematous mucosa with easy bleeding. AFI detects magenta
areas in the corresponding site (Figure 19).
(A) (B)
Fig. 19. HRE reveals the presence of an edematous mucosa with small erosions and
spotty bleeding (A). AFI enhances the erosions as magenta and the bleeding as deep
green areas (B).
3. The diagnostic efficacy of AFI for colon disorders

The significance of AFI for diagnosing intestinal disorders, including colon cancer,
lymphoma and ulcerative colitis are reviewed in this section.
3.1 Adenoma and cancer

During the process of colon carcinogenesis, normal epithelia are thought to initially turn
into benign adenomas, accumulate gene alterations, and then transform into advanced
adenocarcinomas (Fearon ER, et al. 1990) (Lengauer C, et al. 1998). All adenomas are thus
considered to be premalignant lesions. Indeed, several trials on endoscopic resection for
colon adenoma successfully decreased the mortality of colon cancer (Winawer SJ, et al.
1993). However, some patients under close colonoscopic surveillance still develop colorectal
cancer (Robertson DJ, et al. 2005.). This discrepancy may be caused by the rapid
progression of adenomas, as well as the overlooking of colorectal adenoma by endoscopists
with different levels of experience. Indeed, systematic reviews of back-to-back colonoscopies
showed that 15% to 32% of colorectal adenomas were possibly missed by colonoscopy (van
Rijn JC, et al. 2006), particularly flat and depressed adenomas (Rembacken BJ, et al.
2000)(Saitoh Y, et al. 2001).
Several studies have been conducted to assess the efficacy of AFI for detecting colon
adenoma. Matsuda et al. investigated the detection rate of colon polyps at the proximal
colon by AFI using a modified back-to-back method. They showed a higher detection rate of
colon neoplasms by AFI than that by white light endoscopy (Matsuda T, et al. 2008). In
contrast, van den Broek et al. compared the detection rate of AFI with that of HRE using a
procedure to inspect the entire colon twice during withdrawal: once with AFI and once with
HRE by the same endoscopist. They concluded that AFI showed no significant effect on
reducing the adenoma miss-rate in comparison to HRE (van den Broek FJ, et al. 2009). We
previously investigated the efficacy of AFI for the detection of colon adenoma by either less-
experienced physicians or endoscopic experts, and found that AFI improved the detection
rate of colon adenoma, particularly by less-experienced physicians. The effectiveness of AFI
for detecting colon adenoma thus appears to depend on the endoscopist and his/her level of
experience.
Of interest, AFI does not detect hyperplastic polyps as a clear magenta area (Figure 20).
Based on this property, AFI is expected to be used for discriminating colon neoplasms
from non-neoplasms. However, the practical usefulness of AFI in the differential
diagnosis of colon adenoma remains controversial (van den Broek FJ, et al. 2009)(Boparai
KS, et al. 2009)(van den Broek FJ, et al. 2009). We recently investigated the effectiveness
of HRE, NBI, AFI and chromoendoscopy for differentiating colon adenoma from
hyperplastic polyps. From the numerical analysis of the intensity of fluorescence captured
by AFI, the strength of the fluorescence was significantly lower for colon adenoma than
that in hyperplastic polyp. Furthermore, our prospective study indicated that AFI
improved the diagnostic accuracy to distinguish colon adenoma from hyperplastic
polyps, particularly in the resident group (Satoh R, et al. in press). Therefore, it is
suggested that AFI captures a lower intensity of fluorescence from colon adenoma in
comparison to that from hyperplastic polyps, and AFI can therefore contribute to the
differential diagnosis of colon polyps if endoscopists accurately assess the intensity of
fluorescence.
216 Colonoscopy
(A) (B)
Fig. 20. HRE reveals two whitish polyps (A). AFI does not enhance the polyps (B).
3.2 Lymphoma
While the intestinal involvement of lymphoma cells is enhanced as magenta by AFI as
mentioned above, the efficacy of AFI for diagnosing lymphoma has not been thoroughly
investigated. Our study concerning the capacity of AFI (Ueno et al. 2010) for diagnosing
intestinal lymphoma demonstrated the usefulness of AFI (Figure 21). A numerical analysis
of the fluorescence intensity showed that AFI captured a stronger fluorescence from
lymphoma than lymphoid hyperplasia (LH) (Figure 22). A histological analysis of intestinal
lymphoma and LH revealed that the cell density, but not the histological type, is a
significant factor that is inversely proportional to the intensity. Consequently, AFI is a useful
tool to diagnose intestinal lymphoma, but cannot be used for the differentiation of
histological types.
(A) (B)
Fig. 21. HRE reveals a very faint change in the way the light is caught (A). AFI clearly
detects a small lesion (arrow) of an intestinal lymphoma as a magenta spot (B) (These
pictures are cited from Ueno et al. Endoscopy (in press)).
(A) (B)
Fig. 22. HRE reveals multiple polyps in the ileum (A). AFI does not enhance the polyps (B)
(This picture is cited from Ueno et al. Endoscopy (in press)).
3.3 Ulcerative colitis

Ulcerative colitis is a chronic refractory colitis whose etiology is still unknown. Various
therapeutic strategies for ulcerative colitis are performed according to the type and activity
of the disease, thus, the evaluation of the activity is important to choose an appropriate
treatment. While clinical symptoms are essential to assess the activity of ulcerative colitis,
endoscopic assessment helps to predict the relapse or evaluate the grade of mucosal healing
(Fujiya M, et al. 2002).
(A) (B)
Fig. 23. HRE reveals a small amount of redness with minute erosions (A). AFI clearly
describes the lesion as a magenta area, suggesting the limited active inflammation in the
area (B).
Our previous investigation proposed that the intensity of fluorescence captured by AFI was
inversely proportional to the histological activity in ulcerative colitis (Fujiya M, et al. 2007).
Even a small lesion with slightly active inflammation can be clearly detected by AFI
218 Colonoscopy
(Figures 23 and 24). This suggests that when a numerical analysis of the fluorescence
intensity is performed, AFI can evaluate the activity of ulcerative colitis with quite a high
reproducibility and inter-observer consistency. Furthermore, it has been reported that AFI
may be used to detect dysplasia in the inflamed mucosa of ulcerative colitis (Matsumoto T,
et al. 2007). The future analysis of the efficacy of AFI to assess the disease activity and detect
dysplasia is therefore expected to confirm the significance of AFI in the diagnosis of
ulcerative colitis.
(A) (B)
Fig. 24. HRE reveals several minute erosions (A). AFI detects the erosions with the
surrounding inflammation as a magenta area (B)
4. Conclusion
This review describes the typical findings of AFI and the significance of AFI in the diagnosis
of intestinal disorders including colon cancer and adenoma, lymphoma, inflammatory
bowel diseases, intestinal autoimmune diseases and other conditions. While the efficacy of
AFI is still being explored, AFI can definitely be used an efficient tool for objectively
assessing intestinal diseases, particularly by less-experienced physicians. In the near future,
a numerical analysis of the fluorescence intensity will provide a new diagnostic strategy for
intestinal disorders with both high reproducibility and inter-observer consistency.
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15
Intestinal Dynamic Color Doppler

Sonographic Tissue Perfusion Measurement
Thomas Scholbach1, Jörg Hofmann1 and Jakob Scholbach2
1Hospital for Children and Adolescents, Chemnitz Clinincs, 09116 Chemnitz
2University of Münster, Mathematical Institute, 48149 Münster
Germany
1. Introduction
The evaluation of intestinal diseases encompasses morphological as well as functional
aspects. The proper function of any organ depends on a sufficient blood supply to meet its
actual metabolic needs. Blood flow though is a measure of physiological and
pathophysiological tasks which are accomplished by the respective organ. Thus, many of
these tasks can be described by measuring the amount of blood passing through tissues.
Inflammation is an excellent example of such a response to a stimulus which increases tissue
perfusion. The measurement of perfusion intensity would be helpful to monitor
inflammatory processes. In contrast to the obvious advantages of such an approach only
very limited methods exist to quantify perfusion of the bowel today. Contrast media in MRI,
CT and angiography can give a vague impression of the quality of bowel perfusion but are
not usable to quantify perfusion. Doppler ultrasound is used to record changes of blood
flow velocity in the main intestinal arteries to calculate the so called Resistance Index (RI)
and the related Pulsatility Index (PI). Both cannot describe the amount of intestinal blood
since they lack the information of the width of the intestinal vascular network. Besides the
actual flow velocity inside each vessel the vessel width is the other necessary constituent to
calculate flow intensity or volume inside a tissue. We developed a novel method to
overcome these limitations - the Dynamic Color Doppler Sonographic Tissue Perfusion
Measurement (DTPM). The following chapter describes the principle of DTPM and its use in
gastroenterology.
DTPM was developed to meet so far unsatisfied daily needs in clinical practice, to quantify
tissue perfusion in order to answer pressing clinical questions: is the tissue viable, is it
damaged and to which extent, is there an inflammatory hyperperfusion, is the blood supply
to an organ sufficient to fulfill its tasks properly.
2. Dynamic Color Doppler Sonographic Tissue Perfusion Measurement

(DTPM)
2.1 Idea
The idea behind DTPM is that we all are used to estimate by the naked eye the intensity of
blood flow in a tissue by watching the strong or less strong coloration of a tissue during a
routine color Doppler ultrasound examination – but unfortunately this feeling that the blood
222 Colonoscopy
flow is strong or weak cannot be used for a sound decision on treatment. All we see remains
a vague impression. To discuss our findings with others or to refer to our own previous
observations we need a reliable basis for comparison – we need a measurement of what we
see. This is not easily accomplished since the pumping heart causes an ever changing
picture of sparkling color dots inside the tissue under investigation. We need to measure
these changes from beginning to the end of the heart beat to calculate a mean perfusion
value referring to a complete heart beat. Moreover we know that perfusion is blood volume
per time running through the vascular bed of a tissue. Volume per time per tissue unit is but
perfused area multiplied by perfusion velocity (the area is virtually lifted at a certain height
per time thus creating a volume made up of tiny cylinders which stand more or less
dispersed between nonperfused (extravascular) parts (the non-colored background of the
color Doppler image). The product of perfused area and perfusion velocity needs to be
referred to the total area of the tissue section which is actually examined.
2.2 Principle
DTPM is a software assisted method to extract and use color Doppler data from
standardized color Doppler videos in order to measure the perfusion of a tissue (Scholbach
et al., 2004; Scholbach et al., 2005a, 2006; Scholbach et al., 2005b). The perfusion intensity (Q)
is calculated as product of perfusion velocity and perfused area (A) inside a region of
interest (AROI)
Q = v*A/ AROI with the unit [cm/s] = [cm/s *cm²/cm²].

All colored pixels code a certain number of red blood cells moving with a certain velocity
towards the transducer. The color represents the flow direction (red symbolizes flow
towards the transducer and blue the opposite direction or vice versa). The shade of both
colors from dark to light nuances represents a certain velocity value. Each pixel has a certain
area and is the elementary unit of image resolution. Perfused parts of a tissue are depicted
in color whereas nonperfused parts remain non-colored (black, gray or white). DTPM
comprises the complete information, which is necessary to describe the perfusion intensity
i.e. perfused area and velocity values of all pixels, which is extracted and referred to the
tissue area under investigation. This way a description of perfusion is achieved which goes
far beyond existing techniques of conventional Doppler sonographic perfusion evaluation as
RI and PI (Resistance and Pulsatility Index) (Scholbach et al., 2005b). Thus DTPM is
applicable for all tissues which can be depicted by means of ultrasound (Rouviere et al.,
2004; Scholbach & Scholbach, 2009; Wieczorek et al., 2009).
2.3 Technical requirements

The equipment to perform DTPM is a conventional color Doppler ultrasound machine with
transducers that are suitable for a detailed and fast color Doppler imaging. For the
investigation of the intestinal tract a linear transducer is mandatory with a B-mode
frequency above 5 MHz and a color Doppler frequency of at least 3 MHz. The machine must
display the color bar inside the image and must show the maximum values of the depicted
flow velocities at the end of the color bar. Moreover the recording of short videos must be
possible (at least 2 sec duration) and these files should be recorded and transferred to an
external PC via network, USB-stick or other data storage media for the subsequent DTPM
with the PixelFlux-software. DICOM file format is preferred over avi-file format since
Intestinal Dynamic Color Doppler Sonographic Tissue Perfusion Measurement 223
information about image and recording details as well as patient data are included in the
header of the DICOM-file but lack in the avi-file. Despite this avi files are suitable too but
need more manual processing than DICOM files thus requiring more time and manpower to
be processed.
2.4 Standardization
The standardization of image acquisition is crucial for DTPM. A preset of all machine
settings must be defined in the beginning of a DTPM study to define in detail the best
imaging conditions for the tissue in question. The following parameters must be kept
constant in all times to ensure a comparability of the DTPM (others may be also fixed –
depending on the parameters offered by the equipment in use): gain, frequency, persistence,
color bar, time and spatial resolution, transducer type, ultrasound machine type, wall filter,
depth compensation.
If the actual patient requires an other imaging preset then the primary one, it must be
confirmed by statistical comparisons, that the measurement results of both presets are not
significantly different. If significant differences are found in a preliminary investigation with
the same probands or calibrating devices a special reference range must be established to
compare those data with the normal range established with the new preset.
In general daily practice this strict confinement to the own standard preset does not interfere
with a smooth work-up of the imaging requests. It is a general practice to define presets for
special purposes and all manufacturers offer a variety of them as default settings for
different organs and transducers. In most cases these presets can be used or need to be
adapted only slightly. Such a preset should be named and can be reinstituted then by
preselection before starting the imaging.
2.5 Phantom perfusion measurements

DTPM is basically a pixelwise evaluation of perfusion using the color Doppler image data as
delivered by the ultrasound machine. To prove if the concept yields reliable results we made
interobserver correlation studies as well as phantom flow comparisons of the actually
pumped volumes and the perfusion intensities measured by DTPM. In a phantom study
with a perfused tube in a water basin we found a highly significant correlation to the actual
perfusion as pumped by a precision laboratory pump (Pearson’s r = 0,987; p < 0,001)
(Scholbach et al., 2011). Moreover in a clinical setting the ultrasound of the thyroid revealed
a good correlation between two independent researchers measuring the same video
sequences (Spearman’s r = 0,870, p < 0,001) (Scholbach et al., 2011).
2.6 Output
With DTPM the following parameters are calculated from a video sequence recording at
least one full heart cycle.
 Perfusion intensity throughout the entire ROI: Perfusion intensity [cm/s] = mean
perfused area [cm²] * mean flow velocity [cm/s] /area of the ROI [cm²]
 Mean flow velocity throughout the entire region of interest (ROI)
 Mean perfused area in relation to the ROI
 Area of the ROI
 Tissue Pulsatility Index (TPI) of velocity / of area / of perfusion intensity
224 Colonoscopy
 TPI = (maximal systolic value – minimal diastolic value) / mean value - “value” may be
velocity, area or intensity
 Tissue Resistance Index (TRI) of velocity / of area / of perfusion intensity
 TRI = (maximal systolic value – minimal diastolic value) / maximal systolic value -
“value” may be velocity, area or intensity
 Spatial distribution of flow across the tissue
 an overlay of false colors upon the ROI shows local distribution of flow intensity
 Quantitative distribution of perfusion intensity throughout the tissue section
 the whole range of flow intensity (resp. perfused area) over a full video sequence is
divided into percentiles. Each interval’s fraction of the ROI describes the distribution of
perfusion intensity in numerical values.
 Time lines of above explained perfusion parameters of individual patients can be
displayed and statistically evaluated
An example of a DTPM is given below (fig 1a-d).
2.7 Performing a DTPM

The first step to perform a DTPM is to record a standardized color Doppler video of the
respective tissue. In the case of intestinal diseases the bowel or gastric wall is focused on.
Liver, pancreas and lymph nodes are equally useful targets of a DTPM investigation. In the
following a typical procedure for examining the bowel in chronic inflammatory bowel
diseases (IBD) is outlined.
With a linear Doppler probe the respective bowel segment is imaged. Colon segements are
in most cases easily distinguished from small bowel segments by their haustra. Inflamed
bowel segments expose themselves by their typical inflammatory changes: they are much
thicker, darker and less mobile than normal ones (fig 2).
The bowel segment is then imaged with color Doppler ultrasound. The patient is asked to stop
breathing for 3 seconds to prevent movements of the bowel segment. Most inflamed bowel
segments are rather immobile so breathing sometimes can be continued. In all cases flushing
movement color artifacts, which may veil larger parts of the image behind a curtain of a single
color shade (which unmasks them as artifacts easily) have to be avoided. A video of 2 to 3
seconds duration is recorded then and transferred to the PC with the PixelFlux-software. The
video file is then opened and calibrated according to the distances and the color hues. This is
done by the software in DICOM-files and must be supported in avi-files by the investigator.
The calibration is necessary to calculate areas and flow velocities. Flow velocities are calculated
by direct comparison of each color pixel with the color bar. Since the software deciphers the
velocity values from the color bar, it can assign to each pixel inside the bowel wall an
individual velocity value. All pixels are measured and the sum of all colored pixels’ area and
the mean of all color pixels’ velocity values is calculated. This is repeated automatically
from the beginning to the end of a heart cycle. The software recognizes automatically complete
heart cycles. The mean values of all colored areas (A) from one or more complete heart cycles
and of all velocities (v) are calculated and referred to the area of the entire region of interest
(AROI) to calculate the perfusion intensity Q (see above). Besides this most important parameter
of perfusion more than 50 others are displayed and may add to the perfusion measurement
(for details see www.chameleon-software.de) (Chameleon-Software, 2009). The perfusion
intensity is used as the parameter to describe blood flow inside the bowel wall and can be used
to grade hyperperfusion in inflammatory disorders. The grade of hyperperfusion is a measure
of actual inflammatory processes at the investigation site.
Fig. 1a. Color Doppler sonogram of the terminal ileum in a patient with Crohn disease
Fig. 1b. Freehand encirclement of the ROI. Posterior and anterior wall are included
226 Colonoscopy
Fig. 1c. False color map of the terminal ileum in a patient with Crohn disease and diagram
of the distribution of perfusion intensities with quartile boxplot (inset)
Fig. 1d. PixelFlux-output (abridged) indicating clue parameters as table and diagrams. The
diagrams show the time course of flow velocities and perfused areas as well as the
calculated perfusion intensities from the first to the last image of the respective video.
Colored parts of the curves highlight the automatically recognized heart cycles.
Normal colon wall. ( thick bar: 1 cm; thin bar anterior wall with three clearly discernable layers)
Fig. 2a. Color Doppler image of the wall of the ascending colon in a healthy proband
Normal wall of the terminal leum ( thick bar: 1 cm; thin bar thickness of the posterior wall with three
clearly discernable layers)
Fig. 2b. Color Doppler image of the wall of the erminal ileum in a healthy proband
2.7 Interpretation and normal values

Bowel wall perfusion intensity is low in healthy probands (tab.1, fig. 2a and 2b). Significant
differences exist only between perfusion of the terminal ileum and some parts of the large
bowel (tab. 2).
228 Colonoscopy
Median of 25. 75. 90. 95.

Bowel
N perfusion percentile percentile percentile percentile
segment
intensity [cm/s] [cm/s] [cm/s] [cm/s] [cm/s]
TI 13 0,008 0,002 0,015
CA 18 0,007 0,001 0,009
CT 11 0,004 0,001 0,007
CD 15 0,003 0,001 0,007
SI 18 0,003 0,002 0,006
all 75 0,004 0,002 0,009 0,013 0,034

Table 1. Perfusion intensity in healthy probands
Bowel segment TI CA CT CD
CA p=0,230
CT p=0,082 p=0,514
CD p=0,072 p=0,395 p=0,815
SI p=0,036 p=0,319 p=0,770 p=1,000
TI: terminal ileum
CA: ascending colon
CT: transverse colon
CD: descending colon
Table 2. Differences of perfusion intensities of different bowel segments in healthy probands
(Mann-Whitney-U-test)
There are no overt differences of the bowel wall perfusion in fasting probands and probands
examined without regard to the time interval to the last meal (fig 3).
The thickness of large and small bowel segments (terminal ileum) is significantly different in
healthy probands (tab. 3 and 4) (Hormann, 2011):
Median of bowel Maximum of bowel
Bowel segment N
wall thickness [mm] wall thickness [mm]
TI 13 1,9 2,1
CA 18 1,5 2,0
CT 11 1,5 1,8
CD 15 1,5 2,2
SI 18 1,4 2,1
Table 3. Bowel wall thickness of different segments in healthy adult probands
CA p=0,001
CT p < 0,001 p=0,412
CD p=0,008 p=0,817 p=0,357
SI p=0,003 p=0,650 p=0,877 p=0,556
Table 4. p-values of the two-tailed Mann-Whitney-U-test for differences of the bowel wall
thickness of different segment in healthy adult probands
There is a weak inverse correlation (Spearman p=0,018, r=-0,535, n=19) of bowel wall
perfusion intensity and the body mass index (BMI) (fig. 3)(Hormann, 2011).
In contrast to this no correlation was found between BMI and the bowel wall thickness
(fig. 4).
In children similar results as in adults could be found (table 5 and 6) (Hormann, 2011).
Fig. 3. Correlation between bowel wall perfusion and BMI
Fig. 4. Correlation of bowel wall thickness and BMI, n=19

230 Colonoscopy
Bowel Median of 25. 75. 90. 95.

segme N perfusion percentile percentile percentile percentile
nt intensity [cm/s] [cm/s] [cm/s] [cm/s] [cm/s]
TI 8 0,008 0,002 0,016
CA 8 0,002 0 0,005
CT 5 0,007 0 0,015
CD 7 0,007 0,001 0,014
SI 6 0,007 0,001 0,059
all 34 0,007 0,001 0,014 0,028 0,071

