Colonoscopy: Principles and Practice 2nd ed

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Colonoscopy Principles and Practice

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Colonoscopy Principles and Practice EDITED BY

Jerome D. Waye Director of Endoscopic Education Mount Sinai Hospital Clinical Professor of Medicine Mount Sinai Medical Center New York USA

Douglas K. Rex Professor of Medicine Indiana University School of Medicine Director of Endoscopy Indiana University Hospital Indianapolis USA

Christopher B. Williams Consultant Physician Wolfson Unit for Endoscopy St Mark’s Hospital for Colorectal and Intestinal Disorders London UK

SECOND EDITION

Endorsed by the World Organisation of Digestive Endoscopy/Organisation Mondiale d’Endoscopie Digestive

A John Wiley & Sons, Ltd., Publication

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This edition first published 2003 © 2009 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/ wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Colonoscopy : principles and practice / edited by Jerome D. Waye, Douglas K. Rex, Christopher B. Williams. a 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-7599-9 1. Colonoscopy. I. Waye, Jerome D., 1932– II. Rex, Douglas K. III. Williams, Christopher B. (Christopher Beverley) [DNLM: 1. Colonoscopyamethods. WI 520 7179 2009] RC804.C64C63 2009 616.3′407545adc22 2008053971 A catalogue record for this book is available from the British Library. Set in 9/12pt Meridien by Graphicraft Limited, Hong Kong Printed in Singapore by Fabulous Printers Pte Ltd

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Contents

List of Video Clips on DVD-ROM, vii Preface, ix

14 Role of Simulators in Colonoscopy, 154 J. Cohen & S. Bar-Meir

List of Contributors, xi

Section 1 General Aspects of Colonoscopy, 1 1 History of Endoscopy in the Rectum and Colon, 3 H. Niwa & C.B. Williams 2 The Colonoscopy Suite, 19 M.E. Rich 3 Continuous Quality Improvement in Colonoscopy, 41 J. Petrini

Section 2 Preparation—General, 55 4 The Gastrointestinal Assistant during Colonoscopy, 57 C.A. Dykes 5 Cleaning and Disinfection, 67 D.A. Greenwald

Section 3 Preparation of the Patient, 77 6 Informed Consent for Colonoscopy, 79 A.D. Feld 7 Antibiotic Prophylaxis for Colonoscopy, 90 G. Zuccaro 8 Management of Anticoagulation and Antiplatelet Agents, 94 G.M. Eisen & K.M. Hoda 9 Sedation for Colonoscopy, 101 L.B. Cohen & J. Aisenberg 10 Preparation for Colonoscopy, 114 J.A. DiPalma

Section 4 Preparation of Endoscopist, 125 11 Training in Colonoscopy, 127 S. Banerjee & J. Van Dam 12 Teaching Aids in Colonoscopy, 133 R. Sáenz 13 Teaching Colonoscopy, 141 J.T. Anderson

Section 5 Indications, Contraindications, and Screening, 165 15 Indications and Contraindications, 167 M.A. Khashab & D.K. Rex 16 Diagnostic Yield of Colonoscopy by Indication, 178 F. Froehlich & J.-J. Gonvers 17 Screening Colonoscopy: Rationale and Performance, 206 D. Lieberman 18 Cost-effectiveness of Colonoscopy Screening, 216 A. Sonnenberg

Section 6 Reports and Imaging, 233 19 Standardization of the Endoscopic Report, 235 M.M. Delvaux 20 Reporting and Image Management, 254 L. Aabakken

Section 7 Instrument and Accessories, 267 21 The Video Colonoscope, 269 D.E. Barlow 22 The Colonoscope Insertion Tube, 292 J.B. Marshall 23 Capsule Colonoscopy, 301 A. Postgate, C. Fraser & J. Devière 24 Accessories, 306 G.G. Ginsberg 25 Clips, Loops, and Bands: Applications in the Colon, 318 M.J. Bourke & S.J. Williams 26 Principles of Electrosurgery, Laser, and Argon Plasma Coagulation with Particular Regard to Colonoscopy, 328 G. Farin & K.E. Grund

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Contents

Section 8 Neoplasia, 347 27 Polyp Biology, 349 C.R. Boland & A. Goel 28 Colon Polyps: Prevalence Rates, Incidence Rates, and Growth Rates, 358 B. Hofstad 29 Pathology of Colorectal Polyps, 379 N. Harpaz 30 Management of Malignant Polyps, 401 S.J. Winawer & M.J. O’Brien 31 Magnifying Colonoscopy, Depressed Colorectal Cancer, and Flat Adenomas, 412 H. Kashida & S. Kudo 32 Flat and Depressed Colorectal Adenomas in the Western Countries, 423 R. Soetikno & P.J. Pasricha 33 Hereditary Colorectal Cancer, 431 R.W. Burt 34 Colonoscopic Biopsy, 447 W.M. Weinstein 35 Colonoscopic Chromoendoscopy, 462 D.P. Hurlstone 36 Optical Techniques for the Endoscopic Detection of Early Dysplastic Colonic Lesions, 473 R.S. DaCosta, B.C. Wilson & N.E. Marcon 37 Endoscopic Ultrasonography and Colonoscopy, 501 J.W. Stubbe & P. Fockens 38 Narrow-band Imaging, 514 Y. Sano, F. Emura & H. Ikematsu 39 Confocal Laser Endomicroscopy, 527 R. Kiesslich & M. Neurath

Section 9 Technique, 535 40 Insertion Technique, 537 C.B. Williams 41 Missed Neoplasms and Optimal Colonoscopic Withdrawal Technique, 560 K.C. Huh & D.K. Rex

46 Magnetic Imaging for Colonoscopy, 619 B.P. Saunders, S.G. Shah & C.B. Williams

Section 10 Clinical Use and Results of Colonoscopy, 629 47 Colonoscopy and Severe Hematochezia, 631 D.A. Jensen & G.A. Machicado 48 Endoscopy in Inflammatory Bowel Diseases, 646 G. D’Haens, S. Vermeire, G. Van Assche & P. Rutgeerts 49 Infections and Other Noninflammatory Bowel Disease Colitides, 659 C.M. Surawicz 50 Acute Colonic Pseudo-obstruction, 675 M.B. Kimmey 51 Endoscopic Treatment of Chronic Radiation Proctopathy, 683 C.J. Gostout 52 Benign and Malignant Colorectal Strictures, 689 T.H. Baron 53 Complications, 703 J. Church

Section 11 Surveillance, 717 54 Postpolypectomy Surveillance, 719 J.H. Bond 55 Colonoscopy after Colorectal Cancer Resection, 730 C.J. Kahi & D.A. Haggstrom

Section 12 Pediatric Colonoscopy, 747 56 Pediatric Colonoscopy, 749 M. Kay & R. Wyllie

Section 13 Virtual Colonoscopy, 761 57 Virtual Colonoscopy in the Evaluation of Colonic Diseases, 763 P. Pickhardt

42 Polypectomy: Basic Principles, 572 J.D. Waye

Section 14 The Future, 775

43 Difficult Polypectomy, 582 U. Seitz, N. Soehendra & J.D. Waye

58 New Colonoscopes and Assist Devices, 777 S. Bar-Meir

44 Endoscopic Submucosal Dissection in the Colon, 603 N. Yahagi

59 The Future of Colonoscopy, 784 P.J. Pasricha, M.J. Krier & R.D. Brewer

45 Retrieval of Colonic Polyps, 613 B.E. Roth

Index, 791

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Contents: Video clips on DVD-ROM

This book is accompanied by a DVD-ROM with supplementary video clips on the topics listed here.

21. “Alpha” spiral loop (46)

The DVD-ROM is fully searchable and is intended to be used independently; however, the chapters in this book which cover these topics are noted in parentheses.

23. Reversed alpha-spiral loop (46)

A. Colonoscopy: techniques and training 1. History of colonoscopy (1) 2. Bovine colonoscopy simulation model with animal intestine (14) 3. Olympus colonoscopy simulator being used for training a novice colonoscopist (14) 4. Simbionix simulator (GI Mentor): A virtual colonoscopy simulator with the capability of polypectomy and skill training (14) Basic colonoscopy technique: 5. Sigmoid colon (40) 6. Descending colon (40) 7. Splenic flexure (40) 8. Hepatic flexure (40) 9. Ileocecal (40)

22. Pushing-through an “N-spiral” loop (46) 24. Deep looping in the transverse (46) 25. Mobile splenic flexure (46) 26. Sigmoid loop opposed with hand pressure (46) 27. Transverse loop opposed with hand pressure (46) 28. Atypical mobile colon (46)

B. Polyps, cancer, and complications 1. Retroversion to see and remove a polyp (42) 2. Readjusting snare position for safe polypectomies (42) 3. Getting the polyp into position for removal (43) 4. The value of retroversion during polyp removal (43) 5. Polyp in melanosis (49) 6. Endoloop (25) 7. Clips to close a polypectomy perforation (25) 8. Immediate postpolypectomy bleeding controlled with clip (25) 9. Loop on pedunculated polyp (25)

10. Entry into terminal ileum: the bow and arrow sign (40)

10. Clips to control immediate postpolypectomy hemorrhage (25)

11. Why are some colons so long and “difficult” to intubate (40)

11. Endoloop applied after polypectomy (25)

Visits to the experts (2002):

13. Clip for anastomotic bleeding (25)

12. J. D. Waye (40)

14. A benign-appearing flat cancerous polyp (32)

13. C.B. Williams (40)

15. Familial adenomatous polyposis (FAP) (33)

14. S. Kudo (40)

16. Chromoendoscopy for flat adenoma (35)

15. Y. Sakai (40)

17. NBI to delineate the extent of a flat polyp (38)

16. N. Soehendra (40)

18. Large lipoma (37)

12. Clip on polyp stalk after resection (25)

19. Missed lesion in cecum (41) ScopeGuide magnetic imager and examples:

20. Missed lesion in descending colon (41)

17. Introductionbhow ScopeGuide works (46)

21. A crying polyp

18. “Classic” insertion technique explained (46)

22. Cold snare for a small polyp (42)

19. Short normal colon (46)

23. Clamshell sessile polyp (42)

20. Shortening a sigmoid loop (46)

24. Piecemeal polypectomy (42)

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Contents: Video clips on DVD-ROM 25. Piecemeal polypectomy in retroversion (42)

2. A pedunculated dysplastic lesion in ulcerative colitis (48)

26. A polyp located between two folds (42)

3. Cancer in Crohn’s disease (48)

27. Injection of surgical marker (pure carbon in suspension) into saline bleb (42)

4. Cancer in a surveillance patient with chronic ulcerative colitis (48)

28. Resection of a pedunculated polyp (42)

5. Ulcerative colitis: removal of flat polyp (48)

29. A polyp in the appendix (43)

6. Dysplastic lesion in ulcerative colitis (48)

30. Submucosal injection polypectomy (SIP) or endoscopic mucosal resection (EMR) (43)

7. Inflammatory polyps in ulcerative colitis (48) 8. Chromoendoscopy in two cases of ulcerative colitis (48)

31. Piecemeal polypectomy follow-up submucosal injection polypectomy (SIP) (43)

10. Polypoid mucosal lesions in diverticulosis (49)

32. Giant rectal polyp removed over a five-year interval (43)

11. Diverticular colitis (49)

33. Large sessile polyp (a) and (b) (43)

12. Granulation tissue at a diverticulum (49)

34. Lateral spreading polyp (43)

13. Red folds in diverticular disease (49)

9. Clostridium difficile infection (49)

35. Large sessile descending colon polyp (43) 36. Large polyp sent for surgery (43) 37. Endoscopic mucosal resection of a large hepatic flexure polyp (43)

D. Other conditions and topics 1. Foreign body (51)

38. Endoscopic mucosal resection of a sessile rectal polyp (43)

2. Cap polyposis (29)

39. Endoscopic submucosal dissection (ESD) of a large flat rectal polyp (44)

4. Confocal laser endomicroscopy (39)

40. Endoscopic submucosal dissection (ESD): ascending colon polyp (44)

6. Pinworms (49)

41. Accurate localization of bleeding by the water jet (47) 42. Endoscopic submucosal dissection (ESD): sigmoid colon polyp (44)

3. Solitary rectal ulcer syndrome (29) 5. Ascaris in the cecum (49) 7. Red rings in the rectum (49) 8. Ischemic colitis at two weeks (49) 9. Ischemic colitis (49)

43. Endoscopic submucosal dissection (ESD): perforation (44)

10. Ischemic colitis at two days (49)

44. Colon stent descending: self-expanding metal stent (SEMS) for colon cancer (52)

11. Radiation proctopathy (51)

45. Colon stent: self-expanding metal stent (SEMS) for rectal carcinoma (52)

12. Balloon dilation of anastomotic colo-colon anastomotic stricture one year after surgery (52) 13. Anastomotic stricture and balloon dilation (52)

46. Late postpolypectomy bleeding (53 ) 47. Treatment of immediate postpolypectomy bleeding (53)

Acknowledgements

48. Postpolypectomy bleeding (53)

The Editors and other contributors have supplied a range of video clips in the hope that they will be of interest. Particular acknowledgment is made to: Dr. Todd Baron, Dr. M. J. Bourke, Dr. Jonathan Cohen, Dr. Gregory Ginsberg, Dr. Ralf Kiesslich, Dr. S. Kudo, Dr. N. E. Marcon, Dr. J. R. Armengol-Miro, Professor Y. Sakai, Professor N. Soehendra, and Dr. N. Yahagi.

49. Recurrent malignant polyp (54) 50. Recurrent polyp (54) 51. Postpolypectomy bleed (53)

C. Inflammatory conditions 1. Chromoendoscopy reveals a dysplastic lesion in ulcerative colitis (48)

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Clips B28, 37, 38, 39, and 40 are from Dr. Marcon’s Therapeutic Endoscopy course, performed at the Annual Therapeutic Endoscopy Workshop in Toronto, Canada, at St. Michael’s Hospital.

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Preface to the First Edition

Flexible endoscopy of the colon was introduced in 1963, six years after Basil Hirschowitz developed the fiberoptic gastroscope. Since the first attempts at intubating the entire colon, this procedure has now become a primary diagnostic and therapeutic tool for evaluation and treatment of colonic diseases. Using the ability to inspect, obtain tissue samples and remove colon polyps, colonoscopy has expanded our knowledge of the natural history of colonic neoplasia. Multiple large studies have shown that removal of benign adenomas will prevent colorectal cancer. Because of the increasing awareness of colorectal cancer being a common cause of death from cancer throughout the world, and the possibility to interrupt the adenoma to carcinoma sequence by polypectomy, the volume of colonoscopies around the world continues to be driven upward by widespread acknowledgement of the effectiveness of the procedure. Colonoscopy is not merely a tool in the hands of a practitioner, but it is a discipline with an infrastructure built upon many areas of medicine, including internal medicine, the general practice of medicine, and gastroenterology in particular, as well as surgery, pathology, radiology, pediatrics, and molecular biology. The expanding horizon of colonoscopy was the stimulus for us to organize a new comprehensive textbook on this field. The chapters in this volume address every aspect of colonoscopy, and its interface with all of the other sections of medicine. The editors of this book learned and indeed developed many techniques of colonoscopy when imaging was limited to the barium enema and there was no cap ability to visualize the intraluminal topography in the intact patient. This book represents the “state of the art” in colonoscopy. However, colonoscopy is a procedure in evolution and investigators around the world are actively pursuing improvements.

Colonoscopy is a relatively new discipline, and although tremendous strides have been made since its introduction, there are many unanswered questions such as how can we improve training in colonoscopy? Can bowel cleansing be made less toxic and less miserable? Can colonoscopy be made painless? Can we improve the detection of neoplasia? Can we make colonoscopy faster? Can we eliminate complications from both diagnostic and therapeutic procedures? The answers to these questions will determine the future of colonoscopy and its ultimate impact on colorectal disease. We look forward to the continuing pursuit of answers to all questions concerning colonoscopy, and urge future generations of colonoscopists to continue the quest for knowledge and add more information to each of the chapters in this book. For many colonoscopists and certainly for ourselves, colonoscopy is not considered as part of a job, but rather as a passion. Every colonoscopy presents an opportunity to improve a patient outcome, to learn, often to reassure, to identify new questions and problems both clinical and scientific, and to enjoy the application of skills both manual and cognitive in nature. Thus, to edit a volume on colonoscopy has been for us a particular pleasure. We extend our most sincere thanks to the authors who contributed to this volume. The list of authors includes the world’s most foremost practitioners from every aspect of medicine. Their expertise, diligence, and friendship are deeply appreciated. On behalf of all the authors, we thank the many, many thousands of patients who have trusted us and been our teachers. Jerome D. Waye Douglas K. Rex Christopher B. Williams 2003

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Preface to the Second Edition

The first edition of this book was conceived because there was no overall source of information concerning the current status of colonoscopy. The chapter headings were intended to cover the entire range of colonoscopy. With careful editing, attention to detail in each chapter and drawing on the vast clinical and teaching experience of all three editors, the book won first prize in the 2004 prestigious medical society award for gastroenterology conferred by the British Medical Association. In one of the reviews of the first edition, it was stated that Colonoscopy was “a masterpiece of its kind. The authors should be complimented for their successful effort to provide such an important and fascinating book”. “Very rarely has the reviewer examined a monograph . . . which has impressed him so much for its clarity, completeness, attractiveness and its fascination”. This second edition is intended to capture all the changes that have taken place in the field of colonoscopy within the past several years, with six new chapters and 34 new authors, who represent the best minds and practitioners in the field of colonoscopy and colonoscopic imaging. Each chapter has been extensively revised, and many were completely rewritten with a view to bring a focus of current knowledge to this updated second edition. The editors have encouraged all authors to add layers of new information to the data of 5 years ago. As colonoscopy is such a visual imaging field and since the technique of therapy is so closely associated, a DVD has been added to the book to accompany this edition. The DVD has over 100 video segments covering the entire aspect of colonoscopy from history to teaching, from insertion technique to polypectomy, and it also contains many cases of interesting pathology ranging from parasites to perforation.

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Several videos demonstrate the most recent developments of narrow-band imaging, confocal laser endomicroscopy, and endoscopic submucosal dissection. Most of the individual video clips for the DVD were contributed by the editors, many were submitted by the chapter authors themselves, and others represent videos of live cases performed at international teaching courses. Some of the videos have audio commentaries, but most have an accompanying full text description. We hope this second edition of Colonoscopy: Principles and Practice will enhance the knowledge of everyone interested in the field of colonoscopy and colonic imaging. Although intended to be a source of information for physicians, surgeons, residents and fellows, as well as students and gastrointestinal assistants, our goal is to enhance the care and treatment of patients with colonic problems, who are the ultimate beneficiaries of shared knowledge and improved skills. We wish to thank the unflagging efforts of our text editors, Rebecca Huxley from Wiley-Blackwell, Helen MacDonald from Prepress Projects Ltd, and the careful overview of Meg Barton, also from Wiley-Blackwell, in organizing the accompanying DVD section. We would also like to thank William W. Gantt who worked on both the first and second edition of Colonoscopy, rekeying all amendments to the manuscript, in preparation for the publishers. Jerome D. Waye, Douglas K. Rex Christopher B. Williams June 2009

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List of Contributors

L. Aabakken, MD, PhD Professor of Medicine and Chief of GI Endoscopy, Department of Medical Gastroenterology, Rikshospitalet University Hospital, Oslo, Norway

R.D. Brewer PhD Candidate in Mechanical Engineering, Stanford University Department of Engineering, Stanford, CA, USA

C.A. Dykes, CTR, NNMC Senior Nurse Research Coordinator, Colon Health Initiative, National Naval Medical Center, Bethesda, MD, USA

J. Aisenberg, MD

R.W. Burt, MD

G.M. Eisen, MD, MPH

Associate Clinical Professor, Department of Medicine (Gastroenterology), The Mount Sinai School of Medicine, New York, NY, USA

Professor of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA

Professor of Medicine, Oregon Health & Science University, Portland, OR, USA

J.T. Anderson

J. Cohen, MD, FASGE, FACG

Gloucestershire Hospital NHS Foundation Trust, Cheltenham, Gloucestershire, UK

Clinical Professor of Medicine, New York University School of Medicine, New York, NY, USA

S. Banerjee, MD Directory of Biliary Endoscopy, Stanford University School of Medicine, Stanford, CA, USA

D.E. Barlow, PhD Vice PresidentaResearch and Development, Olympus America Inc., Center Valley, PA, USA T.H. Baron, MD, FACP Professor of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

S. Bar-Meir, MD Professor of Medicine and Director, Department of Gastroenterology and Hepatology, Chaim Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

J.H. Bond, MD Chief, Gastroenterology Section, Minneapolis Veterans Affairs Medical Center, and Professor of Medicine, University of Minnesota, MN, USA

F. Emura, MD, PhD Medical Director, Advanced Digestive Endoscopy, Emura Foundation for the Promotion of Cancer Research, Bogotá, and Honorary Professor of Gastrointestinal Endoscopy, School of Medicine, Universidad del Valle, Cali, Colombia

L.B. Cohen, MD Associate Clinical Professor, Department of Medicine (Gastroenterology), The Mount Sinai School of Medicine, New York, NY, USA

G. Farin

J. Church, MD

A.D. Feld, MD, JD

Victor W. Fazio Professor of Colorectal Surgery, Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA

Clinical Professor of Medicine, University of Washington, Seattle, and Rockwood Clinic, WA, USA

R.S. DaCosta, PhD

P. Fockens, MD, PhD Associate Professor of Medicine, Director of Endoscopy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Assistant Scientist, Division of Biophysics and Bioimaging, Ontario Cancer Institute, University Health Network, and STARR Innovation Center, Radiation Medicine Program, University of Toronto, Toronto, Ontario, Canada

M.M. Delvaux, MD, PhD Department of Internal Medicine and Digestive Pathology, University Hospital of Nancy, Nancy, France

G. D’Haens, MD, PhD Gastroenterologist, Imelda General Hospital, Bonheiden, Belgium

C.R. Boland, MD Chief, Division of Gastroenterology, Baylor University Medical Center, Dallas, TX, USA

J. Devière

M.J. Bourke, MB, BS, FRACP

J.A. DiPalma, MD

Director of Gastrointestinal Endoscopy, Westmead Hospital, Sydney, Australia

Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL, USA

Erasme Hospital, Brussels, Belgium

Engineer, Center for Medical Research, Experimental Endoscopy, Tübingen, Germany

C. Fraser, MB, ChB, MD, MRCP Consultant Gastroenterologist, The Wolfson Unit for Endoscopy, St Mark’s Hospital, London, UK

F. Froehlich, MD Assistant Professor of Gastroenterology, Department of Gastroenterology and Hepatology, University of Basle, Basle, and Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland G.G. Ginsberg, MD Professor of Medicine, University of Pennsylvania School of Medicine, Gastroenterology Division, and Director of Endoscopic Services, University of Pennsylvania Health Systems, Philadelphia, PA, USA

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List of Contributors

A. Goel, PhD

D.M. Jensen, MD

J.B. Marshall, MD

Investigator, Baylor University Medical Center, Dallas, TX, USA

Professor of Medicine, UCLA School of Medicine, Director of Human Studies Core, CURE: Digestive Disease Research Center, WLA VA Medical Center/CURE, Los Angeles, CA, USA

Professor of Medicine, Division of Gastroenterology, University of Missouri School of Medicine, Columbia, MO, USA

J.-J. Gonvers, MD Professor of Gastroenterology, Department of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

C.J. Kahi, MD, MSC Assistant Professor of Clinical Medicine, Indiana University School of Medicine, and Director of Endoscopy, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, In, USA

C.J. Gostout, MD Professor of Medicine, Mayo Graduate School of Medicine, Mayo Foundation, Rochester, MN, USA

D.A. Greenwald, MD Associate Division Director, Montefiore Medical Center, and Associate Professor of Clinical Medicine, Albert Einstein College of Medicine, New York, NY, USA

K.E. Grund, MD

M. Kay, MD Director Pediatric Endoscopy, Department of Pediatric Gastroenterology and Nutrition, Children’s Hospital, Cleveland Clinic, Cleveland, OH, USA M.A. Khashab, MD Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, and Clarian Health Partners, Indianapolis, IN, USA

Professor of Surgery, Surgical and Experimental Endoscopy, University Hospital Tübingen, Germany

H. Kashida, MD, PhD

D.A. Haggstrom, MD, MAS Research Scientist, HSR&D, Indianapolis Veterans Affairs Medical Center, and Assistant Professor of Medicine, Indiana University, Indianapolis, IN, USA

R. Kiesslich, MD, PhD

N. Harpaz, MD, PhD Professor of Pathology and Medicine, Mount Sinai School of Medicine, and Director, Division of Gastrointestinal Pathology, The Mount Sinai Medical Center, New York, NY, USA

K.M. Hoda, MD Gastroenterology Fellow, Oregon Health & Science University, Portland, OR, USA

Associate Professor, Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan

Professor, Head of Endoscopic Unit I. Med. Klinik, Johannes Gutenberg University, Mainz, Germany

M.B. Kimmey, MD Tacoma Digestive Disease Center, Tacoma, WA, USA M.J. Krier, MD Fellow, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA

S. Kudo, MD, PhD B. Hofstad, MD Senior Gastroenterologist, Division of Gastroenterology, Ullevaal University Hospital, Oslo, Norway

K.C. Huh, MD, PhD Department of Internal Medicine, Konynag University School of Medicine, Daejeon, South Korea

Professor, Chairman, Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan

D. Lieberman, MD Professor of Medicine, Division of Gastroenterology, Oregon Health & Science University, Portland, OR, USA

Barnsley NHS Foundation Trust, Barnsley, UK

G.A. Machicado, MD Clinical Professor of Medicine, UCLA School of Medicine, Van Nuys, CA, USA

H. Ikematsu, MD

N.E. Marcon, MD

Staff of Gastrointestinal Oncology and Endoscopy, National Caner Center Hospital East, Chiba, Japan

St Michael’s Hospital, Center for Therapeutic Endoscopy and Endoscopic Oncology, Toronto, Ontario, Canada

D.P. Hurlstone

M.F. Neurath, MD, PhD Professor, Head of the Institute of Molecular Medicine, I. Med. Department, Johannes Gutenberg University, Mainz, Germany H. Niwa, MD, DMSc Professor of Medicine, St. Marianna University School of Medicine, Kawasaki, Japan M. O’Brien, MD, MPH Professor of Pathology and Laboratory Medicine, Boston University School of Medicine, and Chief of Anatomic Pathology, Boston Medical Center, Boston, MA, USA P.J. Pasricha, MD Chief, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CA, USA J. Petrini, MD Sansum Clinic, Santa Barbara, CA, USA P.J. Pickhardt, MD Associate Professor of Radiology, Abdominal Imaging Section, University of Wisconsin, School of Medicine & Public Health, Madison, WI, USA A. Postgate Fellow, St Mark’s Hospital, London, UK

D.K. Rex, MD Professor of Medicine, Indiana University School of Medicine, and Director of Endoscopy, Indiana University Hospital, IN, USA

M.E. Rich, AIA, LLED AP Architect PC, 2112 Broadway, New York, NY, USA

B.E. Roth, MD Professor of Medicine and Chief, Clinical Affairs, Division of Digestive Disease, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

P. Rutgeerts, MD, PhD Department of Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium R. Sáenz, MD

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The Latin-American WGO and OMED Gastrointestinal Endoscopy Training Center and Vice Chair, Clinica Alemana, Universidad del Desarrollo, Santiago, Chile

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List of Contributors

Y. Sano, MD, PhD Director and Chief of Gastrointestinal Center, Sano Hospital, Kobe, Japan

J.W. Stubbe, MD Department of Gastroenterology & Hepatology, AZ Sint-Jan, Ostend-Bruges, Belgium

B.P. Saunders, MD, FRCP

C. Surawicz, MD, MACG

Consultant Gastroenterologist, Wolfson Unit for Endoscopy, St Mark’s Hospital, London, UK

Professor of Medicine, University of Washington School of Medicine, Seattle, WA, USA

U. Seitz, MD Chief, Internal MedicineaGastroenterology, Bergstrass Medical Center, Heppenheim, Germany

S.G. Shah, MD, MRCP Consultant Gastroenterologist, Pinderfields General Hospital, Wakefield, UK

N. Soehendra, MD Endoskopie am Glockengiesserwall, Hamburg, Germany

R. Soetikno, MD Stanford University School of Medicine, Palo Alto, CA, USA

A. Sonnenberg, MD, MSc Professor of Medicine, Oregon Health & Science University, and Staff Physician, Portland Veterans Affairs Medical Center, Portland, OR, USA

J. Van Dam, MD, PhD Stanford University School of Medicine, Stanford, CA, USA

G. Van Assche, MD, PhD Department of Gastroenterology, University Hospitals Gaithuisberg, Leuven, Belgium

S. Vermeire, MD, PhD Department of Gastroenterology, University Hospitals Gaithuisberg, Leuven, Belgium

C.B. Williams, BM, FRCP, FRCS Consultant Physician, St Mark’s Hospital and London Clinic, London, UK S.J. Williams, MB, BS, MD, FRACP Senior Gastroenterologist, Westmead Hospital, Sydney, Australia

B.C. Wilson, PhD Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Toronto, Ontario, Canada

S.J. Winawer, MD Attending Physician & Member with Tenure, Gastroenterology & Nutrition Service, Paul Sherlock Chair in Medicine, Memorial SloanKettering Cancer Center, New York, NY, USA

R. Wyllie, MD Calabrese Chair of Pediatrics, Pediatric Institute, Chair, Department of Pediatric Gastroenterology and Nutrition, and Physician-in-Chief, Children’s Hospital, Cleveland Clinic, Cleveland, OH, USA

J.D. Waye, MD Director of Endoscopic Education, Mount Sinai Hospital, Clinical Professor of Medicine, Mount Sinai Medical Center, New York, NY, USA

N. Yahagi, MD, PhD Director, Department of Gastroenterology and Endoscopy Unit, Toranomon Hospital, Tokyo, Japan

W.M. Weinstein, MD

G. Zuccaro Jr, MD, MS

Professor of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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History of Endoscopy in the Rectum and Colon Hirohumi Niwa1 & Christopher B. Williams2 1

St Marianna University School of Medicine, Kawasaki, Japan St Mark’s Hospital, London, UK

2

Introductioncfrom rigid endoscopes to colonofiberscopes Long before it became practicable to examine the proximal colon, a variety of rigid instruments were used to examine the anal canal, the rectum, and the distal half of the sigmoid colon. Even the limited view obtained by rigid “hollow tube” scopes had significant clinical value, as disease of the large bowel is most commonly found in the distal half of the sigmoid colon and rectum. The history of modern colonoscopy therefore begins with such devices, starting with the earliest inventions. This account is substantially limited to the evolution of colorectal endoscopy, but there are excellent more wideranging accounts giving the background of prior developments in cystoscopy, esophagoscopy and gastroscopy [1–3]. Outstanding museum collections of the history of endoscopy can be found in Austria (Nitze-Leiter Endoscopy Museum, Vienna; visitors by arrangement) and America (Dittrick Museum, Cleveland, Ohio), with lesser medico-historical exhibits in Germany (Ingolstadt), France (René Descartes University, Paris), China (First Hospital, Beijing), and elsewhere athough urological exhibits tend to dominate [4].

Rigid endoscopes Primitive specula From the time of Hippocrates attempts were made to observe the inside of the human body. A “speculum” was used to examine the rectum and vagina and to cauterize hemorrhoids. Primitive instruments similar to today’s anoscopes and colposcopes were discovered in the ruins of Pompeii,

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Figure 1.1 Roman speculum from the ruins of Pompeii (79 AD).

buried under volcanic ash after the eruption of Mount Vesuvius in the first century AD (Figure 1.1). The light source for a speculum was sunlight, so inevitably observation was limited to the openings of the body. After these primitive instruments, no significant progress was made until the nineteenth century.

Early endoscopes Although the first telescopes were developed in Europe in the early seventeenth century, it was Phillipp Bozzini who first tried to observe inside the human body, through a rigid tube without optics. He developed an apparatus called the light conductor (lichtleiter) in 1805, which he used in his attempt to observe rectum, larynx, urethra, and upper esophagus [5]. Bozzini was born in Mainz, Germany, in 1773 and started to study medicine there before moving to Frankfurt in 1803. He

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Figure 1.2 Bozzini’s “Lichtleiter” or light conductor (1806)b dotted cutaway diagram shows the spring-mounted candle with a mirror behind it.

was a man with a wide range of cultural accomplishments, including medicine, mathematics, engineering, and the fine arts. Bozzini’s instrument (Figure 1.2) can be seen in replica in the Museum of Medical History in the University of Vienna. It is essentially a lantern with round openings on its front and back walls but separated by a vertical partition into two parts. One side held the light source, a candle with a concave mirror behind it, the position of the candle flame being kept unchanged by a spring mechanism. Observation was from the back opening of the other (unlit) viewing side through a speculum attached to the front. Several different specula were available for observation of different organs. For inspection of the larynx, pharynx, and esophagus, a special lateral-viewing speculum was developed, at the tip of which was both a concave mirror and a flat mirror, the concave mirror giving a magnified close-up view and the flat mirror angling illumination. Using this device, Bozzini conducted experiments on corpses and patients. On December 9, 1806, a public demonstration on corpses using his light conductor was held during a meeting of the Imperial Joseph’s Surgical Academy in Vienna, now the Institute of Medical History, the University of Vienna. The details of this experiment are in the archives in Vienna, describing observation of the rectum, vagina, and uterine cervix of a corpse. In a second gathering of the Academy in 1807, using an improved version, observation was carried out of the rectum and vagina and also through a wound in the abdomen of the corpse. The first attempt to use

4

the device on a living patient was made during the same gathering. Based on these experiments, Bozzini published a book on his light conductor in 1807. However, the Faculty of Medicine of the University of Vienna would not permit further study of the device, which the authorities regarded as no more than a plaything or “lanterna magica in corpore humano,” of no medical value. Use of the light conductor was forbidden, partly because of rivalry between the Surgical Academy and the University, but also because of the conservative attitudes of the Viennese authorities. Bozzini’s death in 1809 stopped any further evolution. In 1826, Segales in France reported on a new method for examining the human bladder using a funnel-shaped metal tube, with a concave mirror and a candle light source. Fischer in America then developed another cystoscope in 1827, and Avery in England developed a similar instrument for observation of urethra, bladder, vocal cords, and esophagus, lit by reflected candle light using a concave mirror. These achievements in development of cystoscopes and urethroscopes were the foundation for subsequent development of gastrointestinal endoscopes, notably the open-tube rigid proctosigmoidoscope. In 1853, Désormeaux (1815–81) in France developed the first instrument of clinical value, primarily for diagnosis and treatment of urological disease, and called it the “endoscope” (Figure 1.3). The endoscope comprised a viewing tube and a light source unit, a “gazogene” lamp lit by a mixture of alcohol and turpentine. The viewing tube, at its junction with the light source, had an angled mirror with a small hole in the center reflecting the light from the flame through the viewing tube into the attached speculum. Observation was through a small hole at the end of the viewing tube, which swiveled at its connection to the light source so that the source stayed vertical. Désormeaux published a book in 1865 to summarize his achievements in observing urethra and bladder with the “endoscope.” In it he mentions that he had succeeded in observing inside the rectum as well, although without details, and predicted that it should prove possible to observe the stomach. Désormeaux’s endoscope was, however, essentially a hollow rigid tube with no lens or optical system. It was Kussmaul who further developed Désormeaux’s methodology, succeeding in making the first functional gastroscope in 1868. Kussmaul had first tried observing the rectum and then the esophagus with Désormeaux’s endoscope, observing cancer of the upper esophagus [5]. Kussmaul then developed a new version with a longer insertion tube, inspired by the performance of a sword-swallower who could insert a straight metal bar from his mouth into the esophagus, and was persuaded to come to the university to experiment. Kussmaul’s gastroscopes were brass hollow tubes of 47 cm in length and 1.3 cm in diameter, either round or oval in crosssection. No lens was used in the optical system, so, although he succeeded in inserting the tube into the stomach, the

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Figure 1.3 Désormeaux’s “endoscope” (1853)bwith (inset) cross-section showing the lens-less view through a perforated mirror, reflecting light from the source.

candle light source of the device was totally inadequate for gastric illumination, and attempts to use it were short-lived.

Electric lightcrigid rectoscopes and proctosigmoidoscopes Before the invention of the electric incandescent light bulb, it was known that bright light could be obtained by passing electrical current through a platinum wire, with water-cooling. This water-cooled electrical lighting system was applied to observation of the larynx in the 1860s and subsequently to other endoscopes, such as that of a German dentist in 1867, described as a “stomatoscope” and used to illuminate the mouthabut apparently also tried up the rectum (Figure 1.4). Nitze and Leiter made a cystoscope in 1879, and subsequently an esophagoscope and a gastroscope. Leiter, a Viennese optical instrument maker, also developed a rectoscope with a similar light source, although whether it was clinically useful is not recorded. With the introduction of Edison’s electric incandescent bulb in 1879 the size of bulbs reduced, while the brightness increased greatly. In 1886, Nitze and Leiter succeeded in developing a cystoscope with a miniature electric incandescent bulb at the tip, which became the basis for the development of subsequent gastrointestinal endoscopes (principally esophagoscopes and gastroscopes), as described in

Figure 1.4 “Stomatoscope” (1867, Breslau, Germany)bdesigned for oral illumination but used up the rectum. Note the water-cooled electric lighting system.

Edmondson’s excellent 1991 account [1]. Nevertheless, this technology was not used in the lower gastrointestinal (GI) tract until 1895, when Kelly in the US produced the first proctoscope of practical value, a metal hollow tube produced in various lengths [6]. It had an obturator for insertion, and

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illumination was by a concave reflector, as used by otorhinolaryngologists. The rectum was well seen but, even with longer versions, there was difficulty observing the proximal sigmoid colon because of poor illumination. In 1899, Pennington [7] sealed the eyepiece of the tube with a glass window, supplied air from a rubber ball to distend the sigmoid colon and inserted a small light bulb at the distal end for better illumination. The same year, Laws used a thin metal rod tipped by a miniature light bulb and inserted it through the proctosigmoidoscope for maximal illumination. In 1903, Strauss, in Germany, following Laws’ approach, developed a proctosigmoidoscope that distended the sigmoid colon with a rubber hand pump and safety bellows. This became the basis of commercially available Strauss-type proctosigmoidoscopes, which were widely used until the arrival of fibersigmoidoscopes. Strauss proctosigmoidoscopes consisted of metal tubes, 2 cm in diameter and of various lengths, inserted into the rectum or distal colon with an obturator in position. For observation the obturator was removed and a thin metal tube with a miniature light bulb inserted to the tip (Figure 1.5). A magnifying apparatus was available that could provide six times magnified images, showing early interest in the possibility of magnification in endoscopy. In 1910, Foges described a proctoscope with a miniature light bulb installed at the eyepiece window, while another proctosigmoidoscope with a light source at the eyepiece end was developed by Yeomans in 1912. Proctosigmoidoscopes from an outside light source with a fiberoptic light guide are still widely used. There are several lengths of rigid endoscopes for use in the rectum and sigmoid colon. Officially shorter ones, for use in the rectum, are called anoscopes, rectoscopes, or proctoscopes. Longer ones, for use in the distal sigmoid colon, have been called sigmoidoscopes or proctosigmoidoscopes. However, the terms anoscope, rectoscope, proctoscope, sigmoidoscope, and proctosigmoidoscope are effectively synonymous. Sigmoidoscopy has been performed in various positions, in lithotomy, lateral decubitus, or “chest–knee” position. It

seems that Kelly was the first to use, and emphasize the significance of, the chest–knee or “knee–elbow” position in order to air distend the sigmoid colon and optimize the view [6].

Rigid scope photography and special proctosigmoidoscopes Sigmoidoscopic photography was attempted using the Strauss sigmoidoscope with special apparatus. However, it proved difficult to take good pictures through sigmoidoscopes until the early 1960s. This was due to the low sensitivity of the available reversal color film used for slides (in 1960 Kodak film was only ASA 10) and the difficulty of achieving sufficient illumination with available built-in sigmoidoscope bulbs. In 1960, Sakita and Niwa and their coworkers developed a different type of picture-taking sigmoidoscope in order to obtain better pictures using a conventional Strauss-type sigmoidoscope equipped with a separate distal xenon lamp for photography. With the introduction of fiberoptic light guides, sigmoidoscopic photography transiently became popular but was supplanted first by colonofiberscopes and then by videoscopes as the means of taking pictures. Other specialized proctosigmoidoscopes which allowed magnified three-dimensional observation of the rectal and

(a) Expanded

Nonexpanded (b)

(c)

(d)

Figure 1.5 Strauss-type proctosigmoidoscopebstill widely used in clinical practice.

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Figure 1.6 Regenbogen’s sigmoidoscope. (a) Slotted end of tube. (b) Wire “extender” mechanism, closed and open. (c) Sigmoidoscope insertion stretches and angulates sigmoid colon. (d) Expanded “extender” grips and straightens colon on withdrawal.

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colonic mucosa were used by Niwa in 1965 [8], the proctoscope being coupled to a surgical stereomicroscope. Staining with pontamine sky blue or toluidine blue was described by Yamagata and Miura in 1961 for intraluminal microscopic observation of rectal mucosa, using a conventional sigmoidoscope with insertion of an “intraluminal microscope” to observe the pit openings with up to ×130 magnification. The first published report of similar dye-spraying methodology in the upper GI tract was not until 1966 [9]. A subsequent example of innovation was a special sigmoidoscope made by Regenbogen in Germany in 1966, attempting to visualize more proximal parts of the sigmoid colon (“high colonic endoscopy”) [10]. His sigmoidoscope had a rounded tip to help insertion through the bends of the sigmoid colon and an ingenious mechanism to assist insertion (Figure 1.6). Two slits in the body of the sigmoidoscope and a rubber covering allowed the atraumatic arms of an “extender” to open out through the slits, fixing the bowel wall so that it could be pulled back over the sigmoidoscopearather as a glove is pulled over the fingers. Regenbogen claimed that he could observe at least 15 cm deeper than with an ordinary sigmoidoscope. His approach anticipates the basis for current colonoscopic technique and even “double-balloon” endoscopy. Figure 1.7 Schaaf’s “device for intragastric photography” (1898) took only a single pinhole photographbso was impractical [12].

Gastrocameras, the “sigmoidocamera” and “colonocamera” Recent literature studies have revealed a number of surprisingly advanced experiments in the late nineteenth century in the US and Germany, attempting to capture photographic images of the stomach over 50 years before Japanese descriptions of functional gastrocameras. Edison’s description of the filament light bulb in 1879 was the breakthrough that was needed, although it was several years before miniaturized bulbs became available. In 1889, Einhorn, in the US (described by Bockus as a “gadgeteer”), tried what he called “gastrodiaphany”ailluminating the water-distended stomach with a light bulb on the end of a rubber tube, and viewing the glow through the abdominal wall [11]. He reported having inserted the device into the colon but failed to achieve his suggestion of incorporating a miniaturized camera. Schaaf, also in the US, in 1898 evolved the concept with a flexible rubber tube device “for intragastric photography” (Figure 1.7) [12]. It had a filament light bulb and miniaturized camera, but could take only a single picture and was therefore impractical. By 1897, Kelling, in Germany, had a relatively sophisticated forward-viewing rigid esophageal tube, tipped by a curved filament lamp surrounding a lens through which multiple photographs could be taken by advancing a (black and white) film strip. A year later, Lange and Meltzing, in Germany, reported a similar but superior device (Figure 1.8), side-viewing but able to take 50 photographs on a cable-controlled film

Figure 1.8 Lange and Meltzing’s surprisingly sophisticated film strip gastroscope (1898)bit failed only because of insensitive film.

strip after bellows inflation of the stomach [13]. This sophisticated instrument largely anticipated later Japanese gastrocamera developments, failing only because of the limitations of the photographic films then available, which were grainy and had poor sensitivity. In 1929, Porges and Heilpern reported their “Gastrophotor” (Figure 1.9), for use in the stomach and rectum [14]. This had an eight-pinhole stereoscopic camera, allowing simultaneous pictures to be taken of a wide area of stomach or rectum. The Gastrophotor set, as supplied commercially, contained two instrumentsaone for the stomach (black shaft) and one for the rectum (red shaft)abut there are no published reports of its clinical use in the rectum. Uji’s (1950) Japanese side-viewing and angulating film strip gastrocamera (Figure 1.10) proved able to take multiple

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Figure 1.9 Gastrophotor (1929)ba flexible multi-pinhole photographic tube. A rectal version was available.

(a)

Figure 1.10 Uji’s gastrocamera mechanism (1953)bnote the 30° angulation capability (and similarity to Figure 1.8). (b)

pictures, but was soon abandoned due to frequent malfunctions and poor-quality photographs. However, Sakita, of the University of Tokyo, made a number of technical improvements and also established the standardized routine for taking gastrocamera pictures, with later review of the images, so making the device practical for clinical use. The “sigmoidocamera” was trialed by Matsunaga and Tsushima in 1958 after modifying the commercialized Olympus type II gastrocamera [15]. A conventional sigmoidoscope was first inserted into the sigmoid colon and the sigmoidocamera passed through it to take pictures. In 1960, Niwa developed the prototype of a new colonocamera (Figure 1.11a) [16], a modification of the mass survey gastrocamera (later called the type V gastrocamera) but with a much longer shaft. The visual angle of the lens was 80° and the film used was 5 mm in width. With this prototype, photography up to the left (splenic) flexure was successful, the first time that observation of the proximal colon had been possible. Figure 1.11b shows an example of the pictures obtained with this instrument. Further improvements were then made and its length extended, which allowed insertion into the proximal colon under fluoroscopic guidance. By 1964, the Olympus gastrocamera with fiberscope (GTF) had been developed, the film-strip facility being retained as the images were much superior to those possible through the

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Figure 1.11 Niwa’s (a) “Colonocamera” (1960) and (b) image of sigmoid colon.

fiberoptic viewing bundle. The colonocamera concept was, however, impractical due to the poor pictures obtainable in the narrow colon lumen, very few of which were satisfactory. Nonetheless, the development of sophisticated insertion tubes and tip angulation mechanisms in these instruments formed the basis for the superior handling and angulating characteristics of later Japanese fiberscopes.

American fiberscope development While gastrocamera and colocamera development proceeded in Japan, Hopkins and Kapany in the UK, in 1954, had demonstrated crude image transmission down a short fiberoptic bundle (Figure 1.12) and speculated on its potential use for gastroscopy [17]. Hirschowitz, Peters, and Curtiss, at the University of Michigan, developed a fiberoptic viewing bundle by 1957 and used it to perform the first flexible gastroduodenoscopy [18]. They then worked with American Cystoscope Makers Inc. (ACMI) to produce prototype endoscopes, and by 1961 the ACMI “Hirschowitz fibergastroscope” was commercially available, creating excitement in Japan and around the world (Figure 1.13).

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Figure 1.12 The image quality of Hopkins’ original fiberoptic bundle.

History of Endoscopy in the Rectum and Colon

Figure 1.14 Prototype fibersigmoidoscope: Illinois Institute of Research (Overholt, 1963).

Figure 1.15 The first functional fibersigmoidoscopebfour-way angling: Eder Instrument Co. (Overholt, 1963).

Figure 1.13 Commercialized Hirschowitz fibergastroscope (American Cystoscope Makers Inc., ACMI, 1964), also used in the colon. Side-viewing, no angulation controls (focusing lever only), with transformer for distal tip light bulb.

Local academic disagreement at the University of Michigan, however, caused a delay in progress to the colon. Overholt, starting in 1961, obtained US government funding to start work on developing fiberscopes for sigmoidoscopy. By 1963, three different US teams had produced prototype short instruments and Overholt was able to perform the first flexible sigmoidoscopy with a relatively crude but four-way angling instrument (Figures 1.14 and 1.15). ACMI, a small company, had been preoccupied with gastroscope development and was unwilling to accept governmental conditions for colonoscope development. ACMI did, however, supply both passive viewing bundles and prototype side-viewing fibergastroscopes, which were used in 1966–68 by pioneer colon enthusiasts in the US [19], the UK [20], and Italy, but it was not until 1967, 10 years after Hirschowitz’s first gastroscopy,

that Overholt could report a series of 40 successful flexible sigmoidoscopies [21]. The US colorectal establishment showed little enthusiasm for the opportunities of fiberendoscopy, except as a superior light source for conventional proctosigmoidoscopes [22]. A fourth company, American Optical, was able to produce fiberoptic bundles [3] and sold some to Japan for use in prototype development. ACMI, partly because of the small and very flexible fibers produced by its development of the Hirschowitz and Curtiss two-glass drawn-fiber method of production (Figure 1.16), was able, by 1971 onwards, to produce highly robust colonoscopes. These were capable of acute tip angulation without damage to the fibers (a problem with contemporaneous Japanese fiber bundles), and had an innovative “flag-handle” method of controlling four-way angulation (Figure 1.17), although their mechanical construction and torque stability characteristics were somewhat inferior to those of Japanese instruments of the same period. The images obtained by later ACMI instruments were of superior size and without visible breakages, although they were often criticized as being “fuzzy” (Figure 1.18). The US medical endoscope companies (ACMI and, later on, Welch–Allyn) were too small to sustain the costs of long-term quality improvement, while larger corporations proved uninterested in the medical market, so, by the late 1980s,

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Figure 1.16 The original patent diagram (Curtiss and Hirschowitz, filed 1957; registered 1971)bdrawing a “two-glass” fiber through an electric furnace.

Figure 1.17 ACMI F9A “flag handle coloscope” (1974) with single lever giving four-way angulation control.

American colonoscope production ceased. ACMI at least had the satisfaction, on behalf of Hirschowitz and Curtiss, of winning the battle to establish their patent rights on the critical underlying principles for fiberoptic manufacture.

Japanese colonofiberscope development After introduction of the Olympus GTF gastroscope in 1964, attempts were made to utilize it for colonic examination. However, insertion into the proximal half of the sigmoid colon proved extremely difficult because of the shaft characteristics of the scope and the very limited field of view due to the side-viewing optical system. To adapt to the narrow and tortuous lumen of the colon, modifications were necessary to

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Figure 1.18 ACMI colonoscopic viewbno visible fiber breakages with the small fibers, but fuzzy.

make the shaft of the colonofiberscope more flexible and to alter the direction of optical view. A prototype forward-viewing “colonofiberscope” was first made by Olympus for Niwa in 1965 [8] (Figure 1.19a and b). Its angle of view was 35°, with fiberoptic illumination, but it was a passive bundle 2 m in length, with no angulation mechanism. Partly because the shaft was too stiff, insertion into the descending colon was very difficult and, when inserting into the proximal sigmoid colon, the tip tended to press into the colonic wall, losing the view. Observation during withdrawal was also difficult because of poor distance illumination. This passive prototype, inserted under fluoroscopic control, therefore proved impractical, although Niwa tried to avoid impaction by attaching a centering balloon at the tip end. The next prototype was a forwardor side-viewing colonofiberscope (Figure 1.20a) which could

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(a)

(a)

(b)

(b) Figure 1.19 (a) Prototype forward-viewing colonofiberscope [8]. (b) Example through the forward-viewing colonofiberscope.

be made forward- or side-viewing by changing the lens at its tip [23]. However, the image was not good, either in forward view (Figure 1.20babecause of poor illumination) or in side view (Figure 1.20cadue to an inner reflection at the cover glass of the lens). A “rotating prism” colonofiberscope was developed next (Figure 1.21) [24,25], the prism being rotated in either direction from the control body. The visual angle was 40°, it had four-way angulation of the bending section, and the shaft was 120 cm in length. Insertion into the descending colon remained very difficult with this model too, because of shaft stiffness and the long rigid metal tip. Once again the image was poor because of internal reflections from the illuminating light. From the experiments carried out on these various prototypes, the conclusions were that the colonofiberscope should have a more flexible shaft and needed a fore-oblique viewing lens. Oblique viewing was adopted to compensate for the narrow angle of view resulting from the limited resolution of the fiber bundle. The result was a prototype short colonofiberscope with only up-/down-angulation

(c) Figure 1.20 (a) The prototype forward- plus side-viewing colonofiberscope [23] (detachable side-viewing lens is on right). (b) Image through forward-viewing lens. (c) Image obtained with side-viewing attachment, showing limited view and unacceptable reflections.

using the same handle mechanism as in the esophagoscope already commercialized by Olympus at the time (Figure 1.22a) [25]. This colonofiberscope was deliberately made shorter than the earlier prototypes, which had proved difficult to use

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Figure 1.21 “Rotating prism” colonofiberscopebside-viewing with 30° view [23].

in the sigmoid colon, Niwa preferring to simplify design to observe the sigmoid colon effectively, as being the most common site of disease. Examinations were much easier with this prototype and images were reasonably goodadespite fiber breakages (Figure 1.22b). The first practical Japanese colono-

(a)

(b)

fiberscope had been invented at this point. Later, the length of the shaft was extended by 25 cm and the forward-oblique view changed from downward to upward, to coincide with the direction of bending of the sigmoid colon. This colonofiberscope became the basis of the CF-SB-type short colonofiberscope manufactured by Olympus (Figure 1.23) [26]. In contrast to the small fibers produced by the two-glass method used by the American manufacturers, the Japanese fiber bundle was, from an early stage, manufactured by the three-glass method [27]. This entailed orderly rows of coated glass rods being drawn out in a matrix of acid-leachable glass, which was finally dissolved away, leaving the characteristic orderly rows of glass fibers at each end. Olympus bundles were therefore better looking than the ACMI bundles, but had thicker fibers, limiting resolution and angle of view, and were more easily damaged (Figure 1.22b), so angulation of early Olympus colonoscopes was restricted to around 90°. This was the basis for problems experienced by Matsunaga and Tajima, whose aim was to reach the right side of the colon. Even using longer passive nonangulating prototypes, inserted

Figure 1.22 (a) Prototype short colonofiberscope (Olympus, 1968). (b) Image through prototypebnote typical broken glass fibers.

Figure 1.23 Olympus commercialized colonofiberscopes (1970–71).

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Other early approaches to the proximal colon

Figure 1.24 Machida fibercolonoscope control body (1970)bnote right- and left-hand controls, giving four-way tip angulation.

under X-ray control, they reported reaching “sometimes to the cecum.” By 1968, they were using a prototype fiberscope with a 120-cm-long shaft and four-way angulation [28], extending its shaft length to 2 m in 1969, the basis of the Olympus LB-type 180-cm-long colonofiberscope (Figure 1.23). However, insertion into the proximal colon was extremely difficult, and their success rate for insertion into the ascending colon was reported to be 8% in 1970. To overcome the problems of passing the sigmoid–descending colon angulation, they emphasized the virtue of “alpha loop” configuration in the sigmoid and the concept of the “alpha maneuver” in trying to achieve it. Yamagata and his coworkers developed yet another type of colonofiberscope, made by Machida. At first they used a scope designed for duodenoscopy in the colon, but insertion proved difficult. They later developed a scope with an oliveshaped tip (type IV) in 1966, other prototypes in 1968 and 1969, finally achieving a practical colonofiberscope with the development of type VII in 1970. The shaft of this prototype was 190 cm long with four-way angulation. It was the basis for the excellent and agile fibercolonoscope (Figure 1.24) manufactured by Machida, a small company which subsequently left the field. Many problems remained after commercialization, including the difficulty of insertion into the proximal colon and blind areas to observation, so research continued into all characteristics including optics, shaft flexibility, and structure [23,29–32]. Further improvements continued subsequently, especially in fiber bundle technology, so current Olympus colonofiberscopes have 140° angle of view, up/down distal angulation of 180°, and left/right angulation of 160°. There are also two channel types for therapy and thinner diameter “pediatric” models. The other Japanese manufacturers, Fujinon and Pentax, have similar products.

During the course of colonoscope development, various pioneering attempts were made to facilitate insertion of tubes, passive viewing bundles, and early prototypes into the proximal colon. Fox, in the UK, originally passed a suction biopsy capsule through a flexible polyvinyl tube inserted under fluoroscopy [33] and then, cooperating with Revignas in Italy, pulled a passive bundle (ACMI) or fibergastroscope into the proximal colon [21]. For intestinal pull-up (“end-toend method”), an intestinal tube was swallowed by the patient the day before examination [33–35]. In the “pulley” approach, a loop was then made in the tube when it emerged from the anus, threaded through with another string connected to the tip of the colonofiberscope; the looped tube was pulled back from the mouth into the proximal colon and used as a pulley, through the loop of which the anal pull-string could tug the endoscope into the proximal colon [34]. For “string guidance,” the tube emerging from the anus was inserted through the biopsy channel as a guide to help insertion proximally [35]. There were many other attempts to facilitate insertion. These included accessories such as a guiding split-sigmoidoscope, which was withdrawn and dismantled after inserting the fiberscope through it, and overtubes [36,37]. “Splinting tubes” or “overtubes” were used to maintain straightening of the colonoscope, but it was necessary to apply the overtube over the colonofiberscope before the procedure, and use of fluoroscopy was desirable for safety because the tube was wire reinforced, stiff, and could traumatize the colon. Improvements were tried (demountable assembly or split-type overtubes), but did not prove popular. Prototype Gortex “split overtubes” overcame this problem and were floppy enough to be inserted without using fluoroscopy. However, with the development of “one-man” colonoscope handling technique and better understanding of loop control, less flexible scopes became more popular and stiffening overtubes are currently rarely used. Spring steel stiffening wires were inserted up the instrumentation channel by some colonoscopists in the early 1970s to maintain straightening. ACMI F9A offered a variablestiffness wire in 1974 that consisted of a core tensioning wire surrounded by a 3.5-mm coil. Tensioning the core wire, the outer coil contracted and stiffened. The large diameter required to achieve effective stiffening, however, restricted its use to large-channel “therapeutic colonoscopes” such as the ACMI F9A. Similar but thinner wires made for standard colonoscopes did not produce the desired stiffness.

Polypectomy Flexible endoscope snare polypectomy (for many years routine in rigid endoscopic practice) was originally pioneered by

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Niwa in the stomach in 1969, presented at Japanese Society meetings and reported in Japanese-language abstracts [38]. Niwa had first experimented with electrosurgery on the basis of avoiding implantation of malignant cells during diagnostic biopsy (anticipating the principle of “hot biopsy,” as later reported [39]). Shortly after Niwa’s Japanese-language reports of successful snaring, Western endoscopists, notably Shinya in New York (with an ingenious home-made snare developed from 1969) [40] and subsequently Deyhle of the Erlangen group (with a commercially available Storz snare) [41], spread the word about the feasibility of colonoscopic polypectomy, instantly transforming the value of colonoscopy worldwide. Deyhle, in 1973, described the feasibility of submucosal saline injection before polypectomy, but this approach was not generally appreciated until the concept of endoscopic mucosal resection, first introduced for management of Japanese upper GI pathology and applied to the colon in 1993 [42] before being adopted around the world.

The transition to electronic endoscopes Fiberoptic endoscopes enabled examination of body cavities, but by only one personathe operator. “Lecture-scopes” (teaching attachments) were developed to overcome this problem. A prism was attached to the scope eyepiece with a fiber bundle to send the same visual information to another eyepiece, so two people could observe the same image. However, the attachment resulted in a darker view for the operator as well as some clumsiness of control, especially during complex maneuvers. To improve image quality, endoscopists began direct connection of video cameras to the scope eyepiece lens. Initially, a three-tube camera was suspended from the ceiling and attached to an endoscope (Ikegami, Tokyo), but this proved cumbersome and the scope often dislodged on rotation. Nonetheless, the images obtained were displayed on a large television monitor and easily recorded on videotape, adding to the interest of the procedure not only for the operator but also for the many observers. A commercially available TV camera was subsequently used (Keymed, London), connection between eyepiece and camera being by 30-cm straight tubes and prismatic joints. Maneuverability was improved, but the scope had to be disconnected for de-rotation and the TV trolley was too large and heavy to move around conveniently. A single-tube camera was eventually developed (OTV-E, Olympus) that could be directly attached to the eyepiece, similarly to a lecture scope. It was rectangular (length 14 cm, weight 290 g plus cable) but caused strain on the examiner’s left hand, because of its attachment to the end of the control body and eyepiece. Compared with the larger cameras, brightness was poor, but nonetheless it proved popular with endoscopists. Units continued to become smaller with the

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introduction of charge-coupled device (CCD) technology, decreasing to 7.5 cm in length and 150 g in weight (OTV-F3, Olympus). However, the poor quality of the enlarged fiberoptic images displayed on the TV monitor encouraged development of electronic endoscopes.

Videocolonoscopes Progress in electronics led to the American development in 1969 of silicon CCDs containing picture elements (pixels) able to generate electric signals in response to light. Even though Japanese glass fibers were reduced down to 7 μm diameter, with minimal “packing fraction” between fibers and superior resolution, CCD images were able to be made several-fold higher in quality. Early CCDs were too large for small-diameter gastroscopes, so the first “videoendoscope” was a colonoscope produced in the US by Welch–Allyn Company in 1983 and reported by Sivak and Fleischer [43]. However, placement of the CCD directly behind the objective lens made the instrument tip more bulky and stiff. The bending section was less agile than that of a fiberoptic colonoscope, so more difficult to retrovert and sometimes restricted angulation and view. Videoendoscopes were initially received with surprise and skepticism by Japanese manufacturers, but market forces soon led to their adoptionavideocolonoscope sales rapidly overtaking those of fiberoptic instruments. Two different methods were devised to display video endoscope images in color, the “sequential system” and the “white light” or simultaneous system (see Chapter 21). “Sequential” CCDs had the initial advantage of smaller CCD size (or higher resolution) and greater opportunity for electronic image manipulation, and on this basis were adopted for use by Japan and the UK. The rest of the world favored the cheaper and more stable “white light” system, the larger CCD resulting in slightly larger-diameter instruments (so many endoscopists therefore favored adoption of thinner, more agile pediatric colonoscopes).

Image manipulation Electronic endoscopes opened up numerous possibilities for image processing, well beyond the simple “iris” automated light control facility built into fiberscope light sources from the earliest days. Switches for freeze frame, image output, or image enhancement have been useful for routine practice, but developments continue and a range of more sophisticated options is available for trial (see Chapters 36–39). Facilities such as magnification or “zoom,” which initially have required specialized instruments (Figure 1.25), could become incorporated into standard colonoscopes and, coupled with the opportunities for electronic enhancement and color manipulation, raise the possibility of “instant histology” or “optical biopsy”aconvenient and time- and money-saving.

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Figure 1.25 Zoom lens mechanism of magnifying videocolonoscopesb piezoelectric actuator adjusts position of the moveable lens.

Shaft characteristics The need for ultra-thin endoscopes is less important in the colon than in the upper GI tract. However, while an external diameter of 11–13 mm permits good maneuverability, the instrumentation channel should have an internal diameter of at least 2.8 mm, but larger if possible, to facilitate the passage of accessories. Ultra-thin fiberscopes were technically easy to manufacture and were commercially available from the earliest days of endoscopyaACMI in the US had a 2.5-mm passive fiber “ureteroscope” in 1967, and a 2-mm angulating fiberscope is available. Very flexible ultra-thin scopes were therefore also developed and manufactured. To produce ultra-thin scopes, the length of the bending section had to be

(a)

(b)

History of Endoscopy in the Rectum and Colon

shortened and the radius of curvature during maximal bending reduced. The technology involved to achieve this was applied to standard adult endoscopes, permitting more acute angulation while also allowing accessories to be passed in easily. However, sometimes looping cannot be avoided, even if a very stiff scope is usedaand formation of a loop in a stiff scope generally causes the patient considerable discomfort. Scopes using the same principle as a stiffening wire were therefore developed, based on a 1975 prototype made for UK use (Figure 1.26a) and commercialized by 2000 (Innoflex, Olympus) (Figure 1.26b). Stiffness is applied by twisting the tensioning ring installed between the control body and shaft. The shaft characteristics are designed to be only slightly stiffer than a pediatric scope when set to “floppy,” but similar to a hard scope when set to “stiff.” A pediatric thin colonoscope incorporating the same mechanism was also produced. More improvements are still needed because shaft looping remains the major problem in colonoscopyabut angulation control mechanisms and control body ergonomics also need to evolve, so as to allow easier handling.

Imaging shaft configuration During the early development of colonoscopy, location of the tip of the scope in the abdomen could be determined only by fluoroscopic imaging. This was a common accompaniment to colonoscopy, which gradually became less useful as doctors became more familiar with the intraluminal anatomy. However, it can be helpful to see the configuration of the scope during colonoscopy (without the use of fluoroscopy), particularly for teaching or when difficult and persistent or atypical looping occurs during the procedure, when the patient suddenly complains of pain, or to confirm the site of lesions.

(c)

Figure 1.26 Shaft-mounted stiffening control of Olympus Innoflex “variable” colonoscopes: (a) 1975 prototype fibercolonoscope; (b) 2000 commercialized version on a videocolonoscopebnote that control body ergonomics are little changed, other than adding switches; (c) views of the same colonoscope shaft flexing under gravity, between “stiffened” (above) and “unstiffened” (below).

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Figure 1.27 Electromagnetic imaging of colonoscopy (ScopeGuide, Olympus). (a) Anteroposterior and (b) lateral (posterior, left: anterior, right) views of a sigmoid spiral loop.

To overcome such uncertainties, two different UK groups produced prototype “3-D magnetic imaging” systems, one in 1993 [44] and one in 1994 [45], which were finally commercialized as the Olympus “ScopeGuide” or “UPD” 3-D imager in 2002, and other manufacturers have prototype systems. Small electromagnet generator coils are installed inside the scope at about 5-cm intervals from the tip, each coil activated at a different frequency five times per second. Sensor coils in the sensor dish detect the magnetic fields produced by each generator coil, and the induced currents and resultant position-sensing information for all coils are processed by the computer and displayed as a 3-D moving image of endoscope shape. The strength of the magnetic fields is minimal by international specifications (comparable to that of a TV monitor), so the system is safe for continuous use. Images showing the shape of the scope can be displayed relating to the patient’s position. In addition, both frontal [anteroposterior (AP)] and lateral views can be displayed simultaneously on a split screen (Figure 1.27). A hand coil can be used during abdominal manipulation to ensure that the assistant’s hand pressure is correctly located over a loop.

the need for easy and rapid colon-screening examinations, so the international endoscopic scene remains lively and creative. Endoscopists around the world, however, have pioneered development of hands-on colonoscopic technique, perhaps inevitably so, because of the greater Western focus on colorectal disease than the Japanese concerns about early gastric cancer. Whereas in Japan and Europe academic hospitals took the lead in colonoscopy, in the US private practitioners rapidly became the leading exponents and best teachers. Thus, Shinya [46] and Waye [47] played a leading role from the 1970s and Waye has enlivened world colonoscopy with his presentations and verve ever since. Deyhle in Germany [48], Rossini in Italy, Williams in England [49], and Sakai in Japan also made important contributions in the early days. Their individual styles of colonoscope handling varied enormously, with corresponding effects on those influenced by them. Shinya and Deyhle tried for a “straight scope” approach with stiffer instruments, probably resulting in Germany favoring 130-cm stiffer instruments, and Australia relying extensively on anesthesia because of stiffer scopes. Waye and Williams taught logical loop management using more flexible and longer colonoscopes. Rossini favored a two-man insertion technique, which became widely used in Italy. Sedation requirements were inevitably affected by the approach used, but in some countries also by the “politics” of hospital practiceawith anesthesiologists tending to dominate (and anesthetize) in France and Italy. The chapters of this book outline the great range of subsequent input from numerous innovative endoscopists around the world, led perhaps by Rex in the US for his stupendous academic output, but with others of considerable distinction making their mark in the literature and on practice locally. Japanese endoscopists have also continued to make outstanding contributions, with special focus on image quality and therapeutic innovations deriving from their upper GI tract expertise, but with increasing focus on the colon and a growing tendency to publish in the Western literature. In this respect Tada [50,51] and Kudo [52] have had outstanding records, but other individual and pioneering contributions are referred to in the chapters of this book.

Summary Other countries’ and individuals’ involvement in colonoscopy Only limited manufacture of short colonoscopes occurred in the rest of the world, and used Japanese fiber bundles. In Germany, the Storz and Wolff endoscope companies achieved small-scale production, while in Russia and China largerscale manufacture was licensed. UK prototype developments were abandoned at an early stage. However, many innovations in optoelectronics, mechanisms, and accessories are emerging from Israel and the US (see Chapter 58), largely stimulated by

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The long history of rigid endoscopy, having started in the genitourinary and upper GI tract, was initially limited to the rectosigmoid area but was transformed by Edison’s invention of the filament light bulb in 1879. Introduction of fiberoptic gastroscopy in the US in 1957 was, because of academic negativism, not immediately transferred to the colon. Gastric cancer was the Japanese national priority and development of gastrocameras by pioneer enthusiasts provided torque-stable shafts and superior angulation and control mechanisms. These, adapted to fiberoptics

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and the colon in prototype development during the 1960s and 1970s, resulted in highly sophisticated fibercolonoscopes by the end of the millennium. Introduction of CCDs allowed application of digital electronics and image enhancement to “videocolonoscopy” after 1983. Other innovations continue to be developed, with competitive and parallel methodologies emerging. Colonoscopy, originally considered the Cinderella of endoscopic techniques, has emerged as the most vibrant and dominant part of the gastrointestinal endoscopy scene, likely to maintain its importance for years to come. Amazingly, Hirohumi Niwa, having been “in at the birth” of colonoscopy, remains president of the Japanese Society of Digestive Endoscopy and a practicing endoscopist over 50 years later.

References 1 Edmondson JM. History of the instruments for gastrointestinal endoscopy. Gastrointest Endosc 1991; 37: 27–56. 2 Modlin IM. A Brief History of Endoscopy. Milan: Nexthealth, 1999. 3 Hecht J. City of Light. Oxford: Oxford University Press, 1999. 4 Villardell F. Digestive Endoscopy in the Second Millennium. Stuttgart: Thieme, 2006 . 5 Solinas A, Classen M. Phillipp BozziniaA true pioneer of endoscopy. Ital J Gastroenterol 1985; 17: 43–5. 6 Kelly HA. A new method of examination and treatment of the diseases of the rectum and sigmoid flexure. Ann Surg 1895; 21: 468–78. 7 Pennington JR. Inflating rectal specula. J Am Med Assoc 1899; 30: 871– 4. 8 Niwa H. The limits of endoscopy and ways of overcoming them: endoscopy of the colon [in Japanese]. Gastroenterol Endosc 1965; 7: 403– 8. 9 Tsuda Y, Aoki S, Kanai T, et al. Endoscopic observation of gastric fine lesions with dye spreading method. Gastroenterol Endosc 1996; 8: 412–13. 10 Regenbogen E. Report about two methods of endoscopy of the upper colon regions. In: Proceedings of the First Congress of the International Society of Endoscopy, Tokyo, 1966: 421–4. 11 Bockus H. The Einhorn story. Gastroenterology 1978; 74: 949–50. 12 Schaaf EO. Photography of the stomach. English Mechanic World Sci 1898; 1754: 271. 13 Lange F, Meltzing D. Die photographie das mageninnern. Munchen Med Wschr 1898; 45: 1585– 8. 14 Porges O, Heilpern J. Besprechung an der Gesellschaft der Artzte in Wien. Wien Klin Wschr 1929; 42: 889. 15 Matsunaga F, Tsushima H. Prototype sigmoidocamera and its clinical application [in Japanese]. Clin All Round 1958; 7: 1378. 16 Niwa H. Photographing mucosa of the colon and other organs [in Japanese]. Gastroenterol Endosc 1960; 2: 77–8. 17 Hopkins HH, Kapany NS. A flexible fiberscope, using static scanning. Nature 1954; 173: 39– 41. 18 Hirschowitz BI. A personal history of the fiberscope. Gastroenterology 1979; 76: 39– 41. 19 Lemire S, Cocco AE. Visualization of the left colon with the fiberoptic gastroduodenoscope. Gastrointest Endosc 1966; 13: 29 –30.

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20 Fox JA. A fibreoptic colonoscope. Br Med J 1969; 3: 50. 21 Overholt BF. Clinical experience with fibersigmoidoscope. Gastrointest Endosc 1968; 15: 27. 22 Turell R. Fiberoptic colonoscope and sigmoidoscope, preliminary report. Am J Surg 1963; 105: 133–5. 23 Niwa H, Utsumi Y, Nakamura T, Yoshitoshi Y. Endoscopy of the colon. In: Proceedings of the First Congress International Society of Endoscopy, Tokyo, 1966: 425–31. 24 Yoshitoshi Y, Oda T, Utsumi Y, et al. Fiberscope of the colon [in Japanese]. Gastroenterol Endosc 1966; 8: 154–5. 25 Niwa H, Utsumi Y, Kaneko E, et al. Clinical application of colonofiberscope [in Japanese]. Gastroenterol Endosc 1969; 11: 163–73. 26 Niwa H, Utsumi Y, Kaneko E, et al. The new colonofiberscope [in Japanese]. Gastroenterol Endosc 1969; 11: 219. 27 Kawahara I, Ichikawa H. Flexible endoscope technology. In: Sivak MV (ed.). Gastroenterologic Endoscopy, 2nd edn. Philadelphia: WB Saunders Co., 2000. 28 Matsunaga F, Tajima T, Uno C, et al. The new colonofiberscope (2nd report) [in Japanese]. Gastroenterol Endosc 1969; 11: 219. 29 Niwa H, Kimura M, Miki K, et al. Evaluation of appropriate stiffness and elasticity of colonoscope proper [in Japanese with English abstract]. Gastroenterol Endosc 1980; 22: 1227–32. 30 Niwa H, Nakamura T, Miki K. Evaluation of optical system in fibercolonoscopeaTrial manufacture of an instrument with 30° deviation optical system [in Japanese with English abstract]. Gastroenterol Endosc 1974; 16: 591–7. 31 Niwa H, Kimura M, Miki K, et al. Clinical evaluation of optical system in colonoscopeaTrial manufacture of a colonofiberscope with a wider view field [in Japanese with English abstract]. Gastroenterol Endosc 1981; 23: 283– 91. 32 Niwa H, Fujino M, Yoshitoshi Y. Colonic fiberscopy for routine practice. In: Advances in Gastrointestinal Endoscopy (Proceedings of the 2nd Congress of International Society of Gastrointestinal Endoscopy, Rome, July). Padova: Piccin Medical Books, 1972: 549–55. 33 Fox JA. Mucosal biopsy of the colon by retrograde intubation aResults and application. Br J Surg 1967; 54: 867. 34 Provencale L, Revignas A. An original method for guided intubation of the colon. Gastrointest Endosc 1969; 16: 11–17. 35 Hiratsuka H. Insertion technique using intestinal string guidance method colonofiberscopeaEspecially in the observation results in ileoceccal area [in Japanese]. J Gastroenterol 1970; 67: 686– 96. 36 Makiishi H, Kitano A, Kobayashi K. A “Sliding Tube” method available for colonofiberscopy [in Japanese with English abstract]. Gastroenterol Endosc 1972; 14: 95–101. 37 Niwa H, Miki K, Fujino M, Hirayama Y, Ikeda M, Oda T. A sliding tube for colonoscopy that can be attached and removed during the examination [in Japanese with English abstract]. Gastroenterol Endosc 1978; 20: 438– 44. 38 Niwa H. Endoscopic polypectomy using high frequency current [in Japanese]. Abstract. Gastroenterol Endosc 1969; 11: 437. 39 Williams CB. Diathermy biopsyaA technique for the endoscopic management of small polyps. Endoscopy 1973; 5: 215–18. 40 Sivak MV. Polypectomy: looking back. Gastrointest Endosc 2004; 60: 977– 84. 41 Deyhle P, Seuberth K, Jenny S, Demling L. Endoscopic polypectomy in the proximal colon. Endoscopy 1971; 3: 103–5. 42 Tada M, Murakama A, Karita M. Endoscopic resection of early gastric cancer. Endoscopy 1993; 25: 445–50.

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43 Sivak MV, Fleischer DE. Colonoscopy with a videoendoscope: preliminary experience. Gastrointest Endosc 1984; 30: 1– 5. 44 Williams CB, Guy C, Gillies D, Saunders BP. Electronic threedimensional imaging of intestinal endoscopy. Lancet 1993; 341: 724–5. 45 Bladen JS, Anderson AP, Bell GD, Rameh B, Evans B, Heatley DJ. Non-radiological technique for three-dimensional imaging of endoscopes. Lancet 1993; 341: 719–22. 46 Wolff WI, Shinya H. Colonofiberscopy. J Am Med Assoc 1971; 217: 1509–12. 47 Waye J. Colonoscopy. Surg Clin North Am 1972; 52: 1013–24.

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48 Deyhle P, Demling L. ColonoscopyaTechnique, results, indication. Endoscopy 1971; 3: 143– 51. 49 Williams C, Muto T. Examination of the whole colon with fibreoptic colonoscope. Br Med J 1972; 3: 278– 81. 50 Tada M, Misaki F, Kawai K. A new approach to the observation by means of magnifying colonoscopy. Type CF-MB-M (Olympus). Gastrointest Endosc 1978; 24: 146. 51 Kudo S, Miura K, Takano M, et al. Diagnosis of minute carcinoma of the colon. Stomach and Intestine 1990; 25: 801–12. 52 Tada M, Inoue H, Yabata E, Okabe S, Endo M. Feasibility of the transparent cap-fitted colonoscope for screening and mucosal resection. Dis Col Rectum 1997; 40: 618– 22.

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The Colonoscopy Suite Martin E. Rich Martin E. Rich Architect PC, New York, NY, USA

Creating a suite for colonoscopy is a balanced orchestration of appropriate space, logical flow, and integration of the tools needed to perform the procedure safely, efficiently, and with consideration for patient comfort. The introduction and general acceptance of the video endoscope in the early 1980s initiated a transformation in the planning of spaces for endoscopic procedures. The 1990s witnessed further expansion of this technological transformation worldwide as the digital revolution unfolded. This coincided with a sharp increase in the cost of medical care and shrinking insurance reimbursements, particularly in the US. Consequently, in the twenty-first century, planning for endoscopy confronts three established conditions: • A technology based on digital video imaging. Gastrointestinal endoscopy is routinely performed with video devices. This technology fundamentally affects the physical space in which the endoscopist works. It influences how equipment is handled, how images are viewed, and how information is processed. It places important requirements on the infrastructure that makes it all possible. • The use of computers and computer connectivity to manipulate, process, store, and transmit images. The dependence on computers in every facet of medicine has been keenly felt in the endoscopy setting. The natural extension of the video endoscopic procedure is the ease with which digital images and information can be utilized. As bandwidth has increased and become readily accessible, the printing, sharing, and moving of information has become routine. The endoscopy practice of the future may very well be a collection of remote sites linked by the Internet, with opportunities for physicians at many locations to participate in procedures, research, or administrative activities. • Economic constraints influenced by managed care and government reimbursement policies. These necessitate careful use of resources and funds in order to provide safe and efficient

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

settings. The benefit of screening colonoscopy and the approval, in the US, of Medicare coverage for this procedure in normal-risk individuals creates additional economic pressure. The challenge of creating a viable facility in light of narrower operating margins underscores the need for properly designed facilities. The need to acknowledge these factors has changed the way we think about and design endoscopy facilities. As in other areas of medicine, they create significant concerns for physicians who are planning facilities, and further complicate the normal problems associated with construction. In addition, environmental concerns worldwide are impacting the planning of medical facilities. In the US, the introduction of high-performance environmental criteria at state and municipal levels will increasingly require interdisciplinary efforts to guide facility design. The overall planning process needs to include strategies for addressing water and energy use, materials and waste minimization, as well as indoor environmental quality. The purpose of this chapter is to offer basic concepts and layout principles that can be generally applied, as well as guidelines and details that will help address current and future needs. While the primary experience of the author is with issues particular to units in the US, most principles are universal and will apply in many other countries. Whether the project is large or small, office, ambulatory center or hospital, or new construction or renovated space, effective planning is critical. The commitment to create, expand, or redevelop an endoscopy center must include provision of appropriate time for planning and construction, and for operational activities to be put in place. A small to medium-sized project can require 12–24 months of effort to achieve fruition (Figure 2.1). The impulse to repeat past experience should be resisted, and planning should focus on understanding underlying principles and preparing a sound analysis of current and future needs. Establishing the requirements for a proposed facility can occupy half of the overall project schedule, depending on the complexity of the facility. It is important to document this decision-making process so that goals, findings, and priorities are kept in focus, particularly when the personnel

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Step 1/start planning Preplanning

Planning

3 months

3 months

Implementation

5 months

Move

1 month

1 year

Figure 2.1 Project schedule.

involved with the process may not see it through from beginning to end. There are four principal stages of implementing any project: Phase 1: defining needs, collecting, and assessing data (a) Location and type; existing or new; office, ambulatory center or hospital. (b) Case load, facility size, and overall objectives. (c) Licensure and accreditation requirements; certification and agency approvals. (d) Outline of requirements to satisfy present and future needs. Phase 2: design and layout (a) Arrangement of components and flow patterns. (b) Block layout and preliminary design. (c) Design development and detailed layout: • equipment type, size, and installation • electrical wiring and video networking • environmental considerationsaheating, air conditioning, and ventilation • procedure room design • operational considerationaquality control • certification and accreditation requirements • interior design. Phase 3: documentation and enumeration (a) Construction documents. (b) Engineering specifications. (c) Equipment integration. (d) Voice and data (including wireless) networks. (e) Agency approvals, licensing certification. (f) Estimation of cost and schedule. (g) Furniture and equipment specifications. Phase 4: implementation and operation (a) Construction and finish work. (b) Equipment and furniture installation. (c) Inspection and approvals. (d) Moving logistics. (e) Organization and operation.

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Before physical planning begins, basic decisions must be made about the character of the project. Generally, an office facility will be small, with few practitioners involved and a relatively simple decision-making process. An ambulatory facility will be more complex, and planning will involve more people to work through the basic issues as well as the necessities of licensing, code compliance, and certification. An endoscopy unit in a hospital must satisfy the requirements of many diverse groups, and planning is needed for manifold and sophisticated procedures. Getting appropriate help is essential since the planning and construction process is a team endeavor. It requires the vision of the physicians and medical staff, and the participation of architects and engineers, medical equipment and technology specialists, computer and communications consultants, and legal, business, and licensing advisors. There is no substitute for an experienced planning professional who can facilitate the process and help integrate the varied requirements into a unified whole. The effort to develop a creative approach to communication will be rewarded with less chance of costly errors later on. Spaces designed for colonoscopy are equally suited for esophagogastroduodenoscopy (EGD) examinations, and rooms for these procedures will be designed in all types of gastrointestinal (GI) units, including hospitals, medical offices, and ambulatory centers. Hospitals have unique and complicated requirements apart from office and ambulatory locations. However, there are significant (and legal, in the US) differences between office units and ambulatory centers that require some clarification.

Offices The GI office is often a place where the practice of gastroenterology is combined with procedure work. Roughly 3% of all endoscopies in the US are carried out in offices. In small practices, procedures often have been performed in any available area that is large enough for both patient and physician. Many of these spaces are inadequate and do not fully bring patient comfort or safety into account. As practices become more established, dedicated areas for performing procedures are usually developed to provide efficient facilities for the increased caseload. Office-based endoscopy has not historically been subject to specific standards other than local building and health codes. This has changed. Legislation in the US is increasingly requiring accreditation of office-based facilities where procedures are performed using moderate sedation. Though it is directed at office-based surgery, it is typically interpreted to include GI procedures. The accreditation review by organizations such as the Joint Commission [formerly Joint Commission on the Accreditation of Healthcare Organizations (JCAHO)], the American Association for Accreditation of

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Ambulatory Surgery Facilities, and the Accreditation Association for Ambulatory Health Care includes planning and construction requirements for office-based GI endoscopy services. Accreditation standards, such as the American Society for Gastrointestinal Endoscopy guidelines, while less comprehensive than licensing criteria for ambulatory centers, will have significant impact upon the size, design, and cost of offices.

Ambulatory facilities In the US, an ASC (ambulatory surgical center) or AEC (ambulatory endoscopy center) is a dedicated and certified facility entitled to receive facility fee reimbursement from Medicare and third-party insurers. This certification is granted to units that comply with state licensing regulations (where applicable) and receive certification from the Centers for Medicare and Medicaid Services (CMS, formerly HCFA) or another accrediting agency. Some state laws do not differentiate between ASCs and AECs insofar as where endoscopy must be performed, while states that do differentiate may have less restrictive requirements for an AEC. As a rule, in the US, requirements in the licensing codes and accreditation standards incorporate recommendations from the Guidelines for Design and Construction of Hospital and Health Care Facilities. This is a manual of performance and prescriptive standards published periodically by the American Institute of Architects and the Facilities Guidelines Institute with assistance from the US Department of Health and Human Services. The 2006 edition has been extensively revised to include specific requirements for GI endoscopy facilities. These guidelines include minimum room sizes, door and corridor widths, as well as functional requirements, construction and plumbing details, and air-conditioning standards. The recommendations ensure a level of safety and quality comparable to those found in hospital facilities but at a higher cost than an office installation. The requirements dictated by codes and regulations in the US for ASCs are summarized on p. 40. Similar codes regulate minimum standards, particularly in the case of hospital ambulatory units, in most industrialized countries (p. 40). The design objectives for any endoscopy facility, whether or not decreed by law, should facilitate the realization of high-quality endoscopy in a safe, efficient, and reassuring setting. If planned well, endoscopic procedures can be handled smoothly and economically in a comfortable and effective work environment. Basic considerations are appropriate, irrespective of the unit size, or whether the space is a hospital endoscopy unit, an AEC, or a GI office.

Assessment and programming After establishing general goals, specific needs should be defined by critiquing existing operations and visiting other facilities in order to define requirements such as range of services, caseload projections, and concepts of how the practice

The Colonoscopy Suite

will be managed. This will have a direct impact on the amount of space needed, which can be expressed in a written program. Architectural services generally include programming, to organize the type, size, and character of spaces and supporting services required in the design. The development of a space program is the opportunity for physician and designer to reach a common understanding of the composition of the facility. Program preparation involves collecting, organizing, and evaluating criteria. The information may be assembled through interviews directly with staff or through a designated person or committee assigned the task of coordinating the collective effort. It is important that planning activities be formalized in order to establish a framework in which the physician and planner can interact without distraction. During the planning phase, 2–3 h per week should be allowed for review meetings. The program is a summary of the area [feet squared (ft2) or meters squared (m2)] requirements of all spaces. The following basic decisions must be addressed: • number and size of procedure rooms; • amount of recovery area; • scope cleaning and storage requirements; • seating requirements of the waiting area; • size of the administrative operation; • amount of space needed for computers and related equipment; • number of physicians’ consultation rooms.

Number of procedure rooms The benchmark for an endoscopy facility is the number of procedures that can be performed in a given time frame. There is a direct relationship between the number of rooms and the number of procedures that can be performed. In hospitals, additional factors, such as teaching requirements, the use of anesthesiologists and fluoroscopy, and the performance of complex procedures, have a notable impact on the number of rooms required to accommodate a given caseload as well as the range of endoscopy services offered. An endoscopist can generally provide data on how many colonoscopies and EGD procedures were performed in the past year, as well as the amount of time required for the completion of each type of examination. From this information, it is possible to project the number of procedure rooms required, as well as the amount of space that will be needed for recovery and other functions. For planning precision it is useful to determine the total number of colonoscopies and EGD endoscopies that will be performed per year and then calculate an average daily caseload. This is done by dividing the yearly case total by the number of working days, generally in the neighborhood of 250 days per year. A growth rate should be estimated from historical data, to

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project a potential volume of cases to be performed in the future. Planning should always be done for a projected volume not solely based on present numbers. It is also important to anticipate whether physicians will be added to current staff, as this will affect how efficiently the rooms will be used due to the increase of scheduling complexities. In addition, some attempt should be made to assess the potential impact on growth rate caused by new technologies such as virtual colonoscopy and wireless imaging capsule endoscopy (Given and Olympus). A raw count of cases is not an absolute measure of volume, since a colonoscopy will occupy an endoscopy room considerably longer than will EGD procedures. The age and healthiness of the patient base will also have an impact on the average procedure times for a unit. Hospitals units will tend to handle older and sicker patients and must add complex procedures to the overall number of cases, which also take more time than standard endoscopies. These procedures include endoscopic ultrasound and endoscopic retrograde cholangiopancreatography. If these procedures are not currently performed, but are possible in the near future, space and time must be factored into the plans. Some assumption must be made as to the balance of colonoscopy to upper endoscopy (and other complex examinations) and to the average duration times of these procedures. An individual assessment of each group’s characteristics (some may have a greater demand for fluoroscopy) should also be made to determine how scheduling issues or other factors might affect the amount of work that may be performed. By assessing the individual practice characteristics, the speeds of the physicians and the efficiency of the staff, the average procedure

time, including room preparation, can be estimated. It should be noted that these data gathered at one facility are not necessarily transferable to any other facility. Dividing the working hours in a typical day by the average procedure time, including room preparation, results in an approximate capacity of procedures per room (PPR). Dividing the projected number of cases per day by the capacity per room will provide the number of rooms required (ER). The formulae below express the relation between time, room output, and the resulting number of procedure rooms required. Daily projected volume (PPD)

(PPR)

(ER)

Annual projected volume Working days per year Number of working hours Average procedure time + turnaround time PPD PPR × 0.8 (efficiency factor)

A minimum of 8–10 procedures per day should be expected from this analysis, a common basis for scheduling in hospital settings, assuming average conditions and an operational efficiency of about 70–80%. This is based on an assumption of equal proportions of upper and lower cases, a 30- to 45-min average turnaround time, and sufficient recovery space. Multiplying room capacity by the number of workdays per year (typically 250) provides a total number of procedures per room

Projected volume Procedures per year (ppy)

Working days per year 4500

÷

Daily volume 250

=

18.001

Procedure profiles Percentage Gastro/GI 1350 ppy

30%

Colon/GI 2700 ppy

60%

30 min

81 000

ERCP 450 ppy

10%

60 min

27 000

Working time per day minutes hours 5.0 hours 6.0 hours 6.5 hours 7.0 hours 7.5 hours 8.0 hours

300 min ÷ 360 min 390 min 420 min 450 min 480 min

Figure 2.2 Endoscopy room projections.

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Average time Total time 20 min 27 000

Average procedure time

30 min

Capacity per room Without loss 70% Efficiency procedures procedures

Average procedure time 30 min 30 min 30 min 30 min 30 min 30 min

=

10.00 12.00 13.00 14.00 15.00 16.00

7.00 8.40 9.10 9.80 10.50 11.20

Procedure rooms

2.57 Required 2.14 Required 1.98 Required 1.84 Required 1.71 Required 1.61 Required

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per year. As time and efficiency factors change, so will resulting room capacity. In highly efficient production-oriented ambulatory centers, much higher rates are routinely achieved and 14–20 PPD can be reached with tight scheduling and preselection of healthier patients. Maintaining a high operational efficiency is dependent on skilled teamwork by staff and good scheduling of procedures, which must take into account the varying times required for completion of specific procedures and the equipment required by different endoscopists. Units that schedule more than 10 procedures per day will generally require more than one dedicated room, with procedures being performed simultaneously by multiple endoscopists, or by a single physician working alternately in two rooms. If 10 cases per day are performed, a single room could accommodate up to 2500 procedures per year (PPY). However, it is prudent to factor in a loss (20–30%) for inefficiencies caused by cancellations, equipment breakdown, and staff absences. In this case, the number of possible procedures drops. Taking inefficiency into account, the same room with supporting recovery, handling an average of six cases per 7-hour day and assuming 250 working days per year, will have a volume of about 2000 procedures performed. This 2000 PPY is a realistic low number to use for planning purposes, and allows some flexibility in scheduling. Increasing the length of the working day above 7 h or decreasing the time allotted per procedure will increase the numbers. However, in the long run, overscheduling will lead to the inability to maintain a steady pace, with loss of flexibility and a resultant lowering of staff morale and patient comfort. Figure 2.2 shows a typical relationship between caseload and the number of required procedure rooms. Altering any of the input parameters (such as hours of operation, number of working days, or the percentage of colonoscopies) changes the required number of rooms. Maintaining room productivity at current levels will be challenged in the future as the number of more therapeutic, and therefore lengthier, procedures increases. Productivity numbers may also be affected by more stringent infection controls, which will require longer room preparation periods.

Recovery space Units that perform more than four procedures per day will require a dedicated procedure room with separate recovery space and skilled staff to operate both these areas. The capacity of the endoscopy room will be limited by the ability of the recovery space to handle the flow. This will be further influenced by whether moderate or deep sedation (propofol) is used. The recovery area should be close to procedure rooms and ample in size to handle the volume of cases. This aspect becomes more important as the complexity of both the procedures and the endoscopy equipment increases.

The Colonoscopy Suite

The cost of equipment and infrastructure in the endoscopy room can only be fully amortized by a continuous and efficient usage. It is impractical to have patients recovering in the procedure room. Through exact scheduling of procedures with varying recovery times, one can create a smooth flow with no fewer than one and a half recovery spaces per procedure room. However, this assumes optimal conditions without inefficiency and it may well lead to scheduling backlogs if, for example, patients are slower than predicted in coming out of sedation. A more practical ratio is two recovery spaces for each planned procedure room. When the recovery space is used for changing of clothing and preparation before procedures, additional capacity should be considered. In this case a better ratio would be two and a half to three places per procedure room or augmented by a more compact step-down area. A recovery space should be secure, comfortable, and appropriate to an ambulatory setting, and to some degree separated from inpatient holding areas in hospital units. During the recovery phase, ambulatory cases will usually have accompanying persons who need some access to the patient. This suggests an extra space requirement and some element of privacy in the recovery area for these visitors. Individual combination dressing and recovery rooms may be used in private offices if permitted under accreditation requirements. This type of space provides the privacy and sound isolation that results in a more comfortable experience, but does require increased monitoring efforts to ensure patient safety. A minimum size for this type of room is 5 ft wide by 9 ft long (1.5 m by 2.7 m). Group recovery spaces are common in hospitals, ambulatory centers, and offices where direct monitoring is required by regulation. Generally designed with curtained cubicles, these are required to be a minimum of 8 ft by 10 ft in size (2.4 m by 3 m). However, they lack the private quality of fully enclosed, separate recovery spaces. Providing solid side walls and glass fronts provides better psychological separation while allowing for adequate observation, and this design approach has been used with some success. Patient privacy regulations in the US [Health Insurance Portability and Accountability Act (HIPAA)] may be more easily addressed with partial or full side partitions where physician–patient conversations routinely occur in recovery rooms. Another compromise is a group-type area used in conjunction with a more commodious separate stepdown or second-stage room. A step-down room is a space in which the ambience is more relaxed and where family can join the patient after the medication has worn off. The stepdown room can be a lounge space with reclining chairs, music, television, etc. Privacy can be further supported with small private discussion rooms adjacent to the recovery area. Private changing areas are desirable in any type of unit, especially in larger ones with combined preparation and recovery areas. The use of individual lockers for clothing and valuables is important and lessens the possibility of damage or loss of personal possessions. Recovery areas should have day

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lighting if possible, pleasant décor, and appropriate artificial lighting. Storage should be provided within or near the recovery space for blankets, bedpans, etc. Oxygen, suction, patient monitoring, and emergency equipment should be provided for. Patient toilets should be located within preparation and recovery areas, particularly in the colonoscopy suite, where patients have been prepared with enemas or cathartics. A good ratio is an average of one patient toilet for every two procedure rooms. Toilet spaces should be designed for disabled access and equipped with grab bars and increased toilet height as well as making appropriate provisions for patients who may still be under the influence of medication after procedures. An emergency nurse’s call system is also advisable.

Scope cleaning and storage Prevention of infection transmission is an important factor in the colonoscopy suite, and following any examination the scopes must be cleaned and fully disinfected. With the problems of HIV, hepatitis B, tuberculosis, and other communicable infections, the risk of contamination must be monitored and eliminated from the GI setting. This involves prevention of cross-contamination between clean and soiled scopes. A scope washing room separate and apart from the procedure room is essential. Proper cleaning is the goal, and cleaning rooms should be planned with adequate space and ample plumbing and power provisions for automatic high-level disinfecting or sterilization equipment. Adequate counter areas for manual scope cleaning are essential, as well as space for accessory cleaning equipment and tubs for soaking scopes if the automatic washing machines are disabled. A rule of thumb is 3–6 ft (1–2 m) of counter space free of sinks, per procedure room. Several large, deep sinks are required whether scopes are washed by hand or automatic equipment is used. The room should be planned with enough space to separate clean instruments from soiled scopes waiting to be processed. An array of hooks at the sink area facilitates the handling of the accessory articles that must also be cleaned each day. Safe and secure storage for the full inventory of clean scopes and accessories should be provided at convenient locations adjacent to, and in, the endoscopy room. Cabinets for storing of endoscopes require ventilation to ensure that any moisture that may be trapped in the instrument after drying does not promote the growth of micro-organisms. Ventilation holes or fan-assisted exhaust can be planned.

Room size standards and the written program A first measure of the success of a facility is whether enough space has been provided for the planned needs. Once the numbers of procedure rooms and recovery places are decided

24

and a list of other space requirements assembled, information on room sizes must be determined to complete the program. Size standards for general spaces can be found in a number of published sources; however, requirements will vary somewhat with the particular circumstances under which the spaces function. Physical measurements of similar spaces are important for reference and comparison purposes. Endoscopy units that perform well should be visited and compared (the program examples in Figure 2.3a and b show typical listings of room and room size requirements). Comprehensive data, including electrical power specifications for equipment, ventilation requirements, and sound privacy and lighting level criteria, are also needed. Building codes, licensing guidelines, and accreditation and certification standards also contain requirements for room as well as corridor sizes, mechanical services, and construction classification information. The impact of electronics has been extensive, and an understanding of the anticipated and evolving equipment technologies is also critical in determining and planning space requirements. Storage requirements for both supplies and records must be calculated. Corridors, storage, and utility rooms will represent 30% or more of the net space in a facility, and this should be reflected in the total. Certification guidelines have specific requirements for medical records, and while record keeping may eventually become fully electronic, presently it relies on paper. Storage for paper records and medical supplies must be estimated. Most record storage should be lockable for both security and privacy reasons. Projections for staff needs should be factored into the program to ensure that enough space has been allotted to provide comfortable and efficient support areas for both physicians and assistants. The capability of the facility to expand if needed and to be versatile and efficient over its years of service is crucial. It is advisable to evaluate the possibility of future additions, such as pathology labs and clinical research areas, which may require added space. Therefore, it is advisable to factor in some expansion allowance of additional area (minimally 10 –20% beyond projected needs) to accommodate growth and change. Examples of two typical programs are shown in Figure 2.3: one for an ambulatory center (Figure 2.3a) and another for a medium-sized office unit (Figure 2.3b). The program for the ambulatory center, for example, has a total net useable requirement of approximately 8700 ft2 (808 m2) for four procedure rooms with a separate general examination zone. The total also reflects requirements most often included in licensed units in the US. The office endoscopy program describes a total need of 3250 ft2 (301 m2) with two dedicated procedure rooms and other needs required for the GI practice. A final program may be represented in different formats. The essential need is a thorough enumeration including a space list complete with dimensions and net areas. Numbers for corridor circulation, utility spaces, miscellaneous functions, and a contingency allowance for growth and unforeseen

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(a)

(b)

Figure 2.3 Endoscopy unit profile: (a) ambulatory center; (b) private office. See also Table 2.1 for the numbering of descriptive notes.

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changes must be factored in for a calculated total gross area need. The completed program is a critical tool in evaluating available locations for a new facility. The total area requirement as estimated from the list may be the first indication that desires are not compatible with the business plan, budget, or available properties, and that compromises must be made. The program can be continually refined and adjusted to reality as well as a more precise awareness of needs. It is a statement of goals, and is useful as a checklist throughout the project to determine whether all the requirements are included in the final drawings and will be included in the finished facility. If thoroughly executed and accurate, significant time will be saved in later design stages and costly mistakes will be avoided in construction.

Tipcinformation to collect A loose-leaf notebook can be helpful for collecting the following information that is developed in the program process. Descriptive notes should be recorded whenever they are thought about, and checked against the plans on a regular basis (Table 2.1):

Table 2.1 Descriptive notes. 1 Remote monitors on procedure imaging network. 2 Walls which surround the procedure rooms, as well as doors to these rooms, should have acoustical ratings to contain procedure sounds. 3 The procedure rooms should be designed with two modes of lighting. 4 A double-monitor system should be planned for the procedure rooms. In a two-monitor system, both physician and assistant can have a comfortable view of the procedure image. 5 Procedure spaces should be equipped with a means of exhaust and ventilation to remove odors. Provide 15 air changes per hour with direct exhaust of used air to outside. 6 In cleaning rooms exhaust grills should be located near the floor and at counter height. 7 Scope washing rooms should be located with pairs of procedure rooms. 8 Oxygen, suction, and medical air should be located in procedure rooms, recovery areas, etc. 9 Emergency call button system. 10 Examination table, writing area, cabinets, and X-ray viewer. 11 Locked cabinets for drugs. 12 Emergency communication system. 13 Emergency (crash) cart.

• caseload and utilization projections; • space sizes and total areas desired; • equipment list; • electrical power demands for equipment; • areas requiring ventilation for hospital suites where colonoscopy is to be performed; • provisions for negative pressure where airborne contagious disease may be prevalent; • areas requiring sound privacy; • lighting needs; • interior design goals.

Arrangement A successful design for an endoscopy facility promotes effective movement or flow patterns of patients and staff, which in turn can be critical in controlling operational costs. Flow patterns, which represent the movement of patients and staff, are shaped by decisions about the relative arrangement of procedure rooms and other key elements made when planning the unit. When a layout is inefficient, causing staff to cover excessive distances to get supplies, clean scopes, and monitor recovery, and when bottlenecks occur in the patient flow, the potential of the unit is limited, additional staff will be needed, and operating expenses will be higher. A dedicated endoscopy facility is composed of two core elements, the procedure zone and the administration operations area.

26

Procedure rooms, changing and prep areas, recovery, and scope cleaning form the heart of the procedure zone, while business office, waiting room, and consultation offices are part of the administration area. The two components function interdependently; however, each may be a self-contained work center with different types of staff. Their functions should not be mixed. For example, medical business records should not be stored in a procedure zone and medical supplies should not be kept in an administration area. Patients should be able to move from one zone to the other without traveling inordinate distances through complicated pathways, which usually necessitates additional staff to monitor traffic. On the other hand, waiting areas should be located remotely from the endoscopy zone for purposes of patient and visitor control, sound isolation, and for esthetic reasons as well. Whether the planning is being done for a large multi-room facility or for the reworking of an existing office for occasional endoscopy, there are fundamental patient-handling and movement principles that should be addressed in planning the space. As facilities become more complex, additional elements surround and interrelate with this core. Hospitals will often have teaching areas, and ambulatory units may have clinical examination areas that operate in close cooperation with the endoscopy activities. In certified ambulatory centers in the US, there are regulations about the separation of endoscopy areas from all other activities, medical or otherwise. In any project, flow diagramming can be a powerful tool for understanding and evaluating arrangement options, prior to preparing preliminary plans. In a simple flow diagram,

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Leave

Ambulatory Enter

Reception

Billing Administrative area outpatient waiting inpatient holding receiving control consultation

Waiting

Administration area

Control point Nurses’ station Leave Enter

Control point

The Colonoscopy Suite

Procedure area (operational) endoscopy recovery cleaning storage

Figure 2.4 Patient movement patterns.

rooms are represented as oval shapes or bubbles. Arrows indicate the relationships between activities and are an expression of adjacencies and resulting movement patterns (Figure 2.4). The following sequence of steps routinely occurs for a typical patient undergoing an endoscopic procedure. This workflow can be translated into a simple, one-directional movement pattern in the final layout: 1 The patient arrives at registration and completes the necessary paperwork and administrative information. 2 The patient waits. 3 The patient is escorted from the waiting to the preparation area, where clothing is stored and exchanged for a gown. 4 The patient is transported from the preparation area to the procedure room. 5 The patient is sedated (anesthesia may be used) and a procedure is performed. 6 The patient is transported from the procedure area to a recovery room. 7 The patient meets with the physician. 8 The patient leaves the procedure zone and completes any unfinished administrative business-related matters. 9 The patient exits the unit through the admit area or directly from the procedure zone. This sequence can be diagrammed as a circle. Patients travel a sequential path from reception through preparation, procedure, and recovery, finally returning to administration for processing and departure. A separate dedicated departure station where the patient can complete paperwork and exit directly from the procedure zone can facilitate smoother patient flow (Figure 2.5). The most efficient layout for a project is achieved by grouping interdependent elements with minimum distances between

Changing

Dressing

Hospital inpatient

Procedure area

Preparation

Recovery

Endoscopy

Figure 2.5 Patient flow sequence.

Reception

Waiting Administration Administration area

Recovery Scope clean

Consult

Procedure area Procedure

Figure 2.6 Endoscopy suitebcritical relationships.

them. Waiting should be reasonably close to preparation/ recovery, which should be adjacent to the procedure areas. Preparation/recovery is a transitional area because of its central role in the patient sequence. In most cases, its placement with respect to the other components is the key to satisfactory design and efficient movement pattern. Likewise, if planning allows, a business office that bridges both zones can facilitate both intake and departure operations (Figure 2.6). The same principles of proximity apply to staff movement patterns. If close together, recovery, procedure, and scopecleaning areas facilitate the many tasks that must be performed by staff. It is desirable to group endoscopy procedure rooms with scope washing and other support functions. The

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Cleaning

Procedure

Scopes

Prep/Dress

Supplies Scope cleaning

Ambulatory

Accessories

Recovery

Endoscopy room

Waiting

Procedure

Equipment

Procedure

Nurses’ station Reception desk Procedure

From preparation

To recovery Patient traffic Staff movement

Scope cleaning

Holding

Inpatients Patient traffic Staff movement

Figure 2.7 Flow pattern in the procedure room. Figure 2.8 Patient and staff movement pattern.

result is a localized travel pattern for staff activities before and after the procedure. Clustering procedure rooms around scope-washing areas with direct access between the rooms is an ideal arrangement for achieving this kind of efficiency. If it is not possible to achieve direct access, the scope-washing room or rooms should be positioned close to the group of procedure rooms. This ideal relationship is expressed in a flow diagram with arrows indicating important functional proximity and patterns of movement (Figure 2.7).

Tipcquestions to ask • How many of the staff are typically assisting in procedures? • Who is responsible for preparation of the procedure area? • How do assistants monitor the recovering patients? • How are scopes and other equipment cleaned? • Who will be responsible for the organizing of supplies and cleaned equipment?

When patient and staff movements are superimposed, maintaining the separation of each activity circulation pattern is optimal. In the hypothetical endoscopy unit diagram (Figure 2.8), patient movement is expressed as a sequential flow extending from the waiting room to preparation and changing, then to procedure and recovery spaces. The patient exits from the recovery room, past the administration area, and through the waiting room or, where possible, by a separate departure door with minimal retracing of steps. The ideal patient path does not overlap or result in conflicts with

28

the movement pattern of the staff. Correspondingly, stretcher traffic and movement patterns of patients on foot should be kept separate. With movement patterns clarified, a schematic or block diagram can be prepared to approximate specific space configuration. Block diagrams vary widely, but are generally a more realistic flow study, can be dimensionally true to scale, and may factor in existing elements such as elevators, stairs, and other conditions. These studies are easy for physicians to understand and are a useful tool for evaluating alternative solutions and confirming flow patterns, without expending large amounts of time and money. The block diagram example (Figure 2.9) represents a mid-sized ambulatory endoscopy unit with four dedicated procedure roomsarecovery space for nine patients. The diagram has been drawn with superimposed arrows indicating the patient flow pattern.

Preliminary planning solutions The purpose of a preliminary plan is to represent a realistic overall layout of the unit or suite, taking into account room size, actual areas, and site conditions. At this stage, a floor plan is prepared, room arrangements are finalized, and length and width dimensions are verified. It is important that preliminary drawings be precise and indicate the general locations of equipment with enough detail to make certain that everything will fit. Details such as door placement and size, pathways between areas, and the particular movement of medicated patients on stretchers from procedure rooms to recovery should be obvious and clearly stated. As the design

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The Colonoscopy Suite

Figure 2.9 Ambulatory endoscopy suite block diagram.

Figure 2.10 Preliminary plan of ambulatory center.

develops toward a workable stage, aspects of the plan should be periodically reviewed for adherence to the original movement and flow objectives. This example (Figure 2.10) of a preliminary plan shows the ambulatory center design in a more developed state. The

patient movement pattern and arrangement is consistent with the block diagram and general goals. The procedure zone of this ambulatory unit is arranged with four dedicated endoscopy rooms flanking a core of preparation, washing, and laboratory support functions.

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Design development Procedure room design Design development furnishes an elaboration of the layout coordinated with other requirements. The drawings and other supporting material, including outline specifications and cost estimates, etc., form a final planning document that describes the full scope of work. In this phase, the location of equipment is finalized, and requirements determined for physically supporting equipment and providing power and communications connections. There is ongoing spirited discussion about appropriate procedure room size and arrangement. Recommendations ranging from 190 to 300 ft2 (17.5–28 m2) have been proposed by experts in the field. These differing points of view have validity in specific situations. Decisions about which room size configuration works in a given situation can be facilitated by analyzing the work flow of the endoscopist and assistant as well as the constraints dictated by umbilicus tube lengths, viewing distances, and clearances required. Licensing laws in the US generally require that rooms have a net or clear area of 200 ft2 (18.6 m2). This area requirement excludes fixed elements such as built-in counters and nonmovable storage cabinets. Carts on casters, and other easily movable components, are permitted to be included within the clear area of the room. Current regulations in the US also state that room arrangements must permit a 42 in. (1.06 m2) clearance around all sides of the stretcher. The well-planned endoscopy room breaks down into three primary components. First is the endoscopist’s work zone, which generally requires a relatively small clear space of approximately 28–32 in. (0.7–0.81 m) between stretcher and equipment. This allows room for the physician to maneuver, and is within the limits of the draped length of the umbilicus. The assistant needs 36–42 in. (0.91–1.06 m) of space, with clearance to move easily around, and adjacent counter space or accessory cart so that supplies and implements are readily accessible. Lastly, a minimum clear floor area of 7 ft 6 in. (2.3 m) between fixed elements is required for positioning, required access to all sides, and rotation of the typical stretcher measuring 31 in. by 83 in. (0.79 m by 2.1 m). These elements are common building blocks in all procedure rooms (Figure 2.11). There are two categories of procedure room organization that directly apply these concepts. Classified here as parallel layout and corner layout configurations, they tend to be appropriate to smaller and larger rooms respectively. In concept, both these configurations closely surround the patient, doctor, and assistant with primary equipment, supplies, and controls. Each arrangement enables monitor locations to be within acceptable distances, with clear comfortable viewing sight lines, and makes possible concealment or elimination of cables from the floor area.

30

Figure 2.11 Basic clearances.

In a parallel room plan, equipment areas 24 in. (61 cm) deep are arranged on the two opposing long walls, establishing work zones and clearances on either side of the stretcher. A 12 ft (3.7 m) dimension is optimal for the width of a parallel configured room, and places the endoscopist at a comfortable viewing distance of 6–7 ft (2 m) from a monitor wall mounted across the space. Since all equipment is on one wall or the other, the 12 ft (3.7 m) width also facilitates the concealed interconnecting of cables through walls and ceiling areas (Figure 2.12a and b). The corner layout approach solves problems inherent in the use of large rooms. Larger (square-shaped) rooms are routinely planned to meet a specific need, such as the minimum 200 ft2 (18.6 m2) required in ambulatory centers and hospitals, and those used for teaching purposes. Additionally, there is a school of thought that convincingly suggests that larger rooms in hospitals allow greater flexibility and accommodate the greater variety of complex procedures encountered there. If rooms are large but not planned well, open floor space becomes excessive, resulting in wasted space and inefficient and tiring movement patterns for those who work there. In these cases, cables can often be found lying across floor areas, creating a tripping hazard. Corner layouts work well by clustering the key building blocks of the work zones in a smaller part of the room, incorporating the same space principles outlined above for the parallel approach. In the corner alternative, the light source and processor are located to the right of the physician; the monitor is located on the perpendicular wall and is to the front of the physician at a distance of approximately 6–7 ft (2 m). Figure 2.12c and d shows examples of both parallel- and corner-designed rooms. Each set shows variations on specific needs, and indicates where specialized or ancillary equipment can be placed.

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15 to 19 feet

The Colonoscopy Suite

15 to 19 feet

4.6 to 5.8 meters

4.6 to 5.8 meters

Endoscop e Storage

Monitor #1

Monitor #1

Endoscope Storage

Accessory Cart

12 feet

3.7 meters

Accessory Cart

Storage Cabinetry

Storage Cabinetry

Light Source Monitor #2

Light Source Monitor #2

Parallel Room with Equipment Cabinets

Parallel Room with Equipment Carts

(a)

(b)

15 to 20 feet

15 to 20 feet

4.6 to 6.1 meters

4.6 to 6.1 meters

Accessory Cart

Monitor #1

Monitor #1

Storage Cabinetry

4.6 to 6.1 meters

O V A

Light Source

15 to 20 feet

O V A

Accessory Cart

Endoscop e Storage Light Source Monitor #2

Monitor #2

Corner Room with Equipment Cabinets

(c)

Corner Room with Equipment Carts

(d)

Figure 2.12 (a–d) Procedure room comparisons.

A 12 ft by 19 ft (3.7 m by 5.7 m) general-purpose colonoscopy room is an example of a parallel configuration that works well and demonstrates the underlying principles. This room size (228 ft2 or 21 m2) provides ample space for equipment and storage, comfortable work zones, clear floor space for stretcher movement, flexibility for future growth,

and the ability to easily conceal most cabling. It also represents room dimensions that satisfy the minimum area of 200 ft2 (18.6 m2) clear of the built-in cabinetry that meets most US license requirements for room size. Where minimum area requirement regulations do not govern, room size may be shortened to 15–16 ft (4.6–4.9 m) in length without

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Figure 2.13 Typical procedure room arrangement (parallel configuration) 200 ft2 (18.6 m2).

Tipckey recommendations • Connection points on the walls, and concealed cabling pathways in the wall and over the ceiling. • Optimal viewing distancesb7 ft (2 m) maximum. • Clear areas in center for work zones and stretcher.

compromising the essential qualities. The resulting total area is 190 ft2 (17.5 m2) including cabinets and fixed elements. This use of this particular room size is advantageous in light of construction cost savings and reduced real estate expenses (Figure 2.13). New regulations which may apply to room size in office endoscopy suites should be fully considered.

Equipment arrangement options Considering the large amount of equipment now routinely found in the procedure room, some form of vertical arrange-

32

ment or stacking of devices is logical. This economizes floor space and helps to concentrate and define the work zone areas. There are three basic approaches to implementing this concept: equipment can be organized in custom-designed cabinetry towers, placed on a combination of tall manufactured equipment carts and wall mounts, or placed on structurally supported articulating arms that float from the ceiling plane. Each system is capable of holding three or more devices on shelves, or mounts one above the other with cables and power connections along the back. Because, in most cases, procedure rooms divide naturally into two work zones (the endoscopist and the assistant), separate and interconnected equipment stacks should be planned opposite each other in the space. The stack behind (or to the side of) the physician will hold a light source and video processor, secondary monitor, and other peripherals. The stack on the GI assistant side will hold recording equipment, an image printer, electrocautery devices, and a principal viewing monitor, with room for more. In a parallel room design, the two stacks will be on the long walls opposite

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each other. In the corner layout, they are at right angles to each other, defining the work zones. Comparative room diagrams and photographs show these three alternative arrangement methods: 1 In Figure 2.14a, two tall cabinetry units house the equipment items (light sources, suction devices, controllers, and monitors), which are arranged vertically. Each cabinet has adjustable shelving and an adjacent vertical compartment that holds a power strip and the necessary cables and wires. 2 Figure 2.14b shows a manufactured cart placed below a wall-mounted monitor on a bracket support. This creates a vertical assemblage of devices interconnected through wall channels or within the cart. 3 Figure 2.14c shows the floating ceiling mounted arm. These are available in many configurations and in varying load capacities. They provide adjustability and can be easily repositioned to suit different individual needs. Cables are fed through the arm from the ceiling and therefore kept off the floor. However, these arms are expensive, require costly

The Colonoscopy Suite

structural provisions to install, and may be realistic only in select circumstances. In all of these options, decisions on where TV monitors are located should be resolved with “sightline” studies. Though some physicians prefer a closer image, monitors generally can be at a distance of 6–7 ft for clear viewing of a 20-in. (51 cm) cathode ray tube (CRT) or flat-screen device. Flat screens will continue to supplant CRT as the differential in cost decreases and consistency of color rendition increases. Monitor height is extremely important. If placed too low, the image can be obstructed from view by other people moving in the room, whereas monitors placed too high on a ceiling bracket can cause unnecessary neck strain and discomfort for the physician. A suggested height is 6 ft (2 m) to the center of the monitor. It is also important for the assistant to be able to view the endoscopic image along with the endoscopist. If the assistant stands opposite the physician, as is common, it is useful to have a second monitor on the physician’s side of the room. If the assistant stands

(b)

(a)

Figure 2.14 (a) Two tall cabinetry units. (Photograph courtesy of Kenneth Perry, Kingsport, TN.) (b) Procedure roombequipment in carts. (Photograph by Norman McGrath, New York, NY. Courtesy of New York Gastroenterology Associates, New York, NY.) (c) Floating ceiling mounted arm. (Photograph by Bernstein Associates, Mt Vernon, NY. Courtesy of Dr B. Kummer.)

(c)

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General Aspects of Colonoscopy Endoscopy carts should be selected with an eye toward wire management and expansion. These include provisions for cable raceways at the rear of the cart, and multiple plug strips to power all the devices directly on the cart. The cart itself is then plugged into a nearby receptacle. When designing cabinetry to house equipment, empty spaces can be incorporated where cables can run freely behind or to the side of the various devices that need to be interconnected. These compartments are made accessible by means of doors or removable panels. Cabinets may also have internal power distribution by utilizing continuous plug mold strips installed within the accessible cabling space. The flexibility to change and add equipment and interconnect devices will prove to be a factor in the durability and longevity of the design. Walls should be constructed with empty metal conduits, 1 in. (2.5 cm) in diameter, leading to points of connection for the required cabling. These usually terminate above the ceiling and provide pathways from one point in the room to all other locations where devices need to be connected. This idea assumes that the ceiling is an empty void that will allow

next to the physician, they can both observe the same screen. Patient-monitoring equipment may be incorporated in stacks, or placed on carts or ceiling arms. Devices including pulse oximeters, blood pressure monitors, and electrocardiogram (EKG) equipment can occupy valuable floor space usually near the head of the stretcher, so integrating them into the overall plan and providing close-by power is important. Additional equipment such as argon plasma coagulators are significant in size and have specific connectivity requirements that must be considered. Usually located on the assistant side of the room, they must be placed so that cabling for the foot pedal control can be easily passed under the stretcher for operation by the physician. Provisions for cables to video monitors, power wiring for equipment, telephone cords, computer network cables, and connections to patient-monitoring devices should be incorporated into procedure room design (Figure 2.15). In order to keep floor areas clear, cable pathways should be hidden in cabinetry, housed in raceways under floors, or placed in accessible ceiling areas.

19'-0"

POWER

TEL/DATA CABLING

Video Monitor #1 Cautery Printer Computer VCR

Broadband modem for computer connectivity Telephone cabling for standard phone or IP connection Wireless network Hub for cable-free connectivity

NETWORK CABLING Monitor #1

CAT-6 LAN Cables to remote computer workstation

Endoscope Storage

Four coaxial cables between video processor and computer

12'-0"

ASSISTANT MONITORING CABLING

VIDEO CABLING

Cable to patient pulse oximeter monitor

Six RGB Coaxial Video Cables between light source and monitor

PHYSICIAN

Video recorder cables Printer and misc cables

Light Source

Coaxial cable to remote video monitors

Monitor #2 Crash Cart

Figure 2.15 Typical cabling and power requirements.

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Patient Monitoring Equipment

CAUTERY CABLING

POWER RECEPTACLES FOR EQUIPMENT

Remote control cable to cautery foot pedal

Pulse Oximeter Blood Pressure CO2 Monitor Crash Cart

Light Source Suction Pump Video Processor Video Monitor #2

Surge Protector CCTV Monitor

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cabling to be extended to the opposite side of the room. Therefore, the ceiling should be constructed with an accessible suspension system or with access doors installed in the gypsum board surface. Conduit pathways in ceiling areas provide additional protection against damage, and shield cables from magnetic field interference caused by fluorescent light ballasts and fans or other motors.

Additional considerations Doors into procedure rooms should be at least 44 in. (1.1 m) wide to allow stretchers to pass freely between rooms and comply with regulations. It is a good policy to have locking devices on the inside of the doors to prevent wandering patients from entering unannounced. A charting surface should be planned for each procedure room. This may be combined with a computer area, be close to the head of the patient, and be within easy reach of the physician and assistant. Suction, where provided through central systems, should have multiple outlet locations, including one in proximity to the patient and one directly behind or adjacent to the light source. Locked drug cabinets are required in or near procedure rooms, and scope storage cabinets can be located in the procedure room or centrally. Ample space should be provided for garbage cans and receptacles for special disposal needs such as sharps, etc. Continuous plugin strips may be installed along the entire length of equipment counters, to cover contingencies and add flexibility.

Soundproofing and privacy Walls that surround procedure rooms should be acoustically constructed to prevent procedure noises and staff discussions from being overheard by patients in recovery areas or adjacent rooms and corridors. Doors and frames in these walls should be sound rated and provided with bottom seals and sound gasketing. There are standard details and special materials for constructing sound partitions, but generally these partitions fully extend to the structural slab above the ceiling. Manufacturers’ installation recommendations must be followed carefully to achieve the full intended sound value. All gaps (around outlets, for example) must be sealed with caulking compounds. Wall systems are generally judged acoustically by their STC (sound transmission class) ratings, which represent average attenuation at selected frequencies. A rating of STC 54 or higher should be used around procedure rooms. Door and frame ratings can be slightly less, but are always the weakest point in a sound isolation system. They must be installed with all gaps closed (gasketing), or sound will pass through and around the perimeter. Periodic maintenance of these perimeter gaskets and seals is required, as they tend to loosen with wear. Acoustic tile ceilings are recommended to further absorb sound and reduce transmission; however, the

The Colonoscopy Suite

exposed surface must be cleanable and free of crevices where dirt and mold can build up.

Materials Wall materials can be light-colored and washable, to present a clean and bright environment. Coated paper wall covering, vinyl fabric or spray-on composite paint application will allow easy cleaning of the surfaces. Prefinished wall panels or ceramic tiles are also possibilities. Flooring should be made of resilient material for comfort, and should be fully washable with no gaps, spaces, or seams to collect dirt. Sheet vinyl, with chemical- or heat-welded seams and an integral coved base, is the best choice. Counters and cabinetry surfaces should be covered in high-pressure laminate materials, stainless steel or metal with baked-on enamel coatings. Counter areas should have full backsplash areas with completely sealed seams at counter joints. All of these materials will take wear and are easily cleaned. Ceiling materials and installation methods must combine to prevent the passage of particles into the procedure room from the plenum above.

Emergency facilities Every endoscopy unit should be equipped for emergency situations. In the ambulatory setting, this means that a patient may have to be quickly transferred to a hospital. For this purpose, it is wise to have an exit area that is discreet, with easy access to an ambulance driveway or street. This exit should be remote from the main entry, to avoid transporting a sick and sedated patient in discomfort through a crowded waiting room. The endoscopy unit should also have an area set aside for storage of emergency equipment that can be moved rapidly to wherever it is needed, usually a small crash cart with oxygen, an EKG machine, and a defibrillator.

Heating, ventilating, and air conditioning Air-conditioning and heating systems should be designed to provide a degree of control appropriate to the different functions within the unit. Endoscopy rooms should be separately zoned and easily adjusted for the range of temperatures required for both patients, who can be sensitive to cooler settings, and staff who are active and desire air conditioning. These spaces should also be equipped with a means of supplemental exhaust capable of extracting odors and refreshing the air, providing 10–15 air changes each hour the room is in use. The endoscope cleaning area must also be well ventilated against the build-up of irritating fumes from disinfection agents, which are unpleasant and potentially harmful. Fume extraction grills in cleaning spaces should be located at counter level and low in the room, to deal with vapors that are heavier than air. New buildings provide central air-conditioning capability. However, the degree of heating/cooling and ventilation control may be inappropriate for colonoscopy procedures, and existing systems can be difficult or costly to modify. Early evaluation of the capability of existing systems will pinpoint

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potential problems that may be encountered, and help to avoid complications later on. If the air-conditioning systems will be self-contained and dedicated to the facility or the procedure zone rooms, adequate space and power must be provided. Dedicated air-conditioning equipment generally requires a separate room with access to the exterior for fresh air. Requirements for negative pressure in specialized circumstances should also be considered.

Plumbing Multiple plumbing connections are required in any endoscopy center. In multistory buildings, the planning of sinks, toilets, and other plumbing items can be complicated by the need to run drainage lines in the ceiling of the floor below. It is important to verify that plumbing lines can be easily run to the many locations required for procedure, scope cleaning, and toilet spaces. If the location for the new unit is on grade, special care must be taken to plan all plumbing connections before the concrete floor slab is poured in place. Local regulations about disposal of chemicals used in the process of disinfecting and washing endoscopes must also be taken into consideration. Backflow prevention systems, while now routinely incorporated in automatic scope cleaning units, may be additionally required by codes, as part of the plumbing infrastructure to prevent contamination of the domestic water supply. Codes are becoming more stringent in requiring water conservation measures through use of reduced (low) flow toilet fixtures and fittings. In addition, the impact of the green building movement, while still uncertain, should be considered, as pressure to reduce water consumption below current level will certainly grow.

Lighting Lighting requirements will vary throughout the office. In endoscopy rooms, good general lighting of approximately 100 fc (footcandles) is required for preparation and cleaning, but excess light must be eliminated during procedures for optimal viewing of video monitors. A dual system that can provide both low-level dimmed light and brighter light is desirable. The dim light will not interfere with the endoscopist’s view of the monitors, while the brighter light will provide enough illumination for staff to work at other points in the procedure. This is easily achieved with two modes of lighting. In a two-mode system, fluorescent fixtures can provide the required level of work light (50–100 fc), while adjustable low-voltage or small-lamp spotlights are positioned to provide lower levels of light during procedures, directed on specific areas where needed. Fluorescent fixtures can be operated with special dimming systems to provide the lower-level needs. However, a few separate directed fixtures are an even better solution. If windows are present, the elimination of light during procedures, with blackout shades or other daylight control devices, will be required. Recovery rooms should be planned with soft, pleasant, and adjustable

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lighting, as well as controlled natural light where possible. Particular attention should be paid to prevention of light sources shining directly into the eyes of a supine patient. This is easily done by using indirect or uplight fixtures, which may also be dimmed. In the administration areas, a good level of general and task lighting (50 –75 fc) is adequate for performing clerical activities. The light should be glare free, with attention given to the placement of light sources to avoid glare on computer monitors. With energy costs and conservation of increasing concern, high-performance systems of lighting and controls are worth considering. Overall reductions may be achieved by reducing general lighting levels, employing task lights at work areas, and by using newer T5 and T2 low-wattage fluorescent lamped fixtures. Systems of lighting control that automatically lower brightness when daylight is sensed are available and might be considered.

Communications systems It is not possible to operate any medical organization without depending heavily on electronic communications systems. The degree to which voice and data communications systems have changed in several years hints at the rapid pace at which these systems will continue to change. The growth of wireless systems is one example of this. The endoscopy facility will benefit from the range of options available. The telephone service network is the communications backbone of every facility and has been traditionally depended upon for contact with the public, as well as with other professionals. It has evolved into a multifaceted system that provides access to wireless networks, pagers, email, fax connections, high-speed Internet access, and Internet voice communications [IP (Internet protocol) telephony]. Competitive internal voice systems with a vast array of features allow great choice. Features such as voicemail, automated answering, call forwarding, and video conferencing are available even in economy systems. The basic requirement is a multiline system with enough expansion capabilities to handle the projected volume of calls. A speakerphone feature in the telephone system is desirable for hands-off use in procedure rooms, and can substitute for a separate intercom system. Modern phone systems with microprocessors have very compact central switching units. These require relatively small dedicated and accessible areas with separate power provisions for the processing units. A basic telephone closet for a small system might require a width of 4 ft (1.2 m) of clear wall space for equipment mounting and cable connections. In larger projects, telephone equipment will be housed in the same space as the computer servers and routers that drive the entire voice and data infrastructure. These rooms will be larger, with specific space and power needs. They may also require supplementary air conditioning to maintain a cooler operating environment for the equipment. Wireless systems are a recent addition to the communications arsenal. Beepers and cellular phones, essential tools for

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medical providers over the last several years, are being supplemented or replaced by wireless network services such as Nextel’s Direct Connect®, which allows small groups to communicate instantly with each other. Wireless charting, email personal digital assistants (PDAs), and BlackBerry-type devices capable of receiving messages are now the norm in communications. As medical informatics becomes more sophisticated, with central databanks of patient information, wireless and broadband connections to these are becoming commonplace. All portable devices will require charging stations, and multiple power receptacles must be provided for this purpose. A good intercom system is still essential for smoothing the internal operation, particularly as the endoscopy unit gets larger with multiple procedure rooms. An intercom should have hands-free operation with selective station calling. Telephone systems with built-in intercom capability can eliminate duplication. The telephone system can also provide link-up to an entry intercom, and activate door release devices where desirable.

Connectivity Cabling pathways for the telephone network must be planned. As mentioned previously, procedure rooms equipped for video endoscopy will have multiple video cabling requirements. For best results, direct connections between a video processor and (analog) monitors are typically made with multiple individual RGB broadcast video coaxial cables grouped together. (This provides for the most accurate depiction of the image recorded by the endoscope.) This cable bundle is bulky and requires a minimum of a 1-in. (2.5 cm)-diameter clear conduit between video processor and remotely located video monitors. Recording of procedures on tape or CD and documentation with digital capture photography require computer interfacing with cabling or wireless networks and multiple connection points. A computer interface requires installation of both video coaxial cabling and high-quality (twisted pair) category 6 cables. Such a network allows viewing of data and captured endoscopy images at multiple locations where a computer is connected to the network server. Software is available to facilitate and speed record entry, of specific case information and images taken during a procedure, to a central server. This information can be retrieved for reporting, research, and distribution purposes. In addition to the connectivity within the room, it might be desirable to have video images transmitted to other locations in the facility for teaching purposes or for viewing convenience by other physicians. This can be accomplished by use of broadcast video coaxial cable networks using NTSC (the US standard) or similar signal transmission. If this type of option is needed or planned for future implementation, then precabling or empty and accessible conduit should be planned and provided (see Figure 2.15). Patient monitoring at recovery can be supported through the use of an open-circuit intercom and/or by closed-circuit

The Colonoscopy Suite

television (CCTV) cameras linked to one or more observation points. With CCTV, assistants can accomplish other tasks while maintaining visual contact with recovering patients. Video cabling from camera locations to monitoring point must be planned. Most facilities will require the installation of a LAN (local area network), using a central computer server for the business office and for record storage, as well as a network for archiving and retrieval of data and digital images recorded during procedures. Connections using high-speed Ethernet (category 6) cable are generally required, as well as operating hubs for an Ethernet cable-type or wireless network. LAN connections may also be provided at copiers to take advantage of multifunction devices (MFDs), which combine printing, scanning, and copying operations. Wireless LAN networks are becoming more dependable and can allow greater flexibility in the office workplace, but have not replaced fixed cable networks for reliability. Broadband Internet connections allow the transmission of reports and images to remote sites for distribution, back-up, archiving, or other purposes. Broadband services, such as DSL (digital subscriber line) and cable, are experiencing rapid growth throughout the US and are increasingly reliable and affordable. DSL is readily available in most areas through phone service or Internet service providers, enabling all sorts of information to be transmitted at high speed. Its use continues to grow significantly as local telephone service providers upgrade cabling and equipment. Many digital cable vendors offer broadband service, which has some advantages over DSL. While at present it is aimed primarily at the residential consumer market, it could be an option for smaller offices or ambulatory units. For larger and/or less budgetconscious practices, dedicated T1 and T3 lines provide superior speed and reliability. This type of connection may also be available through hospital infrastructure to a unit connected to that hospital. Any of the connectivity options listed would need to be considered in early planning, and will require the installation of a high-quality [category 5e or better (category 6)] data cable infrastructure. Wiring plans need to incorporate a host of other connections for various electronic systems. Panic or emergency call buttons at each recovery place and in the patients’ toilet area are important to overall safe operation. Low-voltage cabling needs to be run to a central-monitoring enunciator panel with both audible and visual alarm indicators. Emergency lights above the doors to each room indicate where a call originated. Music systems, CCTV, and commercial cable television service require additional cabling. A built-in sound system should be considered for waiting areas and recovery spaces. This has the added benefit of providing sound masking to reduce background noises. Speaker cables to these locations will be required. Commercial cable television might also be considered for recovery areas or waiting rooms.

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Security systems are common wherever expensive equipment and drugs are present. A secure access and entry door release system with intercom should be enhanced with video cameras and monitors at strategic locations. Miniaturized video surveillance systems allow units to be mounted discreetly and can be built directly into the entry door area. Electronic security systems and central station monitoring should be considered for entry doors and windows. A zone-type motion coverage is useful as a second level of protection. Space must be provided for security control panels with dedicated telephone connectivity and power for the processing devices.

The administration area The same detailed planning should be employed in the layout of the administration area. The complexity of clerical operations in medicine, coupled with the reliance on computers to organize and process information, has placed constraints on the design of this area. At every workstation, space must be provided for computer equipment, the many additional devices it requires, and for the personnel needed to operate it comfortably. Each person working with a computer needs 5–7 ft (1.5– 2.1 m) of desk space, from 26 in. to 30 in. (0.66–0.76 m) deep (depending on equipment), for both machines and paperwork. Computer workstations, desks, or large expanses of built-in counter space can all satisfy the need, if ergonomically designed. Flat-screen monitor brackets and articulating keyboard arms should be installed to help prevent repetitive motion disorders. Additional and ample counter space should be set aside for the various laser printers, color inkjet printers, dot matrix form printers, scanners, and label printers, etc. that may be needed. Space must be provided for copiers, mail-processing equipment, fax machines, surge protectors, uninterrupted power supply units, wireless chargers, PDA cradles, and other devices. As with any machine, particular attention should be given to noise factors, heat output, and adequate electrical provisions. All this equipment requires paper, toner cartridges, ink, and other supplies, and space in supply closets or cabinets must be planned. The administration area and consultation rooms should have extra power receptacles available for the connection of charging stations for wireless and portable devices. The business office should be zoned for defined activities. Space should be allocated to four specific functions: 1 reception; 2 appointments and scheduling; 3 general correspondence, filing, and record keeping; 4 billing and insurance affairs. Other than the reception area, the remainder of the business office works best if it is separated visually and acoustically from the waiting room. A small area should be set aside for discussing bills or insurance matters with patients on their way out of the officeathis activity can function well if located

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Figure 2.16 Reception station. (Photograph by Norman McGrath, New York, NY. Courtesy of New York Gastroenterology Associates, New York, NY.)

closer to the procedure rooms, particularly where a second or direct exit door is available from that zone (Figure 2.16). A constant pressing subject in administrative areas is the filing problem. The amount of filing space required for records that need to be accessed continues to place demand on available space. Records normally increase at a fixed rate per year and at an accelerated rate as a practice grows, and long-term expansion space must be programmed. It is common in poorly planned facilities for medical records to be stored in coat closets, toilets, and procedure rooms. Provide as much file space as possible directly in the business office and provide a separate inactive file storage room or combination supply and file room with space for 100% expansion. Consider some of the more sophisticated paper filing systems with cabinets that slide or rotate, resulting in more efficient use of available floor space. Also, look ahead to what digital storage and archiving systems will do in the next 5–10 years to reduce this pressure. Whether the increased power and mass storage capabilities of computers will ultimately solve this problem is still in question. Scanning of documents and electronic data record operations allow more of the paper to be eliminated or moved to remote locations while keeping the information accessible. Software with an easy and usable interface is being employed to bring scanned paper records and information to any computer on the network. Lastly, legislation (HIPAA) in the US concerning the privacy of patient matters requires that files must be kept locked and all material dealing with a patient must be treated in a sensitive and secure manner. This could include files that might be carelessly left out, computer screens that are easily

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read, and telephone conversations that can be easily overheard by patients in the waiting area.

Waiting room The size of the waiting room depends on the type and volume of the practice. A minimum of 8 to 10 seats is advisable in an office setting, while ambulatory centers will require larger rooms commensurate with the size of the facility. Since each procedure room will have three patients in various stages of treatment and each will have at least one person accompanying, it is recommended that, for each procedure room, six waiting spaces be planned. Therefore, for two procedure rooms a minimum of 12 seats should be planned. Space can be used efficiently by selecting small comfortable chairs, rather than large, deep sofas. Banquette seating offers an alternative and can be more flexible than individual chairs. Variety is important, as the number of seats grow, in order to avoid the look of an airline terminal waiting room. The waiting room must have provisions for visitors’ coats, a toilet, possibly a telephone, and amenities such as magazine racks, umbrella stands, pleasant artwork, etc.

Environmental factors A vision for the physical surroundings should be established with the architect or planner early in the process. A comfortable, safe, and sustainable setting can help to both alleviate patient anxiety and increase staff productivity and motivation to support quality health care. This involves a conscious effort and a sufficient budget to achieve a high level of quality with good materials, appropriate and varied lighting, and color schemes that contribute to the overall impact of a dignified and healthy environment. A professionally executed plan will be complete with furniture selections, artwork, and door signs for room identification coordinated with surface materials. Choosing materials solely on the basis of their ability to withstand the wear of a busy office or hospital suite often results in an institutional setting. On the other hand, a successful interior, if maintained regularly, can age well, and consideration must be given to how surfaces will hold up over the years. Medical spaces take a great deal of wear and tear, and a maintenance program to keep the space in its best possible condition should be established. The current interest and growing body of knowledge in sustainable design has also provided new opportunities to use an increasingly diverse range of materials and techniques. Most manufacturers now offer product information that makes possible more informed selections that consider environmental impact, quality, and safety.

Conclusion This chapter has provided a synopsis of the many issues that must be faced when planning for the endoscopy units. The

The Colonoscopy Suite

purpose here is to give physician and staff an appreciation of the scope and complexity of the planning process and to help them formulate objectives that must be articulated to the design professionals. In summary, there are 10 points worth repeating, which will be useful in getting started and completing a successful planning process. 1 Allow adequate time for planning. 2 Choose experienced design professionals with whom you can work and communicate comfortably. 3 Set aside a regular block of time for discussion, review, and program development. 4 Get staff involved in writing down their needs and wishes. 5 Write a statement of your vision and goals, from which a detailed program can be prepared. 6 Make an inventory of equipment that will be used, including information on potential future acquisitions. 7 Visit examples of facilities whose ideas are worth incorporating. 8 Use flow studies to evaluate where functional elements are to be placed. 9 Use block diagrams to study options. 10 Review preliminary drawings and construction documents carefully against the program.

Summary of regulatory requirements for ambulatory centers in the US 1 Certification steps (a) Application for Certificate of Needasome states require this to apply for a license. (b) Application for State Licenseasome states exempt certain facilities. Some states have no license. (c) Application for Accreditationaaccepted in lieu of licensing in some instances. (d) Application to CMS for Medicare Number. 2 Certification (CMS requirements) • Governing bodyafull legal responsibility. • Written transfer agreementawith nearby hospital. • Ongoing self-assessment of quality. • Complete medical records. • Specific standards for staffing drugs, emergency procedure, etc. • Separate staff and separate records. • Exclusive use of surgical spacesaother parts of the ASC may be used for other purposes when no surgery is being conducted. • Physical separation from officeapermanent walls with 1-hour fire rating. • Comply with state license requirements. • Safe and sanitary environmentaarchitectural and code implications.

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3 Physical requirements (selected examples) A Guidelines for Design and Construction of Hospital and Health Care Facilities, version 2006 1 (3.9–2.3.1.1)a200 ft2 room size (excluding fixed cabinet)/ 3 ft 6 in. clearance around stretcher. 2 (3.9–2.3.1.3)aMedical gases in procedure room (recovery and scope cleaning). 3 (3.9–2.3.1.4)aHand-washing station in suite with handsfree controls. 4 (3.9–2.3.1.6)aEmergency communication system. 5 (3.9–2.3.1.7)aMonolithic floor covering (seamless). 6 (3.9–3.2.1)aDedicated processing room for instruments. 7 (3.9–3.2.2.2)aHand-washing station in processing room. 8 (3.9–3.2.2.5)aVentilation system in procedure room and scope cleaning room. 9 (3.9–2.5.1)aChanging and storage of patient clothing. 10 (3.9–3.2.2.5)aPatient toilet facilities. 11 (3.9–3.2)aClean utility room. 12 (3.9–2.3.2)aDedicated recovery area. 13 (3.9–3.1)aService and support areas. 14 (3.9–5.2.1.1)aCorridor width 60 in. for outpatient areas. 15 (3.9–5.2.1.2)aDoor width 44 in. for stretcher access. 16 (3.9–5.2.2)aFinishes. B Life Safety Code National Fire Protection Association 101 1 (12.6.2.4.2)aTwo means of egress, if facility is 1000 ft2 or more. 2 (12.2.3.3)aCorridor width 44 in. minimum in ambulatory centers. 3 (12.2.3.3)aCorridor width 96 in. minimum in hospitals. 4 (12.1.2.2)aTwo-hour separation if adjacent to another healthcare use. 5 (12.6.3.7.1)aOne-hour separation in mixed occupancy use. 6 (12.6.2.9.2)aEmergency power where general anesthesia is used. 7 (12.6.3.7.2)aOne-hour smoke separation in units over 2000 ft2. C 1 2 3

Americans with Disabilities Act Accessibility (4.1.11)aToilets (public), all must be accessible. (4.1.11)aToilets (private), must be adaptable. (4.1)aGeneral accessibility for path of access to all spaces.

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D 1 2 3

Joint Commission (PL.4.2)aEmergency power source. (SH.1.13.6)aRecovery area equipped and monitored. (SH.1.21.1.14)aCardiac life-support services.

Further reading Joint Commission. Accreditation Manual for Ambulatory Health Care, Vol. 1, Standards. Oakbrook Terrace, IL, 1992; 1996 Edition. AIA/FGI. Guidelines for Design and Construction of Hospital and Health Care Facilities. Washington, DC: American Institute of Architects, 2006. National Fire Protection Association. NFPA 99; Health Care Facilities. Quincy, MA, 2005 edition. Joint Commission. Comprehensive Accreditation Manual for Ambulatory Care. Oakbrook Terrace, IL, 1998; 2007 Edition. US DHHS Office for Civil Rights. OCR HIPAA Privacy TA 164.000.001. General Overview (45 CFR Parts 160 and 164). Available at: www.hhs.gov/ocr/hipaa/. US DHHS Office for Civil Rights. OCR HIPAA Privacy TA 164.501.001, Oral Communications (45 CFR §§ 160.103, 164.501). Available at: www.hhs.gov/ocr/hipaa/. AGA. The American Gastroenterological Association Standards for Office-Based Gastrointestinal Endoscopy Services. Gastroenterology 2001; 121: 440–3. Citizens Against Cross-Contamination website. Available at: www. crosscontamination.org/. US DHHS Office for Civil Rights. OCR HIPAA Privacy TA 164.502B.001, Minimum Necessary [45 CFR §§ 164.502(b), 164.514(d)]. Available at: www.hhs.gov/ocr/hipaa/finalreg.html. Ravich WJ, Kress LA. The endoscopy unit. In: Gastrointestinal Disease: An Endoscopic Approach. Thorofare, NJ: Slack Incorporated, 1997: 50–78. Sivak M. Gastroenterologic Endoscopy. Vol. 1, 2nd edn. Philadelphia, PA: WB Saunders, 2000. Waye JD, Rich M. Planning an Endoscopy Suite for Office and Hospital. New York: Igaku-Shoin Medical Publishers, 1990. Gastroenterological Society of Australia and Gastroenterological Nurses Society of Australia. Standards for Endoscopic Facilities and Services. Sydney, 1998; 3rd Edition 2006. ANSI/IESNA. RP.29 Lighting for Hospitals and Health Care Facilities, Illuminating Engineering Society of North America. January 1, 1995. ADAAG. Americans with Disabilities Act Accessibility Guidelines Public Law 101–336, 104 Stat. 327 (July 26, 1990), codified at 42 U.S.C. § 12101.

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Continuous Quality Improvement in Colonoscopy John Petrini Sansum Clinic, Santa Barbara, CA, USA

Introduction The impetus for establishing quality assurance and continuous quality improvement programs is relatively new. Spurred by reports such as To Err is Human from the Institute of Medicine in 2000 [1], concerned public, government, and industry leaders have called for improvement in healthcare delivery and outcomes. Hospitals and healthcare providers have attempted to develop strategies to improve outcome and reduce errors, but some of the initial attempts were met with hostility, as practitioners viewed them as punitive. The peer review programs already in place were not a good vehicle, for they were not designed to proactively evaluate systems of healthcare delivery since their purpose was to evaluate bad outcomes or behavior. Continuous quality improvement (CQI) developed as a means of including all parties that participate in the delivery of health care, not just administration or practitioners, into the quality assessment program. The theory behind CQI states that “real improvement in quality depends upon understanding and revising the production processes on the basis of data about the processes themselves . . . [It is] the continuous search for opportunities for all processes to get better” [2]. Ideally, the entire spectrum of activities within a practice, from first contact through discharge or termination of the patient–physician relationship, is subject to inspection and evaluation. Input can and should come from all concerned participants in the healthcare delivery process. Input from scheduling personnel, phone operators, patients, housekeeping, and security will often discover areas for improvement that were not apparent to the practitioners within a practice. The CQI process can be well demonstrated in the work of W. Edwards Deming, who popularized the

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

notion that manufacturing (performance) depends upon variables that may be difficult for managers to observe and that continuous quality assessment and improvement was the purview of all involved in the production process, from the lowest level employee to the top manager [3]. The object of a CQI program is to search for areas where changes can be made in the delivery of medical care to effect better patient health outcomes; CQI is a method of reviewing current activities to determine best practice and outcomes. There are examples of the use of quality improvement techniques to alter patient care. One example of improvement in quality care, based upon evaluation of practice, is that of the anesthesia mortality. Mortality due to anesthesia has always been a devastating complication associated with surgery [4]. However, on close evaluation of all variables involved, some avoidable contributors to mortality were found to include incompatible and proprietary connectors on equipment, confusing control systems, a lack of standardization from one machine to another, and poor patient monitoring [5–7]. Multiple concerned parties, including providers, instrument manufacturers, patient care advocates, and researchers, suggested standardization and better monitoring [8]. These changes were associated with a change in anesthesia mortality from approximately 3.7 deaths in 10 000 operations to 1 in 150 000 –250 000 [4,9,10]. Without the rigorous evaluation of problems associated with the provision of anesthesia services, the improvement in mortality might have never occurred. A second example can be observed from recent colonoscopy data. Bowles et al. [11] published results showing a relatively dismal cecal intubation rate of 57% after performing a study of colonoscopy success rates in three regions in the UK. The investigators then analyzed each colonoscopy over a set period of time. They then determined a method of improving completion based upon consensus within a departmental meeting. After instituting an action plan, a second time period was selected and the cases again reviewed. On the basis of this second analysis, modifications in the action plan were again instituted and a third period of review initiated [12].

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The initial review identified three factors: poor preparation, patient intolerance, and “technical factors.” There were indications that the time allotted for the procedure was too short, increasing pressure on the endoscopist to hurry the procedure, leading to technical difficulties and increased patient discomfort. The bowel preparation was particularly problematic in elderly patients, and it was determined that they would be better served by hospital admission for their preparation. After initiating the first action plan, the second observation period review found that the completion rate was highest in the endoscopists who were performing the fewest procedures. By changing schedules to allot more colonoscopies to the most effective colonoscopists, and other procedures to those with lower cecal intubation rates, the completion rate improved. The initial action plan increased the crude colonoscopy completion rate from 57% to 71% and the second action plan increased the crude completion rate to 88.1%. If the patients with a poor preparation and obstruction lesions are excluded, the adjusted completion rate in the second analysis is 93.8%. By instituting a program of systematic review of the cases and the development of an action plan with further review, the delivery of patient care was improved. Defining a high-quality colonoscopic procedure can be problematic. There are wide differences in training experiences and levels of competence to which patients are being exposed. Gastroenterologists are trained over an extended fellowship and are usually observed performing hundreds of cases prior to being certified as competent by their instructor to perform colonoscopy. While there is enormous variability in mechanical skill and ability, studies have shown that success rates for completion of colonoscopy are to some extent dependent on performing a large number of supervised procedures in training [13,14]. Variation in the ability of each trainer to master mechanical skills indicates that competence cannot be based solely on the number of procedures performed. Training institutions are required to closely monitor trainees for progress and deficiencies, and to correct potential problems before certifying a colonoscopist as competent. Not all colonoscopists are similarly trained. Hospital privileges to perform colonoscopy are usually granted by the practitioner’s department, and each specialty defines its requirements for granting privileges. Hospitals may be held accountable if one discipline grants privileges to perform a procedure using different guidelines and training requirements [15]. The standards that are used to grant privileges should apply across all disciplines. It is likely that most physicians, including endoscopists, feel that they provide excellent medical care. The problem is in the definition of excellence. Since experience, technique, training, and skill vary, there is clearly no set ideal for colonoscopy. However, most of us recognize quality endoscopy. To paraphrase Associate Justice Potter Stewart of the United States Supreme Court: “I know it (a quality colonoscopy) when I see it” [16]. Elucidating that quality is difficult.

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Background The principles of high-quality medical practice are in evolution. However, some guidelines exist for defining the processes by which quality measures can be developed. The concepts of medical quality, outcomes research, outcomes management, and CQI are well documented. The quality of health care is defined by the Institute of Medicine as: the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge [17].

The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) has broken high-quality health care into two facets: “doing the right thing” and “doing the right thing well” [18]. The first facet refers to medical decision-making, that is, the appropriateness of medical care. The second refers to factors affecting the delivery of high-quality care, such as skill and competence, timeliness of receiving care, safety, interaction with the patient, etc. These definitions suggest that there is a specific determination of that quality of care, and that the care can be identified and disseminated to all practitioners. However, the optimum care might not be the pathway that is most likely to lead to the best outcome for all patients in all circumstances. One method to ensure that good-quality care is being delivered is to look at the outcome of medical interactions. Outcomes research is a systematic attempt to study clinical practice with a focus on patient-centered data [19]. The distinction is made between efficacy (the treatment most likely to give the desired response in optimum circumstances), effectiveness (the utility of the therapy in real world settings), and efficiency (value to the patient) [20]. In clinical practice, the apparently most effective therapy may not be the most efficient or able to provide the most effective therapy for all patients. For example, a large sessile villoglandular polyp may be best treated with submucosal saline injection to raise the polyp, snare cautery to remove the polyp, and cautery destruction of any residual polyp tissue with argon plasma coagulation. However, in a rural setting, where expertise and specialized equipment are not available, patients may have to wait for several weeks or months, travel hundreds of miles, and pay for meals and hotel rooms to get this treatment. Worse yet, an under- or poorly trained practitioner might attempt the procedure with little prior experience. If an excellent laparoscopic surgeon is able to readily resect the polyp at minimally invasive surgery, the most efficient treatment for that patient might be laparoscopic surgery. Outcomes management attempts to look at the utility of disease-specific guidelines in everyday practice. Once practice guidelines are defined, outcomes management looks at the application of the guidelines in clinical practice situations.

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The guidelines may be easily adopted by large group practices, but may be difficult for individual practitioners to utilize. Outcomes management is directed at the effectiveness of healthcare delivery in clinical practice. The CQI process begins by the identification of any problem, within the delivery of health care, from start to finish; CQI is not intended to examine only the actual event of healthcare delivery. It encompasses all aspects of the practice of medicine, from access to discharge, including scheduling, availability, ease of contact, offices and examination rooms, ambulatory surgery facilities, waiting areas, personnel, equipment, fire and natural disaster safety, emergency provisions, and all other aspects of the provider’s health care. Once an issue is identified, the CQI process requires the systematic collection of data pertinent to that issue, so that a careful analysis of the processes that led to the problem are reviewed and the etiology of the problem determined. Once the etiology is determined, a solution to the problem can then be proposed and implemented. The CQI process then requires a reassessment of the problem with the newly implemented solution in operation to evaluate whether or not the problem has been successfully addressed; if not, the CQI process can be repeated until the problem has been resolved. A critical part of the CQI process is the “managerial philosophy that favors a supportive organizational structure and culture and the widespread use of scientific methods of process understanding and enhancement” [21]. Without the support of an organizational structure that places value on and safety for employees who bring problems to the attention of the CQI process, the likelihood of receiving the information is limited.

Definition of quality in colonoscopy The American Society for Gastrointestinal Endoscopy (ASGE) and American College of Gastroenterology (ACG) jointly published guidelines on endoscopic quality [22]. The document can be used to set standards against which an endoscopy unit or practice can compare results for evaluation of quality and set goals for improvement. Even so, such a document can only serve to establish a baseline or lowest limit of quality. Using this as a guide, endoscopists would be expected to continuously monitor their procedures and to improve on outcomes, gradually raising the baseline of care to a new, higher, level of quality. These quality parameters are by no means all-inclusive, and each unit is expected to expand upon these indicators as appropriate. Colonoscopy can be thought of as fulfilling two broad aspects of patient care. The first is for colon cancer screening. Screening colonoscopy is a diagnostic test. It is used not only to determine whether cancer is present, but also to determine that person’s risk of developing colon cancer. If the patient has precancerous polyps, he or she is at increased risk

Continuous Quality Improvement in Colonoscopy

and therefore needs closer evaluation. On the other hand, if there is no precancerous polyp, the patient’s risk is low and the future evaluation schedule is that of the general population. There are several important aspects to be considered for screening colonoscopy. First, the examination should be complete. Second, there should be a low risk to the patient. Third, the procedure should be effective, and diagnose all lesions that are present. Finally, the patient should not have to undergo the test more often than is necessary. The second aspect of patient care to be considered is in the diagnosis and treatment of colon disorders. Colonoscopy can be used to detect premalignant mucosal changes in chronic ulcerative colitis, diagnose the cause of diarrheal diseases, determine whether diverticular disease is present, dilate strictures, treat bleeding lesions, and remove colon polyps, among other uses. The skills necessary to perform these diagnostic and therapeutic maneuvers at colonoscopy require training and experience. The complication rate from these therapeutic and diagnostic procedures is expected to be somewhat higher than that of screening colonoscopy.

General considerations The colonoscopy procedure itself is only one facet of the entire patient encounter. There can be interactions with the patient outside the time of the procedure that may alter the patient’s health, and these need to be addressed on a continuous basis. For example, if a patient calls to schedule a procedure for some symptom, such as Hemoccult-positive stool, but cannot be given an appointment for several weeks, there is a chance that the lesion or illness responsible may progress and cause a greater risk to the patient. Personnel responsible for scheduling patients for procedures need to be trained in triage, or to have access to appropriate advice so that appropriate access to medical care is obtained. Areas of quality in endoscopy addressed within quality guidelines published by the ASGE and ACG include: • proper indication • proper consent • preprocedure history, and directed physical examination • risk stratification • prophylactic antibiotics where appropriate • timeliness • sedation plan • anticoagulation awareness • team pause. Each area of interaction creates vulnerability for both the patient and practitioner that requires constant surveillance and evaluation to avoid undue risk to the patient. In the intraprocedure phase, there are additional considerations: • photo documentation not only of abnormal findings, but also the extent of the examination; • patient monitoring; • documentation of medications used, including any reversal agents and adverse events.

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There are also postprocedure considerations that can be generalized to all procedures as well. These include: • discharge from the endoscopy unit; • patient instructions; • pathology follow-up; • procedure report; • complications reports; • patient satisfaction; • communication with referring providers; • anticoagulation plan. For specific procedures, each of these concerns can be addressed to develop a quality guideline that can be used to evaluate a given endoscopist’s practice. For instance, the accepted indications for colonoscopy have been published by both the ASGE and ACG [23,24]. These documents can be used to set a standard for each endoscopist, and periodic review of charts can evaluate adherence with the published guidelines. This type of review can identify outliers whose practice deviates from the guidelines, as well as those who follow the guidelines appropriately. While a reasonable rationale may exist for deviations, if the rationale is not defensible, education of the practitioner may help to improve adherence to accepted guidelines. It would take a substantial time commitment to address each of the quality issues during colonoscopy when developing a quality assessment program: in the future, electronic medical records may be able to seamlessly evaluate compliance with each of the areas of concern. It is far less time-consuming to address the quality issues at the time the unit’s records or the patient’s procedure record are set up. The task of documenting the endoscopists’ adherence to the guidelines can then be addressed on an ongoing basis, by review of the records, targeting specific areas to address serially. As new information develops, or if there are changes in the standards for care, adoption of the guidelines can be implemented and then observed for adherence. For colonoscopy, the general concerns listed above are applicable, but the focus of this chapter is the additional issues that help to establish a quality colonoscopic examination. However, the individual CQI program can choose to evaluate any or all of the issues that apply to endoscopy in general. For instance, informed consent for colonoscopy should not be limited to the potential risks, benefits, and alternatives common to any endoscopic procedure, but should also include a discussion about the risks associated specifically with colonoscopy, such as the bowel preparation, sedation, missing lesions, large polyp removal, anticoagulant use, and incomplete examination. This may be particularly true for patients who are seen as part of a free access program of colon cancer screening.

Bowel preparation The ability to provide a complete and thorough examination of the colon is dependent on numerous factors, but bowel

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preparation has been recognized as an essential part of a good examination. Studies demonstrate that poor preparation prolongs cecal intubation time and total procedure time and increases the risk of missing polyps [25,26]. Preparation for colonoscopy should completely clear the colon of solid material, and, ideally, reduce the amount of liquid residua to a relatively small volume, although there is some suggestion that a fluid-filled sigmoid colon may actually facilitate traversing the area [27,28]. A recent review of colonoscopy preparations (Chapter 10) discusses the varied approaches to clearing the colon of residual fecal material [29]. The risks associated with colon preparation have become a matter of public awareness, as one of the more popular preparations was recently shown to be associated with an increased risk of developing acute phosphate nephropathy and renal insufficiency [30]. The preparation should therefore be tailored to the patient to avoid both the inability to carefully view the colon surface as well as undue risk to the patient. The procedure note should document the preparation given as well as the effectiveness of the preparation. When the preparation is not acceptable, the risk of missing lesions is higher, and repeat procedures at an increased frequency may be necessary, thus decreasing the cost-effectiveness of colonoscopy for cancer screening [31]. The ability of a CQI program to effectively resolve poor preparation once defined has been previously mentioned [12]. The quality parameters that should be included in every case report are the type of preparation and the effectiveness of that preparation.

Cecal intubation rates The use of colonoscopy for detection and treatment of colonic disease and colon cancer screening depends upon complete examination of the colon. The ability to view the entire surface of the colon is essential to exclude lesions, particularly in the right colon. Without cecal intubation, the risk of colon cancer cannot be fully removed [32]. The mucosa of the medial wall of the cecum, between the ileocecal valve and the appendiceal opening, can be visualized only when the cecal base has been fully intubated. In some circumstances, the colonoscopy is performed to evaluate the terminal ileum, which can only be accessed via the cecum. Thus, cecal intubation should be attempted and expected in virtually 100% of patients sent for screening colonoscopy. In patients who are being examined in other situations, such as for therapeutic procedures, cecal intubation should be omitted only if the cecum is obstructed by lesions or if there is no need for intended therapy to reach the cecum (such as the shortinterval follow-up of a previously removed sessile villoglandular polyp in the transverse colon). In practice, reported cecal intubation rates vary, from a relatively low 54% to over 99% [33–35]. Rex [36] has shown that experienced colonoscopists can identify cecal landmarks virtually 100% of the time. These landmarks include the confluence of the taenia coli, appendiceal opening with surrounding lymphoid nodules,

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and ileocecal valve. The documentation of cecal intubation should be in each record, and images of the cecal base, while not always incontrovertible, will help to demonstrate that a complete examination has been achieved. The terminal ileum can also be entered in most cases, and photographic evidence showing villi will confirm cecal intubation. Quality assurance programs can easily define the expected rate and documentation of cecal intubation, and review records for outliers. There may be a myriad of reasons that the cecum cannot be reached. The value of a CQI program is that analysis of the cases in which cecal intubation is not achieved may indicate a solution to the problems that prevent full examination of the colon. The causes of each incomplete examination should be reviewed. Each repeat colonoscopy to achieve cecal intubation not only represents additional expense and time away from work for the patients and exposes them to potential complications, but also prevents access for another patient. In some patients, the preparation may not adequately clear the bowel, prohibiting safe and thorough examination of the entire colon. Evaluation of the frequency and causes of poor preparations may identify strategies for improving the quality of the preparation [12]. Some patients experience postoperative changes that prohibit straightening of the sigmoid colon so that the cecum cannot be reached with standard equipment. If a particular endoscopist experiences this problem more often than is usual, education and assistance by more successful colonoscopists may help to improve the cecal intubation rate. The use of an upper endoscope will help to reach the cecum in some of these patients, but not all [37]. In addition, new tools (Chapter 58) to help improve the ability of endoscopists to reach the cecum may be available at some point in the future [38,39]. There may be narrowing of the sigmoid colon through active disease or scarring from diverticulitis or ischemia. There are many causes of incomplete colonoscopy, some of which may not be correlated with the skill of the examiner. The CQI process can help to identify areas of improvement that may reduce the rates of incomplete examination; however, there needs to be a systematic analysis of the incomplete cases, otherwise there is little opportunity to effect a change in the practice that will lead to better patient care. The educational aspects of a CQI program should not be overlooked. The quality parameters that should be measured include cecal intubation rates, which should be at least 90% for nonscreening colonoscopies and at least 95% for screening colonoscopies. It is hoped that these numbers will steadily increase to near 100% as improvements in instrumentation and training develop. Delineation of the extent of the examination should always be included, and, ideally, this should be accompanied by clear photographic documentation of the cecal base or villi in the terminal ileum.

Polyp detection The goals of colorectal cancer screening at colonoscopy are the detection of carcinomas, the detection and removal of

Continuous Quality Improvement in Colonoscopy

neoplastic colon polyps, and the identification of patients at increased risk for the development of carcinoma. The ability to visualize the entire colon with an adequate colon preparation and consistent cecal intubation is only part of the screening process. If lesions that are present are not identified and removed, the examination has not produced maximum patient benefit. The number of patients over 50 years of age who will be found to have polyps on initial screening examination is expected to be at least 25% for men and greater than 15% for women [22]. These numbers, however, were adopted prior to studies on withdrawal time (see below). It is likely that the number of polyps discovered will be higher if more careful screening techniques and additional detection methods such as high magnification, narrow-band imaging, and chromoendoscopy are employed. There have been some serious questions raised by a variety of studies that suggest that colonoscopists are not entirely effective at detecting lesions. Two tandem colonoscopy studies suggested that miss rates for significant lesions may be as high as 27% for small adenomas less than 5 mm in diameter, 12–13% for adenomas in the 6- to 9-mm range, and up to 6% for adenomas larger than 1 cm [40,41]. There is other evidence for the miss rate of polyps during colonoscopy. In CTC (computed tomographic colonography) studies by Pickhardt et al. [42], the sensitivity for detecting adenomas 8 mm or more in diameter was higher for CTC than for standard colonoscopy (92.6% vs. 89.5%). Two other studies have compared CTC with standard colonoscopy in a similar fashion, unblinding segments of the colon sequentially after standard colonoscopic evaluation. They found a miss rate for adenomas larger than 1 cm in diameter of 12% [43] and 17% [44]. A recent abstract noted that the pick-up rate for colon polyps was higher when patients are repositioned during colonoscopy. The investigators noted that the detection of at least one polyp in the colon proximal to the sigmoid colon increased from 33% with the patient in the left lateral decubitus position to 47% (P = 0.03) when the patient changed position during the examination [45]. Recent reports concerning the lack of prevention of colon cancer development after colonoscopy have been alarming. Effective colonoscopy screening should markedly reduce the occurrence of colorectal cancer. Initial colon cancer screening studies suggested that colonoscopy and polypectomy reduced the incidence of colon cancer by as much as 90%, with attendant reduction in mortality [46–48]. Studies in the literature have suggested that patients having colonoscopy and polypectomy may still be at substantial risk of developing colorectal cancer [49,50]. The report from Manitoba documented a fairly high initial cancer rate following colonoscopy. The relative risk of developing a colon cancer was 0.69 at 6 months and 0.59 at 2 years, much higher than in initial studies [46]. The authors found the percentage of right-sided cancer following colonoscopy was higher (47%) than expected (27%), suggesting that some of the examinations did not fully

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evaluate the right colon. Follow-up analysis presented in 2007 documented a higher rate of subsequent colon cancer if the colonoscopy was performed in a rural versus an urban setting (0.8% vs. 0.4%, P < 0.001), and if the colonoscopy was performed in a rural setting by a general practitioner (1%). Primary care physicians have a lower colon cancer detection rate than gastroenterologists, so CQI programs should include evaluation of all endoscopists in the unit or facility to encourage improvement in polyp and cancer detection [51,52]. Another recent abstract found that colonoscopy afforded a higher level of protection against colorectal cancer for men than for women. The authors conducted a retrospective analysis of 4458 colon cancer patients in the California Medicaid system, compared with 43 815 age-matched control subjects. The adjusted risk for colorectal cancer following a negative colonoscopy was 0.55, again lower than the National Polyp Study results. The relative risk of developing a right-sided cancer was higher (0.67) than the relative risk for left-sided cancers (0.16). The relative risk reduction for left-sided cancers was 84% for both men and women, but for right-sided cancers was 62% for men and only 18% for women. This finding cannot be entirely explained by the slightly lower rate of cecal intubation, and the slightly higher risk of rightsided adenomas, in women [53]. The disturbing message from these studies is that colonoscopy may not be removing all of the lesions that are responsible for colon cancer and endoscopists are not providing the level of safety for our patients that we propose. Studies of CTC have largely demonstrated that lesions of significance, that is, wider than 9 mm, are detected by CTC as effectively as by colonoscopy, and that smaller lesions may not require intervention [36– 38]. However, the argument that smaller polyps (< 10 mm) need not be removed is controversial. A recent study by Butterly et al. [54] documents a small but significant risk of advanced histology and carcinoma in polyps smaller than 1 cm. For very small polyps (< 4 mm), the risk of advanced histology was only 1.7%, with no carcinomas found in this group. However, for polyps 5–9 mm in size, advanced histology was found in 3.9% and carcinoma in 0.4%. Two studies presented in abstract form have shown similar results. Japanese investigators found intramucosal carcinoma in 4% of diminutive polyps (< 5 mm) and overall in 7.3% of polyps less than 10 mm. Similarly, Rex and coworkers found advanced histology in 1.26% of polyps less than 6 mm. Advanced histology was found in 5.7% of polyps 6– 9 mm in size. The implication from these studies is that significant advanced histology will be present in some small polyps. Studies are currently under way to determine if polyps in the 6–9 mm size can be safely followed with serial CTC. These findings again reflect the need for careful quality evaluation by all practitioners engaged in the performance of colonoscopy, with removal of all detected lesions to permit safe intervals between subsequent examinations. The goal of screening the greatest number of patients can

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be accomplished only by providing the most thorough initial examination with a maximum safe interval for subsequent examination. It is clear that the polyp to cancer sequence is not uniform, and some patients are at higher risk of developing a cancer in a shorter interval [55]. However, the cost of the procedure per year of life saved, in terms of both actual procedural expense as well as the associated costs arising from time lost from employment, the need for a responsible companion, complications, and related expenses of treatment, can be minimized by an appropriately long interval between examinations. Both the ASGE and ACG recommend intervals of 10 years between examinations for patients with no history of colon neoplasia and a negative family history of adenoma or colon cancer [22]. This interval requires careful initial examination. At present, the quality parameters that should be attained are identification and removal of neoplastic polyps in at least 25% of men and 15% of women over 50 years of age undergoing screening colonoscopy.

Withdrawal times The goal of colonoscopy is to perform the examination completely, carefully, and safely. Previous bravado of a “fast” colonoscopy is no longer appropriate, given the evidence from recent literature. Studies have demonstrated that the rate of colon polyp detection is increased with slower, careful withdrawal after the cecum has been reached. This research confirms that colonoscopists may not be picking up all the potentially neoplastic lesions when performing colonoscopy, as suggested by the lack of complete protection from the development of colon cancer documented above. The lack of complete colon cancer prevention from screening colonoscopy demands improvement in colon preparation, cecal intubation, and, clearly, withdrawal times, which are critical to clear the colon of potential carcinoma-producing polyps. The withdrawal time is defined as the time from beginning of withdrawal of the instrument from the cecum or terminal ileum until the anal verge is reached. This time is measured independent of any therapeutic maneuvers, such as biopsy or polypectomy. Most investigators use a stopwatch technique to determine withdrawal times. Initially noted in 2000, colonoscopists with a longer withdrawal time found more neoplastic lesions during screening colonoscopy [56]. Subsequent studies have confirmed the findings of greater adenoma detection with longer withdrawal times. A Mayo Clinic retrospective analysis of 10 955 sequential colonoscopies found that the median polyp detection rate of 42.7% corresponded with a mean withdrawal time of 6.7 min [57]. This abstract argued that the minimum withdrawal time associated with the best chance of finding significant lesions was more than 6 min. The direct correlation associated with longer withdrawal times and greater polyp detection in this study was less apparent and not significant as the size of the polyps was over 9 mm. A second study, published in

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completed form, again found a direct correlation between withdrawal time and the number of adenomatous polyps detected [58]. The authors again noted that the detection of polyps is increased with longer withdrawal times. In this study, the mean withdrawal time associated with median polyp detection was 6 min. Taken together, these studies document the need for careful, slow, and deliberate withdrawal of the colonoscope after full insertion. A CQI program can easily establish and document this parameter, and each unit should be able to review colonoscopists for compliance with this indicator. The withdrawal of the colonoscope should average at least 6 min for patients undergoing screening colonoscopy, independent of time spent on therapeutic or diagnostic procedures.

Removal of lesions While one object of the screening examination is to assess colon cancer risk, the removal of any potentially premalignant lesion is a part of the procedure. Pedunculated polyps are routinely removed without difficulty by most colonoscopists. Small sessile lesions can be easily removed with biopsy forceps or by snare removal, either cold or cautery assisted. The more significant lesion that requires aggressive intervention is the larger sessile neoplastic polyp. Larger sessile polyps (> 2 cm) may be associated with a greater risk of perforation or postpolypectomy bleeding, but can be safely removed at colonoscopy by skilled endoscopists [59,60]. The recently popularized technique of saline elevation of the polyp by injection of sterile saline into the submucosa below the polyp has increased the safety and effectiveness of endoscopic removal of these lesions [61]. The routine referral of patients for surgical removal of polyps smaller than 2 cm is not supported by the literature. Endoscopists clearly should not attempt procedures with which they are uncomfortable. However, it is equally unreasonable for patients to be subjected to a second procedure when a polyp is found on a colonoscopic examination and is not removed at that time. There are standards for routine polypectomy which should accompany the performance of colonoscopy. The ASGE and ACG guidelines define the level of competence needed to perform standard screening colonoscopy as including the ability to remove pedunculated polyps and sessile polyps that are less than 2 cm in diameter [22]. Polyps that are larger than 2 cm can typically be removed safely, but it is not necessarily outside the standard of care to refer patients with these larger lesions either to a more advanced endoscopist or to a surgeon. The availability of local expertise may affect decisions regarding these larger sessile polyps. However, it is strongly recommended that these lesions be marked with submucosal injections of a permanent surgical marker (formerly India ink, recently pure carbon particles in suspension) to identify the lesions at either future endoscopy or surgery to remove the lesion. Review of endoscopy records for evidence of removal of polyps

Continuous Quality Improvement in Colonoscopy

of appropriate size can easily be included in a CQI program, provided the size, appearance, and location of each polyp is included in the report, as previously recommended [22]. The quality parameter should be that pedunculated polyps and typical sessile polyps smaller than 2 cm are removed during the colonoscopy examination when they are first encountered, without the need for referral for surgery.

Appropriate adherence to guidelines for biopsy in patients with diarrhea Procedures should be performed for appropriate indication, but, when evaluating the quality of the procedure, other considerations may apply. For instance, the use of biopsies to evaluate the colon for dysplasia in long-standing colitis has an established standard protocol. In patients with ulcerative colitis, the relative risk of developing colon cancer depends upon the extent of the disease and the length of time the patient has the disease. The increase in risk of colon cancer appears to become relevant after 8–10 years of the disease [62–64]. Patients with ulcerative proctitis alone may have only a slightly higher risk of colon cancer, whereas patients with left-sided colitis have approximately an eight to nine times higher risk of cancer. However, patients who have pancolitis may be at significant risk of developing colorectal cancer, with reported rates 26 times higher than in agematched control subjects, although some studies do not show this degree of risk [56,65]. The appearance of dysplasia in the biopsy specimens appears to herald a greater risk of synchronous cancer and, if confirmed to be present, suggests that colectomy may be needed [66]. There have been many recommendations made regarding the best method for diagnosis of dysplasia. The current recommendation is to obtain four quadrant biopsies every 10 cm for the affected segments of the colon, or 32 biopsies from the typical patient with pancolitis [67]. Targeted biopsies are to be obtained from any mass or significant polypoid lesions, and their location and appearance documented. The findings of dysplasia need to be confirmed by a second pathologist [61]. Recall systems should be in place to bring patients back at an appropriate interval. In patients who are being seen for long-standing diarrhea, the diagnosis of microscopic colitis should be considered and biopsies obtained during their colonoscopy. This disorder is treatable and can often relieve symptoms in patients who have been diagnosed with either lymphocytic or collagenous colitis. The exact number and location of the biopsies is not established, but there is a suggestion that right colon biopsies are often necessary to establish the disease [68,69]. The parameters that should be measured are that patients with unexplained diarrhea who undergo colonoscopy should have random biopsies from the right and left colon to evaluate for microscopic, collagenous, or lymphocytic colitis, even when the mucosa has a completely normal appearance.

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Complications In addition to a thorough and complete examination, another goal of colonoscopy is to provide a safe procedure. There are always risks associated with interventional procedures, and colonoscopy is not without risk of complication. Since the sedative and analgesia medications used to facilitate comfortable colonoscopy contribute to over 50% of the procedurerelated complications, careful evaluation of any untoward outcomes based upon the use of narcotics and analgesics is imperative [70]. Some authors have suggested that the need to utilize reversal medications to rescue patients who are too heavily sedated should be documented and tracked. However, the downside to this reporting requirement is that if it is seen as a “complication” or potentially placing the endoscopist at some disadvantage, the endoscopist might be less likely to use the reversal agents. This may create situations in which patient safety becomes compromised. The key to successful CQI is to remove any stigma or negative connotations to any and all complication reporting. It is only when physicians are free to present all aspects of their care and involvement (as well as their positive accomplishments) without hesitation that the true educational benefits of CQI can be realized. While many complications have been reported, the most common expected and significant complications are postpolypectomy bleeding and perforation. One issue that makes discovery of complications and methods to correct them difficult is the lag time between the procedure and the occurrence of the complication. For example, postpolypectomy bleeding may occur up to 2 weeks or more after the procedure, and news of the bleeding and subsequent treatment may not reach the endoscopist or the endoscopy unit where the procedure was performed. Efforts to contact patients to gain information on delayed complications may not always be successful, and the true numbers of complications may be underestimated. This is unfortunate, as the lack of information prevents effective analysis of the complications and subsequent efforts to improve outcome. Once again, reporting such occurrences should be viewed as an opportunity to learn from the events and not as an indication of poor performance.

Postpolypectomy bleeding The incidence of postpolypectomy bleeding has been reported to range from 0.2% to over 10% of patients who undergo polypectomy, with the higher rates being found in patients with large, right-sided colon polyps and patients on anticoagulants [71–77]. The bleeding may be immediate, but delayed bleeding can occur up to 17 days or more after the procedure [74]. Bleeding seen after polypectomy in patients on oral anticoagulants is more often immediate rather than late [68]. Recent studies using endoscopic hemostasis clips or loops to seal the polypectomy base may help to reduce the bleeding following polypectomy in anticoagulated patients,

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although not all investigators agree [78–80]. Small sessile polyps (< 1 cm), particularly in the right colon, can be successfully removed without electrocautery, and this technique may result in less postpolypectomy bleeding [81]. In spite of coaptive coagulation with heat sealing of bleeding vessels at the margin of the polypectomy site, postpolypectomy bleeding will occur, and each case that is examined may help to identify factors that could be relevant in assessing the cause of bleeding from that polyp site. The proportion of patients who experience bleeding following polypectomy should be less than 1%. CQI programs should encourage practitioners to present their postpolypectomy bleeding patients for further review.

Perforation Perforation of the colon may occur as a result of the colonoscopic procedure itself or, more commonly, as a result of therapeutic maneuvers during the examination, particularly polypectomy. Since the mortality among patients who experience a colonic perforation is approximately 5%, the incidence of perforation as a result of the diagnostic colonoscopy should be relatively low, especially for patients who undergo screening examinations for colon cancer [71,82,83]. Initial results of a large series suggest a very low rate of perforation for screening colonoscopy [24]. Yet studies continue to show what should be considered an unacceptably high rate of perforation. The recent CTC comparison trial had a perforation rate of 0.22%, or 1 in 452 patients [84]. One large series reported a perforation rate of approximately 1 in 500 for colonoscopy, but less than 1 in 1000 for patients undergoing screening colonoscopy [85]. As would be expected, the perforation rate for therapeutic procedures and polypectomy is higher than that for screening colonoscopy. The risk is also higher with associated disease in the colon, such as inflammatory bowel disease, acute and chronic diverticulosis, ischemia, radiation changes, strictures, colorectal cancer, and chronic corticosteroid use. Perforation at colonoscopy is often the result of mechanical factors. The usual mechanism is pressure from the shaft of the instrument against a relatively fixed segment of the bowel, or from stretching of the left colon from loop formation. One report of 42 perforations showed the perforation in the left side in 23 (55%) [86]. In this report, 93% went to surgery and the mortality was zero. There have also been reports of cecal perforation from excess air pressure in the colon during colonoscopy (barotrauma) [87]. Excess pressure in the cecum can occur when attempting to pass the colonoscope through a relatively narrow segment, such as a tumor or diverticular stricture, when insufflated air passes through, although the instrument may not achieve intubation for a prolonged interval. Perforation may also occur during polypectomy. Most perforations at polypectomy are thought to be caused by electrocautery burn through the wall of the colon. High current

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density and prolonged current application can cause a fullthickness burn of the bowel wall. Polyps that are fixed to the wall of the colon, or immobile when manipulated, are more likely to perforate at polypectomy. Saline injection into the submucosa will often help identify lesions that are adherent, since failure to raise the polyp up on a pillow of saline indicates that the polyp is adherent to the muscular wall [88]. Cold snare polypectomy of small, sessile polyps, particularly in the right colon, offers several advantages over multiple biopsies, hot biopsy forceps, or snare cautery polypectomy. The complete removal of polyps by multiple, cold biopsies has not always resulted in complete removal of the polyp, and hot biopsy forceps have been reported to be associated with a higher rate of complications [89,90]. Snare cautery of small, sessile polyps in the right colon induces a burn deep to the mucosa, which may involve larger vessels. Since mucosal vessels are smaller and less likely to bleed, removing small polyps with the cold snare technique rarely induces significant bleeding, either acute or late, and allows complete removal and recovery of the tissue without cautery artifact [91]. An effective CQI program to detect and evaluate complications at colonoscopy requires that patients be contacted at some time after their procedure, usually 30 days. By then, all relevant complications should have become manifest, although infectious complications, such as endocarditis, and infectious agents transmitted through ineffective terminal disinfection technique and breaks in cleaning protocol may take longer to become apparent. Phone call contact can help to identify complications that occur once patients are outside the area where the procedure was performed. Patients can be given return response cards to mail back to the unit at 30 days with check-off boxes for complications. This may also be combined with a patient satisfaction survey (see below). Each endoscopist should be educated and responsible for reporting complications to the CQI personnel so that evaluation and identification of potential areas for improvement can be established. The goal of the process is better patient care and improved outcomes. Under ideal circumstances, the process of CQI is not punitive but educational. It is expected that fewer than 1 in 500 patients will have a perforation as a result of colonoscopy, and, for screening, fewer than 1 in 1000 will experience a perforation. All perforations need to be documented and reviewed. Some recent investigators have suggested that colonic perforations, at least in an animal model, can be closed with endoclips and the patient managed conservatively, without surgery, but the data are clearly preliminary [92].

Treatment of complications Complications will occur during any invasive procedure, and bleeding after polyp removal is not uncommon. The vast majority of patients who experience postpolypectomy bleeding can be managed conservatively, without surgery, and are well within the standard of care for colonoscopists. Bleeding

Continuous Quality Improvement in Colonoscopy

may be immediate or delayed; immediate bleeding will be seen as soon as a polyp is removed. Pedunculated polyps will often bleed from the vascular bundle in the stalk if the cautery application did not seal the vessel walls together. Several techniques can be used to control such bleeding, with the quickest response being to grasp the residual stalk with the snare and hold it closed for over 5 min. This mechanical pressure will usually start the hemostatic cascade. Pressure can also be applied with a hemostatic clip or endoloop, which will effectively seal the bleeding vessel. Injection of dilute epinephrine (1:10 000) followed by electrocautery [93,94] can also be useful. Large sessile polyps can bleed at the time of polypectomy, and injection of dilute epinephrine and electrocautery are usually effective; argon plasma coagulator therapy can also be used. Delayed bleeding from the polypectomy site may occur up to 2 weeks or more after the polypectomy. The patient can often be managed conservatively, without repeat colonoscopy, but the decision to intervene is made on the basis of clinical parameters. If a repeat examination and treatment is performed, a similar approach to the bleeding site as with acute bleeding may be used. Hemostasis clips, endoloop, and epinephrine with electrocautery can be used to control the bleeding. Care must be taken in the right colon, particularly after the previous application of thermal energy for polypectomy has compromised the colon wall. The goal is for endoscopists to control postpolypectomy bleeding in over 90% of cases. Quality parameters include reporting all complications, with fewer than 10% of patients with postpolypectomy bleeding requiring surgery.

Patient satisfaction The colonoscopy procedure is often perceived as a painful experience by many patients. The judicious use of sedatives and hyponotic medications, as well as anesthetics, has helped to make the procedure more acceptable to patients. Screening saves lives but it is important that the experience be satisfactory for the patient [95]. Each practice should evaluate patient satisfaction. Much can be gained from the patient who experiences difficulty in scheduling, problems with transportation, or dissatisfaction with personnel or the facility. While not all complaints are justified, each negative experience should be reviewed for accuracy and areas for improvement. A standardized and validated survey for determining the level of patient satisfaction has been recommended by the ASGE [96] (Table 3.1). This survey is rapid, short, and provides a meaningful assessment of the endoscopic experience by the patient and can be incorporated into each unit’s practice.

Follow-up Whenever tissue is removed for diagnostic purposes, the patient, referring physician, and endoscopist are all entitled to, and expect to, become aware of the results. Often the

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Table 3.1 American Society for Gastrointestinal Endoscopy Patient Satisfaction Survey [96]. A number of questions are listed below regarding the visit you made The possible responses for questions 1–7 are: excellent, very good, good, fair, poor The possible responses for questions 8 and 9 are: yes, no In terms of your satisfaction, how would you rate each of the following. 1 How long you waited 2 Length of time spent waiting at the office for the procedure 3 The personal manner (courtesy, respect, sensitivity, friendliness) of the physician who performed your procedure 4 The technical skills (thoroughness, carefulness, competence) of the physician who performed your procedure 5 The personal manner (courtesy, respect, sensitivity, friendliness) of the nurses and other support staff 6 Adequacy of explanation of what was done for you (all your questions answered) 7 Overall rating of the visit 8 Would you have the procedure done again by this physician? 9 Would you consider having this procedure done again at this facility?

results will have a major impact on the patient’s future care. Systems should be in place to review pathology findings, establish communication with the referring physician, and define responsibility for giving the information to the patient. In addition to the potential legal consequences of not providing appropriate follow-up, patient care may be compromised. Each unit should establish a mechanism for dissemination of

the results to the appropriate parties. CQI should evaluate the systems for reviewing the pathology findings and disseminating the information. Similarly, the need for future examinations will be largely determined by the pathology findings. The use of appropriate ASGE or ACG guidelines to establish a recall system will provide the best cost-effective mechanism to protect patients at the lowest cost [23,24]. Adherence to guidelines can also be reviewed within the CQI process to be certain that patients are being recalled at an appropriate interval. The quality parameter is for adherence to the ASGE or ACG guidelines for follow-up of patients with premalignant lesions (Table 3.2).

Developing a continuous quality improvement program Each institution, program, and practice should establish a CQI program, and the process may not be identical for any two locations. The key is to establish a mechanism for review of all aspects of the services provided, not just the quality and competence of the physician staff. Each aspect of the practice is and should be evaluated, including the support staff, and the facility and ancillary services. The goal is to develop systems that allow for evaluation and comparison with known standards, and which are able to quantify the extent to which the practice meets those standards. However, the system should be nimble enough to identify problems within the practice rapidly and effectively, before any injury can occur.

Table 3.2 Appropriate age of onset and intervals for colonoscopy relating to screening and surveillance indications. (Adapted from Rex et al. [24].) Indications Screening Average risk Single FDR with cancer (or adenomas) at age 60 or older Two or more FDRs with cancer (or adenomas) or one FDR diagnosed at younger than age 60 Prior endometrial or ovarian cancer diagnosed at younger than age 50 Hereditary nonpolyposis colorectal cancer Postadenoma resection One to two tubular adenomas of < 1 cm Normal follow-up examination or only hyperplastic polyps at follow-up Three or more adenomas or adenoma with villous features, ≥ 1 cm or with HGD Numerous adenomas or sessile adenoma > 2 cm, removed piecemealb Postcancer resection Ulcerative colitis and Crohn’s disease Surveillance after 8 years of pancolitis or 15 years of left-sided colitis

Intervala

10 years (begin at age 50) 10 years (begin at age 40) 5 years (begin at age 40 or 10 years younger, whichever is earlier) 5 years 1–2 years (begin at ages 20–25)

5 years 5 years 3 years Short interval based on clinical judgment Clear colon, in 3 years, then as per adenoma recommendations

2–3 years until 20 years after onset of symptoms, then 1 year

FDR, first-degree relative; HGD, high-grade dysplasia. a Interval recommendations assume adequate preparation and cecal intubation. b The goal is to reexamine the site for residual polyp; repeating a flexible sigmoidoscopy is adequate for a distal polyp.

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The ultimate responsibility for setting up, evaluating, and improving the CQI process lies with the governing body for the service provided. In a hospital setting, the administrators and board of directors are ultimately responsible for the quality of the services provided. In an ambulatory surgery center, the owners of the center are ultimately responsible. This creates some minor difficulty, as the owners may not be the best choice to determine how the practice can and should be evaluated. The process of evaluating a service would be best relegated to those who are most familiar with the nuances of the service, that is, the practitioners. However, the practitioners may not be the most objective evaluators of their own shortcomings. The process should be objective, unbiased, nonthreatening, and positive. JCAHO has defined the steps of a CQI program [18]. The basic steps are: 1 Leaders of organizations should establish a planned, systematic, and organization-wide approach to process design and performance measurement, analysis, and improvement. 2 Data are collected to monitor performance and to identify opportunities for improvement. 3 The information is analyzed and used to draw conclusions about outcomes. The organization should compare its performance over time and with other sources of information. Undesirable patterns of performance and sentinel event are analyzed intensively. (JCAHO defines a sentinel event as “an unexpected occurrence involving death or serious physical or psychological injury, or the risk thereof. The event is called sentinel because it should send a signal or sound a warning that requires immediate attention”.) 4 Changes which will lead to improved outcomes are identified and implemented. 5 Performance is remeasured to help determine the effectiveness of the change and whether additional changes are needed. Improved performance should be achieved and sustained. The design of a CQI program can also be centered on evaluation of performance against a standard. The quality definitions for colonoscopy, such as cecal intubation, set a standard against which any given endoscopist or group can evaluate their own practice. The initial evaluation may be a review of all colonoscopy reports over a given period of time for evidence of completeness. The review can be by an impartial third party, or by any number of other participants, including one or more of the endoscopists. The information derived may indicate that the practice is at, above, or below the benchmark for greater than 90% overall, and greater than 95% for screening examinations. The key is that it may not be possible to rely on memory to determine if endoscopists meet guidelines, and only systematic review will determine if deficiencies exist. Once the practice has been compared with the benchmark numbers, one of several pathways can be taken. The practice may decide that its level of cecal intubation is adequate and no further inquiry is needed. There

Continuous Quality Improvement in Colonoscopy

may be some outliers whose technique may need review and additional training. The failed examinations may be looked at to determine if some common theme emerges that may permit higher completion rates. Even if all practitioners meet the standards, there still may be some differences among the endoscopists, and those with higher cecal intubation rates may have tips or techniques that can be shared with those at a lower level of completion. The benefit to this type of systematic review is that it brings the quality of the services provided into the forefront of everyone’s awareness. Ideally, the CQI process should be open to further development by any participant within the practice. For each individual, observation of the environment will lead to new insights into optimum function. It will be far more informative if the endoscopists develop quality review programs than if the board of directors determine the programs to be used. The practitioners are in the best position to define and create meaningful CQI programs that will best improve patient care outcomes. Conversely, practitioners may not be in the best position to outline fire safety or natural disaster preparedness, and these tasks may be better relegated to maintenance or engineering staff personnel. The quality parameters for colonoscopy defined above form a baseline. The standards of quality will continuously be in flux. The ideal of cecal intubation with all lesions identified, excellent patient satisfaction, and no complications will be met in the vast majority of cases. The goal is to improve the practice of each colonoscopist to reach that ideal for all patients. CQI can and, logically, should be viewed as a means to attain that end. The form of the CQI program is adaptable to each practice so that the outcome of improved health for the patient is a reality.

Summary Colonoscopy is a tool for the evaluation of the large intestine to screen for colon cancer, define the risk of colon cancer relative to the general population, determine the presence of disease, and treat specific disorders related to the colon. Training may be variable, but the parameters that determine a quality examination apply equally to all colonoscopists. The practitioner performing colonoscopy is held to a standard of quality that is defined and applicable to each practice. It is essential to evaluate each provider to determine the extent to which these quality measures are being met and to establish mechanisms to improve the service whenever possible. The opportunity to improve the quality of colonoscopy requires evaluation of each practitioner, so that his or her performance can be compared with the benchmark standards. It is not acceptable to assume that the colonoscopist is providing adequate service. The measures are defined and accessible. The CQI mechanism provides an opportunity to evaluate each provider in an objective, nonthreatening, peer review forum.

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The evaluation of how well the colonoscopy quality parameters outlined above are met results in findings that may indicate average, exceptional, or inadequate service. In the event that the practitioner falls below standard, the CQI process can help to establish solutions that may improve the quality of the colonoscopist. If reexamination fails to demonstrate improvement, additional solutions can be tried until the acceptable minimum is attained. If the practitioner is unable to meet the standards after repeated interventions, the governing body of the healthcare system may have no choice but to recommend further training, or suspend or revoke privileges. However, it is anticipated that with careful analysis, observation, and retraining, each colonoscopist should be able to meet the quality measures defined above. It is likely that with continued improvements in bowel preparation, equipment, and training, the quality measures will continue to be set at higher levels so that the goal of improved patient health care is realized.

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35 Petrini JL, Egan JV, Hahn WV, Hobson JD. Unsedated colonoscopy: patient characteristics and satisfaction in a community based endoscopy unit. Gastrointest Endosc 2007; 65: AB357. 36 Rex DK. Still photography versus videotaping for documentation of cecal intubation: a prospective study. Gastrointest Endosc 2000; 51: 451–9. 37 Paonessa NJ, Rosen L, Stasik JJ. Using the gastroscope for incomplete colonoscopy. Dis Colon Rectum 2005; 48: 851–4. 38 Van Dam J, Eickhoff A, Jakobs R, Kudis V, Hartmann D, Riemann J. Computer-assisted colonoscopy (the NeoGuide System): results of the first human clinical trial. Gastrointest Endosc 2006; 63: AB100. 39 Vucelic B, Rex DK, Pulanic R, et al. The Aer-O-Scope: proof of concept of a pneumatic, skill-independent, self-propelling, selfnavigating colonoscope. Gastroenterology 2006; 130: 672–7. 40 Hixson LJ, Fennerty MB, Sampliner RE, et al. Prospective study of the frequency and size distribution of polyps missed by colonoscopy. J Natl Cancer Inst 1990; 82: 1769–72. 41 Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112: 24– 8. 42 Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 2003; 349: 2189–98. 43 Pickhardt PJ, Nugent PA, Mysliwiec PA, et al. Location of adenomas missed by optical colonoscopy. Ann Intern Med 2004; 141: 352–9. 44 Van Gelder Re, Nio CY, Florie J, et al. Computed tomographic colonography compared with colonoscopy in patients at increased risk for colorectal cancer. Gastroenterology 2004; 127: 41– 8. 45 East J, Stavrinidis M, Arebi N, Palmer N, Bassett O, Saunders BP. Polyp detection rate is improved with position changes during colonoscope withdrawal: a randomized crossover trial Mid-point analysis. Gastrointest Endosc 2007; 65: AB112. 46 Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy: the National Polyp Study Workgroup. N Engl J Med 1993; 329: 1977– 81. 47 Thiis-Evensen E, Hoff G, Sauar J, et al. Population-based surveillance by colonoscopy: effect on the incidence of colorectal cancer: Telemark Polyp Study I. Scand J Gastroenterol 1999; 34: 414–20. 48 Citarda F, Tomaselli G, Capocaccia R, et al. Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence. Gut 2001; 48: 812–15. 49 Robertson DJ, Greenberg ER, Beach M, et al. Colorectal cancer in patients under close colonoscopic surveillance. Gastroenterology 2005; 129: 34–41. 50 Baxter NN, Goldwasser MA, Paszat LP, Saskin R, Urbach DR, Rabeneck L. Association of colonoscopy and death from colorectal cancer. Ann Int Med 2009; 150: 1–8. 51 Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997; 112: 17–23. 52 Bressler B, Paszat LF, Chen Z, Rothwell DM, Vinden C, Rabeneck L. Rates of new or missed colorectal cancers after colonoscopy and their risk factors: a population-based analysis. Gastroenterology 2007; 132: 96–102.

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53 McCashland TM, Brand R, Lyden E, et al. Gender differences in colorectal polyps and tumors. Am J Gastroenterol 2001; 96: 882–6. 54 Butterly LF, Chase MP, Pohl H, et al. Prevalence of clinically important histology in small adenomas. Clin Gastroenterol Hepatol 2006; 4: 343–8. 55 Jarvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000; 118: 829–34. 56 Rex DK. Colonoscopic withdrawal technique is associated with adenoma miss rates. Gastrointest Endosc 2000; 51: 33–6. 57 Simmons DT, Harewood GC, Baron TH, et al. Impact of endoscopist withdrawal speed on polyp yield: implications for optimal colonoscopy withdrawal time. Aliment Pharmacol Ther 2006; 24: 965–71. 58 Barclay RL, Vicari JJ, Doughty AS, Johanson JJ, Greenlaw RL. Colonoscopic withdrawal times and adenoma detection during sreening colonoscopy. N Engl J Med 2006; 35: 2533–41. 59 Doniec JM, Löhnert MS, Schniewind B, Bokelmann F, Kremer B, Grimm H. Endoscopic removal of large colorectal polyps. Prevention of unnecessary surgery? Dis Colon Rectum 2003; 46: 340–8. 60 Sorbi D, Norton I, Conio M, et al. Postpolypectomy lower GI bleeding: descriptive analysis. Gastrointest Endosc 2000; 51: 690–6. 61 Waye J. Saline injection colonoscopic polypectomy. Am J Gastroenterol 1994; 89: 305–6. 62 Greenstein AJ, Sachar DB, Smith H, et al. Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology 1979; 77: 290–4. 63 Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta analysis. Gut 2001; 48: 526–35. 64 Bernstein CN, Blanchard JF, Kliewer E, et al. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001; 91: 854–62. 65 Jess T, Loftus EV, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: A population-based study from Olmsted County, Minnesota. Gastroenterology. 2006; 130: 1039–46. 66 Mpofu C, Watson AJ, Rhodes JM. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database Syst Rev 2004; 2: CD000279. 67 Itzkowitz SH, Present DH. Crohn’s and Colitis Foundation of America Colon Cancer in IBD Study Group. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11: 314–21. 68 Yusoff IF, Ormonde DG, Hoffman NE. Routine colonic mucosal biopsy and ileoscopy increases diagnostic yield in patient undergoing colonoscopy for diarrhea. J Gastroenterol Hepatol 2002; 17: 276– 80. 69 Zins BJ, Tremaine WJ, Carpenter HA. Collagenous colitis: mucosal biopsies and association with fecal leukocytes. Mayo Clin Proc 1995; 70: 430–3. 70 Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the American Society for Gastrointestinal Endoscopy/US Food and Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointest Endosc 1991; 37: 421–7. 71 Silvis SE, Nebel O, Rogers G, et al. Endoscopic complications: results of the 1974 American Society for Gastrointestinal Endoscopy Survey. JAMA 1976; 235: 928–30.

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72 Waye JD, Lewis BS, Yessayan S. Colonoscopy: a prospective report of complications. Am J Gastroenterol 1992; 15: 347–51. 73 Rosen L, Bub DS, Reed JF, Nastasee SA. Hemorrhage following colonoscopic polypectomy. Dis Colon Rectum 1993; 36: 1126– 31. 74 Hui AJ, Wong RM, Ching JY, Hung LC, Chung SC, Sung JJ. Risk of colonoscopic polypectomy bleeding with anticoagulants and antiplatelet agents: analysis of 1657 cases. Gastrointest Endosc 2004; 59: 44–8. 75 Gibbs DH, Opelka FG, Beck DE, Hicks TC, Timmck AE, Gathright JB. Postpolypectomy colonic hemorrhage. Dis Colon Rectum 1996; 39: 806–10. 76 Sorbi D, Norton I, Conio M, Balm R, Zinsmeister A, Gostout CJ. Postpolypectomy lower GI bleeding: descriptive analysis. Gastrointest Endosc 2000; 51: 690–6. 77 Hurlstone DP, Sanders DS, Cross SS, et al. Colonoscopic resection of lateral spreading tumours: a prospective analysis of endoscopic mucosal resection. Gut 2004; 53: 1334–9. 78 Howell DA, Eswaran SI, Lowe BJ, et al. Use of hemostatic clips in patients undergoing colonoscopy in the setting of coumadin anticoaguation therapy. Gastrointest Endosc 2006; 63: AB99. 79 Friedland S, Soetikno R. Colonoscopy with polypectomy in anticoagulated patients. Gastrointest Endosc 2006; 64: 98–100. 80 Shioji K, Suzuki Y, Kobayashi M, et al. Prophylactic clip application does not decrease delayed bleeding after colonoscopic polypectomy. Gastrointest Endosc 2003; 57: 691– 4. 81 Tappero G, Gaia E, De Guili P, et al. Cold snare excision of small colorectal polyps. Gastointest Endosc 1992; 38: 310–13. 82 Fruhmorgen P, Demling L. Complications of diagnostic and therapeutic colonoscopy in the Federal-Republic-of-Germany: results of an inquiry. Endoscopy 1979; 11: 146–50. 83 Nivatvongs S. Complications in colonoscopic polypectomyaan experience with 1555 polypectomies. Dis Colon Rectum 1986; 29: 825–30.

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84 Kim DH, Pickhardt PJ, Taylor AJ, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med 2007; 357: 1403–12. 85 Gatto NM, Frucht H, Sundararajan V, et al. Risk of perforation after colonoscopy and sigmoidoscopy: a population-based study. J Natl Cancer Inst 2003; 95: 230–6. 86 Farley DR, Bannon MP, Zietlow SP, Pemberton JH, Ilstrup DM, Larson DR. Management of colonoscopic perforations. Mayo Clin Proc 1997; 72: 729–33. 87 Woltjen JA. A retrospective analysis of cecal barotrauma caused by colonoscope air flow and pressure. Gastrointest Endosc 2005; 61: 37– 45. 88 Waye J. Advanced polypectomy. Gastrointest Endosc Clin N Am 2005; 15: 733–56. 89 Peluso F, Goldner F. Follow-up of hot biopsy forceps treatment of diminutive colonic polyps. Gastrointest Endosc 1991; 37: 604–6. 90 Weston AP, Campbell DR. Diminutive colonic polyps: histopathology, spatial distribution, concomitant significant lesions, and treatment complications. Am J Gastroenterol 1995; 90: 24–8. 91 Deenadayalu VP, Rex DK. Colon polyp retrieval after cold snaring. Gastrointest Endosc 2005; 62: 253– 6. 92 Raju G, Pham B, Xiao S, Brining D, Ahmed, I. A pilot study of endoscopic closure of colonic perforations with endoclips in a swine model. Gastrointest Endosc 2005; 62: 791–5. 93 Binmoeller KF, Thonke F, Soehendra N. Endoscopic hemoclip treatment for gastrointestinal bleeding. Endoscopy 1993; 25: 860–3. 94 Rex DK, Lewis BS, Waye JD. Colonoscopy and endoscopic therapy for delayed post-polypectomy hemorrhage. Gastrointest Endosc 1992; 38: 127–9. 95 Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2007. CA Cancer J Clin 2007; 57: 43–66. 96 Johanson JF, Schmitt CM, Deas TM, et al. Quality and outcomes assessment in gastrointestinal endoscopy. Gastrointest Endosc 2000; 52: 827–30.

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The Gastrointestinal Assistant during Colonoscopy Cathy A. Dykes National Naval Medical Center, Bethesda, MD, USA

Introduction A trained gastrointestinal assistant (GIA) is a necessary and important part of the endoscopy team. This role is also referred to as a gastrointestinal technician or associate. During the procedure, the GIA works closely with the endoscopist, preparing the necessary equipment in advance of the physician’s request, and anticipates the next set of actions. However, the intraprocedure part of the GIA’s task is only one part of the overall responsibility. Other duties of the GIA include preparation of the room, ordering supplies, cleaning and maintaining the equipment, and coordinating specimens obtained during the procedure. In some settings, duties include assistance with procedures, while in other settings the GIA is primarily responsible for the processing of the scopes and other endoscopy equipment. Many of the remarks in this chapter are written from the actual practice of the GIA in the US, and can be adapted to conditions throughout the world. Safety is a universal obligation for endoscopy units everywhere, and the task of the GIA is generally the same in any setting. Because of the complex nature of the colonoscopic examination, involving multiple elements to be learned, proper training and demonstrated competency are required and must be documented in order to be a GIA. The role and responsibility of the GIA during colonoscopy varies according to training, competency, education, and licensure. The GIA must function within applicable federal and state guidelines and facility polices. There are two categories for the GIA in the gastrointestinal endoscopy setting. The first category is the nurse, which includes the registered nurse, licensed practical nurse, and licensed vocational nurse. The second category comprises unlicensed assistive personnel, which includes the medical assistant, GIA, and

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

gastrointestinal or other medical technician. Staff in the latter category have direct patient care responsibilities and are under direct supervision of a registered nurse [1]. The Society of Gastroenterology Nurses and Associates (SGNA) has published a position statement on minimum registered nurse staffing in the endoscopy center [2]. This standard of care applies to the US, but similar guidelines are necessary for other settingsahospitals, endoscopy centers, and physician offices. One registered nurse should be in the preprocedure area to perform and document the patient assessment. One registered nurse should be in the postprocedure area to perform patient assessment during recovery from intravenous sedation and analgesia. One registered nurse should be in the procedure room to assess and monitor the patient during sedation and analgesia, or anesthesia. A joint statement by the American Society for Gastrointestional Endoscopy (ASGE) and the SGNA states that, during endoscopy under moderate sedation, the nurse may perform interruptible tasks such as assisting with biopsy or polypectomy [3]. Additional recommendations include that one registered nurse and at least one other member of the endoscopy team attend those procedures that are complicated either by the severity of the patient’s illness or by the complex technical requirements associated with the advanced diagnostic and therapeutic procedures. Procedures performed on pediatric patients should be staffed with one registered nurse and at least one other member of the endoscopy team because of the unpredictable response of this population to sedative and analgesic medications. When a patient is scheduled for a colonoscopy, instructions for colon preparation are supplied. The patient’s medical history is important in deciding which method is used for cleansing the colon. It is at this time that the teaching process is begun. Brochures are often helpful for this initial contact, as they give the patient a statement to take home and read in less stressful surroundings. ASGE’s website (www.asge.org) is a source of preprinted brochures. The patient’s visit generates a medical record; this should encompass the entire encounter from the preprocedure phase, through the procedure, recovery, and discharge [4]. Depending on institutional

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policy, a postprocedure or follow-up call may be required and should be documented. Each endoscopy unit is responsible for establishing its own documentation procedure and forms. In addition to printed forms, a number of computer programs are available. These can often be individualized for the needs of the unit and state requirements. Some programs interface with programs used by the physician to document the procedure. A preprocedure assessment is performed after the patient arrives at the endoscopy unit for the procedure. The SGNA has stated that the preprocedure assessment should be performed and documented by the registered nurse [4]. It is critical to obtain a basic medical history, including allergies, current medications, and a record of past surgical procedures. Physical limitations and psychological issues should be assessed and addressed. Of special note are any medical conditions that put the patient at increased risk of developing a complication related to sedation. These include severe cardiac, pulmonary, renal, or central nervous system disorders, and obesity, sleep apnea, pregnancy, and drug or alcohol abuse. The unlicensed assistive personnel may assist with the collection of these data points. The medication list should include all drugs that the patient is taking on a routine or pro re nata (PRN; as required) basis. This includes prescription drugs, over-the-counter medications, vitamins, and herbs. The endoscopist should be notified if the patient is taking medications that affect coagulation or platelet function including warfarin, clopidogrel, aspirin, and nonsteroidal anti-inflammatory drugs. The GIA should be aware of possible adverse medication interaction with agents used for sedation. The effectiveness of the colon preparation should be established during the preprocedure assessment. The nurse should ask if the preparation was satisfactory. If there is a questionable or poor result, the endoscopist should be notified. The endoscopists will make a decision to perform the procedure, order an enema to be given, or reschedule after re-prepping the patient. Informed consent is obtained according to hospital or individual center policy (see Chapter 6). A guideline provided by the ASGE states that the endoscopist should personally obtain the informed consent. This duty is not generally one that can be delegated, although individual state and hospital policies may vary.

Setting up the room It is the GIA’s responsibility to ensure that the appropriate equipment is set up and turned on, such as the light source, processor, and Mavigraph. The scope should be tested to ensure the suction, air/water, and light are all in working order. Water bottles should be sterilized or high-level disinfected, daily. If high-level disinfectant is used, a thorough

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rinse with sterile water should be performed to remove chemical residue. Water bottles should then be filled with sterile water to the level indicated, and the top secured and positioned according to manufacturer’s instructions. The GIA should check the procedure room for the availability of supplies. Water in a syringe for irrigation, lubricant for the rectal examination, lubrication for the instrument prior to insertion, and simethicone to decrease bubbles in the endoscopic view should be set up. Specimen containers should be readily available, as well as a marking pen to label the container. Accessories such as biopsy forceps, snares, and procedure-specific equipment for dilation, clips, and foreign body retrieval devices should be accessible.

Monitoring and sedation The registered nurse should monitor the patient who is receiving sedation and analgesia. In the case of very ill patients and/or complex procedures, a second nurse or associate is required to assist the physician while a registered nurse concentrates on monitoring the patient [3]. Basic life support training is a standard requirement for all healthcare workers. In some centers, advanced cardiac life support certification is required for licensed personnel. Emergency equipment should be available and staff should be familiar with this equipment and its location. Several sizes of oral airways, and mask and bag equipment for respiratory support should be readily available. There should be immediate access to an emergency cart with an automatic electronic defibrillator, emergency drugs, and intubation equipment. Most patients receive medication for sedation and analgesia before undergoing a colonoscopy. For this reason, additional training regarding the role of the registered nurse during administration of these medications may be required. Knowledge of correct doses, possible cumulative effects, interactions with other medications, and the role of monitoring is essential. The registered nurse should also be familiar with pharmacologic antagonists for opioids and benzodiazepines. The patient’s vital signs will be monitored during the procedure. This monitoring should include blood pressure, pulse, respiration and pulse oximetry, and the patient’s level of pain and consciousness. This information should be noted in the patient’s record. Automatic monitoring devices may enhance the ability to accurately assess the patient but are no substitutes for the watchful, educated assessment by a registered nurse [5,6]. Capnography (display of continuous and expiratory carbon dioxide concentration) should be considered when deep sedation is targeted. Recommendations from the American Society of Anesthesiologists (ASA) include that the type and amount of medication administered, length of the procedure, and the general condition of the patient should be the factors to determine

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frequency of vital sign measurement [5]. At a minimum, these measurements should be obtained and recorded prior to the start of the procedure, after administration of sedative/ analgesic agents, on completion of the procedure, during initial recovery, and at the time of discharge. Regular readings and recordings of vital signs should be incorporated into the policy of the endoscopy unit. A baseline assessment of vital signs including blood pressure, pulse, respiration, pulse oximetry, level of pain, and level of consciousness should be obtained. These vital signs should also be measured and documented at frequent intervals during the procedure according to institution policy. Cardiac monitoring is done if the patient has a history of cardiac disease. When the patient is transferred to the recovery area, vital signs should be measured on arrival and at specified intervals, until discharge. The ASA suggests that continuous electrocardiograph monitoring should be available and used selectively for patients with hypertension, significant cardiovascular disease and dysrhythmias, and for all patients in whom deep sedation is targeted [5]. A triple-lead monitor supplies adequate basic information, and the registered nurse monitoring the patient should be familiar with basic arrhythmias. Any changes in rate or rhythm should be immediately reported to the endoscopist. With basic monitoring equipment in place, the registered nurse can detect changes in the patient’s vital signs, permitting early detection and intervention. In addition to monitoring vital signs, the patient’s level of consciousness, and the warmth, dryness, and color of the skin must be observed and recorded and the level of pain assessed [4]. Excessive sedation may result in cardiac or respiratory depression. These symptoms must be rapidly recognized, reported to the endoscopist, and treated to avoid the risk of hypoxic brain damage, cardiac arrest, or death. The registered nurse assigned to monitor the patient should be situated facing the patient and assist only with minor interruptible tasks. A second GIA should be present in the case of severely ill patients and procedures of a complex nature [3]. The ASA recommends the use of oxygen during procedures that require sedation and analgesia [5]. If supplemental oxygen is used, close observation of the patient is critical because the discovery of respiratory depression using pulse oximetry may be delayed. Because this delay can occur, the importance of observing the patient for effective pulmonary ventilation increases. In cases when oxygen is not initiated before the start of the procedure, appropriate equipment should be available at all times during sedation. If hypoxemia occurs during sedation, supplemental oxygen is to be administered immediately. Despite an excellent overall safety record, cardiopulmonary complications, likely due to sedative and analgesic medications, are believed to account for 50–60% of procedure-related morbidity and mortality [7].

The Gastrointestinal Assistant during Colonoscopy

The gastrointestinal assistant during the procedure Staff should put on personal protective equipment before the procedure is started. This includes gloves, protective gowns, masks, and goggles when appropriate. The patient is assisted to the left-lateral position, with knees bent for the start of the procedure. Many endoscopists find that there are benefits to repositioning the patient during the procedure to facilitate scope advancement. The patient may be asked to turn to a supine, right lateral, and occasionally to a prone position. Although it is difficult for an oversedated, ill, or elderly patient to change position, most patients can change position with minimal assistance and verbal cues. The GIA must be aware of multiple safety issues when repositioning the patient. The patient’s position in relation to the edge of the cart or table must be carefully observed. Side rails should be in the up position unless a GIA is situated on the opposite side of the physician. Monitoring wires, grounding pads, and oxygen and intravenous tubing should be checked after any position change is made, to ensure that they remain attached. During the insertion of the scope, at the request of the endoscopist, the GIA may be asked to hold the scope head or secure the insertion tube of the scope at the rectum. It is the position of the SGNA that, while functioning within limitations of licensure, Nurse Practice Act, or institutional policy, the GIA, with documented training and experience, may assist the endoscopist by manipulating the endoscope when required to facilitate an endoscopic procedure [8]. Manipulation refers to the act of advancing or withdrawing the endoscope under the direct supervision of the endoscopist. The nurse or associate manipulating the endoscope must have full view of the lumen by way of a teaching adaptor for the fiberoptic scope, or video screen for electronic colonoscopes. As the scope is advanced during the procedure, loop formation may occur. The GIA may be asked by the endoscopist to apply external abdominal pressure. Properly applied, external abdominal pressure can facilitate scope advancement, which reduces patient discomfort and procedure time. Pressure may be given in various locations: general pressure in the left colon can be used to control the sigmoid colon. The GIA should attempt to feel for the loop made by the scope to establish a site where application of abdominal pressure may be helpful. There is no need for pressure application when the endoscopist withdraws the scope to straighten it, but light pressure may be helpful to maintain the straightened position of the colon as the scope is advanced. Since every patient is unique, the GIA may need to adjust pressure several times until the most effective position is found. When the scope advances past the splenic flexure, midabdominal pressure

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may be applied in an upward motion to support the transverse colon. As the scope progresses from left to right, pressure at a specific site may become more useful. In general, the hand position of abdominal pressure is usually located by the endoscopist, who may request nonspecific pressure at various areas such as suprapubic (when the instrument is in the distal sigmoid) or left lower quadrant pressure when a loop is forming in the sigmoid colon. Alternatively, the endoscopist, while viewing the lumen, may find a specific point by abdominal palpation that aids in scope advance. When this is located, the GIA should replace the endoscopist’s pressure point with his or her hand in the same position before the endoscopist removes pressure. There is rarely a need for application of sustained pressure, as the maneuver is intended to assist in advancing the tip around a fold or a bend in the colon; once that advance is accomplished (or not accomplished), the pressure may be released as another maneuver is performed, or another location for pressure is determined. An adequate number of specimen containers and labels with appropriate patient information should be available before the start of the colonoscopy. The GIA must be observant during the procedure so that the need to remove polyps or obtain biopsies can be anticipated. When a polyp requiring electrocautery is encountered, the grounding pad can be applied to the patient and an appropriate-sized snare readied at the direction of the endoscopist. Biopsy forceps or other equipment can also be readied when need is anticipated. In some settings, an anesthesiologist or certified registered nurse anesthetist may be present, and the patient may be in deep sedation or general anesthesia. The assistant and anesthesia specialist should coordinate monitoring and documentation processes. The assistant should assist in prevention of regurgitation and aspiration, especially when the deeply sedated patient is turned into the supine or right-lateral decubitus position.

Operation of a snare Since there are a number of sizes and shapes of snares available, the choice is made by the endoscopist according to the size and location of the polyp in the colon. The GIA usually opens and closes the snare as requested. Snare cutting is dependent upon a combination of mechanical forces of the wire closing against the plastic sheath and the use of highfrequency current, which is produced by an electrocautery machine. The sheath may compress during snare closure so that the tip of the snare, which withdrew into the sheath when tested outside the patient, cannot be fully withdrawn once around a polyp because the sheath has shortened with compression. This may preclude complete resection and cause an impacted snare. To avoid this problem, verify that

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the tip of the wire snare retracts at least 15 mm into the sheath prior to polypectomy (see Chapter 42). The GIA should be familiar with each electrosurgical unit being used in the endoscopy center. In some cases, current output may vary according to unit or manufacturer. Instructions and use of settings specific to the units available in the department should be readily available for training and reference purposes. If an electric grounding pad is used, the usual placement is on the upper thigh or lower trunk, whichever has the largest tissue mass and is closest to the site of electrosurgical application. To ensure complete contact with the patient’s skin, the chosen area should be dry and as free from hair as possible. Bony prominences should be avoided. If a small polyp is to be removed, a specimen trap should be placed between the scope and the suction tubing to retrieve any tissue suctioned through the scope. The active cord is connected between the snare and the electrosurgical unit, and the dial is set as appropriate according to the manufacturer’s directions, unit policy, and the endoscopist’s preference. Electrical currents that have a pure cutting effect are usually not employed for colonoscopic polypectomy. Electrocoagulation current alone may be used, or a blend of cut and coagulation may be applied. The activation pedal for the unit is placed in position for ready access to the endoscopist. During polypectomy, the endoscopist will position the sheath and give the order to open the snare. The GIA will extend the loop and the endoscopist will position the loop around the polyp. The GIA should be sure that the electrocautery unit is turned on before use and the active cord is securely connected. Upon the direction to close the snare, it is important for the GIA to do so slowly, while maintaining continuous communication with the endoscopist. While visualizing the polyp and feeling for resistance, the GIA will close the loop on the snare slowly until tension is felt and the loop can be seen to be in the proper position. When ready for electrocautery, the endoscopist will depress the foot pedal and give the direction to close. If saline injection is used to lift the polyp tissue from the mucosal wall, an injection needle and normal saline should be available. One or two 10-mL syringes should be prepared depending on the size and number of polyps. The normal saline should be drawn up and, depending on the endoscopist’s preference, a drop or two of methylene blue can also be drawn up in the syringe. The advantage of using methylene blue is that the submucosal tissue becomes blue while the pinkish-colored polyp sitting on the saline mound is clearly delineated and the margins easily seen. Whenever methylene blue is used during a procedure, patients must be advised that their urine may turn green and there may be a color change in their stool as the medication is excreted. Advising them of the possible color change before discharge will prevent a panicked phone call regarding the strange color of their urine.

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The severed polyp may be retrieved in several ways (see Chapter 45). If a biopsy or hot biopsy forceps is used, the tissue is removed with the forceps. Small polyps can be readily retrieved by suction into a small capture bottle (trap) attached to the main suction plug of the instrument. For larger polyps removed with a snare, suction can be used to secure it to the end of the scope. The polyp can be resnared to carry it out of the colon, or an entrapment or retrieval device such as a basket or tripod grasper can be used. For multiple polyps, each polyp specimen should be placed in an individual container with the site clearly identified in addition to the patient information. The ability to keep all specimens in their proper order (size, location, method of removal) is aided by keeping a written log of each event as it occurs.

The Gastrointestinal Assistant during Colonoscopy

by the laboratory, kept moist, and transported immediately to the laboratory for immediate examination by the pathologist. Cytologic or viral specimens can be obtained using a biopsy forceps, a brush manufactured for that purpose, by washing, or by aspiration. The brush should be withdrawn into the sheath during brush cytology, before insertion into the biopsy channel. After the specimen has been obtained, the brush is retracted into the sheath and withdrawn from the scope. A cloth or gauze should be used to wipe the exterior of the sheath during removal, to prevent splatter. The brush is extended again, and thin smears of cells are placed on a microscope slide and fixative solution applied, or the brush is cut and placed in a container with cytology fixative solution. Delay in fixation should be avoided, since air drying affects the interpretation.

Biopsy and cytology Biopsies are obtained for suspected neoplasm, diagnosis and surveillance of inflammatory bowel disease, and diagnosis of chronic diarrhea. Usually, multiple specimens are obtained from each site for histopathologic interpretation. Tissue obtained can be cultured to identify infectious processes including bacteria, parasites, cytomegalovirus, and herpesvirus. These specimens must be carefully handled to ensure that they can be processed for the needed examinations. Specific instructions for processing these specimens should be obtained from the department of microbiology. If numerous specimens need to be obtained during the procedure, an additional staff member should be present and dedicated to obtaining and processing specimens. A registered nurse should concentrate on monitoring the condition of the patient. There are a number of types of biopsy forceps available for use during colonoscopy (see Chapter 24). Some are available with a central spike, which is helpful in holding tissue in place to prevent the forceps from slipping so that an accurate specimen can be obtained. Jumbo forceps and those that can take up to four bites can be used to obtain larger pieces but may require instruments with a large channel to permit free passage without damage to the scope. When ready to obtain a biopsy, the GIA should examine the forceps for any obvious defect, ensure that they are free from kinks, and test them for function. To prevent injuries, the forceps should be closed when handed to the endoscopist. After the biopsy, as the GIA removes the forceps from the channel he or she should also hold a cloth or gauze over the biopsy port to prevent splattering, while also removing secretions from the outside of the forceps. Tissue specimens for viral, bacterial, or fungal culture are obtained and placed on gauze moistened with normal saline or on slides, according to facility policy. If a frozen section is desired, the specimen should not be placed in a preservative of any kind. It is mounted and labeled as desired

Endoscopic tattoo An injection needle is utilized for endoscopic tattooing, to mark a site for later observation. Approximately 1–1.5 mL of the marker solution is used to flush the injection needle and sheath. While injecting into the mucosa, the GIA should state that he or she is injecting, how much resistance is felt, and how much fluid is injected by 0.5- to 1-mL increments. The amount injected should be recorded in the patient’s procedure record (see Chapter 42).

Colorectal bleeding When a bleeding site is encountered, several items of equipment must be available for immediate use. Review of skills on a regular basis is essential, especially with devices that are used rarely. Devices or instruments available include injection needles, bipolar probes, detachable snares, clip devices, argon plasma coagulators, and laser and heater probes. As technology changes and advances, other instruments may be available in the future. Epinephrine 1:10 000 is often the hemostatic agent of choice. Most sites are injected with 1–2 mL as instructed by the endoscopist. A detachable snare (see Chapter 25) may be used in the event that the bleeding area is clearly identified, such as a polyp stalk following transection. The snare is tightened on the bleeding area, and when secure it is detached from the device and left in place. After healing occurs, the snare sloughs off and is passed with the patient’s stool. A second nurse or associate is required to assist the physician with complex procedures [3]. This enables the registered nurse to monitor closely both the patient and the effectiveness of interventions, and ensures efficient room turnover between procedures.

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Postprocedure or recovery care The postprocedure phase is from the completion of the procedure until the patient is discharged from the facility [4]. The frequency of assessment is determined by institutional and/or departmental policy. There are recommendations for documentation in the SGNA minimum data set which include [9]: • time of arrival; • vital signs including blood pressure, pulse, respiration, pulse oximetry, electrocardiogram rhythm (if applicable), and level of pain, until the patient has returned to preprocedure baseline; • patient’s mental status and level of consciousness; • warmth, dryness, and color of skin; • type and dose of medications including oxygen, and response to intervention; • total amount of intravenous fluid administered and the time the intravenous access is discontinued; • unusual events, interventions, and outcomes; • disposition of the patient (to hospital room, home, radiology, etc.); • report that is given to any subsequent caregiver; • mode of transportation (ambulatory, cart, wheelchair, etc.); • name of the person responsible for the patient at discharge (if patient has been sedated); • age-specific discharge instructions, educational materials such as dietary instructions, any prescription given to the patient or responsible adult, and statement of understanding; • statement that discharge criteria have been met; • time of discharge.

Occupational Safety and Health Administration Regulations The US Occupational Safety and Health Administration (OSHA) has specific guidelines to ensure protection of workers from hazardous exposure or injury. Some of the items covered under these regulations are contamination by potentially infectious material and chemical exposure, which includes toxic levels of glutaraldehyde and fumes from chemicals used in the endoscopy unit. These chemicals can include, but are not limited to, formalin, high-level disinfectant concentrate, sterilant, and alcohol. Proper ventilation must be provided and the air quality monitored in environments with fumes such as endoscope-cleaning areas. Each endoscopy unit must have a listing of all hazardous substances that are used in the area. These material safety datasheet list all relevant information about a substance and must be on file in the department, available to every employee for immediate reference. Included is everything contained in the substance, the boiling or evaporation point,

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fire hazard, safety warnings, exposure limitations, directions for resuscitation in the event of overexposure or overdose, and contact numbers for the company which produces the product. Occupational exposure is defined as: “a reasonably anticipated skin, eye, mucous membrane, or parenteral contact with blood or other potentially infectious materials that may result from the performance of the employee’s duties” [10]. Policies and procedures that are followed in the performance of daily duties, reduce the likelihood of exposure by defining the manner in which tasks are performed. These practices include but are not limited to: • washing hands after contact with a patient; • washing hands when gloves are removed, or as soon as possible after contact with potentially infectious material; • providing an area for eye irrigation, in the event of exposure; • prohibition of eating, drinking, smoking, or applying of cosmetics in areas where occupational exposure is possible. It is an OSHA requirement that engineering controls be in place to protect employees from hazards in the workplace. Sharp objects are used daily in the performance of duties in the endoscopy center and must be handled and disposed of with caution. Items in this category include, but are not limited to, needles, scalpels, and broken glass. Equipment used during colonoscopy may include disposable biopsy forceps with spikes, injection devices, and hemostatic clip deployment devices. The wearing of appropriate gloves when contact with blood, mucous membranes, and potentially infectious materials is anticipated reduces the risk of exposure to blood-borne pathogens and is mandated by OSHA. Gowns and protective apparel are worn to reduce the risk of exposure to bloodborne pathogens under specified circumstances and are mandated by the OSHA blood-borne pathogens final rule. Each facility is responsible for implementing regulations regarding hazardous materials. Information listing OSHA standards, as well as publications and assistance, is available at www.osha.org.

Protective gear Blood is not the only source of body fluids which may be potentially infectious. Other potentially infectious materials include, but are not limited to, saliva, peritoneal fluid, stool, and unfixed human tissue [10]. It is possible for almost every employee of an endoscopy center to have occupational exposure to blood or other body fluids. All nurses and associates are regularly exposed to these materials, and even ward clerks or secretaries may be exposed on occasion when they handle specimens. Protective gear should be universally used to provide a physical barrier for staff during interactions with patients

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when there is a potential for exposure to body fluids. Because the same measures are used in every case, body substance precautions protect the healthcare worker from unrecognized or asymptomatic cases of infectious diseases, as well as recognized or symptomatic cases. Protective gear should include a gown, eye protection, a face mask or shield if splash is anticipated, and gloves for every event that presents the possibility of exposure. Radiation and laser protection should be provided if these therapeutic measures are utilized. Semipermeable gowns can be used if excessive splash is not anticipated. Nonpermeable gowns in either plastic or treated fabric are available to protect staff members from any type of splash. Eye protection, either safety goggles/glasses or face shields, should provide adequate protection without restricting movement or vision. The equipment should be provided by the employer and should be durable, easy to clean and disinfect. Staff members should keep safety equipment clean and in good repair. Gloves should meet the needs of the staff member and the patient. Any sensitivity to latex should be noted and taken seriously as anaphylaxis can occur and is a life-threatening event. Gloves should be removed immediately following the procedure or in the event that there is a possibility of a break in the surface integrity. Hands should be washed immediately after gloves or personal protective equipment are removed. In accordance with sound occupational health principles, employee training should occur prior to the time that the employee is placed in a situation where exposure could occur. Training must be provided at the time of the initial assignment or job change that causes exposure, and must be repeated annually [10].

Processing of reusable equipment (see Chapter 5) The Spaulding classification was developed in the 1960s to categorize equipment and patient care items and provide appropriate levels of disinfection [11]. The gastroenterology nurse or associate should be familiar enough with Spaulding’s classification system to be able to sort accessory devices for reprocessing. Reusable items may include scopes, water supply bottles, and power wash bottles, with their tubing, connectors, and caps. This category also includes equipment carts, patient monitoring devices, intravenous pole, fixed surfaces, and the procedure table or gurney. Standards for infection control were published jointly by the SGNA and the ASGE [11]. Reprocessing standards endorsed by the SGNA, the ASGE, the American Gastroenterological Association, the American College of Gastroenterology, and the Association for Professionals in Infection Control and

The Gastrointestinal Assistant during Colonoscopy

Epidemiology require that manual cleaning of the endoscope, including all channels and removable parts, precedes manual or automated disinfection. There must be strict adherence to these standards. Reprocessing refers to the sequence of cleaning, lubricating (if necessary), and sterilizing or high-level disinfecting steps that will ensure that the equipment or accessory is patient ready. The reprocessing of a flexible endoscope is accomplished in two phases: (i) decontamination and (ii) sterilization or high-level disinfection. The objective of decontamination is to remove gross organic material and microorganisms and to prevent drying of these substances. Using instructions from the colonoscope manufacturer, the insertion tube, all channels, external surfaces, and reusable accessories must undergo a thorough mechanical cleaning with an enzymatic detergent and an appropriate-sized cleaning brush designed for endoscopic equipment. In many centers, automatic washing devices are used after the initial manual cleaning process. Automatic endoscopic reprocessors may reduce staff exposure to liquid chemical germicides. Exposure to 2% glutaraldehyde has been the cause of asthma, sinusitis, serious skin sensitivity, and conjunctivitis in staff members. The proper use of these devices as well as personal protective equipment in combination with adequate ventilation may decrease staff exposure problems (see Chapter 5). Once decontamination is complete, the scope is reprocessed and the wash and disinfecting cycles are completed. There are a number of different devices available from several manufacturers. The manufacturer’s instructions must be followed completely for proper, high-level disinfection. Reprocessing should always be performed by trained personnel according to written guidelines or standards of practice, as defined by professional societies. Regular monitoring of the reprocessing process is important for quality control and ensuring patient safety. Rinsing and drying are essential steps to remove the chemical disinfection solution, and to prevent bacterial colonization during storage. The exterior of the scope and accessories should be dried. Seventy percent alcohol should be flushed through the channels followed by air (to remove residual alcohol), before hanging the scopes vertically for storage. After disinfection, all items must be rinsed with filtered or sterile water, and stored as recommended by the manufacturer without valves or devices attached. Water supply bottles for the scope and the power wash, as well as any tubing or connectors, should be changed according to infection control guidelines, manufacturer’s direction, or facility policy. Contaminated areas where accessories and specimens are handled should be separated from clean counter areas. All contaminated areas must be cleaned and decontaminated between patients with an Environmental Protection Agencyregistered hospital-grade disinfectant and used according to the manufacturer’s directions.

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Disposable items Any equipment or supplies that are labeled as non-reusable should be used once and then discarded. It is the position of the SGNA that critical medical devices such as biopsy forceps, injection needles, and snare devices that are manufactured and intended for one-time use on one patient during one procedure are handled as disposable equipment [12]. The devices labeled as single-use devices are not intended by the manufacturer to be reprocessed, or reused. Reprocessing refers to the sequence of cleaning and sterilizing or high-level disinfecting steps that ensures that the accessory is patient ready. A large amount of equipment in this disposable category is not manufactured to enable complete disinfection or sterilization, and reusing the devices may be a source of contamination or may result in breakage or malfunction during use. All items used in the performance of procedures that are to be discarded are considered to be medical waste and must be handled as potential biohazard items. These items include, but are not limited to, electrocautery grounding pads, protective pads, intravenous access catheters, and disposable personal protective equipment used by staff members. These items are to be discarded in a plastic-lined biohazard-labeled trash receptacle according to federal, state, and local regulations. The use of solidifiers in suction canisters before disposal in the waste can reduce contamination by spillage in the event of breakage of a container or the trash bag. The solidifier is a powder substance which, when added to the liquid contents of the suction container, turns the contents into a gel. Some powders are available that also provide some level of disinfection and odor control.

Supply order A stock level should be determined for the unit and, specifically, each procedure room based on normal utilization. This should be reviewed and revised on an ongoing basis. It is optimal to assign one person to order supplies, to prevent duplication or oversight, with an alternate person trained in case of the absence of the primary order individual or for emergency acquisition of equipment or supplies. It should be the responsibility of personnel in an assigned procedure room to ensure that the room is adequately stocked first thing in the morning and/or at the end of the day.

Odors in the endoscopy suite Maintaining control of contaminated waste is the ideal way to control odors in the endoscopy suite. This includes disposal of products such as bed pads, biopsy forceps, suction

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containers, reusable devices, and linens as soon as possible after they are used. For every procedure, there are several measures that should be taken immediately at the end of the case. The scope should be removed from the room in a covered container after appropriate immediate cleaning has begun according to the manufacturer’s instructions. This may include adequate suctioning through the channel to clear solid debris, insertion tube wipe-down with enzymatic cleaner, and air/water channel adapter insertion. If the colonoscopy was highly odorous, the suction canister should be changed and soiled linen removed. Having a high-flow ventilation system in each procedure room as well as in the equipment cleaning area is ideal. This type of system provides rapid turnover of room air so odors do not linger.

Summary The GIA is an integral member of the endoscopy team. It is the responsibility of the GIA to work with the team to keep the endoscopy unit running on a day-to-day basis. It is necessary to train the unlicensed personnel or nurse who functions as a GIA, since the functions are so complex that special training is required to avoid errors which could result in catastrophic events to human life, such as mistakes in setting the electrocautery unit, overly aggressive snare closure, or injection of the wrong solution. The GIA is responsible for multiple functions during the procedure, in addition to monitoring the patientain the case of a registered nurse. The GIA is an important member of the team who ensures a smooth and safe endoscopic experience for the patient. Ongoing communication between the endoscopist and GIA is a link which must function in both directions to ensure the greatest efficiency and safety for the patient.

Troubleshooting tips for the gastrointestinal assistant Prevention and preparation Prevention and proper preparation are the best tools to avoid problems during the procedure. Pretesting endoscope functions can prevent increased length of procedure, the need for more sedation, longer patient recovery, possible use of a second scope, and potential compromise of patient safety. • Ensure that accessories compatible with the diameter of the suction/instrumentation channel of the endoscope are immediately available. • Test air/water suction and light source/visual functions of the endoscope just prior to the procedure. • Monitor useful bulb life on light source and be prepared to replace when appropriate.

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Air/water failure • Check the water bottle assembly: – cap screwed on tight? – water in bottle? – bottle overfilled? – o-ring present at point of insertion of the connector? – o-ring present inside top of water bottle? – crack in water bottle? • Change the water bottle if you think it is a problem: – check for clogged air/water channel. • Disconnect the water bottle insertion tube from the light source: – place fingers over the air and water supply ports – depress air/water buttonathis maneuver may open a clogged air/water channel. • Do not insert the air/water adapter used for precleaning an endoscopeathis may create pressures that are too high in the colon.

Suction failure • Make sure that the suction apparatus is properly assembled. • If applicable, increase the suction from low or medium to high. • Attempt to reposition the scope in the patient: – sometimes the scope rests up against the mucosa and will not aspirate fluid or air because a piece of mucosa has been sucked into the suction port on the colonoscope tip. • Determine if suction still works: – remove the suction tubing from the plug-in module of the umbilicus and place a finger over the suction line to ensure that suction is being delivered to the endoscope. • If suction apparatus is OK: – flush water through the disposable rubber biopsy valve covering the suction/instrument channel – reusable metal accessory introducers make good flush tipsathey require reprocessing following each use – if stool or debris becomes attached to the tip of the scope, flushing through the rubber biopsy valve will usually clear the problem. • Check the patency of the disposable rubber biopsy valve covering the suction/instrument channel: – if the seal has been compromised following multiple insertion of accessories, suction may be sluggish • remove suction trumpet valve • place finger over that hole to see if suction is present – if suction is not felt: • check to see if the suction bottle is full • check to see if the pump is connected – if suction is present, look at the trumpet valve to see if stool has clogged up the side hole: • insert a clean trumpet valve • if no suction is felt, place the wall suction line directly over the empty valve slot, and suction to remove debris clogging the instrument channel

The Gastrointestinal Assistant during Colonoscopy

– if there is still no suction, the umbilicus is plugged: • pass the cleaning brush straight down the insertion tube so it exits at the point where the suction attaches to the endoscopeathis will clear the umbilicus. • Remove the disposable biopsy valve from the instrument channel, and suction here with the wall suction line. • Pass the biopsy forceps or cleaning brush of appropriate length through the instrument channelathis often works to clear debris, which does not respond to a water flush, from the channel. • Backflush the suction port: – remove the wall suction line from the endoscope at the plug-in module suction port – attach the catheter and tubing in its place – attach a 7- to 10-cm (3–4 in.) piece of suction tubing to the tip of a 60-mL catheter tip syringe filled with water – the GIA should communicate with the physician to hold down (depress) the suction trumpet valve prior to flushing; this may result in a backflow of water. As usual, all staff should already be wearing personal protective equipment including mask, face shield, and impervious gown. • If flushing through the biopsy port shows free flow of fluid into the lumen, and suction is present at the trumpet valve slot (and the valve itself is not clogged), and still fluid cannot be suctioned from the colon, the block is between the trumpet valve and the disposable rubber valve over the biopsy port: – to clear this area: • remove the suction trumpet valve • insert a cleaning brush through the trumpet valve in a direction toward the scope shaft • this should be advanced for at least 25 cm (12 in.) to ensure that this area is unclogged • it is possible to continue to pass the brush all the way down to the tip of the instrument and out into the lumen • if passing of the cleaning brush is desired, be sure that the tip of the instrument, at the 5 o’clock position, is pointed toward the lumen so that the suction brush does not inadvertently pass completely through the channel and possibly perforate the colon wall.

References 1 SGNA Position Statement: Role delineation of Assistive Personnel. Available at: www.sgna.org/Resources/statements/statement8.cfm (accessed November 24, 2007). 2 Minimum registered nurse staffing for patient care in the gastrointestinal endoscopy unit. Available at: www.sgna.org/Resources/statements/ statement14.cfm (accessed November 24, 2007). 3 Joint Position Statement: Role of GI registered nurses in the management of patients undergoing sedated procedures. Available at: www.sgna.org/Resources/ASGESGNASEDATIONPOSITIONSTATEMENT0613047.pdf (accessed January 19, 2008).

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4 Guidelines for documentation in the gastrointestinal endoscopy setting. Available at: www.sgna.org/Resources/guidelinesfordocumentation. pdf (accessed November 24, 2007). 5 American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 2002; 96: 1004–17. 6 Statement on the use of sedation and analgesia in the gastrointestinal endoscopy setting. Available at: www.sgna.org/Resources/ sedationrevised.pdf (accessed November 24, 2007). 7 Morrow JB, Zuccaro G Jr., Cromwell DL, et al. Sedation for colonoscopy using a single bolus is safe, effective, and efficient: a prospective randomized, double-blind trial. Am J Gastroenterol 2000; 95: 2242–7.

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8 Position statement: Manipulation of endoscopes during endoscopic procedures. Available at: www.sgna.org/Resources/Manipulation of Endoscopes revised bodversion.pdf (accessed November 24, 2007). 9 SGNA Minimum Data Set. Available at: www.sgna.org/Resources/ minimum_data_set.cfm (accessed November 24, 2007). 10 Bloodborne pathogens. Available at: www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10051 (accessed January 8, 2008). 11 Multisociety guideline for reprocessing flexible gastrointestinal endoscopes. Available at: www.olympusamerica.com/msg_section/files/MSG_ endoreprocess.pdf (accessed January 8, 2008). 12 Reuse of single-use critical medical devices. Available at: www.sgna. org/Resources/ReuseofSUDBODversion0506Postproof9062.pdf (accessed January 8, 2008).

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Cleaning and Disinfection David A. Greenwald Albert Einstein College of Medicine, New York, NY, USA

Background Colonoscopy is safe and effective. It is estimated that, in the US alone, in excess of 10 million endoscopic procedures are performed annually [1]. Endoscopy is a well-recognized diagnostic and therapeutic tool; complications are rare. Effective cleaning and disinfection of the endoscope is an integral part of the procedure. Meticulous attention to detail during the reprocessing of flexible endoscopic instruments is critical. Standards concerning infection control in endoscopy have been developed and disseminated widely since the late 1980s, helping to ensure continued safety in gastrointestinal (GI) endoscopy [2,3].

Colonoscope reprocessing Endoscope reprocessing is a multistep process that renders a contaminated instrument ready for patient use. Flexible gastrointestinal (GI) endoscopes are complex instruments with internal channels for air, water, and accessories. When endoscopes are used for diagnostic or therapeutic procedures, body fluids and contaminants may remain on the instrument. Debris and microorganisms are removed from the endoscope during reprocessing, which involves meticulous cleaning and high-level disinfection. In contrast to rigid endoscopes and some reusable accessories, flexible endoscopes are heat labile and cannot be steam sterilized. Numerous professional organizations, including the American Society for Gastrointestinal Endoscopy (ASGE), the Society for Gastroenterology Nurses and Associates (SGNA), the World Congress of Gastroenterology, the Association for Professionals in Infection Control and Epidemiology, the American Society for Testing and Materials (ASTM), and the Association of Operating Room Nurses, have issued guidance

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

documents for reprocessing GI endoscopes [4–8]. Guidelines exist worldwide [9]. In 2003, the ASGE and the Society for Health Care Epidemiology convened a consensus panel to recommend evidence-based guidelines for reprocessing GI endoscopes, and established the multisociety guidelines for reprocessing flexible GI endoscopes [2]. Such guidelines are intended to aid users of endoscopic equipment to achieve the accepted standard of high-level disinfection, defined as the destruction of all microorganismsawith the exception of high levels of bacterial spores [10].

High-level disinfection versus sterilization High-level disinfection is the current standard for reprocessing of endoscopes [11]. This may be achieved by either automated reprocessors or manual reprocessing. High-level disinfection is defined as a process that results in the destruction of vegetative bacteria, viruses, fungi, and mycobacteria but not necessarily all bacterial spores. Sterilization is defined as a process in which all microbial life is destroyed. High-level disinfection in GI endoscopy is usually achieved through the use of meticulous manual precleaning followed by exposure to a liquid chemical germicide (LCG) [12]. Liquid chemical germicides are chemicals capable of sterilizing accessible and exposed surfaces under appropriate conditions (i.e., adequate precleaning) and with an appropriate length of exposure to the LCG (i.e., longer than that for high-level disinfection). Sterilization of an endoscope is possible through use of steam autoclaving (but it destroys the endoscope), and via ethylene oxide sterilization; the latter is associated with a greater than 24 h turnaround time, which is economically unacceptable in a busy endoscopy center. While sterilization of an endoscope sounds like an attractive goal, it has not been recommended for use in a semi-critical device (see Spaulding criteria below), such as an endoscope within the GI tract, for several reasons: • There are no data to demonstrate that it is possible to reliably and consistently achieve and monitor sterilization of internal channels (i.e., the elevator mechanism in duodenoscopes is inaccessible).

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• There are no data proving decreased infections, improved safety, or improved outcomes when comparing sterilization with high-level disinfection.

Spaulding criteria Criteria exist to categorize medical devices based on their risk of transmission of infection during use. This scheme is based on the Spaulding classification of medical devices [10]. Three categories of medical devices are described: 1 Critical devices: enter sterile tissue or vascular spaces. These devices require sterilization, defined as complete elimination of all forms of microbial life. Examples of critical devices include biopsy forceps and papillotomes. 2 Semicritical devices: contact intact mucous membranes and do not ordinarily penetrate body surfaces. These devices require high-level disinfection, defined as the destruction of all microorganisms, including bacteria, mycobacteria, small or nonlipid viruses, but not some highly resistant spores. An example would be a colonoscope. 3 Noncritical devices: contact only intact skin. These devices do not need to be sterilized or high-level disinfected. Examples would include a stethoscope or a blood pressure cuff.

Transmission of microorganisms during endoscopy Transmission of infection at the time of GI endoscopy is a rare event. At the present time, most cases of infection deemed related to an endoscopic procedure can be traced to failure to adhere to published guidelines for reprocessing [13,14]. They can be further divided into these broad areas: • Procedural errors in the meticulous cleaning and disinfection of the endoscope, leading to retained microorganisms on the endoscope. These organisms may accumulate in the crevices and joints of the instruments. • Insufficient exposure time to LCGs or use of inappropriate disinfectant solutions. • Improper use of automated endoscope reprocessing equipment. • Contaminated water bottles and irrigating solutions. • Inadequate drying and improper storage of endoscopes after reprocessing. The reported frequency of transmission of infection in GI endoscopy has been estimated to be 1 in 1.8 million [15]. Spach, in 1993, reviewed 281 infections related to GI endoscopy, as well as 96 felt to have been caused by bronchoscopy [16]. Of the 281 infections, all but 28 occurred prior to 1988, the year in which the importance of adequate manual cleaning as well as disinfection were stressed in guidelines published by the ASGE and the British Society of Gastroenterology (BSG) [17,18]. The ASGE Technology Committee reviewed Spach’s

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data in 1993 and then estimated that 40 million GI procedures had been carried out in the US between 1988 and 1992. This meant there had been 28 reported infections in approximately 40 million endoscopic procedures, for an estimated rate of transmission of infection by GI endoscopy of 1 in 1.8 million, a rate that is frequently cited (Table 5.1). Some believe that with widespread adoption of the multisociety guidelines in 2003, the actual transmission rate of infection via endoscopy is considerably lower [19]. In any case, it is likely that the reported infection rate is conservative due to factors such as inadequate surveillance, asymptomatic infections, and infections with long incubation periods [20,21]. Some authors have suggested that endoscopists do not capture all their complications because follow-up is too short; infectious complications might not be recognized as having been related to the procedure. These authors recommended 30-day follow-up of GI procedures (as opposed to the “traditional” assessment of complications recognized during and immediately after the procedure) as a better measure to study endoscopic complications [22]. Several clusters of transmission of hepatitis B and C between 2000 and 2008, initially reported to be associated with GI endoscopy, can be traced to lapses in general infection control practices. Well-publicized outbreaks of hepatitis virus infections associated with GI endoscopy have been reported, including in New York in 2001 and again in Las Vegas in 2008; episodes were related to improper reuse of syringes and multidose vials of anesthetic agents in consecutive patients, and were attributed to anesthesiologists attending to the endoscopic procedure [23–25]. While not directly related to endoscope reprocessing, these episodes underscore the critical importance of maintaining proper infection control procedures during all aspects of GI endoscopy.

Viruses The blood-borne viruses that are of most concern include HIV, HBV (hepatitis B virus), and HCV (hepatitis C virus). GI viruses, such as Norwalk virus, rotaviruses, and enteroviruses, which would be contacted by an endoscope inside the GI tract, are also of concern, but they are efficiently eliminated by standard reprocessing protocols. Endoscopic transmission of HBV has been reported in only one patient [26]. In this case, standard reprocessing protocols were not followed, as the endoscope’s air/water channel was not flushed with glutaraldehyde. Several prospective studies of patients harboring HBV have failed to demonstrate its transmission to subsequent patients during GI endoscopy [27]. Patient-to-patient transmission of HCV during colonoscopy has been reported [28]. In this case, HCV was transmitted from an infected patient to two others who subsequently had colonoscopy in that unit; the HCV was confirmed to be

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Table 5.1 Microorganisms transmitted by (or shown to contaminate) endoscopesbmajor factor(s) involved in incidents are indicated by X. Infection (I) or contamination (C)

Cleaning procedure

Disinfection process

Rinsing process

Automated processor

Contaminated processing or water bottle

Before guidelines (A) Gram-negative bacilli Pseudomonas aeruginosa Klebsiella spp. Enterobacter spp. Serratia marcescens Salmonella spp. including typhi Helicobacter pylori Bacillus spp. Proteus spp.

I I I I I I C C

X X X X X X X X

X X X X X X X X

X

X

X

(B) Mycobacteria Mycobacterium tuberculosis Atypical mycobacteria

I I

X X

X X

(C) Fungi Trichrosporon spp. Rhodotorula rubra

C C

X

(D) Parasites Strongyloides

I

X

X

(E) Viruses Hepatitis B

I

X

X

After guidelines (A) Gram-negative bacilli P. aeruginosa

I

X

X

X

(B) Mycobacteria Mycobacterium tuberculosis Atypical mycobacteria

I C

X

X

X X

(C) Viruses Hepatitis C

I

X

X

X

X X

X X

X X

X

X

Modified from Alvarado CJ, Reichelderfer M. APIC guidelines for infection prevention and control in flexible endoscopy. Am J Infect Control 2000; 28: 138–55.

the same by genotyping and nucleoside homology. Transmission of viral infection in this instance occurred likely because of: 1 failure to adhere to proper procedures for manual cleaning of the endoscope after colonoscopyathe biopsy-suction channel was never cleaned with a brush; 2 a breach in proper protocol for sterilizing endoscopic accessories. Additionally, HCV has been reported to have been transmitted during colonoscopy, probably through the use of a multidose anesthetic vial with use of the same needle or syringe between patients [23–25,29]. Several prospective studies have demonstrated that endoscopy is not a risk factor for contracting HCV infection [30–32]. It has been consistently demonstrated that use of current reprocessing guidelines adequately eliminates HCV from endoscopes [33,34].

HIV, much like the other viruses, is very sensitive to highlevel disinfection or sterilization. No documented cases of HIV transmission have occurred after GI endoscopy. Several studies have demonstrated that in endoscopes deliberately contaminated with HIV, the virus is eliminated easily in all cases, using standardized manual cleaning and high-level disinfection techniques [35].

Bacteria Transmission of Gram-negative bacteria, especially Salmonella spp. and Pseudomonas aeruginosa, has been reported following GI endoscopy. Nine publications have cited endoscopic transmission of Salmonella in 84 patients [16]. All of these infections predate the institution of standardized guidelines for

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endoscope reprocessing, and typically involved inadequate LCGs. One report concluded that there was a “lack of scrupulous cleaning of equipment prior to soaking” [36]. Use of a recommended high-level disinfectant, with thorough mechanical cleaning prior to high-level disinfection, should have prevented all of these cases. Forty-five cases of endoscopic transmission of Pseudomonas have been reported, mostly in association with endoscopic retrograde cholangiopancreatography [16]. Infection with this organism generally occurs as a consequence of contamination of the water source (either an inadequately disinfected water bottle feeding the endoscope or contamination of an automated reprocessing machine). Use of an inadequate disinfectant (benzalkonium bromide and alcohol), as well as a breach in accepted cleaning and disinfection procedures have also been reported [16,37]. Sterile or filtered water should be used in the water bottle feeding the endoscope; this water bottle should be cleaned and dried between uses [38]. Transmission of Staphylococcus [37], Enterobacter [39], and Helicobacter pylori [40] has also been reported. However, in each instance, mechanical cleaning, disinfection, or storage techniques were found to have been inadequate. H. pylori has been isolated from used endoscopes and biopsy forceps [41]. Serratia infections have been linked to transmission during flexible and rigid endoscopy [42]. Studies have reaffirmed that following procedures in published reprocessing guidelines effectively eliminates bacteria and other microorganisms from endoscopes [43]. Although bacterial spores are the most resistant to LCGs, there have been no well-documented cases of endoscopic transmission of infections with these organisms [6]. Studies have shown that Clostridium difficile spores can be completely inactivated by standard reprocessing techniques [44].

Mycobacteria Mycobacteria are also difficult organisms to eradicate with chemical sterilants or disinfectants (the most difficult besides bacterial spores), but there have been no reported cases of mycobacterial transmission by GI endoscopy. Glutaraldehyde, hydrogen peroxide, ortho-phthalaldehyde, and peracetic acid have all been demonstrated to adequately eradicate mycobacteria, both Mycobacterium tuberculosis and the atypical mycobacteria [10,45,46]. Mycobacteria spp. have been detected in tap water samples, which raises the specter of possible transmission of the agent, if filtered or sterile water is not used for rinsing the endoscope following high-level disinfection [47].

Fungi, protozoa, and parasites There have been no reported cases of transmission of fungi following GI endoscopy, although contamination of an endo-

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scope with Trichosporon beigelii has been documented [48]. One report exists of Strongyloides spp. esophagitis related to cross-infection from a single endoscope. [49]. There have been reports of difficulties in inactivation of Cryptosporidium parvum oocysts [50,51]. However, such reports demonstrated marked diminution of Cryptosporidium oocyst infectivity when endoscopes were reprocessed using accepted protocols, and air dried for 90 min after reprocessing [50].

Prions Concern has been raised over possible endoscopic transmission of prions and other transmissible spongiform encephalopathies (TSEs) including Creutzfeldt–Jakob disease, kuru, and bovine spongiform encephalopathy [52]. There have been no reported cases of transmission of these agents by endoscopy. The World Health Organization recommends that decontamination of medical instruments should be guided by the infectivity level of the tissue contaminating the instrument. Prions infect central nervous system tissue. Saliva, gingival tissue, intestinal tissue, and blood are regarded as having no detectable infectivity, and, therefore, for the purposes of GI endoscopy, are classified as noninfectious [53]. A statement on TSE and endoscopes from the US Centers for Disease Control concluded that current guidelines for cleaning and disinfection of instruments need not be changed [6,54].

Steps in endoscope reprocessing Four steps have been described for the effective reprocessing of GI endoscopes: 1 manual cleaning 2 high-level disinfection 3 rinsing 4 drying/appropriate storage. Effective reprocessing of GI endoscopes is achievable through strict adherence to published guidelines. These standards are best summarized in the multisociety reprocessing guidelines published in 2003 [2,55]. When transmission of infection through inadequately reprocessed endoscopes has occurred, it has been due to one or more of: • inadequate manual cleaning; • inadequate disinfectant or germicidal concentration; • use of a final rinse with tap water or without adequate drying; • poor compliance with reprocessing recommendations. When reviewed critically, most cases of transmission of infection by GI endoscopy have resulted from a failure or breakdown in the manual cleaning of the endoscope [56]. Avoiding reprocessing altogether could be a solution; endoscopes that employ disposable sheaths and/or valves may provide an alternative to conventional liquid chemical disinfection.

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Mechanical cleaning The initial step in endoscopic disinfectionamechanical cleaningais the most critical [57]. Mechanical cleaning leads to removal of a significant amount of organisms, feces, and foreign material from the endoscope. It is completed immediately after withdrawal of the endoscope from the patient and is usually done with water, brushing, and/or enzymatic detergents. Washing of the exterior of the endoscope and washing/brushing the interior channels and valves prevents build-up of organic debris and decreases the bioburden, or degree of microbial contamination, in GI endoscopes by 4 logsa99.99% [43,57– 60]. The critical nature of the manual cleaning step is widely acknowledged in all published guidelines. Indeed, the importance of manual cleaning cannot be overemphasized. Without adequate manual cleaning, retained biofilm on the surface or in the channel of the endoscope can prevent further adequate disinfection, regardless of the method employed [57]. Biofilm has been shown to occur in endoscopes as a result of inadequate cleaning, disinfection, rinsing, drying, and storage [61]. All subsequent steps in the reprocessing of an endoscope first require meticulous cleaning of the internal and external surfaces. Disturbingly, a survey by Cheung in 1999 [62] found that 9.3% of reporting centers failed to brush the accessory or suction channel, the valves, or suction cleaning solution through the endoscope. Worse still, these results were largely unchanged from a similar survey done in 1995 [63].