Table 5. Median values and percentiles of bowel wall perfusion in healthy children in
different bowel segments
CA p=0,130
CT p=0,524 p=0,621
CD p=0,694 p=0,281 p=0,755
SI p=0,852 p=0,181 p=0,537 p=0,731
Table 6. p-values of the two-tailed Mann-Whitney-U-test for differences of the bowel wall
thickness of different segment in healthy children
Median of bowel
Maximum of bowel
Bowel segment N wall thickness
wall thickness [mm]
[mm]
TI 8 1,9 2,6
CA 8 1,5 2,6
CT 5 1,5 2,5
CD 7 1,5 2,6
SI 6 1,4 2,8
Table 7. Bowel wall thickness of different segments in healthy children
CA p=0,232
CT p=0,524 p=0,755
CD p=0,382 p=0,955 p=0,833
SI p=0,181 p=0,836 p=0,537 p=0,950
Table 8. Differences of perfusion intensities of different bowel segments in healthy children
(Mann-Whitney-U-test)
Between healthy adults and children no significant differences of the bowel wall perfusion
could be demonstrated in comparison of all bowel segments (TI, CA, CT, CD, SI) (figure 5)
and also no significant differences could be demonstrated in perfusion intensity (fig. 6)
(Hormann, 2011).
Fig. 5. Comparison of bowel wall perfusion between healthy adults and children - no
significant differences (Mann-Whitney-U-test: p=0,783; N: number of bowel segements).
Fig. 6. Comparison of bowel wall thickness between healthy adults and children - no
significant differences (Mann-Whitney-U-test: p=0, 680; N: number of bowel segements).
232 Colonoscopy
3. DTPM in gastroenterology
3.1 Chronic inflammatory bowel diseases (IBD)
IBD constitute a diagnostic and therapeutic challenge as their symptoms start creepingly
and are unspecific. Their course is unpredictable and complicated by spontaneous recovery
as well as unexpected outbreaks. The diagnostic gold standard today is the histology and
endoscopic description. The threshold for endoscopy is high due to its invasiveness, need
for preparation, discomfort and pain for the patient, often requiring general anesthesia, and
costs. Non-invasive methods are therefore urgently wanted to make the diagnosis and to
describe the natural course of IBD, their intestinal extent and the effects of treatment. Ideally
complications should be also evaluated with noninvasive techniques. Imaging modalities
hold the promise of being non-invasive (aside from the need of contrast media injection for
CT, MRI or angiography or the necessity to infuse or drink enemas). Ultrasound combines
the advantages of being noninvasive too while offering a spatial resolution which other
techniques cannot achieve. Moreover this is combined with hemodynamic information
displayed as color Doppler signals that give functional information and direct insight into
the local inflammatory reaction which is from ancient times described as a process
characterized by rubor, tumor, calor, dolor and functio laesa. All of them are reflected in
color Doppler sonography as increased perfusion causing redness resp. increased coloration,
heat resp. increased temperature by activated metabolism fueled by hyperperfusion, pain
which can be traced by one finger palpation during the ultrasound investigation directly,
swelling to be detected in B-mode ultrasound images and disturbed function which is
reflected, among others, by stiffness of the thickened bowel wall and dampened peristalsis.
It is therefore a logical step to use color Doppler ultrasound to describe this inflammation.
Unfortunately conventional approaches fall short compared to the inherent potential of the
method. Perfusion estimates from changes of the Resistance index (Britton et al., 1998) in the
superior mesenteric artery do not take into account the blood volumes passing through the
intestines and do not elucidate the specific increase caused by a certain affected bowel
segment. More precise insight is possible by direct evaluation of the affected intestinal
segment. To quantify inflammatory hyperperfusion inside the bowel wall scores have been
proposed which count vessels or perfused area inside a bowel wall segment in still images.
DTPM expands these approaches. It does not only count vessels but measures each pixel’s
velocity value and area but refers these data to the area of the bowel wall and to full heart
cycles. This way changes of these parameters which cause relevant spread of measurements
in still images can be overcome and the error of measurement reduced which on the other
hand is inevitable with the use of still images in describing a dynamic phenomenon as cyclic
perfusion basically is.
The following section describe in detail the advantages of DTPM in Crohn disease and
ulcerative colitis.
3.1.1 Crohn disease (CrD)

CrD is diagnosed in increasing frequency in the industrialized countries (Munkholm et al.,
1993; Pozler et al., 2006; Shoda et al., 1996; Vind et al., 2006). Its main localization is the
terminal ileum which is easily accessible with ultrasound. Other intestinal sites may be also
affected. Even with small bowel affections others than the TI the diseased site can be
retrieved by ultrasound since the inflammation causes prominent swelling and
hyperperfusion which are readily found.
CrD is a transmural inflammation which typically causes a disruption of the clear borders
between the intestinal layers which in healthy intestines can be clearly distinguished in all
parts of the intestines (fig. 2a and 2b). This blurring of the inner wall structure may resolve
and a thickened submucosal layer may point to chronic fibrotic changes. In acute stages
prominent fat wrapping encapsulating the inflamed loops may be quite impressive. This
mesenteric fat may host dilated vessels running in intervals to the inflamed segment to feed
shorter pieces of the intestinal tube. Enlarged local lymph nodes accompany the
inflammation but may be not differentiated in B-mode alone from resting but still enlarged
ones. Here the use of color Doppler ultrasound is quite helpful or even necessary. As in the
bowel wall in the surrounding structures perfusion intensity can be measured and thus
compared to the bowel perfusion. Thus it is possible to discriminate different degrees of
inflammation and to determine its focus. DTPM has proven to give valuable diagnostic and
treatment-relevant information in patients with CrD (Scholbach et al., 2005b).
An example of CrD with transition from normal to inflamed bowel segments is given in
figures 8a and 8b. B-Mode alone is suspicious for IBD but cannot tell resting from exacerbated
disease. Color Doppler, in a standardized fashion of image acquisition, however, can show,
that there is actually an inflammation going on. But to which degree this inflammation has
already evolved cannot be deduced from such an image. To accomplish this, a semiquantiative
method (Heyne et al., 2002; Rogoveanu et al., 2003; Ruess et al., 2000; Spalinger et al., 2000),
contrast enhanced sonographic perfusion evaluation (Girlich et al., 2009; Ripolles et al., 2009)
or even better, since not requiring invasive and costly procedures, DTPM is necessary. An
example of its results is shown in fib. 8b. The red column refers to the perfusion intensity in the
thin-walled segment, whereas the green one describes perfusion intensity on the neighboring
segment. So it is very easy to compare different parts of the intestinal tract with respect to their
actual involvement into an IBD. This holds true for the effects of treatment too. Figure 9 shows
the differing impact of treatment onto various bowel segments highlighting where the disease
is still active. This may aid the planning of future treatment modalities in selected cases. In this
case the ascending colon responded much quicker and stronger than the descendent colon in a
patient with CrD.
Fig. 8a. B-mode ultrasound image of the transition from normal to inflamed colon in CrD
234 Colonoscopy
Fig. 8b. Same image as in fig. 8a in color Doppler mode. Inset showing the results of
dynamic tissue perfusion measurement in both segments.
Fig. 9. Differing response of different bowel segments to Infliximab treatment. Descending

colon (CD) responding later and less pronounced than ascending colon (CA). Normal range
highlighted as semitransparent box.
Complications of CrD as fistulas can be described with great scrutiny. In figure 10a the
cutaneous mouth of a fistula in CrD is shown and its closure is documented shortly after
treatment with Infliximab. One might assume, that a profound suppression of the
inflammation occurred. However, DTPM shows the details of fistula perfusion thus
demonstrating, that there is a clear reduction of hyperperfusion but to a remaining value of
61% of the original one. The investigation of the intestinal opening of the fistula gives more
information (fig. 10b). Here it becomes quite obvious, that further treatment is necessary to
dampen the inflammation in order to prevent a new outbreak of the fistula. Repeated
Infliximab infusions eventually led to a normalization of the initial hyperperfusion and
resulted clinically in a permanent closure of the fistula. The terminal ileum, away from the
fistula bearing colon, showed a different but substantial response too (fig. 10c).
Clinical assessment of disease activity might be difficult, especially in children. Often
activity indices are sought to establish a basis to compare activity scores along with
treatment and over time. These indices are a composition of clinical, anamnestical and
laboratory data. They cannot describe the disease activity at its origin but are used when
other tools cannot be applied (repeated endoscopies) or are lacking. DTPM can fill this gap.
We found a weak but significant correlation of Children’s Crohn Activity Index to bowel
wall perfusion intensity measured with DTPM (fig. 11a). An individual example (fig. 11b)
demonstrates that there may be a clear discrepancy between the locally measured disease
activity and the pediatric CAI. Striking changes of local inflammatory hyperperfusion fail to
236 Colonoscopy
Fig. 10a. Enterocutaneous fistula in CrD evaluated clinically (below) and by means of DTPM
(upper part). Infliximab treatment caused a closure of the cutaneous mouth and a reduction
of fistula’s hyperperfusion to 61%.
Fig. 10b. Same patient as in fig. 10a. Here DTPM of the colonic segment around the enteric
opening of the fistula. In contrast to the proper fistula bowel perfusion drops less readily
and signals the need of further treatments, which, after all, led to a normalization of
perfusion.
Fig. 10c. Same patient as in 10 a and 10b. The terminal ileum responds differently compared
to fistula and colonic fistula origin.
Fig. 11a. Weak but significant correlation of bowel wall perfusion intensity and pediatric
Crohn activity index.
238 Colonoscopy
Fig. 11b. Obvious differences of inflammation evaluation in an individual with CrD by

means of DTPM and pediatric Crohn activity index (CAI). Red columns: Perfusion intensity;
yellow columns: CAI. Perfusion intensity follows the actual inflammation more closely than
CAI leading to diverging assessment of disease activity.
be mirrored by an adequate fluctuation of the CAI. However, this is not surprising with
regard to the different sources of information in both methods. DTPM measures local
perfusion whereas the indices refer to indirect criteria only. Similar results were found by
others comparing bowel wall thickening and biochemical indices of inflammation (Mayer et
al., 2000)
3.1.2 Ulcerative colitis (UC)

As in CrD UC-incidence is increasing too (Jakobsen et al., 2008) but contradictory reports
have been also published (Loftus et al., 2007; Molinie et al., 2004). In less industrialized
regions similar incidences as in industrialized countries were found for both CD and UC
(Sood et al., 2003). This stresses the need for a fast and reliable, cheap and non-invasive
diagnostic tool for these conditions. DTPM, which meets these needs, can affirm the
presence of colonic inflammation and describe its activity quite clearly.
We correlated several histological parameters (table 9) of UC with DTPM at the site of the
biopsies in 19 patients with UC (Scholbach et al., 2010).
Patients with UC demonstrated a weak but significant correlation of their bowel wall
perfusion intensity and wall thickness (fig. 7).
A synopsis of histological, endoscopic and color Doppler images underscores the advantage
of a perfusion measurement (figure 12). It is helpful to describe the degree of inflammation
numerically in order to substantiate the visual impression of imaging and the verbal
description of findings. The columns demonstrate clearly how DTPM can tell severe from
medium and low grade inflammation whereas the images themselves are important and
impressive but cannot convey such precise information that would make them numerically
Score points 0 1 2 3
Changes of crypt architecture

none minor moderate severe
(Bentley et al., 2002)
Depletion of goblet cells(Guindi

& Riddell, 2004; Hendrickson et
no minor moderate severe
al., 2002; Morson, 1971)
Paneth cells distal of the left

colon flexure (Bentley et al., none few some many
2002)
Lymphocytes
(Ajioka et al., 2005; Bentley et normal minor relevant severe
al., 2002; Eksteen et al., 2008) concentration increase increase increase
Plasma cells
normal minor relevant severe
(Bentley et al., 2002; Morson,
concentration increase increase increase
1971)
Eosinophils
(Eksteen et al., 2008; Schmitz-
Moormann & Himmelmann,
1988)
unspecific inflammatory
infiltrates
(Bentley et al., 2002)
PMNs in Lamina propria and

Lamina epithelialis
(Glickman et al., 2004; Reaves et
al., 2005; Wang et al., 2004)
Crypt abscesses
(Bentley et al., 2002; Glickman et
al., 2004; Hendrickson et al., none few some many
2002; Morson, 1971)
Edema
(Hendrickson et al., 2002) none minor moderate severe
240 Colonoscopy
Score points 0 1 2 3
Erosions or ulcerations
(Bentley et al., 2002; large
none erosion ulcera
Hendrickson et al., 2002) erosions
regenerative epithelium
(Lee, 1987; Morson, 1971) none scarce relevant
Fibrosis
(Mitomi et al., 2005; Schmitz-

Moormann & Himmelmann,
1988)
Increased cryptal distance to

muscularis mucosae
(Morson, 1971; Robert et al.,
2004; Schmitz-Moormann &
Himmelmann, 1988)
Table 9. Histological criteria compared with DTPM from the biopsy site
Fig. 7. Correlation of bowel wall perfusion and wall thickness in patients with ulcerative
colitis (Spearman p<0,001, r=0,563)
comparable. With respect to the color Doppler images it must be stressed, that the
information given by single images may be misleading since the image is taken from an
undefined point of the heart cycle. The visual impression changes profoundly from systole
to diastole. DTPM, in contrary evaluates all images of an entire heart cycle, thus ruling out
this error.
Fig. 12. Synopsis of histology (upper row), color Doppler images (central row), endoscopy
(lower row), and perfusion intensity measurement (red columns) of different bowel
segments (TI: terminal ileum, CD: descending colon) in different patients (1-3). Normal
range limit indicated by dashed line.
4. Summary
In IBD, in CrD as well as in UC, a fast, convenient, inexpensive and reliable assessment of
the intestinal inflammation is possible without preparation of the patient. DTPM allows a
true comparison of measurement results in the course of the disease by the use of
standardized imaging conditions, defined ultrasound presets and an objective software-
based calculation of inflammatory hyperperfusion. Significant correlations could be
demonstrated with established histological criteria. DTPM is thus an adjunct to colonoscopy
quantifying inflammation with minimal effort. In some cases it may even replace a control
endoscopy. In all cases it will add to the endoscopic findings what cannot be perceived from
the luminal perspective: the reliable, since numerical description of the periintestinal
242 Colonoscopy
structures and their perfusion as well as a refined description of the changes inside the
submucosal layers of the intestinal wall.
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Pelviperineology 28:59-61
0
16
Towards Intelligent Systems for Colonoscopy

Jorge Bernal, Fernando Vilariño and Javier Sánchez
Computer Vision Center and Computer Science Department,
Universitat Autònoma de Barcelona
Spain
1. Introduction
Colorectal cancer is one of the leading causes of cancer related deaths. Colorectal cancer’s
survival rate depends on the stage in which it is detected, decreasing from rates higher
than 95% in the first stages to rates lower than 35% in stages IV and V (Tresca, A. (2010));
hence the importance of detecting it on its early stages by using screening techniques, such
as colonoscopy (Hassinger, J.P., Holubar, S.D. et al. (2010)), which is still considered the
gold standard for the screening of patients for colon cancers and lesions. Classical focal
colonoscopy has been proved to be a successful tool for colon screening, although other tools
are being also used for this purpose, such as Virtual Colonoscopy, Computed Tomography
Colonoscopy, Chromoendoscopy or Wireless Capsule Video Endoscopy, among others.
In this chapter we present tools that can be used to build intelligent systems for colonoscopy.
The idea is, by using methods based on computer vision and artificial intelligence, add
significant value to the colonoscopy procedure. Intelligent systems are being used to assist in
other medical interventions. For instance, we can build systems that can be used to develop
the knowledge bases used by expert systems, such as KARDIO (Bratko et al. (1990), which
was developed to interpret electrocardiograms. Another example can consist of developing a
system that, in the context of anesthesia, provides a robust/reliable control system that could
determine the optimal infusion rate of the drugs (muscle relaxant, anesthetic, and analgesic)
simultaneously, and titrate each drug in accordance to its effects and interactions. Such a
system would be a valuable assistant to the anesthetist in the operating theater. An example
of such a system can be found in the work of Nunes et al. (2005). More close to our topic
of interest, colonoscopy, we can find many examples of intelligent systems build to assist in
cancer detection. Such is the case of breast cancer detection (Wei et al. (2011)) or prostate
cancer detection (Viswanath et al. (2011)).
The question that arises now is: how can intelligent systems help in colonoscopy? What kind
of applications these systems can be built for? In Figure 1 we depict some of the potential
areas related to colonoscopy where an intelligent system can play a key role.
As shown in Figure 1, we foresee four different areas where an intelligent system can be
introduced and add significant value to the colonoscopy procedure:
1. The most manifest application of this kind of systems could be the assistance in the
diagnosis procedure during the intervention or in post-intervention time. This could be
very useful in order to reduce the miss rate associated to polyp identification.
246
2 Colonoscopy
Will-be-set-by-IN-TECH
Fig. 1. Research lines and potential applications in the scope of intelligent systems for
colonoscopy.
2. We can make use of the scene description provided by an automatic system -including
the presence of salient traits, such as informative frames, anatomical structures, insertion
or withdrawal phases, etc.- in order to automatically annotate colonoscopy videos. This
would potentially provide a very efficient way of case annotation, with multiple uses in
different applications.
3. In addition, an intelligent system may offer a quality assessment of the colonoscopy
intervention, which could provide a non-subjective way of assessment. This could also
be used as a way to train physicians in a way such they can assess and improve their
skills without the cost associated to a real interventions, and it would allow to compare
different performance metrics objectively.
4. We can also build intelligent systems that extend and provide additional information
from colonoscopy data. Belonging to this area we can think of applications such as the
development of patient-specific models, that can be re-used later, when a new study
arrives, to check for coincidences that can help in the diagnosis and enrich in this way
a final case report.
From the examples mentioned above, we can see that intelligent systems can indeed play a
role in the future of colonoscopy. The objective of this chapter is to give an insight into this
future, to expose what tools could be used to build an intelligent system for colonoscopy.
In the next section we present the object of analysis in colonoscopy video by introducing
the endoluminal scene. In Section 3 we deploy the different methods proposed to extract
Towards Intelligent
Systems for Colonoscopy 2473
information from the endoluminal scene by explaining the techniques for image processing,
the methods for scene description, the current proposals for polyp detection, the approaches
pointed for quality assessment, and an insight into the potentiality of developing patient
specific models. Next, we address the problem of the construction of databases of colonoscopy
video and the acquisition of the ground truth. Finally, in Section 4 we fully develop our
contribution with one example of a polyp segmentation algorithm.
2. Endoluminal scene
Before starting with the explanation of the several methods that can be used in building
intelligent systems for colonoscopy, it is necessary to identify what is present on the
endoluminal scene. This is compulsory because by knowing what we may find in images,
we can develop methods that are devoted or attracted to the individual parts or objects of
interest in the image.
As presented in Figure 2, the colonoscopy endoluminal scene shows the intestinal lumen, i.e.,
the inner region of the colon. The colon presents a tubular shape defined by the intestinal
walls. Throughout a colonoscopy screening, the appearance of the intestinal walls varies
in color and texture not only among different subjects but also among some of the different
regions of the colon (ascending, transverse, descending and also sigmoid colon). Regardless
of this intrinsic variability, the endoluminal scene consistently shows the lumen (1), the folds
and wrinkles of the intestinal walls (2), the blood vessels (3), and eventually, diverticulosis
Fig. 2. Complete endoluminal scene: 1) Lumen, 2) wrinkles and folds, 3) blood vessels, 4) a
polyp, 5) fecal content, 6) effect of the color misalignment, 7) specular highlights, and 8)
blurring.
248
4 Colonoscopy
and lesions, such as ulcer, localized bleeding or polyps (4). Due to the flexible and extendible
nature of the colon, and in part owed to the impact of the probe insertion or withdrawal
in its deformation, it is difficult to find a perfect tubular appearance in the colon lumen
because intestinal walls can be bent and folded. In addition, the wrinkles associated to the
colon physiological structure appear in the scene as radial protuberances which modify the
flat surface of the intestinal walls. On the intestinal walls, blood vessels are observed with
their characteristic tree ramifications, presenting a certain variability associated to their width.
Diverticulosis are shown as cavities or holes in the intestinal wall. The lesions related with
bleeding are generally identified by its characteristic color. Polyps present a large variety in
shapes, and seldom show a discriminative change in texture and/or color in comparison to the
surrounding area. Despite a preparation is required for most of the colonoscopy interventions
-with the aim of eliminating all fecal matter so that the physician conducting the colonoscopy
can have a clear view- in many cases intestinal content is still present after the preparation
procedure, and this intestinal content will hinder the right visualization of the intestinal walls.
The procedure of elimination of the remaining fecal matter (5), consisting of the direct injection
of water through the colonoscope in order to dilute the intestinal contents, turns out into the
blurring of the video sequence and the appearance of bubbles. Finally, during the time of
intervention, some tools used by the physician for different tasks -i.e., biopsy, cauterization,
etc-. can be part of the visual scene.
In addition to the difficulties associated to the characterization of the colonoscopy scene due
to its high variability and complexity, there are many visual artifacts the impact of which
should be taken into account in order to tackle a robust system for the automatic analysis
of colonoscopy video. The nature of these artifacts is twofold: 1) On the one hand, image
acquisition systems are usually based on a tree-channel RGB image sensor which acquires
each color component at a different time. In the event of motion, this delay on the acquisition
time can yield to color phantoms (6) (Dahyot et al. (2008)). In addition to the former, and
in order to optimize the dimensions of the image sensor and minimize its price, the video
sequence is usually a composition of two interlaced fields (odd and even), corresponding to
a compound of the RGB channels at different times. The result is an interlacing effect which
is perceptually filtered by the observer during the video screening, but which is present at
a frame level, carrying out the characteristic textured pattern of interlaced video. Finally,
a different artifact, technically designated as specular highlights (7), is produced when the
camera is frontally focusing a reflecting surface, the outcome of which is a white saturation
in the image frame. 2) On the other hand, due to the limited bandwidth and frame rate of
the video capture device, fast movements of the colonoscope can give away blurred images
with diffused visual features (8). All these artifacts can have a potential impact into the
automatic systems, and for this reason these artifacts should be addressed efficiently in order
to guarantee an optimal performance.
Diverse endoscopy techniques, such as capsule endoscopy (both for small bowel and colon),
bronchoscopy, gastroendoscopy, etc. show different endoluminal scenes, each of them
with particular features. Besides, there is a variety of imaging methods to be used to
enhance particular physiological targets, which is the case for narrow band imaging or
chromoendoscopy, just to mention a few. This situation sets up a heterogeneous scenario
from the perspective of automatic analysis using computer vision, and makes it not feasible
to tackle the endoscopic image problem as a whole. However, it is possible to take some
of the methods used in a given technique and adapt them to the specific particularities of
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colonoscopy video. For example, the automatic detection of intestinal content is a topic
addressed in the bibliography of capsule endoscopy (as it can be seen in Vilariño (2006)) by
means of the analysis of color distribution and texture, and its equivalent to the detection
of intestinal content in colonoscopy would require relatively minor modifications. The
identification of elliptical shapes in the image in order to detect potential polyps is a recurrent
subject in virtual colonoscopy, and evolved versions of some of these techniques can be tried
to colonoscopy video by adapting the search context, as we propose in Section 4.
3. Building up an intelligent system for colonoscopy

Once we know what can appear in the endoluminal scene, which is where we will extract all
the information from, we present in this section several tools that can provide information
from the image frames. Since the number of works that apply computer vision and artificial
intelligence is large, we have grouped them into the four potential areas suggested in Section
1. As an introduction, we first analyze which are the preliminary steps that should be
performed in colonoscopy video.
3.1 Image preprocessing