Disinfection High-level disinfection is the current standard for reprocessing of endoscopes. This may be achieved by automated

Cleaning and Disinfection

reprocessors or by manual reprocessing. High-level disinfection requires complete immersion of the endoscope in the disinfecting solution under specified conditions. The use of endoscopes that cannot be fully immersed is unacceptable. Liquid chemical germicides for high-level disinfection have been approved for use by the Food and Drug Administration (FDA) (Table 5.2) [12]. Such LCGs may be used in both manual and automated reprocessing techniques. Glutaraldehyde (> 2.4% concentration) remains the most commonly used LCG. Other commonly used LCGs include hydrogen peroxide 7.5%, peracetic acid 0.2%, ortho-phthalaldehyde 0.55%, and peracetic acid 0.08%/hydrogen peroxide 1.0% [12,64]. Previously used disinfecting solutions such as hypochlorite solutions, alcohol, quarternary ammonium compounds, phenolics, and iodophors may not be efficacious; their use is discouraged. Many standards recommend that, after an endoscope has been mechanically cleaned, high-level disinfection may be achieved by immersion in 2.4% glutaraldehyde for at least 20 min at 20°C [65]. This is in conflict with the product labeling. In 1993, the FDA assumed jurisdiction over the regulation of clinical germicides, and at that time required manufacturers of 2.4% glutaraldehyde [as part of the 510(k)-clearance process for medical devices] to label their product recommending 45 min of exposure to glutaraldehyde at 25°C. This recommendation was based on the length of time and temperature needed for glutaraldehyde to kill 100% of M. tuberculosis without any manual precleaning [66]. Recognizing the crucial role of mechanical cleaning, subsequent guidelines have suggested that once recommended precleaning has been done, 20 min of glutaraldehyde immersion at room temperature is sufficient to achieve high-level disinfection. Current

Table 5.2 Liquid chemical sterilants used in high-level disinfection in reprocessing of GI endoscopes. Liquid chemical sterilant

Advantages

Disadvantages

Glutaraldehyde

Relatively inexpensive Compatible with endoscope materials Long history of use

Vapors cause respiratory irritation Requires ventilation Can fix debris if inadequate cleaning

Hydrogen peroxide

Effective at room temperature No activation needed No odor

May be incompatible with some materials May cause eye damage if contacted Longer contact time

Peracetic acid

Single use Labeled for “sterilization” Rapidly sporicidal

Relatively expensive May be incompatible with some materials No demonstrated advantage to high-level disinfection

Peracetic acid/hydrogen peroxide

No activation required No odor

May be incompatible with some materials Limited clinical experience

Ortho-phthalaldehyde

Rapidly tuberculocidal No odor No activation Effective at room temperature

May require ventilation due to odors May cause staining of clothes Limited clinical experience

Modified from Rutula WA, Weber DJ. Disinfection of endoscopes: review of new chemical sterilants used for high-level disinfection. Infect Control Hosp Epidemiol 1999; 20: 69–76.

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multisociety guidelines reflect this thinking [2]. Glutaraldehyde is currently used in 67% of units at 2.4% concentration; 3.4% glutaraldehyde is used in another 13%. Additionally, 84% of reporting centers use a “20 min soak time,” and only 24% of centers heat their glutaraldehyde solution [67]. Potency testing is critical to the successful use of LCGs. Standards for infection control mandate that when LCGs are used, their concentration is monitored regularly. As LCGs are reused, dilution occurs that can decrease the microbicidal activity of the LCG. Product-specific test strips should be used to make sure that solutions remain above their minimum effective concentration. Unfortunately, in a 1999 survey, 16% of sites did not perform potency testing at all [62].

provide a suitable environment for the multiplication of microorganisms. While the need for thorough drying after reprocessing is not stressed in all guidelines, many consider this step as important to the prevention of nosocomial infection as cleaning and high-level disinfection [74]. Endoscopes should be stored without coiling (again to prevent possible pooling of residual water) in a well-ventilated closet [2,7]. Finally, some guidelines suggest the need for reprocessing endoscopes prior to the “first case of the day.” Several studies examining this have concluded that, when reprocessed according to established guidelines and stored properly, flexible endoscopes remain free from pathogens overnight and for at least 7 days; the practice of additional reprocessing “before the first case of the day” is unnecessary [74–77].

Automated endoscope reprocessors Many endoscopy units now use automated endoscope reprocessors (AERs) as part of their disinfection procedure. These devices are not “washing machines”; the use of an AER does not eliminate the need for manual cleaning [67,68]. Despite the popularity of AERs, studies have not shown a clear advantage for AERs over manual high-level disinfection [69]. AERs offer potential advantages such as decreased exposure of personnel to LCGs, standardization of the disinfection process, and a reduction in manual labor for the staff. Disadvantages include higher cost, inability to disinfect narrow channels (elevator in duodenoscopes), and possibly increased reprocessing time [70]. There was a significant increase in the use of AERs between 1995 and 1999 (41.5% vs. 69.9%) [67]. Of note, one-third of respondents reported problems with AERs, including breakdowns, leaks, and damage to endoscopes [67].

Rinsing Rinsing the endoscope thoroughly after reprocessing with an LCG is critical to prevent residual germicide from contacting the GI mucosa of subsequent patients. The channels and the endoscope’s external surface should be rinsed with copious amounts of water [2]. Glutaraldehyde colitis is a well-recognized phenomenon, and may occur rapidly after exposure of a patient to glutaraldehyde [71]. Hydrogen peroxide exposure to the colonic mucosa leads to a characteristic “snow-white” sign [72]. Recommendations for rinsing suggest that it is done with filtered (through 0.2-μm pores) or sterile water to decrease the risk of microorganisms being reintroduced into the endoscope after high-level disinfection has been completed. Tap water may contain Pseudomonas, mycobacteria, or other microorganisms [73].

Drying/storage The final step in the reprocessing procedure is drying, using 70–90% ethyl or isopropyl alcohol and forced air drying [2]. This step eliminates residual water that may be trapped in the channels of the endoscope, as such standing water may

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Current standards Guidelines for the reprocessing of endoscopes were first widely published in 1988 [17,18], revised and updated through the 1990s, and again in 2000 [5]. Guidelines are now available from the ASGE, ASTM, SGNA, Association of Practitioners of Infection Control (APIC), Association of Perioperative Nurses, and the BSG, as well as the multisociety guidelines [2,3,5–8]. Gastroenterologists must be aware of these guidelines as well as the current reprocessing protocols in their local practice situation.

Compliance Reprocessing errors typically arise from either human error or failure of the automated endoscope reprocessor or of the high-level disinfectant [78]. Strict adherence to ASGE/ ASTM/SGNA/APIC and multisociety guidelines cannot be overemphasized. Despite this, there continues to exist a wide variation in reprocessing practices [79]. Adequate staff training, as well as having dedicated staff with dedicated “back-up,” is critical to the success of any program of endoscope reprocessing. This job must not be relegated to a parttime or temporary worker. Attention to adequate staffing levels in any individual office or endoscopy suite is crucial. Similarly, care must be taken in the scheduling of trained personnel so as to avoid situations where the only personnel available have limited or no expertise in reprocessing of endoscopes [2,7]. Moreover, proper manual cleaning of the endoscope prior to disinfection must be emphasized. Automated reprocessors are not “washing machines”; they do not do the manual cleaning. Without the manual cleaning portion of reprocessing, all other steps are rendered ineffective. Testing of glutaraldehyde and other LCGs for sustained potency must be done uniformly and regularly. Finally, practitioners must be aware of the specifics of reprocessing in their own situation, and correct deficiencies.

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Endoscope design Flexible GI endoscopes are complicated instruments by nature of their design. They have channels and parts that may acquire cracks and nicks over time, as well as movable parts (such as the elevator on a duodenoscope) where debris and possibly microorganisms may become lodged. These areas may be relatively inaccessible to contact with LCGs [10]. Endoscopes are heat-sensitive instruments; they cannot be heat sterilized without destruction of the instrument. Therefore, it is apparent from the design characteristics of heat-labile GI endoscopes that sterilization or even highlevel disinfection cannot be absolutely guaranteed. Destructive testing of model endoscopes after contamination and then reprocessing would be needed to assess for the level of disinfection/sterilization. Thus, while the available evidence suggests that the rate of transmission of infection via GI endoscopy is extremely low, one must accept the possibility that, under rare circumstances, transmission of an infection could occur. Manufacturers have been encouraged to redesign endoscopes to allow disassembly and verification of the cleaning/disinfection process.

Summary Despite concerns about safety with regard to reprocessing of endoscopes, the reported rate of transmission of infection in GI endoscopy is exceedingly low. Reprocessing of endoscopes is effective when published standards are followed. However, strict adherence to published guidelines is critical to avoid the transmission of infectious agents, particularly as endoscopic units become busier and the number of procedures increase. Certain points warrant emphasis: • Close adherence to thorough manual cleaning of the endoscope prior to disinfection is essential. There is no substitute for meticulous cleaning. Automated reprocessors are not “washing machines”; they do not do the precleaning. • Testing for maintained potency of glutaraldehyde or the chosen LCG is not being uniformly achieved. This testing must be done appropriately and regularly to ensure the intended efficacy of the disinfectant. Current guidelines suggest that potency testing be carried out at least daily, prior to each reprocessing cycle. • Only well-trained personnel should perform manual cleaning and disinfection. A quality assurance program to ensure consistent procedures and adequate outcomes should be established in all offices and GI endoscopic units. • Many practitioners remain ignorant of either some or all of the details of reprocessing in their local situation. Practitioners are advised to be aware of the specifics of reprocessing

Cleaning and Disinfection

in their own office or GI unit, and to check regularly for updated recommendations. Further progress in this field will come with modifications of endoscope design that allow them to be more completely disassembled for easy cleaning and disinfection, and with improvements in sterilization technologies that are appropriate for the materials and design of an endoscope. In summary, infections are rare in GI endoscopy. HCV, HBV, and HIV, as well as bacteria and other microorganisms are easily eradicated. Attention to meticulous cleaning and adherence to established standards are crucial.

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Informed Consent for Colonoscopy Andrew D. Feld University of Washington, Seattle, WA, USA

Introduction Obtaining informed consent is a process that goes beyond the event/action of obtaining a signature on a standardized form. It includes assessing the competence of the individual to process information, disclosure of appropriate information necessary to allow an informed decision, and ensuring that the plan chosen by the patient is voluntary. The process involves a mutual communication and decision-making, not merely requesting a signature on a standardized form that lists complications of a procedure. The process of obtaining informed consent may appear to some to be another regulated nuisance slowing down the busy practitioner and hindering efficient medical practice. However, it could better be viewed as a basic ethical obligation in the practice of medicine, one which can be used as a communication tool cementing the provider–patient relationship [1–3]. It is also a risk management tool, transferring known standard procedural risks to the patient, who has understood and accepted the premise that even competently performed colonoscopy has risks. Finally, it is a legal obligation in the practice of medicine. An understanding of the conceptual aspects of informed consent will best allow the healthcare provider to negotiate the many areas of uncertainty regarding the specifics of informed consent.

Conceptual aspects of informed consent History of informed consent Most healthcare providers currently accept the concept of informed consent, which is rooted in patient autonomy and self-determination. Many healthcare providers incorrectly assume that this is a long-standing medical tradition. Prior to

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

the 1950s, the focus of prominent medical personnel was to provide medical benefit and protect the patient from harm. Recall the Hippocratic Oath: first, do no harm. Protecting the patient from harm was felt to ethically justify withholding distressing information from a patient. Thus, patient autonomy and decision-making took a back seat to the precept of “do no harm.” Disclosure of a poor prognosis was felt to be associated with a harmful outcome, and little disclosure probably took place before the nineteenth century [4]. In fact, it was more likely that early physicians concealed their activities from their patients [5]. During the eighteenth and nineteenth centuries, some physicians were credited with enlightened views on disclosure of medical information. However, history of medicine scholars suggest that the purpose of those physicians was to educate patients to understand and follow physician recommendations, rather than to allow them to participate in medical decision-making [4]. It was an early effort to ensure compliance with therapy, not to ensure patient autonomy.

Legal history In 1914, the influential legal scholar, Justice Cardozo, wrote: every human being of adult years and sound mind has a right to determine what shall be done with his body [6].

That landmark case is often cited as the beginning of modern informed consent. This judicial ruling found that a person’s right of self-determination would justify imposing an obligation on the healthcare provider to obtain informed consent. A legal precedent was set, making consent necessary for medical treatment. Further legal developments included the emphasis on the informed part of patient consentathis is the provider’s obligation to give sufficient information for truly informed decision-making, not mere consent. In the 1950s, a patient whose translumbar aortography resulted in a rare complication of hemiplegia successfully sued on the basis that he had not been given sufficient information about the risks of the procedure. The court ruled: a physician violates his duty to his patient and subjects himself to liability if he withholds any facts which are necessary to form the basis of an intelligent consent by the patient [7].

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Several additional cases firmly established the physician’s duty to convey adequate information regarding the nature and probable consequences of the treatment, and the potential risks involved [8]. Initially, the consent process had a provider-based standard. A physician was expected to disclose information about the treatment that reasonable physicians believed relevant for the patient to know, and that reasonable physicians generally disclosed to their patients in similar circumstances. In another landmark case, the court moved toward a patient-based standard for what information should be disclosed in order to obtain truly informed consent [9]. The court was concerned that control of what information needed to be presented to the patient was too important to be left to physician groups, which may have too low a standard, or no generally accepted standard of disclosure. The court noted: respect for the patient’s right of self determination on particular therapy demands a standard set by law for physicians, rather than one which physicians may or may not impose upon themselves [9].

A patient-based standard mandates that a treating physician discloses as much information as a reasonable patient would wish to know. Unfortunately, there is no comprehensive list for physicians to find out what a reasonable patient would like to know in any given situation. A physician must estimate this according to the general principles of informed consent. Thus, this chapter has a conceptual approach, which allows a basic understanding in order to guide a provider’s performance of informed consent. If one goes to court, a jury will decide after the fact whether the physician met the patient’s basic standard of informed consent. The ultimate answer will come only from the jury hearing a disputed case. Some states have a physician standard; other states have a patient-based standard. The prudent medical provider will attempt to convey consent using a “patient-based standard,” since this appears to be the direction in which court decisions are heading.

Shared decision-making Shared medical decision-making is a two-part process between physician and patient. A physician discloses all relevant risk and benefit information and specific treatment alternatives regarding the medical condition and treatment. The patient’s responsibilities are to describe to the physician all relevant personal information that might make one treatment or set of risks more or less important than others. The final step is that both patient and physician use the physician-produced factual information and patient-produced value information to reach a mutual and “shared” medical decision [10]. A group of legal and medical scholars believe that this approach will improve flaws in the current informed consent process [11]. Patients have accused physicians of not providing information they most want and yet physicians have been unable to know which patients desire what information, and thus may be at liability risk for failure to provide sufficiently

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patient-centered informed consent [11]. However, the shared decision-making process has also been criticized as being overly time-consuming, difficult, and of unproven value [12,13]. In order to make this process easier, decision aids or coaches have been recommended. Thus, the patient would receive informational material in advance. This may take the form of video, written information, and/or a conversation with a nonphysician “health coach.” The patient receives a large amount of background information which can then be followed with a briefer confirmation and conversation between physician and patient. Furthermore, these professionally produced tools may aid more effective and comprehensive patient understanding than the traditional physician–patient conversation, and present less bias from the physician. Indeed, the process used by some producers of decision aids may involve focus groups, literature searches, and input from various specialists; this process may take over 6 months at a cost of over $150 000 per decision aid [11]. Care must be taken to ensure that any decision aid is unbiased, thorough, and current. Decision aids have the potential to provide a thorough and impartial review of a common topic, such as colon cancer screening, that can then be briefly discussed with the physician and may allow the patient to focus on the areas of the presentation which are of most importance. For instance, one decision aid regarding colon cancer screening uses a 20-min video; for a physician in an office to personally convey the same amount of information with the same thoroughness of explanation would be impracticable. However, decision aids have also been marketed as methods of reducing practice variation with attendant cost saving. Some reduction in practice variation may be quite appropriate [14] and produce valuable societal cost savings, but there is also the potential to reduce utilization of valuable but expensive services, such as decision aids, which may give it a subtle negative information slant. If a commercial venture producing decision aid markets a product to health insurers, then one must be careful that a product whose goal includes a reduction in unwanted health disparities and variation is not merely cost containment in disguise. Similarly, a specialty society producing information may design the information with an inadvertent bias to promote its radiological or procedural test. Finally, many medical decisions requiring consent are so specific to the individual patient that no commercially feasible decision aid will exist. Research and production of true decision aids, including information on colorectal cancer screening, are currently being performed by the groups such as the Foundation for Informed Medical Decision-making, the Dartmouth–Hitchcock Center for Shared Decision-making, and the Ottawa Health Research Institute [15–17]. However, it has been suggested that, to ensure unbiased and informed disclosure, decision aids should be approved by credentialed, neutral bodies comprising lay persons, researchers, and physicians [11]; these credentialing authorities do not yet exist.

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More basic technologic aids are produced by a number of medical societies. These may not rise to the level of the decision aid, but most likely enhance patient understanding. These may augment, though not replace, personal discussion, and can be shown in court to convince a jury that sufficient information was provided. A goal of the shared decision-making process is to preserve a patient’s autonomy and yet allow physicians to present sufficient information such that they could not be accused of failing to provide the information that a “reasonable” patient would have wanted. The advantage of a shared decisionmaking process is that the patient receives sufficient information tailored to their personal values. The physician not only has an educated patient but may have enhanced legal protection by providing the information a “reasonable” patient would have wanted. The state of Washington is the first in the US to have passed legislation making shared decision-making a valid option for obtaining informed consent [RCW (Revised Code of Washington) 7.70.060]. This law establishes a process whereby the doctor and patient use “patient decision aids”a defined as written, audiovisual, or online tools that provide a balanced presentation of the condition and treatment options, benefits, and harms for each course of treatmentato make a decision about the best course of treatment. The patient decision aid must be certified by a national certifying organization. This method of obtaining informed consent still requires a form that has the patient’s signature, but the form does not have to list the requirements of the traditional informed consent form. The legal advantage to physicians of employing shared medical decision-making is that the patient can only refute an acknowledgment of this by showing that their consent was not properly obtained with clear and convincing evidence, a higher level of proof than the traditional informed consent form’s preponderance of the evidence requirement. This makes a successful law suit on this issue more difficult for the plaintiff to win. If other states follow suit, then the use of shared decision-making for common medical situations, such as cancer prevention, medications with significant risk, procedures, and surgical interventions, may allow a reduction in the informed consent malpractice risk. The level of decision aid needed may become an issue. Are videos or extensive handouts from a specialty society sufficient, or does the agency creating the consent information need to be more independent? Which organizations will qualify as a national certifying organization? The law is, as of yet, untested, the mechanics uncertain, and whether other states will follow suit is unclear.

Material risks Not every possible risk must be disclosed, only those a reasonable patient would wish to know in order to make an appropriate decision. These have been termed “material risks,” and are specific to each procedure and patient situation. However,

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the courts do not define these risks a priori. If the physician’s consent information is challenged and a trial results, what should have been disclosed would be decided by the jury, after the fact. There are no comprehensive legally binding lists available to the physician, although some state statutes have begun to provide some specific guidance [18]. In fact, a Louisiana “Medical Disclosure Panel” has a list of material risks for over 100 medical procedures [19]. Electronic databases may aid physicians in providing information to patients; however, the physician cannot abdicate the responsibility to provide the final individualized communication with the patient [5]. There are guiding principles which can be used to help determine what an average patient (and average jury!) would find significant. The four elements of risk the physician needs to consider include: 1 the nature of the risk; 2 the magnitude of the risk (seriousness); 3 the probability that the risk may occur; 4 the imminence of the risk (i.e., post procedure or decades later). The more serious and the higher the probability of the risk, then the more disclosure is warranted. However, deciding what constitutes a material risk is often not easy. An authoritative text on informed consent notes: the physician must walk a fine line between providing pertinent risk information and overwhelming the patient with frightening statistics. Providing too much extraneous information may be as likely to impair informed decision-making as providing too little [5].

Ironically, it is often impossible to find a legal precedent that would allow the prudent physician to list specific required disclosures related to a specific procedure. Even if a legal ruling were found, medical cases would probably be different enough that one judicial ruling would not necessarily apply to another case. Differing judicial districts may not follow each other’s precedents. Additionally, medical advances may alter “current” list expectations. The best one can do is apply the principles of informed consent and fully involve the patient in decision-makingathis is likely to be sufficient. Thus, it is not possible to give a brief statement that the reader can “cut and paste,” outlining the optimal risks to be disclosed for colonoscopy. However, a spectrum of medical journal articles regarding colonoscopy, gastrointestinal society information, and guidelines on the use of colonoscopy help provide some authoritative basic information about colonoscopic risk. To direct the thinking on informed consent for colonoscopy, consider the information (material risks) an average patient may want: • serious and uncommon risks of colonoscopy, likely to include perforation and bleeding, which could require transfusion or surgery; • serious and uncommon risks associated with colonoscopy and/or the administered anesthesia, which could include

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cardiac or respiratory complications and infection (arrhythmia, infarction, aspiration), as well as undersedation; • common nonserious risks: gas, bloating, self-limited discomfort, i.v. access site complications; • that colonoscopy is an imperfect procedure: there is the possibility of missing a lesion or diagnosis, even with a technically adequate examination [20]. The reader is referred to Chapter 15 for further thoughts on contraindications to colonoscopy due to the likelihood of complications. Finally, should one mention the possibility of death as a result of the procedure? One survey study from England found that barristers (the English equivalent of plaintiffs’ attorneys) felt that serious risks should be mentioned even if as rare as one in one million [21]. Although it is generally legally safer to mention more risks (include risks even if very rare), there is a potential cost in unnecessarily frightening patients away from beneficial procedures by not adequately conveying the rarity of such an event. Many physicians do mention death, feeling that the rarity of the event is outweighed by its seriousness. The author’s own colonoscopy consent discussion does not mention death (unless specifically asked); however, some of the hospital consent forms he is required to use do mention it. The reader must review the concepts of consent, and use his or her knowledge of colonoscopic risks to form an opinion on this matter.

Endoscopic sedation As physicians review the risks and benefits of colonoscopy with their patients, many overlook a discussion of the risks of sedation [22]. In a 1995 US survey, 98% of endoscopists obtained preprocedure consent, but more than one-third (38%) did not routinely discuss sedation, and 30% of the time the endoscopist was not personally involved in the informed consent discussion [23]. A British study suggested that roughly one-fourth of patients were “inadequately informed” regarding the endoscopic procedure, despite having undergone the unit’s informed consent process [24]. As sedation, particularly in frail or elderly patients, may result in serious complications, a discussion of those risks is appropriately added as part of the procedural consent [22,25]. Furthermore, sedation may be considered elective, as some procedures are carried out without it [26]; thus, a discussion of sedation that allows patient choice can be considered, even if opting out is discouraged, based on practitoners’ experience. More commonly than a request for no sedation is the patient-expressed sentiment: “I want/expect to be out.” The patient may even attend with the expectation, derived from the primary care provider in almost guarantee form, that he or she will be completely “out.” The experienced colonoscopist may wish to reassure patients that they will likely be sufficiently comfortable, while dispelling the idea that all patients are “completely out” (particularly with standard moderate/

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conscious sedation). Promises are generally unwise from a medical legal perspective, since most cannot be universally guaranteed. In fact, law suits regarding perceived insufficient sedation and withdrawal of consent have been instituted [27]. An American Gastroenterological Association (AGA) Institute Review of Endoscopic Sedation noted that additional issues related to sedation, which warrant preprocedure disclosure, include the following: • the postprocedure risks related to driving, operating heavy equipment, consuming alcohol, and exercising vigorously; • the possibility that the patient will not recall the procedure and postprocedure discussion; • the risk that despite appropriate sedation the patient will experience pain or discomfort; • the risk of allergic drug reactions and local reactions at the i.v. site; • the risk of cardiopulmonary depression [22]. Also controversial is the issue of consent for gastroenterologist-directed propofol (GD-P) sedation. At publication there was no clear case law addressing the need for separate consent for GD-P. Theoretical arguments could be constructed both for disclosure (the concerns raised by anesthesiologists about propofol risk and lack of reversal agents are pertinent material information that could affect a reasonable patient’s choice) and against the need for specific anesthetic agent disclosure (large epidemiologic studies show the risks of GD-P to be similar to or better than risks of other agents, and general discussion of endoscopic sedation is sufficient). While the author believes the issue is currently unresolved by the courts, it should be noted that the AGA Institute Review of Endoscopic Sedation does advise: . . . the informed consent discussion should inform patient of risks, benefits, and alternatives (including the option of having propofol administered by an anesthesiologist) to GD-P, and of the qualifications and experience of the endoscopist to administer GD-P [22].

Unsettled areas What else should be disclosed for truly informed decisionmaking? Although traditional informed consent doctrine has involved disclosure of the medical and surgical risks of a procedure, a patient-oriented standard of disclosure allows for a broader interpretation of material risk. The language of the seminal legal case, Canterbury v. Spence (“when a reasonable person . . . would be likely to attach significance to the risk . . . in deciding whether or not to forgo the proposed therapy” [9]) has allowed nontraditional interpretations of pertinent disclosure information to include the experience and economic interests of the provider.

Colonoscopy provider metrics and consent Concern has been expressed over the possibility of colorectal cancer missed at colonoscopy [20]. Colonoscopy withdrawal

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time [28] and polyp find rates [29] have been reported to be factors that could impact the thoroughness of colonoscopy. The Quality Assurance Task Group of the National Colorectal Cancer Roundtable has developed a consensus-based reporting and data system for quality indicators for colonoscopy, designed for continuous quality improvement [30]. However, it has been noted that clinical practice guidelines and metrics at the level of the individual may not only improve clinical care and performance, but also pose medical legal risk, particularly if benchmarks are set to reflect aspiration or best practice levels rather than baseline competence levels [31]. For instance, if a patient who has undergone a reportedly normal colonoscopy 3 years previously is found on a subsequent examination to have colon cancer, the plaintiff’s attorney would be interested in checking any available metrics for the gastroenterologist that are below literature or society recommendations, with the hope of asserting a pattern of substandard practice. The attorney may also wish to assert that substandard levels should have been disclosed in the consent process, so that the patient could have sought care elsewhere. In general, providers have not been expected to disclose provider-specific complication rates that are roughly in the range of standard practice. In a legal case involving a complex and risky brain aneurysm operation, the provider was found liable for withholding information regarding his inexperience [32]. While disclosing current complication rates from the medical literature for standard procedures seems appropriate, if the provider has a substantially different rate of complications, courts could find that this information should also have been disclosed [33]. With improving information systems, will provider-specific complication rates become the informed consent expectation? Will provider metrics be requested by patients? Need they, and can they, be protected within peer review legal process protections? After all, they could be perceived as material information that could influence the patient’s choice of provider. On the other hand, there does not seem to be much published about the need to disclose providers’ rank in medical class and medical board scores, which could arguably affect a patient’s choice of physicians. Finally, will the question become moot, as payer groups and institutions use claims-based data to provide aggregate and individual provider metrics, about health groups and individuals, to their healthcare consumers? Given the evolution of thought and publicity regarding the potential importance of flat and depressed colon polyps [34,35], will patients wish to know about a provider’s familiarity with those lesions, or equipment capability for chromoscopy? A colonoscopist may wish to prepare explanations in advance. What about other information which a patient may feel is pertinent to his or her decision to proceed with a specific provider: illness of the provider, alcoholism, social stresses such as divorce, or even lack of sleep after a rough night on call? These issues have been raised, but not yet answered [36].

Informed Consent for Colonoscopy

Issues of conflict of interest and the physician’s fiduciary duties to the patient have led to an expectation of disclosure of significant financial interests. In a case where the physician had a financial interest in developing a cell culture line from a hairy cell leukemia patient’s resected spleen, it was found that the physician had to disclose economic or research interests that might affect his judgment [37]. These principles could apply to colonoscopists being either paid per case for patient entry into a research study, or receiving managed care incentives to reduce service [5]. Given more public interest and skepticism regarding the potential for conflict of interest [38], physicians should ensure that they avoid or disclose financial conflicts of interest.

Failure to obtain informed consent: legal consequences Risk management programs involve understanding the risk of malpracticeaby analysis and legal theoryato develop awareness of risks pertaining to the specific treatment encounters. Medical malpractice most commonly involves the tort of negligence, in which a healthcare provider is felt to have practiced below the standard of care. However, a common and independent cause of malpractice action involves failure to obtain informed consent. Of note, even if a malpractice claim fails with respect to the standard of care allegation, a healthcare provider can be liable for inadequate informed consent. Since informed consent requires a communication between provider and patient, and since studies of malpractice risk note that better communication reduces malpractice risk, the process of informed consent can actually be a tool to reduce malpractice risk. Furthermore, the process of disclosing the inherent risks of a procedure essentially requires the patient to accept that risk as part of the performance of the procedure. This transfers the risk of a nonperfect procedure from the colonoscopist to the patient, who assumes the risk with the decision to proceed despite the knowledge of procedural risks. The risk shift does not apply to substandard care, but would apply to many of the complications of colonoscopy that may occur even with an appropriate technical performance of the procedure [20]. Thus, the process of obtaining informed consent can positively affect malpractice risk, as it: 1 allows a communication process to occur between the healthcare provider and patient, which should strengthen the professional relationship, build trust, and demonstrate the professional’s respect for the patient’s autonomy; 2 performs a risk management function by decreasing the likelihood of a common malpractice claim (failure to obtain informed consent) and also shifts the liability risk of a complication toward the patient, who has accepted the procedure knowing the associated risks; 3 fulfills the legal obligation to obtain consent prior to a medical procedure.

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Possible malpractice actions: negligence or battery Most malpractice claims are made under the legal theory of negligence. A healthcare provider breaches the duty of care to the patient by substandard care or lack of informed consent, causing harm to the patient. However, lack of informed consent is an independent cause of legal action, and can lead to a finding of provider liability, even if the standard of care was met. For instance, a postpolypectomy bleed may occur even in the absence of substandard procedure: complications can occur despite careful technique. The mere existence of a complication is not enough to find the provider liable. However, a patient who has not given informed consent prior to the procedure could successfully argue that he or she would not have chosen to undergo the screening colonoscopy if he or she had known about the risk of bleeding. If there is absolutely no consent, a charge of battery could be brought. By definition, battery is nonconsensual touching that is harmful or offensive. One pictures thugs rather than physicians when one hears a charge of battery. It is a currently disfavored approach in litigation of informed consent cases. However, if there is absolutely no consent (not merely a failure to obtain a signature on a form, but no consent discussion about the procedure), or the procedure is well beyond the scope of consent, a claim of battery could result [33]. Battery is not covered by most malpractice insurance, and thus personal liability could result. (Although most physicians would be more concerned about potential personal liability, many plaintiff attorneys would prefer a negligence action in order to keep the deep pocket of the insurance agency liable.) Battery can be a criminal charge that could affect future hospital credentialing. Hospital credentialing committees often have bylaws rejecting physicians with a criminal record. However, this charge is rare in medical malpractice settings, where the cause of action is usually under the legal theory of negligence.

Physician difficulty in proving informed consent Great variation has been found in patient preferences involving acceptable risk and quality of life trade-offs. Studies document physicians’ inability to predict patient desires regarding cardiopulmonary resuscitation, noting that over 30% of physician predictions were incorrect, and that the “reasonable” patient’s preference varied widely [39]. The implication is that less stark decisions, such as those involving quality of life issues and cancer screening, will be even more difficult to predict. It has been noted that the “materiality” requirement of the patient-based standard leaves physicians vulnerable, by failing to acknowledge that nearly every medical treatment has “an infinite array of evermore remote possibilities for harm” [11,40]. Even the courts, which are required to interpret a successful consent process, have been unable to state expressly how small a risk must be before it no longer requires disclosure [40]. Moreover, even if the material risks are perfectly presented, patients may not remember those

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risks being presented, or could assert a failure of the physician to present in an understandable manner, or develop other unusual consent challenges [41]. A widely cited article asserting the failure of physicians to meet the legal standards of informed consent described six necessary criteria for obtaining successful consent: 1 description of the nature of the condition; 2 discussion of the risks and benefits of treatment; 3 discussion of the alternatives; 4 discussion of the uncertainties; 5 assessment of the patient’s understanding; 6 elicitation of the patient’s preference. In analysis of over 400 audiotaped primary care visits, the authors found that fewer than two of the six criteria were satisfied in an average primary care visit [42]. Despite these difficulties, physicians mostly prevail in law suits.

Practical aspects of informed concept Process (elements) of consent The colonoscopist must ensure that the patient is competent to understand the information disclosed. Note that the medical literature contains information indicating that ordinarily competent older patients may temporarily be unable to adequately comprehend information when hospitalized with a serious illness. Having a family member present may be useful to ensure adequate consent, or at least reduce the likelihood of successful consent challenge later. Informational materials may be given to the patient to facilitate understanding of the procedure. Appropriate institutional forms should be signed and witnessed, and a statement written or dictated as part of the colonoscopy note indicating that informed consent had been obtained. It is preferable if the witness to consent is a family member or friend of the patient who is able to help in the process, as the presence of such an individual suggests that he or she believes that the patient was capable of consent. If a member of staff witnesses the consent, it is advisable that this is not also the person obtaining the consent or helping to perform the procedure. If an issue comes to trial, and those in the procedure room are named as defendants, their testimony witnessing the adequacy of consent may appear to be biased.

Elements of consent The standard core elements of informed consent include the nature and character of the procedure (preferably in nontechnical terms), the material risks of the procedure, the likely benefits, and the potential alternatives (including no treatment). Most consent forms will also include the patient’s name, the date and time of consent, a disclaimer of guarantee of success, the name of the staff members who will perform the procedure, a clause consenting to allow the physician to modify the procedure in the event of unforeseen circumstances

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arising, an acknowledgment that the patient has been given the opportunity to ask questions, and that these have been answered, a clause giving consent to dispose of removed organs, and, with new privacy concerns and regulations, a clause giving consent for transmission of the results to appropriate parties [43].

Who gives consent? Valid consent is given by a competent adult, by an adult for a dependent child, and by an “emancipated minor.” A durable power of attorney for health care may give consent for the named individual. Relatives of the adult patient may give consent. The priority order is usually specified by state statute, and often has an order, such as spouse, children over 18, parents, adult brothers and sisters. However, if there is no designated relative to give consent, and there is obvious family disagreement, it may be prudent to attempt to achieve a degree of consensus before proceeding with an elective procedure. Also, if DNR (do not resuscitate) order exists, it will be important to clarify whether the individual with power of attorney or a family member is willing to suspend this during the procedure. If DNR orders are part of a living will, and it is not possible to suspend them, the issues surrounding this must be clearly discussed with the individual(s) providing consent for the procedure.

Exceptions to informed consent In an emergency situation, a healthcare provider may treat the patient without obtaining consent; consent is presumed or “implied” in legal parlance. The definition of emergency may vary in different jurisdictions, but the principles of imminent harm by failure of prompt treatment can be applied. This issue is less likely to arise with colonoscopy. Further, attempting to obtain even a limited consent from a conscious patient is worthwhile if it will not unduly delay emergency treatment. Implied consent has been found sufficient in nonemergent situations. An old legal case found that consent had been implied by a person standing in line for a vaccine and holding out her arm [44]. With respect to colonoscopy, getting up on the table with an i.v. line in place would likely lead a jury to find enough implied consent to exclude a charge of battery. However, without adequate disclosure and opportunity to ask questions, a modern jury would be unlikely to find that true informed consent had been obtained. Patients are able to waive their right to informed consent. However, they must know they have the right to information necessary to make an informed decision. Thus, when a colonoscopy patient says, “You’re the doctor, you decide what is best,” the careful doctor may accept that responsibility but will first inform the patient of his or her right to information and decision-making. Therapeutic privilege allows a physician to withhold information that generally has to be disclosed, based upon the

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physician’s perception that disclosure will be harmful to the patient [45]. However, this is a disfavored exception; there is concern that it may be used as an excuse for not informing patients. Unless there is clear and convincing evidence of psychological fragility, it would be best to stay away from this exception. Finally, a legal mandate supersedes a patient’s decision regarding a course of treatment. Thus, a patient with infectious tuberculosis or a dangerous mental illness may be required by court order to undergo medical treatment.

Scope of consent The patient consents to a specific treatment course. If an unforeseen problem arises during the course of treatment and the patient is unable to consent to further needed treatment, the physician may undertake the needed treatment, thus “expanding” the scope of the original consent [33]. However, events that should have been foreseeable should be included in the original consent. Thus, if perforation is a known possible complication of colonoscopy, it is best to inform a patient in advance of the colonoscopy that surgery could be necessary to correct such a complication.

Informed refusal An unusual correlate of informed consent is informed refusal. It is clear that patients have the right to refuse treatment. However, it remains the obligation of the physician to educate the patient sufficiently as to the nature and need for the treatment so that the refusal is based upon a clear understanding of what has been proposed. In an older, but often cited, legal case the patient’s chart documented repeated refusal of a pelvic examination. In the law suit after the development of cervical cancer, the patient successfully argued that she had never been told why the test had been recommended. She contended she would have undergone the pelvic examination if she had known that this was a cancer screening test [46]. With modern communication and abundant public health messages, it may be harder to convince a jury that patients did not know the rationale for the refused colonoscopy, but the prudent physician documenting the refusal of a recommended examination is best protected by noting that the patient had been told the purpose of the examination included cancer screening.

Documentation An oft-quoted malpractice maxim is: “if it isn’t written in the chart, it didn’t happen.” Informed consent is a process, more than a signature on a standardized form. While many hospitals and institutions will require specific forms to be signed, it may be even more helpful in the event of litigation to also have a note in the chart documenting consent. However, that note does not need to be a verbatim or encyclopedic recitation of the consent discussion. A mere statement that risks, benefits, and alternatives were discussed and informed

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consent obtained will document that the process occurred. It is impossible to predict what any particular jury would want discussed. One study from England noted that plaintiff attorneys felt that risks as rare as one in one million should be mentioned [21]. One scholar has suggested tape recording the informed consent discussion, which, to this author, seems both impracticable and detrimental to the physician–patient relationship. What is more, a study of taped physician– patient treatment interactions later analyzed for elements of consent discussed revealed a poor performance [42]; unless carefully done, it is unclear if a taped conversation would help or hurt the physician in court. It also seems impractical to list all items discussed and statistics mentioned in one’s documentation. However, a brief mention in the dictated colonoscopy note indicating that “the nature and character of the procedure, as well as risks benefits and alternatives were discussed” may be beneficial. Citing materials given to the patient [ASGE (American Society for Gastrointestinal Endoscopy) patient education materials, for instance] allows those to be introduced as evidence of education and disclosure. It is important to note that no procedure is perfect, and to raise the concept that even competently performed colonoscopy can miss a lesion [20,47]. Moreover, if one dictates specific complications or statistics, it may be helpful to note that this was not the complete discussion: “complications were said to include perforation, bleeding, cardiac and respiratory complications, infection and missed diagnosis.” Documentation includes far more than consent issues. Physicians notoriously do more than they document. This can be problematic in litigation, billing issues, and quality assurance reviews. Documentation should include the reasons for the procedure, a comprehensive procedure report, any complications, and corrective action. State laws specify record retention times. Additional information about documentation specific to gastrointestinal endoscopy can be found in a manual, Risk Management For the GI Endoscopist [43], which can be requested from the ASGE.

Special situations and problem areas for informed consent with respect to colonoscopy When the patient says “Stop!” What should the conscientious gastroenterologist do when, during a colonoscopy, the sedated patient rouses from a conscious sedation haze and says, “Stop!”? A British survey demonstrated uncertainty among gastroenterologists [48]. The nature of conscious sedation is such that a patient may be aware of the context and surroundings, but not sufficiently alert to understand the implications of a demand to stop the procedure: a possible lesser procedure without therapeutic capacity or a repeat colonoscopy after a repeat colon preparation. The discomfort is likely to be short-lived and the

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procedure safe and successful, and often the patient has no recall of difficulty or any request to stop the procedure. Additional medication and techniques allow more comfortable completion. Indeed, the patient may wish the discomfort to stop, not the procedure. However, the colonoscopist and staff must be aware that consent can be withdrawn (by a competent patient). The fact that a patient has received i.v. sedation that would preclude signing a new consent does not prevent the patient, now in pain, from being competent enough to revoke consent. If a physician were to persist after consent was revoked by a competent patient, the physician would then be proceeding without consent, and could be accused of battery. Consider a patient who is not in the sedated–amnesic land of conscious sedation but is alert enough to intend to revoke consent and remembers office staff holding him down while he or she is screaming, “Stop!”. Imagine the patient describing that scene to a jury. The author surmises, on the basis of conversations with experienced colonoscopists, that most requests to stop are not truly withdrawal of consent but an artifact of sedation causing misperception of the context of procedural activity. However, the prudent colonoscopist will carefully evaluate a request to stop, to be as certain as possible that it is not a true withdrawal of consent for the procedure, which would mandate withdrawal of the instrument. The colonoscopist may temporarily desist from further insertion and converse with the patient. This will establish if the patient does wish to proceed or is no longer conscious enough to continue to request the procedure to stop. On the one hand, if a very sedated patient rouses briefly to mumble, semicoherently, “stop,” then the physician who aborts the procedure may have a lot of explaining to do to the unhappy patient, who remembers nothing about the request to stop but a lot about the colonoscopy preparation that he or she must now undergo again. On the other hand, picture a lightly sedated patient (perhaps coaxed into the examination by a concerned spouse) who experiences difficulty with the procedure, who truly changes his or her mind about the procedure and who repeatedly asserts that the procedure should be stopped. If the colonoscopist ignores this request, serious consequences could result. There are no easy answers. Listen carefully to the patient, and to the endoscopy nursing staff. If an experienced nurse is uncomfortable continuing, this is important information for the colonoscopist. Remember also that it is these same individuals who, if this should come to trial, will be asked to testify about exactly what the patient said and their perception of whether this was a revoked consent. Good judgment, prudence, and discretion will keep the colonoscopist out of trouble.

Open-access colonoscopy There are strong practicality, efficiency, and business arguments to support open-access colonoscopy. In a public health

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sense, this may help make a scarce resource more accessible, more convenient, and less expensive. However, the very nature of its efficiency, in which a patient comes already prepared for the procedure, poses problems with respect to informed decision-making [49]. Some patients received significantly less explanation in an open-access setting [50]. However, recall of informed consent is the same whether the consent was obtained immediately or several days before the procedure [51]. As previously noted, consent is a two-way prodecure, which occurs after appropriate disclosure, with time for answering questions in an uncoerced process. In the case of open-access colonoscopy, the patient may not have met the colonoscopist prior to the decision to proceed with colonoscopy, or even prior to undergoing preparation for the procedure and in some cases even before arriving in the procedure room with an i.v. line in place. The issue is whether truly informed consent can be obtained in this setting or whether there will be perceived coercion. Consent must be voluntary as well as informed. If the patient is learning about the procedural risks and alternatives after having been prepped, with an i.v. line running and with the physician and nursing staff impatiently waiting to begin, is that patient in a position to ask questions and make a voluntary decision to proceed? In the case of a complication arising, could a skilled plaintiff’s attorney make a case that the occurrence of a complication, despite an adequate standard of care, constitutes malpractice because of faulty consent? The author is not aware of any litigation that has addressed this issue. Open access is now well established in the medical community, and can claim to be the standard of care for some situations, such as routine colorectal cancer screening. The concept of open-access colonoscopy remains attractive. As gastroenterologists and medical institutions continue to perform open-access colonoscopy, then some attempts to ameliorate consent issues may be warranted. These may include developing processes that show effort to present adequate information in advance, with opportunity to ask further questions in a noncoerced manner. Other strategies that will enhance sedation-related informed consent and which are particularly useful in the case of open-access surgery include the use of simple language and sensitivity to language barriers and literacy limitations, the distribution of simple information leaflets to the patient before the procedure, and repeating explanations (e.g., mailing leaflets to the patient a week beforehand and then again discussing the procedure on the morning of the operation) [22]. The following suggestions are meant to offer one example of these, by no means necessary, nor even tested and necessarily sufficient, but at least an attempt to incorporate the principles of informed consent. 1 Have the patient receive colonoscopy- and screening-specific oral and/or written information from the primary care office at the time of the referral and/or from the gastrointestinal

Informed Consent for Colonoscopy

staff who call the patient to schedule colonoscopy and go over preparation instructions. 2 Ask the patient to call the gastrointestinal office if, after reviewing the materials/information provided, more information is needed before he or she feels able to agree to undergoing the procedure. Document this instruction. 3 On the day of the procedure, have the patient greeted by the office staff (or physician) prior to having the i.v. line inserted. At this time, disclosure information can be reviewed, and the patient can be asked if he or she has any remaining questions that need the physician’s input prior to the start of the admission process.

Transmission of datacthe Health Insurance Portability and Accountability Act Obtaining photographic or video documentation at the time of colonoscopy may be considered a part of the procedure. Privacy and confidentiality of medical information has long been an expectation of medical care [36]. However, the revolution in electronic information technology has heightened privacy concerns. The electronic transfer of information has important business purposes, but also the potential for problems with respect to the privacy and confidentiality of health information. The Health Insurance Portability and Accountability Act (HIPAA) became law in 1996, and underwent extensive comment and revision period, with final privacy regulations established in 2002 [52]. It is beyond the scope of this chapter to address those regulations. Suffice it to say that in general consent will be required for the transmission of colonoscopy reports, photographs or videotapes, and biopsy results to other entities. Office personnel will need to be trained in matters of confidentiality, and office systems will need to be designed in ways that ensure confidentiality. Providers using email should be certain that they can maintain the level of confidentiality required for transmission of medical data, and that they have warned their patients about email confidentiality problems [53]. Many mass-market email vendors, designed for home use, will likely not meet these privacy standards. Failure to comply with HIPAA regulations may result in civil or criminal penalties, fines, or even incarceration!

Summary The ethical and legal requirement to obtain informed consent prior to performing colonoscopy derives from the concept of personal (patient) autonomy. The competent patient, after receiving appropriate disclosure of the material risks of the procedure, understanding those risks, the benefits, and the alternative approaches, makes a voluntary and uncoerced informed decision to proceed. This is a basic ethical obligation in the practice of medicine. It should be a communication tool cementing the provider–patient relationship. It functions as a

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risk management tool, transferring known standard procedural risks to the patient, who has understood and accepted the premise that even competently performed colonoscopy has risks. The procedural elements involved in obtaining consent include a discussion of material risks, a knowledge of who gives and obtains consent, the scope of consent, exceptions to consent, witnessing and documentation of consent, and the use of educational materials and consent forms. Specific areas of legal uncertainty with regard to disclosure include whether it is necessary to discuss certain individual provider metrics (such as withdrawal time or polyp find rate) or attributes (such as level of experience), or how to disclose economic interests of the provider/researcher. Special situations or problem areas, such as how to obtain valid consent for an “open-access colonoscopy,” what to do when a sedated patient says, “stop,” and privacy/confidentiality issues regarding the transmission of patient reports to other providers, were reviewed. Knowledge of informed consent theory will help the provider to address the specific consent issues for an individual patient.

References 1 American College of Physicians. Ethics manual. Fourth edition. Ann Intern Med 1998; 128: 576–94. 2 Beauchamp TL, Childress JF. Principles of Biomedical Ethics. Oxford: Oxford University Press, 2001. 3 Lo B. Resolving Ethical Dilemmas: A Guide For Clinicians. Philadelphia: Lippincott Williams & Wilkins, 2000. 4 Reich WT (ed.). Informed consent. In: Encyclopedia of Bioethics. New York: Simon & Schuster, 1995. 5 Berg JW, Appelbaum PS, Lidz CW, Parker LS. Informed Consent: Legal Theory and Clinical Practice. Oxford: Oxford University Press, 2001. 6 Schloendorff v. Society of New York Hospital, 211 N.Y. 125, 105 N.E. 92 (1914). 7 Salgo v. Leland Stanford Jr. University Bd. of Trustees, 317 P.2d 170 (1957). 8 Natanson v. Kline, 350 bP.2d 1093 (1960). 9 Canterbury v. Spence, 464 F.2d 772 (1972). 10 Kaplan RM. Shared medical decision-making: a new tool for preventative medicine. Am J Prev Med 2003; 26. 11 King JS, Moulton BW. Rethinking informed consent: the case for shared medical decision-making. JLME 2006; 32: 429–93. 12 Bogardus ST Jr., Holmboe E, Jekel JF. Perils, pitfalls, and possibilities in talking about medical risk. JAMA 1999; 281: 1037–41. 13 Woolf SH. The logic and limits of shared decision-making. J Urol 2001; 166: 224. 14 Wennberg JE. Variation in the Use of Medical Services Among Regions and Selected Academic Medical Centers: Is More Better? Dartmouth: Commonwealth Fund Report, 2005. 15 Foundation for Informed Medical Decision-Making. Decision Support and Shared Decision-Making. Available at: fimdm.org/decision_ sdms.php (accessed March 10, 2008).

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16 Dartmouth Hitchcock Center For Shared Decison Making. Available at: www.dhmc.org/shared_decision_making.cfm (accessed April 7, 2008). 17 The Ottawa Health Research Institute. Patient Decision Aids. Available at: www.ohri.ca/DecisionAid (accessed March 10, 2008). 18 Utah Code Ann. section 78–14–5 (1997). 19 Louisiana Rev. Stat. Ann. 9: 2794 (1997). 20 Rex DK, Bond JH, Feld AD. Medical legal risks of incident cancers after clearing colonoscopy. Am J Gastroenterol 2001; 96: 952–7. 21 Mayberry MK, Mayberry JF. Toward better informed consent in endoscopy: A study in gastroscopy and flexible sigmoidoscopy. Eur J Gastroenterol Hepatol 2001, 13: 1467–76. 22 Cohen LB, Delegge MH, Aisenberg J, et al. AGA institute review of endoscopic sedation. Gastroenterology 2007; 133: 675–701. 23 Levine EG, Brandt LJ, Plumeri P. Informed consent: a survey of physician outcomes and practices. Gastrointest Endosc 1995; 41: 448–52. 24 Pereira SP, Hussaini SH, Wilkinson ML. Informed consent for upper gastrointestinal endoscopy. Gut 1995; 37: 151–3. 25 Vargo JJ, Ahmad AS, Aslanian HR, et al. Training in patient monitoring and sedation and analgesia. Gastrointest Endosc 2007; 66: 7–10. 26 Petrini J, Egan JV. Risk management regarding sedation/analgesia. Gastrointest Endosc Clin N Am 2004; 14: 401–14. 27 Fox v. Kramer, 22 Cal. 4th 531 (2000). 28 Barclay RL, Vicarii JJ, Doughty AS, Johanson JE. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 2006; 355: 2533–41. 29 Rex DK. Maximizing detection of adenomas and cancers during colonoscopy. Am J Gastroenterol 2007; 101: 2866–77. 30 Lieberman D, Nadel M, Smith RA, et al. Standardized colonoscopy reporting and data system: report of the Quality Assurance Task Group of the National Colorectal Cancer Roundtable. Gastrointest Endosc 2007; 65: 757– 66. 31 Moses RE, Feld AD. Legal risks of clinical practice guidelines. Am J Gastroenterol 2008; 103: 7–11. 32 Johnson v. Kokemoor, 199 Wis.2d 615 (1996). 33 Boumil MM, Elias CE. The Law of Medical Liability. St. Paul: West Publishing Company, 1995. 34 Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008; 299: 1027–35. 35 Lieberman D. Nonpolypoid colorectal neoplasia in the United States: the parachute is open. JAMA 2008; 299: 1068–9. 36 Hall MA, Ellman IM, Strouse DS. Health Care Law and Ethics. St. Paul: West Publishing Company, 1999. 37 Moore v. Regents of University of California, 793 P.2d 479 (1990). 38 Kassirer JP. On The Take: How Medicine’s Complicity With Big Business Can Endager Your Health. New York: Oxford University Press, 2005. 39 Teno JM, Hakim RB, Knaus WB. Preferences for cardiopulmonary resuscitation: physician patient agreement and hospital resource use. J Gen Int Med 1995; 10: 179–80. 40 Piper A. Truce on the battlefield: a proposal for a different approach to informed consent. J Law Med Ethics 1994; 301: 304–5. 41 Merenstein D. Winners and losers. JAMA 2004; 291: 15–16. 42 Braddock CH, Fihn SD, Levinson W, Jonson AR, Pearlman RA. How doctors and patients discuss routine clinical decisions:

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44 45 46 47 48

informed decision-making in the outpatient setting. J Gen Intern Med 1997; 12: 339– 45. Petrini JL, Feld AD, Gerstenberger PD, Greene ML, Ryan ME. Risk Management For The GI Endoscopist. Massachusetts: American Society For Gastrointestinal Endoscopy, 2001. O’Brien v. Cunard S.S. Co., 28 N.E. 266 (1891). Nishi v. Hartwell, 473 P.2d 116 (1970). Truman v. Thomas, 611 P.2d 902 (1980). Feld AD. Medicolegal implications of colon cancer screening. Gastrointest Endosc Clin N Am 2002; 12: 171–9. Ward B, Shah S, Kirwan P, Mayberry JF. Issues of consent in colonoscopy: if a patient says “stop” should we continue? J R Soc Med 1999; 92: 132–3.

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49 Staff DM, Saeian K, Rochling F, Narayanan S, Kern M, Hogan WJ. Does open access endoscopy close the door to an adequately informed patient? Gastrointest Endosc 2000; 52: 212–17. 50 Seow CH, Leber JM, Ee HC, Yusoff IF. Survey of consent practices for inpatient colonoscopy and endoscopic retrograde cholangiopancreatography at a tertiary referral center. Gastroenterology 2008; 21: 1340–5. 51 Proctor DD, Price J, Mihas BS, Gumber SC, Christie EM. Patient recall and appropriate timing for obtaining informed consent for endoscopic procedures. Am J Gastroenterol 1999; 94: 967–71. 52 Medical Privacy Rule (Federal Register 67: 53182–53273, 2002). 53 Speilberg AR. On call and online: sociohistorical, legal, and ethical implications of e-mail for the patient–physician relationship. JAMA 1998; 280: 1353–9.

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Antibiotic Prophylaxis for Colonoscopy Gregory Zuccaro Cleveland Clinic, Cleveland, OH, USA

Prevention of infective endocarditis The American Heart Association (AHA) has recently published the ninth iteration of its guidelines for the prevention of infective endocarditis [1–9]. Within these guidelines are recommendations for the prevention of infective endocarditis due to procedures such as colonoscopy. Interestingly, there has been a significant change in the recommendations related to gastrointestinal (GI) procedures between the eighth and the ninth version of the guidelines, despite a paucity of new data. There are only a few case reports describing the possible association of sigmoidoscopy or colonoscopy with the development of endocarditis [10–14]. While underreporting is certainly a possibility, it is reasonable to conclude that infective endocarditis is an extremely rare complication of sigmoidoscopy or colonoscopy. The pathogenesis of infective endocarditis is quite complex. When related to endoscopic procedures, two factors necessary for the development of infective endocarditis are sustained bacteremia due to instrumentation and a valvular lesion susceptible to infection. In addition, certain bacteria are more likely than others to adhere to susceptible cardiac valves. Colonoscopy rarely results in sustained bacteremia with organisms likely to cause infective endocarditis. In a previous review, Botoman and Surawicz [15] estimated the rate of bacteremia associated with sigmoidoscopy or colonoscopy at only 2.2%. They report that the majority of organisms identified were skin contaminants, but that other enteric organisms, such as as Escherichia coli and Bacteroides fragilis, were identified in some series. Therapeutic colonoscopy and ancillary procedures such as polypectomy do not appear to increase the likelihood of bacteremia. Low et al. [16] reported on 270 patients undergoing colonoscopy, in whom polypectomy was performed in 105. They report that the rate of positive blood cultures was 4% in the colonoscopy only

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group, compared with 3.6% in the colonoscopy with polypectomy group. As in previous series, a wide range of bacteria were identified, at least some of which were likely skin contaminants. The transient bacteremia was asymptomatic. Levy et al. [17] reported on 100 patients who underwent 471 fineneedle aspiration passes within the lower GI tract. A total of 6 of the 100 patients (6%) had at least one positive blood culture associated with the procedure. In four of these cases, the organism was considered to be a skin contaminant, leaving only two positive blood cultures due to enteric organisms passed into the bloodstream as a result of the procedure. These organisms were B. fragilis and Gemella morbillorum. Again, none of these patients was symptomatic as a result of this transient bacteremia. In summary, bacteremia associated with colonoscopy, whether diagnostic or associated with ancillary maneuvers such as biopsy, polypectomy, or fine-needle aspiration, occurs rarely, is transient, and is asymptomatic. Not all patients are at equal risk for infective endocarditis, whether related to activities of daily living or due to procedures or instrumentation. Valvular lesions have been classified in the past as high, moderate, and low risk for the development of endocarditis (Table 7.1) [2]. The 1997 guideline from the AHA recommended antibiotic prophylaxis for highrisk valvular conditions in patients undergoing endoscopic

Table 7.1 Risk stratification of cardiac lesions for the development of infective endocarditis [2,27]. High risk Prosthetic valve History of endocarditis Systemic-pulmonary shunt Synthetic vascular graft (< 1 year old) Complex cyanotic congenital heart disease Moderate risk Most other congenital abnormalities Acquired valvular dysfunction (e.g., rheumatic heart disease) Hypertrophic cardiomyopathy Mitral valve prolapse with regurgitation or thickened leaflets Low risk Other cardiac conditions

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procedures associated with the highest bacteremia rates; colonoscopy is not in this category. In the case of colonoscopy, with or without ancillary maneuvers, antibiotic prophylaxis was deemed optional for patients with high-risk lesions, and was not recommended for patients with moderate- or lowrisk cardiac lesions undergoing colonoscopy. The most recent AHA guidelines do not recommend antibiotic prophylaxis for colonoscopy for any patient undergoing GI procedures [1]. The committee reasoned that infective endocarditis is much more likely to result from random bacteremia as associated with activities of daily living (brushing/flossing of teeth, bowel movements, etc.) than from bacteremia related to instrumentation of the GI tract. They further reasoned that antibiotic prophylaxis may indeed prevent only a small number of cases of infective endocarditis in patients who undergo procedures of any nature. Another reason for the recommendation change is that the risk of antibiotics may outweigh the benefits; counted among the risks is the societal risk of the development of more antibiotic-resistant bacteria due to overuse of antibiotics [18]. Also mentioned is the rare possibility of anaphylactic or other serious reactions to even a single dose of an antibiotic such as penicillin [19–23].

Vascular grafts Infection of vascular prostheses is most commonly attributed to direct contamination at the time of graft placement. However, vascular grafts can become subsequently infected as well. This risk appears to decrease over time. Moore et al. [24] reported on an animal model in which a newly placed vascular graft was found to be quite susceptible to infection by circulating bacteria. Malone et al. [25] expanded upon this design in a follow-up study in which dogs underwent placement of an infrarenal abdominal aortic graft, and were then challenged at variable time intervals with a single i.v. infusion of Staphylococcus aureus. Up to 1 month after the time of graft placement, the infusion of S. aureus resulted in infection of 100% of the vascular grafts. The proportion of vascular grafts becoming infected lessened as the grafts aged, with a 30% incidence of graft infection 1 year after placement. The authors determined that pseudointimal coverage of the graft was the key to resistance from infection, as it was complete in those vascular grafts resistant to infection. All grafts becoming infected were noted to have either incomplete or absent pseudointimal linings. The pseudointimal linings typically became complete at 1 year from graft placement. In a subsequent study using the same model, antibiotics appeared to significantly decrease the proportion of vascular grafts becoming infected when challenged with S. aureus [26]. The American Society for Gastrointestinal Endoscopy (ASGE) still considers this insufficient data to recommend routine prophylaxis for colonoscopy with or without ancillary maneuvers. The ASGE does state that the endoscopist may consider prophylaxis on a case-by-case basis [27].

Antibiotic Prophylaxis for Colonoscopy

Prosthetic joints and orthopedic prostheses This is a common source of disagreement among specialists. Most colonoscopists do not believe their patients are at risk for development of infection of prosthetic joints as a result of the procedure [28]. According to the ASGE, there have been no reports of prosthetic joint infection related to colonoscopy [27]. However, most orthopedic surgeons favor antibiotic prophylaxis before any procedure or interventions done on their patients, citing the often catastrophic consequences of a prosthetic joint infection [29–32]. However, it has been argued that these consequences cannot justify overuse of antibiotics in circumstances of very low risk [33,34]. The ASGE does not recommend routine prophylaxis for patients with prosthetic joints undergoing colonoscopy [27].

The patient with cirrhosis There have been reports of septicemia after colonoscopy in patients with ulcerative colitis and cirrhosis. In one case series of two patients, E. coli was recovered from the bloodstream in both, and from ascitic fluid in one [35]. In general, however, the overall risk of bacteremia and septicemia, even in the setting of cirrhosis associated with colonoscopy, is quite low. Llach et al. [36] reported on an experience with colonoscopy in 58 cirrhotic patients with or without ascites. They found only six positive blood cultures in six patients, with all organisms being normal skin flora; no enteric bacteria were recovered. Patients with cirrhosis hospitalized with GI bleeding are at increased risk for infection. Deschenes and Villeneuve [37] reported on 140 hospitalized cirrhotic patients without evidence of infection at the time of initial presentation. Twenty percent of these patients developed an infection during the hospitalization. Of those with infection, no specific source was identified in 39% and 32% had spontaneous bacterial peritonitis. Admission for GI bleeding was a risk factor for infection. Prophylactic antibiotics for cirrhotic patients admitted with GI bleeding has been shown to decrease infection risk [38–42]. In most of these patients, bleeding was from an upper GI source, most frequently related to varices. Therefore, while the ASGE recommends antibiotic prophylaxis for patients with cirrhosis experiencing GI bleeding, this recommendation is based primarily on patients admitted with upper GI bleeding due to varices or other upper GI sources.

The immunocompromised patient Colonoscopy is sometimes performed on immunocompromised patients. There are few reports of infection in this patient population. Kaw et al. [43] described 67 procedures performed in 53 endoscopic sessions in bone marrow transplant recipients.

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Table 7.2 Recommendations for routine antibiotic prophylaxis for colonoscopy (from AHA [1] and ASGE [27]). Condition

Recommendations

Any cardiac valve condition

Not recommended (AHA) Optional for “high risk” (ASGE) Not recommended (AHA) Optional (ASGE) Not recommended (ASGE) Recommended (ASGE) Not recommended (ASGE)

Vascular prosthesis within first year of placement Prosthetic joints and orthopedic prosthesis Patient with cirrhosis and GI bleeding The immunocompromised patient

Sixteen of these underwent either sigmoidoscopy or colonoscopy. The authors report no episodes of clinically relevant bacteremia attributable to endoscopic procedures. Lee and Munoz [44] reported the development of septicemia after polypectomy in a single splenectomized patient taking corticosteroids. Listeria septicemia after colonoscopy in a patient with ulcerative colitis receiving immunosuppressive therapy with corticosteroid and azathioprine was reported in a single patient by Minami et al. [45]. Peterson et al. [46] described a case of E. coli peritonitis after left-sided colonoscopy in a patient receiving continuous ambulatory peritoneal dialysis. The ASGE, evaluating these and all other available data, concluded that routine antibiotic prophylaxis is not recommended for the immunocompromised patient undergoing colonoscopy. It does note, however, that these patients may vary in their susceptibility to infection, and therefore prophylaxis may be considered on a case-by-case basis. The choice of antibiotic should similarly be individualized [27].

Summary For colonoscopy, with or without ancillary procedures such as biopsy and polypectomy, the AHA and ASGE do not recommend routine prophylaxis for the majority of patients. There are specific circumstances in which antibiotics should be considered, or given for reasons not related to colonoscopy. A summary of recommendations from these societies is provided in Table 7.2.

References 1 Wilson W, Taubert K, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association. Circulation 2007; 116: 1736–54. 2 Dajani A, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997; 277: 1794– 801.

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3 Dajani A, Bisno A, Chung K, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1990; 264: 2919–22. 4 Shulman S, Amren D, Bisno A, et al. Prevention of bacterial endocarditis; a statement for health professionals by the Committee on Rheumatic Fever and Infective Endocarditis of the Council on Cardiovascular Disease in the Young. Circulation 1984; 70: 1123A–1127A. 5 Rheumatic Fever Committee and the Committee on Congenital Cardiac Defects, American Heart Association. Prevention of bacterial endocarditis. Circulation 1972; 46: S3–S6. 6 Wannamaker L, Denny F, Diehl A, et al. Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis, American Heart Association. Prevention of bacterial endocarditis. Circulation 1965; 31: 953–4. 7 Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis, American Heart Association. Prevention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Circulation 1960; 21: 151–5. 8 Rammelkamp C, Breese B, Griffeath H, et al. Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis, American Heart Association. Prevention of rheumatic fever and bacterial carditis through control of streptococcal infections. Circulation 1957; 15: 154– 8. 9 Jones T, Baumgartner L, Bellows M, et al. Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis, American Heart Association. Prevention of rheumatic fever and bacterial endocarditis through control of streptococcal infections. Circulation 1955; 11: 317–20. 10 Rodriquez W, Levine J. Enterococcal endocarditis following flexible sigmoidoscopy. West J Med 1984; 140: 951–3. 11 Murray J. Enterococcal endocarditis after sigmoidoscopy. West J Med 1984; 141: 689–90. 12 Rigilano J, Mahapatra R, Barnhill J, Gutierrez J. Enterococcal endocarditis following sigmoidoscopy and mitral valve prolapse. Arch Intern Med 1984; 144: 850–1. 13 Watanakunakorn C. Streptococcus bovis endocarditis associated with villous adenoma following colonoscopy. Am Heart J 1988; 84: 311–12. 14 Norfleet R. Infectious endocarditis after fiberoptic sigmoidoscopy. J Clin Gastroenterol 1991; 13: 448–51. 15 Botoman V, Surawicz C. Bacteremia with gastrointestinal endoscopic procedures. Gastrointest Endosc 1986; 32: 342–6.

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16 Low D, Shoehut J, Kennedy J, et al. Prospective assessment of risk of bacteremia with colonoscopy and polypectomy. Dig Dis Sci 1987; 32: 1239– 43. 17 Levy M, Norton D, Clain J, et al. Prospective study of bacteremia and complications with EUS-FNA of rectal and perirectal lesions. Clin Gastroenterol Hepatol 2007; 5: 684–9. 18 Van der Meer J, Thompson J, Valkenburg H, Michel M. Epidemiology of bacterial endocarditis in the Netherlands: antecedent procedures and use of prophylaxis. Arch Intern Med 1992; 152: 1869–73. 19 Van der Meer J, Van W, Thompson J, Wandenbroucke J, Valkenburg H, Michel M. Efficacy of antibiotic prophylaxis for prevention of native-valve endocarditis. Lancet 1992; 152: 1869 –73. 20 Pallasch T. Antibiotic prophylaxis: problems in paradise. Dent Clin N Am 2003; 47: 665–79. 21 Idsoe O, Guthe T, Willcox R, de Week A. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull World Health Organ 1968; 38: 159– 88. 22 Ahlstedt S. Penicillin allergy: can the incidence be reduced? Allergy 1984; 39: 151– 64. 23 Agha Z, Lofgren R, VanRuiswyk J. Is antibiotic prophylaxis for bacterial endocarditis cost-effective? Med Decis Making 2005; 25: 308–20. 24 Moore W, Rosson C, Hall A, Thomas A. Transient bacteremia, a cause of infection in prosthetic vascular grafts. Am J Surg 1969; 117: 342–3. 25 Malone J, Moore W, Campagna G, Bean B. Bacteremic infectability of vascular grafts: the influence of pseudointimal integrity and duration of graft function. Surgery 1975; 78: 211–16. 26 Moore W, Rosson C, Hall A. Effect of prophylactic antibiotics in preventing bacteremic infection of vascular prosthesis. Surgery 1971; 69: 825– 8. 27 Standards of Practice Committee of ASGE. Guidelines for antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 2003; 58: 475– 83. 28 Meyer G. Antibiotic prophylaxis for orthopedic prostheses and GI procedures: report of a survey. Am J Gast 1997; 92: 989–92. 29 Grant A, Hoddinott C. Joint replacement, dental surgery, and antibiotic prophylaxis. BMJ 1992; 304: 959. 30 Howell R, Green J. Prophylactic antibiotic coverage in dentistry: a survey of need for prosthetic joints. Gen Dent 1985; 33: 320–3. 31 Jaspers M, Little J. Prophylactic antibiotic coverage in patients with total hip arthroplasty. J Am Dent Assoc 1985; 111: 943– 8. 32 Shrout M, Scarbrough F, Powell B. Dental care and the prosthetic joint patient: a survey of orthopedic surgeons and general dentists. J Am Dent Assoc 1994; 125: 429 –34.

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33 McGowan D, Hendrey M. Is antibiotic prophylaxis required for dental patients with joint replacements? Br Dent J 1985; 158: 336– 8. 34 Eskinazi D, Rathbun W. Is systematic antimicrobial prophylaxis justified in dental patients with prosthetic joints? Oral Surg Oral Med Oral Pathol 1988; 66: 430–1. 35 Thornton J, Losowsky M. Septicaemia after colonoscopy in patients with cirrhosis. Gut 1991; 32: 450 –1. 36 Llach J, Elizalde J, Bordas J, et al. Prospective assessment of the risk of bacteremia in cirrhotic patients undergoing lower intestinal endoscopy. Gastrointest Endosc 1999; 49: 214 –17. 37 Deschenes M, Villeneuve JP. Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gast 1999; 94: 2193–7. 38 Blaise M, Pateron D, Trinchet J, Levacher S, Beaugrand M, Pourriat J. Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1994; 20: 34–8. 39 Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Levy V. Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection. Hepatology 1996; 24: 802–6. 40 Rimola A, Bory F, Teres J, Perez-Ayuso R, Arroyo V, Rodes J. Oral nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage. Hepatology 1985; 5: 463–7. 41 Benard B, Grange J, Nguyen Khac E, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 1999; 29: 1655–61. 42 Soriano G, Guarner C, Tomas A, et al. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 1982; 103: 1267–72. 43 Kaw M, Przepiorka D, Sekas G. Infectious complications of endoscopic procedures in bone marrow transplant recipients. Dig Dis Sci 1993; 38: 71– 4. 44 Lee M, Munoz J. Septicemia occurring after colonoscopic polypectomy in a splenectomized patient taking corticosteroids. Am J Gast 1994; 89: 2245– 6. 45 Minami M, Hasegawa T, Ando T, et al. Post-colonoscopic Listeria septicemia in ulcerative colitis during immunosuppressive therapy. Intern Med 2007; 46: 2023–7. 46 Peterson J, Weesner R, Giannella R. Escherichia coli peritonitis after left-sided colonoscopy in a patient on continuous ambulatory peritoneal dialysis. Am J Gast 1987; 82: 171–2.

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Management of Anticoagulation and Antiplatelet Agents Glenn M. Eisen & Katherine M. Hoda Oregon Health & Science University, Portland, OR, USA

Introduction Performing colonoscopy can be complicated by patient use of anticoagulants and/or antiplatelet agents. These medications are widely used by the general population. The endoscopist is frequently faced with balancing the added bleeding risks associated with these agents with the potential thromboembolic complications that may ensue when these treatments are discontinued. If anticoagulants or antiplatelet agents are stopped, decisions are required as to when to safely restart them.

Scope of the problem In the US, more than one million patients chronically use anticoagulants on an annual basis for the prevention of thromboembolic complications [1]. The indications for anticoagulant use include a variety of conditions, such as mechanical heart valves, deep venous thrombosis (DVT), and cardiac arrhythmias [2]. Patients who are on warfarin therapy are at increased risk for gastrointestinal (GI) hemorrhage when the international normalized ratio (INR) is elevated [3]. The majority of patients who bleed on warfarin have underlying GI lesions [4]. Patients who are treated with conventional doses of either heparin or warfarin have a 2–4% annual of risk of bleeding requiring transfusion. Major bleeding complications in patients prescribed low-molecular-weight heparin (LMWH) range from 0% to 5%; specific GI bleeding rates have not been reported [5–10]. The most common bleeding sites are GI tract, genitourinary tract, and vagina. Fatal hemorrhage risk is approximately 0.2% yearly [11].

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Risk of discontinuing anticoagulants and antiplatelet agents Many patients are continued on anticoagulation long after the suggested therapeutic period has passed. In these situations, there is little risk in stopping these drugs. The majority of endoscopists stop warfarin use prior to performing colonoscopy. This may put the patient at increased risk for thromboembolic complications. There is little published information on this absolute short-term risk. A retrospective series by Kuwada et al. [12] found that, of 27 patients who were anticoagulated and had warfarin withheld for a median of 4 days because of acute GI hemorrhage, one patient developed thrombosis 24 days after the bleeding episode. In a second series of 32 patients who had completed a course of therapy for DVT, 17 abruptly stopped warfarin therapy and two developed recurrence of thrombosis [13]. A retrospective review of 4278 patients undergoing endoscopy, by Blacker et al. [14], found that the 30-day risk for stroke in atrial fibrillation (AF) patients with adjusted anticoagulation was 1.06%, a rate higher than for patients who had no interruption. The absolute risk of stopping anticoagulation for the short term in patients undergoing colonoscopy remains unknown. The uncertainty in managing these patients is reflected in the following survey published in 1996. Kadakia et al. [15] surveyed American Society for Gastrointestinal Endoscopy (ASGE) members about endoscopy in patients taking anticoagulants and/or antiplatelet agents. Over 3000 ASGE members were invited to participate, including all gastroenterology fellowship program directors; 1269 responses (38%) were analyzed. There was wide variation in practice regarding the discontinuation of anticoagulants as well as antiplatelet agents. Depending on the indication for anticoagulation, 71–82% of physicians stopped anticoagulation before colonoscopy, and 26–51% used a “heparin window” (see later). All physicians restarted warfarin immediately after diagnostic endoscopy, whereas 80% restarted it 7 days or less after therapeutic endoscopy. These findings demonstrate the wide variation in managing anticoagulants/antiplatelet agents in the

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pericolonoscopic period. An attractive alternative for high-risk patients who are anticoagulated and are to have screening colonoscopy or surveillance examinations, in the absence of symptoms suggesting the presence of colorectal neoplasia, is to perform the procedure while on warfarin. If only a small adenoma is found, the patient may be rescheduled at an appropriate interval. If a cancer is discovered, it can be biopsied, whereas another examination may need to be scheduled at a short interval if a significant polyp is discovered. This process should be explained to the patient in detail before embarking on the endoscopy sequence.

American Society for Gastrointestinal Endoscopy guideline Until 1997, no guidelines were published by any of the gastroenterology societies regarding the use of anticoagulants or antiplatelet agents. The first and still the only guideline regarding the periendoscopic management of patients taking anticoagulants or aspirin/nonsteroidal anti-inflammatory drugs (NSAIDs) was published by the ASGE. This guideline was updated in 2002 [16]. Additionally, in 2005, a similar guideline on the management of LMWH and nonaspirin antiplatelet agents for endoscopic procedures was written [17]. The 2002 guideline categorizes endoscopic procedures into high and low risk and also classifies patient conditions in the same manner. The ASGE recommendations for the management of anticoagulation based on risk for thromboembolism are shown in Table 8.1. Diagnostic colonoscopy with or without biopsy is considered a low-risk procedure, whereas colonoscopies that include polypectomy are deemed high risk (for periprocedure bleeding). Colonic polypectomy has been associated with an increased risk of bleeding compared with diagnostic colonoscopy [18]. Postpolypectomy bleeds can occur up to 14 days after the

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procedure [19], and large polyp size (> 2 cm), presence of bleeding disorder, and “poor” cautery technique are risk factors [20]. The short-term bleeding risk for polypectomy in patients not taking anticoagulants appears to be 1.0–2.5% [18]. The likelihood of a thromboembolic complication depends on the condition that necessitates the use of anticoagulants. Patients with mechanical heart valve prostheses have a risk of a major thromboembolic event (in the absence of anticoagulation) of up to 12–91%, even with St. Jude valves [21,22]. Using antiplatelet therapy, this risk is lowered to 2.2 per 100 patient-years, and is further lowered with warfarin to 1 per 100 patient-years [3,23]. The short-term risk of complications in patients who have anticoagulation stopped for only a few days is not known. The absolute risk of thromboembolism also varies based on the location and type of valve. Mechanical valves in the mitral, or mitral and aortic positions have the highest risk [3]. Patients with AF and a mechanical valve are also at high risk. The target INR in this population (patients with mechanical heart valves) is 3–4 [24]. Anticoagulation for DVT is generally continued from 3 months to indefinitely, depending on the situation [25]. Stopping anticoagulation for short periods does not seem to significantly increase the risk of subsequent pulmonary embolus. There are no standardized anticoagulation parameters for patients with hypercoaguable states or endovascular grafts and these patients’ anticoagulation levels need to be individualized. The ASGE has divided conditions prompting anticoagulation into low- and high-risk groups based on their thromboembolic risk. Low-risk conditions include chronic or paroxysmal AF not associated with valvular disease, DVT, mechanical valves in the aortic position, and bioprosthetic valves. Highrisk conditions include mechanical valves in the mitral position, AF associated with valvular disease, and mechanical valves in patients who have had previous thromboembolic events.

Table 8.1 Management of anticoagulation and antiplatelet agents in patients undergoing colonoscopy. High risk of thromboembolism

Low risk of thromboembolism

High procedure risk

Discontinue warfarin 3–4 days before procedure

Discontinue warfarin 3–5 days before procedure. Consider heparin before procedure

Reinstitute

INR is below therapeutic level

Warfarin after procedure

Low procedure risk

No change in anticoagulation. Elective procedures should be delayed while INR is in supratherapeutic range

No change in anticoagulation. Elective procedures should be delayed while INR is in supratherapeutic range

INR, international normalized ratio.

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Short-term heparin substitution for warfarin (heparin window) The ASGE guideline recommends the following for high-risk procedures in high-risk patients: 1 Warfarin should be stopped 3–5 days prior to the planned procedure. 2 If heparin is used, it should be discontinued 4–6 h prior to the procedure and can usually be restarted 2–6 h after the procedure. 3 Warfarin can be restarted on the night of the procedure. 4 Heparin administration with warfarin administration should overlap for a period of 4–5 days or until the target INR has been reached for 2–3 days [15]. One published protocol [26] for the management of patients on chronic warfarin therapy who are undergoing subsequent noncardiac surgical procedures is as follows: 1 Warfarin is discontinued 5 days prior to surgery and begin i.v. heparin at 1000 units/h with adjustments to keep partial thromboplastin time (PTT) levels therapeutic. 2 Heparin is stopped early the morning of surgery and restarted at 200– 400 units/h at 4– 6 h after surgery. 3 Warfarin is restarted as soon as the patient can tolerate it. It is relevant to note that this suggested protocol is based on a single center’s retrospective experience. The absolute risk of an embolic event for patients with a low-risk condition who require the cessation of anticoagulant therapy for up to 1 week is estimated at 1–2 per 1000 patients [27]. It is recommended that elective procedures such as screening or surveillance colonoscopy should be delayed in patients on anticoagulation for DVT until this treatment is no longer indicated. In general, vitamin K should be avoided for elective procedures since, once used, it will significantly delay resumption of therapeutic anticoagulation. Gerson et al. [28] performed a retrospective analysis of 104 patients who were on prescribed doses of warfarin at the Veterans Affairs Palo Alto Health Care System during the period 1996–99. No patient developed bleeding or had a thromboembolic event. In all five of the patients who were deemed high risk by the ASGE guideline, heparin was substituted for warfarin prior to the performance of high-risk procedures. However, heparin replacement therapy was also used in 44 of the 166 procedures (27%) performed in the other patients during this time period: 16 high-risk procedures in low-risk patients and 28 low-risk procedures. Overall, substitution of heparin for warfarin was not indicated by the ASGE recommendations in 90% of the cases. Practice patterns were not significantly different when comparing pre-ASGE with post-ASGE guidelines (P > 0.05). There have been no further studies on practice management/variation in following the ASGE guidelines. Given that the ASGE now publishes the guideline on the web, in the journal Gastrointestinal Endo-

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scopy, and sends all members printed copies, it is possible that adherence has increased.

Low-molecular-weight heparin: is it acceptable to use yet? The use of LMWH may alter the recommended protocol and, in fact, in many settings LMWH is used frequently instead of the conventional heparin protocol described above. Randomized controlled trials have demonstrated superior efficacy of LMWH compared with warfarin for postoperative prophylaxis of DVT in patients undergoing knee and hip arthroplasty, and in the prevention of thromboembolic complications in cancer patients [29–32]. Additionally, LMWH also has demonstrated efficacy in treating acute DVT and acute pulmonary embolism, and in patients with acute coronary syndromes [33–37]. There have been no published prospective studies on the use of LMWH in patients undergoing endoscopy. It has been used as “bridging therapy” for patients on chronic anticoagulation undergoing invasive procedures [38–40]. The 2005 ASGE guidelines regarding the management of LMWH state that LMWH may replace the previous standard of a “heparin window” in high-risk patients. The use of LMWH may result in significant cost savings as it could potentially avoid the need for inpatient monitoring, i.v. heparin therapy, and PTT assessment. LMWH has a predictable anticoagulant effect, and patients with normal renal function do not need to be monitored [41]. A cost modeling study recently assessed the economic outcomes of periprocedure anticoagulation approaches for elective colonoscopy [42]. This decision analysis assessed five different scenarios: (1) outpatient LMWH, (2) inpatient heparin infusion, continuous warfarin with probability of repeat procedure using (3) LMWH or (4) heparin, and (5) discontinuation of anticoagulation. Assumptions included drug therapy options being equally effective for high-risk patients in preventing a thromboembolic event (0.1% risk) and a 0.4% risk for no anticoagulation. There was a 64.4% cost saving with LMWH compared with inpatient unfractionated heparin. The no anticoagulation option had the lowest costs per patient of all treatment scenarios despite being associated with the greatest risk of thromboembolic events and even taking into account the costs of treating those complications. This is because the risk of thromboembolic complications, even when anticoagulation is withdrawn, remains low. Sensitivity analysis revealed that the use of LMWH would become more costly than using heparin when the rate of thromboembolic complications exceeded 32.9% of patients receiving LMWH. This figure is obviously much greater than any reported rate of complications associated with this intervention. Most practitioners would not stop anticoagulation merely because it was the lowest cost option for a population of patients. Data from seven prospective

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Table 8.2 Management of LMWH in patients undergoing endoscopic procedures. Procedure risk

Recommendation

High Low

Consider discontinuation at least 8 h before procedure No change in therapy Reinstitution of LMWH should be individualized

Management of antiplatelet medication (clopidogrel or ticlopidine) in patients undergoing endoscopic procedures High Low

Consider discontinuation 7–10 days before procedure No change in therapy Patients on combination therapy may be at an additional risk of bleeding For acute GI hemorrhage the decision to transfuse platelets should be individualized Reinstitution of clopidogrel or ticlopidine should be individualized

Procedure risk High-risk procedures

Low-risk procedures

Polypectomy Biliary sphincterotomy Pneumatic or bougie dilation PEG placement EUS-guided FNA Laser ablation and coagulation Treatment of varices

Diagnostic EGD ± biopsy Flexible sigmoidoscopy ± biopsy Colonoscopy ± biopsy ERCP without endoscopic sphincterotomy Biliary/pancreatic stent without endoscopic sphincterotomy EUS without FNA Enteroscopy

EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangio pancreatography; EUS, endoscopic ultrasound; FNA, fine-needle aspiration; PEG, polyethylene glycol.

cohort studies and one retrospective study in over 1500 patients using LMWH as bridging therapy for a variety of procedures demonstrate a low risk of both thrombosis (< 1%) and bleeding (∼ 2%). Use of LMWH is currently standard procedure in most US anticoagulation clinics. Current guidelines outlined by the ASGE in 2005 are presented in Table 8.2. The decision regarding discontinuation of therapy before endoscopy must be weighed against the risk of a bleeding complication related to the use of LMWH. Current guidelines suggest that for low-risk procedures, such as diagnostic colonoscopy, no adjustments in anticoagulation should be made, irrespective of the underlying condition. For high-risk procedures, such as colonoscopy with polypectomy, LMWH should be discontinued at least 24 h prior to the procedure. The decision on when to restart therapy should be individualized [43].

The aspirin controversy Aspirin and most NSAIDs inhibit platelet cyclooxygenase, resulting in suppression of thromboxane A2-dependent platelet aggregation. It has been estimated that at least 25% of the adult population use aspirin and/or NSAIDs on a regular basis [44]. However, limited published data suggest that aspirin and other NSAIDs in standard doses do not increase the risk of significant bleeding after esophagogastroduodenoscopy with biopsy, colonoscopy with biopsy, polypectomy, or biliary sphincterotomy [45,46]. Despite this, some authors suggest discontinuing the use of aspirin/NSAIDs up to 14 days prior to a planned therapeutic colonoscopy [47]. The effect of aspirin on platelet aggregation may last as long as 1 week [48]. This is due to irreversible binding and

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inactivation of the platelet cyclooxygenase-1 by aspirin. The platelet lifespan is 7–10 days [49,50]. Nakajima et al. [51] used a novel method to assess colonic bleeding time. They developed a new endoscopic device to make a standard incision (7 mm long) on the colonic mucosa and measured the bleeding time of normal colonic mucosa in 47 cases. The colon bleeding time and skin bleeding time (Simplate method) were measured before and 1 h after aspirin ingestion (990 mg) in 10 healthy subjects. The bleeding time of normal colonic mucosa was 156 ± 71 s. Significant prolongation was noted in both skin bleeding time (357 ± 192 vs. 477 ± 183 s; P < 0.05) and colon bleeding time (155 ± 47 vs. 244 ± 169 s; P < 0.05) after aspirin ingestion (990 mg). This suggests an increased risk of abnormal bleeding in patients on aspirin who undergo colonoscopy, but this does not contraindicate the procedure according to the authors. Outcomes data on concurrent aspirin use and colonoscopy are needed, but for the most part are lacking. In the largest cohort study in the literature, Shiffman et al. [46] reported on a prospective cohort of patients undergoing upper endoscopy or colonoscopy. Of 694 patients, 46% had recently consumed NSAIDs (self-report within 1 week of the procedure). Postprocedure bleeding was assessed by both written questionnaire and telephone follow-up. Minor, selflimited, “clinically insignificant” bleeding occurred in 6.3% of patients taking NSAIDs and in 2.1% of control patients (P = 0.009). Major postprocedure bleeding occurred in only 0.58% of patients (two on NSAIDs/aspirin and two in the control group), all of whom underwent snare polypectomy. No major events were seen in patients undergoing cold biopsy or biopsy with cautery (hot). The authors acknowledge that their study was likely underpowered and the lack of bleeding complications between those on aspirin/NSAIDs and those not may be attributed to type II errors. They estimate that more than 1200 patients would have had to be evaluated to detect a twofold difference between groups. Given the incidence of minor bleeding, even with cold biopsy, the authors recommend that patients discontinue aspirin/ NSAIDs prior to colonoscopy. The ASGE guideline states: In the absence of a preexisting bleeding disorder, endoscopic procedures may be performed on patients taking aspirin and other NSAIDS in standard doses [16].

Nonaspirin antiplatelet agents Two classes of antiplatelet agents are now available: 1 antagonists of the platelet cell-surface adenosine diphosphate receptor (P2Y12 receptor); 2 antagonists of the glycoprotein IIb/IIIa receptor, which normally promotes platelet aggregation. P2Y12 receptor antagonists include ticlopidine, clopidogrel, and prasugrel. Both clopidogrel and prasugrel have fewer

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adverse effects than ticlopidine (neutropenia and thrombotic thrombocytopenic purpura). These agents are generally used in combination with aspirin to reduce the incidence of serious coronary events after stent placement, and are associated with an increased risk of bleeding complications, particularly in combination with aspirin [52,53]. Additionally, clopidogrel in combination with aspirin has indication for use in acute coronary syndromes, reducing thrombotic events in patients with recent myocardial infarction. The combination of aspirin and clopidogrel has no benefit over aspirin in patients with stable atherosclerosis and is harmful in stroke patients [54,55]. The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial reported lower GI bleeding rates with clopidogrel than with aspirin [2.0% (clopidogrel) vs. 2.7% (aspirin)]. The CURE (Clopidogrel in unstable angina to prevent recurrent events) trial reported a higher risk of GI bleeding with clopidogrel plus aspirin (1.3%) than with aspirin plus placebo (0.7%). There are no published reports on endoscopy in patients taking these agents. Antiplatelet agents directed against the glycoprotein IIb/IIIa receptor include eptifibatide, abciximab, and tirofiban. These drugs are designed to reduce the risk of acute-ischemic complications in high-risk patients after coronary angioplasty and in patients with non-ST segment elevation myocardial infarctions. In phase III trials, treated patients had an approximately twofold increased risk of major bleeding, but no increase in cerebral hemorrhage or lethal bleeding [56]. Again, there are no published data to guide the practicing endoscopist; fortunately, patients on these agents rarely undergo elective endoscopy. Data regarding GI bleeding in patients treated with these newer antiplatelet agents are inadequate. The 2005 ASGE recommendations (see Table 8.2) are based on drug pharmacology and known clinical effects. Any decision regarding discontinuation of therapy before endoscopy has to be weighed against the patient’s risk for an adverse coronary event related to cessation of medication (e.g., reocclusion of coronary stents). For elective high-risk procedures, temporary discontinuation of these medications, particularly if the patient is on concomitant aspirin, is desirable.

Summary The management of anticoagulant and antiplatelet therapy in the pericolonoscopy period remains a clinical dilemma. The ASGE has published guidelines on this management. The impact on practice patterns has not yet been demonstrated. For NSAIDs/aspirin, the guideline recommends that: in the absence of a preexisting bleeding disorder, endoscopic procedures may be performed on patients taking aspirin and other NSAIDs in standard doses [16].

However, most practitioners still prefer to temporarily discontinue these medications when feasible. Warfarin manage-

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ment depends on both the procedure risk and the patient’s underlying thromboembolic risk (see Table 8.1). The use of LMWH has increased due to its ease of use in clinical practice and secondary to its superior efficacy in certain clinical situations. LMWH and newer antiplatelet agents have not been included in endoscopic studies yet although GI bleeding rates have been described in large prospective cardiac studies. Current ASGE guidelines on the use of LMWH and antiplatelet agents are based on procedure risk (see Table 8.2). There are significant obstacles to developing an evidencebased algorithm for patient management: • lack of randomized controlled trials; • lack of patient-centered outcome data; • inadequate prospective cohort studies with regard to size and follow-up duration. Randomized controlled trials are unlikely to occur due to logistic and ethical issues. Large prospective cohort studies with appropriate follow-up (i.e., 30-day complication rates) are perhaps our best chance to further assess the benefits and risks of the various management options.

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12 Kuwada SK, Blam R, Gostout CJ. The role of withdrawing chronic anticoagulation because of acute upper GI bleeding. Am J Gastroenterol 1996; 91: 1116–19. 13 Palareti G, Legnani C, Guazzaloca G, et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants. A prospective study. Thromb Haemost 1994; 72: 222–6. 14 Blacker DJ, Wijdicks EFM, McClelland RL. Stroke risk in anticoagulated patients with atrial fibrillation undergoing endoscopy. Neurology 2003; 61: 964– 8. 15 Kadakia SC, Angueira CE, Ward JA, et al. Gastrointestinal endoscopy in patients taking antiplatelet agents and anticoagulants: survey of ASGE members. Gastrointest Endosc 1996; 44: 309–16. 16 Eisen G, Baron TH, Dominitz J, et al. Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 2002; 55: 775–9. 17 Zuckerman MJ, Hirota WK, Adler DG, et al. ASGE guideline: the management of low-molecular weight heparin and non-aspirin antiplatelet agents for endoscopic procedures. Gastrointest Endosc 2005; 61: 190– 4. 18 Waye J. Colonoscopy. CA Cancer J Clin 1992; 42: 350–65. 19 Macrae FA, Tan KG, Williams CB. Towards safer colonoscopy: a report on the complications of 5000 diagnostic or therapeutic colonoscopies. Gut 1983; 24: 376– 83. 20 Tedesco FJ. Colonoscopic polypectomy. In: Silvis SE (ed.). Therapeutic Gastrointestinal Endoscopy. New York: Igaku–Shoin Press, 1985: 269–88. 21 Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart diseaseanative and prosthetic: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(Suppl. 3): 457S–482S. 22 Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(Suppl. 3): 204S–233S. Erratum in: Chest 2005; 127: 415–16. Dosage error in text. 23 Stein RD, Alpert IS, Copeland J, Dalen JE, Goldman S, Turpie AG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1992; 102: 445S–455S. 24 Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJ, Vandenbroucke JP, Briet E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1994; 333: 11–17. 25 Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(Suppl. 3): 401S–428S. Erratum in: Chest 2005; 127: 416. 26 Madura JA, Rookstool M, Wease G. The management of patients on chronic coumadin therapy undergoing subsequent surgical procedures. Am Surg 1994; 60: 542–7. 27 Geerts WH, Jay RM. Oral anticoagulants in the prevention and treatment of venous thromboembolism. In: Poller L, Hirsch J (eds.). Oral Anticoagulants. New York: Oxford University Press, 1996: 97–122. 28 Gerson LB, Gage BF, Owens DK, et al. Effect and outcomes of the ASGE guidelines on the periendoscopic management of patients who take anticoagulants. Am J Gastroenterol 2000; 95: 1717–24. 29 Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthoplasty. A randomized,

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double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 1996; 124: 619– 26. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients. Arch Intern Med 2000; 160: 2199–207. Bergqvist D, Agnelli G, Cohen AT, et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346: 975– 80. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of lowmolecular-weight heparin and wafarin for the secondary prevention of venous thromboembolism in patients with cancer. A randomized controlled trial. Arch Intern Med 2002; 162: 1729–35. Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Low molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A metaanalysis of randomized, controlled trials. Ann Intern Med 1999; 130: 800–9. Merli G, Spiro TE, Olsson C, et al. Subcutaneous enoxaparin once or twice daily compared with i.v. unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001; 134: 191–202. Hull RD, Raskob GE, Brant RF, et al. Low molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. Arch Intern Med 2000; 160: 229–36. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/ non-Q-wave myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II B Trial. Circulation 1999; 100: 1593–601. Berkowitz SD, Stinnett S, Cohen M, Fromell GJ, Bigonzi F. Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non-ST-segment elevation acute myocardial infarction. Am J Cardiol 2001; 88: 1230– 4. Sandofer JM, Lynch S, Weitz H, Fertel S, Merli GJ. Use of Enoxaprin for the chronically anticoagulated patient before and after procedures. Am J Cardiol 1999; 84: 478– 80. Tinmouth A, Kovacs MJ, Cruickshank MK, Brien WF, Morrow B. Outpatient peri-operative treatment with dalteparin for chronically anticoagulated patients at high risk for thromboembolic complications. Thromb Haemost 1999; 23(Suppl. 1): 662–73. Johnson J, Turpie AGG. Temporary discontinuation of oral anticoagulants: role of low molecular weight heparin (dalteparin). Thromb Haemost 1999; 23(Suppl. 1): 623– 34.

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41 Hirsh J, Raschke R, Warkentin TE, et al. Heparin and lowmolecular-weight heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 1998; 114: 489S–510S. 42 Goldstein JL, Larson LR, Yamashita BD, et al. Low molecular weight heparin versus unfractionated heparin in the colonoscopy peri-procedure period: a cost modeling study. Am J Gastroenterol 2001; 96: 2360– 6. 44 Roth SH. Non-steroidal anti-inflammatory drugs, gastropathy, deaths and medical practice. Ann Intern Med 1988; 109: 353–4. 45 Freeman M, Nelson D, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996; 335: 909 –18. 46 Shiffman ML, Farrel MT, Yee YS. Risk of bleeding after endoscopic biopsy or polypectomy in patients taking aspirin or other NSAIDs. Gastrointest Endosc 1994; 40: 458– 62. 47 Williams CB, Waye JD. Colonoscopy and flexible sigmoidoscopy. In: Yamada T, Alpers DH, Owyang C, Powell DW, Silverstein FE (eds.). Textbook of Gastroenterology. Philadelphia: JB Lippincott, 1991: 2249–65. 48 Baldini M, Costea N, Dameshak W. The viability of stored human platelets. Blood 1960; 16: 1669–74. 49 Aster RH, Jandl JH. Platelet sequestration in man. J Clin Invest 1964; 43: 843–55. 50 Hanson SR, Slichter SJ. Platelet kinetics in patients with bone marrow hypoplasia: evidence for a fixed platelet requirement. Blood 1985; 66: 1105– 9. 51 Nakajima H, Takami H, Yamagata K, et al. Aspirin effects on colonic mucosal bleeding: implications for colonic biopsy and polypectomy. Dis Colon Rectum 1997; 40: 1484– 8. 52 Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998; 339: 1665–71. 53 Schror K. Antiplatelet drugs. A comparative review. Drugs 1995; 50: 7–28. 54 Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706–17. 55 Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–7. 56 The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330: 956–61.

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Sedation for Colonoscopy Lawrence B. Cohen & James Aisenberg The Mount Sinai School of Medicine, New York, NY, USA

Introduction Sedation improves the quality and success of colonoscopy, enhancing its technical performance as well as patient tolerance and satisfaction. These benefits, however, must be weighed against the added cost and complications associated with the use of sedation and analgesia. Consequently, the practice of sedation varies from country to country, and even within regions of an individual country. In the US, for example, sedation is used routinely during colonoscopy by more than 98% of endoscopists. The method used most often consists of a benzodiazepine combined with an opioid narcotic. Propofol has gained considerable popularity among endoscopists during the past decade, and is now used during one in four endoscopic examinations nationwide. This practice varies considerably from region to region, with rates of propofol use ranging from 43% in the mid-Atlantic states to 7% in the northeast [1]. The range of sedation practices is still greater within Europe. A recent international study of 21 centers in 10 European countries and in Canada reported that the use of sedation during endoscopy varied from 0% to 100% at different sites. The reasons for such diversity are complex and reflect social, cultural, regulatory, and economic considerations [2].

Understanding sedation and analgesia Sedation may be defined as a drug-induced depression of consciousness. While its effects occur along a continuum, it is useful clinically to define stages of sedation that are based upon the patient’s responsiveness to stimulation, airway adequacy, ventilation, and circulation (Figure 9.1) [3]. The American Society for Anesthesiology (ASA) has defined four stages of sedation:

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Fully awake Minimal sedation Moderate sedation

Deep sedation General anesthesia

Figure 9.1 The continuum of sedation.

1 Minimal sedation, or anxiolysis, is a drug-induced relief of apprehension with minimal effect on consciousness. The patient is awake and alert. 2 Moderate sedation, previously termed conscious sedation, is a depression of consciousness in which the patient can respond purposely to verbal or light tactile stimuli. Airway reflexes, spontaneous ventilation, and cardiovascular function are maintained. 3 Deep sedation is a depression of consciousness in which the patient cannot be aroused but responds purposely to repeated or painful stimuli. The patient may not be able to maintain airway reflexes or spontaneous ventilation, but cardiovascular function is usually maintained. 4 General anesthesia is a state of unconsciousness. The patient does not respond to painful stimuli. Airway intervention is often required and cardiovascular function may be impaired. Knowledge of these stages and the ability to recognize them is essential for anyone involved in the administration of sedation, since it provides a conceptual framework for understanding the impact of sedation on physiologic functions. During colonoscopy, most endoscopists target moderate sedation. However, the lines of distinction between moderate and deep sedation are sometimes blurred, due to changes in the level of patient stimulation that occur throughout the examination. In a recent study of patients undergoing routine colonoscopy with conventional sedation, 45% were deeply sedated at least once during their examination [4]. The

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clinical significance of this observation with respect to the safety of procedural sedation has yet to be fully characterized. Patient variability in response to the administration of drugs used for sedation and analgesia may result in either under- or oversedation. Consequently, patients targeted for moderate sedation may reach deep sedation, or even general anesthesia, if only transiently. For this reason, the ability to rapidly recognize and institute “rescue” maneuvers is essential for an individual(s) providing sedation. Because respiratory events are the major concern during procedural sedation, endoscopists should possess the skills necessary to provide airway support, including the establishment of an airway and positive-pressure ventilation. Training requirements for procedural sedation are designed to ensure that individuals possess the necessary skills to oversee the safe and effective administration of sedation drugs. The minimum qualifications for this should include current certification in advanced cardiac life support (or its equivalent), an understanding of the pharmacologic principles of the drugs used for sedation and analgesia, an ability to assess and monitor patients throughout the entire process, and the capacity for managing sedation-related complications. Respiratory failure, the result of either central hypoventilation or obstruction of the upper airway, is the most important complication of sedation, and appropriate training in airway management is critical. While universal guidelines for sedation training are not established, it is recommended that training should include both didactic and practical experience under the mentorship of an expert [5,6].

Pharmacology of drugs for sedation and analgesia Today, most colonoscopies in the US are performed for colorectal cancer screening or surveillance. These examinations, requiring 20–30 min to complete, usually take place outside an operating room setting. Sedation and analgesia are provided to improve patient comfort, and to maximize the opportunity for a thorough and safe examination. Therefore, the ideal sedation agent should possess sedative, analgesic, and amnestic properties, and a pharmacologic profile that permits rapid onset and fast recovery. It should also be capable of reliable titration within the target range of sedation, exert minimal depressant effect on the cardiopulmonary systems, and an antagonist drug should be available. Unfortunately no drug, or combination of drugs, meets all of these criteria. This section will review the drugs that are currently available and in use for endoscopic sedation.

Opioids The opioid narcotics, possessing potent analgesic but marginal sedative properties, are often combined with a benzodiazepine for endoscopic sedation. Their pharmacologic effects are exerted

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through opioid receptors distributed throughout the central nervous system and peripheral tissue. The unique pharmacokinetic and pharmacodynamic properties of individual opioids can be explained based upon the differences in their chemical structure.

Meperidine Meperidine (or pethidine in the UK), the most widely used opioid analgesic for many years, has been largely replaced by fentanyl, a synthetic opioid with several pharmacologic properties that make it preferable to meperidine for procedural sedation. 1 Meperidine has a longer biologic half-life than fentanyl. 2 Meperidine is metabolized to normeperidine, an active metabolite that accumulates in patients with renal insufficiency, producing cerebral stimulation and, sometimes, seizures. 3 Meperidine may produce tachycardia due to mild vagolytic activity. 4 Meperidine produces orthostatic hypotension at therapeutic doses and myocardial depressant effects at high doses. 5 Meperidine-mediated histamine release results in flushing and, in some instances, hypotension. 6 Meperidine is contraindicated in patients receiving monoamine oxidase inhibitors due to the potential for severe reactions or even death. Dosage: 25–100 mg i.v. with additional boluses of 25 mg titrated to effect.

Fentanyl A pure opioid agonist with high affinity for the μ-receptor, fentanyl is 75–125 times more potent as an analgesic than morphine. Its high lipid solubility accounts for its rapid onset (1–2 min) and short duration of effect (30–60 min). Like other opioids, fentanyl depresses respiratory drive and stimulates vomiting and nausea. Fentanyl may induce chest wall rigidity, making it difficult to ventilate the patient. Unlike meperidine, however, fentanyl metabolites are inactive, so its use is safe in patients with renal insufficiency. Moreover, fentanyl does not produce vasodilation, facial flushing, or depressed myocardial contractility, or cause adverse interactions in patients on monoamine oxidase inhibitors. These features, combined with its pharmacokinetic properties, make fentanyl the preferred opioid during endoscopic procedures. Dosage: 25–100 μg i.v. followed by 25–50 μg as needed.

Benzodiazepines Benzodiazepines produce their effects by binding to specific benzodiazepine receptors in the brain and spinal cord, enhancing the interaction between γ-aminobutyric acid (GABA) and its receptors. The inhibitory effect that results produces anxiolysis, sedation, anterograde amnesia, and, at higher doses, hypnosis and respiratory depression. The effects of benzodiazepines are dose dependent, but are strongly influenced by intravascular status, comorbidities, age, and

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concurrent medications. The synergistic interaction between opioids and benzodiazepines increases the potential for respiratory depression when these two drug classes are used in combination [7].

Diazepam Diazepam, when used alone, has little effect on respiration and circulation. In combination with other agents, such as opioids, its sedative and circulatory depressant effects are potentiated. Thrombophlebitis is common with i.v. administration of diazepam. Diazepam should be avoided in patients with acute narrow-angle or open-angle glaucoma. Dosage reduction is required in the elderly, in individuals with limited pulmonary reserve, and in those receiving opioids or other sedatives. Dosage: 2–10 mg i.v. dose with additional boluses of 2–5 mg titrated to effect.

Midazolam The unique chemical structure of midazolam confers on it both water- and lipid-soluble properties. A water soluble compound at acidic pH, it undergoes physicochemical alteration to become lipid soluble at physiologic pH. Consequently, midazolam is painless upon i.v. administration, yet retains its properties of rapid onset and short duration of effect. Midazolam is 1.5–3.5 times more potent than diazepam. The clearance of midazolam is reduced in the elderly and in patients with hepatic or renal dysfunction. Dosage: 0.5–2.0 mg i.v. bolus followed by 0.5- to 2.0-mg doses titrated to effect.

Antagonists Pharmacologic antagonists, also known as “reversal agents,” block the effects of opioids or benzodiazepines by competitively binding to the receptor sites that mediate chemical activity. Their effects are dose dependent, and they may be titrated to effect in order to avoid significant cardiovascular side-effects (hypertension, excitement, pulmonary edema, cardiac arrhythmia). Caution should be exercised when administering these drugs to patients known to have, or suspected of having, physical dependence on opioids or benzodiazepines. Patients responding to naloxone or flumazenil should be carefully monitored for resedation, since their duration of effect is shorter than that of the agonists.

Naloxone Naloxone is a pure opioid antagonist with no agonist activity. It competitively blocks the opioid receptors, reversing the opioid effects including analgesia, respiratory depression, and hypotension. It possesses no pharmacologic activity in the absence of narcotics. Because the duration of action of naloxone is shorter than that of some opioids, patients who have responded to naloxone should be carefully monitored for up to 2 h due to the risk of resedation. Dosage: 0.2–0.4 mg. Titrate to patient response. Dose may be repeated at 2- to 3-min intervals.

Sedation for Colonoscopy

Flumazenil Flumazenil is a competitive antagonist for benzodiazepines and will reverse sedation, amnesia, anxiolysis, and respiratory depression. The effect is dose dependent and is influenced by plasma benzodiazepine levels. The onset of flumazenil is about 2 min. The elimination half-life of flumazenil is 1 h, shorter than the half-life of the benzodiazepine agonists. Thus, the potential for resedation exists as the effect of flumazenil wears off. Caution should be exercised when administering flumazenil to patients with a history of seizure disorder or substance abuse, due to its potential to induce seizure or withdrawal symptoms. Dosage: 0.2 mg/min. Titrate to effect. Dose may be repeated at 20-min intervals.

Propofol Propofol, an ultra-short-acting hypnotic developed for the induction and maintenance of anesthesia, received Food and Drug Administration (FDA) approval in 1989. The product label, reflecting its approved indications, states “[propofol] should be administered only by persons trained in the administration of general anesthesia.” Since that time, however, propofol’s off-label clinical applications have expanded to include monitored anesthesia care, and, more recently, procedural sedation performed by nonanesthesiologists targeting moderate/deep sedation. A recent effort to change the product label, so that it would better reflect the current standard of practice, was unsuccessful. Consequently, the outdated “propofol warning” remains a major obstacle to more widespread adoption of propofol by endoscopists, due to medicolegal and regulatory concerns [8]. Propofol’s unique pharmacokinetic profile, including rapid onset (30–45 s) and short duration of effect (4–8 min), offers the clinical advantage of “rapid on, rapid off,” which is highly desirable for brief endoscopic procedures. Studies on the mechanism of propofol’s effects indicate that, like other central nervous system depressants such as the benzodiazepines, propofol activates the GABA receptors. Unlike the benzodiazepines, however, propofol has intrinsic activity at the receptor, making its maximal effect greater. The dosage of propofol must be carefully titrated to clinical effect. Factors that influence dosage requirements of propofol include age, weight, preexisting medical conditions, and concomitant pharmacologic therapy. Propofol’s major disadvantage is its lack of an antagonist. That, combined with its lack of a “ceiling effect,” explains why the use of propofol requires appropriate training and experience. Dosage: 10–50 mg i.v. followed by 5- to 20-mg boluses titrated to effect [9,10].

Adjunctive agents Diphenhydramine Diphenhydramine is a histamine H1-receptor antagonist with anticholinergic, antiemetic, and sedative effects. It has been used as an adjunct for endoscopic sedation. Caution is required when given to patients with narrow-angle glaucoma,

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Promethazine possesses sedative, anxiolytic, anticholinergic, antihistaminic, and antiemetic activities. A phenothiazine derivative, it blocks the postsynaptic dopaminergic receptors in the brain and has strong α-adrenergic inhibitory effects. Promethazine is also a histamine H1-receptor antagonist. Promethazine has been used as an adjunct for procedural sedation. Dosage: 12.5–25.0 mg by slow i.v. infusion.

added later if the patient is unable to tolerate an unsedated examination. The success of unsedated colonoscopy can be optimized by preparing the patient in advance of the examination and explaining the potential for temporary discomfort due to stretching or distension of the bowel. Predictors of successful unsedated colonoscopy include male gender, college education, and low-preprocedural anxiety [12]. The practice of colonoscopy without sedation eliminates the complications and additional costs attributable to the use of sedation (see “Sedation and the economics of colonoscopy”), and enables patients to drive themselves home from the procedure and return to work or their usual activities.

Tramadol

Benzodiazepine/opioid sedation

Tramadol is a synthetic opioid that resembles codeine. Compared with other opioids that are used for procedural sedation, tramadol produces less respiratory depression and constipation. Nausea and vomiting are side-effects common to opioids, including tramadol. Dosage: 100 mg i.v.

The benefits of combining an opioid and a benzodiazepine for endoscopic sedation have been well recognized for almost 40 years. Today, approximately three-quarters of all endoscopists in the US perform colonoscopy routinely under sedation, using midazolam plus a narcotic. In combination, these drugs can be readily titrated to moderate sedation, although some patients are more deeply sedated. When administering a combination of midazolam and an opioid (e.g., fentanyl), it is advisable to begin with small doses of each agent, and then to titrate to the desired effect. A standard regimen would consist of 50–75 μg of fentanyl plus 1–2 mg of midazolam. Additional boluses of midazolam (1 mg) may be given every 2–3 min until the desired level of sedation is achieved. A “stacking effect,” leading to oversedation of the patient, may occur if additional boluses of drug are given before the peak effect of the previous dose has been achieved. The average time required for drug titration with opioid–benzodiazepine combinations is 6–12 min, and, generally, it is not necessary to administer additional doses of drug once the examination has begun. Following the completion of colonoscopy, on-site recovery averages 47 min. Full recovery from the effects of sedation requires additional time, however, and 16 h or more may be necessary before the patient is able to resume normal activities [23]. The majority of patients sedated with midazolam and an opioid are satisfied with their experience, in large measure due to the anterograde amnesia produced by midazolam. However, some patients do experience discomfort during their procedure. Patients with high levels of preprocedural anxiety, those with a history of alcohol or substance abuse, and those with a history of being difficult to sedate are more likely to have an unpleasant experience during colonoscopy performed under midazolam and a narcotic. In such cases, referral to an anesthesia specialist should be considered. A recent summary of pooled results from 11 colonoscopy studies using midazolam and a narcotic determined that 88% and 89% of physicians and patients, respectively, were very satisfied with the results of sedation using a midazolam–narcotic combination [24]. Although midazolam–opioid combinations have been shown to be safe, adverse cardiopulmonary events have been reported.

increased intraocular pressure, or bladder neck obstruction. Hypotension, palpitations, and wheezing are potential adverse effects. Dosage: 25– 50 mg i.v.

Promethazine

Current approaches to sedation for colonoscopy Unsedated colonoscopy In the US, endoscopic sedation is generally considered to be standard of care during colonoscopy. Nonetheless, select reports on the success of unsedated colonoscopy have come from both the US as well as other countries. For example, a prospective study in the US found that 84% of 258 patients completing unsedated colonoscopy were willing to repeat the procedure without sedation [11]. However, the vast majority of patients in the US prefer to be sedated during colonoscopy, and only 5–20% of patients express a willingness to undergo the procedure without sedation [1,12,13]. In several studies, unsedated colonoscopy has been associated with a lower procedure completion rate. Unsedated colonoscopy has been somewhat more successful in studies performed outside the US [14,15]. Nonetheless, the results of several large survey studies indicate that sedation is being used increasingly for the majority of colon examinations in most parts of the world [2,16]. Numerous strategies are under investigation to minimize the discomfort related to colonoscopy, thereby encouraging unsedated (and/or minimally sedated) colonoscopy. These strategies include the development of new colonoscopes (e.g., computer-assisted, narrower, more flexible, overtubeassisted, or variable-stiffness) designed to reduce looping within the colon and stretching of the mesentery; three-dimensional magnetic imaging; improved methods of colonoscope lubrication; intraluminal infusion of water and insufflation of the colon with carbon dioxide rather than room air [17–22]. Currently, it is reasonable to offer unsedated colonoscopy to carefully selected patients, provided that sedation can be

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Respiratory depression is the greatest risk, requiring extra caution in the elderly, patients with preexisting neurologic disease, and those with high-risk airways.

Propofol-mediated sedation Numerous studies confirm that the use of propofol is associated with improved patient and physician satisfaction, and more rapid induction and recovery, compared with traditional sedation agents. With propofol, the induction of sedation averages 2–3 min, and recovery is 15–20 min [25]. Psychometric tests performed following recovery confirm that functional ability with propofol is better than with a benzodiazepine/opioid combination [26]. Moreover, studies using driving simulation suggest that driving skills and reaction time return to near baseline levels within 1–2 h following colonoscopy performed under sedation with propofol [27]. Notwithstanding these observations, it is currently recommended that all patients undergoing colonoscopy with sedation, irrespective of the drug(s) used, be discharged in the presence of a responsible companion and refrain from driving for the remainder of that day. Two models have emerged for gastroenterologist-directed propofol administration: single-agent propofol and balanced propofol sedation. The models share several important principles, including an emphasis on training and experience, patient selection and monitoring, and close communication between physician and nurse. However, important differences do exist between these two models.

Single-agent propofol Most of the published experience with gastroenterologistadministered or supervised propofol has been with propofol as a single agent (monotherapy). When the propofol is titrated by a specially trained nurse whose sole responsibilities are patient monitoring and drug administration, the practice has been referred to as nurse-administered propofol sedation (NAPS) [28–30]. Guidelines for dosing of propofol as a single agent vary, with the initial bolus dose of propofol ranging from 20 to 60 mg, and additional boluses of 10–30 mg titrated to effect. A minimum interval of 20–30 s between doses is required to avoid a “stacking effect.” In most instances, patients receiving single-agent propofol are deeply sedated, although success has been reported by groups outside the US targeting moderate sedation [31]. The number of endoscopic assistants required during administration of single-agent propofol remains unresolved, with most practitioners in the US utilizing two individuals. Patient monitoring during single-agent propofol has included visual assessment of the patient along with measurement of standard physiologic parameters including pulse, blood pressure, and oxygen saturation. Quantitative assessment of ventilation using capnography has not been performed routinely. The largest case series of single-agent propofol reported 36 743 cases of NAPS performed at three institutions [32].

Sedation for Colonoscopy

The mean dose of propofol during colonoscopy ranged from 144 to 287 mg. There were no cases requiring intubation, although bag–mask ventilation was performed in 1 in 500– 1000 cases. In another large series from Japan, 27 500 cases were performed during a 6-year period. Although propofol was used as monotherapy, the total dose during colonoscopy averaged only 94 mg. No serious cardiopulmonary complications were recorded in this series [31]. It is unlikely that such low doses of propofol could be used successfully in the US for colonoscopic sedation without the addition of an opioid and/or benzodiazepine. In excess of 400 000 cases of singleagent propofol (primarily as NAPS) have been published to date, and the safety profile for this method of propofol administration remains excellent.

Balanced propofol sedation In contrast to single-agent propofol, balanced propofol sedation (also referred to as combination propofol, or multidrug propofol) combines propofol with small doses of an opioid and/or a benzodiazepine [33]. This practice is designed to maximize each drug’s therapeutic action while minimizing its adverse effects. The synergism between propofol and opioids is profound for both analgesia and sedation endpoints as demonstrated by response surface methodology [34]. As a consequence of this synergy, balanced propofol sedation can be effectively performed at subhypnotic doses of propofol. This conclusion is supported by a prospective, randomized study that compared sedation and recovery parameters during colonoscopy in four treatment groups: propofol, propofol plus fentanyl, propofol plus midazolam, and propofol, fentanyl, and midazolam [35]. The mean dose of propofol during colonoscopy performed under a balanced propofol protocol has ranged from 70 to 120 mg. In published protocols, patients receive a preinduction i.v. dose of fentanyl (25–75 μg) and midazolam (0.5–1 mg). “Induction boluses” of propofol, dosed at 5–15 mg depending upon the patient’s age, weight, and comorbid illnesses, are administered at 30–45 s intervals, beginning 30–45 s following the administration of midazolam and fentanyl. The initiation bolus size is reduced as the patient’s depth of sedation approaches the desired level. Following initiation of the procedure, “maintenance boluses” of propofol are administered as required. The maintenance dose equals 25% of the induction dose to a maximum of 15 mg. All decisions regarding the dosing of propofol are made jointly by the physician– nurse team, and moderate sedation is targeted at all times. The cumulative clinical experience with gastroenterologistadministered or supervised combination propofol sedation is more limited than with single-agent propofol. Nonetheless, its safety and effectiveness is supported by several case series, including a report of more than 28 000 procedures performed using a regimen consisting of fentanyl, midazolam, and propofol. There were no deaths or endotracheal intubations in this series [36].

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Gastroenterologist-directed administration of propofol, irrespective of the model adopted, can be performed safely and effectively. A recent meta-analysis of 12 randomized controlled endoscopy trials comparing the safety of standard sedation using a benzodiazepine plus an opioid with propofol (both administered under the direction of a gastroenterologist) concluded that propofol was at least as safe as conventional sedation [37]. A statement issued jointly by the three major gastroenterology societies as well as a position paper from the American Gastroenterological Association Institute support the practice of gastroenterologist-directed propofol administration [5,38]. Nonetheless, barriers to its widespread adoption do exist. First, the medicolegal implications of off-label propofol use remain uncertain. Second, the ASA continues to oppose propofol administration by nonanesthesiologists. And, third, at least 22 state boards of nursing in the US have declared that the administration of propofol is beyond the scope of practice for registered nurses. Until these issues can be satisfactorily resolved and an accredited program developed that provides training and certification of physicians and nursing personnel, it appears likely that propofol use will remain limited to a minority of endoscopists in the US. Modified formulations of propofol, designed to retain the favorable pharmacologic features of propofol while improving its therapeutic index, are being developed for nonanesthesiologists. The leading compound in this category is fospropofol disodium, a prodrug of propofol that is metabolized by alkaline phosphatases, releasing propofol, phosphate, and formaldehyde [39]. Clinical trials demonstrate that fospropofol can be titrated safely and reliably to moderate sedation.

Patient-controlled sedation A self-contained drug delivery system permits the patient to self-administer medication in response to pain. The system consists of a specialized infusion pump and a handheld device. The pump is programmed to deliver a preset dose of medication in response to the press of a button. A lockout time is selected, based upon knowledge of the pharmacokinetics of the drug(s) being administered, preventing the delivery of additional drug until the previous dose has had its full effect. Propofol, owing to its rapid-on, rapid-off properties, is the drug most often used for this system [40,41]. The safety and effectiveness of patient-controlled sedation has been evaluated in numerous clinical trials [42,43]. Overall, patients undergoing colonoscopy with patient-controlled sedation are satisfied with the level of pain control. The total dose of propofol administered is less than that used with bolus delivery, and recovery time is faster. Not all patients are suitable for patient-controlled sedation, however. Patients with high levels of preprocedural anxiety and young female patients may not be ideal candidates for patient-controlled sedation. A modified version of patient-controlled sedation, referred to as computer-assisted personalized sedation (CAPS), is

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currently under development. CAPS incorporates the unique features of target-controlled propofol infusion, patientcontrolled supplemental boluses of propofol, and an automated monitoring system that is programmed to reduce or interrupt drug infusion in response to clinical or physiologic indications of oversedation. If clinical studies confirm that CAPS represents an effective and safe method of propofol delivery, it is likely to become another option on the sedation menu [44].

Standards of practice for colonoscopic sedation Pre- and postcolonoscopy sedation-related care A precolonoscopy evaluation, designed specifically to assess the risk of sedation-related complications, is fundamental to procedure safety. This evaluation mirrors that required for other ambulatory procedures and ideally should be performed (and documented) just prior to the procedure [3]. A focused history, conducted in lay language, should elicit: • previous difficulties during anesthesia/sedation; • major medical problems; • airway abnormalities including excessive snoring, neck surgery, and sleep apnea (“Do you ever awaken at night gasping for breath?”); • significant alcohol or drug use; • medication and food allergies; • last food intake; • prescription drug history (which may impact sedation drug requirement); and • the possibility of pregnancy. The physical examination should evaluate: • the general robustness of the patient (e.g., Is the patient dehydrated? Is the patient lethargic?); • the physical habitus (e.g., Is the patient obese?); • the anxiety level (which may predict sedative requirement); • vital signs and weight; • the mouth, head, and neck, in order to identify patients (e.g., those with a short neck, small oral opening, thick neck, short hyoid–mental distance) with increased risk for upper airway collapse and/or difficult intubation. In general, electrocardiography and routine laboratory or other testing are not recommended, although they may be appropriate in high-risk cases. A policy for pregnancy testing should be codified in each unit. An ASA physical status classification should be assigned and documented for each patient. The effects of sedative drugs persist after the colonoscope is removed, and careful attention to the patient during recovery is therefore essential. Specifically, experts recommend patient monitoring by observation, plethysmography, and pulse oximetry, until preset recovery criteria are met. The use of the pharmacologic antagonists naloxone and flumazenil, though it may shorten recovery time, is not routine in the US

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[1,45]. Validated recovery scores reflect a return of physiologic and cognitive function to a level approaching baseline, and can be routinely used to confirm readiness for discharge [46]. Patients may experience prolonged amnesia and subtle cognitive impairment after sedation for colonoscopy, and therefore should leave the unit accompanied by a responsible companion, and with written instructions regarding sedation-related postprocedure precautions (e.g., avoiding driving) provided. Documentation of patient recovery must be maintained.

Equipment for sedation The equipment required for sedation during colonoscopy must reflect local (institutional and state) regulations as well as the clinical circumstances (e.g., more resources may be justified for sedation of an elderly, hemodynamically unstable, bleeding patient undergoing emergency colonoscopy than for a healthy 50-year-old undergoing routine screening). The colonoscopy room must permit free movement of staff, and comfortably house the required sedation equipment (e.g., monitors). During colonoscopy, sedation is delivered intravenously through a well-secured angiocatheter (not a metal “butterfly”) placed preferably in the right arm. A new catheter should be placed (and the examination interrupted, if necessary) if the i.v. access ceases to function properly at any time during the procedure. Intravenous access can be maintained either with a continuous fluid infusion or with intermittent flushing using a syringe secured to the patient’s arm. The size of the syringe utilized for drug delivery should be tailored to the concentration of the drug and volume being administered. For example, midazolam, which is generally dispensed at a concentration of 1 mg/mL and dosed in 1-mg increments, is best delivered with a 3-mL syringe. In general, it is preferable to use the smallest syringe appropriate for the drug being administered. This helps to ensure that the correct volume of drug is given, and minimizes the potential for accidentally administering more drug than intended. Most colonoscopists utilize supplemental oxygen, delivered by nasal cannula, during colonoscopy [1]. Several studies have demonstrated a reduction in hypoxemic events when supplemental oxygen is used during colonoscopy, though studies have not established a clinical outcome benefit [47,48]. A nasal cannula designed to deliver oxygen and simultaneously sample expired gases is commercially available, and is useful for real-time capnography. When supplemental oxygen is provided from a tank, a spare oxygen tank and regulator should be immediately available. Monitoring of blood pressure and pulse oximetry are generally recommended during colonoscopy [3,49]. In perioperative care in general, and colonoscopy in particular, pulse oximetry has been shown to detect hypoxemic events, but not to change outcomes [50]. Commercially available oximeters provide both visual and variable-pitch signals, and electronically store data. The routine use of electrocardio-

Sedation for Colonoscopy

graphy during colonoscopy is generally not recommended, but may be useful for a high-risk or unstable patient. Monitoring equipment for all endoscopic procedures including colonoscopy has been the subject of a recent review [51]. “Sidestream” capnography, which provides a real-time waveform reflecting the patient’s respiration, is relatively inexpensive and easy to use, and, in general, is a more sensitive indicator of hypoventilation than either pulse oximetry or visual inspection [52,53]. In endoscopy, capnography has been studied almost exclusively during upper GI procedures, in which it has shown sensitivity for early detection of respiratory events. Although sidestream capnography has not yet gained widespread adoption during colonoscopy, it is the opinion of the authors and others that it is a valuable safety tool during colonoscopy and will be increasingly utilized in the future. Capnography may be of special benefit for sedation of unstable patients, or when gastroenterologist-directed propofol is utilized. Patient awareness monitoring, using processed electroencephalographic activity, has been studied during colonoscopy, but its value as a reliable measure of depth of sedation has not yet been demonstrated [54]. Resuscitation equipment (Table 9.1) must be immediately available to the colonoscopy team. These supplies must be

Table 9.1 Emergency resuscitative equipment (adapted from ref. 5). Assorted syringes, tourniquets, adhesive tape Intravenous access equipment including fluid Basic airway management equipment Oxygen supply Suction machine and catheter Nasal cannulae and face-masks Bag–mask ventilation device Oral and nasal airways (all sizes) Advanced airway management equipment Laryngoscope handles and bladea Endotracheal tubes and styletsa Laryngeal mask airwaya Cardiac equipment Pulse oximeter Cardiac defibrillator Emergency medications Atropine Diphenhydramine Epinephrine Ephedrine Flumazenil Glucose, 50% Hydrocortisone Lidocaine Naloxone Sodium bicarbonate a

All appropriate sizes should be available.