Image preprocessing is needed in order to eliminate or minimize the impact of image artifacts
associated to colonoscopy video, which fundamentally consist of the color phantoms and the
presence of specular highlights.
The problem of color phantoms associated to the temporal misalignment of the color channels
has been addressed in the work of Dahyot et al. (2008). This happens because most
colonoscopy devices use monochromes cameras, in which the RGB components are taken at
different times. This causes a worsening in the quality of the images, as it can be seen in Figure
3 a,b), which may difficult posterior image analysis tasks. The method proposed involves both
color channels equalization and the estimation and compensation of the camera motion. The
experimental results that can be found in Dahyot et al. (2008) show a global improvement in
the quality of the images, failing only in cases when the quality of the original image is very
low, although the evaluation is done qualitatively.
(a) (b) (c) (d)
Fig. 3. Examples of: (a-b) color channel misalignment (c-d) specular highlights.
Adding a solution to a different problem, the work of Arnold et al. (2011) presents a method
to improve the quality of colonoscopy videos. More precisely, the authors offer a solution
for two problems, the already mentioned color channel misalignment and the apparition of
specular highlights. Specular highlights appear on the intestinal surface as an effect of frontal
illumination, as can be seen in Figure 3 c,d). The issue of specular highlights is addressed
using two methods: 1) segmentation based on nonlinear filtering and a posterior color image
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thresholding and 2) fast inpainting method. We have also faced the problem of correction of
specular highlights, as it can be seen in Bernal, J. and Sánchez, J. and Vilariño, F. (2011). In
our case our objective was to provide a fast method that replaces the specular highlights with
an interpolative approximation of what could really be under them, based on the information
that surrounds the specular highlights.
3.2 Scene description for automatic video annotation

The majority of the existing literature devoted to scene description in colonoscopy video
can be grouped according to three different topics, namely: 1) segmentation of the lumen;
2) definition of non-informative frames, and 3) polyp detection. Taking into account the
importance of the latter we will analyze the first two topics, and later on we will deploy the
different approaches to polyp detection in a full subsection.
3.2.1 Lumen segmentation

The detection of the lumen and its position can be crucial, for example, in post-intervention
video processing. Frames where the proportion of lumen out of all the image is large can
be related to the progression of the colonoscope through the patient (Figure 4 a-b)). On the
other hand, frames where the amount of lumen presence is low (Figure 4 c-d)) may potentially
indicate areas of the image where the physician has paid more attention. In addition to that,
an efficient lumen segmentation may lead to remove great part of the image for a further
computational analysis.
Several works are centered on lumen detection, such as the work of Gunduz-Demir et al.
(2010), which aims at decomposing the tissue image (where lumen may be present) into a
set of primitive objects and segment glands making use of the organizational properties of
these objects. In this approach, an image is first decomposed into its tissue components that,
as they are difficult to locate, are approximately represented transforming the image into a
set of circular objects (nucleus and lumen objects). Following a similar line of research, the
work of Tian et al. (2001) presents an automatic segmentation algorithm for lumen region and
boundary extraction from endoscopy images which uses an adaptative Iris filter applied to
the Region of Interest (segmented by an adaptative progressive thresholding method).
The work of Zhang et al. (2010) presents an approach for lumen segmentation which uses the
information that contrast agents provide. Following this trend, the work of Bevilacqua et al.
(2009) addresses lumen segmentation by first estimating the centerline, which can be achieved
by first removing the background and then extracting air regions with a threshold filter.
(a) (b) (c) (d)
Fig. 4. Examples of lumen (surrounded by a yellow boundary): a) and b) full view, c) and d)
partial view.
Towards Intelligent
Although used in CT and virtual colonoscopy respectively, the extension of these methods
to focal colonoscopy may lead to more efficient lumen segmentation techniques due to their
bidimensional nature.
3.2.2 Definition of non-informative frames

The content of the image itself can lead to the definition of informative and non-informative
frames. In this domain of application, non-informative frames are those that, either their
quality is so damaged (by the artifacts, hindering intestinal content, etc.) that it is difficult
to extract information from them, or they are clinically uninteresting for a given task.
For instance, frames where the instrumental take up great part of the image may not be
relevant for polyp detection tasks. An accurate detection of the non-informative frames could
also lead to a great reduction in the processing time of a stored colonoscopy intervention.
Fundamentally, this information may be used for automatic video annotation and efficient
video indexing and retrieval.
There are a few works that are centered on the identification of non-informative frames. The
work of Arnold et al. (2009) addresses the identification of clinically uninteresting frames by
analyzing the energy of the detail coefficients of the wavelet decomposition of a given image,
which is used as the input to the classification system. In this case non-informative frames
are those which do not carry any useful clinical information, such as those that occur when
the camera is covered with liquids or when it is very close (even touching) the mucosa. These
cases do occur frequently in colonoscopy procedures leading to extremely blurry images. This
method is based on the 2D discrete wavelet transform which results in a set of approximation
and detail coefficients. The approximation coefficients represent the low frequency content of
the image while the detail coefficients hold the complementary high frequency information.
The authors use detail coefficients to distinguish between informative and non-informative
frames holding on the fact that the norm of the detail coefficients will be lower for low contrast
images, making them more likely to be classified as non-informative.
The work of Cao et al. (2007) presents a method that extract those frames which correspond to
a diagnostic or therapeutic operation, following work done in other domains (i.e., detecting
important semantic units such as scenes and shots). This work takes profit of several
characteristics that colonoscopy videos present, such as the presence of many blurred frames
due to the frequent shifts of the camera position while it is moving along the colon. The
identification of the operation shots is based on the detection of diagnostic or therapeutic
instruments. In this case the authors map the problem of detecting instruments to the problem
of detecting the cables of these instruments as they are present in the operation, regardless
of their type. The architecture scheme shown in Figure 5 consists of five different steps
which involve: 1) image preprocessing, to remove the effects of the specular highlights; 2)
identification of the insertion direction of an instrument; 3) region filtering, where regions
that are not part of the cable are removed; 4) region merging, which combines regions where
parts of the instrument appears and 5) region matching, which matches the candidate regions
in the image with the cable and without the cable.
Apart from the two methods presented related to the identification of non-informative frames,
other approaches have been carried out such as the work of Oh et al. (2003) where a measure
called the isolated pixel ratio (IPR) is used to classify the frames into informative, ambiguous
and non-informative. The IPR measure is calculated from the edges of the image: an edge
pixel that is not connected to any other edge pixel is defined as an isolated pixel. Those
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Fig. 5. A system architecture for operation shot detection as described in Cao et al. (2007).
isolated pixels are counted for each frame and are put in relation with the total number of
edge pixels to obtain the IPR ratio.
Finally, an example of an endoscopic full multimedia information system for video annotation
implementing many of these approaches is described in the work of Liu et al. (2007).
3.3 Automatic polyp detection

The main objective of the colonoscopy procedures is to check the status of the colon and to
find possible lesions and cancer polyps on it. The general appearance of the polyps has been
covered widely by medical bibliographic sources. However, there is a great variability in
polyp appearance in colonoscopy videos, since there are some challenges that hinder polyp
detection, namely: 1) the non-uniform appearance of polyps (see Figure 6 a-b); 2) their shape,
flat or peduncular (Figure 6 c-d); 3) the effects of image acquisition, such as changes in pose,
blurring, occlusions, specular highlights (Figure 6 e-g), and 4) the high similarity between
the tissues inside and outside the polyp, which disables the possibility of relying only on
texture or color cues (Figure 6 f), just to mention a few. The direct application of the methods
presented in this section can be the potential assistance in the diagnosis, both during and in
post-intervention time.
In the case of polyp detection, the great majority of the approaches is based on the analysis
of features detected in the image. In the context of image processing, features can be defined
as singular visual traits, associated to the visual primitives that constitute an object, such as
edges, corners or lines, among others. The usual procedure is to use feature detection methods
to locate the potential ROIs of the image and then describe them using one or many feature
descriptors. After doing an extensive research on the different types of feature descriptors
(Bernal, J. and Vilariño, F. and Sánchez, J. (2010)), we have divided them into four groups:
shape, texture, color and motion.
Shape-based approaches
These approaches observe the structure of polyps as they appear in images and find the
shapes which polyps commonly have. In general, polyps present two different shapes: flat
or peduncular, as can be seen in Figure 6 a-b). What makes polyp detection by shape features
difficult is that, in many times, we do not have a perfect shot of the polyp but an image where
its pose, size and appearance can vary largely. Thus, many of the approaches presented try to
Towards Intelligent
(a) (b) (c) (d)
(e) (f) (g) (h)
Fig. 6. Challenges in polyp detection: (a-d) non uniform appearance, e) partial (lateral)
views, f) blurred images, g) specular highlights, and h) uniform texture and color inside and
outside the polyp.
detect polyps not by detecting its whole shape but by detecting parts of the image that may
indicate polyp presence.
For instance, flat polyps are meant to have elliptical shapes so one way to detect polyps is
trying to find which structures in the image are surrounded by boundaries that constitute
ellipses. The difficulty in this case is that in many occasions we do not have complete
boundaries or the point of view makes it difficult to fit elliptical shapes (such is the case
of lateral views). The works presented in this subsection could also be classified into two
categories, namely: 1) detection by curvature analysis and 2) detection by ellipse fitting.
As it has been mentioned, curvature analysis is used to perform polyp detection. We can use
curvature in different ways. For instance, we can check the curvature profile of the boundaries
that appear in the image, that may have been detected by means of an edge detector. An
example of the former can be consulted in the work of Krishnan et al. (1998), where the authors
present an approach to polyp detection by means the extraction of contours. These contours
are smoothed afterwards to make them suitable for curvature computation.
The work of Zhu et al. (2010) elaborates on the use of curvature-based shape measures (such
as the shape index, curvedness or mean curvature) to analyze the local shapes in the colon
wall. The problem in this case can appear in spurious calculations indicating high curvature,
which is observed when the kernel contains two surfaces. Another problem that can appear
is the discontinuities in curvature, which is shown when the gradient magnitude necessary to
calculate the curvature vanishes. One possible solution to this is the redefinition of curvature
as the magnitude of the change of the surface normal.
A different approach can be found in the work of van Wijk et al. (2010). The authors present a
method that enables automated detection and segmentation of colorectal polyps, proposing a
method that measures the amount of protrudedness of a candidate object in a scale adaptative
fashion. The work uses the second principal curvature flow as a way to remove protruding
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elements from a curve in 2-D. We can suppose that the the points on the convex region of the
polyp (the polyp head) are iteratively moved inwards, flattening the object. The convex region
expands during the process and will ultimately include the polyp neck. After a certain amount
of deformation, the surface flattening is such that the protrusion is completely removed, as if
the object was never there. The idea here is to observe the second order differential properties
of the implicit surface embedded. If we consider the colon as a long elongated structured tube,
for a perfect perfect cylinder shape the principal curvatures are smaller than or equal to zero
everywhere. However, the colon contains many folds, i.e., structures which are bended only in
one direction: the first principal curvature is larger than zero, whereas, the second principal
curvature is close to zero. Protruding objects, such as polyps, have positive values for the
first and second principal curvature. Therefore, an operator is designed to affect only on
points with a positive second principal curvature and in such a way that the second principal
curvature decreases. The distinction between the head and neck is made by the sign of the
second principal curvature. On the line connecting the inflection points, which in this case
separate head to neck, the curvature is 0. It is clear that this method works well for images
where we have clearly identified what is tissue and what is not so, in this case, the use of
curvature measures can lead to good results in polyp detection.
The other category that collects many works is polyp detection by ellipse fitting. The general
idea is, once we have a set of boundaries in the image, try to fit elliptical shapes in them.
Belonging to this group we can observe in the work of Kang, J. and Doraiswami, R. (2003),
which performs an edge detection in each of the R, G and B channels after applying a contrast
enhancement algorithm. In order to classify the several regions (connected by closed edges)
this method uses area, color and elliptical shape.
An approach that combines both curvature and ellipse fitting can be found in the work of
Hwang, S. and Oh, J.H. and Tavanapong, W. et al. (2007). The method presented consists
of fitting ellipses into the frontiers obtained after a first segmentation, and then classifying
candidate regions by considering curvature, distance to edges and intensity value. Without
entering into many details, in order to detect the ellipses an edge image is needed, where
desirable edges should be grouped. Taking into account the challenges that colonoscopy
images present, only some parts of the polyp boundary will have strong edge information
so, based on this, the method uses the marker-controlled watershed (Vincent, L. , Soille, P.
(1991)) algorithm for polyp segmentation because it can handle the gap between broken edges
properly. Then, using the edges in each segmented region, the method generates an ellipse
using an ellipse fitting method. Finally the number of final ellipses is reduced by removing
those which do not represent actual polyps filtering by curve direction and curvature, by edge
distance and by intensity value.
There are some works that cannot be assigned to an specific category because they use
methods that appear in both curvature and ellipse-fitting categories. For instance, the work of
Dhandra et al. (2006) also starts with a watershed segmentation but it performs its detection
scheme by using color information. As it will be presented later for the case of texture
descriptors, in the work of Coimbra & Cunha (2006), MPEG-7 descriptors are used in polyp
detection tasks. In the field of shape descriptors, region-based shape descriptor is presented. RBS
descriptor belongs to the broad class of shape-analysis techniques based on moments. A set of
separable angular radial transformation (ART) basis functions is defined that classifies shape
along various angular and radial directions. The RBS descriptor obtains 35 coefficients from
the ART transform.
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Finally, the work of Krishnan, S.M. and Goh, P.M.Y. (1997) is devoted to describe polyp
appearance. Several parameters are evaluated, such as the response in the red channel
of the image (which may indicate the presence of malignant tumors), the perimeter, the
enclosed boundary area or the the form factor, which can give indication of possible presence
of abnormalities in the colon (the more irregular the shape of the lumen, the smaller the value
of the form factor).
Our work (Bernal, J. and Sánchez, J. and Vilariño, F. (2011)) cannot be easily assigned to a
single group too, because it also starts with a basic segmentation but in this case it is based
on the definition of a model of polyp appearance. This model defines a polyp as a region
enclosed by intensity valleys. While we will explain it in more depth in Section 4, our results
show that our model is a valid starting point that can be used in polyp detection, applicable
for most types of polyp appearance.
Texture-based approaches
The use of texture descriptors on polyp detection has been gaining interest during last years.
There is a number of works that are based on the use of wavelet descriptors. In this case
the wavelet transform is calculated for each frame and the attention is put on the detail and
approximation coefficients.
The work of Li et al. (2005) takes into account that, when detecting abnormalities in
colonoscopic images, the location, shape and size of the abnormal regions in the image
are unknown and vary across images therefore it is difficult to determine the appropriate
patch-size to use for searching. In this case the solution is to use multi-size patches
and ensemble them in order to achieve good performance. The features extracted from
these patches are taken from both approximating and detail coefficients from wavelet
decomposition of the image patches in the three channels of the CIE-Lab color space.
Also in the context of texture-based approaches we can observe the works of Karkanis et al.
(2003). In these works the first operation that is done to the image is wavelet transformation,
which is combined with other texture descriptors, such as co-ocurrence matrices or local
binary patterns. The same group of researchers developed of a tool to detect colorectal lesions
in endoscopic frame, which was named CoLD (colorectal lesions detector, Maroulis et al.
(2003)). This tool provides a graphical user interface so both novice and experts user can
take advantage of its use. In this case wavelets’ information is used to discriminate amongst
regions of normal and abnormal tissue.
There are some other texture descriptors that have been used to develop polyp detection
method, such as the already mentioned local binary patterns or co-ocurrence matrices. The
work of Ameling et al. (2009) combine both of them, with the novel use of local binary patters
in opponent color space. As the authors state, texture can be seen as a local property and
therefore, each image is divided into small image patches and four different methods were
implemented, which combine co-ocurrence matrices (using different statistical measures such
as energy, homogeneity or entropy) and local binary patterns. The analysis of the performance
results points out that the inclusion of color characteristics (in this case, in local binary
patterns) gives better results so color should be considered as an important feature for polyp
detection.
As in the case of shape-based approaches, MPEG-7 also offers texture descriptors that can be
used to build polyp detection methods. In the work of Coimbra & Cunha (2006), although
applied to a different type of endoscopic process, several texture and color descriptors are
presented. In the sub-field of color descriptors, methods such as dominant color, scalable color
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or color structure are presented (see Bernal, J. and Vilariño, F. and Sánchez, J. (2010) for a
further explanation of them). Related to texture descriptors, homogeneous texture and local
edge histogram are introduced. These methods are evaluated in a big database and, in order to
quantify the performance of each descriptor, several measures were used such as descriptor’s
redundancy or the variation of the descriptors’ value. The experimental results show the
superiority of scalable color over other color descriptors due to its higher resolution. On the
other hand we have the apparently strong local edge histogram that performs worse than other
simpler approaches, such as homogeneous texture, since it pays too much attention to the small
texture variations in the image.
Not all the texture-based methods are built on the use of a certain descriptor. The work of
Tjoa et al. (Tjoa et al. (2002) and Tjoa & Krishnan (2003)) introduces the concept of texture unit
(TU) and texture unit number (NTU). Texture units characterize the local texture information
for a given pixel and its neighborhood, and the statistics of all the texture units over the whole
image reveal the global texture aspects. Without entering into details, each pixel value is
compared with the value of the pixels in its neighborhood and then the value for this pixel in
the TU matrix is assigned according to the comparison. The texture information is presented
in the texture spectrum histogram, which is obtained as the frequency distribution of all the
texture units. Six statistical measures are used to extract new features from each texture
spectrum, which include energy, mean, standard deviation, skew, kurtosis and entropy.
3.4 Quality assessment

Currently, there are several metrics for the assessment of the quality of the colonoscopy
intervention, such as the insertion time and withdrawal time. For instance, current
ASGE (American Society for Gastrointestinal Endoscopy) and ACG (American College
of Gastroenterology) guidelines suggest that, on average, withdrawal time should last a
minimum of 6 minutes. Other works propose the use of additional metrics that include the
quality of preparation, among others (Morán et al. (2009)). In the case of Europe, a very good
work on quality assessment in colonoscopic interventions can be found in the work of Segnan
et al. (2011), which defines from how to prepare conveniently the patient to an intervention
to a classification of the polyps that can be found. These metrics can be potentially used into
training programs for physicians, in order to assess their skills.
3.4.1 Obtention of metrics from colonoscopy videos

Unfortunately, there is not a lot of information about what metrics could be extracted from
a colonoscopy video in terms of computer vision analysis. One interesting approach can
be found in the work of Hwang et al. (2005), which was extended in Oh et al. (2009).
These works presents a method to measure automatically the quality metrics for colonoscopy
videos, based on analysis of a digitized video file created during colonoscopy and produces
information regarding insertion time or withdrawal time. The process to calculate these
metrics involve some results that have been already presented in previous subsections,
such as: 1) detection of non-informative frames; 2) estimation of the camera motions,
performed to find a boundary between insertion and withdrawal phases; 3) segmentation
of the colonoscopy video based on camera motions (proximal and distal direction), with the
objective of finding the end of insertion phase (cecum); 4) lumen identification, performed
to decided if an informative frame contains the colon lumen or not and 5) computation of
seven metrics: insertion time, withdrawal time, clear withdrawal time and ratio, number
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and ratio of camera motion changes and clear operation-free withdrawal time. The authors
have considered a combination of the metrics in a single quality score but the idea has been
abandoned due the fact that several components affect the final quality of a colonoscopy, some
patient-related (such as the preparation of the colon), some equipment-related (quality, color
or contrast of the image) and some endoscopist-related.
3.4.2 Applications for training

Intelligent systems can be used to provide information oriented to build up training systems
for the physicians to improve and test their skills. The work ofVilariño et al. (2009) proposes
the evaluation of the skills of the trainees, and their evolution during learning processes,
by using eye-tracking methodologies as a tool for the assessment of abilities such as active
visual search and reaction time to the presence of polyps, among others. This study presents
a novel method which compares visual search patterns between the skilled specialists and the
trainees. This is done by tracking the eye position of two groups of physicians (experts and
novices) while they are shown a set of colonoscopy videos. Several measures were computed
by analyzing the eye-tracker results, such as eye movement speed or number of fixations. The
obtained results show that colonoscopy experts and novices show a different behavior in their
visual search patterns, and therefore the proposed eye-tracking based procedure can provide
automatic and objective measures for their evaluation. A method similar to the one presented
in Vilariño et al. (2009) can be potentially used both for assessment of the skills of the trainees
during their learning process or to assess the quality of the whole procedure in intervention
time. In addition, the inclusion of the models of appearance and the item categorization from
the tools for scene description can provide an objective ground-truth against which to check
the abilities of the trainee. This can potentially be implemented by analyzing the extent to
which the trainee identifies the regions of interest.
The link between the attention models that guide the physicians visual search and the
visual descriptors which discriminate between the regions of interest is an open and most
paramount line of work, that can help in a twofold way: On the one hand, by providing
essential information for the deepening in the understanding of the processes associated to the
target abilities in colonoscopy (such as the active search of polyps or the accurate navigation
throughout the colon), and on the other hand, by allowing the simulation of these processes
in computer models that can be potentially used for assessment.
3.5 Development of patient-specific models

Approaches identified in the previous sections deploy the state-of-art about a novel
conception regarding the role that computer-assisted technologies may potentially play in
the discipline of colonoscopy. These contributions aim at increasing the quality of the
intervention by adding in complementary information which is not currently at the reach of
the hand of the physician. Since the described methods allow the detection, segmentation
and characterization of anatomical structures, lesions and physiological behavior, there is
a manifest potential to use these strategies in order to endow current techniques with
architectures ready to work with patient-specific models. The patient-specific approach has
been one of the main trends in clinical research lately and it has been one of the pillars of the
research funding schemes for Information and Communication Technologies related to health
care in Europe during the last Framework Programs (ICT Programme Commitee (2011)). The
patient-specific orientation focuses on the adaptation of existing methodologies so that they
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can take profit of the particular information, traits, clinical details or characteristics associated
to each patient. Thus, the patient-specific viewpoint aims at the focalization of the (general)
outcomes provided by each technique onto the (particular) specificities of each case. The
extent to which this perspective can be exploited by using intelligent systems in colonoscopy
is an open field of work. Here, we expose only as a matter of example a tentative list of a few
prospective ideas:
• On the one hand, the use of feature detection in colonoscopy video could provide a
way to the characterization of the inner walls of the colon, based on the identification
of unique traits. This could be used for the tagging or annotation of physiological features
as markers, and apply this information in a further step for the identification of the exact
place of the situation of region close to a polyp.
• A system storing the visual traits of the colon from a given patient could make use
this information in order to find those very specific locations when a new colonoscopy
intervention is performed on that patient. This could provide a method for a precise
spatial localization of regions of interest. The straightforward application of this potential
implementation would be oriented to the registration and study of evolution of lesions
in time (or whatever other item of interest) in the sequential routine interventions carried
out on a particular patient, by automatically providing the specialist with a measure of
certainty about the location of those lesions.
• The generalization of this methodology could be addressed towards the definition of a
patient-specific atlas of the colon, in a way in which the specialist could have track of
landmark positions in intervention time. This perspective presents a scenario in which the
specialist is endowed with a road map for the navigation in intervention time, allowing
the specialist to address specific targets with high reliance, reduced time and a potential
shrinking of the miss rates.
Finally, and since the former ideas can be intrinsically implemented at the intra- and
inter-patient levels, one of the major challenges for a patient-specific approach consists of
the efficient definition of the video database, together with a solid ground truth against which
obtaining qualitative and quantitative performance assessments of the different methods. The
next section deals with the headlines related to the building-up of such databases.
3.6 Ground-truth and database building

In order to carry out an objective assessment of a given method or system, a ground-truth must
exist. The ground truth consists of set of samples from a given number of case studies, with
the corresponding annotations provided by an expert or group of experts. In our context, a
video annotation can be of different natures, among which we can highlight, only to mention
a few: 1) a whole frame, indicating that it is that frame which contains a particular event
-e.g., the first image in a sequence showing a polyp-; 2) a given region of interest (ROI) -e.g.,
indicating the bounding box surrounding the polyp itself-; 3) any textual information -e.g., a
qualitative assessment of the clinical relevance of a polyp-, etc. These annotations are used
to check the performance of a new expert or a new method against the results provided by
the annotator, who is considered the reference. In the ideal case, the annotation procedure
should be repeated by each expert, in order to get a intra-observer variability measure, and by
different experts, in order to get a inter-observer variability measure. A good database with
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a solid ground-truth is an invaluable resource and a key point for the objective assessment of
different methods under a common context of evaluation.
Unfortunately, databases of annotated colonoscopy videos are scarce, and even the access to
small databases is very restricted (few examples can be found at National Cancer Institute
(2011)). The reason of this (without taking into account the natural motivations related
to ethical and administrative issues) has to do with the generalized fact that colonoscopy
video interventions are not routinely saved, since no a-posteriori analysis is needed after the
intervention. In many cases, the only image saved consist of a single picture of the ileo-cecal
valve, which serves as a prove of the its achievement during the phase of introduction
and indicates the start of the withdrawal phase (Malik (2010)). In the computer vision
bibliography, some authors proposed pilot approaches that were validated in a few frames,
with no significant inference for the case of a large video. In other cases, when the number of
cases was higher, the database used for the results was not available. We provide our own test
set of annotated videos with polyp sequences, which is accessible to the interested researchers
by direct email petition to the authors. This dataset will be described in Section 4.
3.6.1 Building up of a database

The building-up of a colonoscopy database consists of two different parts, namely: 1) The
video acquisition system, and 2) the video annotation procedure. The video acquisition
system must be able to grab HD frames from the colonoscopy source and store them to hard
disk, with no lose of frame rate or frame quality. Although the posterior analysis of the frames
must not need HD size, by storing the HD version of the video we assure the maximum image
quality provided by the device. In order to capture the HD frames, a HD frame grabber must
be installed into a PC which will play the role of data repository. Finally, in order to keep the
frame rate and video quality, the frames must be compressed with a fast lossless compression
codec, and stored with a high speed RAID 1 configuration (parallel disc write). Figure 7 a)
shows a graphical representation of the set-up.
3.6.2 Annotation of colonoscopy video

The video annotation procedure can be performed in different ways. In the case of frame
annotation, a keyboard interaction can be potentially enough to select the desired frames.
A navigation system must be implemented if the the expert is allowed to go forward and
backwards in the video sequence. If the annotation task consist of the definition of ROIs, a
mouse, a digital pen, or a tactile device can be used. More sophisticated techniques, such as
the use of eye-tracking (Vilariño et al. (2007)), can be implemented in case that the video is to
be annotated by using attention/perception models -see Figure 7 b) for a general scheme.
4. Polyp detection by means of a model of polyp appearance

Our current work, as it has been stated in Section 3, can be enclosed into polyp detection by
means of shape descriptors. The difference between our work and the works by other authors
is that in order to develop our approach we started by defining a model of polyp appearance.
This model is based on how polyps are shown in colonoscopy videos, and the aim of our
work is to build up our polyp detection system by taking into account as many types of polyp
appearances as possible. Hence, we rely on methods that are based on the detection of the
elliptical shape of flat polyps but we also consider the detection of peduncular polyps.
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(a) (b)
Fig. 7. a) Schematics of the HD colonoscopy data acquisition system. b) Data annotation

scheme.
Our processing scheme consists of three stages (see Bernal, J., Sánchez, J., Vilariño, F. (2011)),
namely: region segmentation, region description and region classification. The segmentation stage
is stated as follows: Given an input image showing a polyp, our objective is to divide the
image into meaningful separate regions, provided that one and only one of these regions
will contain the whole polyp. The resulting regions from the segmentation stage will be then
analyzed for region description. In the region description stage, our plan is to find the descriptor
that best characterizes the region in terms of likelihood for polyp presence. The descriptions
of the segmented regions will be introduced into the region classification stage whose aim is
to decide, considering the data that receives and previous knowledge, if a region contains a
polyp or not. This section focuses exclusively on the region segmentation stage, since its good
performance is crucial for the consecutive phases of the method.
4.1 Region segmentation by means of a model of polyp appearance

As mentioned above, our model of polyp appearance is based on how polyps are shown in
colonoscopy videos. More precisely, the analysis of different frames from our database leads
to the conclusion that the lighting of the probe gives us hints about how the polyps appear.
As light falls perpendicularly to the colon walls, it creates shadows around the surfaces, and
when the light falls into a prominent surface it creates a bright spot surrounded by darker
areas. Finally, the surrounding shadows define boundaries, and boundaries are identified
as edges and intensity valleys in the processed images. We can see in Figure 8 a graphical
example of our method and how it can be valid for both lateral and overhead views.
Although this model of prominent surface appearance under the lighting conditions of the
colonoscope appears to be valid, there are some challenges to be overcome which are those
previously exemplified in Figure 6, namely: non-uniform appearance of polyps, different
point of view, specular highlights, image blurring and color channel misalignment, among
others. Taking all this into consideration, we base our segmentation method on a model of
polyp appearance where we define a polyp as a prominent shape enclosed in a region with presence
of edges and valleys around its frontiers.
Towards Intelligent
17
A complete example of how our region segmentation method works can be seen in Figure 9.
Recall that the objective of this stage was: given an input image, divide it into a minimum
number of informative regions. In our case, the term informative regions is used here for regions
candidate to contain polyps, which will be classified in a later stage into polyp- vs. non-polyp.
Finally, one and only one of the informative regions will contain the whole polyp. Conversely,
non-informative regions are those assumed not to contain a polyp inside, and therefore there
will be no need of further processing for polyp detection (Bernal, J., Sánchez, J., Vilariño, F.
(2010))). The proposed region segmentation scheme consists of 3 different stages:
1. Image Preprocessing: Before applying any segmentation algorithm there are some
operations that should be done: 1) converting the image into gray-scale (Figure 9 b)), 2)
de-interleaving (since our images come from a high definition interleaved video source),
3) correction of the specular highlights (Figure 9 c)), and 4) inverting the grey-scale image
(Figure 9 d)).
2. Image Segmentation: Following some of the approaches presented in Section 3, we apply
watersheds as a first segmentation method. The improvement of our contribution is
that instead of using the original image we use gradient information, which makes the
boundaries between the regions obtained this way closer to the boundaries that separate
the different structures (see Bernal, J., Sánchez, J., Vilariño, F. (2010)).
3. Region Merging: Since it is difficult to obtain perfect segmentation results from a basic
segmentation process, the output of the previous stage will be a high number of regions
(a) (b) (c)
(d) (e) (f)
Fig. 8. a) and d): Simulation of an illuminated prominent surface. b) and e): Grey-scale
profile. c) and f): Example images.
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(a) (b) (c) (d)
(e) (f) (g)
Fig. 9. Complete example of segmentation: a) Original image, b) grey-scale image, c)

correction of reflections, d) complemented image, input to watershed segmentation, e) first
watershed segmentation, f) segmentation results after region information-based region
merging, and g) final segmentation
that should be reduced. In this case our region merging method takes into account the
previously-defined model of polyp appearance to combine neighbor regions into larger
ones. We apply a joint strategy: 1) Region information-based region merging, and 2) Depth
of valleys-based region merging.
a) Region information-based: We first calculate the neighborhood map of the segmented
image (Figure 9 e)) and identify the frontiers between each pair of regions. Next, we
categorize the regions and frontiers in terms of the amount of information that they contain
(Bernal, J., Sánchez, J., Vilariño, F. (2010)). For instance, a low information region will have
a very high (or very low) mean grey level, and also a very low standard deviation of grey
level. We will only merge regions: 1) with the same kind of information, and 2) separated
by weak frontiers. In this case, in order to consider a frontier as weak we propose a frontier
weakness measure as defined in Equation 1. This measure combines the information of
the mean gradient of the frontier pixels (weighted by the coefficient α) and the strength of
the frontiers (weighted by the coefficient β). The latter is measured as the percentage of
frontier pixels remaining after applying two median filters of increasing order -this helps
removing spurious regions created by blood vessels-. We merge and categorize regions
until their number is stabilized or there are no weak frontiers left (Figure 9 f)).
FrontierWeakness = α ∗ gradient + β ∗ strength (1)

b) Depth of valleys-based: We define a depth of valleys measure that combines the output of a
ridges and valleys detector (see López, A.M., Lumbreras, F. et al. (1999) for details) with the
Towards Intelligent
19
(a) (b)
(c) (d)
Fig. 10. Creation of the depth of valleys image: a) Original image. b) morphological gradient
image, c) valleys image, and (d) depth of valleys image.
output of the morphological gradient. This gives information about the depth of the pixels
in the valley image. The pixels that constitute the frontier of the region will have high
values for both the valley and gradient magnitudes (both measures will be smaller for the
inner pixels, as can be seen in Figure 10). Using this information we can continue merging
regions, keeping only those whose frontiers are strong in terms of depth of valleys. We
merge regions until there are no weak frontiers according to the depth of valleys threshold
or when the number of regions is stabilized (Figure 9 g)).
In order to assess the quality of our region segmentation method, we have created a database
with different studies of polyp appearance. We were provided 15 random cases, in which the
experts (physicians) annotated all the sequences showing polyps, and a random sample of 20
frames per sequence was obtained. The experts guaranteed that all these 20 frames showed a
significantly different point of view within the scene by rejecting similar frames. This allows
us to maximize the variability of the images used, while not jeopardizing any bias at all.
We will evaluate the performance of our method by using two different measures:
Annotated Area Covered (AAC) and Dice Similarity Coefficient (DICE). Both measures are
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20 Colonoscopy
complementary as the former calculates the amount of annotated polyp area while the latter
complements it with the amount of non-polyp information that is kept in the region. We
will compare our final segmentation results with the ones obtained using one state-of-the-art
method such as normalized cuts.
We also have to consider that colonoscopy images have black borders around them. Our
region segmentation method consider their presence and use the results of non-informative
region identification (which borders of the image are part of) to avoid further processing of
this areas. In order to test the effect that these borders have in the segmentation results, we
have also created a database that eliminates the borders of the images, although it may lead
to a loss of information.
In Table 1 we show results for polyp region detection, comparing the performance of our
method with the performance achieved by normalized cuts, using the same number of final
regions. We get better results than normalized cuts in terms of AAC and DICE. This means
that our method outperforms normalized cuts by providing regions that do not separate the
polyp, and the polyp is always present in only one region.
The elimination of the borders in the image, in terms of AAC, has almost no effect for our
method but it has more incidence for normalized cuts. DICE results improve for both methods
by using the image without borders (better as the threshold value increases), although
normalized cuts results are better. But, as it can be seen in Figure 11, normalized cuts
non-polyp regions tend to be larger than our non-polyp regions (in our case we know that
the larger region corresponds always to the background).
With Borders
Measure / Method Ours NCuts Ours NCuts Ours NCuts
Threshold Value 0.6 0.7 0.8
AAC 61.91% 63.66% 70.29% 69.06% 75.79% 70.86%
DICE 55.33% 44.97% 44.6% 37.75% 36.44% 34.01%
Without Borders
Measure / Method Ours NCuts Ours NCuts Ours NCuts
Threshold Value 0.6 0.7 0.8
AAC 60.71% 60.2% 70.29% 63.98% 74.32% 64.24%
DICE 55.68% 63.15% 48.01% 61.84% 45.01% 56.73%
Table 1. Comparison between the results obtained by our method and normalized cuts with
respect to the value of the depth of valleys.
In Figure 11 (a-d) we can see examples of the output of each method. It can be seen that
the final regions that our method provides (c) are closer the polyp mask -the ground-truth
segmented by experts-.
4.2 Analysis of results

As it has been shown in the previous subsection, we have developed a region segmentation
method which takes into account the model of polyp appearance. The preliminary results
obtained indicate that our model can be valid for polyp segmentation, although there are
some problems that need to be overcome. Although the numerical results are satisfactory in
terms of accuracy, DICE results must be improved. The number of final regions should be
Towards Intelligent
21
(a) (b) (c) (d)
Fig. 11. Comparison of segmentation results: a) Original images, b) polyp masks, c) output of
our method, and d) output of normalized cuts.
reduced to the minimum possible if we do not want to hurt, in terms of computation time,
the following stages in the pipeline. One possible solution will be to start discarding regions
that will not be passed to posterior stages. We have already used the term of non-informative
regions (as we proposed in Bernal, J., Sánchez, J., Vilariño, F. (2010)) but we can also take
profit of some of the works presented in this chapter: for instance, we can use some results for
lumen segmentation in order to help our description of what is on the scene. Segmentation
results could be potentially improved by applying a size threshold to discard some of the
smallest regions. It would not have an impact in terms of polyp detection if the hypothesis
of a minimum size for detection of polyps is considered. The DICE results could be also
potentially improved by merging some small regions that appear inside the polyp region.
Our efforts now are focused on developing more the approach of depth of valleys. Our idea is
that polyps appear in the image surrounded by intensity valleys and contours where the light
falls perpendicularly on them. We complement the information that a valley detector provides
with the morphological gradient in order to achieve a method that enhances both valley and
contour information, because in certain type of views (in general, in lateral views) we do not
have a whole valley surrounding the polyp. However, non-connected edges are available
in these cases, and once we have this information, that can be complete or incomplete, our
next steps will be focused on finding out the points which are inside or outside the polyp. To
achieve this goal, we will use the depth of valleys image as the seed for an object identification
algorithm. This algorithm is based on the fact that if a point is interior to an object, it will be
surrounded by boundaries (in this case, high values in the depth of valleys image) in many
directions. Conversely, if a point is exterior to an object, it will be surrounded only in a few
directions. This concept can be better understood by following the representation shown in
Figure 12.
Finally, this method needs an accurate and robust boundary detector, although these contours
can be partially incomplete. This method could also be adapted to the idea of ellipse-fitting
(Hwang, S. and Oh, J.H. and Tavanapong, W. et al. (2007)) in order to fit points interior to
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objects to those which would be interior to an ellipse. The development of a method that
identifies accurately which points are interior and which are exterior to objects may lead to an
efficient pruning of the regions obtained from the region segmentation stage.
5. Conclusions and prospective

As mentioned in our introduction, we believe that there is a great potential to use intelligent
systems in colonoscopy. Throughout this chapter we have shown several methods that,
starting from a description of what is on the scene, can be used to add in valuable information
to the output of the colonoscopy intervention.
We have shown how the quality of colonoscopy videos can be improved, by eliminating some
of the artifacts that can alter the performance of computer vision-based systems, such specular
highlights or color channel misalignment. We have also shown that, by a general analysis of
the image and the motion of the camera, it is possible to automatically annotate the different
parts of the intervention for video indexation and retrieval.
There is a vast majority of methods in the literature devoted to lesions and cancer detection.
Several approaches have been carried out, which involve from the direct analysis of the shapes
of the objects that appear on the image to an analysis of the texture of the tissues. We argued
that these methods (included ours) should be tested on a benchmark database with a solid
common ground truth, which is not available yet, in order to have solid inference about
their actual performance. Despite this, the contributions presented show that the particular
results could be potentially used to aid the diagnosis of the physician, both during and
post-intervention.
We have proposed methods that could be used to assess the physician skills in training
programs. By analyzing training results we can improve our systems or, as one method
presented show, we can use the physicians’ reaction of what they see in colonoscopy videos
to learn about what can be relevant in each colonoscopy frame. This provides a baseline to
understand how the attention models are working in intervention time, and which and why
the regions of interest call the physician’s attention.
In the near future, we can think of colonoscopy interventions where intelligent systems add
key information in real-time and allow objective metrics for the assessment of the quality
(a) (b) (c)
Fig. 12. a) Graphical example for the definition of points exterior and interior to objects. Blue
lines indicate directions where the point is surrounded by a strong boundary and red lines
indicate the direction where the point is not surrounded by a strong boundary. b) Original
image, and c) intuitive approximation for the performance of the method in the previous
image.
Towards Intelligent
23
of the intervention. Whether it is an alert to the physician by highlighting some part of the
image where the intelligent system observes some evidence of lesion or cancer presence, or
by automatically storing a patient-specific report of the patient’s colon, intelligent systems are
called to be a relevant tool in the future of colonoscopy.
6. Acknowledgements
This work was supported in part by a research grant from Universitat Autonòma
de Barcelona 471-01-3/08, by the Spanish Government through the founded project
"COLON-QA" (TIN2009-10435) and by research programme Consolider Ingenio 2010:
MIPRCV (CSD2007-00018).
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17
Virtual Colonoscopy - Technical Aspects

Andrzej Skalski1, Mirosław Socha1, Tomasz Zieliński2 and Mariusz Duplaga3
1AGH
University of Science and Technology, Krakow
Department of Measurement and Instrumentation
2AGH University of Science and Technology, Krakow, Department of Telecommunications
3Jagiellonian University Medical College, Krakow
Poland
1. Introduction
Virtual colonoscopy (VC) is a diagnostic method enabling the generation of two-
dimensional and three-dimensional images of the colon and rectum from the data obtained
with relevant imaging modality, usually spiral computed tomography (CT). If CT is used,
the method is also called CT colonoscopy, CT colonography, or CT pneumocolon. The main
advantages of the VC which support its broader application in medical practice include:
limited invasiveness, improved compliance of patients and value for screening for colorectal
cancer.
The introduction of virtual endoscopy technique originates from the extended processing
options of the data sets obtained with available imaging modalities. The Visible Human
Project and related activities (Hong et al., 1996; Hong, 1997) were of key importance for
development of the VC.
The quality of first VC images limited the potential of the clinical use of this technique. But
with next generations of the imaging equipment and advanced processing algorithms, their
applicability in medical practice was established. VC may be performed with all imaging
techniques which result in cross-sections of the abdominal cavity. It can be generated both
from CT and magnetic resonance imaging (MRI) cross-sections. However, the CT remains
the first choice imaging modality for the VC. It is required that spiral acquisition mode with
overlapping reconstructions is applied. The quality of the images generated within VC
techniques depends strongly on the spatial resolution obtained with imaging modality.
Nowadays, multidetector computed tomography (MDCT) is commonly available and this
adds to overall quality of assessment of the colon and rectum resulting from VC.
The patient undergoing helical computed tomography with the intent of obtaining VC
should undergo complete bowel preparation as for other procedures within abdomen, e.g.
endoscopic colonoscopy. The priority is assigned to evacuation of the contents of the colon
before CT. For this purpose, many agents are used including ethylene glycol electrolyte
solution, magnesium citrate or oral sodium phospate. Netherless, the quality of bowel
preparation for VC varies considerably between different centres (Van Uitert et al., 2008).
The trend for the optimisation of the diagnostic procedures and limitation of the burden to
the patient resulted also in a strategy focusing on the performing of the optical colonoscopy
just after VC, if it is positive for pathological lesions in the colon, in order to avoid repetition
272 Colonoscopy
of the bowel preparation procedure. A strategy enabling identification of the artefacts

resulting from fecal contents in the bowel in the process of generation of VC images was
also proposed. This is achieved by labelling it with some type of contrast agent, e.g. barium
or meglumine diatrizoate taken orally before the CT (Iannaccone et al., 2004).
The use of MRI imaging for generating of VC is another attempt to avoid bowel preparation
and exposure to the radiation related to the CT imaging (Florie et al., 2007). Finally, the
techniques enabling “electronic” colon cleansing before generating VC images were
developed to allow for less intensive colon preparation procedures (Lakare et al., 2002). VC
without laborious bowel cleansing preparation preceding is related to higher acceptance
and compliance from patients. This in turn may be a key condition for successful screening
strategy in the society.
Growing use of the VC is supported by its lower invasiveness in the comparison to other
diagnostic procedures and potential for higher compliance from patients. These features
increase the value of the techniques as a screening test for disorders of the colon. The main
indications for VC include screening for colonic polyps or cancer and failure or inadequate
results of optical colonoscopy due to anatomical conditions or pathological lesions, e.g.
obstruction of the colon lumen. Furthermore, the VC enables also for examination of
extracolonic structures not accessible during standard colonoscopy. This may be particularly
important for these patients in whom pathological lesions were detected inside the colon
lumen.
The first studies focusing on the assessment of the sensitivity of the VC reported usually its
lower performance in comparison to optical colonoscopy. The sensitivity of the VC depends
considerably on the size of the polyps present in the colon and is lower in less advanced
lesions. Introduction of MDCT had significant impact on improving the VC efficiency. Most
recent studies indicate that VC sensitivity in detecting polyps of size at least 10 mm is
comparable with optical colonoscopy and exceeds 90% (Regge et al., 2009; Graser et al.,
2009).
The Guidelines issued in 2008 by American Cancer Society, American College of Radiology
and US Multi-Society Task Force on Colorectal Cancer included VC within recommended
screening tests for colorectal cancer, which should be performed at 5 years intervals in
population of at least 50 years or older (Levin et al., 2008). According to the Guidelines, VC
should be performed after complete bowel preparation. The detection of a polyp of size >6
mm in VC necessitates the performance of optical colonoscopy, preferably the same day or
second complete bowel preparation is needed.
During classical (optical or video-) endoscopy, the endoscope is inserted into the internal
space of a tube-like organ. Colonoscopy is performed with flexible endoscope equipped
with a camera. A physician performing examination can bend the tip of the endoscope in
two orthogonal directions using small wheels which are placed on the head of the
instrument in order to navigate and move it through the colon. Colonoscopy may be
associated with different level of discomfort in specific patients and depend on the
medication used during preparation and the procedure itself. The VC may be an alternative
approach to classical endoscopy. In this chapter, technical aspects of the generation of the
VC images are explored. Authors describe all steps which are required to create a 3D
computer model of the colon from the CT data. A procedure which allows one to compute
the VC is presented in figure 1. It includes CT examination of abdomen, electronic colon
cleansing, generation of 3D computer model of the colon with appropriate segmentation
techniques. Then a navigation path for virtual camera may be calculated in order to simulate
Virtual Colonoscopy - Technical Aspects 273
the progression of a real endoscope. Finally, views from colon reconstructed from the CT
data are calculated based on visualisation methods.
Fig. 1. Block diagram of the Virtual Colonoscopy procedure
2. Computed tomography data