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tailored to the patient mix of the individual unit (e.g., pediatric endotracheal tubes must be available in a pediatric colonoscopy unit). The colonoscopy suite must have a communication system which can be used to summon personnel in a sedation-related emergency and must be readily accessible. All sedation-related equipment must be in stock, not expired, and functioning properly; typically, this is accomplished by regular inspection and inventory of equipment by designated nursing personnel.

Staffing and colonoscopic sedation Currently in the US, an anesthesiologist participates in approximately 25% of colonoscopies performed by gastroenterologists. This reflects a growing appreciation, by endoscopists and patients, of the benefits of propofol, as well as the added value of a dedicated sedationist. The leading US gastroenterology societies have opined, however, that the use of an anesthesiologist to deliver sedation for routine procedures is not clinically necessary and is cost-prohibitive [5,55]. It is almost universally recognized that an anesthesia specialist should participate in the sedation of high-risk patients or when an advanced diagnostic or therapeutic procedure is being performed [49]. During routine endoscopic procedures performed under moderate sedation, irrespective of the method of sedation chosen, staffing levels must adhere to local institutional and state guidelines, and must be tailored to the exigencies of the individual colonoscopy examination. The comments that follow address the more common scenario in which an anesthesiologist does not participate. The colonoscopy nurse/assistant generally performs the following sedation-related tasks: • preparation of the medications and infusion equipment; • an abbreviated preprocedure history; • preparation of the monitoring devices; • monitoring of the infusion equipment; • monitoring of patient ventilation and hemodynamic parameters; • administration of drug (under the direction and the responsibility of the gastroenterologist); • initiation and participation in needed support/resuscitation measures. The number and qualifications (licensure) of the assistant(s) utilized during colonoscopy depends upon local regulations and norms. However, there are no outcome data addressing the impact of these variables on sedation safety or effectiveness. In a recent survey, approximately 90% of endoscopists in the US reported that they used a registered nurse to assist with colonoscopy; the remaining physicians enlisted either a licensed practical nurse or an endoscopy assistant [1]. Regarding the number of assistants, a single individual remains the norm in many units. The Society of Gastroenterology Nurses and Associates has taken the position that the

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minimum staffing of a colonoscopy unit should include one registered nurse in the preprocedure area, one registered nurse in each procedure room during the procedure, and one registered nurse in the recovery area [56]. The ASA has stated that, when deep sedation is intended, a dedicated individual for sedation and monitoring should be present, but during moderate sedation the assistant involved in sedation and monitoring may assist with “minor interruptible tasks” [3]. It is our practice to have a single assistant in each procedure room, and an additional trained nurse who is available to float between two procedure rooms, as necessary, to assist with nonroutine tasks (e.g., complicated polypectomy or stricture dilation, or a difficult-to-sedate patient). Clearly, the involvement of additional personnel in colonoscopy must be weighed against the added costs. It is uncertain at the present time whether staffing requirements during propofol sedation should differ from those used during traditional sedation, provided that the intended level of sedation is the same. Many authorities argue that nonanesthesiologist propofol-based sedation requires the presence of at least two persons in addition to the endoscopist, and this is common practice among practitioners of this sedation strategy. However, a recent European report on 27 061 procedures concluded that “an endoscopy team consisting of 1 physician endoscopist and 1 endoscopy nurse can safely administer propofol sedation in a practice setting without additional staff or specialized monitoring” [57]. The training of an endoscopy nurse/assistant should include an understanding of the continuum of sedation; the preprocedural assessment; relevant pharmacology; the ability to recognize relevant complications; the use and interpretation of monitoring equipment; principles of relevant physiology and anatomy; and hemodynamic and airway support. Training may be obtained from nursing or gastroenterology societies or university-based courses. It is also recommended that all nursing staff possess current certification in Advanced Cardiac Life Support.

Technical issues specific to sedation for colonoscopy General anesthesia during laparotomy differs technically from general anesthesia during thoracotomy, and, likewise, sedation during colonoscopy differs technically from sedation during upper GI endoscopic (or other ambulatory) procedures. The following comments pertain specifically to the practice of sedation during colonoscopy: • Pain during colonoscopy occurs principally during sigmoid looping, when forces up to 4 N may be imparted to the colon [58]. Pain may be minimal during instrument withdrawal. Therefore, sedation agents should be titrated so that levels are highest during the period when the sigmoid colon is being traversed. Such a strategy is particularly effective when

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10

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Hepatic flexure

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Figure 9.2 In balanced propofol sedation, administration of propofol and depth of sedation coincides with periods of looping during passage through the sigmoid colon (“front-loading”). Purple arrows correspond to propofol boluses (mg); blue dots to bispectral index (BIS) measurement of consciousness; red squares to depth of sedation measured using the modified observer’s assessment of alertness and sedation (MOAAS) scale. Progress of the colonoscopy is indicated along the x-axis.

Sedation for Colonoscopy

and volume, and thereby may hinder effective diaphragmatic excursion. • A vasovagal reaction may occur during colonoscopy. The increased hemodynamic depression seen during such an episode, combined with the negative hemodynamic effects of sedation drugs, may result in clinically significant bradycardia or hypotension. Such episodes can generally be managed with temporary cessation of scope advancement, administration of atropine and fluids, andaif necessaryareversal agents. • During colonoscopy, the patient is generally positioned in the left lateral decubitus position and the colonoscopist stands behind the patient. In this arrangement, visual inspection by the endoscopist of the patient’s face and anterior chest wall (to monitoring depth of sedation) is limited. The endoscopy assistant should be positioned opposite the doctor and have lighting that is adequate to observe the patient’s face and chest throughout the examination. • Female gender may be an independent risk factor for significant discomfort during colonoscopy, and therefore drug dosing may differ in men and women.

Impact of sedation on the technical performance of colonoscopy ultra-short-acting agents are utilized (Figure 9.2). In theory, such “front-loading” of sedation should also shorten recovery time. • Pain during colonoscopy is mediated by visceral stretchsensitive mechanoreceptors. Therefore, aspiration of insufflated air during scope withdrawal will reduce discomfort if the bowel has become distended during scope insertion. Alternatively, the insufflation of carbon dioxide rather than air during colonoscopy has been demonstrated to reduce postprocedure abdominal discomfort. • Many patients sleep poorly the night before colonoscopy due to the bowel preparation, and thus may require less sedation than if they were fully awake at baseline. • The precolonoscopy bowel preparation may cause serum electrolyte abnormalities, which in turn may lower seizure threshold, alter sedative drug pharmacology, and/or impact cognitive or neuromuscular function [59]. Sidestream capnography is more reliable during colonoscopy than esophagogastroduodenoscopy, because mouth breathing (when exhaled gas is not captured) is less likely to occur. • It has been reported that the use of narcotics agents may alter colonic blood flow, and thereby obscure visualization of angiodysplasia within the right colon. • Because the risk of aspiration may be higher with deeper sedation, strict attention to “NPO time” (nil per os; in the UK “nil by mouth”) must be given when deeper levels of sedation are planned. • The introduction of gas into the colon (and often small bowel) during the colonoscopy increases intra-abdominal pressure

The technical performance of colonoscopy can be affected by the level of sedation [60]. Ideally, a skilled colonoscopist should be able to perform unsedated colonoscopy in appropriately motivated patients, with minimal to moderate sedation for patients who want to avoid deep sedation or are at high risk for deep sedation, and during deep sedation or general anesthesia. A variety of technical points relate to performance according to the level of sedation. Insertion is likely to take longer in unsedated patients. Unsedated colonoscopy requires verbal communication between the colonoscopist and the patient. The patient should be warned that he or she may experience a variety of sensations, including the urge to defecate, bloating, gurgling, and frank discomfort. Patients should be reassured that periods of colonic stretching due to loop formation will be kept to a minimum and that they can change their mind at any time and receive sedation if discomfort is intolerable. Strict attention to prompt loop reduction is essential after passing each turn. Torquing the instrument can also produce pressure on the sigmoid mesentery, and negotiation of turns using the right/left control rather than torquing, in the unsedated patient, can reduce pain. Performance of colonoscopy in the minimally to moderately sedated patient is technically similar to that in the unsedated patient. Both the unsedated patient and the moderately sedated patient can be expected to assist in position change, which is overall the most useful ancillary maneuver to enhance scope advancement [61]. Position change has also been reported to

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be useful during withdrawal, in order to maximize distention of the colonic segment being inspected [62]. The situation is significantly different in the patient in deep sedation or general anesthesia. Because of decreased responsiveness to pain, it is possible for a colonoscopist to “push through” colonic segments and turns without loop reduction. Older textbooks suggest that the patient’s report of pain during loop formation is critical to prevention of perforation. However, recent extensive experience with deep sedation without significant increase in perforation suggests that the pain response is unnecessary for the experienced colonoscopist. However, the colonoscopist must follow the rule of not pushing against fixed resistance in deeply sedated patients. Further, some have suggested that the possibility of more extensive loop formation in the deeply sedated patient could contribute to a risk of splenic injury during colonoscopy. In general, colonoscopy in deeply sedated patients should be performed according to accepted principles of proper technique, in particular prompt loop reduction at every possible opportunity. Colonoscopists should still be willing to use position change during deep sedation, even though patients will require assistance in moving from lateral decubitus to supine or right lateral decubitus, and strict attention to both airway protection from aspiration and airway integrity must be maintained when patients are moved to the supine or right lateral decubitus positions.

Colonoscopy, sedation, and risk management Sedation-related unplanned cardiopulmonary events (including death) complicate approximately 1 in 300 colonoscopies, and account for approximately half of serious adverse events during colonoscopy [47,63,64]. It has also been estimated that medical malpractice claims related to endoscopic sedationrelated adverse events account for roughly 1 in 500 medical malpractice claims in the US. Further, several interwoven factors in today’s environmentasuch as more complex procedures, heightened consumer expectations for painless colonoscopy, open-access colonoscopy, and the controversy regarding gastroenterologist-directed propofolamay increase sedation-related malpractice risk. However, contrary to the belief of many endoscopists, the presence of an anesthesiologist to administer sedation during colonoscopy does not absolve the gastroenterologist of legal responsibility in the event of a sedation-related adverse event. In a 1995 US survey, 38% of endoscopists did not discuss sedation during the informed consent discussion [65]. Because sedation during colonoscopy has risks, benefits, and alternatives, it should be discussed during the preprocedure informed consent. This discussionaideally occurring face to face between endoscopist and patientashould be documented in the body of the colonoscopy informed consent or

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in a separate sedation consent document. Strategies for colonoscopy sedation-related risk minimization have recently been enumerated [5]. These include: • development and implementation of best practice guidelines; • continued clinical research in conjunction with other subspecialties regarding best practices; • implementation of improved fellow and midcareer practitioner training programs in sedation; • implementation of sedation-specific language in the informed consent discussion; • implementation of a sedation-related quality improvement program within colonoscopy units, including analysis of “near-misses;” • strict adherence to institutional and local regulations regarding sedation. Gastroenterologist-directed propofol gives rise to specific medicolegal considerations [66]. In light of the wealth of data indicating the safety of gastroenterologist-directed propofol, the support of the gastroenterology societies, and medicolegal precedents in the US regarding off-label drug use, it has been argued that gastroenterologist-directed propofol is “medicolegally reasonable.” However, adoption of propofol for colonoscopy by gastroenterologists requires adherence to five principles: 1 compliance with professional society guidelines; 2 restriction to low-risk patients; 3 appropriate training in airway management and propofol pharmacology; 4 appropriate staffing and equipment in the colonoscopy suite; 5 an appropriate informed consent discussion regarding risks, benefits, and alternatives.

Sedation and the economics of colonoscopy In the US, approximately 20 million colonoscopies are performed annually, and it is estimated that approximately 8.1 million procedures would be necessary annually if all eligible Americans underwent a screening colonoscopy every 10 years [67]. In certain regions of the US, there are insufficient human resources to meet this demand and the waiting time for colonoscopy may be up to 8 months. The public health costs of colonoscopy screening have been estimated at $9.2–15.4 billion annually. Therefore, strategies to decrease cost and increase efficiency of colonoscopy units are desirable [68]. Typically, sedation accounts for approximately 75% of the total time a patient spends in the colonoscopy suite and approximately 40% of the costs (in one study $104 per case) [60]. Therefore, efforts to improve these statistics offer significant potential for savings and efficiency [69]. In the US, unsedated colonoscopy, which eliminates sedation-related costs, has not achieved widespread acceptance, due principally to procedure-related discomfort. Strategies to reduce

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sedation requirements (and thereby increase efficiency and lower cost) have been explored, including: • the use of antispasmodic agents; • improvements in bowel preparation; • the use of visual distraction; • the use of relaxing music; • the use of hypnosis; • the use of patient-controlled sedation. The use of rapidly metabolized drugs shortens patient recovery and offers significant cost and efficiency benefits. In one randomized study comparing sedation with the ultra-shortacting agent propofol with sedation with a benzodiazepine plus a narcotic, the propofol group recovered significantly faster (40 min vs. 71 min) [70]. In a recently published economic model, this improved efficiency would result in 3.51 colonoscopies completed with propofol for every two completed with benzodiazepine/opioid sedation [71]. Using this model, a break-even cost for the drug (if given by the gastroenterologist) of approximately $71.53 was estimated. Viewed from a different angle, elimination of sedation offers considerable economic benefit by reducing patient workdays missed and eliminating escort workdays missed. Recent estimates suggest that anesthesiologists participate in approximately one in four colonoscopies performed in the US today. This practice is a matter of considerable interest and discussion among payers, endoscopists, patients, and professional societies. Irrespective of which side of the table one occupies, it is agreed by all that the economic impact of this practice is enormous. If the use of anesthesiologists during colonoscopy became the norm, the annual allowed charges for anesthesia services in the US during colonoscopy would exceed $5 billion [72].

Conclusions Despite improving scope technology, colonoscopy still causes discomfort. The elimination of pain during colonoscopy is an inherently important objective; in addition, the comfortable patient is more likely to cooperate during the examination, return for surveillance, and encourage others to undergo screening. On the other hand, sedation increases the risks and costs associated with colonoscopy. In today’s environment, numerous choices exist regarding colonoscopic sedation. For these reasons, an understanding of the science of sedation and the acquisition of skills necessary to administer safe and effective sedation are important attributes for the practicing colonoscopist. Improved training and certification programs for fellows and residents, midcareer colonoscopists, and colonoscopy assistants (nurses and technicians) are in development under the aegis of program directors and the gastroenterology professional societies. The individual colonoscopist must identify a sedation strategy that works for his or her style, culture, and environment. Gastroenterologists

Sedation for Colonoscopy

must understand the nuances that distinguish colonoscopy sedation from sedation for upper GI procedures. Excellence in sedation enhances the safety and effectiveness of colonoscopy, improves patient satisfaction, and will maximize the value proposition of optical colonoscopy, as newer screening modalities become more readily available.

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50 Pedersen T, Dyrlund Pedersen B, Moller AM. Pulse oximetry for perioperative monitoring. Cochrane Database Syst Rev 2003; CD002013. 51 Silverman WB, Chotiprasidhi P, Chuttani R, et al. Monitoring equipment for endoscopy. Gastrointest Endosc 2004; 59: 761–5. 52 Vargo JJ, Zuccaro G Jr, Dumot JA, Conwell DL, Morrow JB, Shay SS. Automated graphic assessment of respiratory activity is superior to pulse oximetry and visual assessment for the detection of early respiratory depression during therapeutic upper endoscopy. Gastrointest Endosc 2002; 55: 826–31. 53 Lightdale JR, Goldmann DA, Feldman HA, Newburg AR, DiNardo JA, Fox VL. Microstream capnography improves patient monitoring during moderate sedation: a randomized, controlled trial. Pediatrics 2006; 117: e1170– 8. 54 Drake LM, Chen SC, Rex DK. Efficacy of bispectral monitoring as an adjunct to nurse-administerd propofol sedation for colonoscopy: a randomized controlled trial. Am J Gastroenterol 2006; 101: 2003–7. 55 Faigel DO, Baron TH, Goldstein JL, et al. Guidelines for the use of deep sedation and anesthesia for GI endoscopy. Gastrointest Endosc 2002; 56: 613–17. 56 Society of Gastroenterology Nurses and Associates (2008). Minimum Registered Nurse Staffing for Patient Care in the Gastrointestinal Endoscopy Unit. Available at: www.sgna.org/resources/statements/ statement14.cfm (accessed October 15, 2007). 57 Kulling D, Orlandi M, Inauen W. Propfol sedation during endoscopic procedures: how much staff and monitoring is necessary? Gastrointest Endosc 2007; 66: 443– 9. 58 Shah SG, Brooker JC, Thapar C, Williams CB, Saunders BP. Patient pain during colonoscopy: an analysis using real-time magnetic endoscope imaging. Endoscopy 2002; 34: 435– 40. 59 Rostom A, Jolicoeur E, Dube C, et al. A randomized prospective trial comparing different regimens of oral sodiumphosphate and polyethylene glycol-based lavage solution in the preparation of patients for colonoscopy. Gastrointest Endosc 2006; 64: 544–52. 60 Rex DK, Khalfan HK. Sedation and the technical performance of colonoscopy. Gastrointest Endosc Clin N Am 2005; 15: 661–72.

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61 Shah SG, Saunders BP, Brooker JC, Williams CB. Magnetic imaging of colonoscopy: an audit of looping, accuracy and ancillary maneuvers. Gastrointest Endosc 2000; 52: 1–8. 62 East JE, Suzuki N, Arebi N, Bassett P, Saunders BP. Position changes improve visibility during colonoscope withdrawal: a randomized, blinded, crossover trial. Gastrointest Endosc 2007; 65: 263–9. 63 Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results from the American Society for Gastrointestinal Endoscopy/U.S. Food and Drug Administration collaborative study on complication rates and drug use during gastrointestinal endoscopy. Gastrointest Endosc 1991; 37: 421–7. 64 Petrini J, Egan JV. Risk management regarding sedation/analgesia. Gastrointest Endosc Clin N Am 2004; 14: 401–14. 65 Levine EG, Brandt LJ, Plumeri P. Informed consent: a survey of physician outcomes and practices. Gastrointest Endosc 1995; 41: 448–52. 66 Aisenberg J, Cohen LB, Piorkowski J. Propofol use under the direction of trained gastroenterologistsaan analysis of the medicolegal implications. Am J Gastroenterol 2007; 101: 707–13. 67 Seeff LC, Richards TB, Shapiro JA, et al. How many endoscopies are performed for colorectal cancer screening? Results from CDC’s survey of endoscopic capacity. Gastroenterology 2004; 127: 1670–7. 68 Ladabaum U, Song K. Projected national impact of colorectal cancer screening on clinical and economic outcomes and health services demand. Gastroenterology 2005; 129: 1151–62. 69 Aisenberg J, Cohen LB. Sedation in endoscopic practice. Gastrointest Endosc Clin N Am 2006; 16: 695–708. 70 Sipe BW, Rex DK, Latinovich D, et al. Propofol versus midazolam/ meperidine for outpatient colonoscopy: administration by nurses supervised by endoscopists. Gastrointest Endosc 2002; 55: 815–25. 71 Vargo JJ, Bramley TJ, Meyer K, Nightengale B. Practice efficiency and economics. The case for rapid recovery sedation agents for colonoscopy in a screening population. J Clin Gastroenterol 2007; 41: 591–8. 72 Aisenberg J, Brill JV, Ladabaum U, Cohen LB. Sedation for gastrointestinal endoscopy: new practices, new economics. Am J Gastroenterol 2005; 100: 996–1000.

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Preparation for Colonoscopy Jack A. Di Palma University of South Alabama College of Medicine, Mobile, AL, USA

Impact of proper colon preparation

Goals of preparation

Adequate cleansing is required for safe and reliable colonoscopy. Poorly visualized mucosa leads to missed diagnoses and increases colonoscopic risk [1–3]. The extent of the examination may be compromised and poor preparation may lead to the inability to reach the cecum. Even a minimal amount of residual stool can obscure small lesions and angiodysplasia [3]. Washing and aspirating the dirty colon during colonoscopy is time-consuming and frustrating, and a clean colon reduces procedure time and sedation requirements [3,4]. Colonoscopy perforation occurs with an incidence of 0.1–0.8% for diagnostic and 0.5–3.0% for therapeutic procedures [5]. The amount of peritoneal soilage by intestinal contents is an important determinant of subsequent septic complications and death after surgical repair [6]. Adequate colon preparation decreases the risk of complications should perforation occur [1,3]. In their study of 400 colonoscopies, Rex et al. [7] underscored the impact of bowel preparation on efficiency and cost of colonoscopy, noting that suctioning fluid and washing occupied a measurable percentage of total examining time and that imperfect bowel preparation led to aborted examinations and earlier repeat surveillance. These problems resulted in an increase in average costs of 12% at the university hospital and 22% at the public hospital studied. Residual fecal matter also poses a risk from ignition of combustible gases during electrocautery [1]. Hydrogen and methane are the two major combustible gases found in the colon and explosions have been reported during colonoscopy and other related procedures [1,3,8–11]. Colon cleansing reduces the concentration of explosive gases [3,5,8,12,13]. Furthermore, in a prospective survey, colon cleansing preparation appears to be the major disincentive to colon cancer screening [14].

A colon preparation regimen should provide safe and rapid cleansing acceptable to patients with minimal discomfort [1]. The ideal method would: 1 reliably empty the colon of fecal material; 2 have no effect on gross or microscopic appearance of the colon; 3 require a short period for ingestion and evacuation; 4 cause no discomfort; 5 produce no significant shifts of fluids or electrolytes [2]. The regimen should be simple and appropriate for use in inpatients and outpatients [15]. The presently available methods do not meet most of these criteria and few have been carefully studied [1]. Problems with patient compliance, safety, and adequacy of cleansing have prompted continued investigation into alternative forms of cleansing [16].

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Colon cleansing methods Traditional cleansing methods evolved from barium enema preparations and local experience, and were modified for colonoscopy and colon surgery. There is a wide variety of methods using diet restrictions with various purgatives and laxatives [17]. Three popular options for colon preparation are diet and cathartic regimens, gut lavage, and phosphate preparations.

Diet and cathartics Early cleansing methods used 48–72 h of clear liquids with laxatives and enemas. Clear liquids (Table 10.1) include clear broth or bouillon, coffee without creamer, tea, fruit juices without pulp, gelatin, carbonated and noncarbonated beverages, popsicles, and water [3]. Milk and milk products should be avoided, as should red juices and jelly, which could mimic blood during colonoscopy. Beans, watermelon, and foods with similar appearance could be confused with polyps. The effect of diet was demonstrated in a prospective study [12]. Three study groups had cleansing enemas and similar

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Table 10.1 Clear liquids. Clear broth or bouillon Coffee without cream Tea Fruit juices without pulp Gelatin Carbonated and noncarbonated beverages Popsicles Water Avoid Milk Milk products Red juices, jello

regimens of laxatives and cathartics. Subjects were fed either a clear liquid diet or a diet designed to leave a minimal colonic fecal residue for 1 or 3 days. The minimum residue diet suggested foods for breakfast, including scrambled egg, white toast with jelly, apple, grape, or cranberry juice, and water, tea, or coffee. Sugar could be added but no milk or cream. For lunch, the diet allowed bouillon soup with crackers and a chicken or turkey white meat sandwich. No butter, mayonnaise, lettuce, or additives were allowed. Noncitrus juice, plain jello with no cream or fruit, and water, tea, or coffee were advised. For dinner, suggestions included bouillon soup, noncitrus juice, jello, and water, coffee, or tea. Fluids, water or noncitrus juice were encouraged between meals. This study showed that cleansing efficacy was superior in patients randomized to receive 1 or 3 days of the minimum residue diet than in those who were randomized to receive 72 h of clear liquids [12]. No difference in cleansing efficacy was observed between the 1- and 3-day minimum residue diet, although patients who received the 1-day minimum residue diet reported less distress from dietary restrictions (P < 0.01). Various laxatives and cathartics are acceptable for use in cleansing regimens [16–18]. Other studies that examined diet modifications and laxatives showed cleansing efficacy and favorable patient acceptance [19–21]. Dahshan et al. [19] reported that bisacodyl without dietary restriction provided unsatisfactory colon cleansing and that magnesium citrate combined with senna X-prep was acceptable with good cleansing. Chen et al. [20] showed magnesium citrate and bisacodyl to be effective and superior to castor oil for colonoscopy preparation. A low-residue meal kit is available (Nutra Prep, EZ Em, Inc., Westbury, NY, US). A companion laxative kit completes the preparation using magnesium citrate and bisacodyl (LoSol, EZ Em, Inc.) [21]. Table 10.2 lists the components of diet and cathartic regimens.

Gut lavage Orthograde peroral gut lavage using saline or balanced electrolyte solutions was found to provide rapid and effective

Preparation for Colonoscopy

Table 10.2 Diet and cathartic regimens. (Modified from Toledo and DiPalma [1].) Diet

Clear liquids for 72 h, or 1–3 days of a diet designed to result in a minimal colonic fecal residue

Cathartic

Magnesium citrate 240 mL of chilled, X-prep liquid 240 mg (extract of senna fruit, Purdue Frederick Co., Norwalk, CT, US)

Additional cathartic

Bisacodyl 20 mg orally and/or two bisacodyl suppositories

Enemas

Tap water enemas until clear the evening before or morning of the procedure

colon cleansing [22–27] but the 7- to 12-L required volume necessitated nasogastric administration and was not well tolerated [23]. These saline and electrolyte solutions led to weight gain, sodium retention, and fluid shifts [15], prompting studies that incorporated mannitol or polyethylene glycol (PEG) for osmotic balance [28] so that there is no net loss or change in the body’s electrolyte composition. In search of a more acceptable solution, Davis et al. [29] formulated an osmotically balanced electrolyte lavage solution, namely polyethylene glycol electrolyte lavage solution (PEG-ELS). In their initial description, these authors presented data showing their solution to have minimal water and electrolyte absorption or secretion [29]. These results, confirmed by others, showed that the osmotic balance in PEG-ELS had significant advantage to saline or electrolyte solutions when compared for water and electrolyte shifts [15]. Intestinal perfusion of PEG-ELS resulted in mean water absorption of 64 mL/h, whereas infusion of a basic electrolyte solution without osmotic balance resulted in water absorption of 799 mL/h [29]. Routine clinical cleansing using 3–4 L over 3–4 h would result in absorption of 190–250 mL of fluid with PEG-ELS and 3400–3200 mL of electrolyte solution without osmotic balance [15]. Since saline lavage frequently requires 7–12 L over 6–12 h, these patients have the potential for over 8 L of water absorption. In their report, Davis et al. [29] claimed that “any solution worth its salt should have a name,” and they chose to call theirs Golytely, which subsequently became the brand name of a commercial product (GoLYTELY, Braintree Laboratories, Inc., Braintree, MA, US). PEG-ELS is also available as CoLyte (Schwarz Pharma, Milwaukee, WI, US). Table 10.3 lists the commercially available gut lavage products.

Polyethylene glycol electrolyte lavage solution Clinical trials established the safety of PEG-ELS for colon cleansing preparation for colonoscopy, barium enema X-ray examination, intravenous pyelograms, and colon surgery [4,12,30–35]. Compared with diet and cathartic methods with enema administration, PEG-ELS had better patient acceptance

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Table 10.3 Cost of colon cleansing. (Modified from Toledo and DiPalma [1].) Price rangea ($) Diet and cathartic methods Magnesium citrate 300 mL Bisacodyl 5 mg Generic (four tablets) Dulcolax (four tablets) Dulcolax suppositories (two) Phosphosoda enemas (Fleet) (two) Total diet and cathartic LiquiPrep (EZ EM, Inc., Westbury, NY, US) NutraPrep diet (EZ EM, Inc.) LoSo Prep system (EZ EM, Inc.)

1.06–2.69

Average price ($)

1.85

1.04–2.19 0.68–4.29 2.23–8.39 3.68–10.98 5.40–22.06

1.62 2.02 4.47 6.41 19.22 6.25 25.00 4.99

Polyethylene glycol electrolyte lavage solution (PEG-ELS) GoLYTELY (Braintree Laboratories, Inc.) Flavored GoLYTELY (pineapple) CoLyte (Schwarz Pharma, Inc., Milwaukee, WI, US) Flavored CoLyte (pineapple) CoLyte with flavor packs (citrus, berry, lemon–lime, cherry, pineapple) PEG-ELS (generic)

21.95–29.99 23.95–32.79 18.94–34.99 27.82–34.99 27.82–34.99 17.42–24.99

26.39 27.68 31.64 30.25 32.44 19.59

Sulfate-free electrolyte lavage solution (SF-ELS) NuLYTELY (Braintree Laboratories, Inc.) Flavored NuLYTELY (cherry, lemon–lime, orange) Bisacodyl with 2 L SF-ELS (HalfLytely, Braintree Laboratories, Inc.) TriLyte (Schwarz Pharma)

28.46–42.99 29.64–39.99 57.99–70.95 28.46–42.99

36.35 36.64 63.37 33.34

PEG, electrolytes, sodium sulfate, and ascorbic acid MoviPrep (Salix Pharmaceuticals Inc., Morrisville, NC, US)

52.16–68.95

58.92

Phosphates Oral phosphosoda (Fleet’s Phospho-soda, C.B. Fleet, Lynchburg, VA, US) Phosphate tablets (OsmoPrep, Salix Pharmaceuticals)

7.64–10.98 65.94–184.58

115.16

a

Average retail pharmacy price, Mobile, AL, US.

[4,12,30–32]. When compared with clear liquid and minimum residue diet methods, PEG-ELS [12] was superior, with cleansing efficacy rated good or excellent in 92% of PEG-ELS, 69% of clear liquid diet, 80% of 3-day minimum residue diet, and 80% of 1-day minimum residue diet groups (P < 0.001). Interestingly, it was noted that the 72-h clear liquid diet, enemas, and cathartic group had the least optimal cleansing [12]. No clinically significant hematologic, biochemical, electrolyte, or metabolic abnormalities have been found with PEG-ELS colon cleansing [1–3,15,16,36].

Sulfate-free electrolyte lavage solution A sulfate-free electrolyte lavage solution (SF-ELS) (NuLYTELY, Braintree Laboratories, Inc., TriLyte, Schwarz Pharma) was developed in an attempt to improve patient compliance by decreasing the salty taste and “rotten egg” smell noted with PEG-ELS [37]. Whereas the mechanism of action of PEG-ELS cleansing is affected by the osmotic properties of PEG and by an electrochemical gradient for ion transport created

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by sodium sulfate, SF-ELS action is primarily based on the osmotic effects of PEG, as sulfate was eliminated from the formulation. The PEG polymer isolates water from the solution [28] and when PEG molecular weight is greater than 1500 (as seen with PEG 3350 in PEG-ELS and SF-ELS), it is poorly absorbed in the gastrointestinal tract. PEG is inert and not fermented by colonic bacteria to combustible gases. Brady et al. [38] showed that the mean percent urinary PEG recovery of orally administered PEG-ELS was minimal and similar for normal (0.06%) and inflammatory bowel disease (0.09%) study subjects. Clinical trials for colonoscopy, barium enema radiography, and elective colonic surgery have shown SF-ELS to be safe and effective [39–43]. DiPalma and Marshall [40] found that, among those who expressed a taste preference, SF-ELS was preferred to PEG-ELS (76.6% vs. 23.4%, respectively; P < 0.001). In a conflicting report, Froehlich et al. compared PEG-ELS and SF-ELS and found no taste preference [41,43]. In a clever attempt to reconcile the conflicting data concern-

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ing taste preferences, Raymond et al. [44] randomly assigned patients to receive PEG-ELS and SF-ELS in random order for the first 2 L of lavage fluid. Subjects were then asked to choose which solution they would prefer to consume for the last 2 L of preparation. More study subjects preferred SF-ELS and more were willing to repeat SF-ELS than the traditional PEG-ELS if colon cleansing was needed in the future.

Flavoring and palatability Flavoring of gut lavage solutions has been tried in an attempt to further improve taste and compliance. Commercial solutions of PEG-ELS have been flavored with pineapple or had flavor packs of pineapple, citrus berry, lemon–lime, or cherry which could be added to a prescribed plain solution. SF-ELS was flavored with cherry, lemon–lime, or orange. Flavorings are carbohydrate based, but a study of SF-ELS solutions found no production of combustible gases in either flavored or unflavored preparations [45]. A small study by Matter et al. [46] revealed a preference among patients for flavored rather than unflavored solutions. These authors used lemon–lime flavoring (Crystal Light Sugar Free Drink Mix, White Plains, NY, US). It is advisable to chill gut lavage solutions to improve palatability. Bottled water should be used to reconstitute powdered solutions as it contains less chlorine and minerals than tap water, and has fewer additional tastes.

Adjuncts In the original studies of PEG-ELS, metoclopramide was used as a premedication in an attempt to reduce the distress associated with lavage [12,30,31,47]. Brady et al. [48] compared the efficacy of pretreatment with 10 or 20 mg of metoclopramide or placebo. There were no differences between the study medication groups and the placebo group regarding the adequacy of feces removal as assessed by colonoscopy. Nor were there differences among the groups in symptoms of nausea, bloating, fullness, or cramps associated with lavage. Comparison of plasma metoclopramide levels in lavage patients and in control subjects not undergoing lavage were not significantly different, confirming that absorption of the pretreatment medication was not influenced by lavage. Cisapride has also been studied as a pretreatment for lavage [49–52] but it was found that it provides no additional benefit in terms of effectiveness or patient tolerance of the electrolyte solution. Although bisacodyl is required to enhance mucosal coating during barium enema radiography [39,53], neither bisacodyl nor senna has been found to be significantly better than placebo in terms of improving the quality of preparation or reducing the quantity of residual colonic fluid aspirated during colonoscopy [54,55]. However, both bisacodyl and magnesium citrate may reduce the volume of lavage required for adequate cleansing [56,57]. Simethicone may decrease residual bubbles or foam seen during colonoscopy [58], but cleansing enemas do not seem

Preparation for Colonoscopy

to improve preparation [59]. Tap water enemas after 4-L lavage did not improve visibility or decrease colon fluid and may cause anorectal trauma [59]. Therefore, enema administration is not necessary when using a balanced electrolyte gut lavage fluid.

Reduced-volume lavage Sharma et al. [57] compared lavage with 4 L of PEG-ELS with lavage with 2 L of of PEG-ELS and magnesium citrate or bisacodyl pretreatment. A second trial by this group evaluated PEG-ELS with magnesium citrate pretreatment [60]. Both studies showed that reduced-volume lavage conbined with pretreatment is as effective as full-volume lavage. Adams et al. [56] found that bisacodyl pretreatment before lavage with 2 L of PEG-ELS was similarly effective as 4 L lavage. Standard cleansing lavage with 4 L of SF-ELS was compared with a reduced-volume preparation using 2 L of SF-ELS and 20 mg of bisacodyl (HalfLytely, Braintree Laboratories, Inc.) in a randomized study involving 200 patients at two centers (University of South Alabama, Mobile, AL, US, and Mayo Clinic, Rochester, MN, US) [61]. All study subjects were allowed normal breakfast and lunch, and clear liquids for dinner. Subjects taking the reduced-volume preparation received bisacodyl 20 mg as four 5-mg tablets taken orally at 12 PM; 6 h later, subjects were given 2 L of SF-ELS. Patients randomized to receive the 4-L preparation also drank the solution at 6 PM. Both groups were instructed to drink the solution at a rate of 1.5 L/h or 280 g (10 ounces) every 10 min. The results showed equivalent good to excellent cleansing in 92.5% of the group taking 4 L of SF-ELS and in 87.1% of the group taking 2 L of SF-ELS plus bisacodyl. Subjects receiving the reduced-volume preparation reported significantly less fullness, nausea, vomiting, and overall discomfort. The reduced-volume preparation requires ingestion of seven 280-g (10-ounce) glasses over 1 h. In an attempt to improve patient preparation experience, a low-bisacodyl dose preparation was developed using 10 mg bisacodyl. A comparison study showed that, in combination with 2 L of SF-ELS, this 10-mg formulation was as effective as the 20-mg regimen, with significantly less cramping, nausea, and overall discomfort [62]. HalfLytely has been reformulated to use the 10-mg dose.

Polyethylene glycol, electrolytes, sodium sulfate, and ascorbic acid When added to an osmotically balanced electrolyte formula with sodium sulfate, ascorbic acid improves taste, contributes to diarrhea, and inhibits bacterial gas generation and reproduction. Given as 2 L of product with 1 L of water in split-dose administration, this formula (MoviPrep, Saliz Pharmaceuticals, Inc., Morrisville, NC, US) has acceptable cleansing efficacy [63].

PEG 3350 Although PEG 3350 (MiraLAX, Schering Plough Healthcare Products, Inc., Summit, NJ, US) is a safe and effective

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over-the-counter agent for constipation [64], it has poor rationale as a bowel preparation. PEG 3350 has been used for cleansing in adults and children with endorsement [65], yet there are no studies confirming its safety. As a preparation with adjuncts such as bisacodyl, or as commonly added to solutions such as Gatorade (Quaker Oats Company, Chicago, IL, US), the solution is not balanced osmotically, does not have electrolyte balance, and may predispose to the production of potentially combustible gases because of fermentation of the unabsorbed carbohydrate [66]. If PEG 3350 is added to Gatorade, sodium absorption is enhanced by the large amount of carbohydrates in the Gatorade solution.

Gut lavage in the elderly To assess tolerance of colonoscopy preparation in older patients, symptoms of nausea, cramps, abdominal fullness, vomiting, and overall discomfort were assessed by self-administered questionnaires in over 550 study subjects who were treated with diet, cathartic and enema preparations, or gut lavage [67]. In general, patients over 60 years tolerated preparations better than those under 60, regardless of the type of preparation. Most rated discomfort as “minimal.” The PEG-ELS method was preferred by 81% of the older group. Age did not influence the adequacy of cleansing with either method. Lashner et al. [68] randomized 124 consecutive patients over 75 years to enema lavage or PEG-ELS. Patients who were 75 years or older seemed to tolerate enemas better than PEG-ELS, without a difference in cleansing adequacy.

Pediatric use of gut lavage Gut lavage has been used in children and infants [19,69–74]. Compliance is limited by the volume required for cleansing, but lavage is preferred because of its superior cleansing and limited adverse effects [19,70]. Dahshan et al. [19] advise that 20 mL/kg PEG-ELS be taken every hour up to 1 L/h, for 4 h.

Safety of gut lavage Several adverse experiences have been reported from gut lavage. Table 10.4 lists reported and potential adverse events [7]. Lavage patients may find the taste disagreeable. If the administered solution is chilled excessively, hypothermia may result. Bloating, nausea, and vomiting can result from the volume of lavage, and esophageal tears have been reported. Pill malabsorption with slow-release drug delivery preparations could occur, but most tested capsules recovered in the colon show them to be a “ghost” of the wax tablet matrix without active medication. Negligible hematologic and biochemical changes have been seen in cleansing investigations, but anecdotes of pulmonary edema and anasarca exist. Metabolic and acid–base abnormalities are unlikely, and several studies have evaluated pH and bicarbonate changes from PEG-ELS in a large number of patients [7]. Overall, PEG-ELS and SF-ELS are preferred to phosphates and cathar-

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Table 10.4 Reported and potential adverse experiences related to colon preparation. Gut lavage cleansinga Disagreeable taste Hypothermia Volume-related symptoms: fullness, nausea, bloating Aspiration Reactivation of bleeding Esophageal tear Perforation Lavage-induced pill malabsorption Allergic reaction: angioedema, urticaria, or anaphylaxis Bisacodyl ischemic colitis Phosphate cleansing Electrolyte disturbances Hyperphosphatemia Hypocalcemia Vomiting Dehydration Colonic aphthous ulcerations Seizures Acute phosphate nephropathy a

Modified from DiPalma and Brady [12].

tics for safety in patients with renal, cardiac, and hepatic insufficiency, in whom fluid balance is tenuous [1]. PEG appears from animal and human studies to be nontoxic [1]. Caution has been raised about PEG toxicity [73–76], but studies show negligible absorption even in patients with disrupted mucosa due to inflammatory bowel disease [38]. The issue of carcinogenesis and mutagenesis with low-molecularweight PEGs is not relevant because high-molecular-weight PEG is used in cleansing solutions [38,75,76]. Concern is also raised for those who need nasogastric administration of PEG. These patients are at risk of aspiration, and the head of the bed should be elevated during and after administration. If a nasogastric tube is placed, careful attention should be given to ensure that the tube is properly positioned. The patient should be carefully observed. Gut lavage by nasogastric tube is contraindicated in the presence of gastrointestinal obstructive symptoms. There are also reports of systemic allergic reaction to PEG, although serious adverse effects have been rare [77–79]. There are also reports of ischemic colitis from bisacodyl used alone or in combination with gut lavage.

Administration options Vilien and Rytkonen [80] used 1.5 or 3 L PEG-ELS in combination with diet and cathartics. Rosch and Classen [81] described a two-stage method, administering 3 L the evening

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before colonoscopy and 1 L the following morning. Early studies administered 4 L of PEG-ELS the day of the procedure [12], while subsequent studies gave SF-ELS the evening before the procedure [40]. Lavage fluid administration on the morning of the procedure has been shown to improve tolerance [82] and detection of colon lesions [83] compared with lavage carried out in the afternoon on the day before the procedure.

Instructions for use Patients should chill the gut lavage solution to improve palatability. The chlorine taste of tap water can be avoided by using bottled water. Patients can be allowed a normal breakfast and a low-residue lunch before the procedure, followed by a clear liquid supper. A lavage rate of 1.5 L/h is advised and can be accomplished by drinking 280 g (10 ounces) every 10 min. A timer should be used. No ice, additives, or flavoring should be added to the lavage solution because osmolarity could be altered and salt and water absorption could occur if sugars are added.

Phosphates Phosphate preparations offer another alternative. They are available as solutions or tablets and are particularly attractive because less volume needs to be ingested. Oral sodium phosphate (Phosphosoda and Fleet Phos-phosoda EZ Prep, Fleet Pharmaceuticals, Lynchburg, VA, US) is administered as 45 mL of solution diluted with water to 90 mL on the evening before the procedure, and repeated 12 h later or 4 h prior to colonoscopy. Oral sodium phosphate has been shown to be at least as effective as, or better than, PEGELS [51,84– 86]. It is also generally well tolerated. Vanner et al. [84] randomized 102 patients to either oral sodium phosphate or PEG-ELS. Overall, patients found sodium phosphate much easier to consume, and colonoscopists rated cleansing achieved with sodium phosphate as better than obtained with PEG-ELS. Hyperphosphatemia was noted, but it was transient and the preparation was considered safe. Sodium phosphate monobasic, monohydrate, and sodium phosphate dibasic, anhydrous (Visicol, InKine Pharmaceutical Co., Inc., Blue Bell, PA, US), are used in a tablet formulation. Clinical trials support their efficacy and patient acceptance [87–89]. Forty tablets are taken with 10 glasses of water (about 2.5 L). Rex et al. [90] found that 28 or 32 tablets are effective, and a new smaller tablet containing less microcrystalline cellulose, thus reducing colonic residue, was approved by the Food and Drug Administration (FDA) in March 2002. The new formulation of Visacol is now marketed as Osmoprep by Salix Pharmaceuticals [91].

Safety Oral sodium phosphate contains 48 g of monobasic sodium phosphate and 18 g of dibasic sodium phosphate per 100 mL, making it very hypertonic. The phosphate salt must be diluted

Preparation for Colonoscopy

to prevent vomiting, and administration should be followed by adequate oral fluids. Although some studies have found no significant (or clinically insignificant) metabolic changes resulting from oral sodium phosphate [84,92], these data were limited and adverse events attributed to phosphate have been recognized [1,15]. The biochemical effects of oral sodium phosphate were studied in seven healthy asymptomatic adult volunteers [93]. Calcium, ionized calcium, phosphorus, sodium, potassium, creatinine, and parathyroid hormone were analyzed 2, 4, 6, 9, 12, 14, 16, 18, 21, and 24 h after the first of two diluted 45-mL oral sodium phosphate challenges. Urinary studies and clinical data were also obtained. Significant hypocalcemia and hyperphosphatemia were observed. The peak range in phosphorus was 3.6–12.4 mg/dL. The minumum calcium level was 8.0–9.8 mg/dL, with a corresponding fall in ionized calcium. Concern was raised for patients with cardiopulmonary, hepatic, or renal disease. An FDA safety review concurs and raises awareness of increased risk in patients with congestive heart failure, ascites, renal insufficiency, dehydration, debility, gastrointestinal obstruction, gastric retention, bowel perforation, colitis, megacolon, ileus, inability to take oral fluid, or patients taking diuretics or medications that may affect electrolytes, who may experience serious adverse events [94]. The review suggests that baseline and post-treatment laboratory evaluations of serum sodium, potassium, chloride, bicarbonate, calcium, phosphate, blood urea nitrogen, and creatinine be obtained, especially in those at risk who take more than 45 mL of oral sodium phosphate in a 24-h period. Nephrocalcinosis usually seen from hypercalcemia has been reported in normocalcemic patients presenting with acute renal failure after bowel cleansing with sodium phosphate solution or tablets [95]. This “acute phosphate nephropathy” is accepted as an emerging issue [96]. In contradiction to reassurance that careful hydration could avoid the complication, Pelham et al. report that hyperphosphatemia after phosphate bowel preparation may not be overcome even with up to 4.4 L of hydrating fluids [97]. Chan et al. [98] noted in a utilization survey of Canadian gastroenterologists that colonoscopists appeared unaware of the potential for complications from phosphates, even in these special circumstances. Another FDA report raises concern about phosphate tablets after seizures were seen to be associated with electrolyte disturbances after Visicol [99]. Phosphate preparation has been noted to induce rectosigmoid aphthous ulcerations, and in one study aphthous ulcers occurred in 5.5% of study subjects receiving sodium phosphate preparation [100]. In 2008, the FDA required a caution on prescription phosphate products to warn of acute phosphate nephropathy and required additional postmarketing studies. The FDA also restricted over-the-counter phosphates for cleansing preparations and the manufacturer removed oral sodium phosphate from the market.

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Table 10.5 Sulfate cleansing efficacy. Sulfate

PEG with electrolytes and ascorbic acid

Evening administration Number of subjects Good–excellent preparation

190 82.4%

192 80.3%

Split-dose administration Number of subjects Good-excellent preparation

179 96.6%

183 95.6%

Sulfates A new formulation of sulfates has been developed as a laxative and bowel cleansing preparation. Preliminary data suggest that this low-volume method has significant efficacy without the safety issues of phosphates (JA Di Palma, unpublished observations). The clinical trials compared the sulfate laxative with PEG with electrolytes and ascorbic acid. One multicenter trial compared the preparations given in entirety the evening before scheduled colonoscopy. A second study compared the products given in split-dose administration. Data shown in Table 10.5 note excellent efficacy from both cleansing methods and what appears to be a significant advantage for split-dose administration.

Other options There are various other ways to prepare for colonoscopy, including intraoperative colonic irrigation [101] and pulsed irrigation [2].

Special considerations Colostomy Colon cleansing in patients with colostomies can be performed using any of the routine preparations [3].

Histology PEG-ELS does not alter the appearance of colonic mucosa [102]. Bisacodyl causes histologic and macroscopic changes in the colonic mucosa [103]. Phosphate preparations may be associated with colonic aphthous ulceration [100].

paration [3]. Those with moderate or severe disease could be prepared with fewer purgatives or no preparation. The PEG-ELS study showed no significant PEG absorption in patients with inflammatory bowel disease, even when mucosal inflammation is present [38].

Contraindications for colonoscopy preparation Preparation should not be performed if there is a contraindication to colonoscopy [3]. Examples include hemodynamic instability, perforation, diverticulitis, or obstruction. If gastric or bowel obstruction is suspected, peroral preparations should not be given, and gut lavage should be avoided in patients with gastroparesis. Incomplete obstruction or gastroparesis could be tested with a 1-L trial of gut lavage solution with careful observation [3]. Peroral preparation may not be effective with ileus. There are no specific data or few consensus recommendations for the clinician faced with a “poor” preparation. There is also little consensus for grading the quality of preparation. Early reports of preparation comparison studies [12] used a grading scale by colonoscopists unaware of the type of preparation used, which visually graded the adequacy of preparation as follows: 1 (poor)alarge amounts of fecal residue, unacceptable; 2 (fair)aenough feces to prevent a completely reliable examination; 3 (good)asmall accumulation not interfering with a thorough examination; 4 (excellent)ano more than small bits of adherent feces. Grades 2–4 were considered acceptable cleansing for colonoscopy; grades 3 and 4 were optimal. Aronchick [107] and Rostom and Jolicoeur [108] have presented “validated” scoring systems for studies and clinical use. There is clearly a need for standardized nomenclature. When a “bad” preparation is encountered, the patients should be questioned about compliance. If the patient was not compliant and there are no preparation-specific reasons such as intolerance, one often advises the same preparation. If there are product-related reasons for noncompliance, another preparation or combination of preparations are advised; however, clinical investigation has not addressed this topic [63]. Some intensify prepreparation dietary restrictions.

Lower gastrointestinal hemorrhage PEG-ELS has been safely used in patients requiring urgent colonoscopy [104–106]. Some require as little as 500 mL for cleansing. In a study of 35 patients, effective cleansing was seen with good tolerance and no complications [99,105].

Inflammatory bowel disease In general, patients with quiescent inflammatory bowel disease can be prepared in the usual manner with any pre-

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Cleansing instructions The importance of proper cleansing cannot be overemphasized to the patient. Patients scheduled for colonoscopy must have adequate instruction about the cleansing procedure. They should understand the need for their collaboration and compliance in order to optimize safety, prevent missed

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lesions, and to avoid having to reprepare and reschedule the procedure. The colonoscopist should take an active role in this process. The cleansing methods should be reviewed by the nurse or gastrointestinal nurse assistant and all instructions provided clearly in writing. Videotape- or computer-based educational programs may help to instruct about preparation. The reasons for doing the procedure and what to expect with preparation before, during, and after the procedure will be helpful, particularly when the effectiveness of pain medications and sedation are explained [3]. A phone call before the colonoscopy is often appreciated and enhances compliance.

“Split-dose administration” Special attention should be given to the timing of administration of cleansing preparation. Traditionally, gut lavage fluids have been given the evening prior to the procedure. Phosphate preparations have been given in split dose, with one dose the evening before and the second the morning of the procedure. Various publications have shown advantage for the split-dose regimen regardless of method used [81,109–111]. Better preparation is seen in the cecum [111], and it seems to be attributed to less mucus and chyme. In the sulfate development studies (Table 10.4), there was an apparent significant advantage of split-dose administration.

Summary Adequate cleansing is required for safe and reliable colonoscopy. Poorly visualized mucosa leads to missed diagnoses and increased colonoscopic risk. Traditional cleansing methods have evolved from barium enema preparations and local experience, modified for colonoscopy and colon surgery. There are a wide variety of methods using diet restrictions with various purgatives and laxatives. Three popular colon preparation options are diet and cathartic regimens, gut lavage, and phosphate preparations. Early cleansing methods used 48–72 h of clear liquids with laxatives and enemas. When compared with clear liquid and minimum-residue diet methods, PEG-ELS was superior, with cleansing efficacy rated good or excellent. Phosphate preparations offer another alternative. The phosphate preparation has been rated as a better cleansing agent than the electrolyte solution but has a number of contraindications that must be considered. The diet has undergone many modifications over the years, and enemas are no longer considered necessary, even with the electrolyte or phosphate preparation. Cleansing practices vary widely, and there are many variations of the approved regimens. Outside the US, most of the preparations are widely available and the diet and laxative methods are popular. The endoscopist must be familiar with the various dietary requirements and the potential problems associated with the preparation regimen in order to ensure a safe and complete examination.

Preparation for Colonoscopy

References 1 Toledo TK, DiPalma JA. Review article: colon cleansing preparation for gastrointestinal procedures. Aliment Pharmacol Ther 2001; 15: 605–11. 2 ASGE Technology Status Evaluation Report. Colonoscopy preparations. Gastrointest Endosc 2001; 54: 829–32. 3 Neidich RL, Zuckerman GR. Patient preparation. In: Raskin JB, Nord HJ (eds.). Colonoscopy: Principles and Techniques. New York: Igaku-Shoin, 1995: 53–82. 4 Ernstoff JJ, Howard DA, Marshall JB, Jumshyd A, McCullough AJ. A randomized blinded clinical trial of a rapid colonic lavage solution (GoLytely) compared with standard preparation for colonoscopy and barium enema. Gastroenterology 1983; 84: 1512–16. 5 Strocchi A, Bond JH, Ellis C, Levitt MD. Colonic concentrations of hydrogen and methane following colonoscopic preparation with an oral lavage solution. Gastrointest Endosc 1990; 36: 580–2. 6 Kavin H, Sinicrope F, Esker A. Management of perforation of the colon at colonoscopy. Am J Gastroenterol 1992; 87: 161–7. 7 Rex DK, Imperiale TF, Latinovich DR, Bratcher LL. Impact of bowel preparation on efficiency and cost of colonoscopy. Am J Gastroenterol 2002; 97: 1696–700. 8 Bond JH, Levitt MD. Factors affecting the concentration of combustible gas in the colon during colonoscopy. Gastroenterology 1975; 68: 1145– 8. 9 Bigard MA, Gaucher P, Lassalle C. Fatal colonic explosion during colonoscopic polypectomy. Gastroenterology 1979; 77: 1307–10. 10 Bond JH, Levitt MD. Colonic gas explosion: is a fire extinguisher necessary? Gastroenterology 1979; 77: 1349–50. 11 Keighley MR, Taylor EW, Hares MM, et al. Influence of oral mannitol bowel preparation on colonic microflora and the risk of explosion during endoscopic diatherapy. Br J Surg 1981; 68: 554– 6. 12 DiPalma JA, Brady CE III, Stewart DL, et al. Comparison of colon cleansing methods in preparation for colonoscopy. Gastroenterology 1984; 86: 856– 60. 13 Monahan D, Peluso F, Goldner F. Combustible colonic gas levels during flexible sigmoidoscopy and colonoscopy. Gastrointest Endosc 1992; 38: 40–3. 14 Beebe TJ, Johnson D, Stoner SM, Anderson KJ, Limburg PJ. Assessing attitudes toward laxative preparation in colorectal cancer screening and effects on future testing: potential receptivity to computed tomographic colonography. Mayo Clin Proc 2007; 82: 666–71. 15 DiPalma JA, Brady CE. Colon cleansing for diagnostic and surgical procedures: polyethylene glycol-electrolyte lavage solution. Am J Gastroenterol 1989; 84: 1008–16. 16 Berry MA, DiPalma JA. Review article: orthograde gut lavage for colonoscopy. Aliment Pharmacol Ther 1994; 8: 391–5. 17 Cotton PB, Williams CB. Colonoscopy. In: Practical Gastrointestinal Endoscopy, 3rd edn. Oxford: Blackwell Scientific Publications, 1990: 160–223. 18 Schiller LR. Clinical pharmacology and use of laxatives and lavage solutions. J Clin Gastroenterol 1999; 28: 11–18. 19 Dahshan A, Lin CH, Peters J, Thomas R, Tolia V. A randomized, prospective study to evaluate the efficacy and acceptance of three bowel preparations for colonoscopy in children. Am J Gastroenterol 1999; 94: 3497–501.

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39 Tomlinson TL, DiPalma JA, Mangano FA. Comparison of a new colon lavage solution (GoLytely-RSS) with a standard preparation for air-contrast barium enema. Am J Roentgenol 1988; 151: 947–50. 40 DiPalma JA, Marshall JB. Comparison of a new sulfate-free polyethylene glycol electrolyte lavage solution versus a standard solution for colonoscopy cleansing. Gastrointest Endosc 1990; 36: 285– 9. 41 Froehlich F, Fried M, Schnegg JF, Gonvers JJ. Palatability of a new solution compared with standard polyethylene glycol solution for gastrointestinal lavage. Gastrointest Endosc 1991; 37: 325– 8. 42 Beck DE, DiPalma JA. A new oral lavage solution vs. cathartics and enema method for preoperative colonic cleansing. Arch Surg 1991; 126: 552– 5. 43 Froehlich F, Fried M, Schnegg JF, Gonvers JJ. Low sodium solution for colonic cleansing: a double-blind, controlled, randomized prospective study. Gastrointest Endosc 1992; 38: 579–81. 44 Raymond JM, Beyssac R, Capdenat E, et al. Tolerance, effectiveness, and acceptability of sulfate-free electrolyte lavage solution for colon cleaning before colonoscopy. Endoscopy 1996; 28: 555– 8. 45 Berry MA, DiPalma JA. Controlled comparison gas changes from cherry flavored and unflavored sulfate-free electrolyte lavage solutions. Gastroenterology 1995; 108: A5 (abstract). 46 Matter SE, Rice PS, Campbell DR. Colonic lavage solutions: plain versus flavored. Am J Gastroenterol 1993; 88: 49–52. 47 Rhodes JB, Engstrom J, Stone KF. Metoclopramide reduces the distress associated with colon cleansing by an oral electrolyte overload. Gastrointest Endosc 1978; 24: 162–3. 48 Brady CE III, DiPalma JA, Pierson WP. GoLytely lavage: is metoclopramide necessary? Am J Gastroenterol 1985; 80: 180–4. 49 Reiser JR, Rosman AS, Rajendran SK, Berner JS, Korsten MA. The effects of cisapride on the quality and tolerance of colonic lavage: a double-blind randomized study. Gastrointest Endosc 1995; 41: 481–4. 50 Ueda S, Iishi H, Tatsuta M, Oda K, Osaka S. Addition of cisapride shortens colonoscopy preparation with lavage in elderly patients. Aliment Pharmacol Ther 1994; 8: 209–14. 51 Martinek J, Hess J, Delarive J, et al. Cisapride does not improve precolonoscopy bowel preparation with either sodium phosphate or polyethylene glycol electrolyte lavage. Gastrointest Endosc 2001; 54: 180–5. 52 Lazarczyk DA, Stein AD, Courval JM, Desai D. Controlled study of cisapride-assisted lavage preparatory to colonoscopy. Gastrointest Endosc 1998; 48: 44–8. 53 Girard CM, Rugh KS, DiPalma JA, Brady CE III, Pierson WP. Comparison of GoLytely lavage with standard diet/cathartic preparation for double-contrast barium enema. Am J Roentgenol 1984; 142: 1147– 9. 54 Brady CE III, DiPalma JA, Beck DE. Effect of bisacodyl on gut lavage cleansing for colonoscopy. Ann Clin Res 1987; 19: 34–8. 55 Ziegenhagen DJ, Zehnter E, Tacke W, Gheorghiu T, Kruis W. Senna vs. bisacodyl in addition to GoLytely lavage for colonoscopy preparation: a prospective randomized trial. Z Gastroenterol 1992; 30: 17–19. 56 Adams WJ, Meagher AP, Lubowski DZ, King DW. Bisacodyl reduces the volume of polyethylene glycol solution required for bowel preparation. Dis Colon Rectum 1994; 37: 229–33.

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57 Sharma VK, Chockalingham SK, Ugheoke EA, et al. Prospective, randomized, controlled comparison of the use of polyethylene glycol electrolyte lavage solution in four-liter versus two-liter volumes and pretreatment with either magnesium citrate or bisacodyl for colonoscopy preparation. Gastrointest Endosc 1998; 47: 167–71. 58 Lazzaroni M, Petrillo M, Desideri S, Bianchi PG. Efficacy and tolerability of polyethylene glycol-electrolyte lavage solution with and without simethicone in the preparation of patients with inflammatory bowel disease for colonoscopy. Aliment Pharmacol Ther 1993; 7: 655– 9. 59 Lever EL, Walter MH, Condon SC, et al. Addition of enemas to oral lavage preparation for colonoscopy is not necessary. Gastrointest Endosc 1992; 38: 369–72. 60 Sharma VK, Steinberg EN, Vasudeva R, Howden CW. Randomized, controlled study of pretreatment with magnesium citrate on the quality of colonoscopy preparation with polyethylene glycol electrolyte lavage solution. Gastrointest Endosc 1997; 46: 541–3. 61 Di Palma JA, Wolff BG, Meagher A, Cleveland MvB. Comparison of reduced volume versus four liters sulfate-free electrolyte lavage solutions for colonoscopy colon cleansing. Am J Gastroenterol 203; 98: 2187–91. 62 Di Palma JA, McGowan J, Cleveland MvB. Clinical trial: An efficacy evaluation of reduced bisacodyl given as part of a polyethylene glycol electrolyte solution preparation prior to colonoscopy. Aliment Pharm Ther 2007; 26: 1113–19. 63 Ell C, Gruss H. Randomised and controlled clinical trial of polyethylene glycol with electrolytes and ascorbic acid in comparison to sodium phosphate for bowel preparation before colonoscopy. Gastrointest Endosc 2007; 65: AB328 (abstract). 64 Di Palma JA, Cleveland MvB, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007; 102: 1436– 41. 65 Wexner SD, Beck DA, Baron TH, et al. A consensus document on bowel preparation before colonoscopy: Prepared by a task force from 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). Gastrointest Endosc 2006; 63: 894– 909. 66 Siegel JD, Di Palma JA. Potential combustible gas production from agents used for colon cleansing. Am J Gastroenterol 2004; 99: S289 (abstract). 67 DiPalma JA, Brady CE III, Pierson WP. Colon cleansing: acceptance by older patients. Am J Gastroenterol 1986; 81: 652–5. 68 Lashner BA, Winans CS, Blackstone MO. Randomized clinical trial of two colonoscopy preparation methods for elderly patients. J Clin Gastroenterol 1990; 12: 405– 8. 69 Sondheimer JM, Sokol RJ, Taylor SF, Silverman A, Zelasney B. Safety, efficacy, and tolerance of intestinal lavage in pediatric patients undergoing diagnostic colonoscopy. J Pediatr 1991; 119: 148– 52. 70 Goodale EP, Noble TA. Pediatric bowel evacuation with a polyethylene glycol and iso-osmolar electrolyte solution. DICP 1989; 23: 1008– 9. 71 Tolia V, Fleming S, Dubois R. Use of GoLytely in children and adolescents. J Pediatr Gastroenterol Nutr 1984; 3: 468–70.

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72 Tolia V, Lin CH, Elitsur Y. A prospective randomized study with mineral oil and oral lavage solution for treatment of faecal impaction in children. Aliment Pharmacol Ther 1993; 7: 523–9. 73 Lifton LJ. On the safety of “Golytely” (letter). Gastroenterology 1984; 86: 214. 74 DiPiro J, Bowden TA, Sisley JF, Tedesco FJ. Golytely solution for colonoscopy preparation (letter). Gastrointest Endosc 1984; 30: 116–17. 75 Smyth HF, Carpenter CP, Weil OS. The toxicity of the polyethylene glycols. J Am Pharm Assoc 1950; 39: 349–54. 76 DiPalma JA, Brady CE III. On the safety of GoLytely. Gastroenterology 1984; 86: 215–16. 77 Stollman N, Manten HD. Angioedema from polyethylene glycol electrolyte lavage solution. Gastrointest Endosc 1996; 44: 209–10. 78 Schuman E, Balsam PE. Probable anaphylactic reaction to polyethylene glycol electrolyte lavage solution. Gastrointest Endosc 1991; 37: 411. 79 Brullet E, Moron A, Calvet X, Frias C, Sola J. Urticarial reaction to oral polyethylene glycol electrolyte lavage solution. Gastrointest Endosc 1992; 38: 400–1. 80 Vilien M, Rytkonen M. Golytely preparation for colonoscopy: 1.5 liters is enough for outpatients. Endoscopy 1990; 22: 168–70. 81 Rosch T, Classen M. Fractional cleansing of the large bowel with “Golytely” for colonoscopy preparation: a controlled trial. Endoscopy 1987; 19: 198–200. 82 Church JM. Effectiveness of polyethylene glycol antegrade gut lavage bowel preparation for colonoscopy: timing is the key! Dis Colon Rectum 1998; 41: 1223– 5. 83 Chiu H, Lin JL, Wang H, Lee YL, Wu M. The impact of colon preparation timing on colonoscopic detection of colorectal neoplasmsaa prospective endocopist-blinded randomized trial. Am J Gastroenterol 206; 101: 2719–25. 84 Vanner SJ, MacDonald PH, Paterson WG, Prentice RSA, DaCosta LR, Beck IT. A randomized prospective trial comparing oral sodium phosphate with standard polyethylene glycolbased lavage solution (GoLytely) in the preparation of patients for colonoscopy. Am J Gastroenterol 1990; 85: 422–7. 85 Frommer D. Cleansing ability and tolerance of three bowel preparations for colonoscopy. Dis Colon Rectum 1997; 40: 100–4. 86 Gremse DA, Sacks AI, Raines S. Comparison of oral sodium phosphate to polyethylene glycol-based solution for bowel preparation for colonoscopy in children. J Pediatr Gastroenterol Nutr 1996; 23: 586– 90. 87 Aronchick CA, Lipshutz WH, Wright SH, Dufrayne F, Bergman G. A novel tableted purgative for colonoscopic preparation: efficacy and safety comparisons with Colyte and Fleet PhosphoSoda. Gastrointest Endosc 2000; 52: 346–52. 88 Kastenberg D, Chasen R, Choudhary C, et al. Efficacy and safety of sodium phosphate tablets compared with PEG solution in colon cleansing: two identically designed, randomized, controlled, parallel group, multicenter phase III trials. Gastrointest Endosc 2001; 54: 705–13. 89 Kastenberg D, Choudhary C, Weiss E, Steinberg S and the INKP-100 Study Group. Sodium phosphate tablets (INKP-100 Diacol) are safe and effective as a purgative for colonoscopy. Am J Gastroenterol 1999; 94: 2673. 90 Rex DK, Chasen R, Pochapin MB. Safety and efficacy of two reduced dosing regimens of sodium phosphate tablets for

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preparation prior to colonoscopy. Aliment Pharmacol Ther 2002; 16: 937–44. Johnason JF, Popp JW, Cohen LB, et al. A randomized, multicenter study comparing the safety and efficacy of sodium phosphate tablets with 2 L polyethylene glycol solution plus bisacodyl tablets for colon cleansing. Am J Gastroenterol 2007; 102: 2238–46. Kolts BE, Lyles WE, Achem SR, Burton L, Geller AJ, MacMath T. A comparison of the effectiveness and patient tolerance of oral sodium phosphate, castor oil, and standard electrolyte lavage for colonoscopy or sigmoidoscopy preparation. Am J Gastroenterol 1993; 88: 1218–23. DiPalma JA, Buckley SE, Warner BA, Culpepper RM. Biochemical effects of oral sodium phosphate. Dig Dis Sci 1996; 41: 749–53. Schwetz BA. Oral sodium phosphate. JAMA 2001; 286: 2660. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD. Acute phosphate nephropathy following oral sodium, phosphate bowel purgative: An underrecognized cause of chronic renal failure. Am Soc Nephrol 2005; 16: 3389– 96. Sica DA, Carl D, Zfass AM. Acute phosphate nephropathybAn emerging issue. Am J Gastroenterol 2007; 102: 1844– 7. Pelham R, Dobre A, Van Diest K, Cleveland MvB. Oral sodium phosphate bowel preparations: How much hydration is enough? Gastrointest Endosc 2007; 65: AB314 (abstract). Chan A, Depew W, Vanner S. Use of oral sodium phosphate colonic lavage solution by Canadian colonscopists: pitfalls and complications. Can J Gastroenterol 1997; 11: 334– 8. Mackey AC, Shaffer D, Prizant R. Seizure associated with the use of Visicol for colonoscopy. N Engl J Med 2002; 346: 2095. Berkelhammer C, Ekambaram A, Silva RG. Low-volume oral colonoscopy bowel preparation: sodium phosphate and magnesium citrate. Gastrointest Endosc 2002; 56: 89– 94. Krawzak HW, Scherf FG, Hohlbach G. Pump-assisted intraoperative colon lavage. Chirurg 1995; 66: 1277– 9.

102 Pockros PJ, Foroozan P. Golytely lavage versus a standard colonoscopy preparation. Effect on normal colon mucosal histology. Gastroenterology 1985; 88: 545– 8. 103 Meisel JL, Bergman D, Graney D, Saunders DR, Rubin CE. Human rectal mucosa: proctoscopic and morphological changes caused by laxatives. Gastroenterology 1977; 72: 1274–9. 104 Schuman BM. When should colonoscopy be the first study for active lower intestinal hemorrhage? Gastrointest Endosc 1984; 30: 372–3. 105 Caos A, Benner KG, Manier J, et al. Colonoscopy after Golytely preparation in acute rectal bleeding. J Clin Gastroenterol 1986; 8: 46–9. 106 Jensen DM, Machicado GA. Diagnosis and treatment of severe hematochezia. The role of urgent colonoscopy after purge. Gastroenterology 1988; 95: 1569–74. 107 Aronchick CA. Bowel preparation scale. Gastrointest Endosc 2004; 60: 1037– 8. 108 Rostom A. Jolicoeur E. Validation of a new scale for the assessment of bowel prearation quality. Gastrointest Endosc 2004; 59: 482– 6. 109 Aoun E, Abdul-Baki H, Mourad F, et al. A randomized singleblind trial of split dose PEG-electrolyte solution without dietary restriction compared with whole dose PEG-electrolyte solution with dietary restriction for colonoscopy preparation. Gastrointest Endosc 2005; 62: 213–18. 110 Rostom A, Jolicoeur E, Dube C, et al. A randomized prospective trial comparing different regimens of oral sodium phosphate and polyethylene glycol-based lavage solution in the preparation of patients for colonoscopy. Gastrointest Endosc 2006; 64: 544– 52. 111 Parra-Blanco A, Nicholas-Perez D, Gimeno-Garcia A, et al. The timing of bowel preparation before colonoscopy determines the quality of cleansing, and is a significant factor contributing to the detection of flat lesions: A randomized study. World J Gastroenterol 2006; 12: 6161–6.

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Training in Colonoscopy Subhas Banerjee & Jacques Van Dam Stanford University School of Medicine, Stanford, CA, USA

Introduction Over 14 million colonoscopies are performed each year in the US, predominantly by gastroenterologists (> 80%), with smaller numbers being performed by surgeons (> 10%), primary care physicians, and nurse practitioners [1]. Colonoscopy is a potentially complex procedure and, even in expert hands, approximately 3–5% of procedures cannot be completed [2]. Similarly, techniques associated with colonoscopy, such as polypectomy involving large or flat polyps or volvulus reduction, may be relatively complex and fraught with risk of complications. To guarantee high-quality colonoscopic practice, it is evident that thorough training in the procedure and stringent credentialing standards are desirable. However, colonoscopists have varied learning experiences: while some receive structured training within fellowships in gastroenterology, others merely receive brief instruction as part of short courses, and some are largely self-taught. The American Society for Gastrointestinal Endoscopy (ASGE) and the American Gastroenterological Association (AGA) have published guidelines for credentialing and granting privileges for colonoscopy [3,4]. However, at present, few endoscopy units appear to follow these credentialing guidelines [5]. In this chapter we seek to define and discuss the goals of training in colonoscopy, measures of competency, and issues related to training/retraining in the procedure.

Training to competency in colonoscopy Training to competency in colonoscopy involves developing a combination of technical skills (ability to manipulate the colonoscope and its accessories) and cognitive skills (interpretation of findings and integration of those findings into a

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

management plan for the patient). The ASGE has defined competence as the minimum level of skill, knowledge, and/or expertise, derived through training and experience, required to safely and proficiently perform a task or procedure [3]. The ASGE guideline further details components of competency acquired in a gastrointestinal (GI) endoscopy training program as including: • sound general medical or surgical training; • the ability to integrate endoscopy into the overall clinical evaluation of the patient; • thorough understanding of the indications, contraindications, individual risk factors, and benefit–risk considerations for the individual patient; • the ability to clearly describe the endoscopic procedure and obtain informed consent; • knowledge of endoscopic anatomy, technical features of the endoscope, and accessory endoscopic techniques and therapies; • the ability to accurately identify and interpret endoscopic findings; • a thorough understanding of the principles, pharmacology, and risks of sedation/analgesia; • the ability to document endoscopic findings and therapy, and communicate with referring physicians; • competent performance of the procedure [3]. The ASGE position is that training should occur within the context of a clinical training program in gastroenterology or general surgery. This allows for the laying of a robust foundation of cognitive skills, prior to embarking on developing technical skills of colonoscopy.

Components of an ideal training program Endoscopy training programs vary widely in the manner of training, the degree of formal structure in the training process, and the content of technical and cognitive input. Thus, each year, colonoscopists with widely disparate skills graduate from training programs across the US. Although there will inevitably be differences in training programs reflecting the local mix of service needs, numbers of trainees, and numbers

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and quality of trainers, certain “core” components of training are essential for any program that aims to graduate competent endoscopists.

Achieving technical skills in “basic colonoscopy” Technical skills in colonoscopy are acquired through a gradual and incremental process of “hands-on” experience under the guidance of a supervising endoscopic trainer, usually an attending gastroenterologist or surgeon. Typically, trainees observe a few procedures prior to attempting to perform limited colonoscopic procedures. Initial attempts may amount to little more than flexible sigmoidoscopy. Careful scope withdrawal techniques maximizing visualization of the colonic mucosa should be introduced early in the learning process. In the initial stages of learning, the endoscopic trainer will probably intervene early and frequently in the interests of patient safety and comfort. As the trainees gradually become more technically adept and acquire a greater understanding of, and control over, colonoscopic manipulation, they will make greater progress and advance the scope more proximally into the colon, until eventually splenic flexure, then hepatic flexure, and cecal and terminal ileal intubation are achieved. Training in techniques of loop reduction will be necessary to allow more proximal advancement of the colonoscope. Subsequently, or simultaneously, with increasing familiarity and comfort with the procedure, trainees will obtain mucosal biopsies and attempt therapeutic interventions such as simple polypectomies. As trainees develop their skills and are able to perform colonoscopy with reasonable safety and patient comfort, the need for intervention by the trainer decreases sequentially to a point at which the trainee can be deemed to have achieved competence in the basic procedure.

Achieving technical skills in advanced colonoscopic techniques Training of fellows in more advanced colonoscopic techniques such as endoscopic mucosal resection of flat polyps and piecemeal resection of large polyps remains difficult logistically. First, training in these techniques can and should be attempted only once the basic skills of colonoscopy and polypectomy have been aquired, typically late into the second year or early in the third year of fellowship training, leaving little time for learning advanced techniques. Furthermore, these pathologies are seen in only a small minority of colonoscopies performed, and the likelihood of the fellow being present for these procedures is even smaller. Finally, the attending physician may not feel comfortable allowing the fellow to take on these increased risk techniques due to a combination of patient safety concerns and liability issues. Many colonoscopists therefore acquire these skills independently following the completion of fellowship. This is consistent with observations that competency continues to improve following completion of fellowship training. How-

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ever, ideally, teaching of these advanced skill sets should be part of the colonoscopy training program. One possible solution is to have third-year fellows based at the endoscopy unit for intensive training blocks in more advanced techniques. During this time, they should be “available” to join any endoscopist detecting large polyps or other advanced pathology in any of the endoscopy rooms. This approach should maximize trainees’ exposure to advanced techniques.

Ancillary training curriculum The colonoscopy trainee must have an understanding of colonic anatomy, diseases of the colon, and the role of colonoscopy in the diagnosis and management of these conditions. This knowledge will be acquired by a combination of didactic learning, directed reading, and endoscopy teaching conferences. It is important that trainees not only understand the indications and contraindications of colonoscopy but also appreciate the limitations of, and complications associated with, the procedure. Similarly, they should be versed in interventional radiologic, surgical and pharmacologic alternatives to colonoscopic therapy. In the course of procedural training, they will concurrently acquire knowledge of safe sedation techniques and sedation reversal agents. Similarly, skills in generation of reports, communicating findings to referring physicians, and integrating findings into an overall management plan will develop over the course of their training.

An ideal fellowship training program for colonoscopy In addition to the basic progression of training as described above, we believe that attention to other details can significantly enhance the process of training.

Availability of additional cognitive resources The American Society for Gastrointestinal Endoscopy guidelines pertaining to endoscopic practice The ASGE website (www.asge.org) has several useful guidelines pertaining to colonoscopic practice, including guidelines on informed consent [6], bowel preparation for colonoscopy [7], conscious sedation for endoscopic procedures [8], and antibiotic prophylaxis prior to endoscopic procedures [9]. In addition, this useful website also has guidelines pertaining to the role of colonoscopy in specific colonic pathologies. Review of these focused guidelines should form the cognitive core of any colonoscopy training program. This will ensure quality in patient selection for procedures as well as satisfactory preparation and processing of patients prior to and following their colonoscopic procedure. These guidelines may be printed out and organized in a binder for easy perusal by trainees. In addition, review of these guidelines should be incorporated into the training core curriculum organized by

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the fellowship director or a series of didactic lectures organized by the director of endoscopy.

The American Society for Gastrointestinal Endoscopy first-year fellows’ endoscopy course The ASGE runs a weekend endoscopy course for first-year gastroenterology fellows at Oakbrook, IL, US, each year. This course offers an excellent primer for the novice endoscopist as it incorporates a select mix of essential didactic lectures, endoscopy videos, and hands-on training in endoscopic accessories. The course is fully funded and trainees attend at no personal cost. Every effort should therefore be made by the fellowship program to free its first-year fellows to attend this course. In addition, many local endoscopy societies offer smaller scale courses for first-year fellows. Additional courses in more advanced endoscopic techniques appropriate for more advanced trainees are available at the Digestive Disease Week and are also run by other academic centers in the US throughout the year.

Endoscopic atlases/video A large amount of cognitive information can be acquired by perusal of endoscopic atlases or by watching previously created videos of procedures. The DAVE (Digital Atlas of Video Education) project is one such development fostered by the ASGE. The underlying philosophy driving this project is that a video clip, rather than a static image, best captures the true essence of endoscopy, which is essentially a dynamic process. The website (www.daveproject.org) is easily accessible over the Internet and has a multitude of videos pertaining to the practice of endoscopy and other instructional material including pathology slides and didactic lectures. Fellows in training should be encouraged to access this website. Ideally, access should be possible through computers at the endoscopy unit. Access may be encouraged by making this the default “home page” of web browsers in the endoscopy unit computers. This will be beneficial in busy programs, where the trainee may have only a few minutes during room turn-around between procedures to access this teaching material. In addition, several excellent videos pertaining to basic and advanced colonoscopy techniques, polypectomy, and management of lower GI bleeding are available through the ASGE. The endoscopy director should consider creating a library of books, atlases, and videos within the endoscopy unit and making them freely available for review by trainees.

Use of simulators for training in colonoscopy (see Chapter 14) Simulators have been available since the late 1990s but have failed to find widespread favor with training programs as their benefits appear to be negligible. Sedlack et al. [10] compared competency at colonoscopy in novice GI fellows who completed a 6-h colonoscopy simulator curriculum and those who were not previously simulator trained. Although

Training in Colonoscopy

simulator-trained fellows outperformed traditionally trained fellows during their initial 15 colonoscopies in most performance aspects, beyond 30 patient-based procedures there was no difference in performance of the two groups in any of several performance parameters. Similar results were noted in a larger multicenter US study [11], in which first-year GI fellows were randomized to receive either 10 h of unsupervised training on a colonoscopy simulator or no simulator experience, following which both groups began performing real colonoscopies. Fellows in the simulator group had significantly higher objective competency rates during the first 100 cases. However, the median number of cases needed to reach 90% competency was 160 in both groups, and patient comfort levels were similar. Thus, the usefulness of simulators remains debatable. Clearly, simulator training is of some benefit, albeit transitory, compared with receiving no training at all. This conclusion is intuitive. It is, however, unlikely that simulator-trained fellows will outperform fellows who receive the same number of hours of training on real patients. Thus, in a study comparing residents simulator trained in flexible sigmoidoscopy with residents receiving traditional supervised training in real patients, the traditionally trained residents outperformed the simulator-trained residents [12]. It is conceivable that simulators may be of some benefit to trainees in specialties whose access to colonoscopic procedures may be limited, or whose certifying bodies demand smaller threshold numbers to determine competence, such as surgical residents training in colonoscopy or internal medicine/family practice residents training in flexible sigmoidoscopy.

Role of endoscopy director and endoscopy trainers The input of the director of endoscopy is essential in creating an environment in which trainees can maximize their learning experience during their rotations through the endoscopy unit. It is important that the chairman of the division and the fellowship program director “buy into” the process, thereby creating the necessary financial resources and trainee time to maximize the efficiency of the endoscopic learning process. The director of endoscopy can define trainee space within the endoscopy unit and can ensure that the cognitive resources and learning library discussed above are available to trainees. The director may also organize a year-round series of didactic lectures and teaching conferences pertaining to endoscopy and may also set up a grading system to assess the progress of trainees. The director may also play a central role in encouraging trainee participation in endoscopic research.

Additional questions Should trainees first master the basics of upper GI endoscopy prior to commencing training in colonoscopy? In many training programs, trainees are required to be reasonably adept at upper GI endoscopy prior to commencing training in colonoscopy. Proponents of this approach argue that

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esophagogastroduodenoscopy (EGD) is a simpler procedure and allows accumulation and consolidation of skills related to eye–hand coordination and manual dexterity. This is therefore seen as an essential building block prior to tackling the more complex manual skill set needed for performing colonoscopy. However, there are no data to suggest that simultaneous commencement of training in colonoscopy is detrimental in any fashion. Rather than have the trainees “stand aside” for colonoscopies early in their training, we feel that any opportunity for “hands-on” scope experience is important and should not be missed. Thus, we would recommend that the novice trainee be at least allowed a small amount of time at colonoscopy procedures with limited goals such as simply negotiating the sigmoid colon.

Is it better for trainees to perform a few cases on a daily basis throughout the period of training or are more intensive blocks of endoscopic training preferable? We believe that in the first and perhaps second year of training, performing a few cases on a daily or near-daily basis is essential to build and maintain manual skills and also to increase trainee confidence. In the third year, intensive blocks of training, during which the trainee is primarily based at the endoscopy unit, may be more suitable for acquiring advanced techniques.

How can trainees maintain colonoscopy skills at graduation? In many academic gastroenterology programs, the third year of fellowship functions as a “specializing” or “career-building” year, when trainees focus on a subspecialty within gastroenterology which they plan to pursue later in their career. A great deal of time may be devoted to research and subspecialty clinics during this year. In addition, fellows on the basic science track may spend the vast majority of their time in the laboratory, with only minimal exceptionsausually their continuity clinic. This approach may result in a dilution of previously acquired endoscopic experience and a loss of confidence in tackling more complex cases. This is unfortunate, as the graduating fellow needs, more than at any previous time, to be as well trained as possible. Immediately following graduation, fellows will be expected to tackle all manner of routine and emergent procedures on their own, without the luxury of having a “trainer” to back them up in difficult situations. This is, therefore, a period of high anxiety for most graduating fellows, and several in academic practice choose to forgo more complex procedures, such as in patients with GI hemorrhage, limiting their practice to diagnostic procedures. This unfortunate “skill drain” burdens the rest of the GI faculty. Training programs should therefore encourage continuation of endoscopic experience during the third year for all fellows and in particular for those planning to pursue clinical gastroenterology in academic or practice settings.

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Assessing training Assessment of competency Assessment of competency is important in the granting of privileges by hospitals, which seek to maximize patient safety and limit potential liability exposure. Assessment of competency and the granting of hospital privileges are largely based on attainment of minimum “threshold” numbers of procedures completed. Although threshold numbers are an inadequate measure of skill, in the absence of other universally accepted criteria they have become a surrogate means of assessing competency. In addition, the threshold numbers required to be deemed “competent” are based on widely disparate expert opinions and vary between differing professional societies. A trend is evident, wherein specialties performing lower overall numbers of the procedure appear to endorse lower threshold numbers (Table 11.1). Thus, the American Academy of Family Practice suggests that short courses are adequate for training in colonoscopy. Their website (www.aafp.org) suggests that numbers as low as five procedures should suffice to allow colonoscopy privileges and argues that the higher threshold numbers suggested by specialty societies are “arbitrary and self serving.” The Society of American Gastrointestinal Endoscopic Surgeons (SAGES) previously recommended 25 procedures [13], although it no longer specifies numbers at its official website (www.sages.org). Surgical residents at our institution are required to complete 50 colonoscopies in the course of their residency training. The ASGE suggests a minimum threshold number of 140 procedures. This number is easily achieved by clinical gastroenterology fellows in training. As trainees acquire colonoscopy skills at varying rates, threshold numbers can never be more than a rough guide to competence. The ASGE suggests, based on available data, that trainees, in addition, should be able to achieve an 80–90% technical success rate at colonoscopy before being deemed competent in the procedure [14]. Others have proposed cecal intubation rates of at least 90% and cecal intubation times of < 15 min in at least half of the colonoscopies performed as measures of competence [15]. If these measures of

Table 11.1 Suggested minimum colonoscopy numbers required to attain competency. US professional societies

Year

Threshold number

American Academy of Family Practice Society of American Gastrointestinal Endoscopic Surgeons American Society for Gastrointestinal Endoscopy

2000 1991

∼ 10 25

1998

140

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competence are to be followed, the ASGE threshold number may be too low. Marshall [16] demonstrated that secondyear fellows achieved success rates of 86% in reaching the cecum after an average of 328 colonoscopies.

Assessing colonoscopy skills in trainees As with most other complex skill sets, a learning curve exists for colonoscopy. Marshall [16] evaluated the success rates of GI fellows in reaching the cecum in < 30 min in the second half of their first and second years of fellowship training; overall success rates increased with experience, with those of first-year fellows being 54%, second-year fellows being 86%, and those of their instructors being 97%. There was a corresponding decrease in time to cecal intubation with increase in the level of training. Acquisition of skills in colonoscopy may be enhanced by objective evaluation and grading of trainee performance at colonoscopy, with provision of feedback and constructive criticism to trainees. It is recognized, however, that it is difficult to get proctors to grade trainees. For full compliance with grading, grading may need to be linked to the production of the colonoscopy report [17].

Maintaining competency Maintenance of competency requires continual performance of procedures. When procedures are performed with reasonable frequency, competency can be expected to continue to improve following completion of fellowship training. However, technical skills and cognitive competence may deteriorate with decreased frequency of performance of procedures [18]. Institutions should therefore define the threshold number of colonoscopies performed per year which would suffice for renewal of privileges [18]. There are few data to indicate how much continuing experience is necessary in order to maintain competency. In a survey of gastroenterologists, respondents indicated that 50 procedures were necessary each year to maintain competency in EGD and colonoscopy [19]. The Joint Commission on the Accreditation of Healthcare Organizations has mandated that endoscopic privileges should be renewed at least every 2 years [20].

Retraining Training in new techniques after completion of fellowship As colonoscopic technologies and techniques continue to evolve, gastroenterologists who have completed fellowship training may wish to be trained in these new techniques. Thus, new technologies for colonic evaluation are being developed, such as capsule colonoscopy and computed tomographic colonography (CTC). In addition, several new kinds of colonoscopes are being developed. Should these become mainstream

Training in Colonoscopy

technologies, gastroenterology and surgical fellows can expect to acquire competence in them during their years of training. However, gastroenterologists already in practice who have not received formal training in these procedures will need to acquire these skills via alternate avenues. By and large, these new techniques and technologies can be expected to represent at most mild to moderate refinements of previously established colonoscopy skills. As such, the use of teaching resources, such as instructional books, manuals, and digital media including DVD and interactive computer programs, together with attending a short course, should suffice for adequate training [14,21]. Thus, the AGA is currently offering courses in CTC to its membership. Should this successfully become a widely accepted technology, one can anticipate training in CTC being part of gastroenterology training programs.

Retraining of a previously credentialed endoscopist In some instances, an endoscopist who has relinquished privileges due to nonperformance of an established minimum number of procedures may wish to reestablish privileges. In this situation, renewal of privileges after proctoring to confirm competence, or granting of conditional privileges with specific requirements for reeducation and/or proctoring, may be reasonable approaches [18]. From time to time, based on evaluation of complication rates, procedure completion rates, overall quality of care, and other measures of competence, endoscopists may be deemed to be suboptimally trained by institutional quality improvement/assurance committees. Less frequently, the endoscopist may be deemed incompetent to perform colonoscopy and his or her privileges denied or revoked. This situation may arise from a failure of the credentialing process, with granting of endoscopy privileges to a suboptimally trained endoscopist. Many GI endoscopy centers in the US have no minimum standards for determining endoscopic competence. Sharma et al. [5] conducted an anonymous mail survey at GI endoscopy centers across the US and received responses from 479 centers in 46 states. They note that, for initial endoscopic credentialing, few centers required a minimum number of procedures, with only 10% meeting ASGE criteria. Even at academic endoscopy centers, only 39% of responding centers met ASGE criteria for minimum numbers of colonoscopic procedures prior to granting of privileges. Suboptimal competence may also arise from deterioration in skills as a consequence of infrequent performance of colonoscopy. The latter situation should easily be detected if ASGE guidelines for renewal of privileges are followed [18]. However, again in the survey of Sharma et al. [5], only 2% of responding of endoscopy centers required > 25 procedures a year to maintain endoscopic privileges. Where incompetence is determined, the gastroenterologist involved may choose to rectify matters by seeking further training. However, the logistics of where and how to seek

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further training may prove difficult. We are aware of gastroenterologists who have contacted their fellowship training programs several years following graduation, for consideration of further training in procedures. However, this has usually not been possible as taking them on would dilute the training experience of current fellows within the program. The gastroenterologist may therefore seek to train with/be proctored by other colleagues at his or her institution. Liability issues may exist, but this avenue may logistically be the easiest one to arrange. Ideally, this form of remedial training should be performed under the supervision of the director of endoscopy at the institution, or at least with an endoscopist with advanced endoscopy training credentials. A further solution may be attendance at a colonoscopy training course. Thomas-Gibson et al. [22] were able to show that a week-long accelerated colonoscopy training course using simulators and live training was able to improve skills of previously inadequately trained endoscopists, as measured at the end of the course and at a median follow-up of 9 months.

References 1 Seeff LC, Manninen DL, Dong FB, et al. Is there endoscopic capacity to provide colorectal cancer screening to the unscreened population in the United States? Gastroenterology 2004; 127: 1661–9. 2 Lieberman DA, Weiss DG, Bond JH, Ahnen DJ, Garewal H, Chejfec G. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. N Engl J Med 2000; 343: 162–8. 3 American Society for Gastrointestinal Endoscopy. Guidelines for credentialing and granting privileges for gastrointestinal endoscopy. Gastrointest Endosc 1998; 48: 679– 82. 4 Hospital credentialing standards for physicians who perform endoscopies. Gastroenterology 1993; 104: 1563. 5 Sharma VK, Coppola AG Jr., Raufman JP. A survey of credentialing practices of gastrointestinal endoscopy centers in the United States. J Clin Gastroenterol 2005; 39: 501–7. 6 Informed consent for gastrointestinal endoscopy. Gastrointest Endosc 1988; 34: 26S–27S. 7 Wexner SD, Beck DE, Baron TH, et al. A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS),

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the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Gastrointest Endosc 2006; 63: 894–909. Waring JP, Baron TH, Hirota WK, et al. Guidelines for conscious sedation and monitoring during gastrointestinal endoscopy. Gastrointest Endosc 2003; 58: 317–22. Hirota WK, Petersen K, Baron TH, et al. Guidelines for antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 2003; 58: 475–82. Sedlack RE, Kolars JC. Computer simulator training enhances the competency of gastroenterology fellows at colonoscopy: results of a pilot study. Am J Gastroenterol 2004; 99: 33–7. Cohen J, Cohen SA, Vora KC, et al. Multicenter, randomized, controlled trial of virtual-reality simulator training in acquisition of competency in colonoscopy. Gastrointest Endosc 2006; 64: 361–8. Gerson LB, Van Dam J. A prospective randomized trial comparing a virtual reality simulator to bedside teaching for training in sigmoidoscopy. Endoscopy 2003; 35: 569–75. Surgery SoAGE. Granting Privileges for Gastrointestinal Endoscopy by Surgeons. SAGES publication no. 11. Los Angeles: Society for American Gastrointestinal Surgeons, 1991. American Society for Gastrointestinal Endoscopy. Principles of training in gastrointestinal endoscopy. From the ASGE. Gastrointest Endosc 1999; 49: 845–53. Chak A, Cooper GS, Blades EW, Canto M, Sivak MV, Jr. Prospective assessment of colonoscopic intubation skills in trainees. Gastrointest Endosc 1996; 44: 54–7. Marshall JB. Technical proficiency of trainees performing colonoscopy: a learning curve. Gastrointest Endosc 1995; 42: 287–91. Cass OW, Freeman ML, Peine CJ, Zera RT, Onstad GR. Objective evaluation of endoscopy skills during training. Ann Intern Med 1993; 118: 40–4. American Society for Gastrointestinal Endoscopy. Renewal of endoscopic privileges: guidelines for clinical application. From the ASGE. Gastrointest Endosc 1999; 49: 823– 5. Wigton RS, Blank LL, Monsour H, Nicolas JA. Procedural skills of practicing gastroenterologists. A national survey of 700 members of the American College of Physicians. Ann Intern Med 1990; 113: 540– 6. Hospitals JCCAMf. 1997. American Society for Gastrointestinal Endoscopy. ASGE Guidelines for clinical application. Methods of privileging for new technology in gastrointestinal endoscopy. Gastrointest Endosc 1999; 50: 899–900. Thomas-Gibson S, Bassett P, Suzuki N, Brown GJ, Williams CB, Saunders BP. Intensive training over 5 days improves colonoscopy skills long-term. Endoscopy 2007; 39: 818–24.

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Teaching Aids in Colonoscopy Roque Sáenz Universidad del Desarrollo, Santiago, Chile

People have one thing in common . . . They are all different. Robert Zen

Introduction Diagnostic and therapeutic endoscopy has been in continuous technological evolution, replacing traditional surgery for many gastrointestinal disorders. Colonoscopy is not the exception, and new techniques, procedures, and instruments are continually being introduced. The neophyte colonoscopist needs supplementary learning materials, and those in practice need to enhance and upgrade their knowledge base and keep abreast of new developments in the field. The performance of endoscopy requires cognitive and technical skills, professionalism, and competency. Historically, endoscopic training has consisted primarily of “learning by doing,” under the supervision of an experienced endoscopist. There are several teaching aids that may be of assistance in enhancing a person’s knowledge base, acquiring information about new or different procedures, and watching the experts perform procedures. In addition to video transmissions, there are multiple other teaching aids for upgrading knowledge in the field of endoscopy. Unfortunately, none of them enhances the skill level of a person in the performance of a procedure, although some may help to understand a new technique to add to skills already learned. Personal trainer/trainee supervision interaction is essential and not replaceable. In spite of the strides taken in the field of transfer of information through books, atlases, scientific papers, videotape recordings, and the Internet, there are no substitutes for the actual performance of a procedure and being tutored by an experienced person. However, enhancing the knowledge base of the endoscopist by exposure to teaching aids in colonoscopy will be of immense assistance in being able to more rapidly acquire the skills necessary for the performance of procedures

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

when exposed to the standard teaching method under the supervision of an experienced endoscopist. Improvement in the performance of colonoscopy and adoption of new technology or applications [magnification, tattooing, NBI (narrow-band imaging), FICE (Fuji intelligent chromo endoscopy), or NOTES (natural orifice transluminal endoscopic surgery), for instance] are requisites for practicing colonoscopy, both for trainees as well as for experienced endoscopists. The American Society for Gastrointestinal Endoscopy (ASGE) and other organizations have prepared guidelines for training in endoscopic procedures for a variety of gastrointestinal diseases [1–3]. However, procedural aspects are one part of the entire information activity for endoscopists. Knowledge of the ongoing thrust for continuous quality improvement will assure the appropriateness of indication and performance, reduce costs, and shorten the endoscopy unit’s waiting lists [4]. The learning process path could be designed as follows: observation, simulation and ex vivo models, hands-on, workshop, and practice. The “quality control” concept in colonoscopy [5] should be considered as the final outcome of the teaching process [6–11]. Those concepts and other guidelines, as well as the assessment of competency, credentialing, and methods of training (including use of ancillary tools such as simulators) [12], are all discussed in other chapters. This chapter reviews the use and availability of teaching aids for both the learning process and updating cognitive and technical skills. Several formats of teaching aids are considered (Table 12.1).

Role of teaching aids Considerable controversy has been engendered by setting a minimal threshold of procedure numbers during training. The actual issue is to achieve competency in procedural performance, but technical competency is difficult to achieve for many procedures, particularly those that involve therapy. Certainly, everyone requires considerably more cases than

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Table 12.1 Teaching aids spectrum. Text and atlases (photographic images) Electronic multimedia, e-training Video, CD-ROM, DVD drivers Internet and Internet 2 Home television Teaching courses Video-based courses, “simulcast” Live courses Small group sessions Live remote transmission Telemedicine centers Video analysis Ancillary tools, animal models (ex vivo) Computerized simulator models (see Chapter 14) Training centers Others . . .

scopy, as have relevant related bibliographies and texts on colonoscopy. However, these images have little, if any, value in the development of technical skills. There are numerous textbooks [18–21] that contain both detailed descriptions of the performance of gastrointestinal endoscopy and highquality photographic images of both normal and pathologic endoscopic anatomy. In addition to the classical texts, a variety of atlases of endoscopic findings are available [22–25], including those digitized online. These compilations enable the reader to upgrade cognitive skills but are not useful for self-development of the manipulative aspects of endoscopic procedures. For example, GastroSlides (formerly the Gastroenterology Teaching Project; www.gastroslides.org), which uses only high-quality images, is a continuing education resource directed by the Education and Training Committee of the American Gastroenterological Association Institute.

Electronic media stated in various guidelines in order to achieve acceptable competency. A large volume of endoscopic procedures is not practical in all training programs and, therefore, many endoscopists add skills themselves after becoming proficient in basic procedures. Although it is important for basic training in endoscopy to be undertaken with an experienced endoscopist, the creation of new procedures or the acquisition of new skills is often undertaken by endoscopists who feel confident about the level of their endoscopic skills [13]. Computer, virtual reality, and model simulation use (Colo EASIE–Erlangen, Simbionix GI Mentor, Accu Touch, etc.) [14–17] are becoming popular, but mentoring and personal targeted training are essential and cannot be replaced. A new diagnostic noninvasive armamentarium that includes three-dimensional imaging, genetic testing, molecular biology, etc., has moved colonoscopy from diagnostic to frequently therapeutic procedures, which require the most skilled endoscopists. Teaching aids for endoscopy are intended to enable endoscopists to perform their work more productively, to shorten the training period, to prevent complications, and to improve patient safety, comfort, and cost-effectiveness. The variety of available formats provides individuals with alternative means to visualize the techniques of procedure performance. These methods of observing the experts “in action” are of use both during the initial learning period and in the upgrading of endoscopic skills. Each of the formats has its advantages and drawbacks.

Text with photographic images The use of slides or photographic endoscopic images (atlases) has definite value for learning the cognitive aspects of endo-

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The “live” patient situation cannot be fully duplicated by modern training models (see Chapter 14) and video formats, although current and developing electronic video formats do offer a substantial library of high-quality images allowing close-up observation of the “expert” and ancillary personnel in the performance of specific procedures. The advantages provided by these information and communication technologies include efficient distribution, low cost, and the ability to access any part of the content at any time and place. Options for distribution and storage of the information have recently expanded, and in addition to media such as videotape, CDROM, DVD, USB flash drive, and VUDU, much information can now be downloaded from the Internet and telephone, television, and satellite networks at little or no cost. Electronic images can be exchanged and viewed via MP4 players, iPods, CD players, computer-to-computer transfer via modem, downloading from the Internet, and direct satellite transmission. With the advent of smartphones and low transmission costs, videos, such as live courses or demonstrations, electronic live consulting, etc., are now readily accessible. The enormous capacity of video storage permits a personal or institutional video library. VUDU can store more than 5000 films obtained from the Internet, TiVo HD can store 180 GBa180 h or 20 h of normal or high-definition recording.

Videotape Videotapes are now an old-fashioned medium and have largely been replaced by DVD format and online storage. In addition, these magnetic tapes progressively lose definition with time whereas digital formats maintain their information permanently. For this reason, much material currently available on videotape is currently being converted into DVD format. However, the ASGE holds a library of videotapes of material presented at the learning centers held at the annual

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Digestive Disease Week in the US and these can be purchased via the ASGE website (www.asge.org). Videotapes are available on a large number of topics. They are sometimes directed to the learning endoscopist with minimal experience, but most are aimed at experienced endoscopists, showing the performance of highly technical cases, or incorporating new technology, new knowledge, or topic-oriented material. Most importantly, videotapes can be viewed on hardware that is available to nearly everyone. The major drawback of videotapes is that they do not enable random access. Forward and rewind functions take time and are not accurate. Frame analysis is usually of poor quality. “Bookmarking” for return to an image or section to allow repeat or rapid review is not possible. Slow-motion function is not precise for individual frames and the resolution quality of both the video and the still images is not as good as that of other formats. In addition, video consumes more storage space than digital media. Since detailed analysis is a desirable part of the viewing process, the videotape format is best used for overall observation of a story or case review, to watch an expert, or for receiving ancillary directions and “tricks” of procedure performance.

Multimedia CD-ROM A variety of video endoscopic materials have become available from both the endoscopic and pharmaceutical industry, primarily for promotional purposes. Many of these are of good quality and offer the advantage of interactivity, which is not available with videotapes. The interactive environment and the ability to use these disks on portable computers have brought another dimension to the learning process. The viewer can navigate through the “menu,” quickly selecting the location for review and re-review. Sections can be eliminated from view, thereby conserving and optimizing viewing time. Study of disk content can be carried out in airplanes, on vacation, or at the office, in effect anywhere that the personal computer laptop can be taken. Other valuable features that can be incorporated include (i) the ability to download slide material or video segments for teaching purposes; and (ii) interactive quizzes. The limitations of the CD-ROM format are its small picture size and relatively inferior resolution. Motion flaws are common, and the limited capacity of the disk does not allow a large number of video cases or additional video material to be included. The disk must be prepared in advance to play on the commonly available hardware platforms. For a variety of reasons, usually related to production costs, not all disks can be played on Macintosh computers. This medium is satisfactory but has not progressed as the most desirable format for teaching or self-learning.

Teaching Aids in Colonoscopy

DVD DVD has become the main video delivery format, because of its capacity and widespread availability. This format offers full-motion high-resolution video with interactive user interfaces at far greater storage capacity than the CD-ROM format. The disks are compatible with personal computer CD and DVD drives, and are often available in multiple language tracks. They offer advantages for medical education such as ultraslow motion, accurate freeze frame, and enhanced audio. Alternate angles of view can be incorporated, which will allow ancillary personnel to study the same material from the perspective of the endoscopic assistant. DVDs are available on diagnostic and therapeutic topics in extended therapeutic areas with self-study quiz sections, and also on specific topics comprising shorter “experts” series. Both CDs and DVDs allow the technical and cognitive aspects of each case performance to be studied, with narration by the performing endoscopist. The endoscopic, fluoroscopic, and ultrasound images are coordinated with the visual technical aspects of procedure performance by the endoscopist and ancillary personnel. Most computers play DVDs and viewers are no longer required to sit in front of their television sets; they can watch DVDs in the car, on the train, or even at work using a laptop computer or a small portable DVD player. The cost of manufacturing these disks is less than half that for a half-inch cassette. DVDs have changed the way individuals watch movies at home. The enhanced video and audio qualities allow elaborate home theater systems. The digital nature of DVD allows viewers to watch only one or two important moments instead of a whole film, much like a favorite track on a CD. This changes video from a linear experience to a more interactive one. It is anticipated that study habits of endoscopic material will follow the same trends. DVD format has become an “ordinary” consumption device. The costs of conversion from videotape to disk are minimal in comparison with other available formats for endoscopic learning. The next generation of DVD is the high-definition DVD, for which Blu-ray has emerged as the format that will be commercially available. High-definition DVDs will enable dissemination of DVDs, with images having equal resolution to that achievable in the endoscopy unit. This should enhance teaching of techniques dependent on high resolution such as NBI (Olympus) and the FICE system (Fujinon).

Internet (e-learning/e-training) The Internet has become the universal broadcast medium and has improved education in medicine [26]. The advantages of streaming media include: • immediate broadcast of the latest innovations; • the presentation of synchronized lecture slides with digitally recorded narration;

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• high-quality moving endoscopic images; • accessibility around the world and around the clock. For teaching or learning purposes (e-learning) this format provides fast access to any content from any location, and there is a growing on-demand archive of diverse multimedia presentations. For example, using the Google search engine, which is freely and universally accessible, a search for endoscopic images will easily find the available image libraries. A new source of interesting teaching videos on endoscopic procedures is the DaveProject.org site. This is one of the most informative single sites on the Internet, and it is free. There are myriad videoclips of every procedure including endoscopy of the esophagus, stomach, duodenum, liver, intestine, colon, biliary, pancreas, and other sites. In addition to a running video with audio explaining the procedure, there is often a text which accompanies the procedure. The text can be translated into 11 different languages, and the DaveProject.org site also has some of the interesting videos from the ASGE. In addition to videos there is also a fellow’s curriculum, a pathology slide set, several interesting grand rounds presentations, journal club presentations, and a link to PubMed. The videos can be downloaded for free, and many of them have accompanying radiologic and pathologic pictures of various lesions which are also available for downloading. In addition, there are more than 100 videos and teaching cases available for downloading onto an iPod. The ultimate purpose of e-learning is to provide a highly accessible educational opportunity equivalent to the live experience. It permits a higher degree of adaptation of the trainee to the training time availabile at a low cost, avoiding the need to travel to distant sites to observe experts in action. E-learning should eventually decrease the training time and shorten the learning curve [27]. Advances in electronic technology have provided a degree of interactivity. It is difficult to find a site on the Internet where new techniques can be learned and experts can be watched performing procedures. The Dave Project is a major advance in electronic endoscopic learning. Reference sources and the ability to print content are recognized advantages of many sites; however, video is required for e-learning of technical concepts. If the Internet is to be a successful format for e-learning in endoscopy, surgery, and other technical disciplines, it must have content that is both useful and practical. Interactive sites allow the participant to manipulate the content (fast forward, slow, and stop motion, alternative angles, replay, and download). Many sites allow the participant to contact the site and participate in discussion. The Internet currently offers video e-learning in multiple endoscopic areas including colonoscopy. Interactive cases combining written, slide, and video materials are available. The Internet is becoming more like television, and the streaming media market is growing rapidly. Texts, atlases, and books are also available on the Internet, and some are free.

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In comparison with DVD and videotape formats, standard Internet access (compared with broadband) provides a picture quality of small size and resolution with a significant delay in access time that can discourage the viewer. “Surfing the Web” and downloading large files is usually too slow to allow practical e-learning. Internet “glitches” often occur and can provoke the viewer into giving up. High-speed Internet connections (broadband) are available to a wide audience and make navigation easy and enjoyable. Rapid and higher resolution formats are available as a digital subscriber line (DSL), as are cable, wireless, and fiberoptic options. The DSL option uses the existing phone system and may be more secure than cable, whereas cable has a large television user base and offers the lower cost–speed ratio. Wireless Internet access is now widespread and is often free; where it is available it enables Internet access from a laptop computer and is very popular. The fluid transmission of high-definition video often requires access speeds of up to 20 megabits per second (Mbps). The greater bandwidths will allow high-definition video. Internet connection speeds of 100 Mbps permit fast upload and skipfree digital video, enabling the Internet to realize its potential and provide a technical experience approaching that currently provided by the DVD format. As high-speed technology advances (and becomes more cost-effective) it allows full-screen interactive selection for more detailed study. The Internet, with its vast information database, can also be accessed directly on new cellphone technology (smartphones) with almost unlimited connection capability including image transmission. The learning process in practical endoscopy is unlimited, awaiting the entry of major sponsors to expand its versatility, course content, teleconsults, and permanent online education.

Internet 2 This is a consortium [28] of providers that intends to construct a smarter and faster technology for education. It is composed of universities, industry, and government agencies committed to developing the provision and delivery of highspeed, high-quality educational content throughout the world (www.internet2.edu). Its goals are to: • create a leading-edge network capability for the national research community; • enable revolutionary Internet applications; • ensure the rapid transfer of new network services and applications to the broader Internet community. Networking centers that allow high-speed communication through fiberoptic lines have been established. Highdefinition video streams can be available on Internet 2. The breakthroughs already demonstrated with this technology give hope that the Internet will realize its potential as “the universal medium for e-learning.”

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Home television One of the incentives of Internet e-learning is to transform the learning experience from being computer oriented to part of the home entertainment center. The technology available in home theaters, game consoles, and set-top boxes allows broadband connections, with subsequent downloading of video. It is anticipated that, along with the emergence of topic-specific television channels for food and sport, the future of e-learning will allow the audience to “tune in” to a variety of technical video e-learning materials through a menu-on-demand system. The interactivity presently available in DVD and Internet formats is just one step in that direction. The future may see the Gastrointestinal Endoscopy around the Clock Channel, “The GIE-Channel.”

Teaching Aids in Colonoscopy

digital technology for filming and playback has further enhanced image resolution. Though video playback courses are highly technique focused, they do not fully reproduce the actual case. The editing procedure emphasizes what the medical editor wants the audience to see and often leaves out decision-making concepts, technical troubles, or patient difficulties. Though a successful conclusion to a case is expected, some of the videotape material can be constructed to emphasize complications and technical difficulties. Edited videotapes are an effective learning tool and should be considered synergistic to the “live” course format. They save time and cost and go straight to the desired teaching goal.

Small group sessions

Teaching courses Teaching courses exist in a variety of formats that include the use of electronic video media, small group observation of live cases in the endoscopy suite, and live transmission by satellite or telephone lines to remote locations. These “programs” have proliferated throughout the world and are mainly attended by endoscopists who want to upgrade their skills by observing experts perform live cases. The discussions that have emerged as to which is the best method for upgrading skills are superfluous, as these programs are complementary and synergistic. They should not be taken as the ultimate or only methods to gain the desired result. Each format has its advantages and drawbacks.

Video-based courses The format that uses playback of highly edited video media has been termed a “simulcast” production [29]. These are usually professionally produced, allow selective views of both the endoscopist and ancillary personnel, and provide splitscreen format for simultaneous endoscopic, fluoroscopic, and endosonographic imaging. The “simulcast,” or attempted recreation of the live environment, is further enhanced by the presence of the endoscopist who performed the procedure. The on-disk narration by the endoscopist explains the procedure and is recorded while the procedure is being performed. In the simulcast production, this narration is interrupted “live” by the endoscopist on site to emphasize, explain, or comment on a point. In addition, a “facilitator,” acting as a moderator and familiar with the tape, will interrupt the endoscopist at predetermined “stop points.” This allows a live interaction for both preselected and spontaneous questions in order to discuss an issue that is relevant to the procedure. Whenever videos of procedures are shown, the addition of “telestrator” technology or the “activboard” allows the presenter to draw over the image for emphasis and to sketch diagrams over the image or on to a blank screen. The use of

This is the traditional, and logically the best, method for learning from an expert. It provides an excellent opportunity for direct student–expert interaction as well as for observation of the endoscopy assistants, room set-up, and use of the ancillary equipment. Its limitation is audience size. Expanding small group sessions to 10–20 attendees progressively dilutes the aims of small sessions. The logistics of space, access to video screens, and the ability to provide one-on-one interaction dictate the size of the session.

Live courses Many large, live video-transmitted courses exist throughout the world. The aim of this format is the same as for the others: to provide exposure of the technical and cognitive aspects of the endoscopic procedure in a learning manner. The success of these programs is measured primarily both by the size of the audience in attendance and by audience feedback. There have been no studies conducted attesting to their learning value compared with other formats. These programs are useful in introducing new techniques rapidly to large audiences and, like all the ancillary modalities, are not intended to replace one-on-one training. The format for “live” courses ranges from small group teaching in the endoscopy room to programs involving hundreds of attendees in large auditoriums. Current technology allows simultaneous transmission to multiple environments of endoscopic and related images along with live video of the endoscopy suite and procedure performance. The intention is to give attendees access to the sounds and images of the local live environment coupled to the voiced instructional comments of the performing endoscopist, the ancillary personnel, and any added expert or moderator instructors. Expert–attendee interaction is stressed during the live procedure. There is some concern about ethical dilemmas that arise during live courses. Endoscopists who are part of these live shows are under stress due to the desire to perform a difficult or perhaps routine procedure in front of a televised audience. The endoscopists are usually given a difficult task to perform and are expected to complete a complex procedure

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outside of their usual environment, oftentimes with nurses and assistants with whom they are unfamiliar and, yet, they are expected to put on an educational “show” of their expertise in these difficult situations. Sometimes, the endoscopists under these circumstances overreach the clinical boundaries that would have caused them to abort the performance of the case if they were in their own endoscopy unit. This environment does create a difficult dilemma and sometimes leads to unnecessary complications [30,31]. One of the main advantages of the large group format is that it allows the gathering of multiple experts to share their knowledge and expertise, both between themselves and with the audience. There is opportunity to see and compare individual nuances as well as discuss alternative approaches with the audience and assembled experts. These programs offer the best opportunity for participation in problem-solving and learning technical “tricks of the trade,” although, when a case is progressing slowly, the moderator often switches to another procedure, while decisions and techniques are made away from the audience’s view. Compared with the small group format, the audience is usually blocked from observation of the total case experience. Interaction is decreased, and downtime for set-up, procedure difficulty, and technical transmission problems can impose restrictions on the amount and quality of the educational experience. The logistical and ethical aspects of this format have been questioned [32]. Opinions on the appropriate considerations in the use of all of these formats for learning have been presented [29], and the ASGE has published a “white paper” addressing guidelines for the development of large courses [33]. It is important that issues concerning patient ethics and the performing endoscopist are addressed, e.g., patient safety, informed consent, use of cases within the expertise of the performing endoscopist, and demonstration of the highest standard of care. The educational goals and relevancy to practice should be reviewed before case selection. The technical arrangements for these programs should include multiple camera angles for transmission of the performance of the live procedure. Highly professional video teams are necessary for on-site presentation of both video images and case performance. The costs of the presentation of large-scale remote transmissions are considerable. Whether these costs equal or exceed the cost of the edited video media format is unknown. The costs of participation are usually high to the attendee and often require additional expense such as transportation and hotel accommodation.

Telemedicine centers A limited number of telemedicine centers have been developed that are involved in training and assisting in procedure

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performance or interpretation, usually within their own units. The outreach intramural technology has been demonstrated to be effective and to provide images and communication of adequate resolution for quality care and monitoring. Numerous improvements are certain to occur. The problems of the telemedicine approach, in which realtime presentations can be sent to remote locations, include the high costs of equipment, ancillary personnel, and communication time. There are medicolegal issues which need to be addressed and a multitude of technical issues yet to be resolved.

Video analysis Direct observation of maneuvers and the technical skills required to perform a procedure can be stored or transmitted via the Internet, in order to assess the colonoscopy performance improvement as a part of the teaching process. Review of such videos permits the trainee to improve or correct the errors and to obtain feedback from the trainers. The required audiovisual and multimedia equipment are usually available in the endoscopy suites if the center takes part in live courses and live endoscopy demonstrations. Having access to video training and feedback will increase the assessment of the training faculty and enhance the quality of information that can be given. This may eventually lead to an increase in the number of trainees [34–37].

Animal models Standardized animal digestive tract models are now available, for diagnosis as well as for therapeutic training. These are prepared locally following directions from companies that set up the models. Some of them are expensive and others not (see Chapter 14). They provide tissue sensation, elasticity, and tactile feedback similar to those experienced in procedures on humans. The ASGE has a practice center in Chicago (Interactive Training and Technology Center) that produces such teaching aids, and has set up several courses using them. Although live models are desired, ex vivo animal models may be of great help [14–16,38,39]. These models are useful for shortening the learning curve, to avoid complications, to assay new techniques or devices, etc. It has been thought to be a useful step in the modern learning process [17,40].

Summary The cost-effectiveness of electronic media is obvious. Though unreported as yet, it is hoped that such tools will be an efficient method of upgrading learning while decreasing the high costs of producing live symposia and eliminating travel costs for conference attendees. The “live” endoscopic demonstration

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and the “edited” case version are not competitive but synergistic. The “live by simulcast” environment has its advantages, particularly as an ancillary learning experience to on-site demonstrations, live conferences, and Internet streaming. The assessment of the impact of these teaching aids on colonoscopy expertise is required. The expert endoscopist should persist in maintaining his or her skills [41] and strive to improve them. Technological improvement implies better storage and data transmission associated with exponential increments in the velocity of image transfer. This will result in the ability to enhance the possibility of colonoscopy information technology and communication, at a lower cost.

References 1 American Society for Gastrointestinal Endoscopy. Principles of privileging and credentialing for endoscopy and colonoscopy. Gastrointest Endosc 2002; 55: 145– 8. 2 American Society for Gastrointestinal Endoscopy. Principles of training in gastrointestinal endoscopy. Gastrointest Endosc 1999; 49: 845– 53. 3 American Society for Gastrointestinal Endoscopy. Guidelines for credentialing and granting privileges for gastrointestinal endoscopy. Gastrointest Endosc 1998; 48: 679–82. 4 Grassini, M, Verna C, Battaglia E, et al. Education improves colonoscopy appropriateness. Gastrointest Endosc 2008; 67: 88–93. 5 Rex DK, Petrini JL, Baron TH, et al. Quality indicators for colonoscopy. Gastrointest Endosc 2006; 63(Suppl. 4): S16–28. 6 American Society for Gastrointestinal Endoscopy. Methods of granting hospital privileges to perform gastrointestinal endoscopy. Standards of training and practice committee. Gastrointest Endosc 1992; 38: 765– 7. 7 Tassios PS, Ladas SD, Grammenos I, Demertzis K, Raptis SA. Acquisition of competence in colonoscopy: the learning curve of trainees. Endoscopy 1999; 31: 702– 6. 8 Cass OH. Training to competence in gastrointestinal endoscopy: a plea for continuous measuring of objective end points. Endoscopy 1999; 31: 751– 4. 9 Waye JD, Toouli J, Guelrud M, et al. Who is permitted to do endoscopy? Endoscopy 2001; 53: 267– 9. 10 Joint Advisory Group on Gastrointestinal Endoscopy. Recommendations for Training in Gastrointestinal Endoscopy. London: British Society of Gastroenterology, 1999. 11 Qureshi WA, Zuckerman MJ, Adler DG, et al. ASGE Guideline: modifications in endoscopic practice for the elderly. Gastrointest Endosc 2006; 63: 566– 9. 12 Neumann M, Hochberger J, Felzmann T, Ell C, Hohenberger W. The Erlanger endo-trainer. Endoscopy 2001; 33: 887– 90. 13 Taylor I. Can performance as an undergraduate assist entry selection into surgical training programmes? Ann R Coll Surg Engl 2005; 87: 1–2. 14 Bar Meir S. A new endoscopic simulator. Endoscopy 2000; 32: 898– 900. 15 Sedlack RE, Kolars JC. Validation of a computer-based colonoscopy simulator. Gastrointest Endosc 2003; 57: 214–18.

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16 Hochberger J, Maiss J. Currently available simulators: ex vivo models. Gastrointest Endosc Clin N Am 2006; 16: 435–49. 17 Sedlack RE. Validation of computer simulation training for esophagogastroduodenoscopy: pilot study. J Gastroenterol Hepatol 2007; 22: 1214–19. 18 Raskin JB, Nord JN (eds.). Colonoscopy: Principles and Techniques. New York: Igaku-Shoin, 1995. 19 Baillie J. Gastrointestinal Endoscopy: Beyond the Basics. Boston: Butterworth-Heinemann, 1997. 20 Cotton PB, Williams CB. Practical Gastrointestinal Endoscopy, 5th edn. Oxford: Blackwell Publishing, 2003. 21 Sivak MV, Jr. (ed.). Gastroenterologic Endoscopy, 2nd ed. Philadelphia: WB Saunders, 2000. 22 Schiller KFR. Atlas of Gastrointestinal Endoscopy and Related Pathology. Oxford: Blackwell Science, 2002. 23 Nagasako K, Fujimori T, Hoshihara Y, Tabuchi M. Atlas of Gastroenterologic Endoscopy by High-resolution Videoendoscope. New York: Igaku-Shoin, 1998. 24 Keeffe EB, Jeffrey RB, Lee RG. Atlas of Gastrointestinal Endoscopy. Philadelphia: Current Medicine, 1998. 25 Maratka Z. Terminology, Definitions and Diagnostic Criteria in Digestive Endoscopy. OMED Database of Digestive Endoscopy. Englewood: Normed Verlag, 1989. 26 Dounavis P, Karistinou E, Diomidus M, Mantas J. Using World Wide Web technology for educating students in the health care sector. In: Pappas C, Maglavera N, Scherrer JR (eds.). Medical Informatics Europe ’97. Amsterdam: IOS Press, 1997: 686–90. 27 The Gastroenterology Leadership Council. Training the gastroenterologist of the future: the gastroenterology core curriculum. Gastroenterology 1996; 110: 1266–300. 28 Lemley B. Internet 2. A supercharged new network with true telepresence puts the needs of science first. Discover 2002: 23. 29 Waye JD, Axon A, Riemann JF, Chung S. Continuing education in endoscopy: live courses or video format? Gastrointest Endosc 2000; 52: 447–51. 30 Hirsh DA, Ogur B, Thibault GE, Cox M. “Continuity” as an organizing principle for clinical education reform medical education. N Engl J Med 2007; 356: 858– 66. 31 Hochberger, Detlev M, Maiss J. ERCP Training in ERCP. Baron T, Kozarek R, Carr-Locke D (eds.). Saunders, Elsevier, 2008: 61– 70. 32 Cotton PB. Live endoscopy demonstrations are great, but . . . Gastrointest Endosc 2000; 51: 627– 9. 33 Carr-Locke DL, Gostout CJ, Van Dam J. A guideline for live endoscopy courses: an ASGE white paper. Gastrointest Endosc 2001; 53: 685– 8. 34 Eisen GM, Dominitz JA, Faigel DO, et al. Guidelines for advanced endoscopic training. Gastrointest Endosc 2001; 53: 246–8. 35 Marshall JB. Technical proficiency of trainees performing colonoscopy: a learning curve. Gastrointest Endosc 1995; 42: 287–91. 36 Chak A, Cooper GS, Blades EW, Canto M, Sivak MV. Prospective assessment of colonic intubation skills in trainees. Gastrointest Endosc 1996; 44: 54–7. 37 Waye JD, Leicester RJ. Teaching endoscopy in the new millennium. Gastrointest Endosc 2001; 54: 671–3. 38 Hochberger J, Maiss J, Magdeburg B, et al. Training simulators and education in gastrointestinal endoscopy current status and perspectives in 2001. Endoscopy 2001; 33: 541–9.

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39 Waye JD. Teaching basic endoscopy. Gastrointest Endosc 2000; 51: 375–7. 40 Taijiri H. Optimal endoscopic training system for gastrointestinal endoscopy: how shall we train gastrointestinal fellows

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effectively in near future? Gastroenterol Endosc 2004; 46: 1153–9 (abstract). 41 Harewood GC, Petersen BT, Ott BJ. Prospective assessment of the impact of feedback on colonoscopy performance. Aliment Pharmacol Ther 2006; 24: 313–18.

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Teaching Colonoscopy John T. Anderson Gloucestershire Hospitals NHS Foundation Trust, Cheltenham, UK

Introduction Endoscopy of the whole colon, colonoscopy, was first described in 1971 [1]. Endoscopy has advanced from a research tool with diagnostic potential to a major subspecialty of gastroenterology, and colonoscopy has become a significant part of its workload [2]. Colonoscopy is now an extremely important diagnostic and therapeutic investigation. For many years there was no formal training in colonoscopy. Most gained expertise from experiential learning during service provision. Learning and teaching under these circumstances required time, dedication, and immense enthusiasm. The exchange and sharing of information and technical advice was essential. From enthusiastic beginnings the best practice of a small group of “experts” was disseminated and colonoscopy technique gradually evolved. Technical advances in colonoscopic equipment have occurred in parallel with the establishment of endoscopy as a subspecialty within gastroenterology. Colonoscopy has become the gold standard investigation for examination of the colon, with ever-increasing therapeutic potential. The advent of population screening for colorectal cancer has focused attention on the need for high-quality colonoscopy and colonoscopists. The current challenge of colonoscopy training is to deliver a workforce of skilled colonoscopists able to meet the demands of modern colonoscopy. This requires the ability to teach trainees to perform safe, complete, and effective colonoscopy within a reasonable duration of time. Training should be motivational and viewed as a springboard to the lifelong challenge of expertise [3]. The object of any colonoscopy training course, fellowship or program should be to ensure that endoscopy trainees achieve a sustainable level of competence when measured

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

against agreed standards. These standards are set in the UK by the Joint Advisory Group on Gastrointestinal Endoscopy (JAG) and in the US by the American Society for Gastrointestinal Endoscopy (ASGE) [4–8]. A minimum required standard common to both is a greater than 90% cecal intubation rate for independent practice. This has to be achieved within the context of patient comfort and consideration of all aspects of safety.

Training provision Enthusiasm for a more structured approach to training in colonoscopy is growing. A good program ensures the trainees acquire all the necessary skills for safe competent colonoscopy. Training should provide the technical skills, which often dominate the trainee’s learning agenda, but also the relevant knowledge and the attitudinal and behavioral aspects necessary to produce fully competent colonoscopists. These endoscopic non-technical skills are critical components in the trainee’s ability to make sound judgments and make appropriate decisions in relation to colonoscopic practice. Effective training requires a combination of competent enthusiastic trainers, an appropriate training environment, modern endoscopic equipment and a culture that ensures sufficient training opportunities are provided to enable the trainee to progress at a satisfactory rate.

Basic training equipment Early colonoscopy teaching was performed using the fiberoptic teaching scope, which was difficult, cumbersome, and often unacceptable to both trainer and trainee in terms of image and light quality. Video endoscopy rectified these deficiencies, and modern-day systems offer excellent image quality. It is essential that any unit offering training in colonoscopy be equipped with a modern video system. Models and simulators have many potential benefits in the early stages of colonoscopy training (see Chapter 14). Current endoscopy training can prolong procedural duration by up

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to a third, and adverse events are more common in the earlier phase of an endoscopist’s experience [9,10]. Models and simulators provide the benefits of hands-on experience and training without patient risk or compromise to service provision. Although major advances in simulators have been made, their exact role in training is still to be fully determined.