The imaging modality of computed tomography (CT) was developed in the results of the
chain of discoveries starting from the year 1895 when Wilhelm Röntgen invented a new type
of electromagnetic radiation, called by him as X-rays. The mathematical principles of CT were
first investigated by Johann Radon in 1917 and then extended by Kirillov in 1961. The first CT
scanner was presented in 1972 by Allan Cormack and Godfrey Hounsfield, who were
awarded the Nobel Prize in medicine in 1979. The detailed description of CT was provided in
1988 (Kak & Slaney, 1988). Nowadays, CT imaging is commonly used throughout medical
specialities for diagnostic purposes and support of interventional procedures.
Because of easier hardware realization, the fan-beam projection is used in medical CT
scanners. In the third-generation CT scanners, the X-ray source and the detector array are
rotated around the patient. In helical or spiral cone beam CT scanners, the patient is lying
during the procedure on a moving bed and the X-ray source and the detector arrays are
rotating around him.
The helical scan method enables for quicker scanning and reduction of the radiation dose
(necessary for given resolution) to which the patient is exposed during the procedure.
Additionally, the number of rows of detectors in helical CT scanners was increasing from
several years. Nowadays, the 64 or 128 multi-slice scanners are frequently encountered in
clinical applications. Currently, 256-slice cardiac CT scanners enables for scanning of the
heart in less than one second. On the other hand, minimizing the radiation risk to the
patient, while maintaining satisfactory CT image quality, becomes urgent especially for
colon screening with CT (Wang et al., 2008). Dose reduction for CT imaging can be achieved
by scanning patient whit low-mAs protocols (less than 100mAs). Unfortunately, these
protocols may result in noisy and streak artefacts in the reconstructed images. This effect
can be compensated by the optimisation of data acquisition and the application of iterative
image reconstruction algorithm (Wang et al., 2008).
274 Colonoscopy
The dataset acquired with the CT scanner can by described by number of slices, the number
of pixels per slice and the voxel distances. The number of pixels in one slice is also referred
to as image matrix. It is usually set of 512 x 512 pixels. The distances between the voxels are
differentiated into the slice distance (out-of-plane) and pixel distance (in-plane). In general,
the medical data are anisotropic (pixel and slice distances are not equal).
The data resolution influences the noise level. The data having higher resolution are more
noisy for the same radiation dose. The computed intensity values represent the densities of the
scanned objects that are normalized into Hounsfield units (HUs). This normalization maps the
12-bit data into two bytes (16 bits). Water is mapped to zero and air is mapped to -1000 value.
Medical images are physically stored together with the data essential for their interpretation.
This information is highly standardized. The DICOM standard (Digital Imaging and
Communications in Medicine) enables the integration of scanners, servers, workstations,
printers, and network hardware from multiple manufacturers into a picture archiving and
communication system (PACS). It includes a file format definition and a network
communications protocol. The DICOM files can be read by many programs and are
supported by numerous libraries (VTK, DCMTK, GDCM).
3. Colon cleansing
The first step of the CT data processing is the electronic cleansing (EC) of the colon,
especially if other means were not undertaken to remove fecal contents from the colon. The
term EC was first introduced by Wax and Liang (Wax et al., 1998). This is a key operation
for ensuring correct segmentation being the next step. In figure 2, we can see fluid (contrast)
in the colon. Classical threshold operation does not remove voxels lying on the border
between air and fluid (see Fig. 2b). The idea of thresholding operation relies on voxels
division into 2 groups making use of a predefined threshold value T:
1 for I ( x , y , z) ≥ T
M( x , y , z) =  (1)
0 for I ( x , y , z ) < T
(a) (b)
Fig. 2. 2D slices of: a) 3D CT data; b) 3D CT data after classical thresholding operation
where: M(x,y,z) is a binary mask (1 - indicates object, in this case it should be the colon, 0 -
background), and I(x,y,z) denotes a CT data.
The threshold value is usually designated on the basis of the histogram of the CT data or
general knowledge about values attributed to anatomical structures. A border between
contrast and tissues (see fig. 2b), unwanted but usually being obtained after thresholding
operation, is a result of limited resolution of detectors and soft property of reconstruction
kernel.
3.1 State of the art

In order to remove voxels representing contrast and residual nutrients, many different
computer algorithms were proposed for the electronic colon cleansing (ECC). They differ
with the image pre-processing steps, local image features (mainly statistical ones, e.g. 23
features in (Lakare et al., 2003) and 35 in (Cai et al., 2011)), the method of reduction of
features dimensionality (vector quantization, principal component analysis), applied
modelling (of multi-material objects and their edges/gradients), the use of the segmentation
techniques (watershed, active contours, level-set) and classification methods (Markov
random fields, expectation maximization, support vector machine). Recent publications in
this area (Cai et al., 2011), (Serlie at al., 2010) provide the state-of-the-art and historical
perspective of the research focused in the EC.
First works on ECC were based on the application of the statistical image features, vector
quantization (for dimensionality reduction), image gradient information and Markov random
field classification (Chen at al., 2000). Later methods paid special attention to the application of
edge modelling during image segmentation, aiming at efficient delineation of tagged regions.
The segmentation ray technique (Lakare et al., 2002) is the most important one in this group. In
this method the rays were designed to analyse the intensity profile and to detect the
intersection between the air and the residual fluid and between the residual fluid and the soft-
tissues. The segmentation rays can accurately detect partial volume regions and remove them
if necessary. The same authors (Lakare et al., 2003) proposed a method based on vector
quantization but it does not assure correct exclusion of the voxels lying near colon wall. In
turn, in another method (Zalis et al., 2004) the image gradient is approximated by Sobel mask
filtering followed by a morphological dilation. Recently, Wang (Wang et al., 2006) proposed
application of statistical features and an expectation-maximization algorithm for
distinguishing voxels belonging to multiple materials while (Serlie at al., 2010) built a scale-
invariant three-material transition model between air, soft-tissue and tagged material/fluid
and used it for classification of each voxel. The most sophisticated and effective algorithm has
been proposed recently in (Cai et al. 2011) that consists of several very carefully designed steps
making use of many image features (descriptors), two segmentation procedures (watershed
transform, level-set method) and very precise SVM classification/cleansing method
(sensitivity 97.1%, specificity 85.3%, accuracy 94.6%).
In order to present problems solved with electronic colon cleansing methods and to
demonstrate typical existing solutions, the ECC algorithm developed by the authors of this
chapter is briefly described below.
3.2 Electronic colon cleansing using non-linear transfer function and morphological
operations
The ECC method proposed by us is based on non-linear value transformation combined
with morphological voxels processing (Skalski et al., 2007a).
276 Colonoscopy
First, if the CT data has HU values without offset, the voxels values are increased by 1024
and unsigned 16-bit fixed-point integer data format is obtained what results in significant
reduction of the calculation time. In order to remove voxels representing contrast one has to
find them in the CT data. To reach this aim, we compute two binary masks: a fluid mask
and a residual mask. The fluid mask is created by thresholding operation described in
section 3: voxels having values greater than 1600 are given value 1. In case of the residual
mask we are looking for values greater than 1350 and equal or smaller than 1600 since
voxels representing stool and fluid remain within this range. Both masks are dilated using
regular hexahedron of size 3. Voxels for which the masks are equal 1 are then processed by
two transfer functions, shown in fig. 3, representing Gaussian intensity transformation:
 ( I ( x , y , z )− 1000 )2  (2)
I new ( x , y , z) = 1000 ⋅ exp  − 
 2 ⋅σ 2 
with σ = 450 for the fluid mask and 100 for the residual one. This operation is desirable due to
necessity to keep smooth changes of intensity on the border between colon and soft tissues.
Fig. 3. Gaussian transfer functions; blue line – for fluid mask σ=450 in (2), red line - for
residual mask σ=100
In the next step a binary data (MBin) are created having 0s for the air (v < 300) and 1s for the
remaining parts. Then, a sequence of two morphological operations is performed: 1) a 3D
erosion operation is applied to each volume by means of a three-cubic matrix, 2) a dilation
operation is done on the data resulted from the erosion process. This way, a new volume
(MDel) is obtained. After subtraction of MDel from MBin one receives a binary matrix in which
1s denote voxels that probably lie on the border between air and fluid (stool). Finally, we
must check also whether voxels received from the subtraction belong to the border. Since,
during the CT scanning the patient lies on his back or abdomen, the border is always
parallel to the body surface.
The whole operation can be summarized by the following formula:
 1 for I ( x , y , z ) ≥ 300
M Bin = 
 0 for I ( x , y , z ) < 300
M Del = dilation ( erode ( M Bin ) ) (3)
M Pr_ Border = M Del − M Bin
(a)
(b)
Fig. 4. The intensity profiles for a voxel which cannot be removed (a) and must be removed (b)
Fig. 5. Exemplary results of usage of the proposed algorithm for colon cleansing
After subtraction we check intensity profile along normal direction to the body surface (fig.
4) for each voxel equal 1 in the MPr_Border volume: if the profile contains voxels belonging to
stool or contrast, this voxel is removed. In figure 4 we can see that the voxel belonging to the
border has different characteristic profile than the voxel belonging to the colon wall what
allows to distinguish them and remove the border voxel.
Exemplary results from application of the proposed algorithm for electronic colon cleansing
are shown in figure 5.
278 Colonoscopy
4. Segmentation
Data visualization methods like surface or volume rendering can be used for showing inner
structure of the colon. However, inspection of the visualized data requires manual virtual
camera movement which make smooth observation difficult. Segmented data may be used
for creation of the automatic navigation path for the virtual camera. If we display only
segmented structure, we can reduce the time required for visualization. Combined
visualization and segmentation algorithms allows for development of 3D models of
anatomical structures (fig. 6). Additionally, structures that are external to the colon can be
viewed, which improves the assessment of the pathological lesions.
Fig. 6. Colon after segmentation process (Skalski et al., 2007a)

The human abdomen consists mainly of three regions: air, soft tissues and high density
materials (bones) and this is reflected by voxels values. Thresholding represents the simplest
approach to abdomen segmentation but has many disadvantages, e.g. it does not remove
partial volume voxels. For example, voxels near the edge of objects are incorrectly classified
when thresholding is used. Therefore, in the VC, segmentation is usually based on region
growing (Vilanova et al., 1999; Xie et al., 2003, Sadleir & Whelan, 2005) or active contour
methods (Jiang et al., 2005). The idea of the region growing technique is linking thresholding
procedure with neighbourhood checking. In first iteration, the algorithm checks membership
condition for all voxels of the neighbourhood of voxel being classified. If the voxels pass the
membership condition test which can be the same as in classical thersholding procedure, the
voxels are added to the object. In next iterations, this process is repeated for all voxels added in
the previous iteration until no new voxel can be added. It allows for local operation in contrast
to thresholding. Even if in the dataset there are voxels which can pass membership condition,
they will not be classified as the object if they have no connection with voxels added before.
Different strategy is applied in the method of active contours, called also “snakes”,
proposed by Kass et al. (Kass et al., 1988). The active contours method is a segmentation
technique in which the problem of object finding in the analyzed data is formulated as
energy minimisation. It is usually calculated in iterative routine where contour evaluation is
guided by external constraint forces and influenced by image forces that pull the contour
towards lines and edges present in the data. The total energy consists of the internal and the
external energies which are responsible, respectively, for contour behaviour and image
influence. The active contours method is a parametric technique which is susceptible to
parameter tuning and this is a one of its main disadvantages. But even then classification of
voxels lying near the colon wall is a source of problems.
Fig. 7. Idea of the watershed algorithm; First row: classic watershed; Second row: marker-
based watershed; description in the text
The 3D segmentation algorithm based on immersion-based watershed method of Vincent
and Soille (Vincent & Soille, 1991) can be also applied. The watershed method exploits
topographic and hydrology concepts for the development of region segmentation methods.
The image may be seen as a topographic relief, in which the value of a pixel (for 2D images)
is interpreted as its altitude in the relief. In case of 2D, the principle of watershed algorithm
can be illustrated by an idea of immersing the image from water sources. When the
neighbouring catchment basins eventually meet, a dam is created to avoid the water spilling
from one basin into the other (Vincent & Soille, 1991). When the water reaches the maximum
value, the edges of the union of all dams form the watershed segmentation results (fig. 7). In
case of 3D, usage of the algorithm leads to receiving 3D objects separated by the dam. If we
use local minima of the image as water sources, oversegmentation problem will appear. In
consequence, we receive a huge number of objects in the resultant matrix which do not
correspond to data.
One of the solutions is a modified strategy of source selection. We used marker-based
Watershed transform, where the immersion processes are started from markers computed
from the image.
In order to improve results, the absolute value of gradient of the filtered data (fig. 8) is
computed using the 3D Sobel’s mask and then the data are immersed by the watershed
algorithm.
Fig. 8. From left to right: slice of a CT data; Absolute value of the gradient; Gradient
visualisation as a topography map
280 Colonoscopy
Neubauer et al. (Neubauer et al., 2002) proposed manual placing of markers inside the data.
On the contrary, we use automatic methods for markers computation: object markers are
obtained from voxels after thresholding operation. We know that voxels having intensity
below 300 units represent air, and background markers are voxels which have intensity
value corresponding to tissues. This approach eliminates the oversegmentation problem.
The 3D watershed segmentation algorithm computes border between the colon and the soft
tissue using the gradient map (fig. 8) calculated as:
GMOD ( x , y , z) = I x2 + I y2 + I z2 (4)
where Ix, Iy and Iz are image gradients in x, y and z directions, respectively.

Thanks to these operations, the colon model, which is traced, reflects details very precisely
what we can observe in figure 6.
5. Calculation of navigation path

Fast and accurate navigation path generation is essential for efficient diagnosis using the VC
since it allows for simulation of the virtual camera movement inside the segmented
structure and the whole colon can be screened by the physician in a short time. The virtual
camera can be stopped if a suspicious image is discovered for more careful assessment.
Computation of the colon centerline is not a trivial process. The algorithm should require
only minimum operator intervention. Additionally, a centreline approximation of the centre
navigation path of the colon must be obtained in reasonable time with acceptable accuracy.
Time constraint is a very important factor to evaluate the algorithm especially in a clinical
practice.
5.1 State of the art

Centreline calculation methods can be subdivided into three categories since they are
mainly based on:
• manual extraction,
• topological thinning (e.g. Xie et al., 2003; Sadleir & Whelan, 2005),
• distance transform (e.g Vilanova et al., 1999).
Manual extraction requires manual identification of the centre of colon slices. It does not
guarantee that marked points lie in the centres of slices and that they are directly connected.
Furthermore, the allocation is difficult because the colon centreline is oriented in different
directions.
Methods based on topological thinning and distance transform are automatic usually. The
idea of topological thinning is based on peeling off the colon surface points using
morphological operations repeatedly until the centreline is obtained. Though the results of
this standard algorithm are well-defined they do not always lie in a proper place.
Additionally, the algorithm is extremely inefficient computationally. Therefore, other
methods were developed that use 3D topological thinning and graph search algorithm (Ge
et al. 1999), optimized 3D topological thinning using Look-up Table (Sadleir & Whelan,
2005), distance transform (Zhou & Toga 1999, Van Uitert and Bitter 2007), minimum energy
path (Deschamps and Cohen 2001) or Dijkstra’s shortest path algorithm (Bitter et al. 2000).
Some approaches rely on the use of the distance transform. In these methods, the centreline
is calculated as a maximum of binary mask representing colon after the distance
transformation.
Below an exemplary algorithm of the VC navigation path calculation is presented.
5.2 Exemplary algorithm based on distance transform

In this section we present the colon centreline calculation algorithm based on the distance
transform (Skalski et al., 2007b). As an input to the algorithm, the matrix with labelled
voxels (label L represents the colon) resulting from the segmentation process is used. The
author's algorithm of the colon centreline calculation consists of the steps presented in table 1.
• compute complement IL of the binary mask L (1 – colon, 0 – others)

• choose N, number of points that you want to generate inside the colon
• iter=0 (number of iteration)
• while (iter < N+1) do:
- iter++
- compute distance transform on IL
- find maximal value maxD of the distance transform
- save location of maxD, path (xiter,yiter,ziter)
- set sphere to IL (value=1; centre=(xiter,yiter,ziter); radius=maxD )
• end
as a result we receive points saved in the matrix path (3xNdim)
• sort the path:
- find a point which has a minimal value of z coordinate or mark a starting point;
replace the first point of the path with the starting point; mark this point
- for (i=1 to N-2) do:
- compute the distance between the last marked point path(i) and each other
not marked point:
- find minimal distance dj based on equation 4 and save its coordinates
(xj, yj, zj)
- replace path(i+1) and path(j)
- mark path(i+1)
- end
• compute interpolating cubic spline
Table 1. Navigation path calculation algorithm
Firstly, complement of the binary mask resulting from the segmentation process is done. It is
a preparation step for the distance transform calculation. The distance transform returns as a
result distance to the nearest voxel which belongs to the colon. In order to calculate the
distance, the Euclidian metric is usually used:
( xi − x j ) + ( yi − y j ) + ( zi − z j )
2 2 2
dij = . (5)
Maximum value maxD is taken from the resultant matrix. It is a point inside the colon in the
widest place. Then, spherical neighbourhood of this point is removed. It prevents
algorithms from finding next points very close to points found before. This process is
282 Colonoscopy
repeated in iterative manner. The points received in the previous step become knots of the
navigation path. Subsequently, points received from the algorithm are sorted. Finally, points
between knots are generated using b-spline cubic interpolation. Exemplary navigation path
is presented in figure 9.
Fig. 9. The colon after the segmentation process with a centreline, number of points N = 24
6. Visualisation
The final step in the Virtual Colonoscopy is the data visualization. There are two main
methods of 3D medical data visualization: indirect (surface rendering) and direct (volume
rendering) (Preim & Bartz, 2007). Both techniques can use fully programmable graphical
pipeline.
Surface rendering is one of the indirect methods. This technique produces surfaces in the
domain of the scalar quantity. Scalar values, contained in 3D medical data, represents tissue
properties, like radiodensity in Hounsfield scale or label mask that contains segmentation
results. Surface represents a specific scalar value, the so-called isosurface value. In fact, one
iso-surface describes only one scalar value. The interior of the object is not described –
surface is the boundary of the volume objects. Surface rendering method includes two
stages: generation of the 3D surface from 3D data and proper visualisation relying on the
image generation by graphics accelerator. There are numerous methods for implementing
the surfaces from a discrete set of 3D data (Preim & Bartz, 2007). One of the most useful is
the Marching Cubes algorithm (Lorensen & Cline, 1987). This algorithm has many
implementations that solve the problem of ambiguities in first cell triangulation method
(holes in surface). Possibly the widely used implementation of the Marching Cubes
algorithm comes from The Visualization Toolkit (Schroeder et al., 2004). In the algorithm a
polygonal mesh of the isosurface is generated from the 3D scalar field. The polygonal mesh
is a collection of vertices (points in 3D) connected to triangles. For high resolution data sets
the number of generated graphical primitives can be extremely high. To reduce the number
of triangles, the mesh can be decimated or smoothed (Schroeder et al., 1992 and 2004).
Surface can be coloured according to the isosurface value or to another scalar field using a
texture mapping technique. To increase the perception of the surface shape in the VC
visualization, the virtual lighting is used. The standard model in the OpenGL Application
Programming Interface is Phong illumination model (Phong, 1975). This is an empirical
model of local illumination. It describes the way a surface reflects the light as a combination
of the diffuse reflection of rough surfaces with the specular reflection of shiny surfaces.
Phong shading includes a model for the reflection of light from surfaces and a compatible
method of estimating pixel colours by interpolating surface normals across rasterized
polygons. In fact, at each point of the screen full Phong model calculations are performed
(per-pixel lighting). Since the interpolation of surface normals is computationally expensive,
the Phong shading is slow. In Gouraud shading algorithm the calculating lighting is
performed only in vertex. Next, the screen pixel colour on the triangle are bilinearly
interpolated from the vertex colour. This method is fast, but the specular highlight will not
be rendered correctly if a highlight lies in the middle of a polygon. This limitation can be
solved by increasing a number of triangles by mesh tessellation or by increasing of spatial
data resolution. The polygonal data can be efficiently processed in modern graphics card.
All shading calculations are done in hardware.
Volume rendering is the process of creating a 2D image directly from 3D volumetric data
that operates on the actual data sample without creation of intermediate surfaces consisting
of triangles (Preim & Bartz, 2007). The purpose of volume rendering is to effectively convey
information present within the volumetric data. It is especially important in case of medical
data. All direct volume rendering algorithms can be classified into two main groups: object-
space and image-space methods. However, many advanced algorithms cannot by easily
classified as one or the other, but fuse aspects from both groups into one hybrid algorithm.
Object-space volume rendering techniques use forward mapping scheme where the data is
mapped onto the image plane. One of such approach is the Splatting algorithm that projects
the data voxels onto image-plane (Westover, 1989). Texture-mapping algorithms are the
other widely used object-oriented algorithms. They are supported by computer graphics
hardware. In image-order (image-space) algorithms, a backward mapping scheme is used
where rays are cast from each pixel in the image plane through the volume data to
determine the final pixel colour. The classic direct volume rendering method is the image-
space oriented ray casting algorithm. Moreover, some algorithms use domain-base
techniques – the spatial volume data is first transformed into an alternative domain, such as
frequency or wavelet, and then a projection is generated directly from this domain
(Malzbender, 1993).
Modern graphics cards are characterized by immense ability of 3D data processing. They are
developed and optimized for processing triangle meshes, which are used for surface
rendering. Furthermore, a fully programmable graphics processing unit (GPU) offer new
opportunities to use graphics cards for general purpose computing, especially for volume
rendering. Ray-casting volume rendering using CPUs is computationally expensive since it
requires the interpolation and shading calculations for every sample point along the ray in
the data. Interactive volume ray casting was previously restricted to high-end workstations.
GPU implementations of ray-casting rendering approaches have received great attention
since they enable interactive visualization of volumetric data (Lee et al., 2009).
The most important in virtual colonoscopy visualization is trustworthy surface presentation.
In figure 10, examples of applying different rendering methods are shown. The fastest
method in interactive visualization is the surface rendering. Unfortunately, the triangle
284 Colonoscopy
structure of reconstructed surface has an influence on image quality. The colour

interpolation (diamond artefact) are visible. Surface in image generated by the direct volume
visualization has better quality (fig. 10 b-d). The shape of wrinkles is kept. However, the
computational cost is considerably larger. The texture-mapping technique, supported by the
GPU acceleration, can be used in interactive visualization. Unfortunately, this method
generates images which contain staircase artefacts caused by interpolation and insufficient
depth sampling (fig. 10.d).
To extend the field of view in virtual colonoscopy the multi-cameras are used, especially for
visual inspection of the colon wall (Serlie I. et al. 2001). The six cameras are located in the
same place, but the view directions are different. They are rotated around, to cover 360
degree of view. Each camera has the 90 degree field of view. Images of this cameras can be
mapped into the unrolled-box surface. The sample of this technique is shown in the figure
11. Additionally, the light source moves along with the camera and the position of light
source is the same as camera position. The light is configured as positional (headlight), and
the cone angle corresponds to camera cone angle. To prevent overexposing nearest surfaces,
the irregular light intensity along the cone angle was used. Light fading attenuation was
used for distance simulation.
Comparison between real colonoscopic image and virtual one is presented in figure 12.
Fig. 10. Exemplary virtual colonography images: a) surface rendering, b) volume rendering
by ray-casting, c) isosurface in volume rendering (ray-casting) and d) texture-mapping
volume rendering
Fig. 11. Extended field of view in virtual colonoscopy by using six cameras: a) surface
rendering and b) surface mesh visualization
286 Colonoscopy
(a) (b)
Fig. 12. a) real endoscopic image, b) virtual colonoscopy image (Bulat et al., 2007).
7. Conclusion
In this chapter virtual colonoscopy has been presented from the point of view of
computational sciences. Problems present in the VC software realization have been pointed
out and their existing solutions have been cited. For clearity of presentation, to help a reader
to understand merits of technical issues associated with the VC, simple examples of
computer algorithms have been given, mainly developed by the authors of the chapter.
Special attention has been paid to the following technical aspects: electronic colon cleansing,
colon lumen segmentation, navigation path calculation and modern 3D visualisation.
8. References
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algorithm, Proceedings of IEEE Visualization 2000, ISBN 0-7803-6478-3, Salt Lake
City, UT, USA, October 2000.
Bulat J., et al. (2007). Data Processing Tasks in Wireless GI Endoscopy: Image-Based Capsule
Localization & Navigation and Video Compression. 29th Annual International
Conference of the IEEE Engineering in Medicine and Biology Society, 2007. EMBS 2007.
ISBN 978-1-4244-0787-3, pp. 2815 - 2818, Lyon, France, August 2007.
Cai W., et al. (2010). Mosaic decomposition: An Electronic cleansing method for
inhomogeneously tagged regions in noncathartic CT colonography. IEEE
Transaction on Medical Imaging, Vol. 30, No. 3, (March 2011), pp. 559-574, ISSN 0278-
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18
Robotic Colonoscopy
Felice Cosentino1, Emanuele Tumino2, Giovanni Rubis Passoni3,
Antonella Rigante1, Roberta Barbera1,
Antonella Tauro1 and Philipp Emanuel Cosentino4
1San Giuseppe Hospital, Milan
2Pisana University Hospital, Pisa
3San Carlo Borromeo Hospital
4Veterinary Medicine,
University of Milan
Italy
1. Introduction
This chapter is focused on emerging robotic techniques for improving conventional
colonoscopy.
Video-colonoscopy is considered the gold-standard for the diagnosis of colonic diseases,
and it is included as first line choice in colon-rectum cancer screening program in high-risk
populations. However, this diagnostic technique shows some technical limitations, such as
invasiveness and patient discomfort, which limit the adherence to the procedure.
To facilitate the conventional colonoscopy procedure, robotic colonoscopy solutions have
been proposed. State of the art of robotic colonoscopy has been thus summarized. In details,
Endotics System and Invendoscope are presented.
The Endotics System is composed of a disposable probe and a workstation. The probe has a
steerable tip, a flexible body and a thin tail. The head hosts both a vision system and
channels for water jet and air in order to provide rinsing and suction/insufflation,
respectively. The workstation allows the endoscopist to fully control the disposable probe
by means of a hand-held console and to visualize on a screen real time images. The operator
can steer the head of the robotic colonoscope in every direction, elongate the body of the
probe in order to move it forward following the shape of the intestine, and control rinsing,
insufflation and suction. This technology thanks its extremely flexible and disposable probe
is highly safe and painless (Cosentino et Al, 2009).
The Invendoscope, a single-use, combines a flexible endoscope and the proprietary “inverted
sleeve” technology that enables a potentially safe and sedactionless colonoscopy. The
instrument is steered by a hand-held device and propelled by a motorized drive unit.
Limitations and advantages of the two devices are reported compared to conventional
colonoscopy. In the last part of the chapter are presented data of pilot studies both in
healthy volunteers and patients in terms of technical aspects (cecal intubation, pain score,
sedation) and clinical results (lesions detection).
292 Colonoscopy
2. Why and how robotic systems in colonoscopy?

The first colonoscopy procedures go back to the 1960’s, when in Japan a device for the
examination of the left colon was developed (Niwa et Al, 1969). In the 1970’s further
progresses were made, and colonoscopy devices able to explore the whole colon were
available (Classen et Al., 2010).
Since then, research efforts were focused towards improvements of the vision system, of the
degrees of flexibility and of the localization systems. Nevertheless, the main characteristics
of the devices, based on a CCD camera or a fiber optic camera on a flexible tube passed
through the anus, remained unchanged till the 1990’s. In those years, robotic technologies
grew up enough to allow an increasing number of robots to be realized and used in various
fields of medicine. The main reasons for including colonoscopy were to try to overcome the
existing limitations of the standard devices, quite rigid, requiring high experience of the
doctor to perform difficult maneuvers to proceed along the tortuous colon walls, and
constructed of materials that could be damaged by heat, pressure, and moisture used during
the decontamination processes. (Sturges & Laowattana, 1993) The stated above limitations
made, and still make, standard colonoscopy a quite invasive technique, with risks related to
perforation, sedation and cross-infections, far for being accepted by massive percentages of
patients as needed in colorectal cancer screening programs. Screening as a matter of fact can
find non-cancerous colorectal polyps and remove them before they become cancerous. If
colorectal cancer does occur, early detection and treatment dramatically increase chances of
survival. The relative 5-year survival rate for colorectal cancer when diagnosed at an early
stage before it has spread is about 90%, but since screening rates are low, less than 40% of
colorectal cancers are found early. Once the cancer has spread to nearby organs or lymph
nodes, the 5-year relative survival rate goes down, and if cancer has spread to distant organs
(like the liver or lung) the rate is about 11%, and as many as 60% of deaths from colorectal
cancer could be prevented if everyone age 50 and older were screened regularly.
Moreover, painless colonoscopy, besides being a remarkable achievement for the patient,
and avoiding any risk related to sedation, has major fallout in terms of prevention. As
matter of fact, colonoscopy could be largely used for screening purposes of healthy and
asymptomatic patients, less willing to feel pain because of an invasive procedure.
Nowadays, colonoscopy is used as screening test just in first-level demonstrative studies
and pilot projects. One of the main limitations to use this survey as primary screening,
besides the feasibility related to allocation of facilities and complications rates, is the
acceptance of the procedure. Participation in the first-level FOB (faecal occult blood)
screening test is always above 50% (Faivre et Al., 2004), while the few available data in
literature about compliance to colonoscopy as primary screening is in a range from 15% to
90% (Swaroop et Al., 2002). Compliance for second level screening programs, which in
principle should be very high since this second examination takes place after positive results
of the first one, is in a range from 30 to 60%, as reported in a study of from AIGO - Oncology
Group Study.
For the above listed reasons, it appears clear how big can be the impact, in terms of survival
rate, of new devices able to perform painless and safe diagnostic colonoscopic procedures.
Thus robotics, as a science that tries to find and develop methodologies that enable
machines to perform specific tasks, could make the difference in developing endoscopes that
pulled themselves, with no risk for stretching the colonic wall outward and causing painful
Robotic Colonoscopy 293
cramps. The main challenge to building such devices involved clutching onto the slippery
walls of the colon in a way that did not damage them. The new endoscopes had to be
disposable, highly flexible, with a particularly suited internal locomotion, and with a direct
vision of the colon tissue, to solve acceptance problems and maintain quality of gold
standard.
2.1 Robotic colonoscopy: state of the art

As for robotic colonoscopy, first studies go back to 1995, with the locomotion system "inch-
worm". Subsequently, a lot of research work was carried out aiming at devising several
robotic colonoscopes based on different types of locomotion such as “snake”, “earthworm”,
“continuum” and “caterpillar”, or other different concepts.
The Inchworm robots were inspired to the caterpillar Geometridae, whose mode of
locomotion is to firmly attach the rear portion of its body to a surface via its foot pads,
extending the remainder of its body forward, attaching it to the surface and bridging the
rear part of its body to meet the forward part. On this principle is based the Endotics
system. (Slatkin et Al., 1995)
The Endotics System is composed of a sterile, disposable probe and a workstation. The
probe has a head, a steerable tip and a flexible body. The head hosts both a vision system
and channels for water jet and air. The locomotion is achieved by two clampers that are
located in the proximal and distal part of the probe. The proximal clamper adheres to the
mucosa and the central part of the body is elongated; the distal clamper adheres to the
mucosa and the proximal clamper is released; the central part of the body is contracted so
that the proximal clamper may adhere to the mucosa; and finally, the distal clamp is
released. The sequence is repeated several times allowing the probe to move in a worm-like
fashion. (Perri et Al., 2010)
Fig. 1. Endotics Workstation and disposable probe

294 Colonoscopy
The Snake robots took inspiration from the sinuous movement of the snake, based on the
temporal shifting of positions and angles of subsequent parts of its body. Movements starts
from the head that, bending and moving forward, is able to avoid obstacles. In robotics, this
is translated in devices with a finite number of independent segments where, during the
progress, the position and the angle of the distal part is encoded by an algorithm and then
associated with the next segment. All segments are associated with the same geometrical
parameters of the previous segment. NES, the NeoGuide System is based on this principle of
functioning.
The NeoGuide Endoscopy System (NES) has many features in common with standard
colonoscopes. In addition to these, there is a “tip position sensor” that continually records
the tip−steering commands of the endoscopist, and an external position sensor placed at the
anus that records the insertion depth of the colonoscope. The scope also contains additional
control elements in multiple segments following the tip of the scope. Each segment is the
same basic length as the tip segment itself, and the orientation of each segment is separately
controlled by the system’s computer. The NES combines data on the depth of insertion of
the scope and the orientation of the tip at each depth, to actively articulate each segment so
that the scope follows the natural shape of the colon. The insertion tube is advanced
manually into the colon and has a conventional CCD for visualization. The device includes a
handle air insufflation7suction and rinsing systems similar to conventional scopes. (Eickhoff
et Al. 2006)
Fig. 2. NeoGuide Endoscopic device

Peristalsis motion like an earthworm has attracted attention because the movement is useful
to progress in small spaces (Saito et Al., 2009). The Earthworm robots were based on the
earthworm’s locomotion, thus moving not only changing length, but also changing
thickness (Zuo et Al., 2005). The Continuum robots worked according to the moving
principle of the elephant trunk or the tongue, i.e. structures without rigid constraints able to
perform complex movements (Hu et Al., 2009). Finally, the Caterpillar robots were
characterized by wheels and caterpillar tracks and their locomotion was similar to a tank.
Other technique of locomotion not based on bio-mimicking, but having relations with
robotics in terms of sensors or automated movements have been developed (Swain, 2009).
The Aer-O-Scope system, is a disposable, self-propelling, self-navigating, endoscope
incorporating a CMOS camera with “omni-directional viewing system”.
A rectal introducer, consisting of a hollow tube with a stationary balloon attached to its
outer surface, is inserted through the anus and, when the stationary balloon is inflated, seals
the orifice. An electro-optical capsule is embedded in the front of a lightweight balloon
vehicle, while low pressure colon insufflation with CO2, between stationary and vehicle
balloon, propels the vehicle balloon, causing it to glide along the ‘slippery' colon walls.
Computer controlled pressure management, coupled with sensors in the workstation, adjust
balloon size and shape to changing bowel anatomy, thus allowing the pressure-propelled
balloon to find its path. The Aer-O-Scope visual system provides simultaneous 360 degree
viewing of the colon mucosal surface. (Pfeffer et Al., 2006)
Fig. 3. Aer-O-scope disposable device

The ColonoSight system uses air pressure assisted pull technology to pull the scope into the
colon. A disposable device consisting of a plastic sleeve, wrapped on a loader, is unfolded
gradually through insufflation of air. The forward force of the device is generated by a
pneumatic mechanism just below the tip of the scope. This force draws the scope in, and the
operator then navigates with the handles, drastically reducing the need to push from the
back. Aside from making the procedure safer, it also reduces the amount of local anesthetic
required. (Shike et Al. 2005)
Fig. 4. The ColonoSight system and scheme of working principle

The InvendoScope system is a single-use, hand-held controlled computer-assisted
colonoscope. A sleeve is pulled over this inner sheath, inverted at each of the respective
ends, and attached to a propulsion connector. The outer wall of the sheath is motionless and
the intubation is achieved by the eversion of an inner portion of the sleeve which carries the
296 Colonoscopy
optical system and the instrument channel. The physician controls the device by activating
the “Forward drive” and the “Backward drive” keys on the handheld control unit. By
manipulating the joystick of the hand control unit the physician can electro-hydraulically
deflect the endoscope tip, steering the colonoscope during the drive through the colon
(Waye et Al., 2009).
Fig. 4. Invendoscope workstation and disposable probe

The above stated overview of the state of the art of robotic devices developed for colonoscopy
procedures shows that the main priority was to realize a system with an internal locomotion
action, able to advance in a hostile environment. The movement of the device is always under
computer control by means of mechanical, electrical, or computer-algorithm based sensors.
Moreover, the robotic colonoscopes generally include the following sub-systems:
• A probe, with at least a disposable part (the one in contact with the colonic mucosa);
• A vision system located at the tip of the device;
• A PC-based workstation or a hand-held unit which controls the propulsion of the probe
in the colon.
Some of the characteristics of the above listed sub-systems, as well as other aspects related to
personnel and sedation during the procedures have of course an impact on the cost saving
issue. Moreover, also the related timings have to be considered, including e.g. the
preparation which non-disposable devices have to undergo to prevent from cross-infections,
the duration of the procedures themselves, the gaining of time in the turn-over of patients
and the recovery time for the patients to go back to work.
Even if several robotic colonoscopes have been tested in vitro and seemed to be ready to be
used in pilot studies on human beings, very few completed the engineering phase and went
through the certification steps, and only one became available off-the-shelf as a real
product. In particular, in the following further details will be presented on the Endotics
System, whose core component is a disposable probe with inchworm locomotion, currently
used in clinical practice in a few hospitals, and on the Invendoscope, based on inverted
sleeve technology, not yet commercially available, but with most recent news than others.
Fig. 5. Colonoscopy innovation history diagram
PRODUCT LATEST COMMERCIALLY

LATEST EVENT
NAME PUBLICATION AVAILABLE
Transformed in
Neoguide 2006 No
laparoscopic device
Aer-o-Scope 2007 DDW 2007 No
Colonosight 2007 Closed business 2008 No
Endotics 2011 Fismad 2011 Yes
Invendoscope 2011 - No
Table 1. Publication & event blatancy
298 Colonoscopy
INITIAL
PRODUCT DEVELOPER/ DEVELOPMENT
NATIONALITY COMMERCIAL
NAME COMPANY NAME STATUS
FOCUS
NeoGuide Systems
Neoguide USA Abandoned * n.a
Inc
Almost
Aer-o-Scope GI View Ltd Israel n.a.
abandoned *
Sightline Almost
Colonosight Israel n.a.
Technologies Ltd abandoned *
Off the shelf
Endotics Era Endoscopy Srl Italy Europe
product
Filed 510(K) notice
invendo medical submission with
Invendoscope Germany USA
GmbH the FDA
(08/03/2010)
Table 2. Commercial information * (Ell, 2008)
2.2 The endotics system

The excessive stretching of bowel and mesenteries and the air insufflation are the main reasons
of the pain felt by the patient during this uncomfortable procedure. In order to avoid
perforation risks, addressed both to pushing action exerted by the endoscopist during the
intubation phase and to the rigidity in the pushing direction of the traditional colonoscope, it is
essential to realize a system with an internal locomotion action, able to advance in a hostile
environment. The ideal screening investigation should be as non invasive as possible and safe
while maintaining a high diagnostic accuracy. Thus, a device extremely flexible and soft,
which gently deforms just locally the colon tissue, represents the optimal solution.
The innovative systems require a lower amount of insufflations and do not stress on
mesenteries resulting in a real painless colonoscopy. Moreover, infective risks, due to
sterilization procedure’s limits, are definitively eliminated by disposable endoscopes.
From a technical point of view, the simplest inchworm device consists of two clampers at
the ends, used to adhere securely onto the “terrain”, and one extensor as its midsection that
brings about a positive displacement. The device of the robot was focused towards a
disposable device, totally pneumatically driven, and very soft and flexible, able to adapt its
shape to the configuration of the bowel. The probe is composed of two main parts: an active
one, including the head, the steering and the flexible extensible body, and the passive
components of the devise including the tail and the tank containing eventual body fluids,
and the connector used to fix the disposable probe to the workstation. The overall
dimensions of the active part are: a diameter of 17 mm and a variable length from 24 to 40
cm, considering the inchworm movements. The head hosts both a vision system, including a
CMOS camera and LED light sources, and channels for water jet and air in order to provide
rinsing and suction/insufflations, respectively. As the Endotics system requires air
insufflations only in the immediate proximity of the head lens, an accurate automatic
insufflations-suction balance prevents painful bowel stretching.
The passive component, a very thin and extremely flexible plastic tail, has a diameter of 7,5
mm and a length of 180 cm. The workstation allows the endoscopist to easily and fully
control the disposable probe by means of a hand-held console and to visualize on a screen
real time images. Thanks to the electro-pneumatic steerable tip, the operator can steer the
head of the robotic colonoscope of 180° in every direction, elongate the soft body of the
probe in order to move it forward and backward following the shape of the intestine, and
control rising, insufflations and suction.
The locomotion phase begins with the automatic adherence of the proximal clamper of the
probe to the colon walls. The next phases can be described as follows:
1. the midsection is elongated under control of the operator;
2. the distal clamper adheres to the colon walls (automatic);
3. the proximal clamper is released (automatic);
4. the midsection is contracted (automatic);
5. the proximal clamper adheres to the colon walls (automatic);
6. the distal clamp is released (automatic).
The purposely developed patented clamping system allows to hold the colonic tissue by
means of a combined vacuum-mechanical action. The clamping mechanism does not create
neither lesions in the bowel wall, nor mucosal lacerations.
Diagnostic accuracy and patient acceptance of robotic colonoscopy have been evaluated in a
first pilot multicentre study, in 40 consecutive volunteers (27 men and 13 women) who
underwent standard colonoscopy also. This pilot study showed that the Endotics System
has a diagnostic accuracy equivalent to the one achievable through the standard
colonoscope. Moreover, the Endotics System was able to visualize two small polyps (sized
below 2 mm), in two different cases, not seen using standard colonoscopy. This probably
due to the fact that during standard colonoscopy a bigger amount of air was insufflated
causing a flattening of the small polyps. Considering the patient acceptance issue, the
Endotics colonoscopy was unanimously rated strongly better than conventional
colonoscopy: in a scale from 0 to 10 for pain and discomfort the procedure performed by
means of the Endotics System scored on average 0.9 and 1.1 (mode 0 for both), compared to
6.9 and 6.8 (mode 9 and 8) of the standard colonoscopy, respectively. (Cosentino et Al., 2009)
Fig. 6. Workstation and disposable probe Endotics

300 Colonoscopy
Fig. 7. Hand-Held device and locomotion sequence of Endotics probe

In a second pilot study which involved 71 patients (40 men and 31 women), diagnostic
accuracy and enhanced patient acceptance of Endotics system compared with standard
colonoscopy, was confirmed showing a sensitivity equal to 93,3% (95% C.I.:68.0-99.0), a
specificity equal to 100% (95% C.I.:88.0-99.9), a predictive positive and negative values, PPV
and NPV respectively, equal to 100% and 97.7%. No patients requested sedation during the
Endotics procedure, while 14 subjects (19.7%) requested the administration of midazolam
and meperidine during standard colonoscopy. In this study has been used a slightly
different Endotics probe version from the one used in the previous pilot study (25 cm length
in the contracted form and 43 cm in the elongated form, with respect to 23 and 37 cm,
respectively, of the previous version) (Tumino et Al., 2010)
In a third study 12 patients with inflammatory bowel diseases were enrolled in order to
compare the diagnostic performance and tolerability of the Endotics System with standard
colonoscopy for the staging of ulcerative colitis. Mean pain/discomfort on a 0-10 scale was
2.08 (SD 1.67) for Endotics system and 4.17 (SD 1.74) for standard colonoscopy, with a
statistically significant difference (p = 0.066) favoring Endotics system.
In conclusion, the Endotics System is a diagnostic instrument comparable to the gold
standard and highly suitable for screening purposes due to the extremely high level of
patients acceptance. (Pallotta et Al., 2011)
2.3 The invendoscope

This computer-assisted colonoscope is based on inverted sleeve technology, where the outer
side of the inverted sleeve stays in position, and the inner side is pulled forward below the
distal tip, moving the colonoscope into the colon by 10 cm each time. Wheels are rolled on the
inner side of an inverted sleeve, so that the sleeve is rolled inside out, drawing the colonoscope
deeper into the colon. With this mechanism there is no relative movement to the colon wall,
and in combination with the small bending diameter minimizes the forces on the colon walls
and prevents looping, minimizing pain and discomfort for the patient. The device is equipped
with a centralized 3.2 mm working channel with the support of the deflectable
electrohydraulic tip; therefore it can be also used for routine therapeutic procedures such as
polypectomy. Both the vision capabilities and the working channels are similar to those of
conventional colonoscopes. All endoscopic activities are controlled by a hand-held unit.
First pilot study (Roesch et Al, 2007) was focused on capability of the device of reaching
cecum measuring time needed and pain/discomfort rate. Were enrolled 24 patients reaching
cecum in 79% of cases, with a mean time 26 minutes. Participants rated the examination on
an overall score (1.77 points; range, 1-3), using a self assessed pain scale (pain scale range
was from 1 = no discomfort to 6 = severe pain).
Fig. 8. Hand-Held device and the instrument tip in the driving unit.
Fig. 9. Disposable probe and scheme of working principle of Invendoscope system.