Training units and training lists Every training unit should perform enough colonoscopic procedures to ensure that trainees have adequate training opportunities. It is difficult to stipulate exactly how many procedures a unit must perform to offer satisfactory training. Larger units with more trainees will require proportionately increased numbers of procedures. Assessment of competence includes achieving completion of the colonoscopy on an intention-to-treat basis of > 90%. It is worth noting that in one study trainees took an average of 341 procedures to achieve this, and a small proportion of trainees may never do so [11]. This is important for certain trainees who may have limited training time available for teaching in colonoscopy. Trainees must then determine whether colonoscopy is likely to be an integral part of their future practice. If so, adequate training time must be allocated to ensure that competence is achieved before the end of the training program. Trainees on shorter training programs need an even greater annual exposure to colonoscopy procedures, either within a single unit or by delivery of training from several units working cooperatively. Structured training programs and improved training techniques may shorten the training period required and the number of procedures needed to achieve competence. The teaching of any practical skill is heavily reliant on a team approach. Each training unit should have an endoscopy training lead and a nursing lead, who are the clinical champions and the driving force behind training. It is their responsibility to create a training environment and culture that is appreciated and accepted by all members of the department. Effective training requires the involvement of managers, clinicians, and support staff. Training will flourish in a unit that is well run, well managed, well respected, and provides an excellent clinical service for its patients. It is difficult to provide high-quality training in a unit that is struggling to provide a good clinical service. Respect for both the patients and the other endoscopy unit personnel is an essential component of delivering effective, high-quality endoscopy training. The whole team needs to be responsive and flexible, balancing the delivery of service and training, whilst being supportive to the training culture. There needs to evolve a commitment to creating a learning environment for all members of staff. This promotes an atmosphere of encouragement and expectation of success. The training process then becomes enjoyable and rewarding

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for all members of staff. Free exchange of faculty and staff between endoscopy units will help lead to an increase in the quality of training and all other aspects of colonoscopic practice. Traditionally, training occurred during service lists. The training was often ad hoc and resulted in accelerated progression to independent practice along the lines of “see one, do one, and then teach one.” This practice is now felt to be totally unacceptable. Modern teaching demands that trainers have time dedicated for endoscopy training, and that the assessment of a trainee’s progression is based on demonstration of increasing competence. Dedicated training lists are the best way to ensure that training is controlled and delivered at a level and pace to meet the learning needs of the trainee. The booking of these lists can then be adjusted over time with satisfactory trainee progression. It is recognized that it is not always possible to dedicate entire lists for training purposes. In these circumstances, the training period on such lists should be well defined and explicit to trainer, trainee, and other endoscopy staff. This ensures that the expectations of the training for trainer and trainee are aligned and the training opportunity fully utilized. Many training units will begin upper and lower endoscopic training simultaneously, whereas others embark on colonoscopic training only after expertise in upper endoscopy has been acquired. The literature on the development of motor skills describes the concept of contextual interference: the practice of two tasks in a random fashion results in performance of each task improving more slowly (i.e., there is short-term interference) than is the case with blocked practice (learning two different tasks by continuous practice of one task followed by continuous practice of the second task). However, random practice is associated with better long-term learning and retention of both skills [12]. Thus, it may be that learning upper and lower endoscopy concurrently leads to slower improvements in initial performance but produces better long-term learning [13].

Trainees Trainees in colonoscopy will come from a variety of backgrounds, including physician gastroenterologists, surgeons, radiologists, and nurses. This may result in the individual training needs of trainees differing in nature and quantity. It must also be recognized that trainees bring a diversity of associated transferable skills which may facilitate their training. Irrespective of this, it is most important that the individual trainee can demonstrate an ongoing commitment to colonoscopic practice and the expectation of reaching competence and hopefully expertise. Training in endoscopy requires both time and commitment from trainers as well as trainees. Trainers are a costly resource. Colonoscopy training

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should not be regarded as a given right of any individual without the realistic expectation that the endoscopic skills will be utilized in future practice. Training in colonoscopy should not be seen as an addition in an individual’s training pathway, if that pathway does not ultimately include colonoscopic practice. There is no published evidence to inform selection of trainees for colonoscopic training based on predetermined criteria of aptitude. However, extensive literature involving medical and surgical trainees indicates that complicated testing based on a variety of parameters, including intellect, dexterity, motivation, stress tolerance, and teamwork, does not identify those who will become experts or those who will not succeed in becoming independent competent colonoscopists [14]. In every group of trainees there will be a minority who appear to be “natural” endoscopists and who learn quickly. However, given time, almost all of the group will achieve an acceptable level of competence with only very few failing to achieve an acceptable standard of practice. A major component of teaching colonoscopy is the training to acquire the actual practical skill, rather than the knowledge, lesion recognition, and management decisions associated with the procedure. It must be recognized that there is a fundamental difference when comparing skills acquisition in colonoscopy and skills training outside of medicineathe patient. In clinical practice, the patient is integral and central to colonoscopy training. Even with patient consideration, acquistion of colonoscopy skills, in common with all skills training, has the essential components of practice, demonstration, motivation, instruction, and feedback.

Practice When possible, colonoscopy training should be continuous. There is good evidence that a lack of opportunity to practice endoscopic skills soon results in their loss; consequently, breaks in training and practice should be minimized [15–17]. Deliberate practice relates to training that requires high levels of effort and attention. Its role in achieving expertise is extremely important. It has been argued that innate talent or ability is relatively unimportant to attaining expertise when compared with prolonged deliberate practice [14]. According to the power law of practice, improvements in performance occur as a function of investment in deliberate practice. An initial rapid rate of learning occurs after the onset of practice followed by a continued but decreasing rate of improvement [18]. The “10-year rule,” supported by studies across such diverse domains as music, chess, and sport, suggests that 10 years’ commitment to high-level training is needed to acquire expertise [14,19,20]. The initial goal for trainees is to train to be competent not expert. However, it should not be lost on the independently practicing colonoscopists that skills improvement is

Teaching Colonoscopy

a continuous process. With motivation, practice, and further training, endoscopists can continue to improve their skill and performance data long after leaving a dedicated training program. In this situation, occasional “top-up training” has been reported to be beneficial.

Demonstration Trainees will benefit from spending time watching colonoscopy as part of their teaching and training. Being familiar with the unit and with normal working practice will add to any induction program. Observing practicing colonoscopists provides learning in relation to skill acquisition. However, it is not known whether watching an expert or a novice is more effective for skill learning. Observing an expert may allow the development of a perceptual “blueprint” for a skill, but motor learning is thought to involve a problem-solving process, and watching an expert reduces any error information generated and observed [21]. It may be possible to learn from watching someone else’s mistakes, and endoscopy video-linked seminar rooms, from which to observe other trainees, are currently recommended as part of JAG training courses in the UK. The optimum amount of demonstration for task learning is unclear, but is likely to relate to task complexity. Demonstration of a practical skill with verbal cues is also thought to improve retention and acquisition, more than demonstration alone [22]. The implication is that endoscopy training videos should be supplemented with these verbal cues. Although it seems obvious that demonstrations should be provided before rather than after attempts to learn a task, this may not necessarily be best practice. If the pretask information decreases the cognitive effort during learning, this may affect the trainee’s retention. In the early stages of skill acquisition it may be better to allow learners to discover for themselves how to attain the required task goals [23]. Initial provision of detailed prepractice information may constrain a learner’s opportunities to discover different ways of performing the task. However, allowing trainees to perform endoscopy on patients before demonstrating what to do is clearly inappropriate and unethical. Perhaps trainees should be allowed the freedom to practice endoscope control on simulators or training models before being shown how the instrument works and specific advice is given on how to manipulate it.

Motivation Motivation to gain expertise is a very important factor in adult learning. It is most valuable when it is intrinsic (based on curiosity and a desire to meet challenges) rather than extrinsic (driven by competition, examinations, or grades), when material retention is often short-lived. The challenge,

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therefore, is to make learning interesting and keep it relevant to the trainee’s needs. It should be recognized that the trainer also has a crucial role to play in this process. An enthusiastic, friendly, patient, and competent trainer generates confidence in the trainee and fosters a desire to succeed. Similarly, some behaviors of the trainer can be very demotivating. For example, unexpectedly taking over the procedure can have a profoundly negative effect, leading to a fear of failure and humiliation. This is especially true if the reasons for taking over are not immediately apparent to the trainee.

Instruction and feedback Instruction is information given either before or during practice but independent of performance, whereas information provided during or after practice is considered feedback [23]. This component of skills training is discussed in detail below in the section on “Practical skills training.”

Trainers It is relatively easy to describe the qualities that make a good trainer (Table 13.1). Trainers must have an intense desire to help their trainees, no matter what they are teaching, and must adhere to basic educational principles, setting specific objectives, especially in the early stages of training. Most importantly, feedback should be timely, structured, and delivered in a constructive manner. It is essential that trainers are friendly and enthusiastic. For example, they should be just as delighted as their trainees in Table 13.1 Key qualities of good trainers. Teaching qualities Proficient, safe colonoscopist Ability to analyze and understand the performance of the trainee, to identify areas of improvement Ability to adapt teaching to meet needs of the trainee Provide constructive feedback Attentive supervision of trainee Ability to concentrate on teaching Personal qualities Motivational Enthusiastic Supportive Positive Patient Good communication skills Empathy with anxious trainees Non-judgmental Confidence in own teaching ability

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the completion of a colonoscopy or just a smaller aspect of colonoscopic technique. Good trainers are team players who value other endoscopy staff, often soliciting their opinions on particular aspects of the training process. It is important that the teachers themselves are subjected to regular and rigorous audit of their own clinical performance in addition to their training. It is recognized that not all endoscopists within a unit will want to be trainers, but those that do should be encouraged to embrace modern teaching methods and their application, using them to teach with enthusiasm. Colonoscopy trainers should have expert knowledge of the technical and practical aspects of diagnostic and therapeutic colonoscopy. Some trainers in colonoscopy have been found to be using the same methodology used during their own training many years earlier. Many of these so-called “expert trainers” have never been subject to either peer review or trainee feedback, so that the value of their highly personalized methods has never been brought into question. All trainers benefit from attending some form of “training the trainer” course, ideally with practical experience embedded into it. While it is helpful, it is not essential to have an educational qualification to teach colonoscopy. Irrespective of qualifications, there are fundamental principles and methods that all trainers should understand and apply, to optimize the training experience for the trainee.

Scaffolding in colonoscopy training It would be unusual for a trainer to oversee a trainee throughout the whole training period from novice to expert. More commonly, trainers have responsibility for one or more trainees for a period of time during a training program. The trainees may be at different stages in their colonoscopic training and abilities, so trainers must be able to adjust their training technique to be able to positively contribute to the further development of each trainee. For the novice endoscopist, the training sessions will involve only a few procedures to accommodate a trainee beginning to aquire the complex psychomotor skill of colonoscopy. As the trainee’s skill and experience increases, the number of procedures can be increased. This ensures a balance between the increasing demands placed on the trainee with increasing numbers of procedures and their increasing competence and associated efficiency in completing procedures. This balance facilitates progressive appropriate and effective training. There are a number of key components in endoscopy training. Central is the scaffolding of one-to-one support by the trainer [13]. Initially, there is high-input supervision which gradually reduces with trainee progression (Figure 13.1). Within this framework of teaching, trainees should be encouraged to reflect on their own practiceaa key

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Novice trainee • Support • Motivation • Demonstration • Direct instruction

Intermediate trainee

Competent trainee

• Reduced volume of input • Change in quality of input: 1 instruction to 2 prompting to 3 questioning to 4 reassurance

Trainer physically withdraws from training process

Teaching Colonoscopy

It may be necessary to confirm any documented evidence presented by trainees (e.g., training log, portfolio, performance data, etc.) of their competence level, or previous training in colonoscopy. This will enable trainers to determine what level the trainees have achieved and how they may be best placed to help when teaching. Patient safety is of fundamental importance, and in addition to evaluation of their basic technical skills, trainees should also have competence in taking consent, sedation practice, and, if relevant, therapeutic techniques.

Aligning agendas Trainer available to deal with difficulties and complex problems

Figure 13.1 Trainer support in colonoscopy training.

for lifelong learning skills. A number of other factors related to endoscopy learning have been identified. The concepts identified appear largely to be mirrored in the wider educational literature. It has also been suggested that there are many concepts in the broader motor and sports skills literature that may be relevant to endoscopy training [24]. Before training commences it is advisable that a number of tasks are performed by the trainee and trainer before commencing hands-on training. Then, after the training intervention, time should be allocated for appropriate feedback and review of the learning objectives, agreeing, if appropriate, new learning objectives for the next session.

Trainees often have a concept of what they expect from the training episode (trainee’s agenda). If the trainer’s agenda differs, there is the potential of failure to maximize the training opportunity. It is important to determine what the trainee needs and then adapt to this. The trainer’s agenda should be structured around a framework of knowledge, skills, and attitudes. Motivation is generated through increasing awareness of patients’ needs, setting an example, and appealing to internal motivation to provide high-quality care. If the teaching episode is driven purely by the trainer, it may well deliver some effective teaching, but it will be less well received by the trainee. It is the responsibility of the trainer to be flexible and respond to this challenge rather than to expect the trainee to significantly shift his or her position. The learning objectives should be a result of the aligning of the trainee’s and the trainer’s agendas.

Learning objectives

Preparation Effective training requires preparation and structure. Trainers prepare for teaching utilizing prior assessments of the trainee, agreeing an educational contract, setting learning objectives with the trainee, and ensuring that there is attentive supervision. Patient safety should not be compromised by training. The trainer has overall responsibility and must feel in control of the environment, procedure, and the trainee. Trainer control is a product of appropriate planning of the training episode and agreed parameters for the teaching during the procedureathe “ground rules.” These ground rules will vary from trainee to trainee and from case to case. They help the trainer and the trainee understand any constraints on the training and how these may affect the training episode. The ground rules also provide the trainer with some pre-defined criteria for which intervention or “taking over the scope” may be expected by the trainee. Control should not be overbearing, and trainers should adopt a “hands in pockets” approach as much as possible.

Learning objectives should aim to be specific, measurable, achievable, relevant, and timely (time limited)aacronym SMART. You can add to this, economical and reviewed (SMARTER). For learning objectives to be effective they need to be reviewed and should be modified by feedback. If learning objectives are recorded and written down they are far more likely to be achieved.

Educational contract The educational contract helps establish commitment from both trainer and trainee. It clarifies expectations from both parties regarding the colonoscopy training. It can be either verbal or documented, but should be reviewed at the beginning of each colonoscopy training session. The educational contract should contain the learning objectives for the trainee, set against a given time frame in which to achieve them, based on previous assessments. These objectives are then reviewed and modified on a regular basis as the trainee progresses.

Hands-on training

Initial assessment

Conscious competence

Training should begin with an initial assessment of trainees’ knowledge, any previous training, and level of competence.

Almost all colonoscopy teachers will be experts and unconsciously competent [25]. Explicit knowledge is conscious,

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Conscious incompetence

Unconscious incompetence Normal sequence for skills acquisition Unconscious competence

Conscious competence Effective trainers

Figure 13.2 Conscious competence and teaching colonoscopy.

rule based, and can be verbalized (conscious competence), as opposed to implicit knowledge, which is unavailable for conscious inspection and difficult to verbalize. Over time, highly practiced or learned performances become automated (unconsciously competent) and experts may have less explicit knowledge of their performance. To be effective in training it is necessary for the trainer to be able to step back from being unconsciously competent to being consciously competent (Figure 13.2). This allows the trainer to analyze the performance and skills of trainees, and to verbalize and teach the skills that they possess. This is a fundamental step in the teaching of practical skills. This technique, which may be intuitive to the trainer, still requires practice. The trainer will recognize that there are some aspects of colonoscopy technique, particularly those in which tactile recognition is paramount, that do not easily translate into verbal instructions. Initially, novice trainees will be unconsciously or consciously incompetent. With well-structured training they will become consciously competent and able to solve most challenges faced in colonoscopy using basic principles supported by the experience gained from performing procedures. Over time, the trainees themselves will become unconsciously competent when they have acquired expertise in the technique and no longer have to think about it.

Dual-task interference Performing two relatively simple tasks concurrently may prove difficult, e.g., continuing a conversation while adding up a bill. This phenomenon, known as dual-task interference or cognitive overloading, has been documented across many different fields and may be due to a bottleneck in mental processing and memory retrieval. Colonoscopy trainees are often encouraged to provide a verbal commentary on their performance. There are no data to support this method for improving practical skills training. Trainees are less able than trainers to describe their actions, views, and tactile perception, and this is most noticeable in difficult situations. This observation is consistent with the presence of dual-task interference. As colonoscopists’ skill and competence develops, their ability to dual task also increases.

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This concept is important particularly at the start of training when demands on attention are highest. For this reason, asking trainees to provide a verbal commentary and describe their performance during practice is counterproductive. One skills teaching model proposes describing each step before it is taken. This approach may be useful for trainers because it highlights a trainee’s decision-making processes and also alerts them to potential hazards. However, colonoscopy and many other practical skills in medicine are dynamic, and it is not always easy to describe such performance in a staccato fashion. Instead, asking questions of the trainee before initiating any action allows trainers to check the trainee’s understanding and reasoning while providing similar information without impairing the actual performance of the trainees. If trainers want to know what trainees are thinking then asking questions intermittently appears preferable to requesting a constant commentary [26]. This is best done during a natural or engineered pause in the procedure.

The role of practice Massed practice conditions are those in which a task is practiced continuously without rest. In distributed practice, rest intervals are provided within practice sessions. Meta-analysis has shown that distributed rather than massed practice conditions are better for learning in terms of both acquisition and retention of skills. However, the optimal rest interval for distributed practice is unknown. It is conceivable that training a novice colonoscopist continuously over the few hours of a whole endoscopy list is less effective than when specific rest intervals in training are made available. This may be more important at the start of training when the attentional demands of task learning are greatest. From a practical perspective, it may be better for a trainee to be trained on alternate procedures, or on only a certain number of procedures on a list, rather than on them all. As skill and competence increases, this becomes less relevant. Then, the emphasis switches to gaining experience, which requires a greater exposure to procedure numbers. Decreasing the high attentional demands of trainees during colonoscopy has already been suggested as being beneficial. Reducing task difficulty to aid learning is referred to as parttask practice. This can be instituted by fractionation, simplification, or segmentation [27]. Fractionation refers to practicing separate components of a whole skill that are normally executed simultaneously, e.g., torque steering in colonoscopy. Fractionation methods are generally less effective than whole-task training but may still be beneficial. Simplification is performing a simplified version of a whole skill, e.g., learning to ride a bicycle aided by stabilizers. Simplification is probably effective for learning complex skills. Practice on endoscopy simulators, regarded as being easier than on real patients, is one way in which simplification can be applied to endoscopy [28]. Segmentation refers to separating a skill into component parts and progressively adding new components to skill

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practice. This has already been applied to endoscopy. Some trainers start by getting trainees to withdraw the scope once full insertion has been achieved by the trainers themselves. ASGE guidelines suggest first learning the more basic component techniques of pyloric intubation and tip retroflexion before progressing to performing the entire procedure [7].

Decision training Decision training improves effective decision-making during performance. This is achieved by focusing on critical cues and then choosing the best response. Decision training has an overt cognitive motor component, and one way in which it can be employed is by asking questions. Questions have the additional aim of increasing cognitive effort and encouraging trainees to think independently. In colonoscopy, when faced with a difficult situation, trainees are encouraged to review all possible options and requested to volunteer the most appropriate action, rather than them simply being informed of the best option. It seems sensible to restrict anything other than the most basic questions until after the trainee has developed reasonable endoscopic skill. Indeed, decision training appears to be best for long-term performance at intermediate and advanced level but not at novice level. Unfortunately, it is recognized that, on occasion, the trainer talks too much, causing problems with dual-task interference and decreasing opportunities for decision training.

Instrument handling Basic instrument-handling skills can be taught on simple models or simulators. The increasing sophistication and realism of electronic simulators means that the teaching of early basic colonoscopic techniques should soon be able to occur without recourse to patients. Modern simulators allow reproducible realistic colonoscopy training and, with suitable software, management of sedation problems, pathology recognition, and therapeutic techniques. The new generation of simulators can estimate the percentage of mucosa examined and the number of missed lesions. They help teach the trainee to be cautious during the procedure and assiduous on instrument withdrawal. Practice on models or simulators should teach the novice torque steering and its importance in minimizing looping. If the trainee is fortunate enough to have access to a modern simulator, some experience of the tactile recognition of loops may have been gained, but from this point onward most of the training will be carried out on patients. It must be recognized that whether the basic skills training is carried out on models, simulators, or patients this must be on a one-to-one basis with the trainer. Letting a new trainee loose, unsupervised, with an expensive instrument on either a sophisticated simulator or an unsuspecting patient is analogous to giving a 10-year-old child the keys to a new automobile.

Teaching Colonoscopy

Trainer – trainee interaction Training sessions must be allocated dedicated time and freedom from service commitments. Interruptions must be kept to a minimum. If either of the two parties is tired, training sessions should be avoided. Idle conversation and irrelevant remarks made during training must be suppressed. The acquisition of practical skills requires intense concentration for long periods, so short breaks are essential for both parties. Both trainer and trainee must also recognize the onset of fatigue and should not persist beyond this. When patients are involved, their comfort, safety, and dignity are of paramount importance, and good communication with the patient will allay anxiety and minimize discomfort. All trainers should aspire to teach a technique that provokes minimal discomfort. With good patient rapport and conscious sedation the patient may also make a sensible and valuable contribution to the training process. The patient should understand that the procedure is to be used for training, and specific consent must be obtained for this. The basis of any good training technique is the relationship between trainer and trainee. The emphasis should be on the expectation and encouragement of success, which is defined as reaching and exceeding personal objectives rather than competing with the peer group. If the trainee is unable to make progress, the trainer encourages a review of options, offering a choice of the most appropriate actions. When the trainer requires a specific maneuver to be performed that the trainee finds difficult, it is advised that the colonoscope is withdrawn to a stable position with the patient comfortable. Specific instructions can then be given to the trainee, and his or her understanding checked, before he or she attempts the maneuver again. If the trainee again fails to make satisfactory progress or is causing the patient discomfort, the trainer must consider the possible reasons for this: 1 Have the instructions been given clearly by the trainer? 2 Have the instructions been fully understood by the trainee, or do they need to be repeated? 3 Has the trainee actually carried out the agreed instructions, or something different? 4 Is the task simply beyond the technical expertise of the trainee? If the task is beyond the expertise of the trainee, the trainer will be required to take over the procedure to complete the maneuver. The colonoscope can then be returned to the trainee. Typically, it is the challenging aspects of the procedure which provide the richest learning for the trainee. Having tried and failed to execute a successful maneuver, good training may provide the trainee with what is required to overcome a similar problem in the future. When to take over a procedure is a difficult area for trainers to evaluate. Trainers must balance training needs against patient safety and comfort and the overall running of the whole list. However, it is usually the complex maneuvers requiring a

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combination of different movements, often simultaneously, in quick succession, or in combination, that the trainees will struggle with, necessitating intervention. Another problem area for trainees is the fine tip control necessary for certain maneuvers. Even didactic instruction cannot always compensate for a trainee’s inability to exhibit the necessary tip control. Unfortunately, the trainer frequently takes over the procedure too early and does not allow sufficient time for the trainee, even one with the relevant skills, to attempt a maneuver. In all stages of training, but particularly the initial stages, the use of a three-dimensional positional imager (e.g., Scopeguide©) may be helpful [29]. The imager allows trainees to make an association between what they feel on advancing or withdrawing the instrument and its actual configuration. Development of tactile discrimination is of vital importance in the recognition of loops and their avoidance and management. This experience is acquired over many cases. Unfortunately, positional imagers are not yet widely available. For trainees without access to a positional imager, a pragmatic series of maneuvers to recognize and correct loops to aid insertion of the colonoscope is an alternative. The trainee will learn to recognize that lack of one-to-one instrument advance, paradoxical movement, and patient discomfort all signify that loops are present and that steps must be taken to reduce or avoid them. Maneuvers that accomplish this include torque steering, withdrawal with clockwise or anticlockwise rotation to straighten loops, and changes to the patient’s position. In addition, when these are unsuccessful, abdominal compression or, if available and relevant, the use of the colonoscope stiffener may be helpful when preventing a recurrence of a previously straightened loop. With increasing experience the trainee learns to recognize the feel of the instrument throughout these maneuvers and will know when and how to apply them. It must be stressed to the trainee that once the cecum has been reached, it should take 6 min or more to withdraw the instrument [30]. This decreases the potential for missing colonic pathology. Often after a difficult colonoscopy, the insertion time and relief at arriving at the cecum conspire to provoke a hurried and less than adequate inspection during withdrawal of the colonoscope. Comprehensive mucosal examination is aided by simple maneuvers such as patient position changes, reinserting the endoscope when slippage occurs, adequate use of insufflation, and judicious use of antispasmodics [31,32]. Acceptance of inadequate bowel preparation should also be discouraged. While poor bowel preparation is sometimes used as an excuse for incomplete colonoscopy, it has also been shown that poor technique is associated with poor judgment of the quality of bowel preparation, which will have consequences on the pick-up rates of pathology [33]. All other members of the unit present during the procedure and who are not immediately concerned with

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Trainee aspects • Motivation • Anxiety • Previous experience

One-to-one supervision Observation Demonstration Practice Explanation Feedback Segmentation Contextual interference

Trainee aspects • Motivation • Patience • Clarity

Training lists Training courses Short courses Simulators Models Service provision

Practice Competence and expertise Scaffolding Decreasing supervision

External aspects • Time • Nurse support • Distractions • Patient factors

Figure 13.3 Model for colonoscopy training. Adapted from Thuraisingam et al. [13].

the direct care of the patient (other doctors, nurses, etc.) should be encouraged to watch the procedure and comment critically on missed pathology or areas of mucosa that were not adequately examined. Patient selection in the initial stages of training can be helpful in trying to avoid the potential risk of failure as much as possible. Preassessment of patients is highly recommended to ensure that difficult cases are not assigned to training lists. Therefore, patients who are excessively apprehensive, those with previous abdominal or pelvic surgery, and those who have had previously failed colonoscopy would be sensible exclusions from the training list. However, as any experienced colonoscopist will testify, it does not necessarily follow that patients without these problems will be any less challenging. As the trainees’ experience increases, they can be exposed to the full range of diagnostic and therapeutic colonoscopy in unselected cases. During this period basic teaching principles will remain the same. Colonoscopy training is complex, with many potential factors affecting the training interaction between the trainer and trainee. A model of important elements in delivering colonoscopy skills teaching is shown in Figure 13.3. Optimizing these factors enables more effective delivery of training. To support this process in the UK, the JAG now applies quality standards to the delivery of endoscopy training through the four training domain of the global rating scale (Training GRS): 1 environment and training opportunity; 2 endoscopy trainers; 3 assessment and appraisal; 4 equipment and educational materials.

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This is supported by an e-based knowledge management system, which provides examples and support to improve the quality of all aspects of training within units (www.grs.nhs.uk/).

Instruction and feedback Instructions directing attention to movement effects are better for enhancing learning than those directing attention to a learner’s limbs or own movements [34]. The implication for teaching colonoscopy is that learning should be improved by instruction focusing on the endoscopic view seen, e.g., “tip up or tip down,” rather than on hand movements, e.g., “thumb down or up on big wheel.” The added advantage to this is that it ensures that the trainee remains focused on the screen image. A trainee whose attention is distracted and who looks away can quickly become disoriented or allow the scope to slip back within the colon, which can be frustrating for both trainer and trainee. There is a need for the trainee to be confident and familiar with the control wheels and buttons on the head of the colonoscope so that they can be located and moved without the need to look directly at them. This requires repetition of movement, which is best practiced on a model rather than on a patient. Paradoxically, instructions are not always beneficial. Performance and learning can be disrupted by instructions that might be expected to improve learning. This has been demonstrated in the acquisition of other psychomotor skills and may relate to the fact that the instructions can be incomprehensible if delivered in too complex a fashion [35]. Instruction has a valuable role in enhancing learning; however, the information provided needs to be carefully considered. Particular areas in which instructions are valuable include specifying a clear task goal and the order in which task components are performed. Establishing a common language for tasks in colonoscopy helps this process, particularly in relation to direct instruction of the trainees. There are a number of common instructions that when used, individually or in combination, help reduce any confusion when teaching. These are: • tip up • tip down • tip left • tip right • clockwise torque • anticlockwise torque • insufflate • aspirate • advance/push forward • withdraw/pull back • stop • slowly. For clarity with direction, the screen image should be referred to using a clock face (e.g., at 2 o’clock).

Teaching Colonoscopy

Giving feedback is an established and effective educational technique that considerably improves learning [36]. Feedback should aim to be objective and based on observable behaviors. The feedback should be delivered at an appropriate time and place. For colonoscopy, this can occur either during the procedure or more formally and structured immediately after the procedure. Feedback should be a two-way process. Frequently, “feedback” is given by the trainer in a monologue, amounting to subjective assessment of the trainee rather than the provision of true feedback. Whenever possible, the feedback should be referenced to specific points during the teaching of colonoscopy. A formal structured feedback template (e.g., Pendleton’s rules) can be a useful initial technique to employ [37]. Often there will be many points to discuss. When this occurs, the trainer needs to decide which are the critical points to improve trainee progress, taking into account the feedback from the trainee. The trainee feedback may alter or adjust the approach initially contemplated. The feedback needs to be regulated in quantityatoo much and it will be difficult for the trainee to rememberaand limited to behaviors which are remediable. After a training session or an individual procedure, it is helpful for the trainer to have a structure of priorities related to the feedback: 1 patient safety 2 basic handling 3 technical skills 4 attitude and behavior 5 interpretation of pathology and management 6 advanced technical points. The order does not necessarily need to be followed. Opportunistic teaching points occur regularly on any list and should be utilized to make the best use of the teaching session. However, it is essential that the trainee understands the need for safety and the importance of being patient focused. In addition, it is difficult to teach more advanced technical points before basic handling of the colonoscope has been mastered. When specific comments are made during feedback, there is an opportunity to make suggestions for improvement directly related to those comments [38–42]. Feedback should be formative, providing the information need to reinforce or adjust the trainee’s knowledge, skills, and attitudes. Providing feedback concurrently with training has strong immediate performance-enhancing effects. Unfortunately, withdrawal of concurrent feedback also results in clear reductions in performance compared with summary feedback given at the end of practice [26,43]. Therefore, some feedback should be provided on a case-by-case basis, with a summary of feedback at the end of a session. The importance of this 5- to 10-min discussion immediately after the colonoscopy cannot be overstressed. Almost all trainees are self-critical and preoccupied with their failures. A sensitive approach of positive critiquing and feedback means that they soon recognize that the trainer is sympathetic

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Colonoscopist

Date

/

• Major criteria Scale: 4 3 2 1 N/A

Trainer / Peer

/

Minor criteria Highly skilled performance Competent and safe throughout procedure, no uncorrected errors Some standards not yet met, aspects to be improved, some errors uncorrected Accepted standards not yet met, frequent errors uncorrected Not applicable

Criteria

Score

Comments

Assessment, consent, communication • Obtains informed consent using a structured approach –Satisfactory procedural information –Risk and complications explained –Comorbidity –Sedation –Opportunity for questions • Demonstrates respect for patient’s views and modesty during the procedure • Communicates clearly with patient throughout, including the results of the procedure with appropriate management and follow-up plan Safety and sedation • Safe and secure i.v. access • Gives appropriate dose on analgesia and sedation and ensures adequate oxygenation and monitoring of patient •Demonstrates good communication with the nursing staff including dosages and vital signs Endoscopic skills during insertion and withdrawal Checks endoscope function before intubation Performs PR* • Maintains luminal view/inserts in luminal direction • Demonstrates awareness of patient’s consciousness and pain during the procedure and takes appropriate action Uses torque steering Uses distension, suction and lens washing appropriately • Recognizes and logically resolves loop formation Uses position change and abdominal pressure to aid luminal views Completes procedure in reasonable time Diagnostic and therapeutic ability • Adequate mucosal visualization • Recognizes cecal landmarks or incomplete examination • Accurate identification and management of pathology • Uses diathermy and therapeutic techniques appropriately and safely • Recognizes and manages complications appropriately

Extremely easy

Case difficulty Average

Fairly easy

1

2

3

Fairly difficult 4

Learning objectives for next case

Figure 13.4 JAG-approved formative colonoscopy DOPS assessment form. *Performs per rectal examination.

150

Very challenging 5

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and working toward a common goal. In this way, a close and valuable relationship is built up between the trainer and trainee, with feedback anticipated, welcomed, and given on a regular basis [42].

Assessment Assessment and feedback are inseparable and are applied from the outset in the initial stages of colonoscopic training. Selected and agreed criteria can be used at any stage, i.e., at the end of a training session, at the end of a skills course, or at the completion of training. JAG’s formative DOPS forms apply 20 criteria within four domains divided into major and minor criteria (Figure 13.4). The four domains are: 1 assessment, consent, and communication; 2 safety and sedation; 3 endoscopic skills during insertion and withdrawal; 4 diagnostic and therapeutic ability. The levels of competence relate to specific objective descriptors for each level. This is a useful tool for both trainers and trainees, indicating areas of practice that require improvement, which can then be linked to specific learning objectives. The scoring within domains also enables a longitudinal monitoring of performance of the trainee, hopefully indicating improving performance with time. The DOPS process has also been applied to independent practicing colonoscopists in the UK, as part of the bowel cancer screening assessment process for colonoscopists wishing to take part in the program. DOPS are just one method of assessing trainees. DOPS are particularly useful for formative training during skills acquisition and subsequently for a structured summative assessment, as with the bowel cancer screening accreditation process for colonoscopists in the UK. It must be remembered that a competent colonoscopist must also display the appropriate attitudes and behaviors. This is best measure by 360degree appraisal. Performance monitoring is not relevant to novice colonoscopists. Their objectives should be related to acquisition of specific skills. However, as the trainees develop and become more competent, they will start to become successful in reaching the cecum. Once this begins to occur, it is reasonable to start to monitor performance data. There is much debate about which quality markers should routinely be measured. This is discussed in more detail elsewhere in this book. For trainees, it seems reasonable to measure a number of performance measures to ensure that competence is being achieved. These should include completion rates as a measure of technical proficiency, but also sedation practice and patient comfort scores to ensure that poor technique is not being compensated for by increased sedation or patient discomfort. Successful completion should be assessed on an intention-to-treat basis. It may be reasonable to independ-

Teaching Colonoscopy

ently monitor how many “failures” relate to an obstructing pathology rather than to basic technical deficiency. Irrespective of the criteria applied, the trainee should aspire to a sustained ≥ 90% completion rate. It is extremely important that trainee fellows keep a detailed log of their colonoscopic experience, ideally in electronic format. This provides a record of their increasing expertise and experience.

Completion of training Early recommendations for the completion of colonoscopic training involved only the number of procedures carried out. Fortunately, numbers are now recognized to be a spurious indicator of colonoscopic competence. Assessment has been addressed earlier in this chapter and standards for endoscopic quality are dealt with elsewhere in the book. Formal accreditation, recredentialing, or revalidation will exert further pressure to ensure adequate and appropriate training is provided. It is recommended that teaching support should be withdrawn gradually (but not abruptly, which can have disastrous effects on the learning process). The JAG advises that, following successful summative assessment, the trainer should be available within the endoscopy unit to supervise the next 50 “independent procedures,” then available within the hospital to supervise 50 subsequent procedures. There is recommended ongoing targeted training on more difficult or complex cases and there should be annual peer review. During this “probationary period,” trainee performance indicators are monitored and assessed against accepted standards. If performance remains satisfactory then accreditation in independent practice can be awarded.

Short skills courses for colonoscopy There are many short courses designed to improve endoscopy skills. It is recognized that, although they may augment colonoscopy training, they themselves do not result in the competence of an individual at the end of a course. Often the courses will have limited or no exposure to hands-on colonoscopy skills training. These types of courses can still play a valuable role in training. Courses can be an ideal method to ensure that a group of trainees has been instructed in the basic practice and principles relating to colonoscopy. The UK has a short skills course approved by JAG, the Basic Skills Colonoscopy Course, which is a mandatory course for all trainees wishing to practice colonoscopy. This course was developed to increase the level of competence and expertise in colonoscopy across the country. The course comprises training in both theory and the practical aspects of basic colonoscopy practice. The course also provides one-to-one hands-on colonoscopy skills training with experienced trainers. The course

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and the trainers are subject to a quality assurance process. There are defined aims and learning objectives, but the overall aim of the course is to introduce the candidates to a safe method of performing successful colonoscopy. These courses will continue to evolve. In the UK, there is a new e-learning educational resource: e-Endoscopy. In the future, much of the basic core knowledge taught in these courses will be delivered through this format, leaving the hands-on skills courses to concentrate primarily on the skills training. There is no reason why similar generic introductory skills courses cannot be provided “in house” at the start of a training program. It is important that the fundamentals of basic handling skills are taught to prevent the development of poor technique. Once basic handling skills are in place the trainee can practice on models and simulators. Formal lectures and videos may have some value at this stage but information is often delivered more effectively (and better retained) as interactive tutorials. The use of a video or DVD recording during skills training allows focused reflection after the practical session. It is a simple matter to record interesting pathology or complicated therapeutic techniques on video when the trainee is not physically present and then to review the procedure later within a dedicated session. If this culture is adopted by all colonoscopists within a unit, trainees soon become familiar with all the common and most of the uncommon findings and procedures. This may be supplemented with professional examples from other centers or via the Internet. During the initial stages of training, novices often benefit by watching their peers being taught on video link and they acquire valuable information that was not experienced during their own colonoscopy training. At the end of a training session a group debriefing often encourages in-depth discussion of colonoscopic technique and does much to encourage group participation during a teaching course. There is increasing evidence that videoing the performance of trainees with subsequent playback and reflection may be extremely helpful in advancing the acquisition of practical skills. As previously discussed, this process seems to have increased value when cueing is used at key points of the procedure by the trainer.

Summary This chapter describes how modern educational principles can be applied to facilitate trainees to perform colonoscopy safely, competently, and comfortably for the patient. Teaching can be very stimulating and challenging, provoking reflection on one’s own practice and standards. If a training culture is promoted, accepted, and welcomed, standards of both clinical practice and training are invariably high. Remember that today’s trainees are tomorrow’s colonoscopists and today’s trainers may be tomorrow’s patients.

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Acknowledgments I would like to recognize the invaluable contribution and help of Dr. Adrian Thuraisingam for his research of the major themes within this chapter. I am also grateful to the contributions of the UK training community and training leads and JAG chairman Professor Roger Barton. I would also like to acknowledge the contributions of Dr. Robin Teague and Mr. Roger Leicester, both for their work in the original chapter and their contribution to endoscopy training in general.

References 1 Wolff WI, Shinya H. Colonofiberoscopy. JAMA 1971; 217: 1509–12. 2 Niwa H, Sakai Y, Williams CB. History of endoscopy in the rectum and colon. In: Waye JD, Rex DK, Williams CB (eds.). Colonoscopy Principles and Practice. Oxford: Blackwell Publishing, 2003: 1–20. 3 Guest CB, Regehr G, Tiberius RG. The life long challenge of expertise. Med Educ 2000; 35: 78–81. 4 American Society for Gastrointestinal Endoscopy. Renewal of endoscopic privileges: guidelines for clinical application. Gastrointest Endosc 1999; 49: 823–5. 5 American Society for Gastrointestinal Endoscopy. ASGE: guidelines for clinical application: proctoring for hospital endoscopy procedures. Gastrointest Endosc 1999; 50: 901–5. 6 Eisen GM, Baron TH, Dominitz JA, et al. American Society for Gastrointestinal Endoscopy: methods of granting hospital privileges to perform gastrointestinal endoscopy. Gastrointest Endosc 2002; 55: 780–3. 7 American Society for Gastrointestinal Endoscopy. Principles of training in gastrointestinal endoscopy. Gastrointest Endosc 1999; 49: 845–53. 8 American Society for Gastrointestinal Endoscopy. Appropriate use of gastrointestinal endoscopy. Gastrointest Endosc 2000; 52: 831–7. 9 McCashland T, Brand R, Lyden E, de Garmo P. The time and financial impact of training fellows in endoscopy. CORI Research Project. Clinical Outcomes Research Initiative. Am J Gastroenterol 2000; 95: 3129–32. 10 Fruhmorgen P, Demling L. Complications of diagnostic and therapeutic colonoscopy in the Federal Republic of Germany; results of an enquiry. Endoscopy 1979; 2: 146–50. 11 Cass OW. Training to competence in gastrointestinal endoscopy: a plea for continuous measuring of objective endpoints. Endoscopy 1999; 31: 751–4. 12 Lee TD, Simon DA. Contextual interference. In: Williams AM, Hodges NJ (eds.). Skill Acquisition in Sport: Research, Theory and Practice. London: Routledge, 2004: 29–44. 13 Thuraisingam AI, MacDonald J, Shaw IS. Insights into endoscopy training: a qualitative study of learning experience. Med Teach 2006; 28: 453– 9. 14 Ericsson KA, Krampe RT, Tesch-Romer C. The role of deliberate practice in the acquisition of expert performance. Psychol Rev 1993; 100: 363–406.

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15 Teague R, Soehendra N, Carr-Locke D, et al. Setting standards for colonoscopic teaching and training. J Gastroenterol Hepatol 2002; 17(Suppl.): S50–S53. 16 Thomas-Gibson S, Williams CB. Colonoscopy training–new approaches, old problems. Gastrointest Endosc Clin N Am 2005; 15: 813– 27. 17 Wexner SD, Garbus J, Singh JJ. The SAGES colonoscopy study outcomes group. Surg Endosc 2001; 15: 251– 61. 18 Newell A, Rosenbloom PS. Mechanisms of skill acquistion and the law of practice. In: Anderson JR (ed.). Cognitive Skills and their Acquisition. Hillsdale: Erlbaum, 1981: 1–55. 19 Monsaas JA. Learning to be a world-class tennis player. In: Bloom BS (ed.). Developing Talent in Young People. New York: Ballantine, 1985: 211– 69. 20 Simon HA, Chase WG. Skill in chess. Am Sci 1973; 61: 394–403. 21 Lee TD, Swinnen SP, Serrien DJ. Cognitive effort and motor learning. Quest 1994; 46: 328– 44. 22 Janelle CM, Champenoy JD, Coombes SA, Mousseau MB. Mechanisms of attentional cueing during observational learning to facilitate motor skill acquisition. J Sports Sci 2003; 21: 825– 38. 23 Hodges NJ, Franks IM. Modelling coaching practice: the role of instruction and demonstration, J Sports Sci 2002; 20: 793–811. 24 Thuraisingam AI, Levine DF, Anderson JT. Can research in sports and other motor skills help improve endoscopy training? Gastrointest Endosc 2006; 63: 276– 9. 25 Peyton R (ed.). Teaching and Training in Medical Practice. Hertfordshire: Mantecore Europe, 1998. 26 Park J, Shea CH, Wright DL. Reduced-frequency concurrent and terminal feedback: a test of the guidance hypothesis. J Mot Behav 2000; 32: 287– 96. 27 Wightman DC, Lintern G. Part-task training strategies for tracking and manual control. Hum Factors 1985; 27: 267– 83. 28 Sedlack RE, Kolars JC. Validation of a computer-based colonoscopy simulator. Gastrointest Endoc 2003; 57: 214–18. 29 Saunders BP, Bell GD, Williams CB, Bladen JS, Anderson AP. First clinical results with a real time electronic imager as an aid to colonoscopy. Gut 1995; 36: 913–17.

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30 Barclay RL, Vicari JJ, Doughty AS, Johanson JF, Greenlaw RL. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 2006; 335: 2533–44. 31 East JE, Suzuki N, Arebi N, Bassett P, Saunders BP. Position changes improve visibility during colonoscope withdrawal: a randomized, blinded, crossover trial. Gastrointest Endosc 2007; 65: 263– 9. 32 East JE, Saunders BP, Boone D, Halligan S, Taylor SA. Comprehensive mucosal visualization at optical colonoscopy: Technique remains the key. Gastroenterology 2006; 131: 975–6. 33 Thomas-Gibson S, Rogers P, Cooper S, et al. Judgement of the quality of bowel preparation at screening flexible sigmoidoscopy is associated with variability in adenoma detection rates. Endoscopy 2006; 38: 456– 60. 34 Wulf G, Prinz W. Directing attention to movement effects enhances learning: a review. Psychon Bull Rev 2001; 8: 648–60. 35 Groeger JA, Clegg BA. Practice and Instruction when Learning to Drive. London: Department of the Environment, Transport and the Regions, 2000. 36 Black P, William D. Assessment and classroom learning. Assess Educ 1998; 5: 7–74. 37 Pendleton D, Scofield T, Tate P, Havelock P. The Consultation: An Approach to Learning and Teaching. Oxford: Oxford University Press, 1984. 38 Ende J. Feedback in clinical medical education. JAMA 1983; 250: 777– 81. 39 Hesketh EA, Laidlaw JM. Developing the teaching instinct, 1: feedback. Med Teach 2002; 24: 245– 8. 40 Sachdeva AK. Use of effective feedback to facilitate adult learning. J Cancer Educ 1996; 11: 106–18. 41 Silverman J, Draper J, Kurtz SM. The Calgary–Cambridge approach to communication skills teaching. II: The SET-GO method of descriptive feedback. Educ Gen Pract 1997; 8: 16–23. 42 Wood BP. Feedback: a key feature of medical training. Radiology 2000; 215: 17–19. 43 Wulf G, Shea CH. Understanding the role of augmented feedback. In: Williams AM, Hodges NJ (eds.). Skill Acquistion in Sport: Research, Theory and Practice. London: Routledge, 2004: 121–44.

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Role of Simulators in Colonoscopy Jonathan Cohen1 & Simon Bar-Meir2 1

New York University School of Medicine, New York, NY, USA Chaim Sheba Medical Center, Tel Hashomer, and Tel Aviv University, Tel Aviv, Israel

2

Introduction The concept of a simulator as a training tool is well established in many areas where eye–hand coordination is important, notably in aviation training [1,2]. Simulators are used to train new pilots and for the annual accreditation of experienced pilots. Training pilots on simulators is both safe and relatively inexpensive, providing the ability to teach judgment and the need to react quickly and precisely in a safe environment in order to avoid errors in actual flight that may be critical and cost lives. It is increasingly feasible for simulators to also be used for training in the medical field. Advanced simulation technology has been introduced into medicine in several fields such as laparoscopy [3], cardiology [4,5], and anesthesiology [6,7]. Performing an endoscopy requires skill and training. For each type of endoscopic examination there is a minimum number of procedures performed before competency can be assessed, ranging from 100 to 300 procedures for esophagogastroduodenoscopy, colonoscopy, and endoscopic retrograde cholangiopancreatography (ERCP) [8–12]. Tassios et al. [10] showed that between 100 and 180 procedures had to be performed for the learning curve of colonoscopy performance to reach a plateau. Cass et al. [11] reported that 140 colonoscopies are required in order to achieve a 90% success rate of cecal intubation. In another regression analysis of all studies that reported the success rate of cecal intubation as a function of the number of colonoscopies performed, it was determined that 341 colonoscopies were needed to reach a 90% success rate of cecal intubation [13]. Particularly at a time when technological advances in development aim to make cecal intubation easier to achieve, it is important to emphasize that cognitive skill in lesion recognition and therapeutic capabilities are also critical components of true overall competency. While it is often used as a surrogate

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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marker, reaching the cecum consistently is not sufficient for the determination of competency. It is clear from the literature that a long period of supervision is required before the trainee achieves an acceptable level of competence. However, in this period of increasing colonoscopic utilization, many supervising endoscopists find that they have insufficient time to properly watch over trainees. An endoscopic simulator that partially decreases the need for hours of one-on-one teaching would therefore be of value. Alternatively, a training device that was able to accelerate the learning curve, even with initially more laborintensive supervision, could also free up valuable time. The theoretical benefits of simulators range from crude devices that allow rudimentary familiarity with dial manipulation and scope advancement, to more advanced tools that mimic the true “feel” of loop formation and reduction and even to allow practice in therapeutic maneuvers in a controlled relaxed environment with no risk or discomfort for actual patients.

Types of simulators Mechanical models Historically, the first endoscopic simulators were mechanical and designed for use with the semirigid upper intestinal gastroscopes. Particular interest has currently focused on flexible sigmoidoscopy and colonoscopy [14–16]. The various models have ranged from a simple slide projection system to rubber models of the colon. In 1974, Classen and Ruppin [17] developed an anatomically shaped plastic dummy of the gastrointestinal (GI) tract. About the same time, Williams et al. [18] used the spiral metal reinforced tube of a hair dryer for colonic simulation (Figure 14.1). None of these mechanical simulators gained popularity and all have been abandoned. The most advanced mechanical model available at the present time has been developed by the University Hospital of Tübingen [19]. This simulator consists of a realistic anatomically correct phantom in dimension, color, structure, and sensation (Figure 14.2). It permits the simulation of all diagnostic and most of the therapeutic endoscopic interventions.

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Figure 14.1 “Mechanical simulator” St Mark’s colon model (1978).

Role of Simulators in Colonoscopy

It is also possible to perform electrosurgical interventions such as polypectomy, ablation of a tumor with either laser or argon plasma coagulator, and stent deployment. Modules for upper GI endoscopy and ERCP together with sphincterotomy are also available. The characteristics of the artificial tissue and its behavior during the application of electrosurgery make it an ideal model for therapeutic procedures. Although beneficial for teaching electrosurgical techniques, the force feedback during endoscopy and the behavior of the GI tract during insertion of a colonoscope is different from that experienced during a real procedure on a human patient, which makes it less valuable for the practice of colonoscopic insertion technique. Since there is no interaction between the trainee and the simulator, the presence of a supervisor is required. The Tübingen simulator is not for sale and current policy is to make it available for workshops only. For workshops outside the University of Tübingen, a technical team accompanies the model, making this teaching tool very costly and impractical for widespread application. However, the demonstration of feasibility for realistic hands-on instruction in therapeutic techniques is an important advance.

Animal tissue models

Figure 14.2 Tübingen model.

The acceptability of this model is related to an artificial tissue, Artitex, which has a wax-like consistency and can be shaped as needed. It can be manipulated and molded to resemble various pathologies such as strictures, polyps, and tumors.

Live animal models are the most realistic simulators, but the cost and the ethical objection to the use of live animals have all but eliminated their use for the purpose of training. However, ex vivo animal tissue-based models, initially used with great enthusiasm in the upper GI tract, have now been adapted for colonoscopy training. In the two Erlangen models (Figure 14.3), known as EASIE™ (Erlangen Active Simulator for Interventional Endoscopy) and the Erlangen Endo-Trainer, the GI tract and pancreaticobiliary system are obtained from slaughtered pigs [20–22]. The ethical issue is eliminated because the pig’s GI tract is obtained from the slaughterhouse, where the animal has already been killed for the supply of meat. In the Erlangen Endo-Trainer, the upper or lower GI tract is installed on a plastic structure shaped like the human organ. In the compactEASIE model, designed by Hochberger, the animal specimen is fastened to a plastic tray that is portable and easy to ship for local workshops. An ingenious perfusion system generates realistic bleeding episodes that respond to therapeutic intervention. Both Erlangen models allow the performance of most GI procedures

Figure 14.3 Erlangen models.

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in a realistic fashion, very similar to the human environment. However, they are more adequate for training in therapeutic procedures than for endoscopic intubation or practice of technique. Procedures such as polypectomy and hemostasis (coagulation and clips) are easily performed. While bleeding simulation has most often been performed in the context of training in hemostasis of upper GI bleeding, this technique is easily adaptable to lower GI ex vivo tissue models. The coloEASIE™ ex vivo porcine model has been adapted specifically for the colon, and its use in training workshops has been reported. Developed in 1999 by Maiss et al. [23], it allows the simulation of multiple sigmoid loop formations by changing the shape of the metal spirals attached to the platform. Such simulators are reusable and require approximately 1 m of pig or bovine colon which can be shipped frozen, thawed, and then attached to the platform using sutures. Besides basic scope manipulation, therapeutic techniques taught on this model include endoscopic mucosal resection techniques, stricture dilation, stent deployment, argon plasma coagulation, hemorrhoid ligation, and polypectomy of lesions created by inverting and suturing tissue (Figure 14.4). Formal validation studies using coloEASIE™ to train individuals in different skills have not yet been conducted. The coloEASIE™ platform is still not widely available commercially and requires some skill in setting up and manipulating the model to create strictures, polyps, and difficult loops. However, the simulator is very compact and potentially easily transportable; porcine specimens are easily obtained for approximately $100. The organs are prepared and shipped frozen and can be kept for long periods before being used. A commercially available all-purpose platform, the EASIE-R™, has been developed (Matthes and Cohen, personal communication) to accommodate various organ preparations to include colon, upper GI tract, Neopapilla™ attachment for ERCP, small bowel endoscopy, and even endoscopic ultrasound (EUS) and NOTES (natural orifice transluminal endoscopic surgery). Validation of this model will be required, but this new platform aims to promote the concept of feasible low-cost local use of simulators for individuals and facilities without access to the larger central workshops (Figure 14.5).

(a)

Figure 14.4 Colo-Easie spiral support for porcine colon.

Sedlack et al. [24] have developed an ex vivo model for colonoscopy training using bovine tissue (Figure 14.6). The bovine colon is longer than the porcine colon, and may more closely approximate the human colon. In the initial validation study, the bovine model received high marks for realism from experts, with the exceptions of the longitudinal rather than the human transverse haustral folds and a relatively easy passage to the cecum; however, it is likely that altering the configuration will allow instructors to increase the levels of difficulty in intubation in future modifications of this model. Importantly, the authors were able to demonstrate construct validity in which experts exhibited significantly shorter cecal intubation times than did novices. Comparison between simulator cecal intubation times and historical data kept on each subject’s actual cecal intubation times on real patients revealed a high degree of correlation. It is important to note that very few data have been reported on any simulator in which a parameter measured on the simulator correlated closely with that on actual patients. While cecal intubation time has not been considered either a quality measure or an indicator of competency, these data may represent a first step toward the development of a simulator that is helpful not only in teaching trainees but also in

(b)

Figure 14.5 Porcine colon specimens (a and b) and internal view after tattooing (c).

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(c)

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Figure 14.6 Bovine colon training model.

accurately assessing their level of skill. In an era of increasing emphasis on quality measurement and increased interest on the part of various practitioners to learn colonoscopy, there will be great value placed on any ex vivo method which is validated to assess competency. At $1500 per platform and $100 per bovine specimen, along with the theoretical possibility of using this model to insert pathology and teach therapeutic interventions, this may become an important adjunct to training in the future. Porcine-based colonoscopy platform simulators also provide similar portability and cost parameters, and future comparisons of these two teaching tools will be needed. While the ex vivo models have great promise for instruction in therapeutic interventions, it should be emphasized that such training is labor intensive and requires a number of instructors who have themselves received adequate training on how to teach using the models. The potential applications include team training of endoscopists along with their technical assistants, a concept emphasized by Hochberger et al. [25]. It remains to be seen whether the future of ex vivo models will be increasing access to central or regional workshops at simulator centers or whether there will be local access to portable simulators with relatively low start-up and maintenance costs.

Computer simulators Computer-based simulators have become increasingly available [26,27]. Their biggest advantage over animal tissue models is their availability for training without any need for previous preparation. Once fellows are oriented to the machine, training may start immediately. In contrast to the animal tissue models, these simulators confer the possibility for unsupervised training. While this can free up valuable time for staff gastroenterologists and accordingly provide financial benefits, it remains to be determined whether computer-based colonoscopy instruction is more effective with a proctor present. Another advantage is a greatly expanded

Role of Simulators in Colonoscopy

potential to incorporate scenes of abnormal pathology and teach the cognitive components of the procedure in addition to its technical aspects. Computer-based simulators are constructed as a threedimensional geometric model. Images and texture of the GI tract are derived from either videotape from real endoscopic procedures or from reconstructed computed tomography scan data from the Visible Human Project. Built into the systems is both global and local deformity, i.e., a change in the configuration of either the entire GI tract due to insertion of the endoscope or only a part of the GI wall due to local pressure by an endoscope or accessories. Sensors on the endoscope continuously transmit its location to a computer, which displays the information on a monitor. Insertion of the endoscope is associated with a sensation of resistance (force feedback) in an attempt to resemble the tactile experience of pushing the instrument though the GI tract of a human subject. Presently, there are two commercially available computerbased simulators of the GI tract: the GI Mentor, which was developed by Simbionix (Tel-Hashomer, Israel) [28], and the AccuTouch, which was developed by Immersion Medical (Gaithersburg, MD, US) [29]. Both companies use real endoscopes; Simbionix uses a modified Pentax endoscope, whereas Immersion Medical has specially designed an endoscope very similar to a standard colonoscope. Both of these simulators allow steering and torque of the endoscope, which also has functional suction and inflation buttons. Both devices provide trainees with sensations that mimic an actual endoscopic examination, interchanging modules for sigmoidoscopy, colonoscopy, or ERCP (Figures 14.7 and 14.8). An EUS module is also available for the GI Mentor. Each module contains several cases that start with a history, including laboratory workup and imaging studies, to allow the trainee to assess the appropriate management of the condition prior to practicing the endoscopic procedure. Upon completion of a tutorial session, instructors can view the recorded events. The GI Mentor simulator also includes a set of eye–hand coordination exercises that mimic a video game in which the trainee must either pop a bubble with a needle accessory by turning the scope and applying torque or grasp basketballs with a forceps and deliver them into nets that appear as the endoscope is advanced (Figure 14.9). Comments can be entered in the trainee file and special notes can be sent to the trainee using a message board. An optional Internet connection allows instructors to connect to the simulator from any remote location and assign programs or send messages in real time from any place in the world. Christopher Williams [30], a pioneer in the field of colonoscopy simulation, is also developing a very realistic colonoscopy simulator based on mathematical modeling in association with the Olympus Corporation. It remains to be seen whether this technology will result in an improved sense of realism compared with the currently available models, on which it is

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Figure 14.9 Simbionix training game.

(a)

(b) Figure 14.7 (a) Simbionix GI Mentor. (b) A snared polyp in the Simbionix GI Mentor simulator. Figure 14.10 Olympus Colonoscopy Simulator.

Figure 14.8 A snared polyp in the Immersion Medical simulator.

notably easier for experts to perform total intubation than it is to do so during actual procedures. A formal validation study of the Olympus simulator is currently being planned. Williams has advocated combining simulator work with use

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of the ScopeGuide magnetic imager, which he has also developed to provide real-time feedback about looping during actual colonoscopies and which can be combined with intensive structured teaching by experienced instructors to accelerate colonoscopy training (Figure 14.10). The Simbionix basic platform costs $15 000, with an additional $5000 for either a straight or a side-view endoscope. There is an additional cost of approximately $10 000 for each of the modules consisting of 20 cases. Immersion Medical charges $30 000 for the platform and the endoscope, and approximately $20 000 for the lower GI endoscopy module. Both simulators are updated regularly and new modules added. There is a growing body of literature validating the role of computer simulators in teaching colonoscopy. Efforts have been made to establish construct validity by demonstrating improved performance on the models with increasing

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levels of endoscopic expertise on patients. Other trials have been conducted to assess the efficacy of training on computer simulators as compared with the performance of actual colonoscopies during the early part of a fellow’s training. Such validation studies provide the strongest evidence that simulators have a benefit in training. There are no studies to show that learning to perform endoscopy on simulators will decrease patient discomfort and increase safety. While some of the training validation studies have looked at patient discomfort, the relatively low incidence of colonoscopy complications makes this parameter very difficult to study without extremely large numbers of subjects and procedures. To date, there are no published studies that demonstrate a role for computer simulators in assessing skill; while experts have repeatedly performed better than novices on various parameters on both available models of simulators, there is no “test” on a simulator yet developed that has been shown to correlate with competent levels of performance on real colonoscopies. The key validation studies of computer simulators for colonoscopy are described below. Gerson [31] has recently reviewed the evidence for the use of computer simulators, and the results for flexible sigmoidoscopy and colonoscopy training are summarized in Tables 14.1 and 14.2. An initial impression of the GI Mentor was obtained during two workshops held in 2000 in Nice and Hamburg [26],

Role of Simulators in Colonoscopy

where 71 gastroenterologists with experience in performing endoscopies for more than 1 year worked on the GI Mentor and answered an evaluation questionnaire. The responses showed that 96% of them felt that the simulator met their expectations, and 83% considered that it would be advantageous to train in an institution where such a simulator exists; 81% would use the simulator in their next training program, if available, and 90% felt that prior training on the GI Mentor would reduce the potential risk of complications to patients. The simulator was considered user-friendly by 97%, and 88% would recommend its use to others. Similar results were reported by Aabakken et al. [46] from the annual Scandinavian Association for Digestive Endoscopy course, where the usefulness of the simulator was rated highest by the least experienced participants. The first study to assess the value of a simulator in teaching endoscopy compared the performance of five trainees in an experimental group with another five who served as a control group [32]. The former group trained on a simulator for 6–10 h before performing their first sigmoidoscopies on volunteers. The experimental group achieved a significantly faster insertion time (211 s vs. 518 s) and a shorter mean overall examination time (323 s vs. 654 s), and visualized a higher percentage of the colon mucosal surface (79% vs. 45%). Sedlack and Kolars [47] reported that the Immersion Medical simulator successfully separated groups of experts,

Table 14.1 Use of endoscopic simulators for flexible sigmoidoscopy training. Reference

Study type and evidence

Subjects and simulator

Outcomes

Findings

Tuggy [32]

Clinical trial (B)

5 control subjects 5 simulator trained Gastro-Sim (Interact) Medical

Hand–eye skills

Simulator group significantly faster insertion times and shorter duration

Datta et al. [33]

Validation (B)

15 novices 15 intermediates 15 experts Immersion Medical

Incremental and significant improvement in all parameters according to experience

Simulator able to distinguish experience level

MacDonald et al. [34]

Validation (B)

10 clerical workers 19 residents 5 experts Immersion Medical

Performance on simulated cases

Experts performed better but had higher perforation rates

Gerson and Van Dam [35]

Randomized clinical trial (A)

Internal medicine residents 9 simulator trained 7 bedside trained Immersion Medical

Ability to reach splenic flexure, perform retroflexion, patient satisfaction and discomfort

Bedside training superior in all outcomes No difference in patient discomfort

Sedlack and Kolars [36]

Randomized clinical trial (A)

Internal medicine residents 19 simulator trained 19 bedside trained Immersion Medical

Ability to reach flexure, perform biopsy, patient discomfort

Less patient discomfort in simulator group No difference in procedural skills

By permission from Elsevier. Adapted from Gerson [31].

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Table 14.2 Published studies using virtual reality computer simulation for colonoscopy training. Reference

Study type and evidence

Subjects and simulator

Outcomes

Findings

Sedlack and Kolars [37]

Validation (B)

10 experts 5 partially trained 2 novices Immersion Medical

Determine optimal usage for simulator

Simulator most effective early in training

Sedlack and Kolars [38]

Validation (B)

10 experts 6 fellows 6 residents Immersion Medical

Performance on two virtual examinations and rating of simulator

Procedure time, insertion time, and time in red out better for experts

Mahmood and Darzi [39]

Validation (B)

10 novices 7 intermediates 5 experts Immersion Medical

Performance on simulator

Experts superior compared with other groups for all parameters

Eversbusch and Grantcharov [40]

Validation (B)

8 experts 10 residents 10 medical students Simbionix

Performance on 10 consecutive trials on simulator

Experts best performance; learning curve plateau on second repetition for experts, fifth for residents, and seventh for students

Mahmood and Darzi [41]

Validation (B)

26 postdoctoral fellows without endoscopic experience Immersion Medical

Repeated same random module five times either with or without feedback

No improvement in skills without feedback

Sedlack and Kolars [36]

Clinical trial (B)

8 novice fellows; 4 simulator-trained for 6 h Immersion Medical

Performance during 15 actual colonoscopies

Simulator-trained fellows outperformed bedside-trained up to 30 procedures except for time of insertion (P < 0.05)

Grantcharov et al. [42]

Validation (B)

8 experts 10 residents 10 medical students Simbionix

Performance on simulator

Experts superior performance; no difference between residents and students

Felsher et al. [43]

Validation (B)

75 faculty, fellows, and residents Simbionix

Performance on two virtual examinations

Experts superior for all parameters

Clark et al. [44]

Clinical trial (B)

5 PGY-1 and 8 senior surgical residents with monthly simulator training Simbionix

Simulator performance over 2 years

Junior residents improved efficiency by 59%, seniors by 88%

Cohen et al. [45]

Clinical trial (A)

45 first-year gastroenterology fellows; 23 randomized to simulator training for 10 h and 22 randomized to no simulator training

Objective and subjective competency during 200 colonoscopies

Simulator-trained group showed higher objective competency during the first 80 cases No difference in patient discomfort

PGY-1, first-year postgraduate medical students.

intermediate endoscopists, and novices. Scores obtained on the simulator permitted differentiation between the performance of staff, fellows, and residents, with better results (less time to perform the procedure and more of the surface visualized) by those with more experience. Datta et al. [33] confirmed previous findings and showed that the Immersion Medical

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simulator was a valid discriminator of flexible sigmoidoscopy experience, permitting numerical distinction between novice, intermediate (5–50 examinations), and trained (> 200 examinations) endoscopists. Other studies of construct validity support the notion that individuals of increasing skill perform better as measured on the simulators [38–40,42,43].

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100 90 Competency (%)

Gerson and Van Dam [35] conducted a controlled trial comparing seven medical residents trained by performing 10 supervised flexible sigmoidoscopies on humans with nine residents who received training only on the Immersion simulator (spending a mean of 138 min on the model). The investigators found that the traditional one-on-one tutorial teaching method was superior to training on the simulator. During the five test cases, subjects in the simulator arm had significantly more difficulty with initial scope insertion and negotiation of the rectosigmoid junction. The simulator group was less likely to reach the splenic flexure without assistance than those trained on human subjects (P = 0.001). Average time per procedure and patient satisfaction and discomfort associated with the procedure did not differ between the two groups. Although the bedside teaching group achieved better results, it is not clear whether a combination of computer simulation training with traditional bedside cases or simply a longer amount of training time on the simulator alone would have improved performance over the standard method of sigmoidoscopy training. The Mayo Clinic in Rochester, Minnesota, established a first-year training program based on the computer-controlled colonoscopy simulator [37]. Performance variables measured by the simulator include time to complete the procedure, distance the scope was advanced, degree to which the mucosa was adequately visualized, possible complications such as perforation, and level of pain experienced by the simulated patient. Based on calculation of the average performance of novice, partially trained, and “expert” faculty colonoscopists, the researchers were able to estimate the minimal performance standards for new trainees. The curriculum consisted of a 1-h multimedia tutorial, followed by 9 h of simulator training (to include 25 colonoscopies). This effort was an important step toward integrating colonoscopy simulation into a general training program. Two randomized studies have been conducted which confirm a benefit of simulator training on the early part of the learning curve of real colonoscopy. The Mayo group evaluated four novice fellows who received 6 h of training on the Immersion simulator and four others randomized to no simulator training as they performed their first real colonoscopies [36]. The simulator-trained group performed significantly better during the first 15 procedures, but the differences were eliminated after the two groups had performed 30 procedures. In a larger multicenter randomized controlled trial of 45 GI fellows using the Simbionix GI Mentor, in which the group randomized to receive simulator experience spent 10 h working on the model, the learning curves were followed for the first 200 procedures performed [45]. In this study, the definition of a competent examination required independent scope passage to the cecum and correct identification of pathology encountered. While the median number of examinations to reach competency was 160 in each group, there

Role of Simulators in Colonoscopy

80 70 60 50 40 30

Nonsimulated group Simulated group

20 10 0 20

40

60

80

100

120 140

160

180

200

No. of Colons

Figure 14.11 Comparison of mean objective competency rates achieved by simulator or hands-on trainees. P < 0.05.

was a significant improvement in the learning curve for the simulator group, with the major benefit being observed during the first 80 cases (Figure 14.11). No difference was found in patient discomfort in either arm of this study [45]. To date, no strong data exist on what is the optimal amount of training on computer simulators. While the Mayo data [36,37] and the multicenter Simbionix trial data [45] suggest that 9–10 h of training does confer a benefit, it is still unknown whether there is any further utility of either spending more upfront hours on the model prior to performing real cases or of continuing work on the simulator throughout the learning process while trainees have begun to perform supervised procedures on human subjects. What about the role of instructor feedback? Mahmood et al. [41] studied the performance of simulated colonoscopies in the Immersion simulator of 26 doctors of varying experience. In the absence of feedback, the subjects failed to show improvement on the simulator during five successive attempts at the same procedure. In contrast, two studies found that simulator work resulted in better colonoscopy performance even though trainees’ simulator time was largely unproctored [36,45]. The question of whether active teaching by experts during computer colonoscopy simulator training is worthwhile remains unanswered. In essence, computer colonoscopy simulators appear to confer the biggest advantage on novices at the early part of their learning curve. There may also be some benefit to patient satisfaction parameters such as comfort level during the early part of actual live colonoscopy for individuals who have had access to simulator training. Generally, in the case of fellows likely to receive several hundred real cases to perform during their training, it is unclear what long-term benefits are conferred by simulator work, apart from the possible early benefit to patients and any reduced financial and time burden for instructors. The potential advantage of using computer models to teach and test for pathology

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recognition and to speed the development of cognitive competency needs further exploration, although the multicenter randomized controlled study of the Simbionix simulator did incorporate correct lesion recognition into its more stringent measure of competency. For therapeutic techniques, the ex vivo models are currently closer to approximating realistic “feel” and accessory use; however, the computer models in the future could expand upon the cognitive aspects of therapeutics with more interactive questions about accessories, settings, and techniques selected to approach the pathology encountered. For the present, the limiting factor for the use of computer models remains the high cost. However, if computer-based competency examinations that are shown to correspond to actual performance variables on real procedures can one day be developed, there may be a great impetus for institutions to purchase models for this purpose.

Summary The introduction of endoscopy simulators will likely change the preliminary aspects of endoscopy training. This is due to multiple factors, including the limited time of supervising physicians, but most important is the ability to gain familiarity with the basic steps of the endoscopic procedure without inconveniencing a human subject. Training on simulators can facilitate eye–hand coordination and allow trainees to practice the repetitive steps involving both the scope and the accessories necessary to learn technical maneuvers and therapies. While simulators may introduce trainees to pathologic findings, the acquisition of knowledge about some of the decision processes needed to perform colonoscopy still requires live supervision and instruction by dedicated teachers. Advanced interactive automated feedback to obviate some of this need remains possible for future computer model development. As simulators become more available, trainers will need increasing instruction on how to take maximum advantage of these new tools. In addition to basic training, simulators may be useful in credentialing and recredentialing endoscopists at intervals during their career, but this will require more realistic simulation of difficult cecal intubation and the development of simulator-based competency tests that are validated by outcome measures on real procedures. Forces supporting the integration of simulators into standard training include the increasing availability of models for training, wider acceptance of simulators in other disciplines such as anesthesiology and surgery, increased public awareness of medicolegal aspects, and the limited time of supervising physicians. Logistic concerns of portability and cost remain major obstacles. In the future, trainees will likely start their training on a computer-based simulator. More advanced training in therapeutic procedures might be obtained with the computer-based simulator first for orientation and then

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progressing to the ex vivo models. Such training will most probably be integrated into large training centers, such as the Interactive Training and Technology Center of the American Society for Gastrointestinal Endoscopy (Oak Brook, IL, US; www.asge.org), where the platform-based animal tissue models will be easily available at reasonably low cost. For the future, simulators will make possible increasing opportunities for individuals in practice who wish to refresh old skills and learn new techniques.

References 1 Helmreich RL, Foushee HC. Why crew resource management? In: Weiner EL, Kanki BG, Helmreich RL (ed.). Cockpit Resource Management. San-Diego: Academic Press, 1993: 3–46. 2 Cohen J, Nuckolls L, Mourant RR. Endoscopy simulators: lessons from the aviation and automobile industries. Gastrointest Endosc Clin N Am 2006; 16: 407–23. 3 Derossis AM, Fried GM, Abrahamowicz M, et al. Development of a model for training and evaluation of laparoscopic skills. Am J Surg 1998; 175: 482–7. 4 Gordon MS, Ewy GA, Felner JM, et al. A cardiology patient simulator for continuing education of family physicians. J Fam Pract 1981; 13: 353– 6. 5 Ewy GA, Felner JM, Juul D, et al. Test of a cardiology patient simulator with students in fourth-year electives. J Med Educ 1987; 62: 738– 43. 6 Gaba DM, Howard SK, Flanagan B, et al. Assessment of clinical performance during simulated crises using both technical and behavioral ratings. Anesthesiology 1998; 89: 8–18. 7 Schwid HA, O’Donnell D. The Anesthesia Simulator-Recorder: a device to train and evaluate anesthesiologists’ responses to critical incidents. Anesthesiology 1990; 72: 191–7. 8 Farthing MJ, Walt RP, Allan RN, et al. A national training programme for gastroenterology and hepatology. Gut 1996; 38: 459–70. 9 American Society for Gastrointestinal Endoscopy Standards of Training and Practice Committee. Methods of granting hospital privileges to perform gastrointestinal endoscopy. Gastrointest Endosc 1992; 38: 765–7. 10 Tassios PS, Ladas SD, Grammenos I, et al. Acquisition of competence in colonoscopy: the learning curve of trainees. Endoscopy 1999; 31: 702– 6. 11 Cass OW, Freeman ML, Cohen J, et al. Acquisition of competency in endoscopic skills during training: a multicenter study. Gastrointest Endosc 1996; 43: 308 (abstract). 12 Cohen J. Training and credentialing in gastrointestinal endoscopy. In: Cotton PB, Sung J (ed.). Advanced Digestive Endoscopy ebook: Endoscopy Practice and Safety. Blackwell Publications, 2001. Available at: www.gastrohep.com. 13 Cass OW. Training to competence in gastrointestinal endoscopy: a plea for continuous measuring of objective end points. Endoscopy 1999; 31: 751–4. 14 Rodning CB, Zingarelli WJ, Webb WR, et al. Postgraduate surgical flexible endoscopic education. Ann Surg 1986; 203: 272–4. 15 Bowman MA, Wherry DC. Training for flexible sigmoidoscopy. Gastrointest Endosc 1985; 31: 309–12.

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16 Greenwald D, Cohen J. Evolution of endoscopy simulators and their application. Gastrointest Endosc Clin N Am 2006; 16: 389– 406. 17 Classen M, Ruppin H. Practical training using a new gastrointestinal phantom. Endoscopy 1974; 6: 127–31. 18 Williams CB, Saunders BP, Bladen JS. Development of colonoscopy teaching simulation. Endoscopy 2000; 32: 901–5. 19 Grund KE, Brautigem D, Zindel C, et al. Interventionsfahiges Tubinger Simulationsmodell Interphant fur die flexible endoskopie. Endoskopie Heute 1998; 11: 134. 20 Neumann M, Hochberger J, Felzmann T, et al. Part 1. The Erlanger endo-trainer. Endoscopy 2001; 33: 887–90. 21 Hochberger J, Maiss J, Magdeburg B, et al. Training simulators and education in gastrointestinal endoscopy: current status and perspectives in 2001. Endoscopy 2001; 33: 541–9. 22 Hochberger J, Neuman M, Maiss J, et al. EASIE (Erlangen Active Simulator for Interventional Endoscopy) a new bio-simulation model: first experience gained in training workshops. Gastrointest Endosc 1998; 47: A116. 23 Maiss J, Matthes K, Naegel A, et al. Der coloEASIE-Simulatoroa ein neues Trainingsmodell für die interventionelle Kolo-und REktoskopie [the coloEASIE-Simulatoraa new training model for interventional colonoscopy and rectoscopy]. Endoskopie Heute 2005; 18: 190–3. 24 Sedlack RE, Baron TH, Downing SM, et al. Validation of a colonoscopy simulation model for skills assessment. Am J Gastroenterol 2007; 102: 64–74. 25 Hochberger J, Euler K, Naegel A, et al. The compact Erlangen Active Simulator for Interventional Endoscopy: a prospective comparison in structured team-training courses on “endoscopic hemostasis” for doctors and nurses to the “Endo-Trainer” model. Scand J Gastroenterol 2004; 39: 895–902. 26 Bar-Meir S. A new endoscopic simulator. Endoscopy 2000; 32: 898– 900. 27 Bar-Meir S. Endoscopy simulators: the state of the art, 2000. Gastrointest Endosc 2000; 52: 701–3. 28 Bar-Meir S. Simbionix simulator. Gastrointest Endosc Clin N Am 2006; 16: 471– 8, vii. 29 Long V, Kalloo AN. AccuTouch Endoscopy Simulator: development, applications and early experience. Gastrointest Endosc Clin N Am 2006; 16: 479– 87. 30 Williams CB, Thomas-Gibson S. Rational colonoscopy, realistic simulation, and accelerated teaching. Gastrointest Endosc Clin N Am 2006; 16: 457–70. 31 Gerson LB. Evidence-based assessment of endoscopic simulators for training. Gastrointest Endosc Clin N Am 2006; 16: 489–509.

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32 Tuggy ML. Virtual reality flexible sigmoidoscopy simulator training: impact on resident performance. J Am Board Fam Pract 1998; 11: 426–33. 33 Datta V, Mandalia M, Mackay S, et al. The PreOp flexible sigmoidoscopy trainer. Validation and early evaluation of a virtual reality based system. Surg Endosc 2002; 16: 1459–63. 34 MacDonald J, Ketchum J, Williams RG, et al. A lay person versus a trained endoscopist: can the preop endoscopy simulator detect a difference? Surg Endosc 2003; 17: 896–8. 35 Gerson LB, Van Dam J. A prospective randomized trial comparing a virtual reality simulator to bedside teaching for training in sigmoidoscopy. Endoscopy 2003; 35: 569–75. 36 Sedlack RE, Kolars JC. Computer simulator training enhances the competency of gastroenterology fellows at colonoscopy: results of a pilot study. Am J Gastroenterol 2004; 99: 33–7. 37 Sedlack RE, Kolars JC. Colonoscopy curriculum development and performance-based assessment criteria on a computer-based endoscopy simulator. Acad Med 2002; 77: 750–1. 38 Sedlack RE, Kolars JC. Validation of a computer-based colonoscopy simulator. Gastrointest Endosc 2003; 57: 214–18. 39 Mahmood T, Darzi A. A study to validate the colonoscopy simulator. Surg Endosc 2003; 17: 1583– 9. 40 Eversbusch A, Grantcharov TP. Learning curves and impact of psychomotor training on performance in simulated colonoscopy: a randomized trial using a virtual reality endoscopy trainer. Surg Endosc 2004; 18: 1514–18. 41 Mahmood T, Darzi A. The learning curve for a colonoscopy simulator in the absence of any feedback: no feedback, no learning. Surg Endosc 2004; 18: 1224–30. 42 Grantcharov TP, Carstensen L, Schulze S. Objective assessment of gastrointestinal endoscopy skills using a virtual reality simulator. JSLS 2005; 9: 130– 3. 43 Felsher JJ, Olesevich M, Farres H, et al. Validation of a flexible endoscopy simulator. Am J Surg 2005; 189: 497–500. 44 Clark JA, Volchok JA, Hazey JW, et al. Initial experience using an endoscopic simulator to train surgical residents in flexible endoscopy in a community medical center residency program. Curr Surg 2005; 62: 59–63. 45 Cohen J, Cohen SA, Vora KC, et al. Multicenter, randomized, controlled trial of virtual-reality simulator training in acquisition of competency in colonoscopy. Gastrointest Endosc 2006; 64: 361–8. 46 Aabakken L, Adamsen S, Kruse A. Performance of a colonoscopy simulator: experience from a hands-on endoscopy course. Endoscopy 2000; 32: 911–13. 47 Sedlack RE, Kolars J. Validation of computer-based endoscopy simulators in training. Gastrointest Endosc 2002; 55: A77.

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Indications and Contraindications Mouen A. Khashab & Douglas K. Rex Indiana University School of Medicine and Clarian Health Partners, Indianapolis, IN, USA

Introduction In general, the indications for colonoscopy have expanded since its inception. In recent years, the largest growth in the use of colonoscopy in the US has resulted from the acceptance of average-risk colorectal cancer screening as a valid indication. The first mention of colonoscopy for average-risk screening appeared in the literature in 1988 [1] and the first studies of colonoscopy for average-risk screening took place in 1990 [2,3]. The first mention of average-risk screening in a guideline was by the GI (gastrointestinal) Consortium in 1997 [4], and this was followed in the same year by a guideline from the American Cancer Society (ACS) [5]. In 2000, the American College of Gastroenterology (ACG) recommended colonoscopy as the preferred colorectal cancer screening strategy, provided expertise, resources, and reimbursement for the procedure are available [6]. Subsequently, the American Society for Gastrointestinal Endoscopy (ASGE) endorsed this recommendation [7]. Recently, Germany [8] and Poland [9] have initiated colorectal cancer screening programs with colonoscopy. In many countries, colonoscopy is not used as a colorectal cancer screening test either because the substantial costs associated with its use for this indication are unacceptable or because the human resources and facilities required to provide the service are unavailable. Thus, indications for colonoscopy are likely to differ between countries, depending on the resources available to provide the service and the perceptions of healthcare experts in that country regarding the benefits, costs, and risks of colonoscopy relative to other diagnostic strategies that are available both in symptomatic and in asymptomatic (screening) patients. The concept of limiting the indications for colonoscopy according to the feasibility of supplying the service can be readily extended beyond the decision of whether to provide the service for screening. Thus, within both the symptomatic and the sur-

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

veillance populations, there is literature that points to a variable yield of cancer diagnosis that is correlated to indication [10]. When resources are limited, it may be appropriate to confine the use of colonoscopy to indications with a higher yield for cancer and to use other diagnostic strategies, such as a barium enema or computed tomographic colonography (CTC), for lower yield indications. In general, this chapter assumes that the resources are available to provide colonoscopy for a broad range of indications. However, emphasis is placed on the relative yields of different indications for both cancers and adenomas. These comparisons are of value in determining what indications are most appropriate when resources are limited. Even in the US, where resources and personnel to provide colonoscopy services are very widely available, it is well recognized that there are patients for whom colonoscopy is inappropriate. Factors that may suggest colonoscopy would be inappropriate include the indication, age, and gender of the patient, and the presence or absence of various other risk factors for disease.

Classification of indications Diagnostic versus therapeutic A common classification of colonoscopic indications is diagnostic versus therapeutic (Table 15.1). From the perspective of individual patient care, therapeutic procedures as a group are generally more justified, since the alternative treatment in many cases is surgery, which is usually associated with greater morbidity, mortality, and cost than colonoscopy. For any diagnostic procedure that does not involve biopsy, there is usually an available alternative, either barium enema or, in some centers, CTC. The distinction between diagnostic and therapeutic colonoscopy also has value in understanding complication rates, since complication rates are expected to be higher in therapeutic than in diagnostic procedures. The distinction between diagnostic and therapeutic colonoscopy lacks relevance to the extent that in most therapeutic procedures, particularly polypectomy, the presence of polyps and therefore the need for polypectomy is unknown to the

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Table 15.1 Diagnostic and therapeutic indications for colonoscopy. Diagnostic indications Evaluation of an abnormality on barium enema (or virtual colonoscopy) such as a filling defect or stricture Evaluation of unexplained gastrointestinal bleeding Hematochezia in absence of convincing anorectal source Melena after an upper gastrointestinal source has been excluded Presence of fecal occult blood Unexplained iron deficiency anemia Surveillance after removal of adenomas (see Table 15.3) Surveillance after resection of colorectal cancer After identification of adenomas during sigmoidoscopy or for clearing the colon of synchronous neoplasia in patients with colorectal cancer In patients with ulcerative pancolitis or Crohn’s colitis of ≥ 8 years’ duration or left-sided colitis ≥ 15 years’ duration Colorectal cancer screening (see Table 15.4) Chronic inflammatory bowel disease of the colon, if more precise diagnosis or determination of the extent of activity of disease will influence management Clinically significant diarrhea of unexplained origin Intraoperative identification of a lesion not apparent at surgery (e.g., polypectomy site, location of a bleeding site) Miscellaneous therapeutic indications (from the American Society for Gastrointestinal Endoscopy guideline) Treatment of bleeding from such lesions as vascular malformation, ulceration, neoplasia, and polypectomy site (e.g., electrocoagulation, heater probe, laser or injection therapy) Foreign body removal Excision of colonic polyp Decompression of acute nontoxic megacolon or sigmoid volvulus Balloon dilation of stenotic lesions (e.g., anastomotic strictures) Palliative treatment of stenosing or bleeding neoplasms (e.g., laser, electrocoagulation, stenting) Marking a neoplasm for localization

colonoscopist prior to the procedure. Thus, the designation “diagnostic” or “therapeutic” can be assigned only after the procedure. Furthermore, it is generally unacceptable for a practitioner to perform diagnostic procedures unless he or she also has the skill to perform any therapeutic maneuvers that are likely to be indicated. Certainly, all colonoscopists must be trained in polypectomy and must be prepared to perform colonoscopy with intent to clear the colon of polyps on the initial examination.

High risk versus low risk A second classification of indications is by risk. Not all factors that increase the risk of colonoscopy are well defined. However, indications that are associated with high risk include decompression of acute colonic pseudoobstruction, polypectomy of large polyps, stricture dilation, and stent placement. Preexisting conditions associated with high risk include acute colonic pseudoobstruction, sigmoid volvulus, cecal volvulus, prior radiation therapy, chronic steroid use, colonic strictures, extensive pelvic adhesions, severe diverticular disease, and severe colitis. Patients with cardiac or pulmonary disease who are graded 3 or higher on the American Society of Anesthesiologists scale (see Chapter 9) are at risk for cardiopulmonary compromise with sedation. These patients and those with severe liver or kidney disease often do not tolerate easily any surgery that is required for the management of colonoscopic complications. Specific procedures that

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are associated with risk follow closely the high-risk indications, including removal of large polyps, particularly sessile lesions in the right colon, stricture dilation (particularly if the etiology is nonanastomotic Crohn’s strictures or radiation strictures), stent placement, and tumor ablation. The potential benefits of the procedure should always be weighed against the risks when determining whether the indication is valid in any given patient. Screening procedures, which are generally performed in asymptomatic persons who are healthy or relatively healthy, have thus far been associated with a lower risk of perforation. In more than 6000 screening colonoscopies reported in early US studies in average-risk persons, no perforations occurred [11–13]. A populationbased study of US Medicare patients reported an overall perforation risk of 1 in 500 but estimated a risk of less than 1 in 1000 screening colonoscopies [14]. A large study of screening colonoscopy in Poland reported a perforation rate of 1 in 10 000 [9]. However, a recent trial in Wisconsin in the US reported a remarkably high perforation rate of 1 in 500 among 3500 screening colonoscopies [15].

High yield versus low yield A final method of classifying diagnostic indications for colonoscopy is by their expected yield for disease, particularly neoplasia. The yield of colonoscopy for cancer is highly dependent on indication. For example, bleeding indications consistently have the highest yield for cancer (Table 15.2).

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Table 15.2 Yield of colonoscopy by indication. Indication

Number of procedures to detect one cancer

Two consecutive positive FOBTs; neither rehydrated Rectal bleedingbnonemergent Positive FOBTbnonrehydrated Melena with negative EGD Acute lower gastrointestinal hemorrhage Iron deficiency anemia Colonic symptoms without bleeding Screening Lynch syndromes Positive FOBTbrehydrated Screening average-risk males ≥ 60 years old Surveillance after cancer resectionbanastomotic recurrence Surveillance after cancer resectionbmetachronous cancer Colonic symptoms without bleeding Screening positive family historybnon-Lynch kindred Screening average-risk persons ≥ 50 years old Screening positive family history prospective studies only Postpolypectomy surveillance Prospective US surveillance

2.7 8.9 9.8 9.9 11.8 13 36 39 45 64 74 82 109 141 143 286 317 360

FOBT, fecal occult blood test(ing); EGD, esophagogastroduodenoscopy; UC, ulcerative colitis. (From Rex [10] with permission.)

The lowest yield indications for cancer are postpolypectomy surveillance and ulcerative colitis surveillance. Within many indications, the yield of cancer increases substantially with patient age. For example, an 80-year-old with rectal bleeding or with a positive fecal occult blood test is many times more likely to have colorectal cancer than a 30-year-old patient with the same findings. The yield of adenomas and advanced adenomas is largely independent of indication, although bleeding indications do have predictive value for large adenomas. However, the prevalence of large adenomas is to a substantial extent independent of indication, and the prevalence of small adenomas is entirely independent of indication; rather the prevalence reflects demographic features, including increasing age, male gender, and, to some extent, family history of colorectal cancer or adenomas [10]. Age is a powerful predictor and male gender is a consistent predictor of both adenomas and advanced adenomas [9,11,13]. Recently, it has been recognized that the person who performs the procedure can be more important than both the patient’s age and the patient’s gender in predicting adenomas at colonoscopy [16]. This issue is discussed further in Chapter 3. In the absence of bleeding (no report of hematochezia, negative stool tests for occult blood, and normal hemoglobin level), symptoms such as abdominal pain and altered bowel habit have no predictive value for colorectal cancer [12,17]. In these persons, the yield of colonoscopy for neoplasia essentially reflects the age, gender, and family history of the patient. This observation becomes the justification for making

a positive diagnosis of irritable bowel syndrome in many women aged less than 50 years with nonbleeding colonic symptoms. On the other hand, colonoscopy in persons aged 50 years and older with only nonbleeding colonic symptoms is justified based on age, and the presence or absence of nonbleeding symptoms is not significant. To summarize, the decision of whether to proceed with a colonoscopy should take into account at least the anticipated risk and the potential benefit of the procedure. The potential for benefit is often best estimated by calculating the potential yield for neoplasia, which is again a function of the indication (with regard to cancer) and the patient’s age, gender, and family history (with regard to adenomas).

Alternatives to colonoscopy The decision regarding whether colonoscopy is indicated must also take into account the cost, risk, and accuracy of diagnostic alternatives. The number of colonoscopies performed in US Medicare recipients has risen progressively, while the use of other screening modalities such as double-contrast barium enema (DCBE), sigmoidoscopy, and fecal occult blood testing has declined [18]. DCBE is several times more likely than colonoscopy to miss colorectal cancer [19] and has a sensitivity of only about 50% for the detection of large adenomas [20]. Similarly, the results of CTC (virtual colonoscopy) are highly variable when all reported studies are considered [21]. A

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recent uncontrolled study of colonoscopy and CTC in screening patients found that the two tests identified similar numbers of patients with advanced adenomas, though colonoscopy found many more adenomas overall [15]. The multicenter US national CT colonography trial found a sensitivity of 90% for detection of patients with polyps ≥ 1 cm in size [22]. However, specificity and positive predictive value were suboptimal [22]. The impact of CTC on cancer incidence may depend on its ability to improve adherence, since any effect that displaces patients from colonoscopy (thereby reducing polypectomy) could increase cancer incidence [23]. Appropriate candidates for CTC would be those with a low prevalence of polyps, based on their age and gender. Thus, the use of CTC or DCBE as a screening test makes relatively more sense in younger patients, especially females, while colonoscopy may have greater value for older patients with a higher prevalence of polyps. The relative use of colonoscopy versus diagnosis-only radiographic colon imaging tests should also take into account the local expertise of both colonoscopy and the radiographic methods. Virtual colonoscopy is available in relatively few centers, and only a limited number of these have proven their ability to achieve adequate sensitivity for colon neoplasms. DCBE sensitivity varies markedly between hospitals and may be a function of the interest and training of radiologists. Colonoscopy effectiveness and risks also vary between examiners. Ideally, one would like to know the local effectiveness and safety of colonoscopy and radiographic imaging studies and take these factors into account, combined with the anticipated risk and yield of colonoscopy and the anticipated prevalence of polyps, in deciding the best diagnostic approach to an individual patient.

Specific indications Bleeding indications Of all the indications for colonoscopy, the highest yield for neoplasia is associated with bleeding indications. A positive fecal occult blood test is perhaps the single best indication for colonoscopy, since it is associated with a high prevalence of cancer (2–12%) [24–26] and incident cancers tend to be early stage (80% stage I or II) and therefore associated with high survival rates. Hematochezia, iron deficiency anemia, and melena with a negative upper endoscopy are all associated with a substantial prevalence of cancer [10], and the positive predictive value of each of these findings increases with age [27]. Blood found only on toilet tissue paper is invariably from an anal source. However, if blood is passed into the toilet, there is no reliable way to determine whether it originates from an anal source or a colonic source and no reliable way to distinguish a distal from a proximal colonic source [28]. Certain features, such as blood dripping from the anus after bowel movements, are more often associated with

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an anal source but do not perfectly separate anal from colonic sources [29]. All persons with positive fecal occult blood tests and all persons aged 50 years and older with any lower gastrointestinal bleeding should undergo initial colonoscopy. In the US, most persons aged 40 years and older with bleeding indications undergo initial full colonoscopy, but practices vary. A cost analysis of approaches to bleeding showed that even persons in their 20s and 30s with rectal bleeding should undergo at least initial distal colon visualization and if no source is identified, should proceed to full colon evaluation [30].

Abdominal pain and constipation The prevalence of irritable bowel syndrome (IBS) in the general population is sufficiently high that abdominal pain with or without constipation in the absence of bleeding (defined as no history of hematochezia, negative stool tests for fecal occult blood, and normal hemoglobin) is unlikely to be associated with colorectal cancer [17,31]. The prevalence of colonoscopy-detected neoplasia in patients with these symptoms is similar to that in the screening population. The indication for colonscopy in patients with IBS depends on the patient’s age. Colonoscopy is justified in patients with symptoms of IBS aged 50 or older; however, many patients younger than 50 with chronic symptoms undergo colonoscopy, sigmoidoscopy, or barium enema and may be reassured by a negative examination, leading to an improved quality of life. When colorectal cancer is the cause of abdominal pain and constipation, the disease is often at a late stage. In general, isolated abdominal pain with or without constipation is a poor indication for colonoscopy, except to the extent that these symptoms help to convince patients to undergo screening that may be indicated on the basis of age or family history.

Chronic diarrhea Colonoscopy is often performed in patients with chronic watery diarrhea, to exclude collagenous or lymphocytic colitis. In this case, random biopsies should be performed even if the mucosa appears normal. The optimal number and location of biopsy specimens are not established. Obtaining proximal colon biopsies improves the sensitivity for collagenous colitis [32]. The yield of microscopic colitis ranges from 5% to 15% and is clearly higher in older women [33]. In patients with collagenous or lymphocytic colitis, biopsy usually reveals some abnormalities of the left colon and thus sigmoidoscopy and biopsy can be used as an initial diagnostic test to screen for these disorders. If chronic diarrhea is accompanied by abdominal pain, full colonoscopy should be performed to include intubation of the terminal ileum to exclude Crohn’s disease.

Abnormal radiographs or sigmoidoscopy Filling defects and strictures identified on barium enema are generally an indication for colonoscopy. However, these

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abnormalities can be ignored in patients with small polypoid defects who are elderly or who have significant comorbidities. Routine abdominopelvic computed tomography (CT) scans sometimes identify areas of colonic thickening, believed to represent tumor or inflammation, and this is also an indication for colonoscopy. However, the false-positive rate is high. Patients in whom positron emission tomography (PET) scans are positive for colonic lesions should be evaluated by colonoscopy since PET scans have reasonable specificity for colorectal cancer and large polyps [34]. Controversy exists regarding which findings on CTC warrant colonoscopy. The American College of Radiology recommends that polyps < 6 mm in size on CTC should not be reported and that patients with one or two polyps 6–9 mm in size may be offered “CTC surveillance” rather than colonoscopy and polypectomy [35]. The ACG [36] and the American Gastroenterological Association (AGA) [37] recommend that patients with any polyp 6 mm or larger on CTC be offered colonoscopy and polypectomy. In addition, it recommends that patients with three or more polyps of any size, read with moderate to high confidence, should be offered colonoscopy and polypectomy and it also advises that patients with any polyps ≤ 5 mm in size, read with moderate to high confidence, should be informed of the result. A decision analysis found that delaying colonoscopy in persons with polyps 6– 9 mm in size would result in substantially increased cancer risk [23]. Colonoscopy is indicated in patients with adenomas at sigmoidoscopy [12], although in some centers colonoscopy is performed only if advanced adenomas are found during sigmoidoscopy [38]. Relying on a diagnostic algorithm for performing total colonoscopy based on the presence or absence of distal adenomas may result in overlooking proximal pathology. In one study, colonoscopy performed only in individuals with distal colonic polyps resulted in 46% of advanced proximal neoplasias going undetected [13]. A more sophisticated analysis of patient data that included age, sex, and distal colonic findings detected 92% of individuals with advanced proximal neoplasia and reduced the need for colonoscopy by 40% [33].

Indications and Contraindications

iveness of medical treatment. The use of colonoscopy in clinical practice for this purpose is less well established. Surveillance in ulcerative colitis refers to interval colonoscopies in persons prospectively entered into a regularly scheduled follow-up program and in whom initial examination before enrollment reveals the colon to be clear of neoplasia. The initial diagnostic examination in an individual with long-standing ulcerative colitis is not considered a surveillance study. Colonoscopy with multiple biopsies is indicated beginning 8–10 years after the onset of symptoms in patients with pancolitis (disease extending proximal to the splenic flexure) and after 15 years of left-sided disease. The purpose is to seek biopsy evidence of dysplasia, a neoplastic morphologic microscopic change in the mucosal cells that can progress to cancer. Surveys in the US and the UK indicate that gastroenterologists are poorly informed about the proper intervals at which to perform ulcerative colitis surveillance, and seldom use an adequate biopsy protocol [40,41]. The yield for cancer of ulcerative colitis surveillance is the lowest of any indication for colonoscopy [42], and experts have argued against its use [43]. However, in the US, performance of colonoscopic surveillance for ulcerative colitis and Crohn’s disease is standard practice. The interval of examination is usually every 2 years until 20 years after the onset of symptoms and then annually thereafter. Cost analyses suggest that the cost-effectiveness of this practice is very low [44]. Patients with primary sclerosing cholangitis appear to be at increased risk of colorectal cancer beginning at the time their colitis is recognized; therefore, surveillance should begin after diagnosis. A family history of colorectal cancer also results in increased cancer risk in patients with ulcerative colitis. Ulcerative colitis patients with endoscopically normal colons have a lower risk of cancer than those with extensive scarring and pseudopolyp formation, which may justify lengthening surveillance intervals to 5 years in these patients [45]. Recent studies indicate that chromoendoscopy with targeted biopsies is more sensitive for the finding of dysplasia than random biopsies [46–51]. This might justify longer surveillance intervals after negative colonoscopy utilizing chromoendoscopy in ulcerative colitis, but this is speculative at this time.

Established ulcerative colitis Colonoscopy can be used to evaluate the extent and severity of ulcerative colitis, which can guide medical therapy and determine where to begin surveillance colonoscopies for cancer. Intubation and biopsy of the terminal ileum can be useful in distinguishing ulcerative colitis from Crohn’s disease, which may be critical in decisions about whether to proceed with surgery or the type of operation that is to be performed. Colonoscopy can also assess disease activity when patients present with symptoms that are not clearly attributable to ulcerative colitis, although in many cases sigmoidoscopy will suffice for this purpose. In clinical trials, colonoscopy and sigmoidoscopy with biopsy are often used to assess histologic improvement as a measure of the effect-

Established Crohn’s disease After establishing an initial diagnosis of Crohn’s disease, colonoscopy has traditionally had a very limited role in clinical decision-making. Patients’ clinical response has generally been considered of greatest value in Crohn’s disease, since mainstay therapies, such as corticosteroids, produced symptomatic relief without endoscopic evidence of healing. It is now recognized that immunomodulatory agents, such as 6mercaptopurine and azathioprine, sometimes produce healing of colonic Crohn’s disease, and infliximab produces healing with some regularity. There is currently no mandate to perform colonoscopy to document mucosal healing in inflammatory bowel disease patients in clinical remission.

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The risk of developing colorectal cancer in long-standing Crohn’s colitis is comparable to that of ulcerative colitis. Cancers tend to occur in areas of active disease. A surveillance protocol similar to that in ulcerative colitis should be utilized, although published experience is limited [52].

Postpolypectomy surveillance Postpolypectomy surveillance accounts for 25% of colonoscopies performed in the US [53] and up to 50% of colonoscopies in some practices. As the use of screening increases, the cost and complications associated with postpolypectomy surveillance will also increase. However, recent data suggest that initial clearing examinations have a much greater effect on colorectal cancer incidence than does subsequent postpolypectomy surveillance [54]. Therefore, recent guidelines have emphasized the limited benefits of postpolypectomy surveillance and the importance of expanding intervals between examinations. The US Multisociety Task Force on CRC (colorectal cancer) and the ACS have recently issued updated joint guidelines on postpolypectomy surveillance [55] (Table 15.3). These consensus guidelines are endorsed by the ACS, the ACG, the AGA, and the ASGE. These new guidelines differ from prior guidelines in a number of ways. They emphasize that a high-quality baseline colonoscopy is a critical factor for effectively reducing CRC risk. Patients with only one or two small (< 1 cm) tubular adenomas may have their first follow-up examination in 5–10 years depending on the judgment of the physician. The guidelines also discourage the use of fecal occult blood testing during surveillance. They highlight the importance of recognizing patients with hyperplastic polyposis syndrome because they are at increased risk for adenomas and CRC and need closer follow-up examinations than patients who have no adenomas. The guidelines call for a 3-year examination in patients with 3–10 adenomas or with adenomas that are ≥ 1 cm and

contain high-grade dysplasia or villous elements. Patients with more than 10 adenomas should be examined at a shorter (< 3 years) interval depending on the judgment of the physician, and patients with large sessile adenomas removed piecemeal require additional follow-ups at 3- to 6-month intervals until it is established that the polypectomy site is cleared of adenoma. In the case of distal polyps, these examinations can be performed by flexible sigmoidoscopy.

Postcancer resection surveillance In the case of both colon and rectal cancer, the primary purpose of postcancer resection colonoscopy is the detection of metachronous disease (see Chapter 55). The rate of anastomotic occurrences with colon cancer is approximately 2%, and most anastomotic recurrences are accompanied by intra-abdominal or pelvic disease that is unresectable for cure [56]. Colonoscopy should be performed in the perioperative period to clear the colon of synchronous neoplasia. This total colon examination is usually the one performed preoperatively (unless the CRC was obstructive). In the obstructed patient, either a barium enema or virtual colonoscopy should be performed, and colonoscopy should be completed 3–6 months after segmental resection, even if the radiographic studies were negative. Guidelines previously differed with regard to the timing of the next colonoscopy. However, consensus recommendations were recently produced jointly by the US Multisociety Task Force on CRC and the ACS [57] (Table 15.4). In this guideline, colonoscopy is recommended 1 year after surgical resection because of high yields of detecting early second, apparently metachronous, cancers. After a normal first surveillance examination, a subsequent surveillance examination should be performed at 3 years. If that colonoscopy is normal, then the next examination should be in 5 years. Intervals between examinations should be shortened if indicated by findings of adenomas. Patients with family or

Table 15.3 US Multisociety Task Force and American Cancer Society Postpolypectomy Surveillance Recommendations [55]. 1 Patients with small rectal hyperplastic polyps should be considered to have normal colonoscopies, and therefore the interval before the subsequent colonoscopy should be 10 years; an exception is patients with a hyperplastic polyposis syndrome, who are at increased risk for adenomas and colorectal cancer and need to be identified for more intensive follow-up evaluation. 2 Patients with only one or two small (< 1 cm) tubular adenomas with only low-grade dysplasia should have their next follow-up colonoscopy in 5–10 years; the precise timing within this interval should be based on other clinical factors (such as prior colonoscopy findings, family history, and the preferences of the patient and the judgment of the physician). 3 Patients with 3–10 adenomas, or any adenoma ≥ 1 cm, or any adenoma with villous features, or high-grade dysplasia should have their next follow-up colonoscopy in 3 years providing that piecemeal removal has not been performed and the adenoma(s) are removed completely; if the follow-up colonoscopy is normal or shows only one or two small tubular adenomas with low-grade dysplasia, then the interval for the subsequent examination should be 5 years. 4 Patients who have more than 10 adenomas at one examination should be examined at a shorter (< 3 years) interval, established by clinical judgment, and the clinician should consider the possibility of an underlying familial syndrome. 5 Patients with sessile adenomas that are removed piecemeal should be considered for follow-up evaluation at short intervals (2–6 months) to verify complete removal; once complete removal has been established, subsequent surveillance needs to be individualized based on the endoscopist’s judgment; completeness of removal should be based on both endoscopic and pathologic assessments. 6 More intensive surveillance is indicated when the family history may indicate hereditary nonpolyposis colorectal cancer.

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Table 15.4 US Multisociety Task Force and American Cancer Society Postcancer Resection Surveillance Colonoscopy Recommendations [57]. 1 Patients with colon and rectal cancer should undergo high-quality perioperative clearing. In the case of nonobstructing tumors, this can be done by preoperative colonoscopy. In the case of obstructing colon cancers, computed tomography colonography with intravenous contrast or double-contrast barium enema can be used to detect neoplasms in the proximal colon. In these cases, a colonoscopy to clear the colon of synchronous disease should be considered 3–6 months after the resection if no unresectable metastases are found during surgery. Alternatively, colonoscopy can be performed intraoperatively. 2 Patients undergoing curative resection for colon or rectal cancer should undergo a colonoscopy 1 year after the resection (or 1 year following the performance of the colonoscopy that was performed to clear the colon of synchronous disease). This colonoscopy at 1 year is in addition to the perioperative colonoscopy for synchronous tumors. 3 If the examination performed at 1 year is normal, then the interval before the next subsequent examination should be 3 years. If that colonoscopy is normal, then the interval before the next subsequent examination should be 5 years. 4 Following the examination at 1 year, the intervals before subsequent examinations may be shortened if there is evidence of hereditary nonpolyposis colorectal cancer or if adenoma findings warrant earlier colonoscopy. 5 Periodic examination of the rectum for the purpose of identifying local recurrence, usually performed at 3- to 6-month intervals for the first 2 or 3 years, may be considered after low anterior resection of rectal cancer. The techniques utilized are typically rigid proctoscopy, flexible proctoscopy, or rectal endoscopic ultrasound. These examinations are independent of the colonoscopic examinations described above for detection of metachronous disease.

personal histories compatible with or suggestive of hereditary nonpolyposis colorectal cancer should continue to be examined at 1- to 2-year intervals. Recurrence rates are much higher in patients with resected rectal cancer than in those with colon cancer, at least if they are operated on by traditional blunt dissection techniques. Conversely, patients operated on by total mesorectal excision have recurrence rates of < 10%, which can be further lowered to recurrence rates comparable to those seen in colon cancer if patients are given neoadjuvant radiation [58], or chemoradiation in appropriate cases. The new guidelines recommend periodic examination of the rectum at 3- to 6-month intervals for the first 2–3 years for the purpose of identifying local recurrence after low anterior resection of rectal cancer. Examination can be done using rigid or flexible proctoscopy, but rectal endoscopic ultrasound is preferred since recurrences typically begin outside the rectum. The rationale for colonoscopy is identical to that of resected colon cancer.

Screening The greatest expansion in the use of, and indications for, colonoscopy has come through its endorsement as a screen-

ing measure in average-risk persons. Recommendations for colonoscopy screening in the US are summarized in Table 15.5. The position of US societies regarding colonoscopy screening in average-risk persons is summarized in Table 15.6. Current screening guidelines tend to separate screening strategies into distinct categories, giving the impression that clinicians would choose either colonoscopy every 10 years or another strategy, such as annual fecal occult blood tests in addition to flexible sigmoidoscopy every 5 years. However, in countries with limited resources, there is a strong rationale for mixing strategies. Thus, the prevalence of adenomas and advanced adenomas doubles between the age of 50 and 60 years, and between the age of 50 and 80 years the distribution of colorectal cancer shifts dramatically from the distal to the proximal colon [59,60]. Therefore, the rationale for colonoscopy is stronger in persons aged 60 and above than it is in younger persons. Mixed strategies such as sigmoidoscopy or CTC at age 50, followed by colonoscopy at age 60 or 65, may maximize impact and conserve scarce resources [23,39]. Cancer screening in the elderly is controversial because of competing mortality risk from noncancer causes and limited life expectancy. On the basis of the available literature, there

Table 15.5 Indications for screening colonoscopy. In average-risk persons: begin at age 50 years, repeat every 10 years. In persons with one first-degree relative diagnosed with colorectal cancer (or adenomas) at age > 60 years: begin at age 40 years, repeat every 10 years. In persons with two first-degree relatives (or adenomas) diagnosed with colorectal cancer (or adenomas) or one first-degree relative with colorectal cancer or adenoma) at age < 60 years: begin at age 40 years or 10 years before age of diagnosis of youngest relative, repeat every 5 years. In persons with hereditary nonpolyposis colorectal cancer: begin at age 20–25 years, repeat every 1–2 years until age 40 years, then repeat every year. In women with endometrial or ovarian cancer diagnosed at age < 50 years: begin at time of diagnosis, repeat every 5 years. In patients with FAP in whom surgery is being postponed: repeat every 6–12 months. In patients with possible or gene test proven attenuated FAP: repeat every year until surgery is performed. FAP, familial adenomatous polyposis.

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Table 15.6 Positions of US societies on average-risk screening colonoscopy. US Multisociety Task Force and American Cancer Society Colonoscopy every 10 years is one of five options for screening; others are annual FOBT, flexible sigmoidoscopy every 5 years, annual FOBT with flexible sigmoidoscopy every 5 years, and DCBE every 5 years American College of Gastroenterology and American Society for Gastrointestinal Endoscopy Colonoscopy is the preferred strategy whenever resources, expertise, and reimbursement are available; an alternative of annual FOBT with flexible sigmoidoscopy every 5 years is also acceptable US Preventive Services Task Force Colorectal cancer screening is a Grade A recommendation (should be offered to all eligible patients). There is insufficient evidence to indicate that one screening strategy is preferred; in particular the superior effectiveness of colonoscopy may not outweigh its risks DCBE, double-contrast barium enema; FOBT, fecal occult blood test(ing).

is at least a 5-year lag between CRC screening and a measurable survival benefit. Several factors need to be accounted for when considering CRC screening in elderly patients, including patient’s age and life expectancy, comorbidities, risk of colon neoplasia, and patient’s preference [61,62].

Miscellaneous indications Miscellaneous therapeutic indications for colonoscopy are listed in Table 15.1. In general, the use of colonoscopy for therapeutic indications has expanded and its use has particularly increased for palliation of cancer. Decompression of acute colonic pseudoobstruction is an area where the use of colonoscopy has declined, with the advent of effective medical therapy (neostigmine). Colonoscopy is now used for this indication primarily when neostigmine is contraindicated or when patients fail to respond to neostigmine. Hemorrhoidal band ligation for symptomatic internal hemorrhoids that conservative management has failed to cure can also be performed effectively and safely during sigmoidoscopy or colonoscopy [63].

Appropriate indications The ASGE and the ACG Taskforce on Quality in Endoscopy have published quality indicators for colonoscopy [64]. Use of appropriate indications for colonoscopy was the first specific quality indicator discussed. In 2000, the ASGE published a list of appropriate indications for colonoscopy [65] (see Table 15.1). Several studies have shown that performing endoscopy for an appropriate indication increases the yield of the procedure [66]. The European Panel of Appropriateness of Gastrointestinal Endoscopy (EPAGE) Internet guideline is a helpful decision support tool for determining the appropriateness of colonoscopy [67]. Physician resources have often been inadequate to meet the high demand of colonoscopy. Eliminating inappropriate procedures allows them to be reallocated to patients with proper indications. A study from the Mayo Clinic showed that one in four referrals for colonoscopy

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in an open-access endoscopy system was not appropriate [68]. The most common reason was inappropriate referral for surveillance of colorectal polyps. Using a triage system to eliminate inappropriate procedures and align surveillance procedures with published recommendations may optimize colonoscopy utilization. Moreover, the specific indication(s) for colonoscopy should be documented and a justification for nonstandard indications should be elucidated.

Contraindications to colonoscopy Contraindications to colonoscopy can be classified as absolute and relative (Table 15.7). Absolute contraindications include a competent patient who is unwilling to give consent and an uncooperative patient for whom consent has been given but in whom adequate sedation cannot be achieved. Toxic megacolon, fulminant colitis, and a known free colonic perforation are also almost always contraindications. Relative contraindications constitute situations in which risk is substantially increased. It may be appropriate to proceed if the expected information that can be acquired by colonoscopy or a treatment that can be given is critical to the welfare of the patient. Relative contraindications include acute diverticulitis and very large abdominal aortic aneurysms (particularly if they are symptomatic); in addition, the procedure is contraindicated in the immediate postoperative period and in patients who have suffered recent myocardial infarction or pulmonary embolism, or who are currently hemodynamically unstable. Severe coagulopathies are a relative contraindication also, particularly for therapeutic procedures (Table 15.7). Colonoscopy can generally be performed safely during pregnancy but should be deferred in most instances if the indication does not require immediate resolution. In general, when the risks to the patient’s health or life outweigh the potential benefits of colonoscopy, the procedure is contraindicated.

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Table 15.7 Contraindications. Absolute Competent patient who refuses to consent Consented patient who is unable to cooperate and cannot be adequately sedated Known perforated viscus communicating freely with the peritoneal cavity Toxic megacolon Fulminant colitis Relative Acute diverticulitis (diagnosis established) Hemodynamic instability Recent myocardial infarction or pulmonary embolism Immediate postoperative stage Very large and/or symptomatic abdominal aortic aneurysm Pregnancy

Summary 6

Colonoscopists must have a working knowledge of acceptable indications, and must know the risks and potential yield associated with each indication. The risks are then further adjusted by consideration of the patient’s age and medical condition and the potential benefits are adjusted for the patient’s age, gender, and family history. The colonoscopist must also consider his or her own skills in colonoscopy relative to the availability and expertise of local radiologists in determining the appropriateness of diagnostic colonoscopy in some patients. Finally, the colonoscopist must consider the national consensus in his or her country regarding whether resources can be expended for indications such as screening or low-yield symptoms. When all of these factors are considered, colonoscopy will be used in a fashion that is best for patients and is compatible with optimal allocation of all medical resources.

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lance biopsies for detecting in patients with ulcerative and Crohn’s colitis: a prospective endoscopic trial. Oral Presentation at: Digestive Disease Week 2007; Washington, DC. Friedman S, Rubin PH, Bodian C, Goldstein E, Harpaz N, Present DH. Screening and surveillance colonoscopy in chronic Crohn’s colitis. Gastroenterology 2001; 120: 820–6. Lieberman DA, De Garmo PL, Fleischer DE, Eisen GM, Helfand M. Patterns of endoscopy use in the United States. Gastroenterology 2000; 118: 619–24. Zauber A, Winawer SJ, Lansdorp-Vogelaar I, van Ballegooijen M, O’Brien MJ. Effect of initial polypectomy versus surveillance polypectomy on colorectal cancer mortality reduction: microsimulation modeling of the National Polyp Study. Am J Gastroenterol 2007; 102: S558. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 2006; 130: 1872– 85. Ballantyne GH, Modlin IM. Postoperative follow-up for colorectal cancer: who are we kidding? J Clin Gastroenterol 1988; 10: 359– 64. Rex DK, Kahi CJ, Levin B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2006; 130: 1865–71. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638– 46.

Indications and Contraindications

59 Nelson RL, Persky V, Turyk M. Time trends in distal colorectal cancer subsite location related to age and how it affects choice of screening modality. J Surg Oncol 1998; 69: 235–8. 60 Kee F, Wilson RH, Gilliland R, Sloan JM, Rowlands BJ, Moorehead RJ. Changing site distribution of colorectal cancer. BMJ 1992; 305: 158. 61 Miller K, Waye JD. Colorectal polyps in the elderly: what should be done? Drugs Aging 2002; 19: 393– 404. 62 Lewis C. The tipping point: balancing the risks and benefits of screening in the elderly. Gastroenterology 2005; 129: 1342–4. 63 Davis KG, Pelta AE, Armstrong DN. Combined colonoscopy and three-quadrant hemorrhoidal ligation: 500 consecutive cases. Dis Colon Rectum 2007; 50: 1445– 9. 64 Rex DK, Petrini JL, Baron TH, et al. Quality indicators for colonoscopy. Am J Gastroenterol 2006; 101: 873–85. 65 Minoli G, Meucci G, Bortoli A, et al. The ASGE guidelines for the appropriate use of colonoscopy in an open access system. Gastrointest Endosc 2000; 52: 39–44. 66 de Bosset V, Froehlich F, Rey JP, et al. Do explicit appropriateness criteria enhance the diagnostic yield of colonoscopy? Endoscopy 2002; 34: 360– 8. 67 Terraz O, Wietlisbach V, Jeannot JG, et al. The EPAGE internet guideline as a decision support tool for determining the appropriateness of colonoscopy. Digestion 2005; 71: 72–7. 68 Baron TH, Kimery BD, Sorbi D, Gorkis LC, Leighton JA, Fleischer DE. Strategies to address increased demand for colonoscopy: Guidelines in an open endoscopy practice. Clin Gastroenterol Hepatol 2004; 2: 178– 82.

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Diagnostic Yield of Colonoscopy by Indication Florian Froehlich1 & Jean-Jacques Gonvers2 1

University of Basle, Basle, and Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland 2 Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

Introduction Colonoscopy is the gold standard for the diagnosis of colon disease. In the hands of an experienced operator, colonoscopy should be complete in over 90% of cases [1,2]. Completion rates of 92–98% are reported in studies performed in expert centers [3–5]. The technical success of colonoscopy is dependent on gender, age, obesity, bowel preparation, history of pelvic surgery, complicated diverticular disease, and/or a history of peritonitis [6]. Diagnostic accuracy of colonoscopy is dependent on the quality of colon cleansing [7–10]. Patterns of endoscopy use in the US were recently assessed based on a large national database. In patients aged < 50 years, the most common indications were rectal bleeding (34%), irritable bowel symptoms (24%), or screening because of a positive family history of colorectal cancer (22%). In patients aged ≥ 50 years, average-risk screening colonoscopy, positive family history, or fecal occult blood test(ing) (FOBT) positivity accounted for 38%, and surveillance colonoscopy in patients with previous cancer or polyp accounted for 22% [11]. The principal focus of colonoscopy is on the diagnosis and removal of adenomatous polyps to prevent cancer development, and on the diagnosis of colorectal cancer [12]. Practice patterns of colonoscopy have also been assessed in Europe in a large multicenter study in 6004 patients [13]. In this study, the main indications for colonoscopy were surveillance after polypectomy or resection of colorectal cancer (19%), hematochezia (17%), uncomplicated abdominal pain (13%), screening for colorectal cancer (12%), chronic diarrhea (8%), and iron deficiency anemia (IDA) (7%) [13]. Traditionally, the clinician has to rely on patient symptoms, clinical signs, laboratory data, expert knowledge of the literature, and personal experience to decide whether colonoscopy should be performed in a given clinical situation. It is

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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possible to determine the diagnostic yield of colonoscopy by linking clinical indications and endoscopic findings. Clinicians are well aware that certain indications produce a higher diagnostic yield at colonoscopy than others. Colonoscopy for bleeding indications [hematochezia, IDA, and melena with negative upper gastrointestinal (GI) endoscopy] has a high yield of cancers (1 in 9 to 13 colonoscopies) while the cancer detection rate is low in nonbleeding indications (1 in 109 colonoscopies) [12]. Depending on the study population and their referral indications, colonoscopy is “normal” or shows nonrelevant findings (e.g., small hemorrhoids, uncomplicated diverticulosis) in 46–76% of patients [13–18]. Diagnostic yield has traditionally been considered the single most important parameter when judging the clinical usefulness of a diagnostic procedure such as colonoscopy [19,20]. Diagnostic yield is a critical parameter when assessing costs and benefits of colonoscopy in the context of an open-access healthcare system. However, diagnostic yield is often poorly defined; in most studies, it simply refers to the sum of pathologic endoscopic diagnoses found in the population under study but without any reference to clinical relevance. Diagnostic yield should certainly be defined in a more stringent manner, as the ability to detect an endoscopic finding that is potentially relevant to patient care. An endoscopic finding is of value in the context of patient management only if it causes the patient’s symptoms and if there is effective treatment. The diagnosis of diverticulosis, for example, may not have a clinical impact until there is a complication, such as diverticulitis or stenosis. A normal (i.e., “negative”) endoscopy may have a positive impact on work lost through illness, use of drugs, and medical consultations by excluding the presence of serious pathology and reassuring the patient. This favorable impact of reassurance on disease behavior has been reported for upper GI endoscopy [21–25] and is likely to be observed also for colonoscopy [25]. Obviously, it is more complex to measure these outcomes than it is to measure the detection rate of colonoscopy. This chapter, dealing with the relationship between clinical symptoms, signs, and endoscopic diagnoses, does not therefore imply that only pathologic findings are “useful” in clinical practice.

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The relationship between clinical presentation and endoscopic findings is imperfect and varies according to the indications and the patient population assessed (patient referral, selection bias). This relationship is far from perfect and is imprecise for nonspecific, albeit frequent, indications such as abdominal pain or constipation, while the correlation varies from acceptable to good for alarm symptoms such as hematochezia or IDA. For example, most adenomas do not produce symptoms [12]; adenoma yields at colonoscopy are, relatively speaking, independent of the indication, as evidenced by the high yield of adenomatous polyps in screening colonoscopy studies, but are best predicted by demographic factors such as male gender and increasing age [12]. For example, the National Polyp Study initially included 9112 colonoscopies in patients without any history of polyps. Only 32.1% of these patients were endoscoped for existing symptoms; most of them had either a positive finding at barium enema or sigmoidoscopy or a positive FOBT. Overall, 28.9% of the patients had one or more adenomas and 6% had cancer [18]. In this chapter, the authors discuss the relationship between clinical presentation and endoscopic results in the light of patient characteristics (age, sex) and the main indications encountered in clinical practice.

Patient characteristics Age Age is correlated to the presence of significant endoscopic lesions. Within a large European prospective multicenter study (European Panel on the Appropriateness of Gastrointestinal Endoscopy) including 6004 patients, we previously reported that the diagnostic yield of colonoscopy increased gradually with age [13] and was significantly higher in patients > 55 years of age than in those < 55 years of age [odds ratio 1.42; 95% confidence interval (CI) 1.05–1.92]. Polyps are found with higher frequency with increasing age [12]. Incidence rates of colorectal cancer increase in a regular fashion with age [26– 28]. Age has been found to be a significant predictor of colorectal cancer in patients referred for colonoscopy [29]. Cancer was found in 5.7% of patients > 55 years compared with 1.0% of patients aged ≤ 55 years (P = 0.008). While polyps and cancer frequency increase with age, other diagnoses, such as inflammatory bowel disease (IBD), seem to follow an inverse relationship. Thus, in 1144 colonoscopies performed for various indications in an open-access system, the overall diagnostic yield was 20.7% in patients < 50 years old compared with 25.2% in patients aged ≥ 50 years [P = NS (not statistically significant)]. In the younger patient group, 5% of the colonoscopies revealed polyps and 11% revealed IBD, compared with 11% polyps and 2% IBD in patients aged ≥ 50 years [15].

Diagnostic Yield of Colonoscopy by Indication

Gender In a large European prospective multicenter study of 6004 patients undergoing colonoscopy [13], the diagnostic yield of colonoscopy was lower in women than in men (21.9% vs. 31.5%; odds ratio 0.59; 95% CI 0.52– 0.68). In a patient sample of 1144 consecutive colonoscopies performed for various indications, significant lesions were found more often in males (28.3%) than in females (19.7%) (P < 0.001; odds ratio 1.63; 95% CI 1.23–2.15). In particular, significant polyps and colorectal cancer were found with higher frequency in males (10.8% vs. 7.5%, P = 0.05) than in females (6.9% vs. 2.2%, P < 0.001) [15]. The National Polyp Study, including 9112 patients at initial colonoscopy, reported a higher frequency of adenomatous polyps in men (61.6%) than in women (38.4%) (P < 0.0001) [18].

Family history A history of colorectal cancer in one or more first-degree relatives is associated with an increased risk of colorectal cancer. The risk is increased with multiple affected relatives and decreasing age of the affected relatives [30]. A meta-analysis of 27 case–control and cohort studies showed that the relative risk of contracting colorectal cancer before the age of 45 years was 1.99 in those with a first-degree relative with adenomatous polyps, 2.25 in subjects with a first-degree relative with colorectal cancer, and 3.87 in those with a first-degree relative with colorectal cancer before the age of 45 years [31]. First-degree relatives of patients with large adenomas have a roughly twofold increased risk (and absolute risk of about 8%) for the combined findings of colorectal cancer and large adenoma [32]. The risk is increased when the index case had the following features: age < 60 years, male gender, or distal adenoma location.

Main clinical indications For the nine main clinical indications, the diagnostic yield of colonoscopy is presented in the following pages in two ways: 1 tables summarizing the published studies for each main indication with their design, the number of patients studied, and the different diagnoses established; 2 box plots (or box and whisker diagrams) to present the results graphically. The box plot, invented in 1977 by the American statistician John Tukey [33], summarizes the following statistical measures: median, upper and lower quartile, and minimum and maximum values. The box contains 50% of the data. The upper edge of the box represents the seventy-fifth percentile, while the lower edge the twenty-fifth percentile. The horizontal line across the box represents the median. The vertical lines or “whiskers” indicate the minimum and maximum data values, unless outliers are present (black dots). Outliers are

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observations below Q1 − 1.5 IQR (interquartile range) or above Q3 + 1.5 IQR, where Q1 is the twenty-fifth percentile, Q3 the seventy-fifth percentile, and IQR = Q3 − Q1.

Hematochezia Lower gastrointestinal bleeding Lower GI bleeding refers to recent-onset blood loss originating from a site distal to Treitz’s ligament and is usually considered to be highly likely when patients report hematochezia (the passage of maroon or bright-red blood or blood clots per rectum). Distinctions based on stool color and volume of bleeding are important when discussing the diagnostic yield of hematochezia, although these distinctions are not absolute. A lack of careful characterization as to the nature of the

bleeding may explain the significant range of variation in diagnostic yield reported in the literature. Hematochezia is a common symptom, and community surveys indicate that between 7% and 16% of the adult Western population report rectal bleeding in a 6- to 12-month period and that blood is mixed with the stools in up to 30% of cases [34]. Rectal bleeding is a well-recognized alarm symptom, and thus patients who present with this condition are likely to be referred for lower GI endoscopy. In a cohort study using the General Practice Research Database, Jones et al. [35] found that rectal bleeding had a positive predictive value for colorectal cancer of 2.4% (2.1–2.8%) in men and 2% (1.7–2.3%) in women. Predictive value increased with age.

Table 16.1 Diagnostic yield of colonoscopy in patients with acute lower gastrointestinal bleeding. Study

Caos et al. [41] Church [42] Forde [43] Green et al. [44]

Guillem et al. [45]

Jensen and Machicado [37] Kok et al. [46] Longstreth [47] Ohyama et al. [48]

Richter et al. [38]

Rossini et al. [49] Schmulewitz et al. [50] Strate and Syngal [51]

Design

Prospective; negative sigmoidoscopy Prospective Retrospective Prospective; RCT; urgent colonoscopy versus standard care Retrospective; proctoscopy and BE attempted in most of the patients Prospective

Mean age (years)

Number (%) of patients with Cancer

Adenoma

Vascular ectasia

Colitisa

Diverticula

Otherb

35

59 (6–85)

1 (3)

3 (9)

5 (14)

2 (6)

8 (23)

3 (9)

27 25 50

3 (11) 3 (12) 0

1 (4) 2 (8) 0

3 (11) 2 (8) 4 (8)

1 (4) 3 (12) 4 (8)

6 (22) 5 (20) 13 (26)

NS 2 (8) 27 (54)

55

62 (53–71) NS 63 ± 3 (group with urgent colonoscopy) 63 (2–94)

7 (13)

5 (9)

6 (11)

5 (9)

19 (35)

3 (5)

80

64.5 (21–93)

9 (11) polyp or cancer

24 (30)

7 (9)

13 (17)

6 (8)

57 (30) 91 (42) 18 (5)

18 (9) 41 (19) 85 (25)

51 (47)

9 (8)

Number of patients

Retrospective Retrospective Retrospective; cecum observed in 55.9%

190 219 345

63 (8–92) 67 50.7

12 (6) 20 (9) 10 (3)

5 (3) NS NS

3 (2) 6 (3) 4 (1)

Retrospective; 78 out of 107 patients had a colonoscopy Retrospective Retrospective; 415 out of 565 patients had a colonoscopy Retrospective; 144 out of 252 patients had a colonoscopy

107

70 (21–93)

2 (2)

9 (8)

13 (12)

49 (25) 35 (16) 153 (44) (including 62 with ischemic colitis) 4 (4)

409 565

NS 66.8 (18–96)

88 (22) 27 (7)

34 (8) NS

16 (4) 14 (3)

85 (21) 61 (15)

60 (15) 171 (41)

17 (4) 64 (15)

252

66

14 (6)

NS

8 (3)

63 (25)

75 (30)

47 (19)

BE, barium enema; NS, not stated; RCT, randomized controlled trial. a Colitis includes inflammatory bowel disease, infectious colitis, radiation colitis, ischemic colitis, and inflammation of unknown origin. b Other includes postpolypectomy bleeding, hemorrhoids, etc.

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patients. Vascular ectasia (or angiodysplasia) are lesions of the elderly. Although massive bleeding may occur, the most common scenario is intermittent, subacute bleeding that ceases spontaneously in up to 90% of cases. Bleeding associated with cancer tends to be occult in most cases. When the bleeding is overt, it tends to be low grade and recurrent. Cancer is responsible for approximately 8% of lower GI bleeding. A lesion as a potential source of bleeding was identified and reported in 2286 of the 2359 patients (97%). A definite site of hemorrhage was identified in 1000 out of 1280 patients (78%) [41–46,48,49,51]. Diverticula were the most frequent source of acute lower GI bleeding, although the detection of the precise bleeding site typically remains presumptive. In a review of seven series in 1333 patients, Zuckerman and Prakash [52] identified the following sources of bleeding: diverticulosis (33%), cancer/polyps (18%), and angiodysplasia (8%). In summary, colonoscopy is recommended in the early evaluation of severe lower GI bleeding. It affords the opportunity not only to identify the source of bleeding, but also to apply therapy to stop bleeding.

Chronic lower gastrointestinal bleeding Chronic lower GI bleeding (nonemergency rectal bleeding) implies the passage of blood per rectum over a period of several days or more, and is generally slow or intermittent. Chronic lower GI bleeding is reported in 9–19% of the population in a given year [34,53,54]. Chronic lower GI bleeding is the second most frequent indication for colonoscopy in the US and Europe, and almost 20% of procedures are currently performed for this indication [11,13]. Table 16.2 and Figure 16.2 show the diagnostic yield of colonoscopy in nonemergency lower GI bleeding.

80

40

60

30

Diagnostic yield (%)

Diagnostic yield (%)

Lower GI bleeding may present in a number of ways: fecal occult blood, IDA, melena, intermittent hematochezia, or acute bleeding. Acute lower GI bleeding is defined as bleeding that is of recent duration (arbitrarily defined as < 3 days’ duration) and that may cause instability of vital signs, anemia, and/or the need for blood transfusion [36]. In most cases, acute rectal bleeding stems from the lower GI tract, although an upper GI origin is found in 11% of patients [37]. Acute lower GI bleeding ceases spontaneously in 80% of patients [38,39]. In patients aged < 50 years, hemorrhoids are the most common cause of rectal bleeding [40]. Patients with severe lower GI bleeding should undergo clinical evaluation and stabilization. Colonoscopy is recommended early on in the evaluation of severe lower GI bleeding [36], and a number of endoscopic treatment modalities can be used to achieve hemostasis when a lower GI bleeding source is identified at the time of colonoscopy. There is a significant degree of variation between studies as to the most common cause of acute lower GI bleeding. Table 16.1 and Figure 16.1 show the 13 published studies on identification of the cause of an acute lower GI bleeding source, one of which [37] makes no distinction between cancers and polyps. The diagnostic yield of colonoscopy for colorectal cancer was found to be between 0% and 22% in the studies reviewed; in all, 187 cancers were diagnosed in 2359 patients with acute lower GI bleeding (8%). Other significant findings were vascular ectasia (108 patients; 5%) and colitis, including IBD, infectious colitis, ischemic colitis, radiation colitis, and inflammation of unknown origin (472 patients; 20%). The presence of diverticula was observed in 25% (587 out of 2359) of

40

20

0

Diagnostic Yield of Colonoscopy by Indication

20

10

0 Carcinoma

Adenoma

Vascular ectasia

Colitis

Diverticula

Figure 16.1 Diagnostic yield of colonoscopy in acute lower gastrointestinal bleeding. Data from 13 studies (four prospective studies), 2359 patients. (Box and whisker diagram; for explanation see Main clinical indications.)

Carcinoma

Adenoma

Vascular ectasia

Colitis

Diverticula

Figure 16.2 Diagnostic yield of colonoscopy in nonemergency lower gastrointestinal bleeding. Data from 24 studies (14 prospective studies), 8567 patients. (Box and whisker diagram; for explanation see Main clinical indications.)

181

182 Prospective; several diagnoses per patient Prospective

Goulston et al. [61]

Graham et al. [62]

Prospective

Retrospective; proctosigmoidoscopy and BE normal or demonstrating diverticulosis Prospective; overt rectal bleeding or FOBT positive Prospective Prospective Prospective; patients with scant hematochezia Prospective

Gonvers et al. [13]

Fine et al. [60]

Church [42] de Bosset et al. [15] Eckardt et al. [59]

Brenna et al. [14]

Bat et al. [56] Berkowitz and Kaplan [57] Brand et al. [58]

Retrospective; minimal passage of blood or FOBT positive Retrospective Retrospective

Acosta et al. [55]

33

145

901

312

174 256 468

194

221

101 123

280

Number of patients

Mean age: 59 (32–81)

Mean age: 58 (15–95) Mean age: 56 (6–99) > 40

Mean age: 56.3 Mean age: 58 Mean age: 54.4

Mean age: NS

Mean age: NS

≥ 80 Mean age: NS

≤ 40

Age (years)

3 (9)

15 (10)

66 (7)

32 (10)

18 (10) 25 (10) 10 (2)

23 (12)

16 (7)

29 (29) 11 (9)

1 (0.4)

Cancer

14 (42)

25 (17)

111 (12)

26 (8)

51 (29) 34 (13) 73 (16)

34 (18)

51 (23)

34 (34) 15 (12)

25 (9)

Adenoma(s)

Number (%) of patients with

NS 10 (8) 11 (5)

25 (13) 8 (5) 21 (8) 31 (7) 54 (17) 58 (6) 5 (3) 3 (9)

9 (4)

NS 4 (2) 3 (1) NS 14 (5) 12 (1) 1 (0.6) 1 (3)

24 (9)

Colitisa

NS 7 (6)

3 (1)

Vascular ectasia

9 (27)

38 (26)

NS

43 (14)

12 (7) NS NS

NS

46 (21)

NS 25 (20)

6 (2)

Diverticula

9 (27)

114 (78)

22 (2)

25 (8)

NS 7 (3) 179 (38)

25 (13)

NS

NS 17 (14)

1 (0.4)

Otherb

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Design

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Table 16.2 Diagnostic yield of colonoscopy in patients with nonemergency lower gastrointestinal bleeding.

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Retrospective; patients < 50 years; 232 out of 570 patients underwent colonoscopy, and 338 underwent flexible sigmoidoscopy Prospective Retrospective; many patients had several diagnoses Prospective

Lewis et al. [65]

Retrospective; negative sigmoidoscopy and BE Retrospective; negative BE Retrospective; patients < 50 years old

Swarbrick et al. [70] 215 223 Mean age: NS 38 –48

Mean age: NS

Mean age: NS (33–84) Mean age: 50.5 (18–96) Mean age: NS

27 (13) 4 (2)

23 (10)

4 (4)

6 (1)

74 (9)

28 (11) 70 (4)

1 (0.2)

39 (10)

5 (7)

33 (15)

29 (14) 22 (10)

31 (30) adenoma > 8 mm 39 (16)

46 (17) 270 (15) adenoma > 5 mm 219 (25) adenoma ≥ 1 cm 77 (18)

64 (16) adenoma < 1 cm; 20 (5) adenoma > 1 cm 52 (9)

19 (27)

51 (23)

BE, barium enema; FOBT, fecal occult blood test; NS, not stated; RCT, randomized controlled trial. a Colitis includes inflammatory bowel disease, infectious colitis, radiation colitis, ischemic colitis, and inflammation of unknown origin. b Other includes postpolypectomy bleeding, hemorrhoids, etc.

Teague et al. [71] Wong et al. [72]

103

Prospective; patients > 45 years old

Segal et al. [69] 239

417

Prospective

861

Puglisi et al. [68]

Neugut et al. [67]

Mean age: NS Mean age: NS

Mean age: 38.7 (16 – 49)

Mean age: 54.7 (16 –91)

Mean age: 63 (3–94) Mean age: 53.5

2 (1) 2 (1)

4 (2)

–

4 (1)

NS

1 (0.4) 76 (4)

14 (3)

20 (5)

2 (3)

5 (2)

24 (11) 13 (6)

24 (10)

8 (8)

42 (10)

NS

14 (5) 117 (7)

82 (14)

89 (22)

4 (6)

19 (8)

2 (1) 19 (9)

45 (19)

NS

44 (11)

NS

NS 640 (36)

45 (8)

65 (16)

18 (25)

36 (16)

5 (2) 149 (67)

NS

NS

265 (64)

NS

NS 1156 (66)

354 (62)

13 (3)

39 (55)

67 (30)

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265 1766

570

405

71

224

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Morini et al. [17] Mulcahy et al. [66]

Lasson et al. [64]

Irvine et al. [63]

Retrospective; colonoscopy and barium enema findings Prospective; flexible sigmoidoscopy and BE followed by colonoscopy; many patients had several diagnoses Prospective; bleeding-related symptoms

Guillem et al. [45]

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183

184 323 100

No anemia Prospective; FOBT positive and/or IDA

1 (1)

2 (1) 6 (6)

Mean age: 69.6 ± 9.7 Mean age: 65.5 ± 7.1 Mean age: 65 (26 –91)

3 (2)

Mean age: 72.2 ± 8.9

115

16 (6)

Mean age: 69.5 ± 10.7

254

Anemia and ferritin > 100 ng/mL

0 11 (11)

Mean age: 38.9 (21–50) Mean age: 60 (20 – 85)

135 100

55

1 (1)

27 (13) 4 (0.4)

Mean age: 39.9 (15–49)

40–60

1 (1) 14 (12) 15 (6)

< 50; mean age: 32.6 ± 8 > 50; mean age: 69.3 ± 13

108

208 924

124 117 241

Anemia and ferritin 51–100 ng/mL

Retrospective; pre- and postmenopausal women Overall Prospective IDA and FOBT positive IDA and FOBT negative Retrospective Asymptomatic premenopausal women with IDA Control group Prospective; endoscopic examination of the upper and lower gastrointestinal tract Retrospective; four groups of male patients: Anemia and ferritin ≤ 50 ng/mL

6 (18)

Mean age: NS

FOBT, fecal occult blood test; IDA, iron deficiency anemia; NC, not clear; NS, not stated. a Advanced adenoma: adenomatous polyp ≥ 1 cm or polyp with villous histology or high-grade dysplasia. b Polyp ≥ 1 cm. c Polyp < 1 cm.

Zuckerman and Benitez [92]

Rockey and Cello [75] Sawhney et al. [91]

Park et al. [90]

Nakama et al. [89]

Nahon et al. [88]

33

Prospective

4 (6)

NS 5 (5)

3 (3)

3 (0.05)

5 (0.02)

0 5 (5)

3 (2) 5 (5)

22 (9)a 18 (7)b 59 (23)c 6 (11)a 6 (11)b 8 (15)c 11 (10)a 8 (7)b 23 (20)c NS 14 (14)

1 (1)

NS NS

0 5 (4) 5 (2)

4 (12)

NS NS

1 (0.01)

0

3 (0.01)

NS 2 (2)

NS

NS NS

1 (1) 0 1 (0.4)

NS NS

58 (50)

23 (50)

107 (42)

NS NS

NS

NS NS

NS NS NS

NS

NS

1 (1) NS

NS

0

6 (9) 6 (9)

2 (1) NS NS 1 (0.5) 0

NS NS 3 (7)

Diverticula

2 (1) 1 (1) 11 (3) 7 (4) 4 (4)

NS NS 8 (18)

Inflammatory bowel disease

NS 5 (6) 7 (2) 5 (3) 0

NS NS NS

Vascular ectasia

1 (1) > 1.5 cm

NS NS

0 10 (9) 10 (4)

7 (10) adenoma > 1 cm 3 (9)

10 (15)

3 (2) 7 (8) 32 (8) 26 (15) < 2 cm 0

NC NC 4 (9)

Adenoma

NS 2 (2)

0

1 (0.02)

2 (0.01)

10 (7) 3 (3)

7 (7)

NS NS

0 2 (2) 2 (0.4)

NS

4 (6)

1 (1)

18 (10) 1 (1) 2 (0.5) 1 (0.5) 1 (1)

NS NS 6 (13)

Other

10:47 AM

Mean age: 63.5 (19–87)

10 (15)

Mean age: 84.6 (70–96)

69 70

6 (3) 6 (7) 44 (11) 16 (9) 3 (3)

Mean age: 43.8 Mean age: NS Mean age: 64 (15–94) Mean age: 69 Mean age: 42.5

8 (9) 1 (3) 1 (2)

Cancer

Number (%) of patients with

186 89 387 170 111

Mean age: NS

74% of patients > 60 years

Age (years)

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Kepczyk and Kadakia [80] Morini et al. [17]

90 38 46

Retrospective; premenopausal women Prospective Prospective Retrospective; patients > 50 Retrospective; premenopausal women with IDA Prospective; patients > 70; 69 out of 96 patients with IDA had colonoscopy Prospective

Retrospective IDA and FOBT positive IDA and FOBT negative Retrospective; cecal intubation 69%

Alemayehu and Järnerot [85]

Number of patients

SECTION 5

Berkowitz and Kaplan [57] Bini et al. [77] de Bosset et al. [15] Gonvers et al. [13] Gordon et al. [78] Green and Rockey [86] Joosten et al. [87]

Design

Study

Table 16.3 Diagnostic yield of colonoscopy in patients with iron deficiency anemia (IDA).

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Iron deficiency anemia In the Western world, IDA occurs in 2–5% of adult men and postmenopausal women and is a common cause of referral to a gastroenterology clinic (4–13% of all referrals) [73]. In this category of patient, IDA is most commonly caused by blood loss or malabsorption. Examination of both the upper and lower GI tracts should be carried out in all patients in whom IDA has been confirmed, unless there is a history of significant non-GI blood loss. IDA may result from an asymptomatic colonic or gastric carcinoma, and the exclusion of these conditions is of prime concern [74,75]. The diagnostic yield of endoscopy (upper GI and colonoscopy) overall in IDA ranges from 12% to 86% [74– 83]. Although upper GI lesions are frequently found at endoscopy (31– 60% of patients), the most significant concern remains the issue of colorectal cancer, particularly in patients > 50 years of age. Among patients in whom an upper GI lesion is identified, colonoscopy has a high detection rate for relevant lesions: in one study, 16% of patients with a benign upper GI lesion were found to have colon cancer [74], while another study found 17% of patients to have both an upper and a lower GI lesion [80], suggesting that colonoscopy should be performed even when an upper GI lesion is found, at least in patients > 50 years of age. Most patients with IDA have no symptoms that might suggest a GI lesion [74,75]. There is controversy as to whether site-specific

40 Diagnostic yield (%)

Colorectal cancer was found on average in 6.6% (563 out of 8567; range 0.2–29%) of patients, which correlates with the 7.1% observed in a European multicenter study published in 2007 [13]. Patient age influences findings at colonoscopy, and thus, in a group of patients aged ≥ 80 years with nonemergency rectal bleeding, 29% had a cancer diagnosed at colonoscopy [56]. Conversely, only 0.2–2% of patients aged < 50 years had a cancer diagnosed at colonoscopy [55,72]. Adenomas were found, on average, in 17% of chronic lower GI bleeding patients, with a range of 8–42%. This wide range probably reflects variations in reporting of patients with small adenomas, and age variations between series. The incidence of vascular ectasia increases with age and the risk of bleeding increases over time. Bleeding from vascular ectasia tends to be episodic and self-limiting. In this review of 24 studies, the incidence of vascular ectasia was on average between 0.4% and 5.7% in 2.8% of patients. Colitides (infectious, ischemic, IBD) can all show hematochezia as an initial manifestation. The mean incidence of colitis was 8.4%, varying between 3% and 22%. A recent European multicenter study confirmed that hematochezia as the main indication for colonoscopy has a higher diagnostic yield than nonbleeding indications (odds ratio 1.5; 95% CI 1.3–17). Colon cancer, in particular, was more often detected in cases of hematochezia (odds ratio 2.6; 95% CI 1.9–3.5) than in nonbleeding indications [13].

Diagnostic Yield of Colonoscopy by Indication

30 20 10 0 Carcinoma

Adenoma

Vascular ectasia

Inflammatory Diverticula bowel disease

Figure 16.3 Diagnostic yield of colonoscopy in patients with iron deficiency anemia. Data from 16 studies (eight prospective studies), 2432 patients. (Box and whisker diagram; for explanation see Main clinical indications.)

symptoms are able to accurately predict the likelihood of a GI lesion in patients with IDA [84]. Most studies have found a weak correlation or no correlation at all between patient history and the anatomical location of any lesion [73,75,78]. Table 16.3 and Figure 16.3 summarize the diagnostic yield of colonoscopy in IDA in 16 studies published between 1992 and 2007. A colon cancer was diagnosed in 184 of the 2432 patients with IDA (7.6%) (range 0.8–15%). Approximately 13 colonoscopies are necessary to diagnose a cancer if the main indication for performing colonoscopy is IDA. In his 1995 review on diagnostic yield of cancers and adenomas, Rex [12] found that 9–13 colonoscopies were necessary to diagnose a cancer. In a European multicenter study published in 2007 [13], 44 cancers were diagnosed in 387 patients with IDA (7.4%), which corresponds to one cancer per nine colonoscopies. In this same study, compared with nonbleeding indications, the diagnostic yield in IDA patients was particularly high for cancer (odds ratio 4.1; 95% CI 2.9–5.9) [13]. The diagnostic yield for cancer is even higher in the case of patients with IDA and a positive FOBT (9–13%) than the 0.4–3% in patients with IDA alone [85,89]. The study by Nahon et al. [88] is interesting because it addresses the problem of GI lesions in women with IDA. In 241 women with IDA, a substantial lesion was detected in 86 patients (35.6%) by upper GI endoscopy and in 33 patients (13.7%) by colonoscopy. Colon cancer was the most frequent lesion detected by colonoscopy. Multivariate analysis revealed abdominal symptoms, age > 50 years, and hemoglobin < 9 g/dL as predictive factors for significant lesion. Among the other diagnoses, and when the corresponding diagnosis was mentioned, 12.3% of patients had one or more adenomas of varying diameters (range 0.9–23%), 9.5% had vascular ectasia (range 0.9–13%), and 4.3% had IBD (range 1–17.6%). In summary, colonoscopy for IDA has a substantial yield for colon cancer (one cancer per 13 colonoscopies). The

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diagnostic yield is even higher when IDA is combined with a positive FOBT.

Follow-up of polyps

Screening colonoscopy is discussed in detail in Chapter 17. In the US and in many other Western countries, there has been a dramatic increase in the performance of direct colonoscopy screening of the average-risk population. In 2002, more than 14 million colonoscopies were performed in the US, of which an estimated 38–45% were for screening and 22% were for surveillance of patients with previous neoplasia [11,116]. In this chapter on the diagnostic yield of colonoscopy, we will briefly review studies dealing with screening colonoscopy. Table 16.5 and Figure 16.5 summarize the published literature regarding diagnostic yield. In the studies quoted, 83 640 subjects were screened for colon cancer by colonoscopy. A colorectal cancer was reported in 571 subjects (0.7%) and adenoma(s) in 16 156 (19%). In a recently published European prospective multicenter trial

80

40

60

30

40

20

20

10

0

0 Adenoma

Advanced adenoma

Carcinoma

Figure 16.4 Diagnostic yield of colonoscopy after polypectomy. Data from 18 studies (12 prospective studies), 19 935 patients. (Box and whisker diagram; for explanation see Main clinical indications.)

186

Screening for colon cancer

Diagnostic yield (%)

Diagnostic yield (%)

Surveillance after polypectomy is discussed in Chapter 54. In this chapter, we briefly summarize the diagnostic yield of colonoscopy for this indication, since postpolypectomy surveillance now constitutes a large part of endoscopic practice [11,13]. Most polyps are asymptomatic [93]. No single symptom has a good predictive value, with the occasional exception of very large polyps. Thus, the indication for performing colonoscopy is not based on clinical symptoms. Table 16.4 and Figure 16.4 summarize the published literature regarding the yield of surveillance colonoscopy after polypectomy. Surveillance intervals vary between studies. The cumulative proportion of recurrent polyps depends on the duration of follow-up. As an example, the proportion of recurrent polyps in the Funen study was close to 20%, 35%, and 50% after 2, 4, and 8 years of follow-up respectively [102]. Despite these limitations, a number of clinically relevant trends are evident regarding adenoma recurrence and the occurrence of colorectal cancer. In this review, metachronous adenomas are reported in 4–73% of patients (mean 41%), among them advanced adenomas (adenoma with a size ≥ 1 cm or with high-grade dysplasia or villous component) in 1–29% (mean 4.5%) of patients and colorectal cancer in 0–3% (mean 0.9%). The National Polyp Study found that the rate of adenoma detection 3 years after initial adenoma resection was 32–42% [112]. Recurrent adenomas were mostly small tubular adenomas with low-grade dysplasia. Only 3.3% of patients in each follow-up group had advanced adenomas (> 1 cm, or with villous tissue or high-grade dysplasia).

In comparison with other indications, the yield of surveillance colonoscopy after polypectomy is thus relatively low for cancer and high for metachronous adenomas. Rex [12] calculated that 317 colonoscopies were necessary to detect one cancer if the main indication is surveillance after polypectomy. Patients who have undergone polypectomy and long-term surveillance have been shown to have a reduced incidence of colorectal cancer [113,114]. Guidelines for colonoscopy surveillance after polypectomy have recently been published [115]. These guidelines are intended to be used by clinicians as a guide in their approach to postpolypectomy surveillance. There is a trend to shift endoscopic resources from postpolypectomy surveillance to screening colonoscopy, by increasing recommended surveillance intervals.

Cancer

Advanced adenoma

Adenoma

Figure 16.5 Diagnostic yield of screening for colon cancer by colonoscopy. Data from 16 studies (14 prospective studies), 83 640 patients. (Box and whisker diagram; for explanation see Main clinical indications.)

Martinez et al. [104]

Lund et al. [103]

Mean age: 63.8 Mean age: 63.5 40–80

Mean age: NS

341

86 134 1287

Mean age: NS

332

Person-years of follow-up: 271 Person-years of follow-up: 261 Two follow-up colonoscopies (1 year and 3 years after qualifying colonoscopy)

Follow-up: 48 months (n = 223) Follow-up: 96 months (n = 48) Follow-up: 48 months (n = 232) Follow-up: 96 months (n = 68)

Follow-up: 5 years

RCT Group A: surveillance colonoscopy every 2 years Group B: surveillance colonoscopy every 4 years RCT Two-yearly colonoscopy Five-yearly colonoscopy Retrospective; participants on the wheat bran fiber diet who had one or more colorectal adenomas

Mean age: NS

Jorgensen et al. [102] (Funen Study)

4046

Colonoscopy at 3 years

Mean age: 58.8 ± 11.2

134

10 (12) 5 (4) 479 (37)

Five years’ cumulative incidence: 1651 (41) 42 (19) 7 (15) 64 (28) 19 (28)

28 (21)

Cumulative incidence: 147 (72) 122 (22)

323 (29)

NS NS 146 (11)

3 (0.4) 1 (2) 13 (6) 4 (6)

NS

18 (13)

41 (7)

NS

14 (1)

0 1 (1) 9 (1)

0 1 (2) 2 (1) 0

88 (2)

0

0

Cumulative results: 1 (0.5)

10 (1)

0

15 (3) at an average of 3.3 years (2–5) 3 (1)

Carcinoma

CHAPTER 16

Gandhi et al. [101]

Follow-up colonoscopy at 3 years

Mean age: 59.1 (35–75)

552

European Fiber Calcium Intervention Trial Retrospective; patients with one or more adenomas; 43 of the 134 had a first-degree family history of CRC Retrospective

Bonithon-Kopp et al. [99] Fossi et al. [100]

Median age: 64 (30–86)

204

Retrospective

Blumberg et al. [98]

Mean time of surveillance: 10.5 years; 5685 colonoscopies performed with a mean of five per subject Two follow-up colonoscopies; median follow-up: 55 months

Mean age: 61 (24–87)

1086

32 (29)

NS

NS

Advanced adenoma(s)a

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Bertario et al. [97]

Colonoscopy at 1 year

Mean age: 57.7 ± 1.7

112

Cumulative incidence: 52 (12) 46 (41)

181 (37)

Adenoma(s)

Number (%) of patients with

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Benamouzig et al. [96]

Mean age: 60.3 ± 9.0

423

Placebo group of an RCT on calcium supplementation for the prevention of colorectal adenoma Placebo group of a RCT on daily soluble aspirin for the prevention of colorectal adenoma Prospective; colonoscopy 1 year after clearing polypectomy and, if negative, subsequently every 3 years

Baron et al. [95]

Colonoscopy between 1 and 5 years; mean time: 2.5 ± 1.4 years Colonoscopy at 1 and 4 years

Mean age: 69 ± 7

484

Retrospective

Avidan et al. [94]

Follow-up

Age (years)

Number of patients

Design

Study

Table 16.4 Diagnostic yield of surveillance colonoscopy after polypectomy.

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187

188 Group B: follow-up colonoscopy at 3 years Prospective Group A: patients with small adenomas (< 10 mm); annual colonoscopy Group B: patients with advanced adenoma(s); annual colonoscopy 323

1818

Mean age at the second colonoscopy: 48.8

First follow-up at 3 years (n = 428)

Mean age: 61.5 ± 9.8

At least three or more colonoscopies; mean follow-up of 2.34 years At least three or more colonoscopies; mean follow-up of 2.19 years

First follow-up at 1 year (n = 545) Second follow-up at 3 years (n = 338)

Mean age: 60.9 ± 10.7

699

719

Colonoscopy at 1 and 4 years

Follow-up: 4 years; median observation period: 3.05 years; colonoscopy at 1 and 4 years

Mean age: 60 (25–78)

Mean age: 61

Mean age: 59.7 ± 9.3

479

1905

Average follow-up: 3.7 ± 0.8 years

Mean age: 57.08 ± 11.25

CRC, colorectal cancer; NC, not clear; NS, not stated; RCT, randomized controlled trial. a Advanced adenoma: adenoma ≥ 1 cm or with severe dysplasia or villous component.

Yamaji et al. [111]

van Stolk et al. [109] Winawer et al. [112]

Schatzkin et al. [108]

2915

Surveillance colonoscopy within 10–42 months (mean: 18 months) At least one follow-up examination

Mean age: NS

Follow-up

142 (44)

781 (43)

150 (28) 73 (21.6); cumulative result at 3 years: 42% 137 (32)

166 (35)

754 (40)

846 (73) single adenomas 246 (21.2) multiple adenomas 1370 (47)

NS

Adenoma(s)

20 advanced lesions (6)

40 advanced lesions (2)

14 (3)

14 (3) 3 (0.9); cumulative result at 3 years: 3%

46 (10)

126 (7)

7 (0.2)

NC

63 (9)

Advanced adenoma(s)a

Number (%) of patients with

0

0

2 (0.5)

0 1 (0.3)

0

14 (1)

5 (0.4) detected after 1 year (one patient) and in other patients after 2, 4, 6, or 11 years of follow-up 19 (0.7)

3 (0.4)

Carcinoma

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Findings of three RCTs: colonoscopy at 1 and 4 years after clearing colonoscopy (two RCTs); colonoscopy at 3 years after clearing colonoscopy (one RCT) RCT: 2079 subjects ≥ 35 years, randomized to a low-fat diet or control group; lack of effect of low-fat, high-fiber diet RCT on antioxidant vitamins for the prevention of colorectal adenoma(s) RCT Group A: follow-up colonoscopy at 1 and 3 years

1159

697

Age (years)

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Robertson et al. [107]

Retrospective

Noshirwani et al. [105] Nusko et al. [106]

Number of patients

SECTION 5

Prospective; 653 patients with a single initial adenoma were reexamined at 4-year intervals, 468 with multiple adenomas at 2-year intervals

Design

Study

Table 16.4 (cont’d )

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Diagnostic Yield of Colonoscopy by Indication

Table 16.5 Diagnostic yield of screening for colon cancer by colonoscopy. Study

Design

Number of patients

Age (years)

792

Number (%) of patients with Carcinoma

Advanced adenoma(s)a

Adenoma(s)

Mean age: 64

1 (0.1)

NS

860

Mean age: 54.4 ± 11.6 (20–90)

9 (1)

39 (5)

126 (16) (only polyps > 5 mm) 120 (14)

Foutch et al. [120]

Prospective Group A Group B Prospective; asymptomatic men ≥ 50

285 333 114

0 0 2 (2)

9 (3) 34 (10) 10 (9)

67 (24) 85 (26) 47 (41)

Gonvers et al. [13]

Prospective

600

40–49 50–59 Mean age: 64 (50–79) Mean age: 53.8 (14–89)

6 (1)

NS

84 (14)

Guillem et al. [121]

Prospective Asymptomatic first-degree relatives of colorectal cancer patients Control subjects

Mean age: 48.2 ± 12.5 Mean age: 54.8 ± 11 Mean age: 44.8 Mean age: 65 ± 2 (51–82) Mean age: 62.9 ± 0.13 Mean age: 48.2 ± 9.3

0

NC

26 (14)

0

NC

8 (10)

0 2 (2)

32 (4) 8 (9)

79 (9) 16 (18)

30 (1)

299 (10)

842 (27)

79 (0.4)

648 (3)

3598 (17)

43 042

Mean age: NS

385 (1)

2168 (5)

6011 (14)

7106

Mean age: NS

31 (0.4)

212 (3)

643 (9)

621

Mean age: NS

3 (0.5)

54 (9)

105 (17)

639

Mean age: 56 (24–85) Mean age: 58.9

5 (1)

41 (6)

84 (13)

1 (0.1)

72 (5)

227 (16)

40–49 50–75 76–80

0 11 (1.2) 2 (3) 13 (1) 4 (1)

2 (1) 50 (6) 9 (12) 61 (5) 59 (12)

16 (9) 145 (16) 11 (14) 172 (15) 78 (15)

Adler et al. [117] Byeon et al. [118]

Eisele et al. [119]

Imperiale et al. [122] Johnson et al. [123] Lieberman et al. [124] Morikawa et al. [125]

Prospective; 39 private practice offices Prospective

Retrospective; patients aged 40–49 Prospective; asymptomatic patients; BE and colonoscopy Prospective; male sex: 96.8%

Strul et al. [130]

Prospective; asymptomatic adults simultaneously underwent FOBT and colonoscopy Screening program Participants aged 50–66 (13.3% with a family history of cancer) Participants aged 40–49 (66.3% with a family history of cancer) Prospective; asymptomatic subjects aged 50–75; negative FOBT Prospective; office-based screening colonoscopy Prospective; women aged 50–79; asymptomatic; average risk Retrospective

Sung et al. [131]

Total Prospective; adults > 50 years

Regula et al. [126]

Rex et al. [127] Rogge et al. [128] Schoenfeld et al. [129]

181 83 906 90 3121 21 805

1463 183 917 77 1177 505

Mean age: 56.5 ± 5.4

BE, barium enema; FOBT, fecal occult blood test(ing); NC, not clear; NS, not stated. a Advanced adenoma: adenoma ≥ 10 mm, adenoma with villous or tubulovillous histological characteristics, or adenoma with high-grade dysplasia.

involving 6004 consecutive patients undergoing colonoscopy for various indications, 600 patients were asymptomatic and underwent the procedure for screening purposes. The diagnostic yield was 1% for cancer and 14% for adenoma(s) [13].

Follow-up after resection of colorectal cancer Patients who have undergone resection of colorectal cancer are at risk of recurrent cancer and metachronous neoplasms in the colon. Complete preoperative evaluation of the colon

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(i.e., clearing colonoscopy) is necessary to detect any synchronous polyps or cancers. If obstruction precludes preoperative colonoscopy, colonic evaluation should be performed within 3–6 months of surgery. The yield of clearing colonoscopy is high: 2–7% of patients with colorectal cancer have one or more synchronous cancers in the colon and rectum at the time of initial diagnosis [132–137], and 27% have synchronous adenomas. It is important to differentiate between clearing colonoscopy and follow-up colonoscopy in the context of surveillance after cancer resection. There are two fundamental goals of surveillance of patients with resected colon or rectal cancer: the first is the detection of an early recurrence of the initial primary cancer at a stage that would allow curative treatment; the second goal is detection of metachronous colorectal neoplasms. Table 16.6 and Figure 16.6 show the results of studies pooling 9066 patients who underwent surveillance colonoscopy after cancer resection. Surveillance intervals varied between studies [132–134,137–163]. Some studies did not clearly separate metachronous tumors from anastomotic recurrences, or anastomotic from local or regional recurrence. Despite these limitations, a number of clinically relevant trends are evident regarding colorectal recurrence, metachronous cancer, and the utility of surveillance colonoscopy in patients after resection of colorectal cancer. Guidelines for colonoscopic surveillance after cancer resection have recently been published [164]. In the setting of surveillance after cancer resection, Rex [12] calculated that 74 procedures were necessary to detect one anastomotic recurrence and 82 to detect one metachronous cancer. In this review, an anastomotic recurrence was found at one or more examinations in 6% of the patients and a metachronous cancer in 2.9%.

Diagnostic yield (%)

25 20 15 10 5 0 Local recurrence

Metachronous carcinoma

Adenoma

Figure 16.6 Diagnostic yield of colonoscopy after colorectal cancer resection. Data from 18 studies (12 prospective studies), 4733 patients. (Box and whisker diagram; the studies of Green, Khoury, Schoemaker, and Togashi are not represented in the graph; for explanation see Main clinical indications.)

190

In summary, complete preoperative evaluation of the colon is important for the detection of any synchronous polyps or cancers. The main purpose of colonoscopic surveillance in follow-up is to identify metachronous cancers and polyps which may occur over an extended period of time, at a surgically curable stage. Intensive efforts by colonoscopy have been shown to be of little benefit in detecting intraluminal recurrences.

Occult gastrointestinal bleeding Occult GI bleeding is bleeding that is not clinically apparent but becomes manifest by laboratory evidence of iron deficiency or chemical evidence of blood in the stools. FOBT followed, in the event of a positive test result, by colonoscopy to detect the source of occult bleeding can reduce colorectal cancer mortality. Five randomized controlled FOBT screening trials performed in the US, England, Denmark, Sweden, and France have reported a reduction in colorectal cancer mortality ranging from 13% to 33% [165–169]. The reduction in mortality was 18% in the Funen study [168] after 10 years of follow-up, 14% in the Nottingham trial [166] after an average follow-up of 6.7 years, 16% in the French study [165] over an 11-year period, and 18% in the Göteborg study [167] during the 10-year period. The US study, which showed a reduction of mortality of 33%, was conducted among volunteers and used rehydrated FOBTs [169]. In addition, all of the major trials showed that most cancers detected by FOBT screening are at an early, more manageable stage at the time of diagnosis. This section summarizes the diagnostic yield of isolated FOBT positivity without particular emphasis on the various FOBT methods, screening intervals, or cancer risk related to family history. Studies assessing the yield of FOBT focus on adenomas and cancer. The yield of colonoscopy for cancer and adenomas is high in otherwise asymptomatic patients with a positive FOBT. Factors influencing this yield are patient age and whether rehydration of the test is done (resulting in reduced specificity). In most studies, rehydration of FOBT was not performed and full colonoscopy was carried out if one or more tests were positive. In these circumstances, colonoscopy will detect colorectal cancer in 10% (range 7–22%) and adenomatous polyps in 35% (range 19–43%) of FOBT-positive subjects [12]. Table 16.7 and Figure 16.7 show the diagnostic yield in patients undergoing colonoscopy for a positive FOBT, irrespective of the study setting (mass screening, case finding). In this group, colon cancer was detected in 8.4% (range 3–17%) and advanced adenomas in 23% (range 12–54%) (tubular adenomas > 10 cm, villous adenomas, adenoma with high-grade dysplasia). It has been calculated that 9.8 colonoscopies are necessary to detect one cancer in patients with one positive FOBT [12]. In this review, 11.5 colonoscopies were found to be necessary to detect one cancer.

Cohort study; total colonoscopy once per year Retrospective; colonoscopy after 1 year and then a 3-yearly examination Prospective 88 patients adhered strictly to a surveillance program with colonoscopy every year 124 patients did not adhere strictly Retrospective; colonoscopy after 2 years and then every 4 years until the age of 70 years

Castells et al. [139]

Chen and Stuart [140]

Green et al. [143]

Granqvist and Karlsson [142]

3278

Mean age: 63.9 ± 11 (15–87)

Mean age: 67.9 ± 10.1 Mean age: 64 (21–85)

124 390

Mean age: 63.5 ± 10.3

80

Mean age: NS

Mean age: 66 ± 11

Median age: 63 (18–82)

Total number of colonoscopies: 600; 256 patients examined once, 87 twice, 30 three times, and 17 four times At 5 years (median follow-up 7.1 years; 63 had been followed for at least 5 years)

Mean follow-up for surviving patients: 90.7 ± 32.9 months 94.1 ± 42.8 months

Mean follow-up period of 5.6 years

Mean follow-up: 62 months (37–142 months); mean time for diagnosis: 25 months (10–73 months) First colonoscopy after a median interval of 8 months; median interval between subsequent colonoscopies: 12 months Median follow-up: 51 months (2–106 months)

NS

14 (4)

17 (14)

9 (10)

0

27 (19) (time to recurrence 13 ± 21 months)

0

34 (7) (rectal cancers)

Local recurrences

Number (%) of patients with

42 (2) (incidence rate of 274 cases per 100 000 person-years)

12 (3)

NS

NS

4 (2) [after a mean interval of 7 years 9 months (3–17 years)]

0

1 (1) (114 months postoperatively)

12 (3)

Metachronous CRC

NS

44 adenomas ≥ 1 cm (11); 104 adenomas < 1 cm (27)

NS

NS

130 (56)

NS

43 (33)

NS

Adenoma(s)

CHAPTER 16

Cohort study; surveillance for second primary CRC within 6 months of surgery, at 12 months, at 18 months, and then annually

129

Retrospective; at least two postoperative colonoscopies; total number of colonoscopies: 546

Carlsson et al. [133]

Mean age: 65.2 (29–89)

Follow-up

10:48 AM

Eckardt et al. [141]

481

Retrospective; colonoscopies 1 year after the operation then at 1- or 2-year intervals

Barillari et al. [138]

Age (years)

4/17/09

140 (compliant patients) 231

Number of patients

Design

Study

Table 16.6 Diagnostic yield of surveillance colonoscopy after curative resection of colorectal cancer.

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191

192

Nava and Pagana [149]

Makela et al. [147]

240

52

Group 2: intensified follow-up Prospective; colonoscopy yearly

54

74

239

RCT: Group 1: conventional follow-up

McFarland et al. [148] Prospective

Prospective; colonoscopy and/or barium enema every 6 months after surgery

Kronborg et al. [134]

Mean age: 69 ± 15 (33–85) Mean age: 63 ± 15 (33–81) Mean age: NS

Mean age: 66

< 75

Mean age: NS

RCT Group 1: colonoscopy at 6, 12, 18, 24, 30, 36, 48, 60, 120, and 180 months after radical surgery Group 2: colonoscopy at 60, 120, and 180 months after surgery

Kjeldsen et al. [146]

Mean age: 65.8 (26–89)

307

389

Retrospective; median interval between all colonoscopies: 13 months

Khoury et al. [145]

Mean age: 61

4 years (304 colonoscopies)

5 years

5 years

6 months (152 patients) 12 months (122 patients) 18 months (86 patients) 24 months (58 patients) 30 months (35 patients) 36 months (18 patients) Mean follow-up: 4.3 years (1–26 years); total number of colonoscopies: 237

First year Second year Third year Fourth year

6 years’ observation; 316 colonoscopies were done

Follow-up

17 (7)

2 (4)

1 (2)

2 (3) (local recurrence)

42 (14) (percentage of patients with given finding at one or more examinations) 32 (11) (percentage of patients with given finding at one or more examinations) 2 (1) 1 (1) 1 (1) 1 (2)

– 1 (0.4) – 1 (1.2)

9 (7) (between 12 and 30 months)

Local recurrences

Number (%) of patients with

11 (46) (25 patients did not have colonoscopy around the time of surgery)

1 (2)

0

0

2 (4) 1 (3)

1 (1)

3 (1)

7 (2)

1 (0.25) – – –

4 (3)

Metachronous CRC

51 (21)

NS

NS

10 + 3 villous 7 + 1 villous 1 (1) 2 (4) 1 (3) NS 26 (35)

NS

NS

30 adenomas ≥ 1 cm (23); 7 villous adenomas (5) 70 (18) 47 (18) 27 (16) 11 (13)

Adenoma(s)

10:48 AM

Mean age: NS

133

Prospective; colonoscopy and barium enema annually

Juhl et al. [144]

Age (years)

4/17/09

290

Number of patients

Design

SECTION 5

Study

Table 16.6 (cont’d )

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Prospective; colonoscopy annually until the colon is polyp free, then 3–5 yearly Retrospective; colonoscopy yearly for the first 5 years, then every 2 years Retrospective; surveillance colonoscopy at least twice during a period of more than 3 years 341

322

611

Average age: 59.6 (27–83)

Mean age: NS

Median age: 66.7 (20–90)

Median age: 67 (34–84)

167

Mean follow-up: 6.2 years (3–17 years)

Median follow-up: 105 months

Median follow-up: 44 months (6–74 months)

5 years (577 follow-up colonoscopies)

5 years (154 follow-up colonoscopies)

5 years

Mean follow-up: 5.5 years (3.2–8.8 years)

5.5–8.8 years after primary surgery

Median follow-up: 70 months

22 (6.8) (patients who underwent resection for rectal or sigmoid cancer) NS (all CRCs detected were defined as metachronous CRC)

13 metachronous or recurrent lesions (8.2) (5 of 13 diagnosed by colonoscopy) 10 metachronous or recurrent lesions (5.9) (3 of 10 diagnosed by colonoscopy) 4 (1) (anastomotic site)

20 (19) (8 cases without distant metastases) 26 (25) (20 cases without distant metastases)

6 (5)

2 (4)

44 (10) (95 patients had recurrence by 48 months)

19 (6) (12 with a depth of invasion limited to the mucosa); incidence of metachronous CRC during a 5-year period: 4.3

5 (2)

5 (1)

NS

1 (1)

2 (2)

1 (2) (rectal carcinoma)

NS

NS

24 (8)

50 (8)

34 (20)

23 (15)

10 (10)

11 (11)

15 (11)

5 (9)

NS

CHAPTER 16

CRC, colorectal cancer; NS, not stated; RCT, randomized controlled trial.

Togashi et al. [157]

Stigliano et al. [156]

Skaife et al. [155]

Median age: 69 (29–83)

Mean age: 64.4 (36 –82) Mean age: 62.2 (41–86)

Median age: 63.5 (35–84)

Mean age: 65.7 (40.6–83.3)

Mean age: 67.2

158

104

103

132

53

444

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Retrospective; recurrence following curative resection of CRC; colonoscopy every 3 years RCT; subgroup with intensive follow-up; colonoscopies at 3, 15, 30, and 60 months after surgery Prospective; colonoscopy at 6, 12, 18, 30, and 48 months after surgery RCT Group A: conventional followup; colonoscopy once a year Group B: intensive follow-up; colonoscopy once a year RCT Group 1: standard follow-up; colonoscopy if indicated clinically and after 5 years Group 2: intensive follow-up; yearly colonoscopy

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Pietra et al. [153]

Patchett et al. [152]

Ohlsson et al. [151]

Obrand and Gordon [150]

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Diagnostic yield (%)

60

40

20

0 Carcinoma

Advanced adenoma

Adenoma

Figure 16.7 Diagnostic yield of colonoscopy in patients with positive fecal occult blood test. Data from 16 studies (14 prospective studies), 8410 patients. (Box and whisker diagram; the study of Mandel is not represented in the graph; for explanation see Main clinical indications.)

The study by Morikawa et al. [125] is interesting because it presents important data on the performance characteristics of a new fecal immunochemical test. The sensitivity of this new immunochemical test for colon cancer was 66%, and 20% for polyps > 1 cm. A 66% sensitivity for cancer is a marked improvement on the 13–39% sensitivity reported for the most commonly used guaiac test. All the recommendations for an FOBT option in colon cancer were made on the basis of findings from randomized controlled trials using a guaiac test. If it appears that the fecal immunochemical tests have better performance characteristics, screening programs with new FOBT methods merit consideration. In summary, colonoscopic evaluation of positive FOBT has a high diagnostic yield for both cancer and polyps. Cancer will be found in 3–18% and advanced adenomas in 12–54% of patients with occult bleeding.

HIV-negative patients with chronic diarrhea Most acute diarrheas are caused by an acute self-limiting infection. These infectious diarrheas are very common and

Table 16.7 Diagnostic yield of colonoscopy in patients with positive fecal occult blood test(ing) (FOBT). Study

Allison et al. [170]

Design

Prospective; three FOBTs; number of screened patients who had colorectal neoplasms in the 2 years after screening Hemoccult II (8065 screened) HemeSelect (7493 screened)

Number of patients

198

Age (years)

≥ 50; mean age: NS

Number (%) of patients with Carcinoma

Advanced adenoma(s)a

Adenoma(s)

35 (18)

107 polyps > 1 cm (54) 102 polyps > 1 cm (23) 102 polyps > 1 cm (43)

NS

82 (29)

12 (4)

29 (10) (adenoma > 1 cm) 47 (12) (adenoma > 1 cm) NS

440

32 (7)

Hemoccult II Sensa + HemeSelect (7847 screened) Retrospective Group I: digital rectal examination Group II: spontaneously passed stools Prospective

233

32 (14)

Faivre et al. [165]

24 099 asymptomatic people screened with Hemoccult not rehydrated

Frommer et al. [172]

Screening for colorectal cancer by immunological technique or Hemoccult II Prospective; Hemoccult

First screening: 429 of the 502 subjects with positive FOBT had colonoscopy 153

Bini et al. [171]

Eckardt et al. [59]

Frühmorgen and Demling [173] Gonvers et al. [13] Grazzini et al. [174]

194

Prospective; Hemoccult Prospective; subjects aged 50–70

282

NS NS

Mean age: 63.2 ± 0.6 Mean age: 62.3 ± 0.5 Mean age: 60.7 ± 11.5 45–74

33 (12)

42 (10)

76 (18)

57 (19) (all adenomas) 42 (10)

Mean age: 56.5 ± 12.5

19 (12)

NS

40 (26)

117

Mean age: NS

13 (11)

49 (42)

121 231

Mean age: 60.9 Mean age: NS

4 (3) 33 (14)

2 (2) (with highgrade dysplasia) NS 63 (27)

390 299

44 (11)

104 (27)

42 (35) 12 (5)

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Table 16.7 (cont’d ) Study

Hardcastle et al. [166]

Kewenter et al. [167]

Kronborg et al. [168]

Lieberman et al. [175]

Mandel et al. [169]

Morikawa et al. [125]

Nakama et al. [89]

Steinmetz et al. [176]

Winawer et al. [177]

Design

RCT (Nottingham trial): 76 466 people screened with Hemoccult not rehydrated versus no screening (76 384); subjects aged 45–74 years RCT (Göteborg trial): 21 347 people screened with Hemoccult II rehydrated versus no screening; subjects aged 60–64 RCT (Funen trial): 20 672 people screened with Hemoccult II not rehydrated versus no screening; complete colonoscopy: 180; incomplete colonoscopy and DCBE: 12; incomplete colonoscopy: 11; subjects aged 45–76 Prospective; asymptomatic subjects aged 50–75; rehydrated Hemoccult II RCT (Minnesota trial): rehydrated Hemoccult Follow-up: 13 years Group I: once a year (15 532 subjects) Group II: every 2 years (15 550 subjects) Group III: control (15 363 subjects) Prospective; 21 805 asymptomatic adults underwent simultaneously one-time immunochemical FOBT and colonoscopy (FOBT positive in 5.6%) Prospective; relationship between IDA, immunochemical FOBTs and colorectal cancer; asymptomatic subjects aged 40–60 years FOBT positive, IDA positive FOBT positive, IDA negative Prospective; 17 917 asymptomatic people were screened with Hemoccult II Prospective study of screening for CRC with FOBT and sigmoidoscopy. Study group: 5806 subjects, nonrehydrated Hemoccult, 4% positive FOBT at enrolment; control group: 6673 subjects

Number of patients

Age (years)

Number (%) of patients with Carcinoma

Advanced adenoma(s)a

Adenoma(s)

837 (first screening)

Mean age: NS

83 (10)

273 (33) (> 10 mm)

38 (5)

942 (first screening)

Mean age: NS

47 (5)

129 (14) (> 10 mm)

NS

203

Mean age: NS

37 (18)

68 (35) (> 10 mm)

NS

239

Mean age: 63 years

12 (5)

61 (26) (tubular ≥ 1 cm, villous adenoma, highgrade dysplasia)

55 (23)

323 (9% Dukes D) 323 (11% Dukes D) 356 (16% Dukes D) 52 (4)

NS

NS

NS

NS

145 (12)

292 (24)

Mean age: NS

27 (13) 52 (8) 22 (5)

NS NS NS

NS NS 84 (19)

Mean age: NS

50 (11)

Cumulative results NS (38% had at least one colonoscopy) NS (28% had at least one colonoscopy) NS

50–80

1231

Mean age: 48.2 ± 9.3

NS

40–60

208 624 440 of the 551 FOBT positive patients aged 50–75 had a colonoscopy 609 subjects with a positive FOBT; 467 received adequate workup

92 (20)

DCBE, double-contrast barium enema; FOBT, fecal occult blood test(ing); IDA, iron deficiency anemia; NS, not stated. a Advanced adenoma: tubular adenoma > 10 mm, villous adenoma, or adenoma with high-grade dysplasia.

195

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short-lived, rarely require specific therapy, and are not, therefore, an indication for colonoscopy. Colonoscopy is of value in the evaluation of the patient with unexplained chronic diarrhea, defined as diarrhea lasting longer than 4 weeks [178]. Evaluation of the colonic mucosa and biopsies are helpful in order to rule out IBD, neoplastic disease, and microscopic colitis. Colonoscopy allows evaluation of the proximal colon and terminal ileum, which is important in patients with suspected IBD, microscopic colitis, or malignancy. Few studies have addressed the prevalence of cancer and adenoma(s) in patients undergoing colonoscopy for diarrhea. Table 16.8 and Figure 16.8 summarize the diagnostic yield of colonoscopy in 3063 patients with chronic diarrhea. Colorectal cancer and adenomas were found on average in 0.9% (range 0–2%) and 8.7% (range 0–17.9%) of patients. Colonoscopy has a significant diagnostic yield for conditions other than neoplasia, such as IBD (range 4–17%) and microscopic colitis (range 1–14%).

20 Diagnostic yield (%)

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15 10 5 0 Cancer

Adenoma

Inflammatory bowel disease

Microscopic colitis

Figure 16.8 Diagnostic yield of colonoscopy in HIV-negative patients with diarrhea. Data from eight studies (four prospective studies), 3063 patients. (Box and whisker diagram; for explanation see Main clinical indications.)

Table 16.8 Diagnostic yield of colonoscopy in HIV-negative patients with chronic diarrhea. Study

Design

Number of patients

Age (years)

Number (%) of patients with Cancer

Adenoma

Inflammatory bowel disease

Collagenous or lymphocytic colitis

Other

NS

4 inflammatory nonspecified (7), 2 benign stenoses (4), 16 diverticula (29) 4 (5)

Adler et al. [117]

Prospective; 39 private practice offices

56

Mean age: 57

0

4 (7)

2 (4)

de Bosset et al. [15] Fine et al. [179] Gonvers et al. [13] Lasson et al. [64] Patel et al. [180]

Prospective

90

Mean age: NS

1 (1)

6 (7)

12 (13)

9 (10)

Retrospective

809

0

0

28 (4)

80 (10)

5 (1)

Prospective

431

Prospective

173

Retrospective; 77 flexible sigmoidoscopy; 128 colonoscopy Retrospective; associated findings: abdominal pain 43%, rectal bleeding 27%, anemia 15%, weight loss 9% Retrospective

205

Mean age: 46 (14–91) Mean age: 51.9 (15–93) Mean age: 54.7 (16–91) Mean age: 49 ± 1.3

168

Mean age: 51 (22–86)

1131

Mean age: 45 (17–85)

Shah et al. [181]

Yusoff et al. [182] NS, not stated.

196

5 (1)

42 (10)

39 (10)

28 (7)

4 (1)

0

11 (6)

30 (17)

24 (14)

0

3 (2)

8 (4)

5 (2)

15 diverticula (9) 4 miscellaneous (2) 7 pseudomembranous colitis (3) 7 miscellaneous (3)

0

1 (1)

16 (10)

13 (8)

3 ischemic colitis (2), 6 infectious colitis (4), 10 miscellaneous (6)

204 (18)

181 (16)

8 (1)

260 diverticula (23), 90 miscellaneous (8)

23 (2)

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Functional bowel disorders (irritable bowel syndrome, functional constipation, functional abdominal pain syndrome) Functional bowel disorders are GI disorders attributable to the middle or lower GI tract [185]. The Rome III classification of functional bowel disorders is based on the premise that for each disorder there are symptom clusters that remain consistent between clinical population groups [186]. IBS is a functional disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habits. The prevalence of IBS is estimated to be between 14% and 24%

in women and between 5% and 19% in men in the US and in Great Britain [187]. Community-based surveys of patients with IBS indicate that up to 50% receive a colonoscopy during the course of diagnostic evaluation [188]. A colonoscopy is recommended for patients aged > 50 years (due to higher pretest probability of colon cancer), but, in younger patients, performing a colonoscopy is determined by clinical features suggestive of disease (e.g., blood in the stools, IDA, unexplained weight loss, family history of colon cancer) [189]. Patients who meet Rome II or III criteria for IBS rarely have a significant organic disease when evaluated by colonoscopy [190]. In functional constipation, data do not exist to strictly evaluate and define tests that need to be done [191]. Patients with constipation should undergo colonoscopy if they have rectal bleeding, heme-positive stools, IDA, weight loss, recentonset constipation, or a change in stool caliber [192]. Evidence to support the use of colonoscopy in the routine workup of patients without alarm symptoms is lacking [193]. In the study by Pepin [194], no colorectal cancer was found in 234 patients with constipation alone compared with eight colorectal cancers in 329 patients with additional indications such as abdominal pain, lower GI bleeding, and anemia. Table 16.9 and Figure 16.9 summarize the diagnostic yield of colonoscopy in patients with abdominal pain, change in bowel habits, and constipation. The diagnostic yield of colonoscopy in these patients is low, as mentioned earlier, especially in patients with constipation alone [194]. Colorectal cancer was found, on average, in 2% (range 0–13%), adenomas in 14% (range 1.2–31%), and IBD in 3% (range 0–13%). Some caution is necessary in the interpretation of these results, and one should not hastily conclude that they reflect the diagnostic yield of colonoscopy in patients with the functional bowel disorders such as those described in the Rome II or III processes. Indeed, the criteria set forth in the Rome II or III

30 Diagnostic yield (%)

Inflammatory bowel disease refers primarily to Crohn’s disease and ulcerative colitis, although other intestinal disorders may be associated with intestinal inflammation. Microscopic colitis is characterized by chronic watery diarrhea. Two different types of microscopic colitis (lymphocytic, collagenous) have been described which produce a similar clinical picture of intermittent watery diarrhea. Diagnosis is made histologically, colonoscopy usually revealing a macroscopically normal mucosa. In a series of 375 patients with chronic or recurrent diarrhea and a colonic mucosa of normal appearance, FernandezBanares et al. [183] diagnosed 62 patients with microscopic colitis (16%) (26 with collagenous colitis and 38 with lymphocytic colitis). Varying inclusion criteria between the studies and the fact that awareness of the diagnosis has changed over time probably explain the wide range of reported diagnoses of microscopic colitis. The diagnostic utility of routine ileoscopy during all colonic procedures has been evaluated by Zwas et al. [184]. In patients complaining of diarrhea, the incidence of a positive diagnosis by ileoscopy was 18% in non-HIV patients with diarrhea compared with 2.7% in asymptomatic patients undergoing surveillance colonoscopy. Patients with irritable bowel syndrome (IBS) present with lower abdominal pain with diarrhea, constipation, or alternating diarrhea and constipation. Diarrhea is usually characterized as frequent loose stools of small to moderate volume. Functional diarrhea has been classified separately from IBS in a recent consensus statement (Rome III) [185]. The diagnostic criterion for functional diarrhea is the presence of loose (mushy) or watery stools without pain, occurring in at least 75% of stools. This criterion must be fulfilled over a period of the previous 3 months with symptom onset at least 6 months before diagnosis [185]. There are few studies in which functional diarrhea was specifically diagnosed as being distinct from IBS and it is thus impossible to provide a precise frequency. In summary, in patients with chronic diarrhea, colonoscopy with ileoscopy is the preferred investigation: it may yield abnormalities in up to 44% of cases, it has a greater degree of sensitivity than barium enema, and it allows histological evaluation of the ileal and colonic mucosae.

Diagnostic Yield of Colonoscopy by Indication

20

10

0 Cancer

Adenoma

Inflammatory bowel disease

Diverticula

Figure 16.9 Diagnostic yield of colonoscopy in patients with abdominal pain or altered bowel habits. Data from 10 studies (six prospective studies), 1155 patients. (Box and whisker diagram; the studies of Lieberman and Morini are not represented in the graph: for explanation see Main clinical indications.)

197

198 Constipation and other symptoms: pain, lower gastrointestinal bleeding, anemia (58%); colonoscopy 358 (64%); sigmoidoscopy 205 (36%) Patients with abdominal pain, altered bowel habits; all with ≥ 1 negative FOBT

Change in bowel habits Prospective Abdominal pain Change in bowel habits Both Retrospective Constipation alone (42%)

Prospective Abdominal pain

Prospective (CORI) ; nonspecific abdominal symptoms

Change in bowel habits or constipation

Prospective Abdominal pain

75

329

234

113 154 44

38

133

1899

37

124

Mean age: 60.6 ± 15.9 years Mean age: NS

Mean age: NS

Mean age: 56 ± 15

Mean age: 57.8

Mean age: 54.7 (16–91)

42 (12)

76 (11)

18 (7) (adenoma > 1 cm or with high-grade dysplasia) 5 (7) 2 (1)

6 (11) 8 (10) 7 (6)

1 (2) (adenoma > 5 mm)

12 (11) (adenoma > 5 mm)

Adenoma(s)

0

8 (2)

0

23 (31)

58 (25); advanced lesionsa: 11 (5) 79 (24); advanced lesionsa: 16 (5)

11 (10) 18 (12) 3 (7)

NS

5 (13) 3 (3) 4 (3) 2 (5)

NS

1 (1)

14 (11) (< 1 cm); 4 (3) (> 1 cm) 9 (24) (< 1 cm); 0 1 (3) (> 1 cm) 138 (7) polyps or mass ≥ 1 cm (histology unknown)

3 (2)

12 (3)

16 (2)

Mean age: 55.3 (12– 95) Mean age: 61.3 (18 –95)

682 350

1 (1) 7 (4)

Mean age: NS ≥ 80

2 (1)

1 (2) 1 (1) 1 (1)

0

0

73 168

Mean age: NS

Mean age: NS Mean age: NS Mean age: NS

BE, barium enema; CORI, Clinical Outcomes Research Initiative; FOBT, fecal occult blood test(ing); NS, not stated. a Advanced lesion: adenoma ≥ 1 cm, adenoma with villous features or high-grade dysplasia.

Rex [12]

Pepin and Ladabaum [194]

Neugut et al. [67]

Lieberman et al. [196] Morini et al. [17]

Lasson et al. [64]

Change in bowel habits

Constipation Retrospective; altered bowel habits Prospective Abdominal pain, recurrent pain

254

55 79 117

Mean age: NS

Mean age: NS

Cancer

Number (%) of patients with

NS

NS

NS

NS NS NS

NS

NS

NS

NS

NS NS NS

NS

NS

NS

NS

NS

NS NS NS

NS

NS

NS

NS NS

NS

1 (3)

11 (30) 0

9 (3)

NS 10 (3)

2 (2)

11 (2)

NS 13 (2)

24 (13)

0 NS

NS NS 0 NS

16 (13)

0

0 7 (9) 11 (9)

8 (6) Inflammatory: 6 Stenosis: 2 1 (2) Stenosis: 1

Other

NS

9 (16) 17 (22) NS

10 (18)

32 (29)

Diverticula

2 (1)

5 (9) 9 (11) 2 (2)

0

1 (1)

Inflammatory bowel disease

10:48 AM

Duncan et al. [195] Gonvers et al. [13]

de Bosset et al. [15]

Retrospective Abdominal pain Abnormal bowel habits Prospective; gastrointestinal symptoms; previous BE 55 (47%) Prospective Abdominal pain

55

111

Age (years)

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Brenna et al. [14]

Berkowitz and Kaplan [57]

Prospective Abdominal pain

Adler et al. [117]

Number of patients

SECTION 5

Constipation and/without changes in bowel habits

Design

Study

Table 16.9 Diagnostic yield of colonoscopy in patients with functional bowel disorders (irritable bowel syndrome, bloating, constipation, abdominal pain).

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30 Diagnostic yield (%)

processes are rarely, if ever, met in the patients covered by the studies mentioned in Table 16.9. In conclusion, although these nonspecific symptoms, such as abdominal pain, change in bowel habits, and constipation, may not by themselves be appropriate indications for colonoscopy, given their low diagnostic yield when they are not associated with alarm symptoms, age-appropriate colorectal case findings may be pursued in patients with these symptoms, as yield is comparable to that in a screening population.

Diagnostic Yield of Colonoscopy by Indication

20

10

0

Diagnostic reliability of colonoscopy Colonoscopy is widely used for the diagnosis and treatment of colonic disorders. It allows the visualization of the entirety of the mucosa of the large intestine and distal terminal ileum. In patients with chronic diarrhea, biopsy specimens from the colon and of the terminal ileum can help to facilitate diagnosis of the underlying condition. Insufficient procedural competence and experience on the part of the endoscopist may decrease the value of colonoscopy [197]. Even in expert hands, there is a significant miss rate of polyps. Rex et al. [198] performed two colonoscopies on the same day (backto-back colonoscopy) in 183 patients randomly assigned to the same or another endoscopist. The overall miss rate of adenomas was 24%; it was 6% for adenomas > 1 cm. In a systematic review of polyp miss rates, van Rijn et al. [199] found a pooled miss rate for polyps of any size of 22% (95% CI 19–26%). The miss rate for adenomas > 10 mm was 2.1% (95% CI 0.3–7.3%). Miss rates of colonoscopy for colorectal cancer have also been identified in two large studies as 5% [200] and 4% [201]. The quality and diagnostic reliability of colonoscopy are further dependent on several other factors. Much emphasis has been placed on the duration of colonoscopy and, in particular, the time needed to reach the cecum. Overall duration may be significant with respect to procedural efficiency in a context of cost constraints, waiting lists at endoscopy units, and the need for endoscopists and endoscopes. However, it is not acceptable that an overly rapid endoscopic technique should render the procedure less tolerable or reduce its diagnostic reliability. Withdrawal time seems to be more critical for diagnostic yield, particularly colonic distension, adequate suctioning and cleaning, and adequate time spent examining the colon. The quality of withdrawal is critical for the detection rate of adenomas [202]. In fact, it has been shown very recently that individual endoscopists’ procedure times correlate with the rate at which they identify multiple or clinically significant polyps [203].

Summary For the clinician, the yield of relevant diagnoses is one of the most important outcomes of a diagnostic procedure such as

Colorectal Screening Functional Iron cancer bowel deficiency resection disorders anemia Diarrhea Nonemergency Polypectomy FOBT lower GI bleeding positive

Acute lower GI bleeding

Figure 16.10 Diagnostic yield of colon cancer by colonoscopy in the different indications. (Box and whisker diagram; for the follow-up after cancer resection only the metachronous tumors have been considered; for explanation see Main clinical indications.)

colonoscopy. While appropriateness of indications refers to the quality of the indication, the diagnostic yield refers to endoscopic lesions that are potentially relevant to the patient’s care, in conjunction with clinical symptoms and signs. Unfortunately, the relationship between endoscopic findings and clinical presentation is imperfect, particularly in light of the fact that endoscopic lesions (e.g., polyps) may be asymptomatic. Patient age and gender have a major impact on the diagnostic yield of colonoscopy, increasing age being associated with a higher rate of lesions. A main focus of the use of colonoscopy is the diagnosis and removal of adenomas and the diagnosis of colorectal cancer. In cancer detection, hematochezia, IDA, and positive FOBT have a high diagnostic yield (Figure 16.10). In contrast, nonbleeding colonic symptoms (diarrhea, abdominal pain, altered bowel habits) and surveillance after polypectomy have a lower yield of cancer. Incidence rates of colorectal cancer increase consistently with age. Patient age is thus an important predictor of colorectal cancer in patients referred for colonoscopy. The yield in the detection of adenomas is less dependent on the indications than the detection of cancer, due to the high prevalence of polyps found in screening colonoscopies or in patients with nonspecific symptoms. The adenoma detection rate is highest in the follow-up of polyps, the follow-up of cancer, and in patients with a positive FOBT or nonemergency lower GI bleeding. IBD is a relatively common finding in hematochezia and diarrhea. Although diagnostic yield is important, it must be kept in mind that colonoscopy may also be beneficial to patients if it excludes a clinically relevant lesion by conferring reassurance.

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162 Rodriguez-Moranta F, Salo J, Arcusa A, et al. Postoperative surveillance in patients with colorectal cancer who have undergone curative resection: a prospective, multicenter, randomized, controlled trial. J Clin Oncol 2006; 24: 386–93. 163 Yusoff IF, Hoffman NE, Ee HC. Colonoscopic surveillance after surgery for colorectal cancer. ANZ J Surg 2003; 73: 3– 7. 164 Rex DK, Kahi CJ, Levin B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2006; 130: 1865–71. 165 Faivre J, Dancourt V, Lejeune C, et al. Reduction in colorectal cancer mortality by fecal occult blood screening in a French controlled study. Gastroenterology 2004; 126: 1674–80. 166 Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472–7. 167 Kewenter J, Brevinge H, Engaras B, Haglind E, Ahren C. Results of screening, rescreening, and follow-up in a prospective randomized study for detection of colorectal cancer by fecal occult blood testing. Results for 68,308 subjects. Scand J Gastroenterol 1994; 29: 468–73. 168 Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O. Randomised study of screening for colorectal cancer with faecaloccult-blood test. Lancet 1996; 348: 1467–71. 169 Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993; 328: 1365– 71. 170 Allison JE, Tekawa IS, Ransom LJ, Adrain AL. A comparison of fecal occult-blood tests for colorectal-cancer screening. N Engl J Med 1996; 334: 155–9. 171 Bini EJ, Rajapaksa RC, Weinshel EH. The findings and impact of nonrehydrated guaiac examination of the rectum (FINGER) study: a comparison of 2 methods of screening for colorectal cancer in asymptomatic average-risk patients. Arch Intern Med 1999; 159: 2022– 6. 172 Frommer DJ, Kapparis A, Brown MK. Improved screening for colorectal cancer by immunological detection of occult blood. Br Med J (Clin Res Ed) 1988; 296: 1092– 4. 173 Frühmorgen P, Demling L. Early detection of colorectal carcinoma with a modified guaiactest. A screening examination in 6000 humans. Acta Gastroenterol Belg 1978; 41: 682–7. 174 Grazzini G, Castiglione G, Isu A, et al. Colorectal cancer screening by fecal occult blood testing: results of a population-based experience. Tumori 2000; 86: 384– 8. 175 Lieberman DA, Weiss DG. One-time screening for colorectal cancer with combined fecal occult-blood testing and examination of the distal colon. N Engl J Med 2001; 345: 555–60. 176 Steinmetz J, Spyckerelle Y, Henny J, Giordanella JP, Emmanuelli J. [Screening for colorectal cancer. Study of a population attending a public health clinic]. Presse Med 2001; 30: 1389– 93. 177 Winawer SJ, Flehinger BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1993; 85: 1311–18. 178 Fine KD, Schiller LR. AGA technical review on the evaluation and management of chronic diarrhea. Gastroenterology 1999; 116: 1464– 86. 179 Fine KD, Seidel RH, Do K. The prevalence, anatomic distribution,

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and diagnosis of colonic causes of chronic diarrhea. Gastrointest Endosc 2000; 51: 318– 26. Patel Y, Pettigrew NM, Grahame GR, Bernstein CN. The diagnostic yield of lower endoscopy plus biopsy in nonbloody diarrhea. Gastrointest Endosc 1997; 46: 338– 43. Shah RJ, Fenoglio-Preiser C, Bleau BL, Giannella RA. Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea. Am J Gastroenterol 2001; 96: 1091–5. Yusoff IF, Ormonde DG, Hoffman NE. Routine colonic mucosal biopsy and ileoscopy increases diagnostic yield in patients undergoing colonoscopy for diarrhea. J Gastroenterol Hepatol 2002; 17: 276– 80. Fernandez-Banares F, Salas A, Forne M, Esteve M, Espinos J, Viver JM. Incidence of collagenous and lymphocytic colitis: a 5-year population-based study. Am J Gastroenterol 1999; 94: 418–23. Zwas FR, Bonheim NA, Berken CA, Gray S. Diagnostic yield of routine ileoscopy. Am J Gastroenterol 1995; 90: 1441–3. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006; 130: 1480– 91. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006; 130: 1377– 90. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology 1997; 112: 2120–37. Yawn BP, Locke GR, 3rd, Lydick E, Wollan PC, Bertram SL, Kurland MJ. Diagnosis and care of irritable bowel syndrome in a community-based population. Am J Manag Care 2001; 7: 585–92. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123: 2108–31. Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review. Am J Gastroenterol 2002; 97: 2812–19. Locke GR 3rd, Pemberton JH, Phillips SF. American Gastroenterological Association Medical Position Statement: guidelines on constipation. Gastroenterology 2000; 119: 1761–6.

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192 Qureshi W, Adler DG, Davila RE, et al. ASGE guideline: guideline on the use of endoscopy in the management of constipation. Gastrointest Endosc 2005; 62: 199–201. 193 Rao SS, Ozturk R, Laine L. Clinical utility of diagnostic tests for constipation in adults: a systematic review. Am J Gastroenterol 2005; 100: 1605–15. 194 Pepin C, Ladabaum U. The yield of lower endoscopy in patients with constipation: survey of a university hospital, a public county hospital, and a Veterans Administration medical center. Gastrointest Endosc 2002; 56: 325–32. 195 Duncan JE, Sweeney WB, Trudel JL, Madoff RD, Mellgren AF. Colonoscopy in the elderly: low risk, low yield in asymptomatic patients. Dis Colon Rectum 2006; 49: 646–51. 196 Lieberman DA, de Garmo PL, Fleischer DE, Eisen GM, Chan BK, Helfand M. Colonic neoplasia in patients with nonspecific GI symptoms. Gastrointest Endosc 2000; 51: 647–51. 197 Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594–642. 198 Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112: 24–8. 199 van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol 2006; 101: 343–50. 200 Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997; 112: 17–23. 201 Bressler B, Paszat LF, Vinden C, Li C, He J, Rabeneck L. Colonoscopic miss rates for right-sided colon cancer: a populationbased analysis. Gastroenterology 2004; 127: 452–6. 202 Rex DK. Colonoscopic withdrawal technique is associated with adenoma miss rates. Gastrointest Endosc 2000; 51: 33–6. 203 Barclay RL, Vicari JJ, Doughty AS, Johanson JF, Greenlaw RL. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 2006; 355: 2533–41.

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Screening Colonoscopy: Rationale and Performance David Lieberman Oregon Health and Science University, Portland, OR, USA

Introduction Colorectal cancer (CRC) is the second leading cause of cancer death in North America and Western Europe [1]. As populations live longer as a result of advances in medicine and public health, deaths due to CRC are likely to increase unless interventions that reduce incidence or mortality are developed. The biology of CRC offers an opportunity for both early detection and prevention. Most cancers evolve from premalignant adenomas over a period of many years; the spread of malignancy from the colon to sites outside the colon likewise occurs over years. It has been shown that cancers are detected at earlier, and at a more curable stage, in screened asymptomatic populations than in unscreened control subjects. Furthermore, studies have demonstrated that detection and removal of premalignant adenomas can prevent incident cancers [2,3]. Thus, if screening tests could identify patients with high-risk adenomas, many cancers could be prevented, mortality would be reduced, and the burden of caring for patients with cancer would be diminished. Some decision models [4–9] have suggested that effective prevention with screening would be more cost-effective than a “no screening” option, particularly as the cost of cancer care increases. If the primary goal of screening is cancer prevention, we should ask: how effectively do screening tests identify patients with advanced adenomas? There is consensus that colonoscopy should be the preferred screening test for individuals known to be at higher than average risk [10]. Higher risk is associated with familial hereditary syndromes (familial polyposis, hereditary nonpolyposis CRC syndrome), chronic colitis due to ulcerative colitis or Crohn’s disease, or a family history of CRC in a firstdegree relative. Patients with a personal history of adenoma or cancer should receive colonoscopic surveillance, and are not considered part of a screening cohort.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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There is consensus across all expert groups that CRC screening should be recommended to average-risk populations. The general criteria for screening tests are presented in Table 17.1, and CRC screening satisfies key requirements. The performance characteristics of several screening modalities in average-risk populations have been scrutinized by the US Preventive Services Task Force (USPSTF) and by expert multidisciplinary panels [10–14]. All of the expert panels strongly recommend that population screening should begin for average-risk individuals at age 50 years. They have noted that colonoscopy is more effective than other screening tests for polyp detection. Recent studies [15–26] have shown that screening large populations with colonoscopy may be feasible and might be preferable in average-risk individuals. Some experts have argued that colonoscopy itself should be the preferred screening test [12], and others have argued that it should be one of several screening options [10,11,13,14]. This chapter will review the rationale for considering colonoscopy as a primary screening test in average-risk populations and discuss implementation issues including compliance, resources, and cost.

Programmatic colorectal cancer screening Screening with colonoscopy should be considered in the context of other screening tests. For each test we should ask: 1 What is the likelihood that the test will detect the target lesion (advanced adenoma or early cancer)? 2 Are there programmatic issues, such as need for repeat testing, which impact effectiveness? 3 What are the potential harms? Tests may be distinguished by their primary goal: (a) tests which primarily detect early cancer; and (b) tests which can detect both adenomas and cancer. The latter tests are more likely to lead to cancer prevention.

Noninvasive tests which primarily detect early cancer Tests which detect blood or DNA in stool may result in early cancer detection. These tests are attractive because they can

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Table 17.1 Criteria for population-based screening test. General criteria

Colorectal cancer

Relatively common disease

150 000 new cases/year 5–6% risk in adults 55 000 deaths/year Second biggest cause of cancer death Increasing public and provider recognition Yes Yes for FOBT Imaging requires preparation; low risk Colonoscopy invasive, higher risk Costs are similar for all screening programs Yes for all tests Colonoscopy more sensitive than other tests Nearly 100% for endoscopic tests Uncertain specificity for imaging studies Poor specificity for fecal studies Uncertain whether there are enough fully trained endoscopists Yes Yes, if early stage

Serious consequences Recognized as problem Asymptomatic phase during which screening could detect disease Screening test is noninvasive, low risk

Screening test is inexpensive Tests are sensitive enough to detect disease at curable phase Tests are specific (high false-positive rates increase cost if patients have expensive evaluations) Available health services for diagnostic follow-up of positive test Therapy during asymptomatic phase will favorably alter natural history Effective therapy if cancer found FOBT, fecal occult blood testing.

be performed at home, and do not require an office or hospital visit, bowel preparation, or invasive procedure. One-time sensitivity for cancer is variable, and program effectiveness depends on repeat testing on a regular basis. In addition, test positivity identifies a high-risk individual, and colonoscopy should be recommended for all positive tests. In clinical practice, programs may be ineffective if patients do not undergo repeat testing after negative tests, or colonoscopy after a positive test. Finally, these tests do not identify most patients with advanced neoplasia, and will be less effective for cancer prevention than programs which identify adenomas.

Guiaic-based fecal occult blood testing Three randomized, controlled trials have compared population screening with fecal occult blood test(ing) (FOBT) with no screening [27–29]. Although there were differences in study methods, the findings are consistent across all of the studies. Cancers are detected at earlier stages in screened subjects than in unscreened subjects, and this translates into significant mortality reduction over time of 15–33% [27–29]. One-time sensitivity for cancer detection for unrehydrated Hemoccult II ranges from 12.9% to 37.4%. Sensitivity increases with rehydration of guiaic-based fecal occult blood test(ing) (gFOBT), although this is not typically done in the US. In the Veterans Affairs (VA) Cooperative Study [30], average-risk subjects (n = 2885) had both a one-time rehydrated FOBT and screening colonoscopy. The FOBT was positive in 50% of patients with cancer, consistent with other studies [31,32]. However, among patients with advanced neoplasia (defined

as adenoma with high-grade dysplasia or villous histology, or tubular adenoma ≥ 1 cm) without invasive cancer, the FOBT was positive in only 21.6%. Recent studies with a more sensitive gFOBT (Hemoccult Sensa) find one-time sensitivity for cancer to be 64.3% for cancer and 41.3% for advanced adenomas [33]. These studies support the hypothesis that population screening of average-risk subjects could reduce CRC mortality. The poor sensitivity of one-time testing of a gFOBT, and the need for frequent repeat testing, and appropriate followup of positive tests with colonoscopy represent important program limitations. Physician surveys have suggested that many patients with positive tests go on to have a colonoscopy [34]. Adherence to annual repeat testing after negative tests is unknown. Therefore, programmatic adherence has an important impact on program effectiveness.

Fecal immunochemical test A fecal immunochemical test (FIT) detects human globin and has technological advantages when compared with a gFOBT, which relies on detection of peroxidase in human blood. Although there have been few head-to-head studies, there is considerable evidence that a FIT is more accurate than a gFOBT. A large study used screening colonoscopy as a gold standard, and found that the FIT detected 65.8% of patients with cancer [24]. Other studies have used a quantitative FIT to set a threshold most predictive of advanced neoplasia and cancer, achieving sensitivity for cancer as high as 94% [33,35]. Programmatic issues include the need for repeat

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testing after negative tests and completion of colonoscopy for positive tests.

Stool DNA Advances in molecular genomics have led to the development of new methods of CRC screening, such as tests that can detect the presence in stool of known DNA alterations associated with colon carcinogenesis. DNA from adenoma and cancer cells is constantly shed into stool, and remains stable. A multitarget DNA stool assay which can identify specific mutations has been developed. The original assays tested for mutations in APC (adenomatous polyposis coli), p53, K-ras oncogene, a marker of microsatellite instability (BAT-26), and a marker of DNA integrity analysis (DIA). Patients provide a stool sample at home, which is shipped to a specialized laboratory for analysis. The largest study comparing stool DNA (sDNA) with colonoscopy found that the DNA test detected 51% of patients with cancer, and 18% of patients with nonmalignant advanced neoplasia [21]. Newer versions have better DNA stabilization, and have simplified the test to detect vimentin hypermethylation and DNA integrity assay [36]. In small studies, sensitivity for cancer is improved (87%). It is clear that this is a promising technology in evolution. The appropriate interval for repeat testing after a negative test is unknown. Future studies are needed to determine if this test will be effective for cancer prevention.

Tests which detect both adenomas and cancer Flexible sigmoidoscopy There is evidence from two case–control studies [37,38] that exposure to sigmoidoscopy is associated with a 60–80% reduction in mortality due to colon cancer in the portion of the colon examined. Both studies highlight an important limitation of flexible sigmoidoscopy: the examination does not reduce the likelihood of fatal cancers of the right colon, because such cancers cannot be detected with sigmoidoscopy. A case–control study in the VA system also demonstrated a benefit of sigmoidoscopy [39]. One study found that flexible sigmoidoscopy may be less sensitive in women, who may be more likely to have proximal advanced neoplasia [23]. Utilization of flexible sigmoidoscopy in the US in Medicare cohorts has decreased over the past few years, which may reflect physician and patient preferences. Several large ongoing studies of the feasibility of flexible sigmoidoscopy screening in Europe and the US have not yet published final results [40– 43]. Two screening colonoscopy studies [15,16] reported the findings of complete colonoscopy, and estimated the potential findings of screening sigmoidoscopy in average-risk subjects. Advanced neoplasia was more likely to be found in the distal colon (55% in the Indiana study; 53% in the VA study). Both studies found that more than 50% of patients with advanced proximal neoplasia (beyond the reach of the sigmoidoscope)

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would not have been identified with sigmoidoscopy, even assuming that any index adenoma would lead to colonoscopy. In addition, both studies found that as average-risk subjects age they are more likely to harbor advanced proximal neoplasia and are less likely to be identified by sigmoidoscopy alone. Sigmoidoscopy is able to detect advanced adenomas and early cancers. The key limitation of sigmoidoscopy is that a large portion of the colon is not examined; some patients with advanced proximal neoplasia would go undetected. There is also concern that sigmoidoscopy may be less effective with increasing age.

Combined flexible sigmoidoscopy and fecal occult blood testing The American Cancer Society has long recommended screening with both FOBT and flexible sigmoidoscopy beginning at age 50 [13], among other options. Intuitively, this combined approach should have a greater impact on CRC mortality than either test alone. In one study [44], patients receiving both flexible sigmoidoscopy and gFOBT had better long-term survival after detection of cancer than patients screened with flexible sigmoidoscopy alone. In the VA Cooperative Study [15,30], combined screening with one-time FOBT and sigmoidoscopy would have identified 76% of patients with advanced neoplasia, only slightly better than sigmoidoscopy alone (70%). With increasing age, there was a trend for decreasing efficacy of the combined screening approach. Decision models [45] have suggested that the combined approach could be more effective and less costly than other screening approaches if tests are performed programmatically on a regular basis, as is recommended (annual FOBT, and sigmoidoscopy every 5 years). However, the models require assumptions about compliance with initial testing and follow-up colonoscopy after positive tests, which may not be realistic in clinical practice.

Radiographic colon imaging with barium No large studies have evaluated colon imaging with barium for screening in an average-risk population. The USPSTF rates the barium enema as “unknown” with regard to effectiveness in reducing incidence and mortality from CRC, and only “fair” with regard to ability to detect cancer and advanced neoplasia [11]. In the National Polyp Study, patients with adenomas underwent double-contrast barium enema followed by colonoscopy. The sensitivity of barium studies for the detection of polyps larger than 1 cm was 48% [46].

Radiologic imaging with computed tomographic colonography Over the past few years, there has been a growing body of research into the use of computed tomographic colonography (CTC) for screening, which is attractive because it is minimally invasive (Chapter 57). The method uses multidetector

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computed tomography (CT) to render two- and threedimensional images of the colon. Currently, a thorough bowel preparation is required for adequate imaging. Large studies comparing optical colonoscopy with CTC in the past few years have highlighted potential advantages and limitations of this test. Studies by Cotton et al. [19] and Rocky et al. [20], with more than 600 subjects, observed per patient sensitivity of 55% and 59%, respectively, for the detection of polyps ≥ 10 mm. Pickhardt et al. [18] studied more than 1200 patients using stool tagging and three-dimensional imaging, and reported 94% sensitivity for polyps ≥ 10 mm. A new multicenter study, using state-of-the art technology (American College of Radiology Imaging Network Study 6664), has observed 90% sensitivity for polyps > 10 mm in a preliminary report. These studies have demonstrated that CTC can identify large polyps. However, they raise several important issues. First, the management of CTC findings is uncertain. There is consensus that all patients with polyps > 10 mm should be referred for colonoscopy. Patients whose largest polyp is 6–9 mm may have a 2–7% risk of high-grade dysplasia, and up to a 1% risk of invasive cancer. Most gastrointestinal experts recommend that these patients should be offered colonoscopy [47,48]. The risk of advanced neoplasia in diminutive polyps < 6 mm is low. Current CTC technology cannot accurately identify polyps of this size, so they are not reported. A second issue is the use of radiation in average-risk asymptomatic individuals. Current methods employ very low-dose radiation, which most experts believe is not associated with an increased risk of other cancers [49]. A third issue is the management of extracolonic findings that may be incidentally discovered. The overall rate of such findings is 15–69%, with clinically important findings in 4.5–11.0%. Evaluation of such extracolonic findings is associated with cost and risk, so it will be important to carefully determine if the finding of other abnormalities during screening CTC merits further evaluation. In summary, CTC is an evolving new technology which can detect both polyps and early cancer. If CTC findings will require colonoscopy, patients would need to have a second bowel preparation unless there is coordination with colonoscopy centers to enable same-day colonoscopy. The costeffectiveness of CTC will depend on the rate of referral for colonoscopy and the extent of evaluation of extracolonic findings.

Possible future tests There are other screening modalities which show promise. When specific gene mutations were identified in patients with familial polyposis (APC gene on chromosome 5) and hereditary nonpolyposis CRC syndrome (mismatch repair gene mutations), there was great hope that molecular genetics would provide a simple blood test to risk stratify otherwise average-risk subjects. Such screening was touted to the

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public in The New York Times in the 1990s. The reality is that genetic testing has not developed into a clinically useful procedure, but there has been recent progress. The “holy grail” of CRC testing would be risk stratification with a serologic test. Using genomics or proteomics, it may be possible to identify a panel of circulating genes or proteins which create a specific “fingerprint” in patients with CRC or, perhaps, premalignant polyps.

Colorectal cancer screening with colonoscopy Colonoscopy is one of the most commonly performed medical procedures in the US, with estimates of up to 14 million procedures performed in 2003 [50]. Prior to 2000, most colonoscopy procedures were performed for evaluation of symptoms or for surveillance. Since 2000, there have been widespread reports of screening colonoscopy throughout the world (Table 17.2) and an increase in utilization in the US [51–54]. Many payers in the US, including Centers for Medicare and Medicaid Services (CMS), include colonoscopy screening for average-risk individuals as a benefit.

Rationale for screening colonoscopy Colonoscopy is the most accurate test for evaluation for neoplasia in the colon, but there are no prospective randomized controlled trials of screening colonoscopy which demonstrate a reduction in incidence or mortality of CRC. However, since colonoscopy is used to evaluate positive screening tests with FOBT and sigmoidoscopy, there is evidence to indicate that colonoscopy and polypectomy result in mortality and incidence reductions in randomized controlled trials of the other screening tests. Lang and Ransohoff [55] performed a post hoc analysis of the Minnesota FOBT study, in which 38% of the subjects in the screened group received colonoscopy over 13 years of study. They attributed much of the mortality reduction to high rates of colonoscopy, with only a portion of benefit derived from performance of the FOBT. In the follow-up of the Minnesota study, the subsequent incidence of CRC was reduced by 20% in patients who had been screenedaa benefit attributed by the authors to colonoscopy with polypectomy [3]. Despite the lack of controlled trials showing the effect of colonoscopy on incidence and/or mortality of CRC, there are many reports of its beneficial effects. Some of these can be extracted from the literature on sigmoidoscopy. In a randomized controlled trial of flexible sigmoidoscopy versus no screening, and with follow-up colonoscopy and polypectomy performed for any polyp detected at sigmoidoscopy, the screening group experienced an 80% reduction in the incidence of CRC [56]. The evidence for the effectiveness of screening colonoscopy is extrapolated from the case–control studies of sigmoidoscopy. These studies found a significant

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Table 17.2 Screening colonoscopy experience: 2000–2006 (studies with > 1000 subjects). Study

US Veterans Affairs Cooperative Study Indiana Study Computed tomographic colonography studies Fecal DNA study Women Seattle, elderly population

Number of subjects

Reference

3121 1994 2447 4404 1463 1244

15 16 18–20 21 23 26

Europe Spain Poland

2210 50 148

17 25

Asia Taiwan Japan

1708 21 805

22 24

reduction in fatal colon cancers in that portion of the colon which was examined. There was no reduction in mortality from proximal colon cancers [37]. It is logical to assume that, if more colon is examined, the benefit could be extended to as much of the colon as can be examined. A case–control study in the VA population found that patients diagnosed with CRC were less likely than patients without CRC to have had prior colonoscopy [39]. The risk reduction of 53% for colon cancer and 39% for rectal cancer was significant. The third line of evidence comes from the National Polyp Study [2], in which patients underwent complete colonoscopy with polypectomy and were followed over the next 5 years. When compared with reference populations, the incident rates of CRC were reduced by 76– 90% in the study subjects. In an Italian adenoma cohort study of patients in whom at least one adenoma ≥ 5 mm was removed, there was an 80% reduction in the incidence of CRC compared with that which would be expected in a reference population [57]. Although the comparison groups differed from the study subjects, the marked reduction in expected incidence is compelling. There is evidence that rates of colon cancer over the next 10 years will be lower in patients with a negative colonoscopy than the expected rates in the general population [58]. Finally, many decision models conclude that colonoscopy screening would substantially reduce CRC incidence and mortality [45]. This body of literature provides compelling indirect evidence that screening colonoscopy could effectively reduce colon cancer mortality and incidence.

colonoscopy if the test is positive. Fecal tests require frequent repeat testing to be effective, which represents a programmatic challenge to attain adherence. Based on the natural history of colon neoplasia, the interval between normal colonoscopic examinations can be 10 years for average-risk individuals. When compared with more complicated programs which require a pretest, followed by repeat testing (if negative) or colonoscopy (if positive), colonoscopy may offer a simpler program for informed decision-making.

Issues and uncertainties about colonoscopy screening General criteria for screening tests applied to the population are summarized in Table 17.1. In general, colonoscopy does not satisfy these criteria. It is an invasive and expensive test. The benefit versus risk is unknown in clinical practice. There has never been a clinical trial comparing colonoscopy with other forms of screening. However, since only 5–6% of the adult population will develop CRC, most patients will not benefit from colonoscopy. Nevertheless, other current screening tests lack sensitivity and/or specificity, and are not likely to result in high rates of cancer prevention. Colonoscopy has emerged as a leading screening test by default, due to lack of risk stratification of average-risk individuals and poor sensitivity of other screening options. This section will discuss some of the uncertainties surrounding the use of colonoscopy for screening.

Safety

Advantages of colonoscopy screening Colonoscopy screening has the advantage of offering patients a one-time test that is diagnostically accurate and therapeutic, in contrast to a screening program, which uses a risk stratification test (fecal test, sigmoidoscopy, imaging) followed by

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The quality and complication rates of colonoscopy in clinical practice settings are largely unknown. The most comprehensive review of events comes from the VA Cooperative Study #380, which carefully documented all 30-day events [59]. Serious complications definitely attributed to colonoscopy

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occurred in 0.3% of patients receiving screening colonoscopy. The most common important complications were serious bleeding and myocardial infarction or arrhythmia. Death within 30 days occurred in three patients, and in one case was attributed to colonoscopy. Most complications occurred in association with polypectomy. The serious complication rate of a diagnostic colonoscopy was 0.1%. Less serious complications were commonaincluding vasovagal events (5.4%), transient oxygen desaturation (4.4%), abdominal pain requiring termination of the procedure (0.9%), and minor gastrointestinal bleeding which did not require hospitalization or intervention (0.2%). Since these procedures were performed by experts, it is not known if complications would be more common in community practice. There have been several other reports in various clinical settings which provide data about the range of adverse events associated with colonoscopy [60–67]. Korman et al. [60] reported perforation rates of 0.03% during 116 000 colonoscopies in a network of 45 ambulatory surgical centers. From the UK came an article revealing perforation rates several-fold higher (0.13%) from 68 endoscopy units [61]. A community gastrointestinal practice in the US [62] described the complications that were seen in more than 12 000 procedures, including bleeding requiring hospitalization (0.2%) and perforation (0.016%). Two other reports (n = 750) have emphasized the importance of common minor complications, including procedure-related discomfort [63] and unexpected emergency department visits [64]. A study of cardiopulmonary complications in diverse clinical practice settings in the US found that such untoward events were common (1.1%), and often associated with an unplanned intervention [65]. Levin et al. [67] reported on complications of colonoscopy in more than 16 000 members of the Kaiser system in northern California. Serious complications (0.5%) included perforation (0.09%), bleeding (0.48%), and 10 deaths within 30 days, one of which was attributable to colonoscopy. Perforations and bleeding were most common in patients undergoing polypectomy or biopsy. In conclusion, colonoscopy may commonly be associated with adverse events, some of which are serious. Serious events occur more often with polypectomy, but may happen during diagnostic colonoscopy. Two ongoing studies are examining 30-day events in large, diverse cohortsaMedicare beneficiaries and the Clinical Outcomes Research Initiative consortium. These studies are specifically designed to provide “real-life” clinical practice data (C.W. Ko, personal communication; C.N. Klabunde, personal communication).

Cost The cost-effectiveness of colonoscopy has been scrutinized carefully because of the high upfront cost associated with a colonoscopy screening program. The cost of colonoscopy screening relative to other screening programs has been examined in several decision models. In 2005, The Institute

Screening Colonoscopy: Rationale and Performance

of Medicine convened a workshop which included five research teams which had published decision models [45]. Each group was provided with similar assumptions and, working within their own models, developed cost-effectiveness analyses. Despite variability among the models, the conclusion of the exercise was that several colon screening programs (FOBT, flexible sigmoidoscopy, colonoscopy, imaging) could reduce CRC mortality and be cost-effective. Each model found that screening would cost more than a “no-screening” option. It should be noted that the costs of cancer treatment in these models were conservative, and may not reflect current costs of surgery and chemotherapy. As the cost of cancer care rises, screening with tests that are more likely to prevent cancer (i.e., colonoscopy) may become more cost-effective.

Resources The resources and expertise needed to offer colonoscopy to all individuals aged 50 and older are substantial [68–70], and, in some locations, unavailable. However, any assessment of capacity must account for current overutilization of colonoscopy. Colonoscopy is often used for the evaluation of young individuals with irritable bowel symptoms [52], which is associated with a very low yield of significant findings. More importantly, there is evidence for overutilization in surveillance [71,72]. Physician surveys indicate that many providers recommend colonoscopy at shorter than recommended intervals for patients with hyperplastic polyps and small tubular adenomas [71]. This exposes patients to unnecessary cost and risk, and utilizes valuable colonoscopy resources which could be used for screening. Therefore, capacity depends partly on appropriate utilization. Capacity is also dependent on the availability of fully trained endoscopists who can perform high-quality procedures.

Quality of colonoscopy Unfortunately, in the lay media, a mythology has grown around the use of colonoscopy. Many medical consumers believe that if they have colonoscopy their personal risk of developing CRC will be eliminated. This is not a realistic expectation. All screening programs depend on performances of high quality. The quality of colonoscopy in clinical practice settings is largely unknown. There is new evidence that colonoscopy, even in the hands of experts, is not perfect. Recent chemoprevention studies evaluating aspirin, COX-2 inhibitors, calcium, or diet have demonstrated that 0.3–0.9% of adenomabearing patients will develop invasive CRC within 3 years of a baseline colonoscopy, during which all polyps are removed [73–77]. There are several possible reasons for these interval cancers, including the development of new fast-growing lesions, missed lesions, or incomplete removal of adenomas [78]. The last two issues are related to quality of colonoscopy. Missed lesions have been noted in CTC studies comparing optical colonoscopy with CT, which found that colonoscopy

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Table 17.3 Proposed colonoscopy quality indicators [82]. Documentation of procedure indication If indication is surveillance of polyps, documentation of prior examination Bowel preparation qualityb% adequate to detect polyps > 5 mm Cecal intubation rate Rate of photo-documentation of cecal landmarks Mean colonoscopic withdrawal time in patients without polypectomy or biopsy Documentation of polyp descriptors (location, size, morphology, method of removal, retrieval) Adenoma detection rate in first-time screening examination based on patient’s sex and age Adverse or unplanned events occurring within 24 h of colonoscopy Rates of Hospitalization Bleed requiring transfusion Bleed requiring unplanned endoscopic intervention Perforation Surgery Rate of documentation of recommendations for follow-up

carefully performed by experts missed 2–12% of adenomas > 1 cm [18–20]. Reasons for missed lesions could include anatomic location, poor preparation, and operator expertise. Recent studies have highlighted an important relationship between endoscope withdrawal time and the detection rate of adenomas [79], suggesting that longer withdrawal times result in higher rates of polyp detection (see Chapter 41). Incomplete removal of lesions may also reflect a quality issue. If one goal of colonoscopy screening is cancer prevention through adenoma detection and removal, quality improvement should focus on optimizing detection of adenomas, particularly advanced adenomas. Report cards on colonoscopy performance do not currently exist, despite the fact that specific quality indicators have been identified by expert panels. The Multisociety Task Force on Colorectal Cancer published a list of quality indicators in 2002 [80] followed by a report of levels of evidence supporting specific indicators [81]. A task group from the National Colorectal Cancer Roundtable published a tool for routine endoscopic reporting (Colonoscopy Reporting and Data System), which incorporates the indicators into every report, and enables quality assurance programs [82]. Single-center studies suggest that important indicators can be monitored in the flow of clinical practice through endoscopic reporting [62,79]. Proposed quality indicators are summarized in Table 17.3. Diagnostic tools such as colonoscopy have inherent limitations, which may be both technical and operator dependent. New technology may improve our ability to see some lesions. Many experts in the field believe that operator-dependent issues may be important contributors to interval cancers and that quality can be improved.

Screening interval for colonoscopy Expert groups have recommended that colonoscopy screening be performed at 10-year intervals, based largely on the

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expected natural history of progression of colonic neoplasia [10]. The recommended 10-year interval is based on the assumption of a high-quality examination to the cecum at baseline colonoscopy. There has not been a study evaluating the effectiveness of a 10-year interval between normal examinations. In prior case series, 1427 polyp-free subjects underwent colonoscopy within 5.5 years of a baseline examination [83–88]. The rates of any adenoma were 16–41%, and the rates of advanced adenoma were 0.6–3.4%. A case– control study from Canada found that patients in whom colonoscopy was negative had a lower than expected rate of CRC over a 10-year period [58]. Thus, indirect data support the recommendation of a 10-year interval between negative colonoscopy examinations.

Issues common to all screening tests When to start and stop screening Current guidelines call for screening of average-risk men and women of all races beginning at age 50. Imperiale [89] reported that detection of serious pathology is uncommon in asymptomatic average-risk persons aged 40– 49. Based on CRC incidence rates, the pretest probability of cancer in individuals less than 50 years is very low.

Risk stratification based on age, gender, and race Differences in CRC risk based on age, gender, and race have long been recognized. African-Americans may be more likely to develop CRC at a younger age, and some groups have recommended that screening be initiated at age 45 for AfricanAmericans [90]. Women have a lower risk of CRC than men of the same age, a finding that has been attributed to hormonal factors and possibly other genetic factors. In general, there is a 7-year difference in the incidence of CRC per 100 000 population between an average-risk man and woman [1]. In addition, there is some evidence that women may be more likely

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than men to have proximal neoplasia [23,25]. Finally, with increasing age (> 60 years) in both men and women, there is a higher likelihood of developing advanced neoplasia and cancer in the proximal colon than with younger (50- to 59year-old) individuals. What is not known is whether customized recommendations for screening based on age, gender, or race would have an impact on CRC incidence or mortality. Screening rates among all of these groups remain low under existing guidelines. There is genuine concern that providing different, customized screening options has the potential to increase confusion and lower the likelihood of screening.

Summary CRC screening in average-risk populations with colonoscopy has advantages over other forms of screening, including the ability to accurately examine the entire colon and remove pathology during the examination. Uncertainties exist about the application of the procedure in practiceawould completion and complication rates be similar to those reported from clinical trials? Further study is needed in community practice. Would one or two examinationss during a lifetime be sufficient if they are negative? Are there sufficient resources to provide colonoscopy to large populations? Despite these questions, there is little doubt that colonoscopy screening would have a large impact on CRC incidence and mortality [5]. Until selective screening can be targeted at those individuals most likely to develop CRC, colonoscopy screening may offer the most effective means to reduce mortality.

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43 Weissfeld JL, Schoen RE, Pinsky PF, et al. Flexible sigmoidoscopy in the PLCO cancer screening trial: results from the baseline screening examination of a randomized trial. J Natl Cancer Inst 2005; 97: 989– 97. 44 Winawer SJ, Flehinger BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1993; 85: 1311–18. 45 Pignone M, Russell L, Wagner J (eds.). Economic Models of Colorectal Cancer Screening in Average-risk Adults. Washington, DC: The National Academies Press, 2005. 46 Winawer SJ, Stewart ET, Zauber AG, et al. A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. N Engl J Med 2000; 342: 1766–72. 47 Rex DK, Lieberman D. ACG colorectal cancer prevention action plan: update on CT colonography. Am J Gastroenterol. 2006; 101: 1410–13. 48 Rockey DC, Barish M, Brill JV, et al. Standards for gastroenterologists for performing and interpreting diagnostic computed tomographic colonography. Gastroenterology 2007; 133: 1005–24. 49 Amis S, Butler P, Applegate K, et al. American College of Radiology White Paper on Radiation Dose in Medicine. J Am Coll Radiol 2007; 4: 272– 84. 50 Seeff LC, Richards TB, Shapiro JA, et al. How many endoscopies are performed for colorectal cancer screening? Results from CDC’s survey of endoscopic capacity. Gastroenterology 2004; 127: 1670–7. 51 Phillips KA, Liang S-Y, Ladabaum U, et al. Trends in colonoscopy for colorectal cancer screening. Medical Care 2007; 45: 160–7. 52 Lieberman DA, Holub J, Eisen G, Kraemer D, Morris CD. Utilization of colonoscopy in the United States: results from a national consortium. Gastrointest Endosc 2005; 62: 875– 83. 53 Cram P, Fendrick AM, Inadomi J, Cowen ME, Carpenter D, Vijan S. The impact of a celebrity promotional campaign on the use of colon cancer screening: the Katie Couric effect. Arch Intern Med 2003; 163: 1601–5. 54 Harewood GC, Lieberman DA. Colonoscopy practice patterns since introduction of Medicare coverage for average-risk screening. Clin Gastroenterol Hepatol 2004; 2: 72–7. 55 Lang CA, Ransohoff DF. Fecal occult blood screening for colorectal cancer. Is mortality reduced by chance selection for screening colonoscopy? JAMA 1994; 271: 1011–13. 56 Thiis-Evensen E, Hoff GS, Sauar J, Langmark F, Majak BM, Vatn MH. Population based surveillance by colonoscopy: effect on the incidence of colorectal cancer. Telemark Polyp Study I. Scand J Gastroenterol 1999; 34: 414–20. 57 Citarda F, Tomaselli G, Capocaccia R, Barcherini S, Crespi M. Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence. Gut 2001; 48: 812–15. 58 Singh H, Turner D, Xue L, Targownik LE, Mernstein CH. Risk of developing colorectal cancer following a negative colonoscopy examination. JAMA 2006; 295: 2366–73. 59 Nelson DB, McQuaid KR, Bond JH, et al. Procedural success and complications of large-scale screening colonoscopy. Gastrointest Endosc 2002; 55: 307–14. 60 Korman LY, Overhot BF, Box T, Winker CK. Perforation during colonosocpy in endoscopic ambulatory surgical centers. Gastrointest Endosc 2003; 58: 554–7. 61 Bowles CJA, Leicester R, Romaya C, et al. A prospective study of colonoscopy practice in the UK today: are we adequately pre-

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76 Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873– 84. 77 Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95. 78 Pabby A, Schoen RE, Weissfeld JL, et al. Analysis of colorectal cancer occurrence during surveillance colonoscopy in the dietary polyp prevention trial. Gastrointest Endosc 2005: 61: 385–91. 79 Barclay RL, Vicari JJ, Doughty AS, Johanson JF, Greenlaw RL. Adenoma detection rates and colonoscoic withdrawal times during screening colonoscopy. N Engl J Med 2006: 355: 2533–41. 80 Rex DK, Bond JH, Winawer S, et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society task force on colorectal cancer. Am J Gastroenterol 2002; 97: 1296–308. 81 Rex DK, Petrini JL, Baron TH, et al. Quality indicators for colonoscopy. Am J Gastroenterol 2006; 101: 873–85 and Gastrointest Endosc 2006; 63: S16–S28. 82 Lieberman D, Nadel M, Smith R, et al. Standardized colonoscopy reporting and data system (CO-RADS): Report of the Quality Assurance Task Group of the National Colorectal Cancer Roundtable. Gastrointest Endosc 2007, 65: 757–66. 83 Squillace S, Berggreen P, Jaffe P, et al. A normal initial colonoscopy after age 50 does not predict a polyp-free status for life. Am J Gastroenterol 1994; 89: 1156–9. 84 Neugut AI, Jacobson JS, Ahsan H, et al. Incidence and recurrence rates of colorectal adenomas: a prospective study. Gastroenterology 1995; 108: 402– 8. 85 Rex DK, Cummings OW, Helper DJ, et al. 5-year incidence of adenomas after negative colonoscopy in asymptomatic averagerisk persons. Gastroenterology 1996; 111: 1178–81. 86 Avidan B, Sonnenberg A, Schnell TG, Leya J, Metz A, Sontag SJ. New occurrence and recurrence of neoplasms within 5 years of a screening colonoscopy. Am J Gastroenterol 2002; 97: 1524–9. 87 Imperiale TF, Rogge JD, Glowinski EZ, Lin-Cooper CY, Larkin GN, Ransohoff DF. Five-year risk of colorectal neoplasia among persons with no neoplasia on baseline screening colonoscopy. Gastroenterology 2004; 126: A36. 88 Lieberman DA, Weiss DG, Harford WV, et al. Five year colon surveillance after screening colonoscopy. Gastroenterology 2007; 133: 1077– 85. 89 Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF. Results of screening colonoscopy among persons 40 to 49 years of age. N Engl J Med 2002; 346: 1781–5. 90 Agrawal S, Bhupinderjit A, Bhutani MS, et al. Colorectal cancer in African Americans. Am J Gastroenterol 2005; 100: 515–23.

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Cost-effectiveness of Colonoscopy Screening Amnon Sonnenberg Portland VA Medical Center and Oregon Health & Science University, Portland, OR, USA

Introduction Colonoscopy has a wide range of clinical applications, from its use as the primary diagnostic tool for all colonic diseases to a treatment modality in an ever-increasing variety of clinical indications. In each instance, the use of colonoscopy is governed by the interplay between its medical effectiveness and costs, as well as the availability of other competing medical options. A large portion of the clinical use of colonoscopy is still focused on the diagnosis and prevention of colorectal cancer, and this chapter deals with the cost-effectiveness of colonoscopy in the prevention of colorectal cancer. The primary goal of any medical intervention relates to medical success rather than inexpensive management. Cost is of only secondary relevance compared with the primary concerns about the most efficacious prevention, diagnosis, or therapy. Costs become relevant if assessed in conjunction with medical effectiveness. In comparing two competing management options, four potential scenarios can arise. If the first option is cheaper and better than the second option, the decision in its favor is easy. The decision against the first option is similarly easy if the first option is more expensive and worse than its alternative option. It is the mixture of medically better but more expensive or medically worse but less expensive outcomes that is difficult to decide upon unequivocally. Ideally, comparison of cost-effectiveness ratios would provide a means for comparison of such options [1,2].

General principles of cost-effectiveness analyses In cost-effectiveness analyses (CEAs), one calculates the ratio of costs per effectiveness of the medical intervention [1,2].

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The effectiveness is measured in terms of quality-adjusted life-years (QALYs) gained through the intervention. Healthrelated quality of life (HRQL) is measured on a scale between 0 (death) and 1 (perfect health) and is used as a multiplier for life-years to adjust for the different values of lifetime spent in various disease states. A low cost-effectiveness ratio indicates a highly cost-effective medical intervention with low investment costs per yield. The general use of CEA and QALY is encouraged, because it potentially allows one to compare the cost-effectiveness of a large variety of health measures (e.g., appendectomy, vaccination, or tooth filling) and design policies that distribute scarce healthcare resources according to an objectively measured need. Effectiveness of screening is measured in terms of lifeyears saved through the prevention of colorectal cancer, and improved survival by detecting cancer at earlier cancer stages. The cost-effectiveness of colonoscopy or other alternatives for screening is calculated as the average costs per life-years saved (average cost-effectiveness ratio, ACER). Rather than calculate an absolute value, cost-effectiveness is frequently calculated in comparison with other strategies. The marginal or incremental cost-effectiveness ratio (ICER) corresponds to the additional costs needed to spend in order to save one additional life-year in comparison with another strategy. In mathematical terms: ICER =

Cost1 − Cost2 QALY1 − QALY2

(18.1)

where the indices 1 and 2 refer to the first and second medical strategy, respectively, compared with each other. Frequently, the cost-effectiveness of prevention is compared with a strategy of no cancer prevention or no screening. A strategy is said to dominate another if its effectiveness is higher and its costs are lower [1]. It has been argued that, in making a decision, a policymaker could rely directly on the various cost-effectiveness ratios published in the medical literature [2]. The outcome of CEAs is heavily dependent on the types of variables considered by the analyses and the assumptions built into the decision model. Despite multiple efforts at standardization,

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no two diseases are alike and submit to similar types of cost analyses. If one truly tries to include all factors that contribute to the management of a disease and tally even its most remote implications, the actual medical question becomes diluted by a large variety of nonmedical issues, such as cab fare to the hospital or patient placement in a nursing home. QALY is an effectiveness parameter that does not apply to all diseases and does not provide a reliable measure for all medical achievements (e.g., in treating dental cavities, managing irritable bowel syndrome, or just ruling out the presence of a serious disease with a negative test). Although costs were initially introduced only as an accounting trick to make the heterogeneous variety of social and medical items commensurable, their introduction into the analysis has brought into the fray economists, who harbor a completely different set of interests from physicians. Economists are primarily concerned with scarcity of resources and the maximization of resource utilization. Although in many CEAs the focus has shifted from a medical to an economic perspective, physicians may still misread them to provide guidance on the best medical management. From the perspective of a physician, medical arguments should prevail over economic arguments. Costs are relevant to a physician only as a general way of accounting for the large variety of otherwise incommensurable quantities that may bear on a medical decision. CEAs are helpful and most reliable when striving to compare different medical management strategies, such as fecal occult blood testing versus colonoscopy or repeat versus single colonoscopy. If done properly, comparative CEAs subject all management options to a similar set of constraints, assumptions, and costs. CEAs are less suited to providing absolute measures of cost-effectiveness or general guidance about the actual implementation of a particular medical strategy.

Small costs in a great many as opposed to great effects in a small few At least in principle, the decision for or against screening is governed by a rather simple balance: the end result must justify the initial investment in screening. The risks and costs of screening affect the entire population, whereas preventive measures benefit only a small fraction of the population (Figure 18.1). This interplay between the entire population and a subfraction prone to develop cancer adds the perspective of probability to the analysis. The costs of the screening procedure are usually small when compared with their potential benefit. For instance, a single colonoscopy costing $1000 can save a life worth, for instance, $1 000 000. However, the relatively inexpensive test must be applied multiple times to a large population of subjects in order to gain a benefit in one or a few patients. In other words, colonoscopies may need to be performed 1000 times before one single cancer case is

Cost-effectiveness of Colonoscopy Screening

Few positives

Benefit of prevention

Cost of screening

Many negatives

No benefit

Figure 18.1 Decision tree demonstrating the general principles of screening. The costs of screening are accrued in the entire population, whereas its benefits affect only a minority of patients.

detected in a timely fashion to save a single life. The balance may shift in disfavor of screening if the screening procedure itself results in life-threatening and costly complications. On the other hand, if screening is associated not only with lifesaving measures in one patient but also with extended life in another case and with prevention of cancer altogether in yet another set of patients, the balance may shift yet again, this time in favor of screening. To avoid the contentious issue of assigning a monetary value to human life, health economists have largely abandoned cost–benefit analyses and resorted to CEAs. Instead of translating medical benefits into costs, the end result is usually measured in terms of QALY, life-years saved, or some other outcome parameter indicating the effectiveness of screening. The investment in screening and its potential risks and adverse effects are still measured as monetary cost. Cost lends itself to being used as the common denominator for the multitude of heterogeneous entities touched upon by the analysis. It is a widely used means of measurement, and people are intimately familiar with its meaning and ubiquitous applicability. These items include cost of the screening procedure and its potential complications, costs of cancer care, and absenteeism from work. The tree in Figure 18.1 represents only a crude presentation of the issues involved in screening. In Figure 18.2, the initial tree is expanded to depict in more detail other potential events and outcomes associated with screening. Besides screening, the option of nonscreening is added as a lower branch to the tree. The results of screening are broken down into true and false. The more detailed outcomes differentiate between patients who do and do not fully benefit from prevention. It is obvious that even this tree is far from complete and that it could be expanded much further (e.g., by considering the influence of repeat screening procedures, the concomitant or subsequent use of different screening tests, or patient noncompliance with the screening procedure).

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$ intervention True positive

Cure

Extended life

$ tests Death

Positive

False positive $ screen Screening

$ therapy False negative

Cure

Extended life

Death

Negative

Figure 18.2 Expanded decision tree of screening. The arrows symbolize transitions that are associated with costs.

True negative

Cost-effectiveness of decennial colonoscopy The decision tree shown in Figure 18.2 becomes an unhelpful instrument when tackling decision problems that involve many screening options, test outcomes, and therapies. The tree is difficult to appreciate and the reader is overwhelmed by the amount of detail. It is also less well suited for handling the impact of decisions and events that occur repetitively and change over time, such as surveillance colonoscopy after polypectomy, time-dependent decline in compliance, or agerelated rise in cancer incidence. The transition from polyp to cancer and the time-dependent evolution of cancer are better modeled by a Markov process [3]. In a Markov process, medical events are modeled as transitions of patients among a set of predefined health states, the occurrence of each transition being governed by a probability value (Figure 18.3). The circles in Figure 18.3 symbolize the various health states, while the arrows symbolize transition probabilities among them. The time frame of the analysis is divided into equal increments of 1 year, during which patients may cycle from one state to another. The initial population comprises 100 000 subjects aged 50 years who at the start are offered screening colonoscopy. Depending on the initial compliance rate, subjects undergo a colonoscopy or enter the pool of noncompliant persons. After a normal colonoscopy (without adenomatous polyp), subjects enter a new state labeled “status post colonoscopy.” In subjects compliant with a repeat screening, a colonoscopy is scheduled every 10 years. In the case of an adenomatous polyp, surveillance colonoscopy is repeated every 3 years until adenomatous polyps are no longer found. Subjects in any Markov state can develop colorectal cancer, the probability being given by the age-specific incidence rate.

218

Death

CRC

s/p colonoscopy

Noncompliant

10 years

Start

no polyp

Colonoscopy

3 years polyp

s/p polypectomy

Figure 18.3 Markov state diagram of screening for colorectal cancer (CRC) by repeat colonoscopy. The arrows symbolize transitions between the various states. Noncompliant, subjects noncompliant with repeat colonoscopy; s/p, status post.

The likelihood of developing cancer is reduced in subjects after a normal colonoscopy or after polypectomy, depending on the rate of preventive efficacy assigned to the procedure. The length of time for which colonoscopy and polypectomy provide protection against colorectal cancer is equal to the screening interval. The population in each state is also subject to the annual age-specific death rate of the US population. The transition probabilities built into the model are taken from the literature, including a 40% mortality from colorectal

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cancer, a 75% efficacy of colonoscopy in preventing colorectal cancer, and a 1% annual incidence rate of colorectal adenomas. In a set of sensitivity analyses these values vary across a wide range. The costs for medical, surgical, and diagnostic services represent the average payments allowed for each service by the US Centers for Medicare and Medicaid Services (CMS), previously known as the Health Care Financing Administration (HCFA). The costs also include the possibility of hospitalization for bleeding or perforation after colonoscopy with or without polypectomy, and cost estimates for the medical care of subjects with colorectal cancer. The costs accrue every time subjects pass through transitions that are associated with healthcare utilization. Effectiveness is measured in terms of life-years that accumulate in subjects who stay alive after each cycle. The number of life-years saved through screening corresponds to the difference in life-years lost from cancer-related deaths between two Markov models with and without screening. All future costs arising from the screening or care of colorectal cancer and all future life-years saved through screening are discounted at an annual rate of 3% [4]. The ACER of colonoscopy every 10 years is $28 000 per life-year saved. The ICER of colonoscopy compared with no screening amounts to $11 000 per life-year saved. In comparison with other medical interventions, such ACER and ICER values are considered quite cost-effective and colonoscopy appears to be a strategy worth pursuing [5]. More frequent colonoscopies (e.g., every 5 instead of 10 years) increase the ACER and ICER of cancer prevention by making the screening procedure more costly. Changes in the surveillance interval after polypectomy exert only a small influence without affecting the relative differences among competing screening programs. Any decrease in the efficacy of colonoscopy and polypectomy in preventing colorectal cancer also increases the ACER and ICER of colonoscopy. Multiple decision analyses relying on cost data from the US have been published. In spite of the variety of models used to simulate the natural history of colorectal cancer, all studies alike show decennial colonoscopy to be a cost-effective screening strategy, with values for ICER varying between $10 000 and 20 000 per life-year saved [3,6,7].

Cost-effectiveness of Colonoscopy Screening

colonoscopy is between 65 and 70 [11]. At this age, a balance is achieved between a declining life expectancy (leading to a reduced impact of any life-saving measures) and a rising incidence of colorectal cancer. Screening by a single colonoscopy at age 65 is modeled similarly to screening by multiple colonoscopies, as shown by Figure 18.3 [12]. However, no repeat colonoscopy is scheduled after the initial colonoscopy or after a successful polypectomy. From the age of 50 to 64 years and after the age of 75 years, subjects are exposed to the age-specific incidence rate of colorectal cancer without any potential protection from colonoscopy and polypectomy. The smaller fraction of cancers prevented by a single screening colonoscopy is associated with fewer life-years saved. The ACER of a single colonoscopy is $55 400. Compared with no screening, a single colonoscopy represents an extremely costeffective screening strategy of less than $3000 per life-year saved.

Flexible sigmoidoscopy The cost-effectiveness of screening by flexible sigmoidoscopy is modeled similarly to screening by decennial colonoscopy (Figure 18.4) [3]. Instead of colonoscopy, the simulation is started with 100 000 subjects being offered screening through flexible sigmoidoscopy. The transitions out of this initial state depend on whether a polyp is found during sigmoidoscopy. After a normal (negative) flexible sigmoidoscopy without adenomatous polyps, subjects stay in the pool waiting for the next screening sigmoidoscopy in 5 years. The remainder of the model is similar to that of colonoscopy. In addition to the states shown in Figure 18.4, the actual model was simulated with an additional status to account for noncompliant patients regarding repeat flexible sigmoidoscopies or follow-up

3 years

Cost-effectiveness of alternative screening procedures

Death

CRC

Colonoscopy

Noncompliant

10 years

polyp

Single colonoscopy Although repeat colonoscopies every 5–10 years represent the most effective screening strategy for colorectal cancer, it has not been widely used because of its associated high costs and relatively low patient compliance. To escape these shortcomings, some authors have suggested a one-time only screening colonoscopy after age 50 [8–11]. In a previous study, it was shown that the best age to schedule a single

5 years Start

FS No polyp

s/p FS

Figure 18.4 Markov state diagram of screening for colorectal cancer (CRC) by flexible sigmoidoscopy (FS). Noncompliant, subjects noncompliant with repeat colonoscopy; s/p, status post.

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colonoscopies after a positive flexible sigmoidoscopy. About 45% of all polyps are within the reach of flexible sigmoidoscopy [13–15]. According to the model, screening by flexible sigmoidoscopy prevents 34% of all colorectal cancers. Although the investments in screening with flexible sigmoidoscopy reduce the number of colonoscopies used for screening, an ACER of $74 000 and an ICER of $36 500 compared with no screening make this strategy far more expensive than any strategy using colonoscopy. Screening by flexible sigmoidoscopy is most sensitive to the costs of the procedure itself. The only way to salvage sigmoidoscopy as a screening procedure would be to offer it at very low cost. Currently, flexible sigmoidoscopy costs $400, compared with $695 for a simple colonoscopy and $1004 for a colonoscopy and polypectomy. If the cost of flexible sigmoidoscopy drops below a threshold of $170, its ICERacompared with no screening or with screening using fecal occult blood test(ing) (FOBT)amakes it a cost-effective alternative to colonoscopy as a secondary screening procedure. Moreover, if polyps are removed during flexible sigmoidoscopy without a followup colonoscopy, this strategy also becomes a cost-effective screening alternative [6]. Although infrequent in the US, such use of flexible sigmoidoscopy as a primary tool for the screening and removal of left-sided polyps appears to be more common in other countries. Accordingly, European decision analyses tend to show flexible sigmoidoscopy to be far more cost-effective than corresponding US studies [16–18].

Fecal occult blood test In prospective trials, the FOBT was shown to reduce colorectal cancer-related mortality by an average of 18% [19]. Since it also appears to be a cheap test, it has been suggested that it would represent a cost-effective alternative for screening colorectal cancer [6,8,20– 22]. In our own analysis, its costeffectiveness was assessed using a Markov process very similar to the one shown in Figure 18.4 for flexible sigmoidoscopy [3]. In the case of FOBT, the lower two states of Figure 18.4 represent “FOBT” and “status post FOBT.” The simulation begins with 100 000 subjects being offered screening through FOBT. The transitions out of the initial FOBT state depend on whether the test is negative or positive. After a negative FOBT, subjects stay in the pool waiting for the test repetition in a year’s time. In case of a positive FOBT, subjects undergo a colonoscopy. After a negative colonoscopy, FOBT is abandoned for a period of 10 years. In addition to many similar transition probabilities from the previous models, the present Markov process assumes a 40% sensitivity and 97.5% specificity of FOBT for colorectal cancer. Compared with no intervention, screening by FOBT prevents 16% of all colorectal cancers. In detecting earlier cancer stages, FOBT leads to an additional 2% reduction in mortality beyond cancer prevention alone. Compared with no screening, only $9700 (ICER) is spent to save one additional life-year.

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FOBT represents a relatively cost-effective option when compared with no screening. The outcome of the simulation is mostly influenced by the costs of the FOBT itself and the test characteristics. The baseline cost of $3.50 for the FOBT may be overly optimistic because it does not include any cost for physician visit and test management. The ICER of FOBT is linearly dependent on the costs of delivering the test. A rise in costs (from baseline $3.50) to $7 or $14 raises the ICER of FOBT in comparison with no screening to $12 600 or $18 400, respectively. An increase in both test sensitivity and specificity reduces the ICER. Within the broad ranges tested in the sensitivity analysis, the overall influence of sensitivity and specificity on the ICER does not exceed $2000. Because both screening based on flexible sigmoidoscopy and screening based on FOBT depend on colonoscopy as their final arbiter, shortening of the interval between repeat colonoscopies also renders these two screening strategies more expensive and less cost-effective. Similarly, any decrease in the efficacy of colonoscopy and polypectomy in preventing colorectal cancer increases the ACER and ICER of other screening methods as well. Under base case conditions, patient compliance with the screening program is assumed to be perfect. Since the initial compliance determines how many persons enter the screening program, it influences the overall number of cancers prevented and the total costs, in a linear fashion. However, the initial compliance rate does not affect the cost-effectiveness ratio of any individual program. A decrease in compliance associated with test repetition results in higher costs per lifeyear saved. FOBT is particularly sensitive to changes in compliance with repeat testing because it is carried out more frequently than colonoscopy. Only a slight decrease in compliance with repeat FOBT increases its ICER (compared with no screening) far above the ICER of colonoscopy. A low compliance with colonoscopy following a positive FOBT also renders the initial FOBT less efficacious and increases its associated costs per saved life-year. Because it depends on several types of patient compliance, screening by FOBT is generally far more sensitive to changes in compliance than a colonoscopy screening program.

Fecal DNA testing Cancers and polyps originating from the colonic mucosa continuously shed cells that contain abnormal DNA into the fecal stream. The DNA of cancer-associated genes can be extracted from stool samples and detected by means of molecular biology. The panel of abnormal fecal DNA consists of mutations in the K-ras gene, the APC gene, the p53 gene, and the microsatellite instability marker BAT-26 [23,24]. Several studies have analyzed the cost-effectiveness of fecal DNA testing based on data available between 2003 and 2006 [16,25,26]. In all studies alike, fecal DNA testing was less cost-effective than colonoscopy, flexible sigmoidoscopy, or FOBT. Being less effective and more costly than any of these

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techniques, a screening strategy involving fecal DNA was dominated by any of these other screening modalities. In their Markov state model, for instance, Song et al. [25] assumed that fecal DNA testing would be associated with a sensitivity of 64% for cancer and 41% for advanced adenoma, and a general specificity of 95%. The authors also assumed that the test would cost $695. Compared with no screening, fecal DNA testing every 5 years cost $47 700 per life-year saved. Decreasing the test cost to $350 decreased the ICER to $21 000. In the same decision analysis, the ICER of colonoscopy versus no screening was only $17 700. The methods for extracting fecal DNA are undergoing constant improvement and the panel of screened genes is expanding. One can expect that in the future the sensitivity of the test will improve and its cost will markedly decrease. However, even under the best of circumstances, any positive fecal DNA test will still require a follow-up colonoscopy.