A second single-arm, pilot study (Invendoscope 1st) on 39 paid healthy volunteers was
carried out. Again, cecum reaching rate and time were the focus of study, with some
attention towards the patient acceptance. The cecal intubation rate was of 82% (95% C.I., 66-
92). Two incomplete colonoscopies had to be stopped at the sigmoid colon because of pain,
and in other four volunteers the procedure was terminated at the hepatic flexure. Bloating
was reported in four volunteers after that an endoscopy intravenous administration of 20 to
40 mg of hyoscine butylbromide was allowed to facilitate endoscope passage. It should be
noted that only limited time was spent on inspection of the mucosa while withdrawing the
instrument. The volunteer rating showed a mean score of 1.96 (range 1-6; 1 = no discomfort).
Study was divided into two phases. On the basis of experience during phase 1, the
instrument was made longer (from 170 to 180 or 200 cm) and a few other modifications (e.g.,
stiffening below the endoscope tip, improved coating) were also made to achieve better
performance in the right colon, however, a comparison between the two instruments was
302 Colonoscopy
not the main aim of the pilot study. To date, no data concerning diagnostic accuracy and
comparison with conventional colonoscopy are available.
Moreover, a third prospective single-arm study (Invendoscope 2nd) on 61 paid healthy
volunteers was conducted. There were 34 men and 27 women with a mean age of 57.5 years
(range 50 – 70) and a mean body mass index of 26.3 kg/ m 2 (19.5 – 36.8). Main outcome
parameters were safety, as measured by the frequency and severity of device related
adverse events, and device effectiveness, as shown by cecal intubation rate. Secondary
outcome parameters were utility of the device in the documentation and biopsy of
pathological findings, and pathological findings. Pain/discomfort rating and
introduction/withdrawal timing were also recorded. Comparison with standard
colonoscopy was not included in the parameters of the study. Cecal intubation was reached
in 60 volunteers (98,4%): introduction mean time was 16.4 min as also withdrawal mean
time. Abdominal compression and/or position change were used in approximately two-
thirds (66%) of the patients, to help in further advancing the scope. Sedation was used in
three participants (4.9%); the Propofol doses used were 120, 130, and 180 mg. The mean
ratings from the screenees, immediately after colonoscopy, for overall assessment and
pain/discomfort were 1.6 (range 1– 3) and 2.3 (range 1– 6). A rating of 6 was automatically
given immediately after the procedure in cases where sedation was used. CO 2 was used for
insufflation in all cases. Water immersion, administered via a foot pump, was used during
insertion at the discretion of the endoscopist. Follow-up at 24 h and 7 days was complete for
all the study participants. The mean overall ratings at 24 h and at 7 days were 1.4 and 1.3
(range 1–5). The mean pain/discomfort ratings at 24 h and at 7 days were 1.5 and 1.3 (range
1–6). Only three screenees had previous colonoscopy. (Groth et Al., 2011)
2.4 Endotics Vs Invendoscope: a data comparison coming from published results

Before to compare the two technologies it is mandatory to uniform data recovered from
studies:
• In the calculation of cecum reaching rate Endotics included procedures where device
had technical problems, while Invendoscope not. For the calculation, procedures with
technical failures are excluded also for Endotics.
• Both systems presented two models, where the second one was intended as a
ameliorative system. For the calculation of caecum reaching rate and time for both
devices is considered the second device
• According to observational studies (Rex et Al., 2002 - a) and as reported in guidelines
(National Guidelines Clearinghouse-NGC 4969, 2006) , cases in which procedures are
aborted because of poor preparation or severe colitis need not be counted in
determining cecal intubation rates. Thus, such procedure are not counted in the
presented data. Moreover, because of the protocol of third study afferent Endotics
system is focused on the assessment of ulcerative colitis endoscopic activity with
Endotics system, related data are not included in the comparison.
• Pain score is calculated on the basis of different ranges, from 0 to 10 for Endotics and
from 1 to 6 for Invendoscope. Pain score is indicated in the following table as
percentage of maximum value of the respective range. Moreover, should be noted that
Endotics system used air for insufflation, while Invendoscope, in the last paper,
described the use of advanced reduction discomfort techniques, such as CO2
insufflation instead of air and water immersion during insertion.
• For all devices, comprising standard colonoscope, “time to cecum” does not include the
time spent to carefully analyze the colonic mucosa with diagnostic purposes, except for
Endotics, that, due to its working principle, makes observations useful for diagnosis
while proceeding towards cecum. Thus, to make a consistent comparison, data related
to colonoscopy completion timing should be taken into account. As regards the
Endotics system, time to cecum and time to complete diagnosis is slightly different,
while for other colonoscopes that make diagnosis during withdrawal is substantially
different. According to ASGE guideline, physicians performing a colonoscopy should
have an average withdrawal time of six minutes or more for a thorough exam (ASGE-
Media Backgrounder, 2010). Moreover, colonoscopist with a low miss rate of lesions
have a mean withdrawal time of about nine minutes (Rex et Al., 2000) (Simmons et Al,
2006) (Barclay et Al., 2006) (Overholt et Al, 2010)
Endotics Invendoscope
Disposable Yes Yes
Tool channel No Yes
# Studies 3 3
# Patients enrolled 123 124
For the following data comparison, Tumino, Roesch and Groth papers are considered
Endotics Invendoscope 1st Invendoscope 2nd
Comparison with Standard
Yes No No
Colonoscopy
Asymptomatic volunteers No Yes Yes
Paid volunteers No Yes Yes
Mean Age 51.9 49.7 57.5
One to One procedure* Yes No No
Sedation (Propofol) 0% 0% 4.9%
Antispasmodic given 0% 79% Not mentioned
Insufflation of CO2 No No Yes
Water immersion technique No No Yes
Pain range 9% fs 32.6% fs 26.6% f.s.
Discomfort range 11% f.s. Not mentioned 38.3% f.s.
Abdominal compression 0% Occasionally 66%
Sensitivity 93.3% n.a.** n.a.**
Specificity 100% n.a.** n.a.**
NPV 97.7% n.a.** n.a.**
PPV 100% n.a.** n.a.**
Cecal intubation rate 93,6% 90% 98.4 %
Mean time to cecum (min) n.a. 23 16.4
Mean completion time procedure
45,3 n.a. 32.8
(min)
* One to one procedure is intended procedure conducted without any additional personnel
** Data are not applicable because they require a comparison with standard colonoscopy
Table 3. Data comparison: Endotics Vs Invendoscope
304 Colonoscopy
• Moreover it has to be considered that studies carried out with Endotics have eligibility
criteria that include mainly people with prior diagnosis of colorectal diseases (about
70% of patients in the second study) thus procedures’ timing should be compared with
a similar study population where completion of the procedure is reached in a mean
time of 33 min (range 10-80) (Rex. et Al. 2002 – b).
The problem with studies reporting a very high completion rate is that they are screening
endoscopies in asymptomatic individuals. These populations are different from normal
daily practice. Patients undergo colonoscopy for all kinds of clinical indications (Loffeld et
Al., 2009). For this reason it is very important, in order to fully understand carry out an
exhaustive comparative analysis a comparison between different clinical trials, to study also
eligibility and exclusion criteria adopted. The Endotics and Invendoscope systems are
described and compared with parameters advocated to predict a difficulty colonoscopic
procedure. Parameters are listed in table 3 (Anderson et Al., 2001). Sometimes difficulty’s
parameters could be described in different ways, e.g. “previously failed colonoscopies can
usually be characterized as an angulated sigmoid colon or redundant colon “ (Rex, 2008). In people
with high BMI, percentage of redundant colon is much higher than people with lower BMI,
whereas people with low BMI has probably very angulated bends.
Exclusion Criteria
Difficulty’s parameters Endotics Invendoscope 1st Invendoscope 2nd
Age > 50 No Not described No
History of abdominal surgery No Not described Yes
History of pelvic surgery No Not described Yes
History of diverticular disease No Not described Yes
Body mass index No Not described Yes
Inflammatory bowel disease Yes Not described Yes
Table 4. Difficulty’s parameters and exclusion criteria
3. Conclusion
In this chapter main reasons for including robotic colonoscopy in common practice of
colonoscopy screening have been considered. Standard devices are quite rigid, require high
experience of the doctor to perform difficult maneuvers to proceed along the tortuous colon
walls, and are constructed of materials that could be damaged by heat, pressure, and
moisture used during the decontamination processes. The stated above limitations, that
could be overcome with robotic colonoscopies, made, and still make, standard colonoscopy
a quite invasive technique, with risks related to perforation, sedation and cross-infections,
far for being accepted by massive percentages of patients as needed in colorectal cancer
screening programs. Nowadays, colonoscopy is used as a matter of fact as screening test just
in first-level demonstrative studies and pilot projects. Participation in the first-level FOB
(fecal occult blood) screening test is above 50%, and compliance for second level screening
programs, is very low compared to expected values, since it is in a range from 30 to 60%.
Other important issues that have to be taken into account are related to timing and
personnel. As a matter of fact, timing affects all the procedure phases, starting from the
preparation which not-disposable devices have to undergo to prevent from cross-infections,
and including the duration of the procedures themselves, the gaining of time in the turn-
over of patients and the recovery time for the patients to go back to work. As for the
personnel, both the number of operators needed and their specific competences.
A state of the art related to working principles of robotic devices have been described as
well as main robotic devices proposed for pilot studies. Among these devices two robotic
colonoscopes are deeply described and compared: Endotics System and Invendoscope. The
comparison included:
• If the device is disposable or not
• Age of the patients and if they are asymptomatic and/or paid
• Presence of tool channel
• Number of studies, with related number of patients enrolled
• Comparison with standard colonoscopy, in terms of pain range, sensitivity, specificity,
NPV and PPV
• Sedation or antispasmodic administration
• Procedure details, such as cecal intubation rate and timing, abdominal compression
maneuvers
An additional table related to the difficulty’s parameters in colonoscopy and exclusion
criteria adopted in clinical trials has been filled. In this table parameters related to the age of
patients, their surgical and/or colonic disease history, and their BMI are considered.
Endotics system appears to be a promising diagnostic instrument comparable to the gold
standard and highly suitable for screening purposes due to the extremely high level of
patients’ acceptance even without the adoption of advanced discomfort reducing techniques
like CO2 insufflation and water immersion during insertion.
The introduction of this diagnostic instrument in clinical practice could facilitate the
adoption of colonoscopy as first-level screening, with a further reduction in the incidence of
the colon cancer, estimated in the order of 76-90%. In conclusion a painless colonoscopy,
besides being a remarkable achievement for the patient and avoiding any risk related to
sedation, has major fallout in terms of prevention.
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19
Experimental Small Animal Colonoscopy

Terrah J. Paul Olson and Richard B. Halberg
University of Wisconsin-Madison
United States of America
1. Introduction
Diseases of the colon and rectum produce a large burden of morbidity and mortality.
Inflammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis, affects as
many as 1.4 million people in the United States and 2.2 million people in Europe and leads
to significant utilization of healthcare resources (Loftus, 2004). Crohn’s disease (CD) is a
chronic inflammatory disease that can affect the entire gastrointestinal tract from mouth to
anus, and typically manifests itself with abdominal pain, diarrhea, and weight loss, as well
as intestinal strictures, obstruction, perforation, or fistulae formation. CD most often
manifests in the second to third decade of life. The usual disease course is periods of
abdominal pain and diarrhea alternating with relatively asymptomatic periods. Over time,
the symptomatic periods become longer, more frequent, and more severe. Ulcerative colitis
(UC) is limited to the colon and occasionally the terminal ileum, and typically presents with
diarrhea, passage of mucus, and rectal bleeding. UC is also most commonly diagnosed in
patients younger than 30 years of age. IBD and colorectal cancer (CRC) are intimately
linked, as long-standing IBD leads to an increasing risk for CRC over time. In patients with
UC, the risk for CRC begins to increase after approximately 10 years of disease. The
estimated risk of CRC is 25% after 25 years with the disease, 35% at 30 years, 45% at 35
years, and 65% at 40 years (reviewed in Townsend, 2008).
CRC is the third most commonly diagnosed cancer and the third-leading cause of cancer-
related death in the United States in both men and women (American Cancer Society, 2011).
In 2010, the American Cancer Society estimated that there were 142,579 new cases of CRC
and 51,370 deaths attributed to this disease in the US (National Cancer Institute, 2011). The
incidence of CRC is rising in many countries, in part because a western-style diet is being
widely adopted (Center et al., 2009). CRC is currently the fourth leading cause of cancer
deaths in the world (World Health Organization, 2011).
IBD and CRC are active areas of research, and a number of useful animal models of these
diseases have been generated. Some of the most widely studied are rodent models,
including various rat and mouse models. Mouse models are particularly attractive. Mouse
genetics have been extensively studied, and there is a detailed knowledge base describing
hundreds of inbred mouse strains as well as a variety of transgenic, knockout, and knockin
models (reviewed in Rosenberg et al., 2009). Both genetic and chemically induced models of
IBD and CRC have been validated (reviewed in Kanneganti et al., 2011; Rosenberg et al.,
2009). These models are continually used to more fully understand the natural history of
colonic diseases as well as test strategies for prevention and treatment. See Table 1 for an
overview of genetic and chemically induced mouse models of IBD and CRC.
310 Colonoscopy
Models of Inflammatory Bowel Disease

Genetic
Human
Model Mechanism Phenotype
Disease
SAMP-Yit CD High IFN-γ production Spontaneous terminal
ileitis, occasional
perianal ulcers and
fistulae
C3H/HejBir UC Increased IFN-γ and IL-2 Spontaneous ileocecal
production and right-sided colonic
ulcers and crypt
abscesses
TNFΔARE/TNF 3’ UTR-/- CD Increased constitutive Polyarthritis and
and inducible TNF transmural intestinal
inflammation
T-cell receptor-α-/- UC Increased aberrant TH2- Pancolitis with soft
type T-cells producing stools
IL-4
STAT4 transgenic UC Overproduction of Severe transmural colitis
STAT-4, leading to CD4+
T-cell production of
TNF-α and IFN-γ
STAT3 deficient CD Disruption of STAT3 in Enterocolitis with high
macrophages and incidence of colorectal
neutrophils, decreased adenocarcinomas
IL-10
IL-10-/-/CRF2-4 deficient CD Decreased IL-10 with Chronic enterocolitis
increased IL-12 and TNF- with lesions in
α, loss of downregulation duodenum, proximal
of TH1-type T cells, NK jejunum, and ascending
cells, macrophages colon primarily
IL-2 -/-/IL-2 receptor α-/- UC Decreased IL-2 (key Pancolitis with ulcers
regulatory immune and wall thickening,
cytokine) crypt abscesses, mucin
depletion, and epithelial
dysplasia
IL-7 transgenic UC Initial IL-7 increase, then Initial acute colitis,
IL-7 deficiency followed by chronic
colitis with proctoptosis
and anal bleeding
CD4 CD45RB T-cell
+ Hi UC Decreased IL-10, Diarrhea, weight loss,
transfer increased IFN-γ transmural colonic
inflammation, and death
Heat shock protein 60- CD Presentation of bacterial Severe small intestinal
specific CD8+ T-cell protein on MHC class 1 inflammation, death
transfer with action of TNF-α
Experimental Small Animal Colonoscopy 311
Human
Disease
A20 deficient CD Lack of inhibition of Intestinal inflammation,
TNF-induced NFκB cachexia, death
activity
IKK-γ (NEMO)/IKKαβ UC Complete shutdown of Severe chronic pancolitis
deficient NFκB signaling, leading
to massive inflammatory
cell infiltration
MDR1 deficient UC Spontaneous Intestinal inflammation
inflammatory response
triggered by intestinal
bacterial flora
Keratin 8-/- UC Primary intestinal Colitis and colonic
epithelial cell defect hyperplasia
leading to inflammation
from intestinal bacterial
flora
Double negative IBD Disrupted intestinal Chronic inflammation in
N-cadherin mucosal barrier leading chimeric regions of
transgenic/chimeric to inflammation from intestinal epithelium
contact with intestinal
bacterial flora
Chemical
Human
Disease
Acetic acid UC Enema; epithelial Epithelial necrosis and
inflammation and edema extending from
damage lamina propria to as deep
as muscularis layer
Iodoacetamide UC Enema; sulfhydryl Diarrhea, dilation,
blocker that decreased adhesions, mucosal
amount/action of erosions to deep
protective sulfhydryl ulcerations, inhibited
groups weight gain
Indomethacin CD In diet; inhibition of Ulceration and
protective prostaglandin transmural inflammation
synthesis (PGE1, PGE2, of mid-small intestine
prostacyclin)
Trinitrobenzene sulfonic UC Enema; haptenization of Acute and chronic colitis
acid (TNBS) colonic autologous or
microbial proteins
making them
immunogenic – delayed
hypersensitivity
response
312 Colonoscopy
Human
Disease
Oxazolone UC Enema; haptenization of Distal colitis
colonic autologous or
microbial proteins
making them
immunogenic – delayed
hypersensitivity
response
Dextran sodium sulfate UC Drinking water; directly Colitis with bloody
(DSS) toxic to epithelial cells in diarrhea, ulcerations,
basal crypts granulocytic infiltration,
weight loss, shortening of
intestines
Models of Colorectal Cancer
Genetic
Human
Disease
ApcMin/+ mutations FAP Truncating mutations of Multiple small intestinal
Apc (codons 850, 716, adenomas
1638, and others)
Mismatch repair gene HNPCC Mutations in various Adenomas and
mutations (Msh2, Msh3, mismatch repair genes adenocarcinomas of
Msh6, Mlh1, Mlh3) entire GI tract, some
mutations prone to
lymphomas, squamous
or basal cell carcinomas
β-catenin stabilizing FAP Stabilization of β-catenin Hundreds of small
mutations leading to activation of c- intestinal adenomas
Myc and cyclin D
Smad3-/- CRC Loss of cellular signaling CRC with occasional
protein in TGF-β metastasizes to regional
pathway lymph nodes
K-rasV12G CRC Activation of mutated K- Colorectal tumors
ras ranging from
microadenomas to
invasive
adenocarcinomas
without metastasis
Muc2-/- IBD- Mutation of Muc2, which Adenomas and
related controls gastrointestinal adenocarcinomas in the
CRC mucin intestines without
distant metastasis, rectal
cancers
IL-2-/-/ UC- Chronic inflammation Adenocarcinoma of
β2-microglobulin-/- related from decreased IL-2 and colon and rectum
CRC β2-microglobulin
Human
Disease
IL-10-/- CD- Chronic inflammation Adenocarcinomas
related with decreased IL-10 in without metastasis or
CRC setting of colonic mutations in K-ras, p53,
bacterial infection Apc, and Msh genes
RAG2-/- Inflam- Induced with Helicobacter Intestinal dysplasia,
mation- hepaticus infection tubular adenomas,
related and adenocarcinomas
CRC of cecum and colon
RAG2-/-/Tgfβ1-/- Colitis- Downregulation of TGF- Locally invasive
related β signaling pathway adenocarcinomas in
CRC cecum and colon
TCRβ-/-/p53-/- UC- Dysregulation of T-cell Dysplasia and
related function with lack of p53 adenocarcinoma of
CRC tumor suppression ileum and cecum
Gpx1-/-/Gpx2-/- Ileo- Loss of glutathione Dysplasia,
colitis- peroxidase 1 and 2 adenocarcinomas, signet
related leading to peroxidative ring cell carcinoma seen
CRC stress with in ileum and colon
bacteria-associated
inflammation
Gαi2-/- UC- Loss of G protein Colonic ulcerations,
related function atypical colonic glands
CRC
Conditional Apc-/- Meta- Floxed Apc mutation Invasive colorectal
static activated by adenovirus- cancers with metastases
CRC delivered cre to liver
recombinase
Xenografts Meta- Implantation of human Invasive CRC with
static CRC tumor cells in metastases
CRC immunocompromised
mice
Chemical
Human
Model Mechanism Disease/Pathology
Disease
1,2-dimethylhydrazine CRC Intraperitoneal injection; Distal colon tumors
(DMH)/ procarcinogens
Azoxymethane activated to DNA-reactive
(AOM)/methyl- products which alkylate
azoxymethanol (MAM) molecules in liver and
colon
Heterocyclic amines CRC In diet; mutagenic and Colon cancers,
(PhIP, IQ, etc.) tumorigenic agents in mammary tumors,
broiled food prostate tumors
314 Colonoscopy
Human
Disease
Aromatic amines (DMAB) CRC Subcutaneous injection; Adenomas, invasive
tumorigenic agent adenocarcinomas of
colon and mammary
glands, salivary gland
sarcomas, skin and ear
squamous cell
carcinomas, stomach
squamous cell
papillomas,
sarcomas/lymphomas/
urothelial carcinomas of
bladder
Alkylnitrosamides CRC Enema; direct alkylating Sessile and polypoid
(MNNG, MNU) agent adenomas and
adenocarcinomas, rare
metastases
Table 1. Mouse models of inflammatory bowel disease (IBD) and colorectal cancer (CRC).
This table provides a summary of currently utilized mouse models of IBD and CRC. In
addition to these singly listed models, various models are often combined, e.g. DSS and
AOM or DSS in ApcMin/+ mice. (Reviewed in Hung, 2010; Jurjus et al., 2004; Kanneganti et
al., 2011; McCart et al., 2008; Rosenberg et al., 2009; Taketo, 2006; Taketo & Edelmann, 2009;
Wirtz & Neurath, 2007)
Abbreviations: CD: Crohn’s disease; IFN: interferon; UC: ulcerative colitis; IL: interleukin;
TNF: tumor necrosis factor; UTR: untranslated region; STAT: signal transducer and
activating transcription; MHC: major histocompatibility complex; IBD: inflammatory bowel
disease; Apc: Adenomatous polyposis coli; Min: Multiple intestinal neoplasia; FAP: familial
adenomatous polyposis; HNPCC: hereditary nonpolyposis colon cancer; CRC: colorectal
cancer; TGF: transforming growth factor; PhIP: 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine; IQ: 2-amino-33-methylimidazo[4,5-f]quinoline; DMAB: 3,2’-dimethyl-4-
aminobiphenyl; MNNG: N-methyl-N’-nitro-N-nitrosoguanidine; MNU: methylnitrosourea
Although murine models of colonic diseases are powerful, one limitation has been the large
number of animals needed to complete an adequately powered study. Traditionally,
experiments had a cross-sectional design in which mice from different groups were
sacrificed at a set point in time, and the intestinal tract was examined at necropsy. This
limitation has been overcome with recent advances in technology. A variety of imaging
tools have been developed, allowing longitudinal assessment of the large intestine in
animal models. Currently utilized methods include computed tomography (CT), magnetic
resonance imaging (MRI), and direct visualization with colonoscopy. The ability to
serially assess changes in the large intestine allows more detailed information about
diseases to be gathered with a smaller cohort of experimental animals (Durkee et al.,
2009).
This chapter will discuss the use of colonoscopy in rodent models of IBD and CRC. The
method of performing colonoscopy in experimental animals will be described as well as the
various adjuncts that can be combined with colonoscopy to enhance the amount of data that
can be gathered. The strengths and limitations of colonoscopy will be discussed. Finally,
colonoscopy will be compared and contrasted with alternative methods of imaging the large
intestine, such as CT and MRI.
2. Colonoscopic technique
Colonoscopy is the gold standard for screening, evaluating, and potentially treating diseases
of the colon, including IBD and CRC. In humans, this procedure in its current manifestation
involves inserting a flexible endoscope through the anus, using compressed gas to insufflate
the colon, and carefully advancing to the cecum and terminal ileum. The camera at the tip of
the colonoscope displays images on a monitor. As the colonoscope is withdrawn, the colonic
mucosa is carefully inspected. The colonoscope has channels allowing insertion of various
tools (biopsy forceps, snare cautery, needles for injection, etc.), allowing collection of
biopsies, removal or destruction of potentially neoplastic lesions, or other interventions.
The power of this tool was recognized by researchers, and various groups have attempted to
adapt it for use in animal models of IBD and CRC. Colonoscopy has been successfully
adapted for use in rat models. Using modified bronchoscopes (Hull et al., 1990) or other
small-caliber flexible endoscopes (Haughn et al., 2006), total colonoscopy of the rat has been
performed successfully, as well as other variations of this procedure (Zhang et al., 1994).
Colonoscopy in mice was first attempted with a pediatric cystoscope with good results,
although because of anatomic and instrumental limitations, the entire colon to the cecum
could not be visualized (Huang et al., 2002). High resolution endoscopy can now be
performed with colonoscopes designed specifically for work with rat and mouse models of
colonic disease.
Becker, Fantini, and Neurath published a description of high-resolution colonoscopy in live
mice (Becker et al., 2006). This procedure is followed by our lab with modifications. We use
the Coloview miniendoscope system (Karl Storz, Tuttlingen, Germany), which includes an
colonoscope (0 degree, 1.5 mm, rigid) with operating sheath and light source, video monitor,
and camera with the capability to record video as well as obtain still images during
colonoscopy, and a small air pump. See Figure 1 for an illustration of the set-up that we use.
The mouse is anesthetized with inhaled isoflurane, and is placed ventral-side down on an
operating platform. An oral gavage needle on a syringe is used to introduce Dulbecco’s
phosphate buffered saline (PBS) via the anus as a pre-procedure enema for bowel
preparation to ensure adequate visualization. This step can be repeated as needed to ensure
adequate clearing of colonic contents prior to colonoscopy. We do not fast the mice prior or
provide any additional bowel preparation other than the PBS enema, and we are nearly
always able to obtain adequate visualization of the colonic mucosa. Note that we initially
did fast the mice and provide oral NuLytely (an osmotic bowel preparatory agent), but we
found that this step was unnecessary to obtain excellent visualization of the colon. The PBS
enema also serves as lubrication prior to insertion of the colonoscope. The air pump is
attached to the colonoscope to provide insufflation of the colon for adequate visualization
throughout the procedure. Figure 2 shows an experimental mouse undergoing colonoscopy
while under general anesthesia.
The mouse colon has relatively simple geometry, unlike the tortuosity that is associated with
the human colon. The mouse colon extends in a fairly straight line for approximately 4 cm
cranially from the anus toward the left kidney, where it turns approximately 90 degrees and
316 Colonoscopy
Fig. 1. Colonoscopy set-up.