Computed tomographic colonography Computed tomographic colonography (CTC) is a new technique that uses data generated from computed tomography or magnetic resonance imaging (MRI) to create two- and three-dimensional scans of the colon. Advanced imaging software creates axial and reformatted two-dimensional images of the colon, as well as simulated endoluminal images. When computer-generated endoluminal images are displayed at a fast rate, virtual colonoscopy provides the illusion of traveling through the colon. For both techniques, the bowel needs to be cleansed in the same way as for a barium enema or colonoscopy. The colon is then inflated with a single contrast of gas or a water-based enema [27–30]. The technique has been reported to yield a sensitivity and specificity of 80–90% in detecting colorectal cancer and polyps of 10 mm or more in size [31,32]. Using CTC or MRI colonography for screening of colorectal cancer would reduce the number of colonoscopies. This cost saving is gained at the expense of exposing all subjects with suspected polyps or cancers to two procedures (i.e., CTC and colonoscopy). To reduce the number of subjects who have to undergo both procedures, Lin et al. [33] proposed a mixed strategy of reserving colonoscopy for populations with a high risk for developing advanced neoplasia and using CTC as a primary screening tool for all other lowrisk populations. A high risk could be determined by a simple cumulative score that includes male gender, older age, or a positive family history of colorectal cancer. According to their model, such a risk-stratified mixed screening strategy would detect 92% of all advanced neoplasia, require colonoscopy in 68% and CTC in 36% of subjects, with only 4% having to undergo both procedures. Using a similar Markov state model as presented above to calculate the ICER of decennial colonoscopy or flexible sigmoidoscopy, we did not find universal (MRI or CT) colonography to be a cost-effective method that could presently compete with colonoscopy [34]. The ICER of CTC every 10 years

Cost-effectiveness of Colonoscopy Screening

versus no screening was $11 500 per life-year saved. In comparison, the ICER of colonoscopy versus no screening was $10 400 per life-year saved. (The small variation from the value reported above reflected slightly different cost assumptions and the inclusion of less than perfect patient compliance with screening.) This outcome of the analysis varied in response to changes in the sensitivity of CTC for detecting colonic neoplasms. A low sensitivity reduced the efficacy of the procedure in preventing colorectal cancer, and increased its cost per life-year saved. CTC could become as cost-effective a screening option as colonoscopy if its initial compliance rate were 15–20% better than that of colonoscopy. A low compliance with colonoscopy after a positive CTC would render the CTC itself less efficacious and increase its costs per lifeyear saved, because any large fraction of CTCs done without colonoscopic polypectomy would result in diagnostic cost without preventive effect. The analysis also indicated that procedural costs will be a major factor in determining any future success of CTC as a screening tool for colorectal cancer. According to our analysis, CTC must be cheaper than colonoscopy by more than 50% to be able to compete economically with colonoscopy. Although subsequent authors have used different transition probabilities and cost assumptions, and shorter screening intervals, a similar pattern to the one found from our study has emerged from their studies. Using US data, Vijan et al. [35] found that CT colonography every 5 or 10 years was a cost-effective option relative to no screening. However, in a head-to-head comparison, the technique was dominated by conventional optical colonoscopy. Similar results were obtained using cost data pertaining to the health care in Australia and Canada [36,37]. In general, the ICERs of CTC and colonoscopy do not differ by large amounts. In tweaking the procedural costs of CTC, the sensitivity of CTC for detecting colonic neoplasms, and some of the other transition probabilities in the model, it is relatively easy to bias the analysis in favor of one or other strategy. In contradistinction with the aforementioned studies, a cost-effectiveness analysis made by radiologists found decennial CTC to be associated with a smaller ICER (relative to no screening) than either flexible sigmoidoscopy or optical colonoscopy [38]. The sensitivity of CTC improves markedly with polyp size. Therefore, the ICER of CTC can be further reduced if all polyps less than 6 mm in diameter are ignored without subsequent polypectomy by optical colonoscopy. A discussion has ensued between radiologists and gastroenterologists about the proper management strategy for polyps less than 6 mm or 10 mm. Radiologists have argued that for polyps less than 6 mm or 10 mm, the ICER of CTC leading to subsequent polypectomy (relative to no screening), amounts to $464 407 or $59 015 per life-year saved, respectively, and that this may not represent a worthwhile management strategy [39]. Gastroenterologists have argued that even small polyps can still harbor advanced neoplasia and that expectant management of small polyps would result in more deaths

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Indications, Contraindications, and Screening with its clinical utilization will render capsule colonoscopy yet another diagnostic alternative for colorectal cancer screening. High test specificity will reduce the need for optical colonoscopy following capsule colonoscopy for workup of false-positive test results. High test sensitivity will save lives and reduce the potential costs associated with missed or unprevented colorectal cancer. However, even with excellent test characteristics, an appreciable fraction of patients will eventually undergo two sequential tests, that is, capsule colonoscopy followed by optical colonoscopy. This approach is cost-effective only if the costs of the initial capsule colonoscopy can be kept low. Ultimately, the same principles of cost-effectiveness apply to capsule endoscopy as to CT colonography or fecal DNA testing.

than immediate colonoscopy with polypectomy [40,41]. This argument between radiologists and gastroenterologists is unlikely to be resolved by analyses of cost-effectiveness alone. If further refinements and simplifications of the technique can render CTC more sensitive, cheaper, as well as less invasive with regards to colonic preparation and radiation exposure, it has the potential of becoming an attractive screening alternative.

Capsule colonoscopy Multiple studies have shown capsule endoscopy to be a reliable means to assess the mucosal appearance of the small intestine and diagnose inflammatory bowel disease, arteriovenous malformations, tumors, and nonsteroidal antiinflammatory drug (NSAID)-induced lesions. The technology of capsule endoscopy can also be modified for screening of the large bowel. By increasing the battery lifetime and keeping the capsule quiescent during its initial passage through the small intestine, colonoscopy becomes technically feasible. A new capsule has been designed specifically for use in the large bowel by providing better depth and larger views than in capsules designed for the small bowel (see Chapter 23) [42,43]. In preliminary reports, the sensitivity and specificity of capsule endoscopy for detecting any colonic neoplasm were about 72% and 80%, respectively. It is to be expected that technological advances and more experience

Cost-effectiveness analyses comparison of competing screening strategies Table 18.1 illustrates a comparison of various analyses that use variations of a similar Markov process to estimate the cost-effectiveness of competing strategies to prevent colorectal cancer in the general population. All analyses assume perfect compliance and do not include costs or quality adjustment of the life-years saved. As highlighted in the previous sections, all values shown in Table 18.1 can easily be shifted

Table 18.1 Outcomes of competing programs to prevent colorectal cancer. No prevention

Effectiveness Expected number of CRC without screening Number of prevented CRC Life-years saved Reduction in mortality (%) Resource utilization Number of FOBT Number of sigmoidoscopies Number of colonoscopies Costs Costs of FOBT ($) Costs of sigmoidoscopy ($) Costs of colonoscopy ($) Cost of care for CRC ($) Total costs ($) Cost-effectiveness ACER costs/saved life-years ($) ICER compared with no prevention ($)

FOBT

Sigmoidoscopy

Single colonoscopy

Decennial colonoscopy

5904 0 0 0

5904 926 1896 18

5904 2027 3636 34

5904 1352 2604 23

5904 4428 7952 75

0 0 0

2 464 606 0 69 794

0 623 597 27 319

0 0 86 184

0 0 365 456

0 0 0 136 452 922 136 452 922

5 497 809 0 33 640 016 115 715 753 154 853 577

0 163 313 218 16 281 508 89 619 575 269 214 301

0 0 41 091 209 103 124 901 144 216 110

0 0 189 667 598 34 113 230 223 780 829

∞

81 678 9705

74 032 36 509

55 386 2981

28 143 10 983

Numbers in the table relate to a cohort of 100 000 persons aged 50 years and followed on average for 28.5 years until the time of death. Future life-years saved and future costs were discounted using an annual rate of 3%. ACER, average cost-effectiveness ratio; CRC, colorectal cancer; FOBT, fecal occult blood test; ICER, incremental cost-effectiveness ratio.

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upward or downward by assuming a set of more or less favorable costs and prevention outcomes. Based on the limited evidence provided by the analyses, the ACERs of all six medical interventions fall between $28 000 and $82 000. When compared with no prevention, single colonoscopy, FOBT, and decennial colonoscopy are associated with the smallest ICER and appear to be the most cost-effective strategies. Compared with no screening, a single colonoscopy represents a very cost-effective screening strategy of less than $3000 per life-year saved. Repeat decennial colonoscopies could save two to three times more lives than a screening program based on a single colonoscopy. If third-party payers are able to provide the financial resources and subjects are willing to participate, a screening program comprising repeat colonoscopies represents the better yet more expensive alternative. Under tighter economic conditions with only limited funds available for cancer screening, a single colonoscopy between the age of 65 and 70 offers a relatively cheap and highly cost-effective means of screening for colorectal cancer. The ICER of colonoscopy compared with no screening amounts to $11 000 per life-year saved, which is only slightly higher than the ICER of FOBT. Colonoscopy is also associated with a relatively modest ICER when compared as an addon with FOBT alone (i.e., $11 400 per life-year saved). In screening using flexible sigmoidoscopy, the costs saved on colonoscopies are partly offset by the additional expenses for two procedures in all patients with distal polyps and the higher expenses for cancer care among patients with missed proximal cancers.

Cost-effectiveness of Colonoscopy Screening

Alternative procedure

P 1–P

P

Negative: $0

Positive: $colonoscopy

Negative: $0

Colonoscopy 1–P

Positive: $0

Figure 18.5 Decision tree for calculating the threshold probability when a test becomes a viable alternative to colonoscopy. Both procedures (colonoscopy or its alternative) are associated with the same two potential outcomes, i.e., negative versus positive finding. A positive finding of the alternative procedure needs to be followed by an additional colonoscopy.

no further testing is necessary. In the case of a positive test outcome, a subsequent colonoscopy becomes necessary. The lower decision branch, representing screening colonoscopy, results in the same two outcomes and probabilities as in the upper branch, but with different implications. No further diagnostic workup is needed in case of neoplasm or any other positive finding. In summary, the decision tree weighs the higher costs of a colonoscopy against the savings obtained through a cheaper alternative procedure with the occasional need to perform two procedures in patients with positive findings. For the upper branch to cost less than the lower branch: Alternative + (1 − P) × Colonoscopy < Colonoscopy

Costs of inconclusive tests and colonoscopy as the final arbiter Using fecal DNA testing, CT colonography, or capsule colonoscopy for screening of colorectal cancer reduces the total number of colonoscopies utilized for screening purposes. This cost saving is gained at the expense of exposing the subgroup of subjects with suspected polyps or cancers to two screening procedures. In principle, all such inconclusive tests are associated with a similar scenario in which suspicious findings need to be followed by a subsequent colonoscopy. In Figure 18.5, this medical scenario is modeled as a simple decision tree. A threshold analysis is used to determine the probability of a normal finding (i.e., no colorectal polyps or cancers that would render screening with colonography the less expensive approach) [44]. The decision between colonoscopy and another screening alternative is symbolized by the small filled square on the left-hand side. The upper branch, representing the screening alternative to colonoscopy, has two possible outcomes, both governed by chance. The alternative test can reveal a normal finding or a neoplasm. The probabilities associated with these two outcomes are P and 1 – P, respectively. In the case of a normal finding,

(18.2)

Simple algebraic manipulations yield: Alternative < P × Colonoscopy

(18.3)

In essence, any alternative test procedure needs to cost less than colonoscopy multiplied by the expected fraction of subjects with normal findings. For instance, expecting 30% of all subjects at age 50 years to harbor polyps and a colonoscopy to cost $1000, P = 70% and the alternative procedure < $700. The usefulness of this type of threshold analysis relates to the fact that it can be similarly applied to many different screening techniques that require a colonoscopy as a followup test for their positive results. As indicated above, such screening techniques include FOBT, flexible sigmoidoscopy, CTC, capsule colonoscopy, and fecal DNA testing. It needs to be kept in mind that threshold analysis represents a rather crude, back-of-the-envelope type of calculation that ignores, for instance, the different costs associated with simple colonoscopy versus polypectomy and the impact of false-positive or false-negative outcomes of the alternative test procedure. Of course, the analysis could be refined by using more detailed assumptions or one could use a more

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detailed Markov model, as done previously to assess the costeffectiveness of these new technologies.

Other aspects of colon cancer prevention Variations in colonoscopy costs and cost-effectiveness ratios The cost of colonoscopy is one of the most important parameters to enter any decision analysis dealing with the costeffectiveness of colorectal cancer screening and prevention. Obviously, lower colonoscopy costs render screening colonoscopy more cost-effective. Even within an individual country the cost of a single colonoscopy can vary, for example in the US there is a threefold variation in the costs charged for an individual colonoscopy [45]. In the US, most studies have utilized the reimbursement schedule of the CMS to estimate colonoscopy cost. In 2007, colonoscopy with and without polypectomy and surgical pathology cost about $720 and $650, respectively. Most studies do not include the nonhealthcare costs associated with colonoscopy. In a prospective study between July 2001 and June 2002, Henry et al. [46] used microcosting and time-and-motion techniques to determine the total societal costs of colonoscopy, which included the direct healthcare and nonhealthcare costs, as well as costs related to patients’ time. The median direct healthcare costs were $379, the direct nonhealthcare costs were $226, and the patient time costs were $274. The total societal costs associated with colonoscopy amounted to $923. Jonas et al. [47] have analyzed the patient time loss resulting from screening colonoscopy. According to the results of this study, the overall time requirement of colonoscopy was 37.8 h. Of this overall time, 16.5 h was spent on bowel preparation, 3.7 h was spent on travel, waiting, sedation, colonoscopy, and onsite recovery, and 17.7 h was spent on recovery to routine after the colonoscopy. Based on the results of these two studies by Henry et al. and Jonas et al., it would appear that all US studies using the CMS data to estimate colonoscopy cost probably underestimate the true costs of colonoscopy and provide overly optimistic cost-effectiveness ratios. The cost-effectiveness of colonoscopy, flexible sigmoidoscopy, FOBTs, and various other colorectal cancer preventive strategies has been analyzed in a large variety of countries. Irrespective of their varying cost structures, in all countries alike, colonoscopy, flexible sigmoidoscopy, and FOBT were found to be cost-effective screening methods to prevent colorectal cancer, and their implementation was recommended by the authors. Compared with other countries, the US cost for colonoscopy appears to lie in the highest quartile. For instance, the cost of diagnostic colonoscopy without polypectomy was $597 in Australia [36], $533 in Canada [37], $368 in England [18], $770 in France [48], $170 in Germany [17], $1038 in Hong Kong [49], $211 in Israel [16], and $66 in Taiwan [26]. In countries with low costs of colonoscopy, such

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as Germany, Israel, or Taiwan, the potential costs spent on cancer screening are expected to be less than all costs incurred through cancer treatment and cancer death. Therefore, in these countries, screening by colonoscopy or FOBT dominates the nonscreening option, because it is cheaper and also more effective.

Cost-effectiveness of individual features of colonoscopy In addition to measuring and calculating the cost-effectiveness of colonoscopy itself in preventing colorectal cancer, one could theoretically subject individual features of the endoscopic procedures to a cost-effectiveness analysis. For instance, one could study the cost-effectiveness of different instrument types, various means of conscious sedation, and preprocedural colonic cleansing. One could also study the cost-effectiveness of the length and type of training of the endoscopist or compare the cost-effectiveness of a colonoscopy performed by trained nurse practitioners versus board-certified gastroenterologists. Two examples of such studies dealing with individual paracolonoscopic features are cited below. Shankaran et al. [50], for instance, measured the costs and cost-effectiveness of a low-intensity patient intervention to promote colorectal cancer screening. Patients in the intervention arm received a customized mailed brochure that included a reminder to schedule a screening colonoscopy and general information about colorectal cancer. The costs and ICER of this patient-directed intervention were measured, using the completion of a screening colonoscopy as the desired end point. Rates of cancer screening for the intervention versus control group were 71% and 59%, respectively. The cost per patient in the intervention group was $5, and the ICER was $43 per additional patient screened by colonoscopy. The authors did not, however, translate their results into cost-effectiveness measured in terms of costs per life-years saved. Saini et al. [51] developed a Markov model to compare the clinical and economic effects of slow colonoscopy withdrawal associated with a higher physician reimbursement versus standard colonoscopy (with potentially faster withdrawal of the colonoscope). Physicians were assumed to receive a $50 bonus per colonoscopy for maintaining an average withdrawal time of 8 min. The screening population comprised patients with previously diagnosed colonic adenomas undergoing surveillance colonoscopy. The authors assumed that a slower withdrawal technique would increase the detection of polyps with sizes over 10 mm by 20%. According to the model, slow withdrawal resulted in a 17% reduction in colorectal cancer incidence and a 22% reduction in cancerrelated deaths compared with fast withdrawal. These lower rates of cancer were also associated with lower costs, making the slow withdrawal dominant over the fast withdrawal strategy. In a sensitivity analysis, the ICER of slow withdrawal remained under $50 000 per life-year saved even

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when the improvement in polyp detection increased by only 5% or the reimbursement bonus for slow withdrawal was raised to $200 per colonoscopy.

Chemoprevention of colorectal cancer Since colonoscopy is an expensive and relatively invasive diagnostic test, alternative strategies to prevent colorectal cancer have been sought. Multiple epidemiologic studies have shown that regular intake of NSAIDs causes regression of colonic polyps and reduces the risk for developing colorectal cancer by 40– 50% [52–57]. In prospective randomized clinical trials, daily doses of 81 mg or 325 mg of aspirin also reduced the recurrence of adenomatous polyps [58,59]. Chemoprevention of colorectal cancer by means of regular intake of aspirin or other NSAIDs could thus represent a viable option to reduce morbidity and mortality from colorectal cancer. However, NSAIDs are associated with multiple sideeffects, such as gastrointestinal bleeding, and cerebrovascular accidents, that can lead to excessive consumption of healthcare resources [60– 63]. Any policy to prevent colorectal cancer through NSAIDs has to weigh the benefits of chemoprevention against their costly side-effects. Several studies have compared the cost-effectiveness of chemoprevention, colonoscopy, and no intervention. In our own study, the ICER of chemoprevention alone, using a daily dose of 325 mg of aspirin, versus no intervention, was $47 250 [64]. This value was more than fourfold higher than the value associated with decennial colonoscopy (Table 18.1). The ICER of adding chemoprevention to decennial colonoscopy to potentially reap the benefit of both preventive strategies was $227 600. If aspirin prevention were already implemented in the general population, the addition of one colonoscopy per 10 years to prevent more deaths from colorectal cancers would result in a relatively low ICER of $34 836 compared with chemoprevention alone. In other words, chemoprevention on top of screening colonoscopy would not be cost-effective, whereas screening colonoscopy on top of chemoprevention still represents a cost-effective addition. Similar results were obtained by different groups of authors using separate Markov models to analyze prevention of colorectal cancer [65,66]. There are two reasons why chemoprevention alone is not cost-effective when compared with colonoscopy alone. The first reason for the poor outcome of chemoprevention relates to its relatively low efficacy in preventing colorectal cancer. The second reason relates to the overall high costs associated with regular intake of NSAIDs. The common occurrence of adverse effects during the treatment with NSAIDs renders this drug class costly, even if the expenses for the drug itself may appear relatively cheap. To reduce the side-effects of NSAIDs, specific cyclooxygenase-2 (COX-2) inhibitors have been developed [67– 69]. Like conventional NSAIDs, these newer compounds with a potentially lower gastrointestinal toxicity also protect against colorectal neoplasm [70,71]. The cost saved by the drugs’ safer profile and lesser side-effects,

Cost-effectiveness of Colonoscopy Screening

however, becomes spent on the drug itself. A year’s supply of daily doses of 100 mg of Celecoxib (Celebrex) costs $350–500. These costs exceed by far the threshold for chemoprevention to become a cost-effective alternative. In two separate decision analyses devoted solely to the role of COX-2 inhibitors, the overall costs associated with these agents proved to be far too expensive to justify any such policy for the prevention of colorectal cancer [72,73]. In the study by Ladabaum [72], for instance, the ICER relative to no intervention was $233 000 per life-year saved, and this strategy was clearly dominated by endoscopic procedures.

Surveillance and prevention in ulcerative colitis Patients with long-standing extensive ulcerative colitis harbor an increased risk of developing colorectal cancer [74–77]. After 40 years, about 30% of all patients with pancolitis have developed colorectal cancer [74–77], compared with a 6% cumulative lifetime risk in the general population [78]. Because of the increased risk of cancer, surveillance colonoscopy in patients with long-standing pancolitis has been widely recommended [79–81]. The rationale of surveillance colonoscopy is to detect cancer at an early stage when treatment is more likely to be curative. Little evidence exists, however, that surveillance is truly efficacious and cost-effective in preventing deaths from colorectal cancer. Considering the obstacles to a clinical resolution, one can again use the techniques of medical decision analysis to assess the feasibility and usefulness of surveillance. However, the values of ACER or ICER would provide little guidance to the clinician, since no other comparative measures of prevention are available to put such parameters in perspective. Instead of expressing the outcome of a simulation in terms of ACER or ICER, a threshold analysis is used similarly to the example given in the previous section [82]. The analysis tries to answer the following question: How high does the cumulative probability of colorectal cancer need to be for biannual surveillance to be more beneficial than nonsurveillance? This question is translated into the decision tree shown in Figure 18.6. Its structure is explained as proceeding from left to right and from top to bottom. The filled square on the left-hand side symbolizes the initial decision for or against surveillance. The chances of developing or not developing colorectal cancer are denoted as P and 1 − P respectively. In the case of cancer, surveillance, colonoscopy, and histology can yield true-positive or false-negative test results. Cancers prevented or detected as a consequence of surveillance are associated with proctocolectomy. The mortality (mort1 = 15%) reflects the impact of cancers that cannot be prevented through surveillance and proctocolectomy. The life gained becomes reduced by the impaired HRQL after proctocolectomy. The final outcomes of true-positive and false-negative

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TP 80% P

CRC, timely operation life x HRQL x (1 – mort1) $686 375 a

CRC FN 20% Surveillance

Missed CRC, late operation life x HRQL x (1 – mort2) $444 125 b

No CRC life $850 000 c

TN 60% 1–P No CRC FP 40%

P CRC

No surveillance

No CRC, unneeded operation life x HRQL $807 500 d

CRC, late operation life x HRQL x (1 – mort2) $444 125 e

1–P No CRC

surveillance tests are quite similar, except for the higher mortality rate (mort2 = 45%) associated with cancers missed during surveillance. Colonoscopy in patients without dysplasia can yield true-negative or false-positive tests. Life and its quality remain unaffected by true-negative surveillance procedures. False-positive tests lead to an unnecessary proctocolectomy and a reduction in HRQL. The main lower branch of the tree represents the decision against surveillance. It has only two possible outcomes governed by the probability of developing cancer. In the case of cancer, the outcome is identical to that of a missed cancer as a consequence of falsenegative surveillance tests. Without cancer, the outcome is identical to the outcome associated with true-negative surveillance tests (i.e., life unaffected by cancer or proctocolectomy). The decision tree is applied to the example of a 45-year-old patient with ulcerative colitis first diagnosed at age 35. Since the patient’s life expectancy is about 34 years, a biannual surveillance program would require 17 colonoscopies at a total cost for surveillance of 17 × $1000 = $17 000. Using the human capital approach, the value of life is equated with the life expectancy multiplied by the average annual earnings (i.e., value of life = 34 × $25 000 = $850 000). The HRQL after proctocolectomy is assumed to be 95%, compared with 100% for an unoperated healthy individual. A recent study reported a cancer mortality rate of 15% (mort1) in a population

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No CRC life $850 000 f

Figure 18.6 Decision tree for threshold analysis of surveillance in patients with ulcerative colitis. FN, false negative; FP, false positive results of surveillance colonoscopy; HRQL, health-related quality of life (95%); mort1 (15%) and mort2 (45%), cancer-related mortality in patients with and without surveillance respectively; P, cumulative probability of developing colorectal cancer (CRC); TN, true negative (specificity); TP, true positive (sensitivity).

with surveillance, as opposed to 45% (mort2) in a population without surveillance [83]. The sensitivity of colonoscopy in detecting premalignant lesions and preventing cancer-related death is estimated as true-positive rate (TP) = 80%, while the specificity is estimated as true-negative rate (TN) = 60% based on data taken from Connell et al. [84]. For surveillance to be the preferred management strategy, the upper main branch of the decision tree should result in a higher yield than the lower main branch: − Surveillance + P(TPa) + P(FNb) + (1 − P)(TNc) + (1 − P)(FPd ) ≥ P(e) + (1 − P)( f )

(18.4)

where TP is true positive, FN is false negative, TN is true negative, FP is false positive, and a–f are short forms to indicate the various outcomes. The cost for surveillance enters the equation with a minus sign, as opposed to the plus sign associated with the benefit of life-years saved. Equation 18.4 can be solved for the probability value of P: P≥

− Surveillance + (TNc + FPd − f ) (TNc + FPd − f ) − (TPa + FNb − e)

(18.5)

Although the formula may look daunting, the P-value is readily calculated on a spreadsheet. A probability of P = 16%

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is obtained using the values introduced in the preceding paragraph. This P-value suggests that, if the probability of developing cancer exceeds 16%, surveillance would represent a decision preferred over no surveillance. In the present example of a 45-year-old patient with a 10-year history of ulcerative colitis, the cumulative probability of developing cancer over the patient’s remaining lifetime of 34 years equals: P = 10 years × 0.5% + 10 years × 1.0% + 14 years × 1.5% = 36% (18.6) Considering the high risk of developing colitis-related cancer, biannual surveillance appears to be the better medical decision to make. Since the 36% probability of developing cancer exceeds the threshold P-value of 16%, surveillance becomes the preferred management strategy. The strength of the argument in favor of surveillance is directly proportional to the threshold value. A low threshold value would argue strongly in favor of surveillance. In contrast, a high threshold value that exceeds the lifetime probability of developing cancer would speak against the use of surveillance colonoscopy. Since the value of life appears as a variable in the final outcomes of all six branches in Figure 18.6, the actual costs calculated by the human capital approach exert little influence on the outcome of the analysis. The cost of surveillance pales in comparison with the benefit of life-years saved. Therefore, variations in the cost of surveillance also exert relatively little influence on the threshold probability. However, the outcome of the analysis very much depends on the other assumptions built into the model. It has been suggested, for instance, that HRQL remains largely unaffected by proctocolectomy [85]. Increasing HRQL from baseline 95% to 100% halves the threshold value from baseline 16% to 8%. In the baseline analysis shown in Figure 18.6, the following set of values were chosen: mort1 = 15%, HRQL = 95%, and TP = 80%. Slight variations lead to a second set of values: mort1 = 25%, HRQL = 85%, and TP = 70%. The resulting threshold value P = 45% lies outside the cumulative lifetime risk of the patient to ever develop colorectal cancer. The second set of assumptions is by no means extreme and seems to fall well within a reasonable range of the decision tree shown that might be expected by a widely distributed surveillance program. As these examples show, one can conceive similarly reasonable sets of assumptions that result in either excessively high or excessively low thresholds. Based on one’s preferences, one can use the decision analysis to either defend or refute the usefulness of surveillance colonoscopy. To narrow down the possible range of each assumption built into the decision analysis, a better set of data would be needed that can be obtained only through clinical studies. More refined decision models can be envisioned that account for the timedependent development of dysplastic lesions and their multistep transition into cancer [86]. Instead of comparing the two

Cost-effectiveness of Colonoscopy Screening

main branches of Figure 18.6, one can compare the outcome of two separate Markov chains that simulate the age- and timedependent occurrence of colorectal cancer. Other more complicated models also consider the transition from dysplasia to cancer, the expenditures arising from medical and surgical therapy, as well as the indirect costs of surveillance. However, a more detailed model provides a similar answer as the present threshold analysis. The argument in favor of or against surveillance depends on the assumptions built into the model) for which definitive data are lacking [86]. The decision analysis shows which factors are most relevant for the success of a surveillance program, but fails to provide a clear-cut answer as to whether such a program would be truly beneficial.

Limitations of cost-effectiveness analyses The decision for or against screening and prevention of colorectal cancer depends on many partly interrelated factors. These factors include the following: • family history of adenomatous polyps and cancer; • patient demographics; • presence of other comorbid conditions; • incidence and prevalence of colorectal polyps; • progression of various polyp types and other premalignant conditions to cancer; • sensitivity and specificity of competing diagnostic techniques; • invasiveness and risks of various diagnostic modalities; • surgical success at different disease stages; • adverse effects, disability, and mortality from surgery; • effectiveness of other treatments; • availability of medical interventions; • medical and nonmedical costs; • natural history, including mortality, of colorectal cancer. Many of these parameters do not remain constant but vary as the patient ages and the disease progresses. For instance, the sensitivity and specificity of all screening methods improve as the disease progresses from a small mucosal lesion, to a polyp, to small and eventually large cancer [87,88]. For the vast majority of associations, sufficiently reliable data do not exist. Different factors contribute differently to the disease and its prevention. Medical decision analysis helps to weigh the contribution of these factors and to choose between competing management options. Because the available evidence is often crude or incomplete, economic and medical decision analyses have to include many assumptions in their models. Although the individual assumption may have a small margin of error, the sheer multitude of assumptions built into a model can render its overall outcome susceptible to large variations. Even if the influence of individual factors is known and clinically well established, their interaction and joint influence often remain untested and unknown. For instance, it is known that colonoscopy is a

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good technique for diagnosing colon cancers and removing polyps, but less conclusive evidence exists that these single achievements actually prevent cancers or cancer-related deaths [89–91]. Even if screening colonoscopy prevented deaths from colorectal cancer, it would still remain to be proven that such a strategy actually saved lives and extended life expectancy [92,93]. It may well be that patients who are saved from death through colorectal cancer soon succumb to other diseases. Screening itself could be associated with untoward medical or social effects that, in the final balance, completely negate its seemingly obvious benefits [94]. In the review process of decision analyses submitted for publication, reviewers almost invariably suggest additions that make already complex models even more complicated and difficult to appreciate. The inclusion of many less relevant side issues distracts from the few important associations. Unfortunately, simple models are often misjudged as being primitive or inconclusive rather than transparent, insightful, or elegant. There is a general failure among medical reviewers to understand that, instead of painting a detailed picture of reality, ideal models are supposed to contain a simplified and condensed representation of a medicine that focuses on the few essential parameters. It does not help the clinician to have the complexity of his or her medical reality be replaced by the black box of an overly complicated model whose conclusions have to be taken at face value because the model has become too large and too detailed to fit the confinements of a journal article. Even experts may find it difficult to disentangle the intricacies of individual models and compare their outcomes [95]. To publish their decision analyses investigators are forced to oversell the relevance of their modeling efforts and present their outcomes as definitive answers to lingering medical problems. They restrict the ranges tested in the sensitivity analyses or avoid pointing out variables that shift the model out of balance. The investigators make their results appear more conclusive than they really are and advertise them as mathematically derived rigorous evidence for or against a particular medical strategy. Various medical specialists and their professional organizations pursue a political and economic agenda. Gastroenterologists, for instance, are interested in studies that confirm the relevance associated with endoscopic procedures, whereas radiologists want to emphasize the benefit of their imaging techniques, and generalists want to preserve the use of FOBT and flexible sigmoidoscopy as screening methods accessible to the nonspecialist. Rather than look at details of the analysis, CEAs are often accepted based on their outcome alone and whether they succeed in confirming a set of preconceived notions. However, medical decision analyses are generally less suitable for implementing a specific policy, but more suitable for highlighting which variables are important in influencing the medical decision or its outcome. It needs to be kept in mind that models serve only as guidance for assessing the potential outcome of a

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medical strategy. Economic and decision models do not obviate the primacy of clinical data gathered through controlled clinical trials.

Summary In comparing two competing screening strategies, the following scenarios may arise. If one strategy is cheaper and more effective than the alternative one, the decision in favor of the dominant strategy is made easy. The mixtures of more effective but more expensive or less effective but less expensive outcomes are sometimes difficult to decide upon without a formal cost-effectiveness analysis. However, physicians should not misread a cost-effectiveness analysis as guidance toward the best medical strategy. Compared with no screening, a single colonoscopy represents a very cost-effective screening strategy of less than $3000 per life-year saved. Repeat decennial colonoscopies save two to three times more lives than a screening program based on a single colonoscopy. The ICER of decennial colonoscopy compared with no screening amounts to $11 000 per life-year saved. Colonoscopy is also associated with a relatively modest ICER when used in addition to FOBT (i.e., $11 400 per life-year saved). In screening using flexible sigmoidoscopy, the costs saved on colonoscopies are partly offset by the additional expenses for two procedures in all patients with distal polyps and the higher expenses for cancer care among patients with missed proximal cancers. All other currently available alternatives, including CT colonography, fecal DNA testing, and NSAIDs for cancer prevention, are presently less cost-effective than a screening colonoscopy every 10 years. Economic and decision models are generally unreliable in predicting the exact outcomes of a specific screening policy, but more suitable for demonstrating which variables are most important in influencing its expected result. Models can only guide in comparing the potential outcomes of competing strategies: they do not obviate the primacy of clinical data gathered through controlled clinical trials.

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61 Bloom BB. Direct medical costs of disease and gastrointestinal side effects during treatment for arthritis. Am J Med 1988; 84(Suppl. 2A): 20–4. 62 Smalley WE, Griffin MR, Fought RL, Ray WA. Excess cost from gastrointestinal disease associated with nonsteroidal antiinflammatory drugs. J Gen Intern Med 1996; 11: 461–9. 63 Rahme E, Joseph L, Kong SX, Watson DJ, LeLorier J. Gastrointestinal health care resource use and costs associated with nonsteroidal antiinflammatory drugs versus acetaminophen. Retrospective cohort study of an elderly population. Arthritis Rheum 2000; 43: 917–24. 64 Suleiman S, Rex DK, Sonnenberg A. Chemoprevention of colorectal cancer by aspirin: a cost-effectiveness analysis. Gastroenterology 2002; 122: 78–84. 65 Ladabaum U, Chopra CL, Huang G, Scheiman JM, Chernew ME, Fendrick AM. Aspirin as an adjunct to screening for prevention of sporadic colorectal cancer. A cost-effectiveness analysis. Ann Intern Med 2001; 135: 769– 81. 66 DuPont AW, Arguedas MR, Wilcox CM. Aspirin chemoprevention in patients with increased risk for colorectal cancer: a cost-effectiveness analysis. Aliment Pharmacol Ther 2007; 26: 431–41. 67 Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–55. 68 Hawkey C, Laine L, Simon T, Beaulieu A, et al. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Arthritis Rheum 2000; 43: 370–7. 69 Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000; 95: 1681–90. 70 Baron JA, Sandler RS, Bresalier RS, et al. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 2006; 131: 1674– 82. 71 Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885– 95. 72 Ladabaum U, Scheiman JM, Fendrick AM. Potential effect of cyclooxygenase-2-specific inhibitors on the prevention of colorectal cancer: a cost-effectiveness analysis. Am J Med 2003; 114: 546–54. 73 Arguedas MR, Heudebert GR, Wilcox CM. Surveillance colonoscopy or chemoprevention with COX-2 inhibitors in average-risk post-polypectomy patients: a decision analysis. Aliment Pharmacol Ther 2001; 15: 631– 8. 74 Gyde SN, Prior P, Allan RN, et al. Colorectal cancer in ulcerative colitis. A cohort study of primary referrals from three centres. Gut 1988; 29: 206–17. 75 Gilat T, Fireman Z, Grossman A, et al. Colorectal cancer in patients with ulcerative colitis. A population study in central Israel. Gastroenterology 1988; 94: 870–7. 76 Maratka Z, Nedbal J, Kociánová J, Havelka J, Kudrmann J, Hendl J. Incidence of colorectal cancer in proctocolitis: a retrospective study of 959 cases over 40 years. Gut 1985; 26: 43–9.

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77 Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990; 31: 800– 6. 78 Ries LAG, Kosary CL, Hankey BF, Millaer BA, Harras A, Edwards BK. SEER Cancer Statistics Review, 1973 –1994. NIH Publication no. 97–2789. Bethesda, MD: National Cancer Institute, 1997. 79 Choi PK, Kim WH. Colon cancer surveillance. Gastroenterol Clin North Am 1995; 24: 671– 87. 80 Bauer WM, Lashner BA. Inflammatory bowel disease and intestinal cancer. Practical Gastroenterol 1998; 22: 20–9. 81 Rex DK. Surveillance colonoscopy in ulcerative colitis. Clin Perspect Gastroenterol 1999; 2: 9–15. 82 Delcò F, Sonnenberg A. The unsolved problem of surveillance for colorectal cancer in ulcerative colitis. Can J Gastroenterol 1999; 13: 655– 60. 83 Connell WR, Talbot IC, Harpaz N, et al. Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis. Gut 1994; 35: 1419–23. 84 Connell WR, Lennard-Jones JE, Williams CB. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994; 107: 934–44. 85 Provenzale D, Shaerin M, Phillips-Bute BG, et al. Health-related quality of life after ileoanal pull-through: evaluation and assessment of new health status measures. Gastroenterology 1997; 113: 7–14. 86 Delcò F, Sonnenberg A. A decision analysis of surveillance for colorectal cancer in ulcerative colitis. Gut 2000; 46: 500– 6.

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87 Eddy DM. Screening for Cancer: Theory, Analysis, and Design. Englewood Cliffs, NJ: Prentice Hall, 1980: 79–95. 88 Morrison AS. Screening in Chronic Disease, 2nd edn. Oxford: Oxford University Press, 1992: 60–6. 89 Selby JV, Friedman GD, Quesenberry CP, Weiss NS. A case– control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326: 653–7. 90 Müller A, Sonnenberg A. Prevention of colorectal cancer by flexible endoscopy and polypectomy. Ann Intern Med 1995; 123: 904–10. 91 Müller AD, Sonnenberg A. Protection by endoscopy against death from colorectal cancer: a case–control study among veterans. Arch Intern Med 1995; 155: 1741–8. 92 Koretz RL. Is routine screening for colorectal cancer justifiable? Postgrad Med 1997; 102: 49–62. 93 Koretz RL. Surveying the masses. Gastroenterology 2000; 119: 1403– 5. 94 Hoff G, Thiis-Evensen E, Grotmol T, Sauar J, Vatn MH, Moen IE. Do undesirable effects of screening affect all-cause mortality in flexible sigmoidoscopy programmes? Experience from the Telemark Polyp Study 1983–1996. Eur J Cancer Prev 2001; 10: 131–7. 95 Pignone M, Saha S, Hoerger T, Mandelblatt J. Cost-effectiveness analyses of colorectal cancer screening: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 137: 96–104.

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Standardization of the Endoscopic Report Michel M. Delvaux University Hospital of Nancy, Nancy, France

Computer technology has entered daily life and dramatically modified the management of medical data. Electronic endoscopes are currently used in most endoscopy units for colonoscopy. The use of these electronic endoscopes has allowed the capture of high-quality images to illustrate the report [1], and, more recently, significant advances have increased the diagnostic yield of endoscopy to detect colonic lesions, including the development of magnification endoscopes and the improvement of image quality and electronic chromoendoscopy [2]. Additional equipment tends to provide the examiner with pathologic patterns of the colonic mucosa [3], and, finally, new endoscopic techniques, including capsule endoscopy [4] and self-propelled endoscopes such as the Aer-O-Scope [5] have been introduced and are currently under investigation for examination of the colon. Consequently, the number of data describing the findings during a colonoscopy increases and deserves precise description. Over the same period, computer technology has grown at a tremendous rate, and the decreasing prices of hardware have made it accessible to all endoscopists. This situation constitutes a unique opportunity for developing cooperative studies sharing data issued from multiple endoscopic units. The CORI (Clinical Outcomes Research Initiative) project in the US has successfully demonstrated that the use of a common software in several endoscopy units could support such cooperative studies [6]. However, standardization of endoscopic data is far from being achieved in current practice. Exchange of data between existing systems is difficult and standard data formats have so far not been widely accepted by the community. Standardization encompasses both the text data and the images. The electronic formats of endoscopic pictures do not differ from those in use in commercially available software for digital cameras [i.e., TIFF

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

(tagged image file format), JPEG (Joint Photographic Experts Group)], which often include a certain level of data compression. A standard format has been proposed for radiology images, the DICOM (Digital Imaging and COmmunication in Medicine), which now includes a supplement for visible lightacolorapictures [7]. However, endoscopic images are necessarily linked to the text description of the findings, which remains currently the most important part of the information to be shared between the physician performing the endoscopic procedure and the referring physician. For many years, attempts have been made to standardize the endoscopic report and the format of endoscopic data. Initiatives aimed at developing a common software supported by scientific societies failed [8]. On the other hand, general software currently in use, such as word processors, support an easy exchange of data with the larger use of XML (extensible markup language) files. Nevertheless, software supporting databases of endoscopic data and processing of endoscopic reports remains remarkably heterogeneous, including old home-made databases, software provided by the manufacturers of endoscopes, and commercially available programs. These applications use different user interfaces and data structures so that they are poorly compatible with each other. Moreover, the interface between database applications and hospital information systems (HIS) is improving all the time, enabling sharing of data with other applications used for the management of patiens. For all these reasons, it is evident that endoscopic text data need to be standardized. This standardization should not only enable an easier exchange of data, but also increase the quality of the medical content of the endoscopic report [9]. Two standardization efforts deserve particular attention, as they should actually enable standardization of endoscopic reports and data exchange. The Minimal Standard Terminology (MST) has been designed as a “minimal” list of terms that could be included within any computer system used to record the results of a gastrointestinal endoscopic examination [10]. It followed the initial attempt by Maratka [11] to systematize nomenclature in digestive endoscopy. In

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this chapter, we shall discuss these two aspects of the endoscopic report: the data elements that should be present in the report and the way endoscopic terms can be standardized to describe some specific data fields, such as the reasons for which an examination is performed, the endoscopic findings, and the endoscopic diagnosis. The DICOM supplement for visible light images [12] supports the standardization of the data surrounding an endoscopic image so that it can be exchanged between different information systems, not imposing a unique picture format but organizing the data that describe the picture.

Organization of the endoscopy report Type of data managed in an endoscopy unit The performance of an endoscopic examination requires that data be available and managed before the procedure and generates other data as its result (Figure 19.1). Data used before the procedure include scheduling the procedure, the administrative data of the patient and his or her clinical antecedents, clinical history, and results of other tests. These data, when recorded in a computer system, are managed in the HIS. Input of data into the system is not performed in the endoscopy unit, except in case of direct admittance of the patient to this unit for a specific procedure. By contrast, a link needs to be established between the HIS and the endoscopy information system in order to avoid duplicate data entry and decrease the risk of errors between data recorded in the two systems.

Data managed in the endoscopy unit can be divided into two categories: the text data and the images. The text data include all the descriptors of the procedure, the endoscopic findings, and the endoscopic diagnosis or conclusion of the examination. The images include still color images and, possibly, video sequences recorded during the procedure. It is important to understand how these different types of data are generated during an endoscopic procedure to design software solutions that will accurately manage them. In the last few decades, the initiative was to develop large and complex software solutions for computer-based editions of the report, but this failed. Currently, data input into the recording system varies widely from unit to unit: handwritten and dictated reports are the most common ways of entering data, both of which are based upon the use of natural language. Shifting to a computerized recording system imposes, to some extent, the use of a structured language that can be analyzed and handled by the application (see below).

Organization of the data in an endoscopic database Several types of endoscopic databases have been proposed. However, the most effective one is the “object-oriented” database of the relational type. The database is made of several separate folders in which data are stored according to their nature. Therefore, one patient whose demographic data are stored in one file can undergo several examinations, for each of which a separate file will be created. Each examination will contain text data and images, the latter being stored in a separate folder, so that an examination can include an unlimited number of images (Figure 19.2). When data are

Hospital Information System Patient administrative data Name, first name Age, gender Address Social security, Insurance...

HL-7

Patient clinical information Clinical history Antecedents Laboratory tests

Results other procedures X-rays Functional testing Pathology

DICOM CORBA Med

ICD SNOMED

Endoscopic Report

HL-7

Physician administrative data Name, first name Address Qualification... Schedule

MST

Unit administrative data Planning Nursing staff Devices available Safety, disinfection Device available

Procedure data Type Date, time Examiner Room Devices Reasons for performing Indication

Endoscopic Information System

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Endoscopy results Findings Diagnostic procedures Therapeutic procedures Endoscopic diagnosis Complications Recommendations

DICOM

Images

Figure 19.1 Data sets to be managed in the endoscopic information system and relationship with the hospital information system. For each set of data, standard data formats are figured. MST, Minimal Standard Terminology for Digestive Endoscopy.

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PATIENT

Date of visit Referring physician Place of visit

VISIT

STUDY

Figure 19.2 Architecture of a relational database showing the various files that contain the data and the multiple relationships that can be established between them.

recorded, they are stored in the relevant files. The software of the database is organized in a way that allows it to retrieve data from the different files to build an “object” made of the data set relevant for a given examination and send it back to the screen or the printer as the response to a query. Figure 19.3 shows the structure of an object that would contain all of the information needed to describe an endoscopic procedure, which will then be included in the endoscopic report.

Findings Site Term Attribute Attribute value(s)

Study time Type of procedure Operator Anesthesia (multiple elements) Indication/reason for Extent of examination...

RESULTS

DIAGNOSIS Therapy Term Attribute Attribute value Treatment Follow-up Complications

Patient name Date of birth Sex Patient ID type internal Patient ID SSN

Initial diagnosis Pathology results Final diagnosis Codes: ICD9/10...

THERAPY

The content of the endoscopic report The text data constitute the core of the endoscopic report: they include the data describing the endoscopic procedure and the endoscopic findings. Historically, the text data have been the only information included in the endoscopic report, which was often handwritten or dictated. The endoscopic report was the method for delivering the results of the procedure to the physician managing the patient. The American Society for Gastrointestinal Endoscopy (ASGE) provided minimal guidelines for the content of this endoscopic report, with a list of the necessary items that should be present (Table 19.1) [13]. The data set logically includes all the data that describe the visit of the patient to the endoscopy suite and the study that is performed. The data follow the stream of the visit, as shown in Figure 19.3. This figure represents the minimal level of information that needs to be included in the report. However, some difficulties are encountered when data are generated outside the endoscopy unit (e.g., administrative data) or after the end of the endoscopic procedure (e.g., the pathologic results of the biopsies or other samples obtained during the colonoscopy). Finally, it may be questionable to consider whether or not the final diagnosis (i.e., the one based on the results of the biopsies) and sometimes further clinical or biologic data available post hoc must be regarded as part of the endoscopic report. The evolution of the endoscopic practice and the increasing importance of information concerning the details of the

Figure 19.3 Organization of the data elements belonging to the endoscopic report in a structured object that can be used as a model for standardization of the data set.

Table 19.1 Structure of an endoscopic record. 1 Patient demographic data 2 Date of procedure 3 Endoscopist 4 Type of endoscopic examination performed 5 Instruments used 6 Reasons for examination 7 Medication details (anesthesia, anesthesiologist, analgesia, sedation . . . ) 8 Anatomical extent of examination 9 Limitation(s) of examination 10 Findings and specimens obtained 11 Endoscopic diagnosis 12 Therapeutic interventions and results 13 Notation of images captured 14 Complications 15 Discharge arrangements 16 Comments 17 Results of biopsies and other late tests 18 Final diagnosis

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procedure have led to the addition of new data to the ASGE data set. Disinfection procedures need to be described, and the exact serial number of the endoscope and therapeutic accessories must be recorded, in addition to the sequence of events during the procedure. This dramatically increases the number of items included in the report. Moreover, some of these items will be recorded according to local regulations for coding of the procedure, reimbursement, and insurance. An adapted template of the report can also be proposed for specific research purposes or clinical situations. A good example of this adaptation is the “standard” colonoscopy report recently proposed by the US National Colorectal Cancer Roundtable [14]. This group suggests an exhaustive list of data that should appear in any colonoscopy report in order to improve the quality of the procedure. The proposal is mainly oriented toward an increase in the yield of epidemiologic data about colorectal cancer screening and the rate of detection of polyps. However, some of the items are relevant to any endoscopic procedure.

The Minimal Standard Terminology for standardization of the endoscopic report Background and principles The initial attempt to systematize endoscopic nomenclature was made by Maratka [11] and published as the OMED [Organisation Mondiale d’Endoscopie Digestive (World Organization of Digestive Endoscopy)] Terminology. Despite its clever design, acceptance was very low in the endoscopic community and it was never implemented in practical reporting systems. Therefore, a project was started by the European Society of Gastrointestinal Endoscopy, in cooperation with the American and Japanese Societies for Gastrointestinal Endoscopy [15]. The major aim of the project was to devise a “minimal” list of terms that should be included within any computer system used to record the results of a gastrointestinal endoscopic examination. It was decided that the terms selected must have wide acceptability and provide a means for recording the findings in the majority of examinations performed. Excessive detail was to be avoided and rare findings were to be recorded using “free text” fields. Each term was selected on the basis that it would be expected to be used in at least 1 out of 100 consecutive examinations. The only terms included that did not fit this criteria were descriptive terms (e.g., parasites) that could be found only in certain areas of the world where they might be relatively common. To facilitate implementation and allow a more complete description of observations, when necessary, qualifying attributes were attached to terms which provided additional detail. The attributes were a list of descriptive concepts, such as size, number, extent, for which there were a series of values appropriate to that term. Every described lesion was placed in its location by the use of a list of sites relevant to the

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organ being examined. By this construction, the lists of terms with the specifications given by the attributes translated the concepts evoked by the users into a structured language.

Structure of the Minimal Standard Terminology and sections of the endoscopic report The Minimal Standard Terminology (MST) is structured in lists of terms that cover the main types of endoscopic examinations (i.e., upper gastrointestinal endoscopy, colonoscopy, and endoscopic retrograde cholangiopancreatography), with an additional complementary list of therapeutic procedures that might be performed (Figure 19.4). These lists contain terms that define concepts describing the medical fields of the endoscopic report.

Reasons for examination The lists of terms describing the reasons why an endoscopy is performed are presented as “reasons for performing an endoscopy.” The concept is broader than the list of indications, as some examinations may have been performed for reasons that are not accepted as indications. An “indication” is used to define the reason for an endoscopy that complies with generally accepted standards of practice. There may be reasons for an endoscopy which are not indications. For example, a patient may want to undergo annual colonoscopy for colorectal cancer surveillance even though there is no prior history of polyps or family history of colon cancer. The reason for colonoscopy is to exclude a tumor, but there is no “indication.”

Extent of the examination This section refers to the characteristics of an examination and is defined as the anatomic extent of the examination. Limit of the examination is defined as any limitation that impedes adequate execution of the procedure. It is recognized that there is some overlap in the concepts of extent and limit. The intent of this section is to convey in an explicit manner those characteristics of the examination that affect the completeness of the examination, any limitations that prevent a complete examination, and any maneuvers necessary to execute a complete examination. For colonoscopy, if the cecum is reached, then the anatomic site “cecum” specifies the extent of examination. The quality of bowel cleansing is a major factor for the quality of the procedure, especially when small and flat lesions are sought. Poor preparation is considered a limit of the examination.

Findings Findings cover the description of observations made during an endoscopic procedure, without necessarily linking them to a global diagnosis. One must distinguish “elemental” lesions that are described individually (such as a polyp) from a collection of abnormal patterns, each of which could be an elemental lesion (ulcer) but taken together constitute

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Procedure

Reasons for

Examination data

Symptoms

Extent

Diseases

Conditions

Assessment

Maneuvers

Organ

Findings

Additional procedures

Diagnosis

Normal

Diagnostic

Main diagnosis

Lumen

Therapeutic

Other diagnosis

Sampling Content Therapeutic Flat lesions Protruding lesions Excavated lesions

Figure 19.4 Organization of the Minimal Standard Terminology and hierarchy of terms as they are displayed in the tables. This hierarchy follows the logical pathway used by endoscopists to build in an endoscopy record.

a finding. In the colon, the typical example would be an ulcerated mucosa which is almost always a combination of ulcers and congested and friable mucosa. Terms used to describe functional changes, such as contractility and elasticity of the wall, increased or decreased peristalsis, functional narrowing, or extrinsic distortion, have been excluded from the MST, as they were considered to be too subjective and imprecise to aid in making a diagnosis. In addition, these terms were too open to misinterpretation for use in any multicenter studies. Particular attention has also been given to avoiding synonyms and terms that describe concepts that are too narrow and in daily practice were observed to frequently overlap and lead to unnecessary detailed descriptions. As an example, the original OMED terminology proposed many terms describing stenosis of the lumen. However, stenosis, stricture, narrowing, compression and obstruction have been discarded to be replaced by the unique term “stenosis”.

of all of the findings recorded. This is particularly true when a number of different lesions are described, such as with inflammatory bowel diseases at colonoscopy. It is also recommended that it should be possible to record a “negative conclusion” as well as a positive one. It is often as important to record that a feature is not present as it is to describe that it is, for example the failure to find any sign of bleeding when a patient presents with an apparent gastrointestinal bleed. It is suggested that it be possible to qualify a diagnosis by “certain,” “suspected,” “probably not present,” and “definitely excluded.”

Therapeutic and diagnostic procedures This section is intended to describe the additional maneuvers that are undertaken in the frame of an endoscopic procedure to either increase its diagnostic yield by sampling tissue or biological fluid from the examined gut segment, or treat a disease with an endoscopic technique.

Endoscopic diagnosis This indicates the diagnosis, single or multiple, that the endoscopist feels is most likely on the basis of macroscopic findings. This is not necessarily the final diagnosis, which takes into account the findings of any additional procedures performed such as biopsy or cytology. The list of diagnoses has been split into two parts: (i) main diagnoses, ordered by expected prevalence; and (ii) other (rarer) diagnoses listed alphabetically. The decision on which list a particular diagnosis appears is based upon the expected frequency of this finding in a routine clinical context. This “diagnosis” could be used to implement a “conclusion” field within any report generated. Such a conclusion would be based on a synthesis

List of terms for colonoscopy and difficult terms Lists of terms in the MST have been customized to the pathology specific for each gut segment, according to the frequency of lesions and the particular relevance of pathologic conditions. To facilitate the implementation in endoscopic reporting software, the terms have been classified under headings that cover large categories of lesions found in each section (Table 19.2). Headings have been defined according to the relationship of lesions to the mucosa, which is the main anatomic area investigated and is always examined during the endoscopic procedure. Table 19.3 shows the list of terms that have been selected to describe findings in the

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Table 19.2 Major headings for grouping of terms in the structure of the Minimal Standard Terminology. 1 Normal 2 Lumena

3 Contents 4 Mucosa

5 Flat lesions 6 Protruding lesions 7 Excavated lesions

Should be used if the organ has been entirely examined and everything in it is normal Contains all terms regarding an abnormality of the size of the organ, any deformity, any compression, and evidence of previous surgery Terms describing the presence of various materials within the organ Terms describing patterns of the mucosa that are mainly diffuse and may involve all the mucosa of one limited area. These terms are not applicable to individual lesions Terms to be used for individual lesions which remain in the plane of the mucosa Terms to be applied to lesions growing above the plane of the mucosa Terms to be applied to lesions whose surface is beneath the plane of mucosa

a

This heading also includes some terms classified under “Wall” in the OMED [Organisation Mondiale d’Endoscopie Digestive (World Organization of Digestive Endoscopy)] terminology.

colon. Some of the terms proposed in this list may be difficult to use in the proper way, as surveys during the development and validation phases of the MST have shown that they were used with a wide variability in their meaning or that multiple synonyms were used. On the other hand, the selection of a term had to take into account the need for a very precise descriptive word and the acceptability of these words among physicians from different countries with different native languages. The following terms appeared difficult to use in view of the results of the validation studies (see below) and deserve further explanation: • Stenosis is replacing several descriptions of a narrowed segment of the gut, such as “narrowed,” “strictured,” “stenosed,”

and “compressed” (Figure 19.5). The same term has been used to describe the narrowing of a sphincter that either prevents the passage of the endoscope or requires force to traverse it. Functional terms such as “spasm” have been avoided because of their subjective nature. Once a stenosis has been described it is qualified by attribute values such as “extrinsic,” “intrinsic benign,” or “intrinsic malignant,” depending on the probable cause. In the case of an extrinsic compression, when actual stenosis of the lumen does not occur (e.g., the aortic prominence), the term stenosis should not be used. • Red mucosa, erythema, congested mucosa, and hyperemia were found to be used frequently in a random manner to describe roughly similar lesions or mucosal patterns. Two terms were selected: erythematous mucosa, defined as either a focal or diffuse reddening of the mucosa without any other modification; and congested mucosa, defined as a combination of erythema with an edematous, swollen, or friable mucosa (Figure 19.6). Owing to the large overlap between these terms, it was agreed that hyperemia was equivalent to erythema, and edematous was equivalent to congested mucosa. So these words could be used as an alternative but not added to the list of terms proposed by the software. • Erosion and aphtha are frequently understood as similar lesions. In the original OMED terminology, the term erosion was avoided because it was considered to be imprecise and required histological confirmation; aphtha was, therefore, the preferred term. However, the term erosion appears to be in such common use in many languages that it was included among the minimal standard. Erosion is defined as a small superficial defect in a mucosa, of a white or yellow color, with a flat edge. This may bleed, but the term should be used only when the mucosa is clearly seen and is not covered by blood clot (Figure 19.7). It was decided to retain the term aphtha for lesions of the colon, as it was agreed that aphthae were identified more frequently in this area and were recognized as a diagnostic feature of “Crohn’s disease.” In this context, aphthae are defined as yellow or white spots,

Figure 19.5 Example of colonic stenosis from a benign process (left) or a malignant one (right).

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Table 19.3 List of terms, attributes, and attribute values describing the findings at the level of the colon. Headings

Terms

Attributes

Normal Lumen

Normal Dilated Stenosis

Appearance

Evidence of previous surgery

Length (cm) Traversed Type

Suture material visible

Attribute values

Extrinsic Benign intrinsic Malignant intrinsic Yes/no Colocolonic anastomosis Ileocolonic anastomosis Coloanal anastomosis Ileoanal anastomosis Colostomy Specify

Sitesa Site(s) Site(s) Site(s)

Site(s)

Contents Blood

Kind of blood

Red Clot Hematin (altered blood)

Foreign body Parasites Exudate Stool Stent

Type

Specify

Vascular pattern

Appearance

Normal Increased Decreased Localized Segmental Diffuse Localized Segmental Diffuse Localized Segmental Diffuse Localized Segmental Diffuse Localized Segmental Diffuse Yes: spontaneous Yes: contact bleeding No Discontinuous Continuous Yes No Yes No Few Multiple Localized Segmental Diffuse Localized Segmental Diffuse

Site(s)

Site(s) Site(s) Site(s) Site(s) Site(s)

Mucosa

Extent

Erythematous (hyperemic)

Extent

Congested (edematous)

Extent

Granular

Extent

Friable

Extent

Bleeding

Ulcerated mucosa

Continuity Bleeding Stigmata of bleeding

Petechiae

Number

Pseudomembrane

Extent

Melanosis

Extent

Site(s)

Site(s)

Site(s)

Site(s)

Site(s)

Site(s)

Site(s) Site(s)

Site(s)

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Table 19.3 (cont’d ) Headings

Terms

Attributes

Attribute values

Angioectasia

Number

Single Few Multiple Small Medium Large Localized Patchy Diffuse Yes No Yes No

Sitesa

Flat lesions

Sizeb

Extent

Bleeding Stigmata of bleeding

Protruding lesions Polyp(s)

Number

Extentc

Size Pedicled Bleeding

Pseudopolyps

Extent

Lipoma

Size

Tumor/Mass

Diameter Size

Diameter Length Type

Obstructing Circumferential Bleeding

Stigmata of bleeding

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If fewer than five, specify If more than five, specify: many or multiple Localized Segmental Diffuse In mm Sessile Pedunculated Yes No Stigmata of bleeding Localized Segmental Diffuse Small Medium Large In mm Small Medium Large In mm In cm Submucosal Fungating Ulcerated Infiltrative Frond-like/Villous Partial Complete Yes No Yes: spurting Yes: oozing No Yes No

Site(s)

Site(s)

Site(s)

Site(s)

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Table 19.3 (cont’d ) Headings

Terms

Attributes

Attribute values

Sitesa

Hypertrophy anal papillae Hemorrhoids

Bleeding

Suture granuloma

Number

Yes No Single Few Multiple

Site(s)

Condylomas Excavated lesions Erosion

Number

Extent

Bleeding Stigmata of bleeding Aphtha

Number

Extent

Bleeding Stigmata of bleeding Ulcer

Number

Size Bleeding

Stigmata of bleeding Scar

Number

Diverticulum

Number

Opening Fistula Anal fissuree

Single Few Multiple Localized Segmental Diffuse Yes No Yes No Single Few Multiple Localized Segmental Diffuse Yes No Yes No Single (solitary) Few Multiple Largest diameter in mm Yes: spurting Yes: oozing No Yes No Single Multiple Single Few Multiple Small Large

Site(s)

Site(s)

Site(s)

Site(s) Site(s)

Site(s)

a

Site recording should mainly be multiple for colonic findings. Size could, in this case, also be given in mm for small angioectasia. c This attribute will apply only when describing multiple polyps. d In case of multiple polyps, the application would allow the recording of multiple entries. e Fissure is the preferred term instead of erosion, which could be confused with colonic erosions. b

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Figure 19.6 Erythematous mucosa in the colon, defined as an increased redness of the mucosa, due to an increase in its hemoglobin content because of increased blood flow (left), which should be distinguished from a congested mucosa, defined as a swelling of the mucosa due to an increase in the mass of the mucosa, occuring most often in association with an inflammatory process where permeability of cell membranes is altered and the extracellular osmolarity is modified (right).

Figure 19.7 Erosions of the rectal mucosa (left) and typical aphthae (right).

surrounded by a red halo, and frequently with a spot in the center. Aphthae are frequently seen within a congested or erythematous mucosa and are often multiple (Figure 19.7). • Tumor and mass are regarded as synonyms that have been introduced to comply with local habits in some parts of the world. The word tumor is preferred to describe any lesion that appears to be of a neoplastic nature but is without any attempt to say whether it is benign or malignant. It is not used for small lesions such as granules or papules, or for other protruding lesions such as polyps, varices, or giant folds. The conjoint ASGE review revealed difficulty with this term as, in the US, a patient might assume that a tumor is a malignant lesion. For this reason, it has been agreed that the term mass could be used as an equivalent term when needed. • Angioectasia has been selected as a generic term encompassing both telangiectasia and angiodysplasia. This is because there are no precise visible diagnostic criteria that will allow one to distinguish between these two lesions. This term can also be applied to congenital and acquired vascular malformations within the mucosa of the gastrointestinal tract.

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• Scar is preferred to the term fibrosis as the latter implies a histologically confirmed process. The cicatricial aspect of the mucosa after healing of an ulcer or following a therapeutic maneuver (e.g., injection sclerosis, laser photocoagulation) seems to fit better with the word scar. • Occlusion and obstruction, although frequently regarded as synonyms, should be distinguished, as obstruction means blockage of a tubular structure by an intraluminal obstacle (e.g., foreign body), while occlusion implies complete closure of the lumen by an intrinsic lesion of the wall (e.g., fibrosis from a healing process). Although obstruction and occlusion can be either partial or complete, the use of these two terms was felt to be confusing and created difficulties when translated into other languages. In the case of the colon, the use of the term obstruction is restricted to the presence of an exophytic tumor in a tubular organ that partially or completely occupies the lumen of a gut segment. • Ulcerated mucosa is defined as an endoscopic pattern made of multiple ulcers frequently joining each other and diffusely distributed over a gut segment, usually the rectum (Figure 19.8). Mucosa between the ulcers appears congested, friable,

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Figure 19.8 Similar elements describable by the same aggregate of words (ulcers, erythema, congested mucosal) can represent different clinical diagnoses (left, ulcerative colitis; right, Crohn’s disease). Structured language manages this by following the descriptor words with the probable specific diagnosis.

and swollen. It is emphasized that this term should be used only in the case of a diffusely ulcerated mucosa when the endoscopist distinguishes this concept from “ulcers” that are multiple (Figure 19.8). However, it is recognized that the use of this term needs to be evaluated in prospective trials, in order to better define its meaning and whether it is a distinct concept from the term ulcer.

Validation of the Minimal Standard Terminology Validation of the MST has been performed in two multicenter studies, one undertaken in Europe and the other in the US [16,17]. The MST has been designed to meet the requirements of routine endoscopy, without addressing specific details related to particular clinical studies or rare findings and diagnoses. Thus, the following criteria were applied during the testing: terms covering less than 1% of recordings should be discarded, analysis of free text fields should detect synonyms, and subjective descriptions, or terms lacking specificity and prone to misunderstanding, should not be

included. When analyzing the results, it appeared that the threshold of 1% of routine recordings was inadequate because of the high prevalence of normal examinations and of a few findings, including, in the case of colonoscopy, polyps and diverticula. A total of 6232 reports were analyzed, including 1743 colonoscopies in the European study [16]. Overall, terms originally contained in the MST could fully describe 91.0% of all examinations in which “reasons for” were described, 99.5% of examinations in which “findings” were described, 95.8% of all examinations containing descriptions of “endoscopic diagnosis,” 98.9% of examinations containing descriptions of “additional diagnostic procedures,” and 94.8% of examinations containing descriptions of “additional therapeutic procedures.” Free text fields were only used in the other cases (less than 5% of cases on average). Results are presented in Table 19.4. Data on over 17 000 procedures were analyzed in the US study, to determine the utilization of the MST [17].

Table 19.4 Number of descriptions described using terms originally in the Minimal Standard Terminology’s Results of the European Testing (GASTER Project). Esophagogastroduodenoscopy Number of examinations described

Reasons for Findings Endoscopic diagnosis Additional diagnostic procedure Additional therapeutic procedure

Colonoscopies

Number of examinations fully described

%

4125 11 803 7180 1856

3499 11 448 6803 1850

178

166

Number of examinations described

Number of examinations fully described

%

84.8 97.0 94.7 99.7

2076 2901 1821 505

1745 2790 1611 497

93.3

260

252

Endoscopic retrograde cholangiopancreatography Number of examinations described

Number of examinations fully described

%

84.1 96.2 88.5 98.4

1267 4267 2068 110

1125 4023 1615 89

88.8 94.3 78.1 80.9

96.9

691

638

92.3

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Table 19.5 Results of the testing in the US Minimal Standard Terminology (MST) Lexicon Testing Project: total number of examinations and findings. Examination type

Number of examinations

Number of abnormal findings

Number of findings described with MST

Percentage of findings described with MST

All EGD Colonoscopy ERCP

17 426 8136 8296 994

33 115 20 310 11 310 1495

31 079 19 030 10 614 1435

94 94 94 96

EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancreatography.

The use of a structured language for producing endoscopic reports may require users, i.e., endoscopists, to make the effort to become familiar with the structure of that language, modifying their previous routine in order to transmit the concepts that they would intend in their natural language, while conforming to the dataset available. This action of splitting the data into elements requires the design of data models that will meet the actual situations in which the users are working.

logical integration of the data along the pathway that should be followed by the endoscopist building a report in natural language (see Figure 19.3). Using such a structured language offers the possibility of integration of all the data elements in an “object” (i.e., a set of data that is organized in a rigid structure and which can be shared and understood by different systems). These objects can then be easily transferred from one system to another. Moreover, these objects can be easily retrieved from databases, as relational databases currently used in medical informatics are increasingly being built as “object-oriented” databases. Another advantage of this database architecture is that data can be retrieved in the form of structured subsets, in a fast and secure process.

The modeling of a structured language as a basis for standardization

Clinical benefits for the use of a structured language

An endoscopy report can be thought of as a file which contains a series of documents defined by the needs of practice and filled in with the data generated during a procedure. A standardization process of these data supposes that all the data elements that can be potentially introduced in an endoscopic report are kept in consideration and integrated into the model. On the other hand, a model integrating these data elements must be comprehensive for the user, as the data must be introduced in a logical way in the database and then retrieved to build up the report. Therefore, when all the data elements have been identified, one must create a coherent grouping of these elements. The MST lists provide these data elements. However, they need to be organized in a logical way. As DICOM has integrated all data elements related to medical images in a standardized list of fields [7], the MST attempted to utilize a similar interdependent message/ terminology architecture. In the near future, this effort should result in the SNOMED (Systematized Nomenclature of Medicine) DICOM microglossary for digestive endoscopy, which will enable the creation of templates for the content of the endoscopic report and thereby suggest value sets for the coded entry of the various fields of the report [18]. This structure platform of the data presupposes a detailed analysis of the data elements and their mutual relationship. Based on the results of this analysis, the model can be proposed as a

Although advances in endoscope technology have allowed the production of high-quality video images to be transmitted, captured, and stored by modern, high-speed integrated circuits, image documentation and reporting have not progressed as quickly. However, the constant increase in the use of computers for the management of medical data has induced a strong need for the standardization of the data to be exchanged. Standardization means the coding of the data in a common format that can be read by multiple information systems, operated on different platforms. This goal is achieved by actions such as DICOM or HL7 (Health Level Seven), but also goes far beyond the medical needs: image formats such as JPEG, TGA (Truevision Graphics Adapter), and TIFF have been developed for purposes other than medicine. However, a medical image without the relevant associated data is of no value [19]. Thus, the need for standardization of medical text data has become stronger over the last decade. Exchange of medical data presumes a mutual understanding between users at both ends of the chain along which exchange will occur: this statement encompasses the standardization of definitions of terms, the multilingual approach to terms and descriptions, and the fact that there are sufficient data to express the clinical situation. This very important issue can be addressed only by intensive testing of

Detailed data have been obtained from esophagogastroduodenoscopies, colonoscopies, and endoscopic retrograde cholangiopancreatographies and are presented in Table 19.5.

Advantages of the use of the Minimal Standard Terminology for the editing of endoscopic reports

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any standard system in actual clinical settings. Prospective trials must be undertaken for validation of the standards. In turn, these standards, when used for clinical research, will enable cooperative studies, large-outcome research protocols, and quality assurance processes. The use of structured reports in endoscopy, based on a structured language like the MST, will allow the statistical analysis of the databases based not only on the coded data using rigid coding systems (such as the International Classification of Diseases), but also on the complete set of available data. Indeed, in a database structured with the MST, not only can the terms themselves be analyzed, but the attributes and attribute values can also be counted. The analysis of the data will thus be more detailed. The advantage for clinical research is obvious: standardization of the data in digestive endoscopy will support multicenter trials, overcome the problems of multilingual data recording in cooperative studies, and promote outcome research. The last point will become very important in the near future. Advances will be obtained only with the analysis of large sets of data and will be based on the evaluation of the following features: 1 adequacy of data descriptions of observations; 2 measurement of appropriateness of diagnostic and therapeutic decisions made for the patient; 3 precise description of technical approaches to diseases; 4 multidisciplinary understanding and management of diseases. All of these actions need an integration of medical data, initially at the level of each specialty but also as data exported from the specialized unit (i.e., the endoscopy unit) to the integrated care unit, through the HIS. In the past, large standardized systems have failed to cover medical data as a whole. This justifies the approach of the SNOMED to now promote the validation of microglossaries in specialty-related domains and to integrate these microglossaries at an upper level, making them interoperable through a common structure [20].

Standardization and exchange of images in digestive endoscopy For many years, standardization of image format in medical applications has been driven by radiologists, as they had the technical possibility of handling digitized images far before other specialties. However, when the technical advances have introduced digitized images in endoscopy practice, the need for a standard allowing the exchange of images between various systems has raised the possibility of adapting the DICOM system for the exchange of color pictures generated during endoscopic procedures. Initially produced as “an endoscopy supplement” to DICOM 3.0, the scope of this supplement has quickly been extended to other modalities that produce images in visible light, such as ophthalmology, dentistry, and pathology [12].

Standardization of the Endoscopic Report

On the other hand, the increasing use of digital cameras in daily life has stimulated the development and acceptance of standard formats for digital color images. Endoscopic images are processed with the same compression algorithms, known as JPEG and TIFF [21]. The specific needs for the medical use of these images encompass the link with the text data constituting the report, the exchange of these images with the HIS and the databases containing the patient file, and the liability of the data for protection of personal medical records. It is not the intent of this chapter to discuss technical issues in standardization of endoscopic images; however, the points that are covered are related to the medical use of these images, in relation to the production of the report.

Production of digital endoscopic images Only electronic video endoscopes provide endoscopic images with resolutions high enough to support their digitization and use in computers. Video endoscopes create analog images made of a video signal stream that is transformed into a digital signal by the frame grabber board of the computer linked to or included in the endoscopic workstation (Figure 19.9). The size of the electronic file containing the image depends on the number of color levels: usually 16.8 million are required to obtain a high-quality definition of the original image created by the endoscope. Until recently, the various types of endoscope-created images ranging from 160 000 to 240 000 pixels, resulting in files of about 500 kB (kilobytes) in size. Using compression algorithms, the size can be reduced between 2 and 10 times without any significant loss of image quality, depending on the compression method. For instance, the compression type that can be selected is based on the compression algorithm that was initially developed by JPEG, which evaluated a compression algorithm that takes into account the fact that the human eye is more sensitive to brightness changes than to small color changes. Therefore, the compression algorithm reduces the color information more than the brightness information in the image. Although the compression algorithm is lossy by definition, it is optimized for “real-world” photos and is especially appropriate for images with a relatively small number of different colors, without extremely sharp edges (i.e., high levels of contrast), and without too many relatively small details of different colors. Endoscopic images fit fully into this frame since they contain a limited color spectrum and no sharp contrast areas. More recent electronic endoscopes are equipped with high-resolution charge-coupled devices (CCDs) generating images of one million pixels. This high resolution not only increases the quality of the image but also enables the use of magnification to examine details of the mucosal surface.

Management of endoscopic images in computer systems When an image has been captured by the frame grabber board, it must be transferred to the storage device where it

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Endoscope

Electronic light source

Keyboard

Digital

Analog

Camera pictures

will be hosted. This step is processed according to common standard formats for color images. The DICOM protocol organizes the transfer of images between computers based on different operating systems. Thereby, the DICOM protocol ensures the following features: 1 promotion of the communication of digital image information, regardless of the equipment or manufacturer producing this image; 2 facilitation of the development and expansion of picture archiving and communication systems (PACS) that can also interface with other systems within the HIS; 3 creation of diagnostic information databases that can be interrogated by a wide variety of geographically distributed devices. To achieve these goals, the DICOM standard organizes the data describing each image and the text data of the examination to which it belongs into an entity that is called an object (see section Organization of the data in an endoscopic database). This object is made of various data that are each identified with a specific header telling the computer what kind of data are stored. Data are organized in three levels, depending on their importance for a proper reading of the file. Mandatory data are those that need to be present for any image (e.g., the content of each pixel that composes the image, or the total number of pixels). Conditional data are required only in some circumstances (e.g., the name of the patient or his or her identifier in the HIS, which are required only when a nominative report needs to be created). Optional data are regarded as not necessary for the accurate transfer of the data and are left to the particular requirements of a given application (e.g., the patient’s address and insurance numbers will be used only in specific applications but are not part of the endoscopic report). The structure of the DICOM standard, whatever the type of image exchanged between systems, is based on the model of distributed processing. Distributed processing has at least two

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Figure 19.9 Process of digitization of endoscopic images in an endoscopic workstation including an electronic video endoscope and a computer equipped with a frame grabber card for capture of images. This computer can be further linked to the hospital network to make the images captured during endoscopic procedures available in the hospital information system.

processes sharing information, each doing its own processing but relying on the functionality of the other. An example can be found in the endoscopy unit. The endoscopic workstation, placed in each endoscopy room, generates images. These images must be stored somewhere and they also need to be displayed on the clinical unit’s computer, on request by the clinician. Image acquisition, storage, and remote control are distinct services based on the information contained in the images. The different processes on which these services are based are distinct, can be performed by different systems, but share the same information. In this scenario, which is called a distributed process, the application generating or displaying the images is strongly decoupled from the communication process, which coordinates data transmission between systems and compensates for the different ways in which data are internally represented on different systems (Figure 19.10). Hence, the role of each system must be clearly defined. The most important distinction is the one defining the role of server (i.e., the application that offers functionalities to others) and the role of client (i.e., the application that uses the functionalities generated by others). These relationships are managed by TCP/IP (transmission control protocol/Internet protocol), which essentially organizes relationships between servers and clients (e.g., on the Internet). Once the roles have been defined, the systems must organize the information that they want to share. This information is defined by the context of the service implemented. In our example, the storage of images in large reference databases will not require the same information as the display of the image in the clinical unit. However, if the clinical unit wants to retrieve images from the large database, the information used by each of these processes must be consistent, and this is achieved by the definition of a global context to which each process will refer in order to organize information.

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Hospital information system Accounting and management data

Medical images archiving

Demographic data Clinical data

Endoscopic information system Patient's data Procedure data Text

Report Local archiving

Images

Remote access to medical data

Figure 19.10 Schematic representation of the pathways along which data are transferred between the endoscopy unit and the other components of the hospital information system or for various services inside the endoscopy data management system.

Educational applications

Patient cards Telemedicine Local health networks

DICOM-based exchange DICOM-based exchange but needs further improvements of DICOM

The exchanged information is organized in objects (i.e., the information related to one object of the real worldathe patient, the image, and the procedure are distinct objects which each contain a number of data fields). These information object definitions (IODs) are divided into normalized IODs containing a single information entity, or composite IODs containing multiple information entities; then, the system must link different objects. In our example of the endoscopy unit, the patient (who is an IOD) may undergo a procedure (another IOD) which will generate multiple images (image IODs). This is typically a composite IOD, which is organized in successive layers, so that, at the end, an object is created containing the whole information in addition to the relevant links. The whole object represents a service that is generated by the server application or service class provider, and which will be used by the client application or service class user. Table 19.1 shows the object that can be generated during an endoscopy procedure. The data fields that are included in this object are not specific to endoscopy, but some of them have particular importance in the case of endoscopic color pictures. Finally, the DICOM organizes the actions performed on the images. These actions are called service elements. These

elements determine the operations allowed on information objects: get, move, store, delete . . . Service elements can be organized in service groups. The whole procedure results in an encoded data set that organizes the byte stream during the exchange between systems. The method of encoding is defined by the transfer syntax, which is part of the work done by the service provider. However, the service user or client must be able to recognize this syntax and must learn it. Although the general principles of the DICOM can be quite easily understood, its implementation in data management systems has been delayed because of the complexity of the data to be managed and the difficulty in creating the link between the various systems. These problems have recently been solved with the development of the Internet technology and the use of XML. In that format, data are described in a document type definition (DTD) that describes all the data elements that are needed for a specific action or service. The DTD is an easier way than the DICOM of organizing the data elements contained in the IOD.

Use of endoscopic images in clinical practice Various scenarios have been investigated for the clinical use of digitized endoscopic images [22]. The obvious advantage is

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the production of a complete endoscopic report associating text data and images, improving the quality of the report. The insertion of images into the endoscopic report supposes that it will be produced by a computerized report generator. Moreover, this report must then be transfered to the HIS to be included in the patient file that is contained in the database of the HIS. Production of computerized endoscopic reports will also foster several clinical applications, including outcome studies, quality assurance processes, and large multicenter trials. Such achievements will become successful when endoscope manufacturers and software developers will integrate computers and electronic endoscopes into actual endoscope workstations. Software applications must have a userfriendly interface and be built on a modular model which can be customized for various types of practice [23]. On the other hand, upcoming applications need to integrate the new standards for data formats and ensure compatibility with existing software. DICOM is an example of this as it was formed from the joint activity of the manufacturers of radiology equipments and pushed forward by the strong willingness of the scientific associations of radiologists. In digestive endoscopy, a similar momentum is needed to hasten the process of data management computerization. Technical solutions exist but their implementation has been delayed for various reasons. Nowadays, the wider use of electronic endoscopes and the challenge of endoscopy with other imaging techniques constitute a unique opportunity to make possible the computerization of data management.

Adaptation of the Minimal Standard Terminology to new technologies and procedures Since the MST was published in full [15], several new diagnostic and therapeutic procedures have been introduced in clinical practice and deserve accurate description.

New diagnostic procedures Chromoendoscopy Chromoendoscopy is nowadays extensively used for the diagnosis of flat or early neoplastic lesions. It can be performed by spreading a dye such as indigo carmine over the mucosal surface [24]. On the other hand, electronic chromoendoscopy is developed by several manufacturers to enhance the contrast of the mucosa by filtering different wavelengths in the light spectrum [25,26]. According to the settings used, the vascular pattern of the mucosa will be enhanced and the abnormal vasculature will be recognized in adenomatous lesions with dysplasia. In the report, the technique of chromoendoscopy and the additional findings should be carefully described, due to the important clinical implications. The description of the technique should include

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the type of dye or the electronic algorithm used, the use of magnification, and the extent of the gut segment on which chromoendoscopy was applied. The description of the findings should be closely related to the primary description of each item in white light or in the absence of dye, so that the lesions can be adequately located. Several classifications have been proposed to describe the changes in the pit pattern of the colonic glands which are suggestive of either the adenomatous nature of a lesion or the presence of dysplastic changes [27]. The description should include the vascular pattern, the pit pattern, and the morphology of the lesion on the mucosal surface. Terms for these descriptions have so far not been standardized.

Magnification Endoscopes of a new generation are characterized by a much more powerful optical system described as “high-definition endoscopy.” This high definition is defined by the number of pixels of the CCD or complementary metal oxide semiconductor generating the image (see section on Production of digital endoscopic images). On top of these advances, most endoscopes are currently equipped with zoom facilities that allow magnification of the image. As with digital cameras, magnification can be obtained by an electronic zoom, which is a postprocessing of the image, or by an optical zoom that is based on the use of a set of optical lenses placed at the tip of the endoscope. Some endoscopes combine these two techniques. The use of magnification should be mentioned in the report, specifying the lesion that was examined and that the conclusions obtained are added to the classical description. It should also be specified whether the magnification sequence was performed in white light or after chromoendoscopy.

Endoscopic microscopy Several techniques are being introduced that allow a detailed examination of the mucosal surface that reaches the level of a microscopic view, such as confocal microscopy [28,29]. These techniques are still under development and require validation in clinical practice. Their increase in diagnostic yield from classical endoscopy with chromoendoscopy is not yet known. When standardization of the descriptions will be discussed, the difficulty will be to adapt pathologic descriptions to the endoscopy practice. As for other techniques, the method used, the settings of the system, and the precise location of the lesion should be provided before starting to describe the findings.

New therapeutic procedures Advances in therapeutic colonoscopy include the larger possibilities of resection of neoplasms, the dilatation of stenoses, and the insertion of colonic prosthesis for palliative treatment of malignant stenoses. Dilatations and prostheses were already included in the original version of the MST and do not deserve additional description.

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Resection of colonic neoplasms includes polypectomy, endoscopic mucosal resection (EMR) often named “mucosectomy,” and endoscopic submucosal dissection (ESD). Polypectomy has been used for decades and is well described in the original MST. EMR and ESD have been introduced more recently to treat sessile lesions by injecting fluid into the submucosa, in order to raise the base of the lesion and safely dissect it from the deeper layers of the colonic wall [30,31]. A careful description of the technique performed should be provided in all cases. This complete description will include the sequence of actions, the material used, the type and amount of fluid injection, the completeness of the resection, and the retrieval of the specimen.

New endoscopic methods Recently, new endoscopic techniques have been proposed for examination of the colon. Although the description of findings is not different with these techniques, some adaptations are needed to take into account their innovative differences. The most advanced technique is that of capsule endoscopy. This discussion shall be limited to this technique, which has been available for 2 years and should be used mainly for screening for colorectal cancer [32]. The principle of the technique is similar to that used for several years for investigation of the small bowel [32]. Most items used for the report of a classical colonoscopy are relevant for capsule colonoscopy [33]: quality of bowel cleansing, extent of examination, findings, and diagnoses. However, some specific points must be underlined: • The location of the lesion is often not precise on capsule recordings. The software allowing the reading of the recordings provides an indication of the location of the capsule based on the identification of some anatomic landmarks (Figure 19.11). However, the unpredictable movements of the capsule and the lack of specificity of some landmarks makes locating lesions difficult. The ileocecal valve and the hepatic flexure can be easily recognized while the splenic flexure and the limits of the sigmoid colon are more difficult to recognize. • The size of lesions is also difficult to measure in the absence of air inflation or because of an immersion view that tends to magnify the size of the lesions. A feature of the software for reading of the recordings that would help to better measure the size of the lesion is currently being tested. • The extent of a mucosal abnormality is often difficult to determine as the technique is unlike endoscopic evaluation, in which the operator moves the endoscope to examine the entire abnormal segment. The specificity of the report of capsule procedures has previously been discussed and an adapted terminology has been proposed [33], built on the same principles as the MST itself, for the small bowel. This adapted terminology has been validated by cross-checking it with more than 700 capsule

Figure 19.11 Layout of the software for reading of colonic capsule recordings. In left lower part of the panel, one can see the graphic representation of the capsule locator, aimed at helping the reader locate the lesions.

reports [34]. For the colon, the list of terms proposed for classical endoscopy can be used with a few alterations and adaptations taking into account the technical characteristics of capsule recordings. A group of experts is currently working to propose an adapted terminology for capsule colonoscopy.

Maintenance of Minimal Standard Terminology and perspectives Maintenance of the MST is a long-standing activity that must be integrated into the framework of a scientific society but, at the same time, remain an open process that will ensure a fair response to new features. The lack of an institutional framework for the development of standardization activities may indeed lead to dissolution of the work in multiple concurrent initiatives. It may also impair the necessary actions for dissemination of the standards and acceptance by the community. On the other hand, the MST must remain a living and evolving system. It must be able to adapt to local needs and to different aspects of practice. The prevalence of some digestive disorders is much higher in some countries, and techniques that have limited application in one disease may be useful in other conditions. In some situations, the level of detail of the information contained in the report may be higher than the one fixed in the MST: cooperative studies on a specific topic may require additional information that was not required for the minimal set of data that should be described in any endoscopic report; local prevalence of a disease may justify some specific descriptions in some areas. To solve these problems, in the future, the MST should be organized on the same basis that SNOMED is organizing microglossaries [35]. This means that, apart from the backbone of the MST, the current list of terms, one should be allowed to develop secondary lists of

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terms and/or attributes that would describe a given pathology in more detail. To maintain the compatibility of these more detailed versions of the MST with the original one, each detailed list should refer to an existing term of the MST and it should be agreed that the exchange of data takes into account either the headline in the original MST or the complete set of descriptions for a particular type of findings, depending on the setting. In this case, the structure of the MST would not be altered and an extended list of terms would be transferred with reference to the original term, to which it would belong.

Summary The imaging possibilities offered in digestive endoscopy have dramatically improved over the last decade as a result of the use of electronic endoscopes and the combination of them with computers. Hence, the data generated during an endoscopy procedure include images and text. The fastgrowing use of computers for data management in medicine requires that these data be stored in standard formats which are the basis for a proper exchange of information between systems [35]. For digestive endoscopy, the emerging standards fulfilling these requirements include the Visible Light Supplement of the DICOM 3.0 and the MST.

References 1 Rex DK, Helbig CC. High yields of small and flat adenomas with high-definition colonoscopes using either white light or narrow band imaging. Gastroenterology 2007; 133: 42–7. 2 East JE, Suzuki N, Stavrinidis M, Guenther T, Thomas HJ, Saunders BP. Narrow band imaging for colonoscopic surveillance in hereditary non-polyposis colorectal cancer. Gut 2008; 57: 65– 70. 3 Kiesslich R, Goetz M, Angus EM, et al. Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. Gastroenterology 2007; 133: 1769–78. 4 Schoofs N, Devière J, Van Gossum A. PillCam colon capsule endoscopy compared with colonoscopy for colorectal tumor diagnosis: a prospective pilot study. Endoscopy 2006; 38: 971–7. 5 Arber N, Grinshpon R, Pfeffer J, Maor L, Bar-Meir S, Rex D. Proof-of-concept study of the Aer-O-Scope omnidirectional colonoscopic viewing system in ex vivo and in vivo porcine models. Endoscopy 2007; 39: 412–17. 6 Liebermann DA, de Garmo PL, Fleischer DE, Eisen GM, Chan BKS, Helfand M. Colonic neoplasia in patients with nonspecific GI symptoms. Gastrointest Endosc 2000; 51: 647–51. 7 Digital Imaging and Communication in Medicine (DICOM), NEMA PS3.1–PS3.12. The National Electrical Manufacturers Association, Rosslyn, VA, 1992, 1993, 1995, 1997. 8 Kruss DM. The ASGE database: computers in the endoscopy unit. Endosc Rev 1987; 4: 64–70.

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9 Rex DK, Bond JH, Winawer S, et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2002; 97: 1296–308. 10 Crespi M, Delvaux M, Schapiro M, Venables C, Zweibel F. Minimal standards for a computerized endoscopic database. Am J Gastroenterol 1994; 89: S144–S153. 11 Maratka Z. Terminology, Definitions and Diagnostic Criteria in Digestive Endoscopy, 3rd edn. Bad Homburg: Normed Verlag, 1994. 12 Digital Imaging and Communications in Medicine (DICOM) NEMA PS 3 Suppl. 15: Visible light image for Endoscopy, Microscopy, and Photography. The National Electrical Manufacturers Association, Rosslyn, VA, 1997. 13 Computer Committee. Standard format and content of the endoscopic procedure report. American Society for Gastrointestinal Endoscopy, 1992. 14 Lieberman D, Nadel M, Smith RA, et al. Standardized colonoscopy reporting and data system: report of the Quality Assurance Task Group of the National Colorectal Cancer Roundtable. Gastrointest Endosc 2007; 65: 757– 66. 15 Delvaux M, Crespi M, Armengol-Miro JR, et al. Minimal Standard Terminology for digestive endoscopy. Endoscopy 2000; 32: 159–88. 16 Delvaux M, Crespi M, Armengol-Miro JR, et al. Minimal Standard Terminology for digestive endoscopy: Results of prospective testing and validation in the GASTER project. Endoscopy 2000; 32: 345–55. 17 Cass OW, Korman LY, Brugge W, Harford W, Roberts I. Testing of the Minimum Standard Terminology in the United States. Gastrointest Endosc 1998; 47: AB27 (abstract). 18 Digital imaging and communication in medicine (DICOM), NEMA PS3 Supplement 23: Structured reporting. The National Electrical Manufacturers Association, Rosslyn, VA, 1997. 19 Delvaux M. Image management: the viewpoint of the clinician. Gastroenterologist 1996; 4: 3–5. 20 Korman LY, Delvaux M, Bidgood D. Structured reporting in gastrointestinal endoscopy: integration with DICOM and minimal standard terminology. Int J Med Inform 1998; 48: 201–6. 21 Wallace GK. The JPEG Still Picture Compression Standard. Communications of the ACM 1991; 34: 30–44. 22 Fujino MA, Morozumi A, Nakamura T, et al. Electronic endoscopy in perspective. J Gastroenterol 1994; 29: 85–90. 23 Brown NJG, Britton KE, Plummer DL. Standardisation in medical image management. Int J Med Inform 1998; 48: 227–38. 24 Hurlstone DP, George R, Brown S. Novel clinical in vivo roles for indigo carmine: high-magnification chromoscopic colonoscopy. Biotech Histochem 2007; 82: 57–71. 25 Pohl J, Nguyen-Tat M, Pech O, May A, Rabenstein T, Ell C. Computed virtual chromoendoscopy for classification of small colorectal lesions: a prospective comparative study. Am J Gastroenterol 2008; 103: 562–9. 26 Atkinson RJ, Hurlstone DP. Narrow-band imaging: the next frontier in colonoscopy? Gastrointest Endosc 2007; 66: 317–19. 27 Kudo SE, Kashida H. Flat and depressed lesions of the colorectum. Clin Gastroenterol Hepatol 2005; 3(7 Suppl. 1): S33–6. 28 Kiesslich R, Goetz M, Vieth M, Galle PR, Neurath MF. Technology insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer. Nat Clin Pract Oncol 2007; 4: 480–90.

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29 Becker V, Vercauteren T, von Weyern CH, Prinz C, Schmid RM, Meining A. High resolution miniprobe-based confocal microscopy in combination with video-mosaicing. Gastrointest Endosc 2007; 66: 1001–7. 30 Tanaka S, Oka S, Kaneko I, et al. Endoscopic submucosal dissection for colorectal neoplasia: possibility of standardization. Gastrointest Endosc 2007; 66: 100–7. 31 Conio M, Ponchon T, Blanchi S, Filiberti R. Endoscopic mucosal resection. Am J Gastroenterol 2006; 101: 653– 63. 32 Delvaux M, Gay G. Capsule endoscopy: technique and indications. Best Pract Res Clin Gastroenterol 2008; 22: 813–37.

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33 Korman LY, Delvaux M, Gay G, et al. Capsule endoscopy structured terminology (CEST): proposal of a standardized and structured terminology for reporting capsule endoscopy procedures. Endoscopy 2005; 37: 951–9. 34 Delvaux M, Friedman S, Keuchel M, et al. Structured terminology for capsule endoscopy: results of retrospective testing and validation in 766 small-bowel investigations. Endoscopy 2005; 37: 945–50. 35 Korman LY, Delvaux M, Crespi M. The minimal standard terminology in digestive endoscopy: perspective on a standard endoscopic vocabulary. Gastrointest Endosc 2001; 53: 392–6.

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Reporting and Image Management Lars Aabakken Rikshospitalet University Hospital, Oslo, Norway

Introduction Gastrointestinal endoscopy is a visual clinical discipline. All examinations, findings, descriptions, and recommendations are based on the images created during the endoscopic examination. In interventional work, the images are the sole guiding material for correct procedures. The traditional mode of reporting these images has been a written report. This report ideally contains the description of what is seen, followed by an expert interpretation of the significance of the findings. The conclusion is typically a diagnosis, with or without a qualifier of confidence. This model for reporting is not necessarily ideal. The imaging which is the basis for the interpretation of findings should be available as a part of the report. The lack of report imagery in endoscopy results from lack of technical feasibility, not of clinical utility. Thus, with the rapid dissemination of image-enhanced reporting systems, the inclusion of report images should be a prerequisite. This chapter deals with some of the issues that text and image reporting generate. It also covers the present status of terminology and standardization in this area.

Text report

Recently, a task force of the American Society for Gastrointestinal Endoscopy (ASGE) published recommendations for the colonoscopy report, pertaining specifically to quality assurance of screening colonoscopy [1]. However, this document covers most aspects relevant to the endoscopy report in general. Similar documents are lacking in Europe and Asia, but it is reasonable to assume that most of the principles are global.

Patient demographics The patient’s full name, birth date, medical record number, or other unique identifier should be included initially and should be easily recognizable (in bold type). The name (minimum) should be repeated in the header of all additional pages of the report in order to avoid misplacement of orphan pages. In a hospital context, the inclusion of an identifying barcode may be useful for efficient paper handling.

Referrer information The referring unit/physician is typically identified as the addressee of the report. However, all the recipients of the report should be listed in each copy. This is important for ensuring that all of the units involved with the patient know who received the pertinent information and, even more importantly, who did not. This is a vital step in preventing patients from becoming lost to follow-up.

Report elements The endoscopy report is the core means of communication for the endoscopist, and it should be meaningful to endoscopists, general gastroenterologists, and referring practitioners alike. It is also a legal document that may be scrutinized in a court of law to determine if the standard of care has been fulfilled. The various elements of the report are of varying importance to the different readers and this must be taken into account.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Endoscopist The attending and endoscopic fellow, as well as other doctors attending the procedure, should be included in the report. Even though the fellow typically formulates the report, it is usually important for the reader to realize who was responsible for the interpretations and recommendations presented. In a complex case where the surgeon and possibly the radiologist are summoned, this information should be included as well; alternatively, this information can be detailed in the interpretation or conclusion of the report.

Indication/clinical history The reason for the procedure should be clearly stated in the report. This may be a suspected illness, workup of a specific

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symptom, follow-up of a known disease with or without sampling, or screening purposes. There is a subtle difference between an indication and a reason for the procedure, since indications may have implications for reimbursement. A reason for a procedure, on the other hand, has both clinical and practical implications. In this section, a focused clinical history is also of value. It serves to put the endoscopic procedure and findings into context even for readers unfamiliar with the specific patient. There is no need for a complete medical history, but issues of relevance to the endoscopy are important. This includes symptoms and previous workup of the disease in question. Relevant family history should be noted, particularly in the context of screening or surveillance endoscopies. It should also include comorbidities or problems that are of potential relevance to the endoscopy (e.g., in the context of possible complications). Diabetes, cardiopulmonary problems, anxiety disorders, and hemorrhagic diathesis are a few examples of possibly relevant diagnoses which can be explicitly stated as part of the endoscopy report or reported in a separate history section. This will show the reader that the procedure was done only after a thorough evaluation of all aspects of the particular patient. Information on previous endoscopies is highly relevant, from a medical as well as a technical point of view. The patient’s reaction to the procedure or the sedation, specific technical issues in intubation, and previous findings that require consideration or follow-up will all help to improve the quality of the present procedure. Parts of this information belong in the endoscopy report (e.g., findings for follow-up), while other aspects are important for the endoscopist but not necessarily as a part of the current report.

Risk assessment An explicit statement on the assessment of risk is of value, legally, but even more so medically, to ensure that the endoscopist takes into consideration all issues that may influence the risk of the procedure. The ASA (American Society of Anesthesiologists) score is used by anesthesiologists, and has been proposed as a reasonable stratification even for endoscopy, However, other endoscopy-specific risk factors may be of greater value. These include the use of anticoagulants or hemorrhagic diathesis from other causes, immunosuppression, cardiovascular prostheses or otherwise increased risk of endocarditis, panic anxiety disorders, or previous endoscopy complications.

Informed consent/disclaimer The endoscopy report should state that information about the procedure was given to the patient and, to some extent, what that information was. In many countries, written informed consent is required prior to the procedure, and referral to such a document will be sufficient. Most law suits that are filed after mishaps are based on the patient’s perceived lack of information on possible complications, and written documentation is

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vital to document the standard of care. In special cases (e.g., a high-risk dilation procedure), a specific account of the discussion with the patient is even more helpful.

Sedation Drugs given as part of the procedure should be documented within the endoscopy report. This includes the type of drug, the dosage, and the time and route of administration. The effect of the drug is of interest (e.g., response to midazolam) partly for the follow-up of the patient but also as guidance for future procedures in the same patient. An important piece of information that should be recorded is the odd patient with an adverse reaction to midazolam who becomes agitated. In the case of need for antidotes, this must be documented as well, including drug, dose, and timing. Sedation given by an anesthesiologist will often be documented separately. In this case the principle of sedation (and success) will suffice for the endoscopy report (e.g., deep sedation, propofol, general anesthesia).

Technical information Technical aspects of the procedure are important for interpretation of the procedure, indication for repeat endoscopy, and as guidance for other endoscopists seeing the patient in the future. The colonoscopy report should include the type and effect of the cleansing procedure,and the ability to visualize the mucosa adequately. In the case of incomplete cleansing, the level of adequate cleansing (if any) should be noted, to enable a more specific repeat study. As a quality control benchmark, the ASGE recommends that adequate cleansing should allow detection of all lesions > 5 mm. The completeness of the endoscopy is recorded, including any uncertainty about it and the reason for incomplete study. Even the choice not to enter the distal ileum should be noted; the reason may be perfectly valid (polyp screening). In the case of particular difficulties in passing the instrument, the specific solutions should be included in the report. It is possible that these solutions may need to be repeated at a later date. If the distal ileum is not intubated, the features used to determine cecal intubation should be stated explicitly, unless pictures are taken for this purpose (see below). The time spent on insertion and withdrawal of the endoscope is of interest, although the withdrawal time in cases of therapy is less relevant. However, increasing focus on withdrawal time as an item of high-quality colonoscopy warrants its inclusion in the endoscopy report as well as the starting and total procedure times.

Findings The description of findings is the core information of the report. An objective, systematic, and detailed account of what was seen, or not seen, is the main result of your procedure. This may sound simple but there are caveats:

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• Findings should be described completely and objectively, based on features that are visualized not interpreted. To achieve this, a standardized terminology is indispensable (see below). • Mixing objective features and interpretation is very easily done, but all interpretative comments should be reserved for the Impression section. Thus, the expert reader can more easily evaluate your findings and determine the rationale for your conclusions. • Documentation of normal findings and/or lack of pathology may be important. For example, the normal retroflex appearance of the anorectal transition is vital in patients with unexplained anemia. To ensure this type of completeness, the report should be constructed systematically. Most computer software includes a template that ensures that all segments are described, but in a free text dictation setting omissions may easily occur. In this case, the question “Was it really specifically looked for?” remains unanswered for the reader.

Table 20.1 Actions and outcomes for adverse events. Actions

Outcomes

a

Endoscopic interventiona Aborted procedurea Medical intervention Admission to hospital (days) Admission to ICU Repeat endoscopy Radiologic intervention Surgery Recovery Permanent disability Died (days after procedure)

These two actions pertain to intraprocedure events only.

endoscopic procedure. The distinction between findings and impressions may appear artificial, but adhering to this structure allows the endoscopy report to be a versatile piece of information useful for expert and novice readers alike.

Procedures Diagnostic, but even more so therapeutic, procedures must be documented. This usually relates to findings; thus, most reports will integrate the procedures that have been performed into the findings section. It may not be necessary to keep a record of specifics on the equipment used, but principles, results, and samples retrieved should be documented. For dilation therapy, balloon caliber should be included as a minimum.

Conclusion and recommendations The conclusion should summarize the Impression section, with a tentative diagnosis, recognizing the lack of a path report, etc. It should also offer a follow-up plan or a recommended course of action for the referring doctor responsible for the follow-up of the patient. If the findings require repeat endoscopy, the timing and arrangements for this should be explicitly stated in order to ensure that all involved parties are informed.

Complications and adverse events All unplanned events must be recorded as a part of the colonoscopy report. This includes general complications, such as desaturation and hypotension, accidental events such as tooth or denture damage, as well as endoscopy-specific complications (e.g., bleeding or perforations). The severity of the complication may be determined by the actions and outcomes, which should be explicit as part of the complication account (Table 20.1). It must be recognized that the periprocedure events that may be recorded in the endoscopy report do not necessarily account for all adverse events related to a procedure. Late complications (e.g., late bleeds or secondary perforations after lengthy coagulations) will be noted only after the report is finalized. Software solutions may allow follow-up data to be recorded linked to the procedure (complications and path reports).

Diagnoses and procedures

Impression

Free text versus structured input

This section summarizes the findings described above, including interpretation based on the endoscopic appearance and additional information about the clinical context. For nonexpert readers, this will be the main piece of information that allows them to make sense of the specifics of the

Traditionally, the endoscopy report was dictated into the general medical record, similar to surgical procedures or consultation notes. This model is still prevalent, at least in Europe, and it is efficient and convenient for the endoscopist. Even in dedicated endoscopy reporting systems, unstructured

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Most reporting templates require the entry of formal diagnoses and procedures, including the appropriate codes. International Classification of Diseases (ICD) and Nomesco Classification of Surgical Procedures (NCSP) codes are used most frequently, although there are inherent shortcomings in both these coding schemes when applied to endoscopy. Sometimes the discrepancy is nonexistent (e.g., in the case of a hiatal hernia). Other findings may be more equivocal (e.g., esophageal erosions in a patient with severe immunosuppression). In this case, only the pathology report will allow an accurate ICD code to be entered, long after the endoscopy report is finalized and dispatched. Thus, there is a need for a linking structure between the “endoscopic diagnosis” and the pertinent ICD code. Similar issues relate to the procedure coding. This should be automated within reporting software.

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input is the rule rather than the exception. Some systems require some degree of uniformity of the text (i.e., separating clinical history from findings and impressions, entering the endoscopist’s name in a separate box). This model allows the endoscopist maximal flexibility in the descriptions, lesions, and impressions being described in natural language. In the context of an endoscopy report produced as a document describing the procedure in the individual patient, free text is a good choice but there is a strong possibility that key elements of the report may be omitted [2].

Images as part of the report The increasing availability of digital endoscopic images is paving the way for their role in standard reporting of endoscopic procedures. Accompanying a textual description of a finding with one or more pictures of the same finding, together with a location diagram, significantly enhances the value of the report, particularly for other endoscopists who may interpret the images independently. Also, in the setting of repeat endoscopies for follow-up of a finding, the ability to compare the appearance of a lesion with previous images is invaluable for determining any progress or healing. Color images require specialized printers, increasing the cost of preparing the endoscopy report. A possible option is to print images on a separate sheet of paper, while the standard text report is printed on regular noncolor laser printers. With the further development of cheaper color laser technology, this problem will probably diminish.

The digital revolution Initially, the mere view into the intestine was a revolution. However, the revolution was a very private one, conveyed through the eyepiece of the fiberoptic endoscope, without the ability to share or store the endoscopic view. Endoscopists had little or no means of communicating what they saw, apart from the written endoscopy report, which was an interpretation of the images. Twin eyepieces and mountable cameras were steps in the right direction, allowing discussion and exchange of image information, but these were cumbersome gadgets with limited dissemination. The introduction of video-based imaging systems created a host of new opportunities. The eyepiece was replaced with the greatly enhanced viewing experience of a large monitor screen, enabling the endoscopic examination to become a shared experience with colleagues and assistants. In addition, still image printers could be connected for paper prints of important findings. The video signals received and processed in the endoscopy equipment can also be stored electronically, as captured electronic images or digital video. In combination with other existing technologies, this enables access and use of endoscopic images far beyond what was previously feasible. The increasing availability of electronic image-capturing systems

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opened up new ways of documenting procedures. Where the reader was previously confined to the endoscopist’s concept of a “large ulcer,” “profuse bleeding,” or “moderate inflammation” in a text report, the addition of images allows better understanding of what is actually found. This development parallels what radiologists have been doing for a long time: relating their diagnostic considerations directly to recorded image material. The ability to share information in text and image permits everyone to understand what endoscopists are talking about. The need to label our findings with medical terms has emphasized the need for language standardization; everyone must mean the same thing when using the same words. The content of a written report will be of value only if the “image-to-word” coding algorithm is the same. The task of establishing a common language of gastrointestinal endoscopy has been taken on by the World Organization of Digestive Endoscopy (Organisation Mondiale d’Endoscopie Digestive, OMED) and also by the European and US societies for endoscopy (see Chapter 19). Once the words are in place, there is a need to structure information as well. The endoscopy report should be composed in a standardized way, similar to what we have come to expect in the medical history and physical findings of a patient on admission. The introduction of computerized reporting systems for endoscopy mandates a structured report. The use of these systems for statistical analysis requires rigorous coding. The digital revolution in endoscopy laboratories has the potential to change the way endoscopists work and communicate, offering great improvements in the service to the patient and referring doctors. However, this advance requires a nontrivial investment of money, time, and thought on the part of the endoscopist. This section deals with some of these issues.

Digital imaging Imaging the gastrointestinal tract using a video endoscope requires several steps: illumination by fiberoptic light transmission, surface reflectance, magnification, charge-coupled device (CCD) conversion of the reflected light to an electrical signal, reconstruction of the signals to an image, and projection onto a monitor. Personal computers with image capture boards and network capabilities permit these images to be captured, stored, printed, and transmitted.

Pixel density Pixel density (sampling density) is the number of pixels into which an image is divided by the frame grabber. The greater the number of pixels per unit area, the higher the resolution of the image (Figure 20.1).

File size The final size of an uncompressed image is calculated simply by multiplying width (in pixels) by height by color depth.

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Original image

(b) Low-resolution pixelation

Figure 20.1 Difference between (a) higher (100 dpi) and (b) lower (10 dpi) resolution. Pixelation is clearly seen at lower resolutions. The same phenomenon is seen if a picture is zoomed beyond its generic resolution.

Figure 20.2 Compressing a typical endoscopic image from 140 kb (already compressed from around 800 kb) to 12 kb is hardly noticeable.

Thus, a VGA (video graphics array) resolution 24-bit image (typical for an endoscopic image) would be 640 × 480 × 8 × 3 = 7 372 800 bits, or about 900 kB (kilobytes) (1 byte = 8 bits). File size affects storage requirements, display delays, and transfer times, and becomes important in the everyday use of images. Transferring a 900-kB image with a 28.8-kB modem takes 4.3 min, and a 1-GB (gigabyte) disk drive would be filled with 1100 such images [1]. Thus, all the factors determining file size should be considered in order to optimize the composition of endoscopic images. In some clinical situations resolution is not important (e.g., a large mass or a pedunculated polyp may be easily identified as such even at low resolution). On the other hand, subtle findings such as the granularity of the mucosa or disruption of the vascular pattern may require a higher pixel ratio. It is also of interest how the image will be used. To show the image on a computer screen, the resolution of the screen determines the optimal resolution (e.g., super video graphics array, SVGA); however, printing via a high-quality printer (e.g., glossy prints for a

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journal manuscript) requires a higher resolution, typically two to three times screen requirements. At present, there is definitely an upper limit to the resolution feasible for endoscopic images. The CCD chip in the tip of the endoscope has a pixel resolution in the SVGA range. Thus, even if we had capture boards with higher resolution, the image quality would only be marginally better (Figure 20.2). However, high-resolution endoscopes are being developed that may change this situation.

File compression For practical purposes, uncompressed images are almost a relic of the past. With the increasing utility of network- and Internet-based computer applications, the need for smaller files is indisputable. File compression is a computational processing technique that effectively reduces the size of a file, removing redundancies in large binary data sets. Full-motion video requires a display rate of 30 frames per second (fps). If each frame is 0.5 MB, then 1 s of digital video contains

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15 MB of data. Disk storage would be rapidly exceeded and image transmission even on high-speed networks would be slow. Compression is measured as a ratio of the size of the original data divided by the compressed data. There are two general categories of compression techniques: lossless and lossy. Lossless compression techniques preserve all the information in the compression and decompression processes. This may be vital for compressing documents or computer program files, but these techniques can only achieve moderate compression ratios, which may not be sufficient for medical images, especially radiologic grayscale images. However, when images are used as a means of primary diagnosis, they require lossless compression, storage, and transmission. Most picture archiving and communication systems (PACS) use lossless compression but require high-end hardware and dedicated high-speed networks. For the purpose of practical archival storage and the transmission of medical images, compression ratios of 20:1 or higher are required. In order to achieve this amount of file size reduction, lossy compression techniques need to be employed. Lossy compression implies that some information is lost in the compression and decompression processes, but algorithms can be designed to minimize the effect of data loss on the diagnostic features of the images. JPEG (Joint Photographic Experts Group) compression is one of the three file formats used for graphical images on the web, the others being GIF (graphical interchange format) and PNG (portable network graphics). JPEG files have the advantage of remaining 24-bit truecolor files during compression, while GIF files are limited to 8-bit color (256 colors). The PNG file format shows promise as a lossless compression method for the web but has not yet gained acceptance at this time. The issue of standard web formats is an important one because an increasing number of relevant software solutions rely on browser technology for screen display. There is one final note about JPEG and grayscale images in general. While color images using JPEG can typically achieve compression ratios of 10:1 to 20:1 without visible loss and can compress 30:1 to 50:1 with small to moderate defects, grayscale images do not compress by such large factors. Because the human eye is much more sensitive to brightness variations than to hue variations, JPEG can compress hue (color) data more heavily than brightness (grayscale) data. A grayscale JPEG file is generally only about 10–25% smaller than a full-color JPEG file of similar visual quality. However, the uncompressed grayscale data are only 8 bits/pixel or one-third the size of the color data, so the calculated compression ratio is much lower. The threshold of visible loss is often around 5:1 compression for grayscale images, substantially different from color images [3].

JPEG 2000 and beyond The importance of image handling and compression for Internet applications creates a huge momentum for development. The JPEG working group has developed a new standard,

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which is only just becoming available (accepted as an ISO standard in December 2000). This standard is called JPEG 2000, with the file extension.jp2. This standard offers a host of advantages over the existing JPEG standard, the most significant being lack of pixelation at high compression rates and significantly more effective compression. Although the file size of individual endoscopic images is not a major issue at this point, we should keep in mind that, when the display and transfer of large numbers of images and videos become a significant part of our daily workflow, even minute delays for every picture will have an impact. Thus, the continuing search for more efficient file compression will be of major significance to medical imaging. PACS development currently suffers from the high cost of high-end workstations and networks to handle huge image data sets.

Digital Imaging and Communication in Medicine Digital Imaging and Communication in Medicine (DICOM) is a standard for imaging that contains very specific information about the images, as well as the images themselves. DICOM relies on explicit and detailed models of how the “things” (patients, images, reports, etc.) involved in imaging operations are described, how they are related, and what should be done with them. This model is used to create an information object definition (IOD) for all the imaging modalities covered by DICOM. An information object is a combination of information entities, and each entity consists of specific modules. A service class defines the service that can take place on an information object (e.g., print, store, retrieve). In DICOM, a service is combined with an information object to form a service– object pair (SOP). For example, storing a computed tomography (CT) scan or printing an ultrasound scan is an SOP pair. A device that conforms to the DICOM standard can perform this function. Thus, in a DICOM-conforming network the devices must be capable of executing one or more of the operations that the SOP definition prescribes. Each imaging modality has an IOD. The result is that different imaging modalities, such as computed tomography, magnetic resonance imaging, digital angiography, ultrasound, endoscopy, pathology, imaging workstations, picture archiving systems, and printing devices, can be networked and execute a high level of cooperation. In addition, these imaging networks can be connected to other networks found in a hospital or facility. It is not sufficient to define a standard. It is also necessary to develop a mechanism to enable vendors and purchasers to understand whether the system conforms to the standard. DICOM defines a conformance statement that must be associated with specific implementation of the DICOM standard. It specifies the service classes, information objects, communication protocols, and media storage application protocols supported by the implementation. The conformance statement is provided by the vendor and identifies the system capabilities.

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DICOM in gastrointestinal endoscopy The ASGE in collaboration with other medical and surgical societies, such as the European Society for Gastrointestinal Endoscopy (ESGE), American College of Radiology, College of American Pathologists, American Academy of Ophthalmology, and American Dental Association, has defined a new supplement to the DICOM standard [4]. This supplement to the DICOM standard specifies a DICOM image IOD for visible light images. This standard enables specialists working with color images to exchange images between different imaging systems using direct network connections, telecommunications, and portable media such as CD-ROM, DVD, and magneto-optical disk. The DICOM standard for endoscopy is part of a larger standard for color images in medicine that has been provisionally approved by the DICOM committee. The current version will go through a process of public comment and testing. This ensures that any interested party can review the document and suggest changes to a committee responsible for creating the final version. This process is timeconsuming but ensures that the standard is comprehensive and meets the needs of a broad group of users. Through the ASGE and ESGE, the endoscopy community has also suggested that the DICOM standard be expanded to incorporate other information associated with the imaging study. These expanded standards would include image labels and overlays, sound, and waveform. The goal of a true multimedia report will be achieved only when these standards have been thoroughly tested and implemented as part of the daily clinical activities of gastrointestinal endoscopists throughout the world. The cooperation of endoscopists, professional societies, and industry is absolutely necessary for improved endoscopic information systems, and will result in improved patient care.

Clinically acceptable compression Because of the specific nature of endoscopic images, the amount of compression that can be employed without com-

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promising important information contained within the image must be determined by the endoscopist. Moreover, the acceptable compression rate would likely differ substantially depending on whether we are looking at a polyp or a case of mild gastritis. These issues have major impact on the utility of digital images in endoscopy but can be resolved only by endoscopists themselves. We have to be involved in deciding what imaging is required to be useful for clinical purposes. Although the topic has been reviewed by Kim [3], very few studies have been published on this subject. Vakil and Bourgeois [5] conducted a trial to determine the amount of color information required for a diagnosis using an endoscopy image. The least amount of color information in an endoscope image that carries sufficient diagnostic information was unknown. Ten upper gastrointestinal lesions were presented in an 8-bit, 16-bit, and 24-bit format blindly side by side on a Macintosh II system with a 19-in. (48.26 cm) monitor that could display 24-bit color. Eleven observers (six nurses and five endoscopists) were asked to rank each format for each lesion. There were a total of 330 observations, and for each format and total the results were similar: the observers correctly identified 22% of the images; incorrectly identified 37% of the images; and could not see a difference in 41% of the images. In addition, all of the lesions were correctly identified. From this study of endoscopic images, color resolution does not appear to affect an endoscopist’s ability to make a diagnosis (Figure 20.3). CY Kim (personal communication) presented a set of six images to 10 expert gastroenterologists, using software that allowed them to determine their personal cut-off level of acceptable compression for each of the images. Different types of lesions were studied and the acceptable compression ratio was predictably variable as well, but in general a compression ratio of between 1:40 and 1:80 was deemed acceptable (Table 20.2). This type of study provides important information about the order of magnitude that can be expected from compression. However, the clinical context

GIF, 256 colors

Figure 20.3 Intelligent reduction of the number of colors in an endoscopic image does not ruin the image, because the color range is limited to the gray–yellow–red hues.

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Table 20.2 Clinical acceptability of compressed gastrointestinal images. (Adapted from Kim [1].) Lesion

Original file size (kb)

Mean compressed file size (kb)

Arteriovenous malformation Barrett’s esophagus Chromoscopy polyp Arterial bleed Pseudomembranous colitis Duodenal ulcers

903.3 903.6 904.7 182.2 185.7 183.6

14.1 10.6 18.4 2.4 6.6 5.6

is of interest as well: the arterial bleed was probably easily identified as such even at a high rate of compression, but the endoscopist who might need to intervene at a rebleed would likely favor additional details about the exact location, structures next to the vessel, and so on. Thus, additional studies like this with a broader range of cases are needed to ascertain an ideal compression scheme. The area of image compression is a moving target. Compression schemes are evolving quickly and, at the same time, the requirements for minute files are becoming less crucial. Storage space is rapidly becoming cheaper and networks faster. The 28.8-kB modem is no longer a reasonable yardstick for download time. The virtue of compressing images remains but there is no reason to compromise image quality in order to achieve the tiny file sizes that yesterday’s technology recommended. The endoscope manufacturers have been struggling hard to offer high-resolution endoscopes, structure enhancement, and magnification; it would be counterproductive to lose these advantages for a few kilobytes of file size reduction. As for clinical utility, we need to establish a general standard for compression and formats that will work across diagnoses. This will have to aim at a quality sufficient for our most difficult diagnoses: subtle diffuse lesions such as mild gastritis or tiny erosions, or delineation of the vascular pattern of a colitis.

Pictures or live video? Increasingly, digital video is becoming an option for endoscopic documentation. Many capture boards have the capability of storing video as well as still images, and in certain situations video may offer a definite advantage. This is particularly true for teaching purposes although even clinical documentation can be enhanced by live footage in certain situations. Obvious examples are documentation of distensibility or propagating waves of the stomach, spasticity of the colon, or imaging in difficult areas (the cardia). However, video clips come at a cost in terms of processing, storing, and even presentation. While still images can be vividly reproduced in

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the printed endoscopy report together with the recommendations, a video clip is forever tied to the computer or network. In the future, when electronic medical records become mainstream and wide-area networks (WANs) a tool for medical purposes, these concerns may vanish, but for now a paper-based report is a prerequisite in most endoscopy laboratories. Then there is the issue of storage and transfer. Studio-quality video displays at 25 or 30 fps. Although reasonable-quality video can be obtained with 10–15 fps, this still produces enormous files quickly and we need to determine if this cost of digital video can be justified by added value. Again, fortunately, things are moving rapidly in the right direction. Compression algorithms allow significant compression of digital video file size with acceptable results. The best known are probably the Quicktime and MPEG-1 formats, but this is a field of continuous development, MPEG-4 being the most promising option at the moment. Most of the compression algorithms use similar techniques, as discussed above for still images. For example, if a segment of the movie image is unchanged for a period of time (the sky, or the black portion to the left of the endoscopic image), the only information that needs to be stored is the boundaries of the area, the color value, and the start and stop timecodes. With this type of compression, a video of a newsreader, for example, can be reduced to a still picture with a small moving segment representing the mouth. This technique, in addition to a multitude of others, allows for increasingly efficient compression of video clips, offering efficient storage, as well as network-based distribution, with no or minimal depreciation of the diagnostic value.

What images are needed? In parallel with the technological developments in digital imaging and video, there are important decisions that need to be made by the endoscopic community. A crucial one is: What pictures are needed? If we want to report a polyp in the sigmoid colon, a single picture might be sufficient if it is a good one, showing the size and shape, stalk, amount of luminal obstruction, surface texture, and so on. But what about a distal rectal lesion? An extra picture of its relation to the anal verge might be important, not least if a surgeon was to remove it. A retroflexed view as well as a standard forward one would be reasonable in this situation. For diffuse pathology, typically more than one image might be preferable, and perhaps high resolution becomes an issue for minimal changes. More complex still is the issue of nonpathology. Which images are needed to exclude a lesion in order to document a normal colonoscopy? We obviously cannot picture every single fold, let alone behind them, but there may still be reasons to document normality (e.g., to show what kind of view, cleansing, and distension were available to the endoscopist). The virtue of this becomes even more obvious in the context of referrals and second opinions. When we are

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6

Standardized terminology (see Chapter 19) 3

7

8 2 1

Figure 20.4 Standard positions for default endoscopic imaging of the colon.

asked to evaluate a polyp for possible removal and pictures are sent from a referral source, too often we discard that study because the images we receive are not the ones we expect. This expectation needs to be incorporated into a standard that will allow more efficient collaboration on patients, based on images alone. Too many repeat endoscopies are performed because images are inadequate, although the study may have been excellent. The ESGE [6] has made an attempt to establish guidelines for standard endophotographs at specific sites in the colon (Figure 20.4) and has proposed a set of images at various areas of the colon to aid in the visual identification of each area (Figure 20.5).

Image enhancement The impact of video endoscopes has been substantial yet what they provide are still just natural light images showing the gastrointestinal mucosa in a lifelike manner. Novel technologies are now emerging that offer modification of the original images, which may increase the diagnostic output of the endoscopic procedure. These technologies do not relate to digital imaging itself, but they all rely on such imaging as the core technology for endoscopy. Color manipulation methods deal primarily with the color characteristics of the pixels representing the image. This is a simple way of enhancing the contrast features of the image, but sometimes at the cost of resolution. These methods are so far only available for manipulation of still images, and a live version of the technology would be needed to make this clinically applicable. Narrow-band imaging and spectroscopy are just two examples of a host of other technologies that will enhance the diagnostic yield. In these technologies, parallel “imaging” is used to extract information about the imaged tissue, and

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Endoscopic findings are conveyed with words, although the findings themselves are images. Thus, the coupling between what we see and how it is described becomes crucial, and standardization of our endoscopic language is an integral part of this concept. Endoscopic teaching includes descriptions of what is found, but the definitions of terms used have been weak or nonexistent. If the conclusion of the endoscopy report is the only item of value, then the specifics of the findings are of less importance. However, if the findings themselves are important, then the descriptive language also becomes interesting. For research purposes, particularly collaborative research, the utility of this is obvious, but even for general clinical purposes the objective description of lesions may be of interest (e.g., in a second-opinion referral of a case when the referral center needs to decide whether a repeat endoscopy is needed). Likewise, follow-up endoscopy in a patient with a known lesion will profit from an unequivocal initial description of what was seen, at least when no image documentation is available.

The World Organization of Digestive Endoscopy’s definitions and standardized terminology OMED initiated the drive to standardize endoscopic language through the pioneering work of Professor Zdenek Maratka, who developed the first “terminology, definitions and diagnostic criteria in digestive endoscopy,” later revised and translated into numerous languages. This terminology is a codified list of terms with explicit definitions that allows endoscopic findings to be matched to a hierarchical nomenclature and assigned a code, thus enabling international collaboration. This terminology has since been supplemented with images to exemplify the various terms. Despite deficiences, this remains the de facto standard for describing the various findings of digestive endoscopy.

Minimal Standard Terminology The OMED terminology, while defining the framework for the terminology efforts within digestive endoscopy, proved too complex for practical use in everyday endoscopy. A simplification was needed and the ESGE teamed up with its US counterpart, the ASGE, to develop Minimal Standard Terminology (MST) for endoscopy [7]. This terminology is completely based on the OMED terminology, but the lists of terms are limited, aiming to cover 95% of the terms needed for typical endoscopic practice and omitting the definitions, which are available when needed in the OMED terminology book. MST is meant to be a standardizing prerequisite for software companies developing reporting programs for digestive endoscopy, assuring

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Figure 20.5 Sample image set showing a colonoscopy of a normal colon (see also Figure 20.4).

that a joint language is used in the various available software solutions. The MST work has been endorsed and supported by all the major vendors of such systems (Figure 20.6). The initial version of MST was thoroughly tested within the GASTER (Gastrointestinal Endoscopy Applications for Standards in Telecommunication, Education, and Research) project [8] and this experience led to a number of adjustments as to the selection and definition of terms.

Issues and shortcomings The principles of MST have been endorsed almost universally and the utility of a joint standardized language of endoscopy is readily acknowledged. However, the knowledge, dissemination, and implementation of MST are at present insufficient, even disappointing. Why is this? One issue is the MST term lists, which are still not perfect. They are designed to be “minimal lists,” meaning that in a substantial number of

cases the term that is required is not included. This is partly a software issue, because the lists were never meant to be all-inclusive, and individual additions will be needed in most centers. Still, incomplete choice lists are difficult to accept. More fundamental, though, is the whole concept of structuring the language of the endoscopist. We are used to formulating our findings and recommendations in natural language, and any superimposed structure will take extra time, be felt as cumbersome and limiting, and will clearly be something that yields less informative reports. The solution to this has not yet been found, and MST is at present primarily an excellent initiative. The utility of standardized terms is indisputable; the challenge is to embed this into software that allows them to be sufficiently transparent. Also, it is unlikely and probably unnecessary that the endoscopy report be produced exclusively by “point-and-click”. Segments of the endoscopy report will probably remain free text blocks with natural language.

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Figure 20.6 Sample endoscopy report including indexed color images.

Summary

Acknowledgments

Gastrointestinal endoscopy is a visual clinical discipline. The traditional mode of reporting these images has been through a written report. The endoscopy report is the core means of communication for the endoscopist and it should be meaningful to endoscopists, general gastroenterologists, and referring practitioners alike. The report should contain certain fixed elements in order to convey fully the results of the examination, the diagnosis, and any recommendations. Modern communication methods now permit the transfer of pictures of endoscopy along with the written report. Elements of interest are detailed in this chapter.

I would like to thank Dr. Louis Korman and Dr. Chris Kim for valuable input to specific segments of this manuscript, and for their efforts in the field in general.

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References 1 Lieberman D, Nadel M, Smith RA, et al. Standardized colonoscopy reporting and data system: report of the Quality Assurance Task Group of the National Colorectal Cancer Roundtable. Gastrointest Endosc 2007; 65: 757– 66.

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2 de Lange T, Moum BA, Tholfsen JK, Larsen S, Aabakken L. Standardization and quality of endoscopy text reports in ulcerative colitis. Endoscopy 2003; 35: 835– 40. 3 Kim CY. Compression of color medical images in gastrointestinal endoscopy: a review. Stud Health Technol Inform 1998; 9: 1046– 50. 4 Korman LY, Bidgood WD, Jr. Representation of the gastrointestinal endoscopy minimal standard terminology in the SNOMED DICOM microglossary. In: Proceedings of the AMIA Annual Fall Symposium. 1997: 434– 8. 5 Vakil N, Bourgeois K. A prospective, controlled trial of eight-bit, 16-bit, and 24-bit digital color images in electronic endoscopy. Endoscopy 1995; 27: 589– 92.

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6 Rey JF, Lambert R. ESGE recommendations for quality control in gastrointestinal endoscopy: guidelines for image documentation in upper and lower GI endoscopy. Endoscopy 2001; 33: 901–3. 7 Delvaux M, Korman LY, Armengol-Miro JR, et al. The minimal standard terminology for digestive endoscopy: introduction to structured reporting. Int J Med Inform 1998; 48: 217–25. 8 Delvaux M, Crespi M, Armengol-Miro JR, et al. Minimal standard terminology for digestive endoscopy: results of prospective testing and validation in the GASTER project. Endoscopy 2000; 32: 345– 55.