On the left is the portable tower containing the monitor, light source, camera, and computer
used for recording and saving videos and still images. On the right is the benchtop set-up
for colonoscopy in mice. A: air pump for insufflation of the colon. B: biopsy forceps. C:
colonoscope with working sheath in place, connected to air pump (blue tube) and light
source (gray cable). D: nose cone for administration of inhaled anesthetic attached to
operating platform. E: PBS for pre-operative enemas. F: flexible catheter to be inserted
through working channel of colonoscope with scale markings for standardization of images
and in situ measurments. G: gavage needle attached to syringe with PBS for administration
of pre-procedure enemas. H: soft brush for cleaning lens of colonoscope.
extends across the upper abdominal cavity, connecting with the generous mouse cecum
near the right kidney. The colonoscope is carefully introduced into the anus and advanced
about 4 cm, or until the first area of curvature of the colon (corresponding to the splenic
flexure) while observing progress on the monitor. We typically record video and obtain still
images as the colonoscope is slowly withdrawn. The entire procedure takes approximately 5
minutes or less. The mouse is then allowed to awake from anesthesia. Figure 3 demonstrates
the appearance of normal mucosa on colonoscopic examination.
This procedure is very well tolerated by experimental animals. However, some
complications should be mentioned. Mice that are ill or moribund may not tolerate general
anesthesia, so careful assessment of the animal’s overall state of health should be made prior
to the procedure. The wall of the colon is quite thin, so care must be taken not to cause
perforation. Perforation can occur at the time of enema with the gavage needle or with the
colonoscope. This injury is most likely to happen at the time of insertion, as inadvertent
trauma to the colon becomes less likely under direct visualization. Care needs to be taken
during insufflation as two potential complications could occur. Over-insufflation can cause
air to travel throughout the length of the gastrointestinal tract to the point that gastric
Fig. 2. Mouse colonoscopy. Image of colonoscopy being performed in a living mouse under
general anesthetic. Insufflation is provided by air via the blue tube shown above. The
amount of insufflation is controlled by placing a finger over the opposite opening of the
working sheath. The graduated flexible measuring catheter is seen protruding from the
working channel of the colonoscope.
Fig. 3. Normal intestinal muscosa. Colonoscopy image showing normal intestinal mucosa.
contents are forced up the esophagus and lead to aspiration. In addition, over-distention of
the intestines can lead to respiratory compromise if the abdomen becomes sufficiently
distended to affect diaphragmatic function. Such complications are rare for experienced
operators. Incorporation of additional procedures, such as biopsies, during the colonoscopy
has the potential to increase complications. Reported mortality rates range from <1% to 2.9%
(Becker, 2005; Hensley, 2009).
318 Colonoscopy
2.1 Experimental uses and adjuncts

Colonoscopy allows visual grading of colitis and repeat assessment over time. Both video
and still images can be obtained and stored for analysis. Scoring systems of colitis have been
developed and published. The criteria that can be easily visualized include the thickness of
the colon, changes in vascular pattern, presence of fibrin, mucosal surface granularity, and
stool consistency (Becker et al., 2005, 2006). In order to better visualize crypt patterns and
detect aberrant crypt foci, which some consider early neoplastic lesions, the colonic
epithelium can be stained with a 1% solution of methylene blue and then examined with the
colonoscope. By performing this procedure, termed chromoendoscopy, according to
previously published protocols, aberrant crypt foci can be identified that would be
undetectable without staining, potentially enabling early recognition of pre-neoplastic
lesions prior to tumor formation (Becker et al., 2005, 2006).
Colonic tumors that are at or distal to the splenic flexure (approximately the distal 3-4 cm of
colon) can be followed serially by colonoscopy. This allows study of the natural history of
tumors. Figure 4 demonstrates the progression of a single tumor in one mouse over the
course of four months. Several groups have published methods of visually grading the size of
tumors assessed on colonoscopy. Becker and colleagues have published a method of scoring
tumor size relative to the lumen of the insufflated colon (Becker et al., 2005). However, the still
images must be taken at a consistent distance from the tumor and the colon must be
consistently insufflated in order for meaningful comparisons to be made between time-points.
Hung and colleagues describe using the relative lumen size of a fully insufflated colon as a
normalization factor when obtaining images (Hung et al., 2010). Various tools can be inserted
through the working channel of the colonoscope to provide a visual frame of reference and
guide for standardization of view. A tool that has a known diameter and has markings
Fig. 4. Intestinal tumor development. Colonoscopy images showing the development of an

intestinal tumor in a single mouse over time. Panel A: Early neoplastic lesion. Panel B: Small
flat tumor approximately 1 month after image in A. Panel C: The tumor has continued to
increase in size and is now pedunculated after 10 weeks. Panel D: The same tumor after an
additional 4 weeks, with noticeable increase in size.
at set intervals can be used to quantify the size of tumors seen on endoscopy. Hensley and
collegues have described a method using biopsy forceps. The 1-mm-diameter flexible metal
biopsy forceps was inserted through the working channel of the colonoscope and advanced
until it was visible in the field of view adjacent to the tumor. Still images were taken in this
configuration, and the images were analyzed using a specifically written software program
that allowed estimation of the tumor size by performing geometric reconstruction based on
the position of the cylindrical forceps relative to the adenoma (Hensley et al., 2009). We use
a flexible embolectomy catheter that has been marked at 1 mm intervals to standardize our
images (see item F in Figure 1).
Biopsy forceps are available from Karl Storz which can be passed through the instrument
channel of the operating sheath. Using these small, flexible forceps, tissue can be taken from
tumors or areas of colon wall thickened by colitis. Figure 5 demonstrates the endoscopic
biopsy of a single tumor in an experimental mouse. Care must be taken, however, not to
biopsy normal colonic mucosa as the colon wall in the mouse is quite thin, and biopsies of
this tissue would have an unacceptably high rate of perforation. Biopsies can be snap frozen
with liquid nitrogen, placed in stabilizing media, or fixed in formalin for
immunohistochemistry, molecular analysis, hematoxylin-eosin staining, or other
biomolecular studies (Becker et al., 2005, 2006). In addition, Becker and colleagues have
described directly injecting individual tumors with reagents via a small-gauge needle under
endoscopic guidance. They inserted a 26-gauge needle mounted on a small tube through the
working channel of their endoscope and injected fluorescein isothiocyanate into a tumor
under direct visualization. On necropsy, the tumor was dissected free from the mouse colon
and cryosections were analyzed by immunofluorescence, which showed fluorescein
isothiocyanate throughout the tumor (Becker et al., 2005).
Fig. 5. Colonoscopic tumor biopsy. This series of images shows the steps in obtaining a
biopsy of a tumor during colonoscopy. Panel A: insertion of biopsy forceps. Panel B:
opening biopsy forceps. Panel C: grasping tumor with forceps. Panel D: bleeding from the
tumor after biopsy ensures that adequate tissue was obtained.
320 Colonoscopy
An exciting recent development in small animal research is the use of bioluminescent and
fluorescent molecules to image diverse cellular, molecular, and tissue processes. Fluorescent
probes have been developed for specific antibodies, protein ligands, and other substrates
(see Citrin & Camphausen, 2004, and Luker & Luker, 2008, for reviews of these techniques).
These technologies can be combined with endoscopy to provide real-time imaging of
fluorescent probes to detect perfusion and protease activity, as was demonstrated by
Funovics and colleagues with their miniaturized multichannel near-infrared endoscope.
They designed an endoscope that also allowed simultaneous fluorescent imaging of murine
colonic tumors, allowing them to superimpose fluorescent perfusion and protease activity
over white-light images (Funovics et al., 2003). This method has been shown to be useful for
imaging adenomas as well as adenocarcinomas (Funovics et al., 2006). Hung and colleagues
have reported using protease-activated synthetic probes to identify colonic lesions with
near-infrared colonoscopy (Hung et al., 2010). Fluorescent probes such as this may prove
useful in identifying early neoplastic lesions that are not easily visible on white-light
endoscopy or in monitoring action of novel preventive or therapeutic agents.
3. Strengths and limitations

3.1 Strengths
Utilizing colonoscopy in mice has a number of distinct advantages. One of the most striking
is the ability to monitor changes in colonic pathology over time. Within the same mouse, the
initiation and evolution of colitis as well as response to treatment can be followed. Similarly,
tumors can also be followed longitudinally, potentially from their earliest manifestation and
as they progress from a benign to invasive state over time. This allows the study of a single
tumor in a single mouse over time. Researchers are able to gain valuable information about
the morphology of the tumor, i.e. flat vs. pedunculated, smooth vs. lobulated, as well as
visualize vascular patterns in and around the tumor mucosa. Small sessile lesions that are
missed on other in vivo imaging modalities can be easily identified on colonoscopy.
Additionally, tissue can be obtained by biopsy at multiple time points for histology as well
as for molecular analysis. Prior to use of colonoscopy, in order to study the natural history
of colonic disease, multiple mice would have to be sacrificed at various time points, and the
results of the examinations aggregated. With colonoscopy, diseases such as colitis or colon
neoplasm can be studied at multiple time points in the same mouse, allowing the mouse to
serve as its own control, thereby eliminating variation owing to genetic and environmental
effects. In addition, being able to serially study the same mouse greatly reduces the number
of mice needed in order to design an adequately powered study (Becker et al., 2005, 2006;
Durkee et al., 2009; Hensley et al., 2009).
Colonoscopy in mice is a relatively simple and cost-effective procedure that is well-tolerated
by experimental animals. Colonoscopy is portable and relatively inexpensive, although
there is an initial cost to purchase the equipment. Other methods of imaging murine colonic
disease, such as microCT colonography or MRI, require more expensive scanners as well as
a dedicated space for the necessary equipment.
3.2 Limitations
There are significant limitations of colonoscopy that deserve discussion. Although
colonoscopy is a relatively safe procedure, there is still an associated morbidity and
mortality, as discussed earlier in the section on colonoscopic technique. There are also
limitations inherent in the procedure itself. The quality of the data gathered by colonoscopy
is operator-dependent, and there is a learning curve before the scope can be safely and
effectively used. The images that are obtained are two-dimensional, so estimating the
volume of a tumor is difficult. Most significantly, current technology only allows
visualization of the distal half (3-4 cm) of the mouse colon. A flexible colonoscope that can
be used safely in mice is unavailable, which means that any lesions proximal to the splenic
flexure are inaccessible in vivo.
4. Comparison to other imaging modalities

4.1 Micro-computed tomography colonography
A number of methods for imaging the colons of experimental mice are becoming available.
Micro-computed tomography (mCT) colonography is a useful tool for examining colonic
disease, in particular neoplasia. Also known as virtual colonoscopy, this modality uses x-
rays to image the colon and surrounding tissues, and can be used to generate either two-
dimensional or three-dimensional reconstructions of individual tumors. Virtual colonoscopy
has been shown to be an accurate screening tool for detecting colon polyps in humans (Kim
et al., 2007), making its utilization in murine experiments very clinically relevant. Several
groups have modified this technology for use in the mouse, allowing longitudinal study of
mouse models of colonic disease (Durkee et al., 2010). Choquet and colleagues have used
mCT with luminal and intraperitoneal contrast to detect azoxymethane-induced cecal
heterotypia and colon tumors. They identified 9 of 9 areas of heterotypic thickened cecal
wall and 11 of 11 colon tumors with no false positives (Choquet et al., 2007). Pickhardt and
colleagues showed that by modifying feed and providing bowel preparation with an
osmotic agent, mCT could detect colonic tumors ≥2mm in maximum diameter with 93.3%
sensitivity and 92% specificity (Pickhardt et al., 2005). These investigators went on to
demonstrate tumor volume measurements by mCT were accurate predictors of actual tumor
size (Durkee et al., 2008). Good quality mCT scans had a mean standard deviation in tumor
volume measurements of 8%, meaning that changes in tumor volume of >16% are detectable
with a 95% confidence interval. Thus, colon tumors can be reliably identified and followed
over time by mCT in order to determine if they grow, regress, or remain static either
spontaneously or in response to therapy (Durkee et al., 2009). This imaging platform is very
powerful when testing therapeutic interventions.
mCT colonography offers several advantages over colonoscopy. This is a non-invasive
procedure, so there is minimal risk of morbidity or mortality to the experimental animals,
although general anesthesia and colonic insufflation are not without risk. Current
technology allows three-dimensional rendering of tumors, allowing accurate measurement
of volume, as opposed to the size estimates that can be made using flat two-dimensional
images from colonoscopy (Durkee et al., 2008). Importantly, the entire colon from cecum to
anus can be assessed by mCT colonography, rather only the distal 4 cm as is currently
visible on colonoscopy. In addition, extracolonic manifestation of disease, specifically
metastatic lesions, can be seen on mCT in vivo.
There are advantages offered by colonoscopy, however. Compared to mCT colonography,
colonoscopy is faster (an average of 5 minutes versus 20 minutes), requiring less time under
anesthesia for experimental animals (Durkee et al., 2009). The equipment and set-up for
322 Colonoscopy
colonoscopy are also less expensive than mCT, both in terms of actual hardware required as
well as the dedicated space needed for a CT scanner. Colonoscopy is also able to detect
small or sessile tumors that are not visible on mCT colonography, which relies on the
contrast between the appearance of colonic contents and tissue structures, and is thus
unable to detect lesions <2mm or flat lesions. Colonoscopy can also be used to monitor
colonic inflammation, which is not easily appreciated on mCT colonography. mCT
colonography does employ ionizing radiation, and the length of the scan currently exposes
experimental animals to approximately 0.25 Gray, which is to up to 10 times the amount
used on humans. The effects of this level of radiation on mice are unknown. Finally,
colonoscopy offers the opportunity to perform additional procedures concurrently under
direct visualization. mCT colonography does not offer the opportunity to obtain biopsies,
perform in vivo staining as with chromoendoscopy, or add any of the other adjunctive
procedures discussed above.
4.2 Magnetic resonance imaging

Another imaging modality used to study colonic disease is magnetic resonance imaging
(MRI). Hensley and colleagues described a protocol whereby the entire colon is visualized
by MRI. Using this imaging platform, polypoid tumors 1.5 mm in largest dimension could
be reliably identified, with 17 correctly identified tumors, 2 false negatives, and 2 false
positives. Volumes of the tumors were estimated from MRI and correlated well with tumor
weight (Hensley et al., 2004). Young and colleagues were able to accurately measure the
volume of polypoid colonic tumors at multiple time points (Young et al., 2009). Estimates of
cross-sectional area made on colonoscopy, MRI, and necropsy were compared by Hensley
and colleagues, and were found to have a strong correlation (Hensley et al., 2009). In
addition to colon tumors, numerous investigators have demonstrated that colitis can be
visualized on MRI. A number of groups have been able to appreciate acute experimentally
induced colonic inflammation when imaging mice after treatment with dextran sodium
sulfate, a commonly used agent to model acute colon inflammation in the mouse. Acute
inflammation seen on MRI was confirmed on histological examination of the colon after
sacrifice (Larsson et al., 2006; Melger et al., 2007; Mustafi et al., 2010; Young et al., 2009). The
colon wall thickness, T2-weighted imaging, and quantitative analysis of contrast uptake and
wash-out were all significantly different in inflamed colons. These studies show that MRI
colonography is a viable option for longitudinal study of experimentally induced colitis,
allowing the longitudinal study of inflammatory colon diseases (Larsson et al., 2006; Melger
et al., 2007; Mustafi et al., 2010; Young et al., 2009).
MRI colonography offers the same advantages over colonoscopy that mCT colonography
does with the additional advantage that no ionizing radiation is used. However, there are
reasons to choose colonoscopy over MRI. MRI colonography requires the use of contrast
agents, either intravenously, intramuscularly, or rectally; in addition to being difficult to
administer, the exact effects of these agents on experimental mice are unknown. As with
mCT, set-up and maintenance of an imaging facility are expensive. MRI is also less than
ideal for identifying flat tumors when compared to colonoscopy as these are not as readily
apparent as polypoid tumors. Table 2 compares and contrasts these modalities for imaging
colon tumors in vivo in mice.
Imaging Platform Advantages Disadvantages

Colonoscopy Quick Occasional mortality in
Relatively safe for experimental experimental animals
animals Initial cost of equipment
Relatively inexpensive Unable to visualize
Serial examinations proximal to splenic flexure
Direct visualization of colonic Unable to visualize extra-
mucosa luminal disease
Visualization of flat or polypoid 2-dimensional images only,
lesions so difficult to accurately
Ability to perform in vivo staining assess tumor size and
Ability to obtain tissue biopsies volume
Ability to combine with Quality of images
fluorescent probes for protease or operator-dependent
vascular imaging
mCT colonography Non-invasive with minimal risk of More time required for
mortality in experimental animals procedure
Ability to measure tumors in 3 Ionizing radiation with
dimensions, resulting in accurate unknown effects
and precise measurements of Expensive
tumor volume Inability to identify sessile
Ability to image entire length of lesions or lesions <2 mm
colon Unable to perform
Visualization of extracolonic additional procedures
lesions, i.e. metastases (biopsy, staining, etc.)
MRI colonography Noninvasive with minimal risk of Contrast required
mortality More time required
No ionizing radiation Expensive
Ability to visualize inflammation Inability to identify small or
Ability to measure tumors in 3 sessile lesions
dimensions Unable to perform
Ability to visualize extracolonic additional procedures
lesions
Table 2. Comparison of imaging modalities.
This table compares and contrasts colonoscopy, mCT colonography, and MRI colonography
for colorectal cancer in mouse models.
5. Conclusion
Colonoscopy is a powerful tool for studying pathology in mouse models of colonic disease.
This is a safe, relatively quick procedure that enables researchers to study the natural history
of colonic diseases, to visually assess response to therapeutics or interventions, and to obtain
tissue from living animals. By allowing serial examinations of the colon, it decreases the
number of mice needed to adequately power a study. Colonoscopy can be combined with
staining techniques or fluorescent probes to gather data about a variety of cellular,
molecular, or tissue processes simultaneously. Colonoscopy is comparable to other imaging
modalities available to study the murine colon, such as mCT or MRI colonography.
324 Colonoscopy
6. Acknowledgements
The authors would like to thank Linda Clipson for critical review of the manuscript and
Brian Olson for technical help and critical review.
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To publish a book on colonoscopy suitable for an international medical audience,

drawing upon the expertise and talents of many outstanding world-wide clinicians,
is a daunting task. New developments in videocolonoscope instruments, procedural
technique, patient selection and preparation, and moderate sedation and monitoring
are being made and reported daily in both the medical and the lay press. Just as over
the last several decades colonoscopy has largely supplanted the use of barium enema
x-ray study of the colon, new developments in gastrointestinal imaging such as
computerized tomographic colonography and video transmitted capsule study of the
colonic lumen and new discoveries in cellular and molecular biology that may facilitate
the early detection of colon cancer, colon polyps and other gastrointestinal pathology
threaten to relegate the role of screening colonoscopy to the side lines of medical
practice. This book draws on the talents of renowned physicians who convey a sense
of the history, the present state-of-the art and ongoing confronting issues, and the
predicted future of this discipline.
ISBN978-953-307-568-6
ISBN 978-953-51-6466-1
Photo by Gunnar Pippel / shutterstock

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Colonoscopy

Edited by Paul Miskovitz

© The Editor(s) and the Author(s) 2011

First published in Croatia, 2011 by INTECH d.o.o.

Legal deposit, Croatia: National and University Library in Zagreb

Additional hard and PDF copies can be obtained from [email protected]

4,200+ 116,000+ 125M+

Our authors are among the

Selection of our books indexed in the Book Citation Index

Interested in publishing with us?

Dr. Paul Miskovitz is Clinical Professor of Medicine

A Brief Overview of Selected Aspects

Part 1 The Technique 1

Chapter 1 Preparing for Colonoscopy 3

Chapter 2 Sedation and General Anaesthesia

Chapter 3 Quality of Screening Colonoscopy:

Chapter 4 Maintaining Quality in Endoscopy 61

Chapter 5 The Impact of Colonoscopy

Chapter 6 Post-Polypectomy Colonoscopy Surveillance 97

Chapter 7 Endoscopic Manifestations

Chapter 8 Endoscopic Approach in Ulcerative Colitis 129

Chapter 9 Pathological Issues of Ulcerative Colitis/Dysplasia 139

Chapter 10 Pathology of Staging of Early Colorectal Lesions

Chapter 11 Endoscopic Submucosal Dissection

Chapter 12 Portal Hypertensive Colopathy 171

Part 3 The Future? 177

Chapter 13 Research and Therapeutic Innovation:

Chapter 14 Autofluorescence Imaging

Chapter 15 Intestinal Dynamic Color Doppler

Chapter 16 Towards Intelligent Systems for Colonoscopy 245

Chapter 17 Virtual Colonoscopy - Technical Aspects 271

Chapter 18 Robotic Colonoscopy 291

Chapter 19 Experimental Small Animal Colonoscopy 309

To publish a book on colonoscopy suitable for an international medical audience,

Paul Miskovitz MD, AGAF

Paul Miskovitz, MD, AGAF

2. The historical development of colonoscopy

The development that irreversibly altered the field of gastroenterology forever, by

As we will see, the future of (particularly therapeutic) colonoscopy seems assured,

4. Indications for colonoscopy

Colonoscopy is most useful in diagnosing and treating patients with neoplasms,

World-wide, colorectal cancer is the third most commonly diagnosed cancer in

region or healthcare setting needs to determine whether colorectal cancer screening

5. Contraindications to and risks of colonoscopy

majority (96%) of post-procedure hemorrhages that required hospital admission

As with many decisions in clinical medicine, the decision to perform colonoscopy on a

6. Informed consent for colonoscopy

7. Bowel preparation for colonoscopy

missed lesions, cancelled procedures, increased procedural time, and a potential

8. Antibiotic prophylaxis for selected patients undergoing colonoscopy

Heart Association and the American Society for Gastrointestinal Endoscopy,

9. Antithrombotic agents in patients undergoing colonoscopy

10. Sedation for colonoscopy

11. Patient monitoring during colonoscopy

12. The electronic endoscopic record and colonoscopy

13. The future of colonoscopy

“Prediction is extremely difficult, especially about the future”—Danish physicist Niels

“640 K should be enough for anybody”-CEO of Microsoft® Corporation Bill Gates,

It is likely that current videocolonoscopes with only minor modifications will be