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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The Video Colonoscope David E. Barlow Olympus America Inc., Center Valley, PA, USA

Introduction The modern video colonoscope embodies more than two decades of refinements in solid-state imaging technology and mechanical design. The basic components and controls of the video colonoscope are illustrated in Figure 21.1. The instrument is designed to be held and operated by the endoscopist’s left hand. Some physicians use their index finger to alternately control the suction and air/water valves, while the rest of the left-hand fingers grip the instrument. Others use the index finger for the suction valve, the middle finger for the air/water valve, and the final two fingers to grip the instrument. The up/down angulation knob is manipulated by the left thumb. The left/ right angulation knob is controlled either by the left thumb and first two fingers of the left hand or, alternatively, by the right hand. The endoscopist’s right hand is primarily used to control the insertion tube, pushing, torquing, and withdrawing as necessary. Although alternative designs for the control section have been proposed (e.g., “pistol grip”), the basic shape and layout of the instrument are relatively unchanged since the first fiberoptic colonoscope was introduced.

Insertion tube While endoscopists may prefer using a particular model of colonoscope for a variety of reasons, it is perhaps the instrument’s insertion tube characteristics that more than anything else influence an endoscopist to select a particular colonoscope as the instrument of choice. Indeed, if any single specification of the instrument can determine the speed and ease with which the endoscopist can insert the instrument, it is the mechanical characteristics of the insertion tube.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Endoscope manufacturers have put significant effort into refining the construction of the insertion tube and selecting appropriate materials. Figure 21.2 illustrates the internal components of a typical colonoscope insertion tube. The insertion tube contains tubes for suction (biopsy), air and water feeding, and often an additional tube for a forward water jet. Four angulation control wires run the length of the insertion tube to deflect the tip at the end. The very fine electrical wires that connect the charge-coupled device (CCD) image sensor located in the distal tip of the endoscope to the video processor also travel through the insertion tube. These wires are in a protective sheath, to prevent them from being damaged. The delicate glass fibers bringing light from the light source to the distal end of the endoscope also travel through the insertion tube in a protective sheath. Colonoscopes with adjustable insertion tube flexibility have an additional component, a tensioning wire used to control insertion tube stiffness. It is the job of the endoscope designer to pack all of these individual components into the smallest area possible in order to minimize the outer diameter of the insertion tube but still provide enough free space to allow the components to move about without damaging the more fragile components (CCD wires, fiberoptic strands) as the instrument is torqued and flexed during use. A dry powdered lubricant is applied to all internal components to reduce the stress they place on each other during insertion tube manipulation.

Flexibility As previously mentioned, the handling characteristics of the insertion tube are extremely important. For easy insertion, the instrument must be capable of accurately transmitting torque to its distal tip. Any rotation that the endoscopist applies to the proximal portion of the shaft must be transferred to the distal tip of the instrument in a one-to-one ratio. The torque ability of the instrument is facilitated by flat spiral metal bands that run just under the skin of the insertion tube (see Figure 21.2). Because these bands are wound in opposite directions, they lock against one another as the tube is torqued,

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Suction Valve

Distal Tip

Vent Hole

Bending Section

Air/Water Valve

Remote Switches

Anti-Reflux Valve

Insertion Tube

Biopsy Valve Channel Opening

U/D Angulation Lock

Insertion Tube Stiffness Control

U/D Angulation Knob

Control Section Boot

R/L Angulation Lock R/L Angulation Knob

Connection to Video Processor Air Pipe Quartz Lens

Universal Cord

Suction Connector

Light Guide Air Supply Connector Water Supply Connector

Light Source Connector

Air Channel Biopsy/Suction Channel

Outer Spiral Metal Band

Water Channel

Stainless Steel Wire Mesh

CCD Signal Wires

Wire For Adjustable Stiffness

Light Guide Bundles

Angulation Wires

Inner Spiral Metal Band Forward Water Jet Channel

Polymer Cover

Figure 21.2 Insertion tube: internal components and construction.

accurately transmitting rotation of one end of the tube to the other. At the same time, gaps between these spiral bands allow the shaft to flex freely. The bands also give the insertion tube its round shape and prevent the internal components of the insertion tube from being crushed by external forces. Fine strands of thin stainless-steel wire, braided into a tubular mesh, cover the spiral metal bands. A plastic polymer layer, typically black or dark green, is then extruded over this wire mesh to create the smooth outer surface of the insertion tube. The polymer layer provides an atraumatic, biocompatible, watertight surface for the insertion tube. It is usually marked with numbers to gauge the depth of insertion.

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Figure 21.1 Colonoscope: components and controls.

Colonoscopists ideally want a tube that is flexible yet highly elastic. They want the instrument to be sufficiently floppy (nonrigid) to conform easily to the tortuous anatomy of the colon and to not exert undue force on the colon or attached mesentery. On the other hand, they want the instrument to have sufficient column strength to prevent buckling when the proximal end of the instrument is pushed. (By comparison, a wet noodle, which is extremely flexible, has no column strength and buckles easily when pushed.) In addition to its flexibility, the colonoscope should have sufficient elasticity to pop back into a straightened condition whenever it is pulled back. This aids the endoscopist in removing colon loops. The goal in designing the proximal portion of the insertion tube is the prevention of the reformation of bowel loops. Obtaining the best combination of flexibility, elasticity, column strength, and torque ability is the art and science of insertion tube design. To further improve insertion ability, the flexibility of the insertion tube typically varies over its length. As Figure 21.3 illustrates, the distal 40 cm of the insertion tube is significantly more flexible than the proximal portion of the tube. This variation in flexibility is achieved by changing the formulation of the tube’s outer polymer layer as it is extruded over the wire mesh during manufacturing. As Figure 21.4 illustrates, the extruder typically contains two types of resin, one significantly harder than the other. Initially, as the distal end of the insertion tube passes through the machine, a layer of soft resin is applied to the distal 40 cm of the wire mesh. This soft resin is gradually replaced by the hard resin within a transition zone (T-zone in Figure 21.3). The proximal portion of the insertion tube (50–160 cm) is then constructed entirely from the hard resin [1]. The end result is an insertion tube that has a soft distal portion for atraumatically snaking through a tortuous

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Setting = 3 Setting = 0

Flexible 160 cm

0 cm

Proximal Portion

T-Zone

(more rigid)

Distal Portion (more flexible)

Bending Section

Figure 21.3 The flexibility of the insertion tube varies over its length. It can be further stiffened by changing the setting on the adjustable stiffness control.

colon, with a stiffer proximal portion that is effective at preventing loop reformation in those portions of the colon which have already been straightened by the colonoscope.

development of an insertion tube with adjustable stiffness [2]. Colonoscopes with adjustable stiffness have a tensioning wire that runs the length of the insertion tube (see Figure 21.2). The amount of tension in this wire is controlled by rotating a ring at the proximal end of the insertion tube, just below the control section (Figure 21.5). When the inner wire in the stiffening system is in the “soft” position, the stiffening system provides no additional stiffness to the insertion tube beyond that provided by the wire mesh and polymer coat. However, as Figure 21.5 illustrates, when the control ring is rotated to one of the “hard” positions, the pin at the end of the pull wire is stretched via an angled slot and is put under heavy tension. This stiffens the coil wire surrounding the pull wire and adds significant rigidity to the insertion tube. As Figure 21.3 illustrates, the base stiffness of the insertion tube (setting = 0) is established by varying the mixture of hard and soft resins in the outer polymer coat of the insertion tube. However, this base stiffness can be further enhanced by increasing the tension in the variable-stiffness pull wire (setting = 3).

Adjustable flexibility

Distal tip

Clinical experience has shown that endoscopists often disagree over what constitutes the “ideal” insertion tube. This may be due to differences in the endoscopist’s training, insertion technique, and past experience. In addition, some endoscopists have expressed a desire to change the characteristics of the insertion tube during the procedure itself, based on insertion depth or the patient’s anatomy. This has led to the

An end view and a cross-section of the distal tip of a typical colonoscope are shown in Figure 21.6. Light to illuminate the interior of the colon is carried through the instrument via fiberoptic illumination fibers. This light is then evenly dispersed across the colonoscope’s field of view via a light guide lens system. Some instruments have a single illumination system. Other instruments have two fiberoptic bundles and

Soft Resin

Polymer Top Coat

A

B

Hard Resin

Mixing Chamber

Stainless Steel Wire Mesh Inner Spiral Metal Band

Base Polymer Layer

Outer Spiral Metal Band

Figure 21.4 Insertion tube manufacturing method.

Angled Slot Pull Wire

Fixation Point Stiffened Portion

Figure 21.5 Colonoscopy insertion tube: adjustable stiffness tensioning system.

Coil Wire Setting Marks

Slide Pin

Stiffness Control Ring

Fixation Point

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Air/Water Nozzle Objective Lens Water Jet Light Guide Lens

Plastic Distal End Cap

Water Jet Tube

Illumination Fibers

END VIEW

CROSS-SECTION

two light guide lenses to improve illumination on both sides of the biopsy forceps (snare, etc.) and to facilitate the packing of components within the insertion tube. The CCD unit, the solid-state image sensor that creates the endoscopic image, is placed behind the objective lens of the endoscope. This image sensor sends a continuous stream of images back to the video processor for display on a video monitor. It is very important that the objective lens and CCD unit be well sealed, to prevent condensation from fogging the image and to protect the imaging system from damage if fluid were to accidentally enter the instrument. The channel used for biopsy and suction exits close to the objective lens on the distal tip. The position of the biopsy channel relative to the objective lens determines the location at which accessories appear to enter the visual field. For example, on some instruments, the snare or biopsy forceps appears to emanate from the lower right corner of the image. On other instruments, these accessories enter the visual field from the lower left corner; and so forth. The small tubes that carry air and water through the insertion tube (see Figure 21.2) are typically merged into a single Up/Down Angulation Knob

Light Guide Protection Tube Figure 21.6 Colonoscope distal tip.

tube just above the bending section of the instrument (see Figure 21.8). This combined air/water tube then connects to the air/water nozzle on the tip of the instrument. Under control of the endoscopist, water can be fed across the objective lens to clean it, or air can be fed from the nozzle to insufflate the colon. Some colonoscope models have an additional water tube and a waterjet nozzle on the distal tip, used to wash the wall of the colon (see Figure 21.6).

Bending section and angulation system The most distal 8–9 cm of the insertion tube can be angulated under the control of the endoscopist. This deflectable portion is referred to as the bending section, and is constructed quite differently from the rest of the insertion tube. As Figure 21.7 illustrates, the bending section is composed of a series of metal rings, each one connected to the rings immediately preceding and following it via a freely moving joint. These joints are constructed using a series of pivot pins, each one displaced from its neighbors by 90°. This construction allows

Chain & Sprocket

Bending Section

(b) Up Angulation Wire

Down Angulation Wire BENDING SECTION

Up Angulation Wire

Down Angulation Wire

(a) Figure 21.7 Construction of bending section and angulation system.

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Ring

Pivot Pin

End of Angulation Wires

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the bending section to curl in any direction. The direction of the curl is controlled by four angulation wires running the length of the insertion tube (see Figure 21.2). These four wires are firmly attached to the tip of the bending section in the 3, 6, 9, and 12 o’clock positions, respectively. Pulling on the wire attached at the 12 o’clock position will cause the bending section to curl in the “up” direction and achieves what endoscopists refer to as “up” tip deflection. Pulling on the wire attached at the 3 o’clock position will cause “right” tip deflection. Pulling the other two wires will cause “down” and “left” deflection respectively. The endoscopist is able to pull on each of these wires in turn by rotating either the up/down or right/left angulation knobs. (For simplicity, Figure 21.7 illustrates only the up/down angulation system.) Rotating the two knobs together will produce a combined tip movement (e.g., upward and to the right). By using the two angulation knobs together, the endoscopist can sweep the tip of the endoscope in any direction. Colonoscopes typically have 180° of deflection in the up and down directions. Deflection in the right and left directions is typically limited to 160° to avoid overstressing the internal components of the instrument.

Air, water, and suction systems A schematic of a typical colonoscope air, water, and suction system is shown in Figure 21.8. An air pump in the light

The Video Colonoscope

source provides air under mild pressure to a pipe protruding from the endoscope’s light source connector. This air is carried by an air channel (tube) to the air/water valve on the control section. If this valve is not covered, the air simply exits from a hole in the top of the valve (see Figure 21.1). This vent hole allows the air pump to pump freely when air is not needed, thus reducing wear and tear on the pump. To insufflate the colon, the endoscopist covers the vent hole with his or her fingertip. This closes the vent and causes air pressure to build up inside the air feeding system. With the vent closed, the increasing air pressure forces air down the air channel, exiting the instrument through the nozzle on the distal tip. Colonoscopes typically have a maximum air flow rate of 30 cm3/s. A one-way valve is incorporated into the shaft of the air/ water valve (see Figure 21.1). This antireflux valve is necessary to hold air in the colon during patient examination. During examination, the colon is insufflated to a pressure above atmospheric pressure. If it were not for this one-way valve in the system, air from the colon would flow back into the nozzle, up the air channel in the insertion tube, and out of the hole in the air/water valve whenever the operator removes his or her finger from the air/water valve. This antireflux valve is necessary to keep the colon insufflated. Water is used to clean the objective lens of the instrument during the procedure, and is stored in a water bottle attached to the light source or cart (see Figure 21.8). In addition to feeding air for insufflation, the air pump also pressurizes this water container, forcing water out of the bottle and into the

Suction Valve Air/Water Valve Biopsy Valve

Insertion Tube Nozzle

Water Bottle Tube

Universal Cord

Water-Jet Connection

Biopsy/Suction Channel

Water Channel

Air Channel

Water-Jet Channel

Light Source Connector

Suction Connection

LIGHT SOURCE

Air Pipe

Air Pump WATER BOTTLE

Figure 21.8 Schematic representation of a typical colonoscope air, water, and suction system.

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endoscope. Water from the water bottle is carried via a tube on the water bottle cap to the light source connector of the endoscope. It is then carried by the water channel up the universal cord to the air/water valve. When the endoscopist depresses the air/water valve, this allows water to continue down the water channel in the insertion tube and out of the nozzle on the distal tip. The nozzle then directs this water across the surface of the objective lens, thereby cleaning it. Suction is also controlled by a valve. A suction line, either from the hospital’s wall suction system or from a portable suction pump, is connected to the light source connector of the endoscope. A slight vacuum is applied to the suction channel in the universal cord. When the endoscopist depresses the suction valve, suction is further applied to the biopsy/ suction channel within the insertion tube. Any fluid (or air) present at the distal tip of the endoscope will be drawn into the suction collection system. A channel-opening valve (also called a biopsy valve) closes off the proximal opening of the biopsy channel and prevents room air from being drawn into the suction collection system. There are several inherent safety features in the design of the air, water, and suction system shown in Figure 21.8: • There is no air valve, which could stick in a continuously “on” position and result in accidental overinsufflation of the patient. Rather, the air simply exits the vent hole in the valve unless the physician covers this opening. • In the event that the suction system becomes obstructed and the endoscopist has difficulty with possible overinsufflation, all valves can quickly be removed from the endoscope. This will stop all feeding of air and water and will allow the patient’s colon to depressurize through the open valve cylinders.

Illumination system Colonoscopes use an incoherent fiberoptic bundle to carry light from the external light source to the distal tip of the endoscope. This fiber bundle is composed of thousands of hair-like glass fibers (30 μm in diameter) that are optically coated to trap light within the fiber and to transmit it from end to end via a phenomenon known as total internal reflection. Light rays entering one end of such a fiber reflect off the walls of the fiber many thousands of times before exiting the opposite end of the fiber. The types of glass used to make the core and cladding of the light guide fiber and the dimensions of the core and cladding are all carefully chosen to enable the fiber bundle to carry as much light as possible (for a more complete discussion of fiberoptics, see reference 3). Endoscopic light sources typically employ 300-W xenon arc lamps to produce the bright white light needed for video endoscopy. These lamps also produce considerable heat. Heat sinks, infrared filters, and forced-air cooling systems within the light source prevent the light guide fiber bundle from overheating and burning. A close inspection of the tip of a

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colonoscope’s light guide will reveal a burn-resistant quartz lens that serves to collect light from the light source lamp and direct it into the endoscope (see Figure 21.1). At the other end of the endoscope, the light guide lens at the distal tip of the instrument spreads this light out uniformly over the visual field (see Figure 21.6). An automatically controlled aperture (iris) in the light source controls the intensity of the light emitted from the endoscope (see Figure 21.30). When the endoscope is looking down the lumen of the colon and bright light is required, the aperture in the light source opens up, allowing the colonoscope to transmit maximum light. On the other hand, when the colonoscope tip is very close to the colon wall and the illumination is very bright, the aperture in the light source automatically closes down to reduce the amount of light exiting the light source. If illumination is too low, the image on the monitor will be dark and grainy. If the illumination is too strong, the image on the monitor will be washed out (i.e., “bloom”). The video processor automatically keeps the brightness of the illumination within a range that is acceptable for the CCD image sensor by carefully controlling the amount of light produced by the light source.

Solid-state image capture The image sensors used in video colonoscopes are typically referred to as CCDs. These sensors are solid-state imaging devices made of silicon semiconductor material. The silicon on the surface of the sensor is responsive to light and exhibits the photoelectric effect. When a photon of light strikes the photosensitive surface of the CCD, it displaces an electron from a silicon atom on the surface. This produces a free, negatively charged electron in the silicon material and a corresponding positively charged “hole” in the crystalline structure of the silicon where the electron was previously bound. As additional photons hit the surface of the sensor, more free electrons and more corresponding holes are created. The charges built up on the surface of the sensor are directly proportional to the amount of light falling on the CCD. Although a single photosensitive element can be used to measure the brightness of the light falling on the device (as in a light meter), it cannot reproduce an image. In order to reproduce an image, the photosensitive surface must be divided into a matrix of thousands of small independent photosites. When an image is focused on the surface of such a sensor, the brightness of the image is automatically measured at each individual photosite. Knowing the brightness of every point in the image allows the processing system to subsequently reproduce the image on a viewing monitor or to generate a printed copy of the image. The surface of a CCD sensor, therefore, is divided into a rectilinear array of discrete photosites, individually referred

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Photosensitive Area

CCD IMAGE SENSOR

The Video Colonoscope

Pixel

(a)

(b)

OPTICAL IMAGE Amplifier Horizontal Shift Register

(c)

(e)

(d)

# of charges

20

OUTPUT SIGNAL

15 10 5

time 2

4

6

8

pixel row # Figure 21.9 Schematic representation of how a line transfer charge-coupled device captures an optical image. The “electrical representation” of the image is then read off in an orderly manner.

to as picture elements (“pixels”). Figure 21.9 illustrates a sensor with such an array. For simplicity, the array illustrated in Figure 21.9 contains only 64 pixels in an eight-row by eightcolumn matrix. An actual endoscopic CCD contains several hundred thousand or more pixels. The greater the number of pixels on a CCD, the higher the resolution of the reproduced image. In a video colonoscope, the CCD is located in the distal tip of the instrument directly behind the objective lens (see Figure 21.6). The objective lens focuses a miniature image of the observed mucosa directly on the surface of this sensor (see Figure 21.18). The pattern of light falling on the CCD (i.e., the image) is instantly converted into an array of stored electrical charges, as a result of the photoelectric effect previously described (see Figure 21.9b). Because the charges stored in each of the individual pixels are isolated from neighboring pixels, the sensor faithfully transforms the optical image into an electrical replica of the image. This electrical representation is then processed and sent to a video monitor for reproduction. Pixels in dark areas of the image develop a low voltage, due to the generation of fewer charges. Pixels in brighter areas of the image develop a proportionately higher voltage, due to the creation of more electron–hole pairs. Each pixel is able to develop any charge, from some minimum to some maximum, depending on the brightness of the incident light. This process is linear. Doubling the number of photons of light falling on a pixel doubles the number of charges generated at the

pixel until they reach the maximum storage capacity of the photosite. This conversion of an optical image into an electrical replica of the image is illustrated in Figure 21.9.

“Reading” the image created on the CCD After the CCD is exposed to the image, the charges developed in the CCD must be “read” in an orderly manner and then processed to reproduce the original image. The manner in which the charges are moved about within the CCD as they are read depends on the configuration of the CCD. The three most common types of CCD are the line transfer CCD, the frame transfer CCD, and the interline transfer CCD [4]. Each of these CCD types has specific advantages in terms of the CCD’s sensitivity to light (i.e., the brightness required of the colonoscope illumination system), the type of light source required (strobed or nonstrobed), the size of the CCD (which in turn affects the size of the distal tip of the endoscope), and the speed at which the charges can be transferred out of the CCD. The method used to read an image from a line transfer CCD is used here as an example. The CCD schematically illustrated in Figure 21.9 is a line transfer CCD. Figure 21.9a illustrates the projection of an optical image onto the photosensitive surface of the CCD. Electrical charges are developed at each photosite in the array following brief exposure to the image (see Figure 21.9b and c).

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(For simplicity, Figure 21.9 illustrates an array with only a very few pixels and resulting charges. These charges are represented by small + signs within the photosites.) The charges within each pixel are then controlled and shifted over the surface of the CCD via electrodes adjacent to each photosite (not shown in Figure 21.9). By varying the voltages applied to these electrodes, the electrons within individual pixels are transferred as “charge packets” from one pixel to another. Sequential voltage changes on these electrodes march the charges toward the bottom edge of the CCD and into a horizontal shift register (see Figure 21.9d). The charges in the horizontal shift register are then passed through an output amplifier and converted into an output signal. The output signal fluctuates in direct proportion to the number of charges stored in each pixel. At the point in the process illustrated in Figure 21.9e, the bottom row of the original image is being read out and sent to the video processor for reconstruction. The electrical representation of the entire image has shifted down one row on the CCD. Once the horizontal shift register has been read and cleared (emptied), the charges in each pixel of the array are then sequentially transferred down to the pixel below, resulting in a second shift of the image replica. This fills the horizontal shift register with the charges that were originally in the second to bottom row of the array. The charges in the horizontal shift register are again read out, resulting in an output signal that is representative of the brightness of the image falling on the second to bottom row of the original image. The processing of the image replica continues, in a step-by-step fashion, until the entire CCD has been read. Once the CCD is read and cleared, it is ready for another exposure. The “charge-coupling” process (i.e., the transfer of charges from pixel to pixel as packets) gives the CCD its name. The charges in the furthermost corners of the CCD are actually moved sequentially through several hundred photosites before they reach the horizontal shift register. In current video endoscopes, the CCD is exposed, read, and reexposed 60–90 times each second. To maintain image fidelity during these repetitive transfers, it is essential that these charge packets remain intact with no loss or gain in charge quantity as they undergo hundreds of thousands of transfers per second as the CCD is being read. One characteristic of a line transfer CCD is that the photosensitive area of the CCD (the photosite array) must be shielded from light during the entire time that the image is being transferred and read. This is necessary to prevent mixing information from the image being transferred through the photosite array with new charges being generated at the photosites due to the light still falling on them. To preserve the original image, the photosites must be completely dark while the image replica is being transferred. One method of doing this in an endoscopic application is to strobe, or momentarily interrupt, the light emitted by the endoscope as the CCD is being read. This creates a momentary burst of light to expose the image

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sensor, followed by momentary darkness, as the CCD is read and cleared. Endoscopists who have used a red, green, and blue sequential endoscopy system (typically called a “black and white” CCD system) are quite familiar with the concept of strobed endoscopic light sources.

Types of charge-coupled device As mentioned above, as an alternative to the line transfer CCD, some video endoscopes use a frame transfer CCD (Figure 21.10). The frame transfer CCD differs from the line transfer CCD in that the frame transfer CCD has a second CCD UNIT

Pixel

Sensor Array

Storage Array

OUTPUT

Amplifier

Horizontal Shift Register

Figure 21.10 Schematic representation of a frame transfer chargecoupled device.

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array, used only for charge storage. The first array is a photosite (sensor) array, which generates an electrical replica of the image, similar to the line transfer CCD. After creating the image replica, all of the charges in the sensor array are immediately transferred to the storage array (illustrated by the long arrows in Figure 21.10). Here they are held until they can be read out, line by line, in a process similar to a line transfer CCD (illustrated by the short arrows in Figure 21.10). The red arrows illustrated in Figure 21.10 define the path taken by the charges in the upper right corner pixel of the sensor. Charges in other pixels take a similar path. The advantage of the frame transfer CCD is that the device can continue to collect light and generate charges in the sensor array while the storage array is being read and processed. Since the frame transfer CCD has more time to gather light, it does not require as much illumination as a line transfer CCD. As a result, the number of light guide fibers in the endoscope can be reduced. The disadvantage of frame transfer CCDs is that they are physically larger than line transfer CCDs because of the addition of a storage array. This additional size is a distinct drawback in many endoscopic applications. In addition, frame transfer CCDs also require illumination strobing. The interline transfer CCD is a hybrid of the previous two types. This type of CCD has vertical shift registers placed adjacent to each column of photosites (Figure 21.11). Immediately after exposure, the charges developed at the photosites are transferred in one quick step to the adjacent vertical shift registers. Owing to the rapid one-step transfer of charges, illumination of the CCD does not need to be interrupted and the CCD can continue to collect light. In the meantime, the

CCD UNIT Photosite (Pixel) Vertical Shift Register

The Video Colonoscope

charges in the vertical shift registers are transferred, step by step, down to the horizontal shift register, where they are then read in an orderly manner. (The red arrows in Figure 21.11 illustrate the path of charges generated in the upper right corner pixel.) The vertical shift registers are shielded from light, allowing them to be emptied as the CCD is continuously exposed to light. The CCD thereby collects a second image as the first is being read. When the vertical shift registers are finally empty, the process repeats. A big advantage of the interline transfer CCD is that it does not require strobing of the illumination. Since the entire sensor array is cleared to the vertical shift registers in one step, the sensor array is immediately ready to capture the next image. So-called “colorchip” endoscopes, which use continuous nonstrobed light sources, are examples of interline transfer CCD systems. All three types of CCD described above have been used in commercial video colonoscopes. Each type has its own advantages and disadvantages in terms of physical size, circuit complexity, light sensitivity, and illumination requirements.

History of endoscope charge-coupled device development The first video colonoscope was introduced in 1983 by Welch Allyn [5]. The market launch of this system was made possible when advancements in image sensor technology allowed the CCDs used in handheld video cameras to be reduced to a size that would fit within the distal tip of an endoscope. Since then, technology has continued to advance, allowing further reductions in the physical size of the CCD, while at the same time increasing the number of pixels in the sensor array. This has allowed video colonoscopes to become progressively thinner, with larger channels and higher image resolution, with each new generation. Figure 21.12 illustrates the progress made in reducing the size and increasing the resolution of sensors over the last two decades. The CCD in Figure 21.12b is smaller in size yet has the same resolution as the CCD in Figure 21.12a. The CCD in Figure 21.12c is approximately the same size as the one shown in Figure 21.12a but has

OUTPUT

Amplifier

Horizontal Shift Register

Figure 21.11 Schematic representation of an interline transfer chargecoupled device.

(a)

(b)

(c)

(d)

100-Series 1989

130-Series 1994

140-Series 1996

EXERA 2000

("Q" Models)

(Thin Scopes)

Figure 21.12 History of charge-coupled devices used in Olympus EVIS colorchip endoscopes.

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(a) Test Chart

(b) Test Setup

(c) Results

d

Limit of Resolution

Figure 21.13 Bench-top test to quantify resolving power. (a) Test chart. (b) Test set-up. (c) Results.

Test Chart

much greater resolution. The CCD in Figure 21.12d is the world’s smallest endoscopic CCD and is used in the very thinnest video endoscopes.

b X/4

Standard Colonoscope

c

“Zoom” Mode Close Focus HD Colonoscope

X/2

e

The recent addition of high-definition image sensors to video colonoscopes is the latest step in the continuing quest to observe the colonic mucosa with increasingly higher resolution. What endoscopists are interested in is increased “resolving power” in their colonoscopes. Engineers who design endoscopes test their resolving power using the method shown in Figure 21.13. A standardized test chart with increasingly smaller sets of black and white lines (Figure 21.13a) is used as a test object. This test chart is placed in front of the endoscope’s objective lens, and the distance between the test chart and the distal tip of the endoscope is carefully measured (Figure 21.13b). The image of the test chart, as seen on the endoscope’s video monitor is carefully studied. The larger, more widely spaced lines are easily distinguished. However, the more closely spaced lines eventually merge together as they become smaller than the resolving power of the endoscope. As Figure 21.13c illustrates, the limit of the endoscope’s resolving power at the distance under test is the spacing between the closest pair of lines that can still be distinguished as individual lines. When the endoscope is placed far from the test chart, only the most widely spaced lines can be clearly seen. However, as the endoscope is moved closer and closer to the test chart, smaller and smaller line pairs can be distinguished. If these data were plotted, the result would look like Figure 21.14. For a standard colonoscope, when the distal tip is looking at the target from a far distance (e.g., 100 mm), the resolution of detail is very low. However, as the endoscope is brought closer to the target, finer and finer detail can be observed, until at point (a) in Figure 21.14 the standard endoscope reaches its maximum resolving power. Moving the endoscope closer to the target actually degrades the image since the target exceeds the close-focus point of the lens system. The dashed lines in Figure 21.14 therefore illustrate “out of focus,” and therefore basically unusable, conditions. The solid lines represent the actual working range of the endoscope’s optics.

278

X

Resolution (µm / line pair)

Image resolution

a As endoscope moves closer, more detail can be seen

d Past the close focus point, the image blurs

1

10

100

1000

Distance to Target (mm)

Figure 21.14 Resolving power of standard, zoom, and close-focus colonoscopes.

Zoom (optical and electronic) For many years, endoscopes with adjustable focusing (or a so-called “zoom” feature) have been available. These endoscopes have a means of mechanically moving the small lenses in the distal tip of the endoscope in order to change the point of close focus. This is typically accomplished by moving a control on the body of the endoscope which puts the endoscope into its “zoom” mode. When the endoscope is placed in its zoom mode, it can typically approach the tissue to within 2–3 mm and still be in focus. Because of its closeness to the tissue, the endoscope obtains a very detailed image of the tissue’s surface. A zoom endoscope’s resolving power, as measured by the spacing between the closest distinguishable line pairs on the test chart, is approximately four times greater than a standard endoscope. However, this increased resolution comes at a price. At such high magnifications, the depth of field, similar to the depth of field of a microscope, is extremely limited [see (b) in Figure 21.14]. Moving the endoscope either closer than 1.5 mm or further than 2.5 mm from the tissue causes the image to go out of focus and become unusable. Therefore, when in the “zoom” mode, these endoscopes are quite difficult to keep in focus.

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A compromise between these two extremes is the recent introduction of “close-focus” colonoscopes. The optical system on close-focus colonoscopes is fixed, but is designed to allow the endoscope to approach the target tissue to within 3 mm before going out of focus. The Olympus CF-H180 colonoscope is one such close-focus instrument. Not only can it approach the tissue much more closely than previous models, but it also contains a high-definition CCD which also improves its resolving power. Therefore, at any chosen working distance, the high-definition imaging system produces a sharper image of the mucosa than a nonhigh-definition endoscope [see (d) in Figure 21.14]. In addition, due to its closer minimum clear focus point, the endoscope can move closer to the tissue for a more magnified view, further increasing its resolving power. The result is an overall resolving power that is more than twice that of standard colonoscopes [see (e) in Figure 21.14]. The maximum resolving power of the Olympus CF-H180 is not equal to that of zoom endoscopes; but without the focusing problems of zoom endoscopes, it is no more difficult to use than a conventional colonoscope. The foregoing discussion refers to optical zoom technology. While few endoscopes have optical zoom capability, most video endoscopes do have an electronic “zoom” function. Unlike optical zoom, which truly increases the resolving power of the endoscope, electronic zoom simply enlarges the display of the image captured by the center portion of the CCD without adding additional detail, and discards the image information captured by the outer edges of the CCD. Therefore, although the image detail seen on the monitor may be larger when electronically zoomed, no new information is added.

The Video Colonoscope

the CF-H180 colonoscope has three light guide bundles instead of the usual two. In addition, these light guide bundles are splayed slightly outward to illuminate the wider field of view.

Shape of displayed image All endoscopes emit a conical beam of light from their distal tip (see Figure 21.18). Likewise, the round objective lens at the tip of the instrument produces a circular-shaped image of the tissue being viewed. Because of these geometric considerations, fiberoptic colonoscopes typically use round image fiber bundles, and a round image is presented in the fiberscope’s eyepiece. In contrast, the photosensitive area of a CCD is always square or rectangular, since all CCDs use pixels arranged in a matrix composed of columns and rows to capture and transfer charges. The manner in which the video colonoscope designer attempts to make best use of the mismatch between the round endoscopic image and the square/rectangular image sensor determines the shape of the video endoscopic image as it appears on the monitor. If the magnification of the lens system is adjusted to fit the endoscopic image entirely within the borders of the photosensitive area, then a round endoscopic image will be reproduced on the observation monitor (Figure 21.15a). The advantage of this design is that the entire wide-angle view of the colonoscope is captured. The disadvantages are that the image on the monitor is relatively small and has low resolution because pixels in the corners of the CCD are not illuminated and therefore not used. If the designer enlarges

Angle of view

VIDEO MONITOR Unused Pixels

Several recent studies have looked at the “miss rate” of colonoscopy [6–8]. Viewing behind haustral folds via thin endoscopes with retrograde optics and extended withdrawal times have been studied with the hope of improving the detection of polyps located behind haustral folds. One way to increase coverage of the colon wall without increasing endoscope tip manipulation time is to increase the angle of view of the colonoscope. Early colonoscopes had an angle of view of approximately 100°–120°. Today 140° is typical. The recently introduced Olympus CF-H180 colonoscope now has an angle of view of 170°. This instrument also has a high-definition CCD and close-focusing optics [9,10]. To increase the depth of field on this endoscope required the light aperture in the distal lens assembly to be dramatically reduced. Reducing the aperture increased the depth of field and improved its resolving power, as discussed above, but it also reduced the amount of light which is able to pass through the iris onto the CCD. Because of the additional need for light to illuminate the wide 170° field of view, and to make up for the diminished light of the close-focusing optics,

(a) CCD UNIT

Wasted Light

(b)

Wasted Light Unused Pixels

(c)

OBJECTIVE LENS

Figure 21.15 Design and magnification of objective lens affect the shape of the image displayed on the monitor.

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the image so that it covers the entire CCD, a square image will result (Figure 21.15b). In this case the full CCD is used but large portions of the endoscopic image fall outside the photosensitive array and are not captured and not displayed. This wastes light produced by the endoscope and makes large portions of the peripheral endoscopic field of view unobservable. A compromise between these two extremes is illustrated in Figure 21.15c. In this case the objective lens is designed to produce an intermediate-sized image. This allows the CCD to capture most but not all of the projected image, while minimizing the number of unused pixels at the corners of the CCD. This results in an eight-sided image on the observation monitor. All three imaging configurations have been used by video endoscope manufacturers.

Reproduction of color All solid-state image sensors are inherently monochromatic devices. They can reproduce only black and white images. The silicon photosites employed on the surface of the CCD develop charges in proportion only to the intensity (brightness) of the light falling on the array. The pixels cannot distinguish the color of the incident light. For an endoscope to reproduce the necessary attribute of color, the system must have an additional means to analyze the color (wavelength) of the light falling on the sensor. To understand the process of color reproduction, it is helpful to first understand how humans perceive color. All photographic and electronic imaging systems attempt to mimic the way in which the human eye and brain respond to color. The sensitivity of the human eye to light intensity varies with the wavelength or color of the light (Figure 21.16). The human eye is most sensitive to green and less sensitive to reds and blues. The CCD has a similar but broader sensitivity, ranging from infrared light (wavelengths > 780 nm), through the visible spectrum, to ultraviolet light (wavelengths < 380 nm). Anyone who has mixed paints or dyes knows that when two or more colors are mixed the original colors disappear and a single, newly created color is produced. When observing a

mixture of colors, the human eye is nonanalytical and cannot distinguish the original component colors. The hue of this newly created color is determined by a phenomenon that scientists refer to as trichromatic vision.

Trichromatic vision Nearly any color to which the human eye is sensitive can be matched by mixing the light of three specific colors: red, green, and blue (RGB). If three light projectors were fitted with these special RGB filters and the projected light were overlapped, the resulting image would appear similar to that shown in Figure 21.17. The color resulting from the overlap of the red and green projectors would be indistinguishable from monochromatic yellow light. Likewise, light from the overlapping green and blue projectors would produce the mental sensation of looking at pure cyan light. The overlap of red and blue produces the color magenta. It is somewhat amazing that where all three of the projectors overlap in the center, the observer will see an area of pure white, with no hint of the three component colors. If the intensities of each of the three projectors were accurately controlled and varied, it would be possible to reproduce essentially any spectral color in the central area of overlap. In the early 1800s, Thomas Young performed such experiments with projectors and was the first to propose the theory that humans possess trichromatic vision. His experiments, and those of his successors, have caused scientists to postulate that humans perceive color through the stimulation of three different types of neural cell (cone) located in the retina of the eye. These cells are presumed to have the approximate sensitivity curves depicted for the RGB cones in Figure 21.16. Since our eyes perceive color based on a trichromatic system, we can trick the eye into seeing full color when looking at a brochure printed using inks of only three colors. A chemist can manufacture color film using emulsions of only three colors. An engineer can design a color video monitor using only RGB phosphors. In fact, the basis of all color reproduction technology is tightly linked to the concept of trichromatic vision. WHITE

Relative Sensitivity

1.0 Green Cones

Red Cones

HUMAN EYE 0.5

RED

Yellow

CCD

Blue Cones

Magenta

GREEN 0.0 300

400

500 600 Wavelength (nm)

700

Figure 21.16 Light sensitivity of charge-coupled devices (CCDs) compared with the human eye.

280

BLUE

800

Cyan Figure 21.17 Color theory: additive primary colors.

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Theory of color video All video images are reconstructed using the three component colors of RGB. Because these three colors can be additively combined to mimic all other spectral colors, they are commonly referred to as the additive primary colors. It is these three colors that are in fact the colors of the phosphors used to create fullcolor images on the face of a video monitor (see Figure 21.18). These same colors are also used in LCD (liquid crystal display) and plasma flat-panel monitors. There are currently two very different types of color imaging system used in commercial video endoscopes. The first commercial video image endoscope system, the VideoEndoscope introduced by Welch Allyn in 1983 [5], was based on an RGB sequential imaging system. Many current endoscopes continue to use this system. A second competing imaging technology, the so-called “colorchip” endoscope, despite being developed later, has now become the predominant system worldwide. Each color reproduction system has its own advantages and disadvantages, as explained below.

Red, green, and blue sequential imaging The components of an RGB sequential videoscope system are schematically shown in Figure 21.18. The endoscope has a monochromatic (black and white) CCD mounted in its distal tip. The objective lens at the tip of the endoscope focuses a miniature image of the endoscope’s field of view on the photosensitive surface of this CCD. This image is illuminated via a fiberoptic bundle running through the endoscope (not shown), carrying light from a lamp within the light source to

The Video Colonoscope

the distal tip of the endoscope. Unlike the light used for fiberoptic or colorchip endoscopes, this light is not continuous but is strobed or pulsed. The high-intensity xenon lamp within the light source emits continuous white light with the approximate color temperature of sunlight. A rotating filter wheel with three colored segments (RGB) is placed between this lamp and the endoscope’s light guide post. This filter wheel chops and colors the light falling on the endoscope’s light guide bundle. When observed at the distal tip of the endoscope, this illumination appears to be a flickering white light rather than actual sequential bursts of RGB. Rotating at 20–30 revolutions per second (rps), these three primary colors appear to merge, creating white illumination when observed with the unaided eye. The purpose of this unique illumination system is to produce three separate monochromatic images, each obtained when the field of view is sequentially illuminated by the three primary colors in turn. During the fraction of a second when the red filter is in the light path, the interior of the colon is illuminated only by red light. The CCD image sensor captures a monochromatic (black and white) image of the colon as it appears under this red illumination (Figure 21.19). Areas of the colon that are naturally reddish in color reflect heavily under red light and appear to be bright. Areas of tissue with less red reflect red light weakly and appear dark under red illumination. After a monochromatic image of the colon wall is obtained under red illumination, the filter wheel rotates to the adjacent opaque area of the wheel. At this point the endoscopic Memory Banks Processing & Timing Circuits

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Figure 21.18 Schematic representation of a red, green, and blue sequential endoscope imaging system. The rotating primary color filter wheel results in sequential monochromatic illumination of the field of view.

Wires For CCD Signal Magnified Phosphor Dots Electron Guns

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Figure 21.19 Red, green, and blue (RGB) sequential imaging system. The tissue is sequentially illuminated by RGB light while monochromatic (black and white) images are captured in sequence. These component images are then fed to a video monitor, which generates RGB component images that the observer’s eye fuses into a full-color image.

illumination goes momentarily dark and the image on the CCD is read, directed through a processing and switching circuit, and stored in the “red image” memory bank of the video processor (see Figure 21.18). After the red image is stored, the filter wheel rotates to place the green filter in the light path. A monochromatic image of the colon wall as it appears under green illumination is then obtained by the CCD (see Figure 21.19). This image is then read and sent to the video processor for storage in the “green image” memory bank. In a similar manner, a third monochromatic image is obtained when the filter wheel rotates to the blue segment; this image is correspondingly stored in the “blue image” memory bank. This sequence of capturing a set of images for each of the three primary colors is repeated 20–30 times each second, the precise speed being determined by the video processor. Synchronization circuitry matches the rotation of the filter wheel with the readout of the CCD, and sequences the switching circuit to direct each new image to the proper memory bank (see Figure 21.30).

Colorchip video imaging A colorchip CCD is essentially a black and white image sensor with a custom-fabricated, multicolored, mosaic filter bonded to its surface (Figure 21.20). Each colored filter element is precisely aligned with the photosite (pixel) behind it. The color mosaic filter allows the CCD to directly and simultaneously resolve the component colors of the image. Engineers use the term instantaneous single-plate CCD to emphasize that all three color components are obtained concurrently by a single plate, or CCD. In order to understand how a colorchip CCD works, it is essential to understand how colored filters can separate the

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incoming light into the respective primary colors of RGB. Referring back to Figure 21.17, it is clear that cyan is the mixture of blue and green. Therefore, a cyan filter will pass green and blue light, but block (or absorb) red light (Figure 21.21). In a similar fashion, a magenta filter will pass blue and red, but block green light; and, a yellow filter will pass green and red, but block blue light. There are many possible combinations of filter colors that can be used to create the color mosaic filter needed to fabricate a colorchip CCD. However, the cyan/yellow/magenta/ green filter shown in Figure 21.20 is a typical color combination used in colorchip endoscopes. Although Figure 21.20 shows a CCD sensor with only 36 pixels, in fact, a typical colorchip endoscope may have more than a million pixels, each overlaid with a microsized filter segment of cyan, yellow, magenta, or green. As Figure 21.20 also shows, the color information received by each of the pixels behind these filter segments (except for the green pixels) is a mixture of RGB primary color information. Therefore, electronic color processing circuits must separate out the incoming color information into the pure RGB component images required by the display monitor. One may question why it is desirable to use a mosaic filter with nonprimary colors (cyan, yellow and magenta), when if primary colors (RGB) were used instead, there would be no need for the complex color processing circuitry required to convert the captured image into its primary components? The answer lies in the fact that the nonprimary-colored filters allow more light to reach the CCD’s pixels, and therefore the CCD sees a brighter image. Referring to Figure 21.21, it is obvious that a red filter allows only red light to pass, but a magenta filter allows both red and blue light to pass.

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Colorchip CCD Unit Color Mosaic Filter

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Figure 21.20 A color mosaic filter matched to the pixels in a colorchip chargecoupled device allows the image sensor to simultaneously capture full color information from images projected on its photosensitive surface.

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colorchip endoscopes use color mosaic CCDs with nonprimarycolored filter segments.

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Figure 21.21 Cyan, magenta, and yellow filters pass more than one primary color (red, green, or blue).

Therefore, a pixel placed behind a magenta filter will see more light than a pixel placed behind a red filter. Likewise, pixels behind yellow and cyan filters will be more heavily illuminated than pixels behind green or blue filters. The increase in brightness achieved by using nonprimarycolored filter segments is obtained at the expense of the additional processing required to later separate the mixed color signals into their primary components. However, due to the increased light sensitivity, color mosaic CCDs allow the videoscope designer to construct an endoscope with a smaller light guide fiber bundle, to maximize the endoscope’s angle of view, and to increase its depth of field. All these features improve the optical performance of the colonoscope, but require additional light. For this reason all commercial

The preceding sections explain the technology used to capture images with an RGB sequential imaging system versus a colorchip imaging system. However, the technology used to display the resulting images is common to all video systems. The face of a color video monitor is actually composed of thousands of RGB phosphor dots, typically arranged in a repeated triangular matrix. The monitor also contains three electron guns, each of which scans over the face of the picture tube in an orderly manner (see Figure 21.18). The physical arrangement of the “red” gun will allow it to hit and activate only the red phosphor dots. The “green” and “blue” guns are restricted to hitting and illuminating only the green and blue phosphor dots respectively. By feeding the signal from the red memory bank of the video processor to the red electron gun in the monitor (see Figure 21.18), the monitor will reproduce an image of the colon wall as it appeared under red illumination. This is illustrated by the red component image depicted in Figure 21.19. Likewise, feeding the images from the green and blue memory banks to the green and blue electron guns respectively will reproduce the green and blue components of the original image. Although three guns are described here, some monitors achieve the same end result using a single electron gun. In addition, LCD monitors achieve a similar result using a matrix of miniature RGB cells, of which three together make up one “pixel” in the display. It is a phenomenon of human vision that when two or more sources of color are placed close together (but not overlapping) and are viewed from a sufficient distance, the colors will blend together to form a third color. This third color is

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the color predicted by the theory of trichromatic vision. This fusion of color sources is referred to as the juxtaposition of color sources. Because of this phenomenon, the three intertwined RGB images on the video monitor appear to fuse together into a single, full-colored, natural appearing image, rather than appearing to be a confusing collection of intermixed colored dots.

Reproduction of motion The colorchip videoscope has an inherent advantage over RGB sequential videoscopes in reproducing motion. The filter wheel in current RGB sequential video processors typically rotates at 20–30 rps. Since each of the color component images is captured individually in sequence, it takes 1/30 s (with a 30-rps filter wheel) to capture the three component images that make up a single video image (Figure 21.22). If there is relative motion between the endoscope and the object being viewed, as often occurs during endoscopy, the three component images may differ slightly with respect to object size and position. When these three RGB images are subsequently superimposed on the video monitor, it is likely that they will be misaligned. This misalignment will be clearly visible if the endoscopist happens to freeze the image while it is moving rapidly. This color separation is present, to a greater or lesser extent, continuously throughout the entire examination. It gives the images an unnatural, highly colorful, stroboscopic appearance whenever there is rapid motion of the endoscope, the object being viewed, or both. This type of color separation is especially apparent when the endoscopist feeds water to clean the objective lens. The water droplets produce a colorful but distracting flicker across the endoscopic image. Second-generation RGB sequential video processors are engineered to reduce the problem of color separation on captured images. These processors incorporate an anticolorslip circuit to analyze the video signal in real time and to freeze the image at the moment when color separation is at a minimum (Figure 21.23). In early RGB systems, the processor “froze” the image that was displayed on the monitor at the exact

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Figure 21.23 An “anticolorslip” image capture system identifies the set of images obtained during the capture period which has the least amount of color slip due to motion.

instant that the image capture function was activated (i.e., the moment the “freeze” button was depressed). Instead of capturing this initial image, activation of the freeze function on newer RGB video processors (e.g., Olympus CV-240 and CV-260 video processors) triggers a special capture circuit that analyzes the stream of incoming images for the next 0.25 s, i.e., during the next five rotations of the filter wheel (Figure 21.23). From these five complete images (a total of 15 RGB component images), the circuit selects the set of RGB component images that exhibits the least amount of color separation. In the example shown in Figure 21.23, the capture circuit has found that relative motion was minimal during RGB component images 7, 8, and 9athese being the third set of images captured after the “freeze” button was depressed. The circuit then holds these three RGB component images in memory and displays them on the observation monitor as the best possible still image of the mucosa. Even though the system is able to choose only from images obtained within a 0.25-s period, the circuit is remarkably effective in reducing color separation within captured still images. This system does not, however, reduce the strobing, color separation, and water droplet flicker observed during real-time endoscopy. While the RGB sequential videoscope has difficulty reproducing motion, the colorchip videoscope has inherent advantages in imaging moving tissue. Because a colorchip endoscope captures all three color components of the image simultaneously, there is never any color separation with either moving or “frozen” images. Since illumination is continuous and unstrobed, and the frame rate is consistent with contemporary television standards, reproduction of moving images is always smooth and always appears natural.

Advantages of colorchip videoscope The colorchip videoscope has several inherent advantages over the RGB sequential system. Those discussed previously include: 1 smooth, natural reproduction of motion; 2 absence of color separation on frozen images.

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Advantages of red, green, and blue sequential videoscope Having considered the advantages of the colorchip videoscope, it is appropriate to do the same for the RGB sequential videoscope. One of its major advantages is the opportunity for increased resolution in small CCDs. Image resolution is heavily dependent upon the number of pixels in the original image. The colorchip system requires information from several different pixels, which is then processed via an algorithm, to obtain the RGB component values for each single point within the image. In the RGB sequential system, each pixel is illuminated by RGB light sequentially. Each pixel thus provides information on each of the three color components in turn. The fact that a single pixel can provide all three color components is an advantage for small imaging devices like endoscopes. The physical size of an endoscopic CCD is restricted to the space available within the distal tip of the endoscope. This limits the size of the CCD and the number of pixels that it can contain. Since the colorchip CCD uses several pixels to provide the same information obtained from a single pixel in the RGB system, the RGB system can theoretically produce the greatest image resolution (based on equivalent numbers of pixels). In practice, this advantage is not significant when designing a video colonoscope, since even colorchip colonoscopes now have high-definition CCDs, but it is an advantage when the thinnest possible endoscope is required (e.g., video choledochoscope). Because the RGB sequential videoscope uses primary color filters, and since the color components are isolated, captured, and processed separately within the video processor, this type of videoscope provides very accurate color information. Although both systems produce natural appearing images, the RGB sequential system can theoretically produce a truer color signal. In addition, the filter segments can be easily

customized to make the endoscope suitable for emerging optical technologies like autofluorescence imaging.

Narrow-band imaging A new method of endoscopically observing tissue has recently been introduced under the name “narrow-band imaging” or “NBI” [11–13]. The purpose of NBI is to optically enhance the contrast between the tissue’s vascular and microvascular structures and the surrounding tissue. To do this, both the endoscope’s illumination and imaging systems are modified to increase the optical contrast of hemoglobin, a major tissue chromophore. Figure 21.24 shows the absorbance spectra of oxyhemoglobin. It can be seen that oxyhemoglobin heavily absorbs blue light, with peak absorbance at 415 nm. Oxyhemoglobin also shows some absorbance of green light, with a secondary peak at 540 nm. Therefore, if one were to design an optical system to detect hemoglobin, it would appear that taking advantage of oxyhemoglobin’s characteristic absorption at 415 nm of blue light and at 540 nm of green light would help increase the selective identification of areas rich in hemoglobin. This is in fact what NBI does. To help understand how objects can be selectively enhanced based on their light absorption characteristics, refer to Figure 21.25. Figure 21.25a illustrates the appearance of a group of variously colored objects (balloons) illuminated with “white light” (i.e., the entire visible spectrum). If these same objects are illuminated with broadband red light (i.e., no green or blue wavelengths), the objects that under white light appear red, yellow, and orange now become brighter, while those that are green and blue are dark (see Figure 21.25b). In contrast, if the same objects are illuminated with blue light, the objects that appear blue under white light appear brighter, but red, orange, and yellow objects appear darker (see Figure 21.25d). It is clear that, by changing the color of the illuminating light, it is possible to enhance selected objects based on their color absorption characteristics.

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Additional advantages include: 3 a fast shutter mode that prevents image blur of even the fastest moving subject; 4 compatibility with standard (nonstrobing) xenon light sources; 5 increased transillumination. With RGB sequential endoscopes, transillumination is problematic since its strobed light output is substantially weaker than that of nonstrobed systems. Many RGB sequential light sources have a means for temporarily removing the spinning filter wheel from the light path during the “transillumination” mode. This produces a steady intense white light ideal for transillumination. However, once the filter wheel is removed, the image is lost, since in most cases the illumination is so intense that it saturates the CCD, thus producing a totally white screen. Even if an image is visible, it will be in black and white, since the filter wheel must be in its proper position to reproduce color.

The Video Colonoscope

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Figure 21.24 Absorbance spectra of oxyhemoglobin.

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Figure 21.25 Changes in illumination affect the appearance of objects due to differences in spectral absorbance.

This is the basis of NBI. However, for even greater selectivity, rather than using broadband illumination, NBI uses a filter in the light source that produces just two very narrow bands of illuminationablue light centered around 415 nm, and green light centered around 540 nm (Figure 21.26). These are the wavelengths that are selectively absorbed by oxyhemoglobin (see Figure 21.24). Figure 21.26 illustrates the process of NBI in an RGB sequential endoscope system. Note that a special NBI filter has been inserted into the illumination path between the xenon lamp and the rotating RGB filter wheel. This limits the full spectrum white light from the xenon lamp (Figure 21.26–1) to a mixture of narrow-band blue light at 415 nm and narrow-band green light at 540 nm (Figure 21.26–2).

Video Image Signals

The process of creating an NBI image with this system is as follows: 1 When the red segment of the rotating RGB filter wheel is in the light path, no light is produced by the endoscope since the red filter totally blocks the blue and green light passing through the NBI filter. Therefore, no image is stored in the “red” memory bank of the video processor for this part of the cycle. 2 When the green filter segment is rotated into the light path, green narrow-band light (540-nm wavelength) passes through the filter and the endoscope, and illuminates the tissue with 540-nm illumination. The resulting image from the tissue is captured by the black and white CCD at the tip of the endoscope (Figure 21.26a) and is sent to the video processor

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Figure 21.26 Narrow-band imaging with a red, green, and blue sequential video endoscope system. (Endoscopic images courtesy of Y. Sano and S. Yoshida.)

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DISTAL TIP OF ENDOSCOPE Video Image Signals

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Figure 21.27 Narrow-band imaging with a colorchip video endoscope system.

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for storage. However, it is sent not to the “green” memory bank, but rather to the red one (Figure 21.26c). Therefore, there is an intentional color reassignmentathe image obtained under green illumination will be displayed as a red component image on the video monitor. 3 When the blue filter segment is rotated into the light path, blue light (415 nm) passes through the videoscope and illuminates the tissue. The image of the tissue captured under blue light (Figure 21.26b) is sent to the blue image memory bank in the video processor (Figure 21.26e). In addition, the same image is also sent to the green image memory bank (Figure 21.26d). Again, this is an intentional reassignment of the color of the final image. 4 After the RGB rotating filter has made a complete revolution and all three memory banks contain images, the three RGB component images are then displayed simultaneously on the video monitor. The result is an NBI image, as illustrated in Figure 21.26f. Figure 21.26g is a corresponding image of the same tissue taken under normal white light conditions. Note that the NBI image (Figure 21.26f) produces enhanced contrast between vascular structures and the surrounding tissue. Note also that, owing to the intentional reassignment of colors, the blood vessels in the NBI image are now blue–green, the background tissue is more yellowish, and the lesion is more brownish than in the white light image. In addition, the selective absorption of hemoglobin has enhanced the microvascular pattern and surface morphology of the tissue. NBI with a colorchip video endoscope is similar to NBI with a RGB sequential endoscope. As shown in Figure 21.27, the same NBI filter is inserted into the light path between the

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xenon lamp and the endoscope’s light guide fiber bundle. When in the NBI mode, the endoscope therefore simultaneously illuminates the target tissue with both 415-nm blue light and 540-nm green light. The resulting image is captured by the colorchip CCD in the tip of the endoscope and is sent to the video processor for processing (Figure 21.28). As with the RGB sequential system, there is an intentional reassignment of the color information. The colorchip CCD actually obtains no “red” information since there are no red wavelengths in the illuminating light. The image information that would normally appear on the monitor as green is intentionally reassigned to appear as a red component image on the monitor. The blue image information from the CCD is directed to both the blue and the green inputs of the video

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Figure 21.28 Narrow-band imaging color processing with a colorchip video endoscope system.

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monitor. The end result is similar to that obtained with the RGB sequential system. Owing to the selective absorption of the special NBI incident light and the reassignment of color information, vascular structures are highlighted and mucosal surface features are enhanced. Endoscopy systems that employ NBI can be easily switched back and forth between NBI and white light endoscopy at the touch of a button (endoscope control switch or keyboard key).

Image processing When an image is in a digital format, it is relatively easy to perform various image processing functions on the image. Some researchers and endoscope manufacturers are therefore experimenting with digital processing of white light endoscopic images as an alternative to NBI. One such image processing schema referred to by Osawa et al. [14] as “optimal band imaging” has been commercialized by Fujinon as the Fuji Intelligent Color Enhancement (FICE) system. All such image processing algorithms operate on the final natural-colored endoscopic image. There is no modification to the light source, and there is no change in the spectrum of light used to illuminate the tissue. This “postprocessing” of white light images is typically performed by software running within the video processor. Alternatively, the endoscopic image can be exported to a computer and the image processing performed by an external personal computer. Figure 21.29 is an illustration of just one of the countless image processing manipulations that can be performed on digital images. (A nonendoscopic image is shown, since the wide variety of colors facilitates understanding the process.)

Figure 21.29a shows a standard white light image of a hot-air balloon launch. With software it is easy to select a particular color of interest and to choose only those objects in the image that exhibit that particular color. In the case of Figure 21.29b, a certain color of blue found in the upper sky and a certain color of green found in the grass were chosen as colors of interest. With the target colors selected, the software easily scans through the image and shows portions of it that are very close in hue to the preselected colors. In Figure 21.29b the software has selected a narrow range of blue and green hues for display. If the software parameters are changed to allow the algorithm to select from a broader range of color tones around the selected central color tones, a result similar to Figure 21.29c is produced. In this case, almost all of the sky (except for the clouds) and almost all of the grass (except for the shadows) have been selected from this broader palate. However, note that the two blue hot air balloons that are similar in color to the sky have also been selected; along with the green and blue stripes on the upper hot air balloon. Since the algorithm is looking only for matches within a specific color range(s) it cannot discriminate between different objects having the same color. Once objects have been selected based on their color, it is possible to manipulate this color, reassign this color, enhance the prominence of these objects, etc. Figure 21.29d illustrates a reassignment of the colors identified in Figure 21.29c, as one example of postprocessing. The blue sky has been reassigned to green and the green grass to blue. Note, however, that the two blue hot air balloons also changed to green since they fell within the designated color range. The other colors in the photo are unaffected.

Figure 21.29 Example of image processing: (a) original image, (b) selection of colors with a narrow range of hues, (c) selection of colors with a broader range of hues, and (d) color reassignment of the selected hues.

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Figure 21.30 schematically illustrates the functions of the various electrical circuits within a typical RGB sequential video processor. The CCD image sensor (located in the distal end of the endoscope) receives both power and timing signals from the video processor. The timing signals control the readout of the CCD and the transfer of charges to and from the horizontal shift register (see earlier discussion). From the shift register, the image signal is fed through an amplifier on the CCD and then into the preprocess circuitry of the video processor. The preprocess circuitry is responsible for electrically isolating the patient from the potentially dangerous high-voltage circuitry of the video processor, initiating automatic brightness control, and adjusting the chroma (color) and white balance of the image. The preprocess cir-

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cuitry further amplifies the signal and often performs additional image processing functions such as edge or structure enhancement. The signal then passes through an analog-to-digital (A/D) converter, changing the signal from an analog to a digital format. The digitized image is then directed through a switching circuit for storage in one of the red, green, or blue image memory arrays. Images from the digital memories are next passed through a size adjustment circuit that scales the relative size of the endoscopic image for presentation on the video monitor. A second circuit then adjusts the relative position of the endoscopic image, and sizes and positions any subscreen image that may be added to the screen along with the main image. An example of a typical subscreen image is a reduced display of the real-time endoscopic image, added to the screen whenever the main image is frozen. At this point, the developing image is still in a digital form but has been adjusted in size and position, with subscreen images (if any) added. The image then passes through a digitalto-analog (D/A) converter to change the image back to an analog format. A masking circuit then adds a mask (typically black) around the image(s) to provide a uniform background color. Finally, the image passes through a postprocessing circuit that encodes the video signal to conform with a recognized video signal standard (e.g., NTSC, National Television System

Subscreen Creation & Screen Position

It is clear that if certain endoscopic structures such as capillaries, glands, pits, etc. always had a unique characteristic color, it would be possible to design a software algorithm to identify and enhance them. There is currently no image processing schema that has been standardized or validated for routine clinical practice. However, research is ongoing to identify image processing algorithms that enhance surface morphology, capillaries, pit patterns, etc.

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Committee; PAL, phase alternating line), allowing the image to be displayed on any standard video monitor. Figure 21.30 also schematically illustrates some of the mechanical components of the video processor and light source. Light from the light source lamp first passes through an infrared filter to remove nonvisible heat rays. The light then passes through a lens that focuses it on the tip of the fiberoptic light guide bundle within the universal cord of the endoscope. An iris in the light path controls the brightness of the light transmitted to the endoscope, and a filter wheel modifies the color of the light (described earlier). The motor rotating the filter wheel is regulated by a control circuit to ensure that the wheel spins at the precise speed required by the video processor. Detectors placed adjacent to the filter wheel identify which filter segment (red, green, or blue) is currently in the light path. Figure 21.30 also illustrates the synchronization circuitry which ensures that all functions of the video processor and light source are coordinated with the video output signal. These functions include synchronization of filter wheel rotation, exposure and readout of the CCD, memory transfers within the video processor, and image freeze control. Video processors also generally require endoscope identification circuitry to identify the model (or type) of endoscope connected to the processor. Endoscope identification allows the system to compensate for differences in CCD type. A major portion of the circuitry within a video processor is designed around the specific CCD(s) with which the processor is intended to operate. First-generation videoscopes used the same CCD for all model endoscopes, from the largest colonoscope to the slimmest gastroscope. Current video processors are designed to drive a family of CCDs, each of which differs in size and image resolution capability (see examples in Figure 21.12). An advantage of this strategy is that a family of compatible CCDs allows a wide range of videoscopes, old and new (including large-diameter high-definition instruments, specialty endoscopes, thin pediatric endoscopes, and large-channeled therapeutic instruments), to be compatible with the same video processor. In particular, the video processor must specifically compensate for differences in pixel number, illumination requirements, data transfer rates, and drive circuitry. Despite the range of CCDs available for current video processors, there are no video processors that are compatible with both colorchip and RGB sequential endoscopes; nor is it possible to interchange endoscopes or processors made by different manufacturers. Endoscopy units typically select one type of system from a single manufacturer. To do otherwise would require the purchase of additional video processors and would result in the accumulation of incompatible equipment. Although Figure 21.30 summarizes many of the basic functions of a video processor, some standard functions are not illustrated for the sake of simplicity. These include connections to an external keyboard for text input, circuitry for superimposing text on the monitor image, and circuitry for

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communicating with external computers, printers, and image documentation devices.

Factors to consider when evaluating a video image colonoscope The video image endoscope is a technologically advanced and complex clinical tool. When these instruments first entered the market, published comparison reports of various commercially available models were common [15–17]. Now that the technology of video endoscopy has matured, such published comparisons are rare. It is difficult to identify any single design criterion as the deciding factor in selecting the best videoscope for a particular clinical application. When evaluating a video colonoscope, the following criteria should be considered: 1 Image quality. Does the instrument have a sufficiently wide angle of view, with good depth of field, high image resolution, good image contrast, accurate color, clear frozen images, and a wide dynamic range (ability to see clearly in both light and dark areas of the image)? 2 Illumination characteristics. Does the instrument have adequate image brightness under all clinical conditions? Is illumination evenly distributed from image center to image edge? Does the system have responsive automatic brightness adjustment as viewing distances change? 3 Basic endoscope functions. Does the instrument have responsive handling and appropriate insertion tube characteristics? Does it have smooth tip angulation, a control section of appropriate shape and weight, conveniently positioned angulation knobs and valves, and good suction, insufflation, and lens washing performance? 4 Basic specifications. Does the manufacturer have a full range of instrument models, with a variety of insertion tube diameters and biopsy channel capacities? 5 Suitability for special therapeutic procedures. Is the colonoscope well protected against image noise from electrosurgical generators? Is image quality acceptable when using lasers? 6 System features. Are the video processor controls easy to understand? Are the endoscope switches for the control of remote devices easily accessible? Does the size and weight of the equipment allow for easy transportation? 7 Special features. Does the system provide the latest diagnostic features, such as the capability for NBI? 8 System expansion and integration. Is the system capable of easily interfacing with hard-copy devices, videotape recorders, and computerized image management systems?

Summary During the 1990s, the video colonoscope supplanted the fiberoptic colonoscope as the preferred instrument for colonoscopy.

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The availability of two distinct technologies for generating color images (colorchip versus RGB sequential) provides the endoscopist with a choice of basic systems, each with its own advantages and disadvantages. Although the basic shape and function of the instrument have remained unchanged, recent advancements (including the development of smaller diameter insertion tubes, instruments with adjustable stiffness, high-definition imaging, NBI, and advanced video processor features) have continued the evolution of the colonoscope.

References 1 Moriyama H. Engineering characteristics and improvement of colonoscope for insertion. Early Colorectal Cancer 2000; 4: 57– 62. 2 Moriyama H. Variable stiffness colonoscope: structure and handling. Clin Gastroenterol 2001; 16: 167–72. 3 Kawahara I, Ichikawa H. Flexible endoscope technology: the fiberoptic endoscope. In: Sivak MV Jr. (ed.). Gastroenterologic Endoscopy, 2nd edn. Vol. 1. Philadelphia: WB Saunders, 2000: 16–28. 4 Barlow DE. Flexible endoscope technology: the video image endoscope. In: Sivak MV Jr. (ed.). Gastroenterologic Endoscopy, 2nd edn. Vol. 1. Philadelphia: WB Saunders, 2000: 29–49. 5 Sivak MV Jr., Fleischer DE. Colonoscopy with a video endoscope. Preliminary experience. Gastrointest Endosc 1984; 30: 1–5. 6 van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol 2006; 101: 343–50. 7 Harrison M, Singh N, Rex DK. Impact of proximal colon retroflexion on adenoma miss rates. Am J Gastroenterol 2004; 99: 519–22.

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8 Shehadeh I, Rebala S, Kumar R, Markert RJ, Barde C, Gopalswamy N. Retrospective analysis of missed advanced adenomas on surveillance colonoscopy. Am J Gastroenterol 2002; 97: 1143–7. 9 Deenadayalu VP, Chadalawada V, Rex DK. 170 degrees wide-angle colonoscope: effect on efficiency and miss rates. Am J Gastroenterol 2004; 99: 2138– 42. 10 Rex DK, Helbig CC. High yields of small and flat adenomas with high-definition colonoscopes using either white light or narrow band imaging. Gastroenterology 2007; 13: 42–7. 11 Gono K. An introduction to high-resolution endoscopy and narrowband imaging. In: Cohen J (ed.). Advanced Digestive Endoscopy: Comprehensive Atlas of High Resolution Endoscopy and Narrowband Imaging. Oxford: Blackwell Publishing, 2007: 9–22. 12 Atkinson RJ, Hurlstone DP. Narrow-band imaging: the next frontier in colonoscopy? Gastrointest Endosc 2007; 66: 317–19. 13 Lambert R, Kuznetsov K, Rey JF. Narrow-band imaging in digestive endoscopy. ScientificWorldJournal 2007; 7: 449–65. 14 Osawa H, Yoshizawa M, Yamamoto H, et al. Optimal band imaging system can facilitate detection of changes in depressed-type early gastric cancer. Gastrointest Endosc 2008; 67: 226–34. 15 Knyrim K, Seidlitz H, Vakil N, et al. Optical performance of electronic imaging systems for the colon. Gastroenterology 1989; 96: 776– 82. 16 Schapiro M. Electronic video endoscopy. A comprehensive review of the newest technology and techniques. Pract Gastroenterol 1986; 10: 8–18. 17 Anonymous. Video colonoscope systems. Health Devices 1994; 23: 151–205.

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The Colonoscope Insertion Tube John B. Marshall University of Missouri School of Medicine, Columbia, MO, USA

Introduction Colonoscopy practice has evolved considerably since the introduction of the first commercial flexible colonoscopes into routine clinical practice in the 1970s [1,2]. When it comes to equipment, the colonoscope insertion tube is the largest contributor to overall endoscope performance, including the ease and speed of scope insertion to the cecum [3,4]. The insertion tube has been gradually modified, fine-tuned, and improved over time. Yet even with our improved insertion tubes and techniques, colonoscopy is still frequently not an easy procedure. Without sedating medications, it is also usually painful. The most expert colonoscopist will occasionally be humbled by two nemeses: looping in a long, tortuous colon and the fixed, angulated sigmoid colon. One also wants to avoid overstretching the colon and the supporting mesentery to reduce discomfort and minimize the risk of perforation. Over the years, there have been a number of attempts to modify the insertion tube to make colonoscopy easier under a variety of anatomic situations, for both endoscopists and patients. Modern adult and “pediatric” colonoscopes have both been found to be suitable for routine colonoscopy in most adult subjects. However, the perfect colonoscope has not yet been developed, and we now know that scopes with different insertion tube characteristics are useful under different circumstances. For instance, stiffer colonoscopes are preferred by many endoscopists for long, floppy colons as they permit better loop reduction and sustained “straightening” [5]. Thinner, more floppy (“pediatric”), colonoscopes are often better at traversing fixed, angulated sigmoid colons [6–9]. The relatively recent introduction of adjustable stiffness colonoscopes permits the endoscopist to adjust the stiffness of the

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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instrument’s insertion tube using a dial. In theory, this should give the endoscopist the best of both worlds. However, the experienced endoscopist knows that even with accessibility to modern instruments, there nonetheless remain challenging patients with challenging colons. This chapter will focus on the insertion tube of the stateof-the-art conventional video colonoscopeathe type used today in thousands of practices worldwide. However, it is to be recognized that we stand on the threshold of a new era in colonoscopy, heralded by many technological breakthroughs that would not have been imaginable 15 or 20 years ago except by a few visionaries. For instance, besides the radiologic technique of “virtual colonoscopy” (computed tomographic colonography), we have many “futuristic” colonoscopes which are currently being tested, such as the wireless colon capsule, the Aer-O-Scope (a pneumatic, self-propelling, selfnavigating colonoscope), and the NeoGuide Endoscopy System (which uses an articulated computer-controlled insertion tube) [10–15]. While the conventional colonoscopes of today look remarkably similar to the instruments in use in the 1970s, we can expect much more dramatic changes over the next decade. These technologies of the future are discussed elsewhere in the book.

Overview of the insertion tube The insertion tube, which is attached to the control section, is that portion of the endoscope which is inserted into the patient. It is an engineering marvel of and by itself. The preceding chapter, “The Video Colonoscope” (Chapter 21), gives excellent detailed information, including diagrams, about the design and construction of today’s mechanically complex colonoscope insertion tube. The internal components of the insertion tube include the light guide bundles, charge-coupled device (CCD) signal wires (which transmit the image), an air channel, a water channel, a forward waterjet channel (newer models), an instrument/suction channel (two in therapeutic scopes), angulation wires (to deflect the bending section of the insertion tube), and a wire coil for adjustable stiffness in models with this feature. The CCD signal wires and light

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Figure 22.2 Adjustable stiffness colonoscopes contain a tensioning coil on the inside. When the hand dial is rotated, the coil wire is stiffened, adding rigidity to the insertion tube. (Courtesy of Olympus America.)

detailed in the preceding book chapter on the video colonoscope (see Chapter 21). Figure 22.1 Hand dial for increasing insertion tube stiffness with the Olympus adjustable stiffness colonoscope. The four possible dial settings are 0 (baseline stiffness), 1, 2, and 3 (maximum stiffness). (Courtesy of Olympus America.)

guide bundles are fragile, and travel in protective sheaths to help withstand flexion and torque. Yet, the insertion tube is more than just the internal components. The components are encased by a complex structure of spiral metal bands, stainless-steel wire mesh, and finally by a multilayer cover, all of which ultimately give the insertion tube its important handling characteristics and protect the inner components. The goal is to obtain the right balance of flexibility, column strength, torque ability, and elasticity. The insertion tube must have the right amount of flexibility/ floppiness to conform to the turns of the colon, yet have sufficient column strength that it does not buckle, so that it can be advanced forward. It must also be capable of accurately transmitting torque, when applied by the endoscopist, to the distal end of the instrument. Elasticity is also required to permit the colonoscope to resume a straightened position when it is pulled back. The flexibility of the insertion tube also varies throughout its length. The distal 40 cm is considerably more flexible than the proximal portion, of which the most distal 9 cm or so is the “bending section,” which can be angulated under the control of the endoscopist. The distal end is able to “snake” through a tortuous colon, while the stiffer proximal portion is effective at preventing loop formation in those areas of the colon which have been straightened [4]. The Olympus Corporation has incorporated an additional feature into the insertion tube of its standard adult and pediatric colonoscopes: an adjustable stiffness tensioning system. Such scopes contain a tensioning wire (coil), which can be activated when desired by the endoscopist by rotating a control dial, to provide additional stiffness to the insertion tube (Figures 22.1 and 22.2). The adjustable stiffness cable wire connects at 23 cm from the tip of the scope (personal correspondence with Olympus Corporation). The adjustable stiffness colonoscope is discussed further later in this chapter. The engineering details of this type of colonoscope are also

Various available instruments for colonoscopy In addition to the standard adult video colonoscope, other types of colonoscope have been designed for certain purposes. In addition, scopes routinely used in other anatomic areas of the gastrointestinal tract have also been used for colonoscopy, when the endoscopist is faced with various challenges.

Pediatric colonoscope A thinner, more flexible, “pediatric colonoscope” introduced in the late 1980s quickly found applications in adult patients, beyond their occasional use in the situation of a stricture too tight to allow passage of the standard adult colonoscope. What we refer to as a “pediatric colonoscope” is really just a colonoscope with a smaller diameter. In fact, we could just refer to it as a “thin colonoscope.” Its greater flexibility (or “floppiness”) allows it to traverse fixed, angulated sigmoid colon segments, such as can sometimes occur in individuals with prior diverticulitis or hysterectomy through which a stiffer standard adult colonoscope could not be passed [6–9]. Pediatric colonoscopes are also helpful when an examination is thwarted because of painful looping [6]. In addition, pediatric colonoscopes have been shown to be suitable for even routine colonoscopy in adults [8,16]. While the pediatric colonoscope can make it possible to navigate an otherwise impassable sigmoid colon, the downside of its use is that it tends to loop as one navigates the proximal colon. Colonoscopists using pediatric colonoscopes must pay careful attention to loop withdrawal. Also, ancillary maneuvers, such as manual abdominal pressure, are more frequently needed with pediatric colonoscopes than with standard adult colonoscopes [9]. Even thinner video colonoscopes, not commercially available in the US at this time, have been reported to be useful for both routine colonoscopy and difficult colonoscopies [17,18]. Such thin scopes would seem to be most useful in patients with difficult sigmoid colons, when even a pediatric colonoscope cannot be passed.

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The adjustable stiffness (“variable stiffness”) colonoscope This type of instrument, manufactured by the Olympus Corporation, is generally referred to in the literature as a “variable stiffness” colonoscope. However, it is probably better termed an “adjustable stiffness” colonoscope, because, as mentioned previously, the flexibility of all modern colonoscopes, even those without the adjustable stiffness feature, displays variable stiffness over the length of the insertion tube. The adjustable stiffness assembly lets the endoscopist increase the stiffness of the insertion tube when desired, by rotating a dial. The “0” setting is the base setting, also referred to as the “soft” setting. At this setting, the stiffening system provides no additional stiffness to the baseline stiffness of the insertion tube. The endoscopist can rotate the control dial to one of the “hard” positions, numbered 1, 2, and 3. Each adds progressive rigidity to the insertion tube (Figures 22.3 and 22.4). Tightening the internal stiffener does not change the

Figure 22.3 The stiffness of the insertion tube of the adjustable stiffness colonoscope is shown in the four settings (from bottom to top): 0, 1, 2, and 3. (Courtesy of Olympus America.)

Stiff CF-H180AL CF-Q180AL

PCF-Q180AL Stiffness level

characteristics of the bending section or the adjacent transition section of the colonoscope. The adjustable stiffness feature is available on Olympus pediatric and standard adult model colonoscopes. The method of use of the adjustable stiffness feature has never been standardized. The author’s own preference is to start all examinations in the most flexible mode (“0”). If problematic looping is encountered during the examination, the scope is straightened and the stiffening dial set at “3.” I rarely use the “1” or “2” settings. While some endoscopists leave the stiffness feature activated until it is time to withdraw, I use it only intermittently, reactivating it if problematic looping recurs. Also, in the presence of a significant loop, it should not be activated until the loop has first been reduced. Changes in patient position and manual abdominal pressure are also employed as needed. The stiffener is turned off during withdrawal. How effective is the adjustable stiffness feature? The published trials which have compared adjustable stiffness colonoscopes with standard colonoscopes are summarized in Table 22.1. They reflect considerable heterogeneity in their design, in how the stiffening mechanism was employed, and in the type of adjustable stiffness colonoscopes which were used [16,17,19–26]. The studies variably used an adjustable stiffness adult colonoscope, an adjustable stiffness pediatric colonoscope, and an even thinner adjustable stiffness pediatric colonoscope (or some combination of scopes). Regarding cecal intubation frequency, no significant differences were found between any of the various types of scope employed, whether or not they were of adjustable stiffness. The time required to reach the cecum was reported to be significantly quicker with an adjustable stiffness scope in only 3 of the 10 trials. Lower doses of sedative medications with an adjustable stiffness scope were found in only one of the six trials in which the information was reported. Use of an adjustable stiffness colonoscope resulted in improved patient tolerance and/or decreased pain in just three of eight trials in which the information was included. Thus, based on available evidence, it must be concluded that the adjustable stiffness feature is, at best, only modestly effective in improving colonoscopy performance.

Tapered colonoscope

Flexible 11

11.5

12

12.5

13

13.5

Insertion tube outer diameter (mm)

Figure 22.4 Graph depicting the relative stiffness of Olympus pediatric (PCF-Q180AL) and adult (CF-H180AL and CF-Q180AL) adjustable stiffness colonoscopes.

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Olympus has recently developed an interesting prototype colonoscope with adjustable stiffness capacity, called a tapered colonoscope [27,28]. It tapers from an “adult diameter” of 12.8 mm to a “pediatric diameter” of 11.3 mm, with the transition occurring at about 25 cm from the tip. The rationale for the design was to permit easier navigation of the distal end of the insertion tube through the sigmoid colon, while the increased rigidity of the proximal portion would decrease looping. A pilot study in female patients found that the tapered colonoscope reached the cecum faster with a decreased need for ancillary maneuvers, particularly abdominal pressure [27].

Randomized Nonrandomized

Randomized Nonrandomized

Randomized

Randomized Nonrandomized Randomized

Randomized

Randomized

Brooker et al. [19] (UK)

Rex [20] (USA)

Sorbi et al. [21] (USA)

Odori et al. [22] (Japan)

Shumaker et al. [23] (USA)

Yoshikawa et al. [24] (Japan)

Kaffes et al. [25] (Australia)

Horiuchi et al. [17] (Japan)

Al-Shurieki and Marshall [16] (USA)

Lee et al. [26] (China) ASAC, AC-1, AC-2

ASPC, AC

ASTPC, ASPC, AC

ASPC, AC

ASAC, AC

ASPC, AC, PC

ASAC-1, ASAC-2, AC-1, AC-2

ASAC, AC

ASAC, ASPC, AC, PC

ASAC, AC

Scopes tested

335

240

374

797

467

363

352

50

358

100

Number of patients

No difference (ASAC 97%, AC-1 94%, AC-2 93%)

No difference (ASPC 96%, AC 97%)

No difference (ASTPC 98%, ASPC 95%, AC 91%)

No difference (ASPC 98%, AC 96%)

No difference (ASAC 98%, AC 96%)

No difference (ASPC 94%, AC 90%, PC 97%)

No difference (ASAC-1 100%, ASAC2 96%, AC-1 97%, AC-2 97%)

No difference (ASAC 100%, AC 84%)

No difference (ASAC 100%, ASPC 100%, AC 98%, PC 99%)

No difference (ASAC 96%, AC 91%)

Cecum intubated

No difference

No difference

No difference

Less with ASPC

No difference

No difference

Less with ASAC-2

No difference

No difference

Less with ASAC

Time to reach cecum

Less with ASAC

No difference

No difference

Not reported

Not reported

No difference

Not reported

No difference

Not reported

No difference

Doses of sedative medications

Less with ASAC

No difference

Not reported

Not reported

Less with ASAC

No difference

No difference

No difference

No difference

Less with ASAC

Patient tolerance

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AC, adult colonoscope; ASAC, adjustable stiffness adult colonoscope; ASPC, adjustable stiffness pediatric colonoscope; ASTPC, adjustable stiffness even thinner pediatric colonoscope; Less, significantly less; No difference, no statistical difference; PC, pediatric colonoscope.

Type of study

Reference (country)

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Use of an upper scope and push enteroscope for colonoscopy Small-diameter upper endoscopes have also been used to perform colonoscopy in the setting of a fixed, angled sigmoid colon or colon stricture which cannot be traversed with a conventional colonoscope [29]. While they often permit the endoscopist to get through the challenging segment, it can be difficult to reach the cecum with them, because of their short length and floppiness. One group reported reaching the cecum with an upper scope in 60% of patients [29]. Use of an upper scope to perform total colonoscopy generally requires extensive and repeated shortening of the instrument, and extensive use of abdominal pressure [30]. If the upper endoscope is not able to reach the cecum, one option is to place a guidewire and then backload it through the biopsy channel of the pediatric colonoscope [30,31]. Before running the guidewire into the tip of the pediatric colonoscope, one must first pass an open-ended catheter through the biopsy channel and out the tip. The guidewire is backloaded through the tubing [31]. Interestingly, a group working out of South Korea recently reported a trial comparing an upper endoscope with a standard colonoscope for routine sedation-free colonoscopy, and found similar success in reaching the cecum with both instruments [32]. Cecal intubation rates were actually better with the upper scope in patients with low body mass index (BMI). Procedures were better tolerated with the upper scope [32]. However, it seems doubtful that these results can be extrapolated to a US population, given that Americans are on average considerably taller and heavier, and have much greater BMIs. The push enteroscope has also been used successfully to perform total colonoscopy in the setting of an incomplete examination with the standard adult colonoscope, such as because of a fixed, angulated sigmoid colon, or when the colon is redundant [33]. One group reported completing colonoscopy in 69% of patients with a push enteroscope at such settings [33]. There have been no comparisons of using a push enteroscope for colonoscopy versus a pediatric colonoscope.

Intermediate-length colonoscope There are some endoscopists who prefer intermediate-length colonoscopes (e.g., 13.3-cm insertion tube) to the standard long colonoscope (e.g., 16.8 cm), although there are no published data to show that one is superior to the other. Successful use of the intermediate-length colonoscope does force an endoscopist to consistently reduce loops and to “keep the scope short,” or he or she will frequently “run out of scope.”

Therapeutic colonoscope Dual-channel therapeutic colonoscopes may be useful for some therapeutic applications or when added suction is needed. There have been some endoscopists who have employed them

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through the years in the setting of severe looping, because of the significantly greater stiffness imparted by the larger diameters of their insertion tubes [3]. However, in the current era of modern colonoscopes, this is now rare.

Adjuncts to improve insertion tube performance A variety of mechanical adjuncts have been used through the years to improve insertion tube performance in the setting of a difficult colonoscopy.

Internal stiffeners Endoscopists have employed a variety of devices over the years to stiffen the insertion tube of colonoscopes in an effort to traverse long floppy colons. These devices, inserted through the biopsy channel of the colonoscope, sometimes permitted completion of the colonoscopy. They have included the use of a closed biopsy forceps, piano wires, and several stainless-steel cable devices where tension could be varied by twisting a handle. The latter, which had the potential to be the most effective, was ultimately abandoned because of its potential to cause internal endoscope damage [3,34]. The development of the adjustable stiffness colonoscope, discussed below, has obviated the need for such devices.

Overtubes Overtubes made of rigid tubular plastic were introduced as early as 1983 in an effort to splint the sigmoid colon in place to facilitate passage through a long floppy sigmoid colon [3]. Many [3,35], though not all [30], reported them to be cumbersome to use, painful, and associated with a high rate of perforation. Such reports have largely led to their abandonment [3,35]. A novel “smart” overtube called “Shape-Lock” (USGI Medical, San Clemente, CA), which allows the stiffness of the device to be controlled and locked, has recently been shown through human and animal testing to be safe and easy to use [35–37]. While the device appears to be useful in some difficult colonoscopies [30], its role in routine colonoscopy has not been defined. Other new-generation overtubes, Endo-Ease (Spirus Medical, Stoughton, MA) and EndoGuide (Syntheon, Miami, FL), are also being evaluated [38,39].

Magnetic endoscopic imaging Magnetic endoscopic imaging has been reported to be a useful adjunct in helping the colonoscopist reduce loops, in selecting the best site for hand compression, and perhaps in accelerating a trainee’s learning curve at colonoscopy [40– 43]. While intriguing, this aid to colonoscopic insertion is still used at just a few centers. Magnetic imaging of colonoscopy is discussed later in this book (see Chapter 46).

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adjustable stiffness adult colonoscope, unless the patient is small in stature, has had extensive pelvic surgery, or has a history of a previous difficult colonoscopy with an adult scope. Because the pediatric colonoscope is more flexible, it generates less force against the colon wall. Some experts choose a pediatric colonoscope when the colon may be at increased risk of mechanical perforation from colonoscope passage, such as in the patient with radiation colitis or patients on long-term corticosteroids. The pediatric colonoscope can be easier to retroflex in some portions of the colon than the adult colonoscope, which may facilitate removal of certain polyps on the proximal side of haustral folds. The pediatric colonoscope can facilitate passage and treatment of colonic and ileal strictures, and may facilitate intubation of the terminal ileum in difficult cases. A pediatric colonoscope should be available if needed, such as when a difficult sigmoid colon prevents the adult scope from passing, or when there is painful looping and no further progress can be made. The small suction channel diameter of the Olympus pediatric adjustable colonoscope (3.2 mm) is a disadvantage if the bowel preparation is marginal. As previously discussed, based on the available data, the benefit of the adjustable stiffness feature seems fairly limited. While the author personally likes the feature, there are obviously many endoscopists successfully performing colonoscopy who don’t have routine access to scopes with adjustable stiffness. Also, while most US colonoscopists routinely use longlength colonoscopes, there is a cadre of endoscopists who prefer to routinely use intermediate-length scopes.

Choice of instruments Table 22.2 lists the specifications of the latest generation of video colonoscopes produced by the three major endoscope manufacturers in the US. All the colonoscopes listed in the table have the same bending section angulation range: up/ down 180° and right/left 160°. Each of the three major endoscope manufacturers market adult, pediatric, and dual-channel therapeutic colonoscopes. Olympus offers long-length and intermediate-length models for all three types. Olympus is the only manufacturer to incorporate the adjustable stiffness system into its models. As discussed above, trials comparing adjustable stiffness colonoscopes with conventional colonoscopes only suggest that the feature holds a mild advantage. A major goal of colonoscopy is to reach the cecum reliably and expeditiously, and to do so comfortably and safely. Given the variety of insertion tube options available, which type of colonoscope should the endoscopist begin a routine examination with? The decision to start an examination with a conventional adult colonoscope or a pediatric (slim) colonoscope is to a large degree a matter of the personal preference of the endoscopist. Both types of scope are suitable for routine use in most adult patients, although endoscopists using pediatric colonoscopes must be particularly attentive to keeping loops reduced. The author of this chapter, who has extensive experience with both adult and pediatric colonoscopes, personally prefers to start most adult colonoscopies with an

Table 22.2 Specifications of video colonoscopes. Manufacturer

Model number

Insertion tube length (mm)

Insertion tube diameter (mm)

Biopsy channel diameter (mm)

Field of view (degrees)

Comment

Olympus

CF-H180AL/I

L:1680 I:1330 L:1680 I:1330 L:1680 I:1330 L:1680 I:1330

12.8

3.7

170

Standard adult (with high definition and NBI)

12.8

3.7

170

Standard adult

11.5

3.2

140

Pediatric (slim colonoscope)

13.7

A: 3.7/B: 3.2

140

Therapeutic with dual channels

CF-Q180AL/I PCF-Q180AL/I CF-2T160L/I

Pentax

EC-3890L EC-3890LK EC-3470LK EC-3872TLK

1700 1700 1700 1700

13.2 13.2 11.6 12.8

3.8 4.2 3.8 A: 3.8/B: 2.8

140 140 140 140

Standard adult (with high definition) Standard adult Pediatric (slim colonoscope) Therapeutic with dual channels

Fujinon

EC-450HL5 EC-450LS5 EC-450DL5 EC-250DL5

1690 1690 1100 1690

12.8 11.5 12.8 12.8

3.8 3.8 A: 3.8/B: 2.8 A: 3.8/B: 2.8

140 140 140 140

Standard adult Pediatric (slim colonoscope) Therapeutic with dual channels Therapeutic with dual channels

A, channel A; B, channel B; I, intermediate length; L, long length; NBI, narrow-band imaging.

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Endoscopy laboratories should have at least one pediatric colonoscope. Such scopes are very useful for certain circumstances, as has been discussed. It is difficult to always predict beforehand which patients will benefit from the use of a pediatric colonoscope. Also, as previously mentioned, upper scopes and push enteroscopes can also be helpful in some cases in which a pediatric colonoscope is not successful at getting through a fixed angulated sigmoid colon. In large individuals and individuals with long, redundant colons, starting the examination with a standard adult colonoscope is reasonable. If colonoscopy in such an individual is unsuccessful with an adult scope without the adjustable stiffness feature, the options include switching to a scope with the feature [44,45], or employing an overtube, such as ShapeLock. The choice of insertion tube type is also a consideration in patients undergoing unsedated colonoscopy. This group constitutes only a small fraction of patients undergoing routine colonoscopy in the US. Factors which tend to predict willingness to attempt and tolerate unsedated colonoscopy include male gender, older age, absence of abdominal pain, and higher levels of education [46]. Some endoscopists prefer the use of a pediatric colonoscope for many patients undergoing unsedated colonoscopy in the hopes of causing less stretching of the sigmoid mesentery and, therefore, less pain [46]. Specific mention about colonoscopy in women is warranted: colonoscopy tends to be more difficult in women and is associated with less complete examinations [28,47,48]. Anatomic differences between the male and female colon appear to be important [28]. For instance, the total colon length is greater in females, the transverse colon is longer and more likely to dip into the pelvis, and a deeper pelvis creates the potential for more acute angulation of the sigmoid. Also, the combination of a longer colon and a smaller abdomen predisposes to more angulation and tortuosity. At this time, there is no proof that one type of scope is clearly better than others. However, endoscopists should have both adult and pediatric colonoscopes available. The prototype tapered colonoscope, discussed above, warrants further investigation [27,28]. Rex et al. [30] recently reported their experience in a large group of consecutive patients referred for prior incomplete colonoscopy. At the time of the referral, it was possible to ascertain the reason for the previous failure in most of the 119 patients. The reasons included redundant colon (n = 54), difficult sigmoid colon (n = 33), and sedation difficulty (n = 8). Complete colonoscopy was ultimately possible in 117 of the 119 patients. Successful complete examinations were possible in 86 of the patients using a standard adult colonoscope (n = 51) or a pediatric colonoscope (n = 35), by paying careful attention to technique. However, comment was made that the use of propofol sedation appeared to be a critical factor in seven of these cases. Special equipment/techniques were needed in 31 cases: overtube with a standard colonoscope (n = 9), upper endoscope alone (n = 9), upper endoscope with

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guidewire placement and exchange for a pediatric colonoscope (n = 8), enteroscope alone (n = 1), and enteroscope with overtube (n = 4). Double-balloon endoscopy is another option that has recently become available in patients in whom colonoscopy has been incomplete. While primarily developed for complete small bowel endoscopy, the technology has the potential to permit complete colonoscopy in patients with a long redundant colon, if examination with a conventional colonoscope has been unsuccessful and the indication for total colonoscopy is strong enough [49]. In the 1990s, the expectation was that practicing endoscopists should be able to routinely reach the cecum in more than 90% of cases [50,51]. However, with improved equipment, particularly as it relates to insertion tube technology, and with improved techniques, an expert can now be expected to perform a complete examination in 95–98% of patients.

Summary There has been a gradual improvement in insertion tube design since the first colonoscopes were introduced into practice in the 1970s. Insertion tubes today exhibit a better balance of flexibility, column strength, torque ability, and elasticity. We also have many more options in terms of colonoscopes with different design features, including pediatric scopes and scopes with an adjustable stiffness feature. There is no definitive “best” colonoscope, and choice today for most routine cases is largely a matter of the personal preference of the endoscopist. However, when various challenges arise in this day and age, like the long redundant colon and the difficult sigmoid colon, we have many more options. The endoscopist can select the scope with the most appropriate insertion tube characteristics for the situation. Improvements in insertion tube technology and in colonoscopic manipulative technique have increased our ability to reach the cecum in a higher percentage of patients over the past 15–20 years. We are edging closer to our goal of achieving 100% completion rates, less patient discomfort, and decreased rates of perforation. However, we are still not yet there. What is the future of the conventional colonoscope? Clearly, additional engineering improvements will continue to be made in insertion tube technology. However, as virtual colonoscopy (computed tomographic colonography) is incorporated into clinical practice and as new advanced nontraditional colonoscopes are developed, one will soon see the day when today’s conventional colonoscope will primarily be a therapeutic instrument. The insertion tubes of today will ultimately be replaced by new technology, perhaps on the order of the computer-assisted NeoGuide Endoscopy System or any of a variety of other variants and innovations. It will be fascinating to see what the next decade holds.

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References 1 Modlin IM. A Brief History of Endoscopy. Milan: MultiMed, 2000. 2 Niwa H, Sakai Y, Williams CB. History of endoscopy in the rectum and colon. In: Waye JD, Rex DK, Williams CB (eds.). Colonoscopy: Principles and Practice. Malden, MA: Blackwell Publishing, 2003: 1–20. 3 Howell DA. The colonoscope insertion tube. In: Waye JD, Rex DK, Williams CB (eds.). Colonoscopy: Principles and Practice. Malden, MA: Blackwell Publishing, 2003: 259– 64. 4 Barlow DE. The video colonoscope. In: Waye JD, Rex DK, Williams CB (eds.). Colonoscopy: Principles and Practice. Malden, MA: Blackwell Publishing, 2003: 238–58. 5 Ginsberg GG. Colonoscopy with the variable stiffness colonoscope. Gastrointest Endosc 2003; 58: 579–84. 6 Bat L, Williams CB. Usefulness of pediatric colonoscopes in adult colonoscopy. Gastrointest Endosc 1989; 35: 329–32. 7 Marshall JB. Use of a pediatric colonoscope improves the success of total colonoscopy in selected adult patients. Gastrointest Endosc 1996; 44: 675– 8. 8 Saifuddin T, Trivedi M, King PD, et al. Usefulness of a pediatric colonoscope for colonoscopy in adults. Gastrointest Endosc 2000; 51: 314–17. 9 Marshall JB, Perez RA, Madsen RW. Usefulness of a pediatric colonoscope for routine colonoscopy in women who have undergone hysterectomy. Gastrointest Endosc 2002; 55: 838– 41. 10 Swain P. Colonoscopy: new designs for the future. Gastrointest Endosc Clin N Am 2005; 15: 839– 63. 11 Bar-Meir S, Wallace MB. Diagnostic colonoscopy: the end is coming. Gastroenterology 2006; 131: 992– 4. 12 Vucelic B, Rex D, Pulanic R, et al. The Aer-O-Scope: proof of concept of a pneumatic, skill independent, self-propelling, selfnavigating colonoscope. Gastroenterology 2006; 130: 672–7. 13 Eickhoff A, Van Dam J, Jakobs R, et al. Computer-assisted colonoscopy (The NeoGuide Endoscopy System): results of the first human clinical trial (“PACE Study”). Am J Gastroenterol 2007; 102: 261– 6. 14 Eliakim R, Fireman Z, Gralnek IM, et al. Evaluation of the PillCam Colon capsule in the detection of colonic pathology: results of the first multicenter, prospective, comparative study. Endoscopy 2006; 38: 963–70. 15 Schoofs N, Van Gossum A, Devière J, et al. PillCam COLON capsule endoscopy compared with colonoscopy in detection of colon polyps and cancer: interim analysis of a prospective multicenter trial (abstract). Gastroenterology 2007; 132: 2585– 6. 16 Al-Shurieki SH, Marshall JB. Is the variable-stiffness paediatric colonoscope more effective than a standard adult colonoscope for outpatient adult colonoscopy? A randomized controlled trial. Dig Liver Dis 2005; 37: 698–704. 17 Horiuchi A, Nakayama Y, Kajiyama M, et al. Usefulness of a small-caliber, variable-stiffness colonoscope as a backup in patients with difficult or incomplete colonoscopy. Am J Gastroenterol 2004; 99: 1936– 40. 18 Okamoto M, Kawabe T, Kato J, et al. Ultrathin colonoscope with a diameter of 9.8 mm for total colonoscopy. J Clin Gastroenterol 2005; 39: 679– 83.

The Colonoscope Insertion Tube

19 Brooker JC, Saunders BP, Shah SG, et al. A new variable stiffness colonoscope makes colonoscopy easier: a randomised controlled trial. Gut 2000; 46: 801–5. 20 Rex DK. Effect of variable stiffness colonoscopes on cecal intubation times for routine colonoscopy by an experienced examiner in sedated patients. Endoscopy 2001; 33: 60–4. 21 Sorbi D, Schleck CD, Zinsmeister AR, et al. Clinical applicability of a new colonoscope with variable insertion tube rigidity: a pilot study. Gastrointest Endosc 2001; 53: 638–42. 22 Odori T, Goto H, Arisawa T, et al. Clinical results and development of variable-stiffness video colonoscopes. Endoscopy 2001; 33: 65–9. 23 Shumaker DA, Zaman A, Katon RM. A randomized controlled trial in a training institution comparing a pediatric variable stiffness colonocope, a pediatric colonoscope, and an adult colonoscope. Gastrointest Endosc 2002; 55: 172–9. 24 Yoshikawa I, Honda H, Nagata K, et al. Variable stiffness colonoscopes are associated with less pain during colonoscopy in unsedated patients. Am J Gastroenterol 2002; 97: 3052–5. 25 Kaffes AJ, Mishra A, Ding SL, et al. A prospective trial of variable stiffness pediatric vs. standard instrument colonoscopy. Gastrointest Endosc 2003; 58: 685– 9. 26 Lee DWH, Li ACN, Ko CW, et al. Use of a variable-stiffness colonoscope decreases the dose of patient-controlled sedation during colonoscopy: a randomized comparison of 3 colonoscopes. Gastrointest Endosc 2007; 65: 424– 9. 27 Anderson JC, Walker G, Birk JW, et al. Tapered colonoscope performs better than the pediatric colonoscope in female patients: a direct comparison through tandem colonoscopy. Gastrointest Endosc 2007; 65: 1042– 7. 28 Streett SE. Endoscopic colorectal cancer screening in women: can we do better? Gastrointest Endosc 2007; 65: 1047–9. 29 Kozarek RA, Botoman VA, Patterson DJ. Prospective evaluation of a small caliber upper endoscope for colonoscopy after unsuccessful standard examination. Gastrointest Endosc 1989; 35: 333–5. 30 Rex DK, Chen SC, Overhiser AJ. Colonoscopy technique in consecutive patients referred for prior incomplete colonoscopy. Clin Gastroenterol Hepatol 2007; 5: 879– 83. 31 Ness RM, Gottlieb K, Rex DK, et al. Difficult sigmoid colon intubation: guide wire exchange technique. Gastrointest Endosc 1996; 44: 99–101. 32 Park CH, Lee WS, Joo YE, et al. Sedation-free colonoscopy using an upper endoscope is tolerable and effective in patients with low body mass index: a prospective randomized study. Am J Gastroenterol 2006; 101: 2504–10. 33 Lichtenstein GR, Park PD, Long WB, et al. Use of a push enteroscope improves ability to perform total colonoscopy in previously unsuccessful attempts at colonoscopy in adult patients. Am J Gastroenterol 1999; 94: 187– 90. 34 Ruffolo TA, Lehman GA, Rex D. Colonoscope damage from internal straightener use. Gastrointest Endosc 1991; 37: 107–8. 35 Hawari R, Pasricha PJ. Going for the loop: a unique overtube for the difficult colonoscopy. J Clin Gastroenterol 2007; 41: 138–40. 36 Raju GS, Rex DK, Kozarek RA, et al. A novel shape-locking guide for prevention of sigmoid looping during colonoscopy. Gastrointest Endosc 2004; 59: 416–19. 37 Rex DK, Khashab M, Raju GS, et al. Insertability and safety of a shape-locking device for colonoscopy. Am J Gastroenterol 2005; 100: 817–20.

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38 Cantero D, Monier C, Toor A, et al. Spirus EndoEase: multi-center experience with a new colonoscopy assist device. Gastrointest Endosc 2007; 65: AB126 (abstract). 39 Rothstein RI, Cimis R, Palmer M, et al. Syntheon Endoguide: a novel overtube to assist colonoscopy [abstract]. Gastrointest Endosc 2007; 65: AB345. 40 Shah SG, Brooker JC, Williams CB, et al. Effect of magnetic endoscope imaging on colonoscopy performance: a randomised controlled trial. Lancet 2000; 356: 1718–22. 41 Shah SG, Brooker JC, Thapar C, et al. Effect of magnetic imaging on patient tolerance and sedation requirements during colonoscopy: a randomized controlled trial. Gastrointest Endosc 2002; 55: 832–7. 42 Shah SG, Brooker JC, Williams CB, et al. The variable stiffness colonoscope: assessment of efficacy by magnetic endoscope imaging. Gastrointest Endosc 2002; 56: 195–201. 43 Shah SG, Saunders BP. Aids to insertion: magnetic imaging, variable stiffness, and overtubes. Gastrointest Endosc Clin N Am 2005; 15: 673–86. 44 Shumaker DA, Zaman A, Katon RM. Use of a variablestiffness colonoscope allows completion of colonoscopy after

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failure with the standard adult colonoscope. Endoscopy 2002; 34: 711–14. Rex DK, Goodwine BW. Method of colonoscopy in 42 consecutive patients presenting after prior incomplete colonoscopy. Am J Gastroenterol 2002; 97: 1148– 51. Rex DK, Khalfan HK. Sedation and the technical performance of colonoscopy. Gastrointest Endosc Clin N Am 2005; 15: 661–72. Shah HA, Paszat LF, Saskin R, et al. Factors associated with incomplete colonoscopy: a population-based study. Gastroenterology 2007; 132: 2297–303. Kim WH, Cho YJ, Park JY, et al. Factors affecting insertion time and patient discomfort during colonoscopy. Gastrointest Endosc 2000; 52: 600–5. Yamamoto H, Kita H, Sunada K, et al. Clinical outcomes of doubleballoon endoscopy for the diagnosis and treatment of smallintestinal diseases. Clin Gastroenterol Hepatol 2004; 2: 1010–16. Waye JD, Bashkoff E. Total colonoscopy: is it always possible? Gastrointest Endosc 1991; 37: 152– 4. Marshall JB, Barthel JS. The frequency of total colonoscopy and terminal ileal intubation in the 1990s. Gastrointest Endosc 1993; 39: 518–20.

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Capsule Colonoscopy Aymer Postgate1, Chris Fraser1 & Jacques Devière2 1

St. Mark’s Hospital, London, UK Erasme Hospital, Brussels, Belgium

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The case for capsule colonoscopy Colorectal cancer (CRC) remains the second most common cause of cancer death in the US after lung cancer; despite significant improvements in 5-year survival rates over the last 30 years due to earlier diagnosis, over one-third of the 145 000 people currently diagnosed annually will eventually die from the disease [1]. Despite these statistics, CRC is a preventable disease whose precursor lesions can be readily detected and removed using standard endoscopic techniques. Large-scale follow-up studies have now confirmed that endoscopic polypectomy significantly reduces the rate of subsequent CRC development [2–4], and consequently CRC screening programs are evolving at local and national levels, employing a variety of screening modalities including fecal occult blood testing, flexible sigmoidoscopy, colonoscopy, and computed tomographic colonography as the primary screening modalities [5–7]. However, despite increasing public awareness, uptake of screening procedures remains poor with, at best, around half of all eligible patients undergoing screening [8–11]. Nonparticipation in screening is multifactorial and complex, but test inaccuracy, inconvenience, embarrassment, and fear of invasive or painful procedures remain significant factors [10,12–14]. Colonoscopy remains the gold standard investigation for the evaluation of the colon, but it is expensive, invasive, and inconvenient, and there is an associated risk of bowel perforation even for purely diagnostic procedures [15–18]. In addition, colonoscopy may be limited by low-quality bowel preparation [19], a significant miss rate determined by backto-back colonoscopy [20,21], and the considerable infrastructure required for an endoscopy-based colonoscopy screening program. Virtual colonoscopy (VC) is an evolving technology which has emerged over recent years as a potential alternative to optical colonoscopy, and now offers comparable sensitivity to colonoscopy for the detection of large polyps and cancers

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

[22–24]. Although less invasive than colonoscopy, it is still a highly specialized procedure and there is no evidence to date indicating that compliance would be superior to that of standard colonoscopy. The technology requires significant doses of radiation for image acquisition, and with it there are concerns over the potential lifetime cancer risk from cumulative exposure [25]. In addition, complications including bowel perforation can sometimes occur [26], and a VC-based screening program would similarly require a considerable expansion in infrastructure [27]. These factors have contributed to the continuing interest in new minimally invasive modalities for colonic imaging that allow accurate assessment of colonic pathology in a format that is both acceptable and convenient to as many people as possible. Such a minimally invasive modality could also act as a filter and free capacity for therapeutic colonoscopy.

The PillCam Colon® capsule endoscope PillCam Colon® capsule endoscopy (PCE, Given Imaging Ltd., Yoqneam, Israel) is the most recent advance in video capsule technology. Since the technology is portable, it offers the possibility of an out-of-hospital, or even home-based, examination and with it the likelihood of significantly improved compliance. Consisting of an ingestible pill-sized video camera similar to the small bowel capsule, PCE has redesigned optics that are specifically configured for surveying the colonic mucosa: automatic light control; a wider 125° field of view that is captured at two frames per second by a CMOS (complementary metal–oxide semiconductor) chip at each end of the capsule; and an increased depth of view to 40 mm to allow for the more distant views of the colon. A preprogrammed “sleep” mode is incorporated into the design in order to preserve battery life following initial activation during a 2-h period after first ingestion as the capsule traverses the small bowel, extending the overall battery life to around 10 h. The capsule is larger as a result of these modifications (32 mm by 11 mm), which are made to both accommodate the revised optics and achieve a specific weight-to-volume ratio that optimizes capsule progression through the colon. The capsule

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Figure 23.3 Pedunculated polyp as seen at colonoscopy (left) and PillCam Colon capsule endoscopy (right).

Figure 23.1 PillCam Colon capsule endoscope pictured next to the PillCam small bowel capsule.

is pictured against the original small bowel capsule for size comparison in Figure 23.1. The sensor array, data recorder, and workstation used for reporting purposes are similar to those required for small bowel capsule endoscopy. The Rapid5 software (Given Imaging Ltd., Yoqneam, Israel) allows images captured by each end of the capsule to be viewed individually or simultaneously, but in other respects is familiar to anyone used to reporting small bowel capsule endoscopy studies.

The bowel preparation regime The bowel purgative regime is of key importance to the success of the procedure as it must allow adequate cleansing of the colon and panenteric transit of the capsule within the 10-h window, but without impairing view quality, introducing bubble artifact, or reducing lesion detection because of insufficient transit time. In addition, the purgatives must compensate for the lack of air insufflation and suction provided by colonoscopy by distending the bowel and allowing “submarine” luminal views of the colon to be captured during capsule transit (Figures 23.2 and 23.3). Preliminary work on

Figure 23.2 ”Submarine” luminal views of the colon obtained at PillCam Colon capsule endoscopy demonstrating a normal transverse colon (left) and a colorectal cancer (right).

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healthy subjects tested a variety of different combinations and timings of bowel purgative regimes and revealed that polyethylene glycol (PEG) was superior to sodium phosphate for capsule colonoscopy, and that additional boosts of purgative given while the capsule was in the colon improved excretion rates. A further pilot study combined oral Tegaserod as a prokinetic agent with the purgative regime, and observed a capsule excretion rate of 78% within 12 h of ingestion. No significant adverse events or cases of capsule retention occurred in over 270 healthy volunteers involved in these initial trials.

Initial pilot studies On the basis of these encouraging results, three pilot studies were conducted on at-risk patients to assess the feasibility of PCE for the detection of colonic polyps and other colonic pathology. Schoofs et al. [28] recruited 41 patients with a mean age of 56 years who required screening for CRC/polyps or had colonic symptoms. Five patients were excluded for technical or procedural reasons and 36 patients were submitted for final analysis. The purgative regime consisted of restriction to clear fluids on the day prior to the examination, followed by 4 L of PEG on the evening prior to and morning of the procedure. The PCE was then ingested following 20 mg of oral domperidone, with a further boost of 45 mL of oral sodium phosphate in 1 L of water 2 h later assuming that the capsule had exited the stomach (using a real-time viewer). An additional boost of 30 mL of sodium phosphate in 1 L of water was given at 2 PM, and a light snack was taken at 3 PM. Finally, if the capsule had not yet been excreted, a bisacodyl enema was given at 4.30 PM, prior to the comparative colonoscopy being performed by a blinded investigator on the evening of the same day. The preparation was rated as good or excellent in 88% of patients and the capsule was excreted within 10 h in 30 patients (84%), with the remainder of patients having it residing in the rectosigmoid colon, transverse colon, and cecum. No adverse events were reported. The sensitivity of PCE compared with colonoscopy as the gold standard was 76% for any polyp, with a specificity of 64%, and 60% for polyps ≥ 6 mm in diameter, with a specificity of 73%

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Table 23.1 Summary of trials comparing PillCam Colon capsule endoscopy against colonoscopy. Study

n

Schoofs et al. [28]

36

Eliakim et al. [29]

84

Lewis et al. [30] Devière et al. [31]

51 320

Finding

Sensitivity (%) (95% CI)

Specificity (%) (95% CI)

PPV (%) (95% CI)

NPV (%) (95% CI)

≥ 3 polyps Any polyp ≥ 6 mm polyp Any polyp ≥ 3 polyps/polyp ≥ 6 mm ≥ 3 polyps/polyp ≥ 6 mm Any polyp ≥ 6 mm polyp ≥ 10 mm polyp ≥ 3 polyps/polyp ≥ 6 mm

63 (29–96) 76 (59–93) 60 (30–90) 56 (39–72)a 50 (26–75)a 56 (38–71) 73 (69–76) 64 (56–72)b 60 (51–66)b 66 (61–72)b

68 (51–85) 64 (35–92) 73 (56–90) 69 (56–82)a 83 (73–91)a 76 (66–84) 77 (70–83) 84 (81–87)b 98 (96–99)b 82 (78 – 85)b

36 (11–61) 83 (67–98) 46 (19–73) 57 (41–74)a 40 (19–61)a 56 (38–71) 86 (82–90) 60 (53–67)b 83 (70–92)b 72 (66–78)b

86 (72–100) 54 (27–81) 83 (67–98) 67 (54–80)a 88 (79–96)a 76 (66–84) 59 (54–64) 86 (83–89)b 93 (91–94)b 77 (73–81)b

CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value. a At first reading by principal investigator. b A 50% margin of error is assumed for PillCam Colon capsule endoscopy size estimation.

(Table 23.1). In addition, the Z-line of the esophagus was visualized in 60% of the patients. Eliakim et al. [29] conducted a similar study in which the results of 84 patients were analyzed, having excluded seven patients for technical or procedural problems. The bowel preparation regime was similar to the one used by Schoofs et al. (above) other than for the use of 3 L of PEG in place of 4 L, and for the use of Tegaserod as a prokinetic taken in two doses in place of domperidone. A low capsule excretion rate of 70% was observed in the first 44 patients and as a result a second “boost” of sodium phosphate was introduced for the remaining 46 patients, which increased the excretion rate to 78% with the remaining capsules localized to the rectosigmoid colon. Bowel preparation was rated as good or excellent in 84%, and no significant adverse events occurred. The learning curve in reporting colon capsule endoscopy studies was well demonstrated in this study by the increased detection rates observed as the study videos were reviewed by a second external reviewer and, finally, consensus reported by an expert review panel. At initial reading, the sensitivity of PCE compared with colonoscopy for “significant” polyps (i.e., ≥ 6 mm in diameter and/or ≥ 3 polyps) was 50% with a specificity of 83% (see Table 23.1), whereas a sensitivity of 70% was achieved by the expert panel review, with a specificity of 100%. A third study was performed by Lewis et al. [30], and has been published in abstract form. In this three-arm study involving 51 “at-risk” patients, PCE was performed 3 weeks prior to same-day VC and optical colonoscopy. The PCE preparation regime was similar to that reported by Eliakim et al. (above), and visualization was reported as excellent or good in almost 90% of cases with a 10-h capsule excretion rate of around 85%. The VC was reported blinded to the results of the PCE; however, the PCE and VC results were serially unblinded when the (gold standard) optical colonoscopy was

performed. Polyps of any size were found in 29 (57%) patients. The number of polyps seen at PCE, VC, optical colonoscopy, and unblinded colonoscopy was 94, 26, 55, and 60, respectively. The sensitivity of colonoscopy, PCE, and VC for significant polyps (i.e., ≥ 6 mm in diameter and/or ≥ 3 polyps) was 89% [95% CI (confidence interval) 77–89%], 56% (95% CI 38–71%), and 33% (20–38%), respectively, with a specificity of 100%, (95% CI 93–100%) 76% (95% CI 66–84%), and 97% (95% CI 90–99%), respectively.

Multicenter comparative study A pivotal multicenter trial performed in eight centers across Europe has recently been completed. A total of 332 patients were recruited, with the results of 320 patients submitted for final analysis. Eligible patients were over the age of 50 years and symptomatic, or over the age of 18 years and due a surveillance colonoscopy for a personal history of colorectal cancer/polyps or positive findings on a recent gastrointestinal radiographic study. The bowel preparation used was identical to that described by Schoofs et al. [28], and achieved good or excellent colonic cleansing in 87% of patients at colonoscopy but only 72% at PCE, representing a statistically significant difference in all bowel segments. The 10-h capsule excretion rate was excellent at 93%, and no significant adverse events were reported. The overall sensitivity and specificity of PCE for the detection of polyps of ≥ 6 mm were 64% and 84%, respectively, and for polyps of ≥ 10 mm were 60% and 98%, respectively (see Table 23.1). In the subgroup of patients with a good to excellent colon cleansing level at PCE examination, the sensitivities and specificities for polyp detection were improved, 75% and 84% respectively for polyps of ≥ 6 mm, and 76% and 98% respectively for polyps of ≥ 10 mm [31]. Diverticulosis was detected with a sensitivity of 78% and inflammatory lesions with a sensitivity of 56%.

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Capsule colonoscopy—where are we now and where are we going? PCE has been demonstrated to be a safe and acceptable procedure in the four comparative trials that have been performed to date, and is now CE marked for European use. The sensitivity for “significant” polyp detection varies from 56% to 75% and appears to be heavily dependent on the quality of the bowel preparation achieved. The results from the multicenter trial demonstrated that adequate bowel preparation was more difficult to achieve for PCE than it was for colonoscopy, but that when achieved there was a marked improvement in the diagnostic yield. Further clinical trials investigating alternative types and timings of bowel purgative regimes are currently under way and may yet translate to further improvements in diagnostic yield. In addition, it is evident that the lesion detection properties demonstrated by PCE differ from those of either optical colonoscopy or VC, in which sensitivity drops off rapidly with decreasing polyp size. In contrast, PCE outperforms VC for the detection of diminutive polyps and may offer similar performance for polyps up to 1 cm in size [22–24]. However, detection rates for PCE do not appear to improve for larger (≥ 10 mm) polyps which may be missed, a characteristic that has been noted in small bowel capsule endoscopy [32–35]. Consequently, at present, both VC and colonoscopy outperform PCE in its current form for the detection of large polyps, which are known to carry a higher rate of histological progression, high-grade dysplasia, and carcinoma in situ [36,37]. The use of PCE for the detection of advanced neoplasia in high-risk individuals as a direct alternative to colonoscopy is therefore not clear, except in special circumstances such as when colonoscopy is incomplete [38] or contraindicated, or when patient choice demands it. PCE may play a role in noninvasive colorectal imaging for screening average-risk individuals. In this setting, patient acceptability, compliance, and cost-effectiveness are key determinants of success rather than optimal test sensitivity. Unlike other imaging modalities, PCE offers the possibility of out of hospital examination, which could potentially be carried out in the home environment at a convenient time. The feasibility of home examination and improved patient acceptance and compliance of PCE are yet to be formally examined in a prospective trial, but this evidence will be required if the role of PCE for CRC screening is to develop. The cost-effectiveness of PCE compared with colonoscopy for CRC screening has recently been examined by Hassan et al. [39]. In this model, both modalities achieved acceptable cost-effectiveness relative to no screening when performed every 10 years, although colonoscopy was more cost-effective than PCE with an incremental cost-effectiveness of $16 165 per life-year saved compared with $29 244 for PCE. However, if there is a theoretical drop in colonoscopy compliance of 17% relative to PCE, this would result in dominance for PCE in terms of life-years saved,

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and a drop of 30% would result in greater cost-effectiveness for PCE than colonoscopy. In addition, this analysis assumed a relatively high unit cost for PCE which has a key influence on overall cost-effectiveness. As a new technology the cost is likely to decrease significantly in comparison to the more stable costs of colonoscopy as an established modality, especially if widespread application in population screening becomes a reality. Since PCE offers views of the distal esophagus during the first few minutes of activation prior to the “sleep” mode, the possibility of detecting Barrett’s esophagus raises the intriguing possibility of “one-stop” screening for both esophageal and colorectal cancer. Problems to be addressed in the future prior to incorporation of capsule colonoscopy as a screening test include the vigorous preingestion preparation as well as the intraprocedure need for further purgatives, the inability to ensure a total examination of the colon as noted by the capsule excretion rate, and the possibility of missing lesions in the large bowel. The current sensitivity needs improvement, which could result from advances in frame speed, angle of view, and quality of preparation. An additional problem is the need to repeat the preparation to perform subsequent colonoscopy in patients with significant polyps, or to provide same-day colonoscopy after completion of the capsule study and its interpretation. This may require extending colonoscopy service into the late afternoon or early evening. The future of noninvasive microtechnology for imaging, sampling, and potentially delivering therapy to the gastrointestinal tract no longer seems far-fetched, and preliminary work examining methods of self-propulsion and tissue sampling at capsule endoscopy is already under way [40–42]. Capsule colonoscopy represents a major step in the evolution of these technologies, and may develop a role for examination of the colon over the coming years.

References 1 Centers for Disease Control and Prevention (2008). United States Cancer Statistics. Available at: apps.nccd.cdc.gov/uscs (accessed September 2008). 2 Winawer SJ, Zauber AG. The advanced adenoma as the primary target of screening. Gastrointest Endosc Clin N Am 2002; 12: 1–9, v. 3 Atkin WS, Morson BC, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 1992; 326: 658– 62. 4 Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993; 329: 1977– 81. 5 Whynes DK. Cost-effectiveness of screening for colorectal cancer: evidence from the Nottingham faecal occult blood trial. J Med Screen 2004; 11: 11–15. 6 Atkin WS, Cuzick J, Northover JM, Whynes DK. Prevention of colorectal cancer by once-only sigmoidoscopy. Lancet 1993; 341: 736– 40. 7 Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and

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adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008; 134: 1570– 95. Klabunde CN, Vernon SW, Nadel MR, Breen N, Seeff LC, Brown ML. Barriers to colorectal cancer screening: a comparison of reports from primary care physicians and average-risk adults. Med Care 2005; 43: 939– 44. Segnan N, Senore C, Andreoni B, et al. Comparing attendance and detection rate of colonoscopy with sigmoidoscopy and FIT for colorectal cancer screening. Gastroenterology 2007; 132: 2304–12. Golder S, Vogt W, Lichti H, et al. Acceptance of flexible sigmoidoscopy as a screening examination for colorectal cancer in an outpatient clinic. Int J Colorectal Dis 2007; 22: 387– 94. Brotherstone H, Vance M, Edwards R, et al. Uptake of populationbased flexible sigmoidoscopy screening for colorectal cancer: a nurse-led feasibility study. J Med Screen 2007; 14: 76–80. Worthley DL, Cole SR, Esterman A, et al. Screening for colorectal cancer by faecal occult blood test: why people choose to refuse. Intern Med J 2006; 36: 607–10. Giorgi RP, Federici A, Bartolozzi F, Farchi S, Borgia P, Guasticchi G. Trying to improve the compliance to colorectal cancer screening: a complex study design for a complex planning question. Contemp Clin Trials 2005; 26: 323–30. Denberg TD, Melhado TV, Coombes JM, et al. Predictors of nonadherence to screening colonoscopy. J Gen Intern Med 2005; 20: 989– 95. Tulchinsky H, Madhala-Givon O, Wasserberg N, Lelcuk S, Niv Y. Incidence and management of colonoscopic perforations: 8 years’ experience. World J Gastroenterol 2006; 12: 4211–13. Rathgaber SW, Wick TM. Colonoscopy completion and complication rates in a community gastroenterology practice. Gastrointest Endosc 2006; 64: 556– 62. Levin TR, Zhao W, Conell C, et al. Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med 2006; 145: 880– 6. Bowles CJ, Leicester R, Romaya C, Swarbrick E, Williams CB, Epstein O. A prospective study of colonoscopy practice in the UK today: are we adequately prepared for national colorectal cancer screening tomorrow? Gut 2004; 53: 277– 83. Ponchon T. Colon tumors and colonoscopy. Endoscopy 2007; 39: 992–7. van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol 2006; 101: 343–50. Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112: 24– 8. Halligan S, Altman DG, Taylor SA, et al. CT colonography in the detection of colorectal polyps and cancer: systematic review, meta-analysis, and proposed minimum data set for study level reporting. Radiology 2005; 237: 893– 904. Mulhall BP, Veerappan GR, Jackson JL. Meta-analysis: computed tomographic colonography. Ann Intern Med 2005; 142: 635–50. Sosna J, Morrin MM, Kruskal JB, Lavin PT, Rosen MP, Raptopoulos V. CT colonography of colorectal polyps: a metaanalysis. AJR Am J Roentgenol 2003; 181: 1593– 8.

Capsule Colonoscopy

25 Berrington de González A, Darby S. Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet 2004; 363: 345– 51. 26 Burling D, Halligan S, Slater A, Noakes MJ, Taylor SA. Potentially serious adverse events at CT colonography in symptomatic patients: national survey of the United Kingdom. Radiology 2006; 239: 464–71. 27 Hassan C, Laghi A, Pickhardt PJ, et al. Projected impact of colorectal cancer screening with computerized tomographic colonography on current radiological capacity in Europe. Aliment Pharmacol Ther 2008; 27: 366–74. 28 Schoofs N, Devière J, Van Gossum A. PillCam colon capsule endoscopy compared with colonoscopy for colorectal tumor diagnosis: a prospective pilot study. Endoscopy 2006; 38: 971–7. 29 Eliakim R, Fireman Z, Gralnek IM, et al. Evaluation of the PillCam Colon capsule in the detection of colonic pathology: results of the first multicenter, prospective, comparative study. Endoscopy 2006; 38: 963–70. 30 Lewis B, Rex D, Lieberman D. Capsule colonoscopyaa Pilot three arm, blinded trial of capsule colonoscopy, virtual colonoscopy and colonoscopy. Am J Gastroenterol 2006; 101: S559 (abstract 1470). 31 Devière J, Munoz-Navas MA, Fernandez-Urien I, et al. PillCam® colon capsule endoscopy compared to colonoscopy in detection of colon polyps and cancers. Gastroenterology 2008; 134: A38. 32 Chong AK, Chin BW, Meredith CG. Clinically significant smallbowel pathology identified by double-balloon enteroscopy but missed by capsule endoscopy. Gastrointest Endosc 2006; 64: 445–9. 33 Madisch A, Schimming W, Kinzel F, et al. Locally advanced smallbowel adenocarcinoma missed primarily by capsule endoscopy but diagnosed by push enteroscopy. Endoscopy 2003; 35: 861–4. 34 Ross A, Mehdizadeh S, Tokar J, et al. Double balloon enteroscopy detects small bowel mass lesions missed by capsule endoscopy. Dig Dis Sci 2008; 53: 2140– 3. 35 Postgate A, Tekkis P, Fitzpatrick A, Bassett P, Fraser C. The impact of experience on polyp detection and sizing accuracy at capsule endoscopy: implications for training from an animal model study. Endoscopy 2008; 40: 496– 501. 36 Regula J, Rupinski M, Kraszewska E, et al. Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia. N Engl J Med 2006; 355: 1863–72. 37 Lieberman D, Moravec M, Holub J, Michaels L, Eisen G. Polyp size and advanced histology in patients undergoing colonoscopy screening: implications for CT colonography. Gastroenterology 2008; 135: 1100–5. 38 Spada C, Riccioni ME, Petruzziello L, Marchese M, Urgesi R, Costamagna G. The new PillCam Colon capsule: difficult colonoscopy? No longer a problem? Gastrointest Endosc 2008; 68: 807–8. 39 Hassan C, Zullo A, Winn S, Morini S. Cost-effectiveness of capsule endoscopy in screening for colorectal cancer. Endoscopy 2008; 40: 414–21. 40 Swain P, Mosse S, Mills T, Green J, Ikeda K, Fritscher-Ravens A. Development of wireless capsule endoscope mechanisms for brush cytology, tissue fluid aspiration and biopsy. Gastrointest Endosc 2005; 61: AB106. 41 Swain PC, Mosse A, Burke P, et al. Remote propulsion of wireless capsule endoscopes. Gastrointest Endosc 2002; 55: AB88. 42 Swain P. The future of wireless capsule endoscopy. World J Gastroenterol 2008; 14: 4142–5.

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Accessories Gregory G. Ginsberg University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Introduction Accessories for colonoscopy are used for snare polypectomy, tissue sampling, endoscopic mucosal resection, object retrieval, size measurement, marking, image enhancement, hemostasis, ablation, and stenting. Accessory overtubes have been developed to facilitate colonoscope insertion. This chapter provides an overview of accessories used during colonoscopy. Specific applications of these accessories are detailed in other chapters.

Polypectomy snares The capacity to identify and remove colorectal polyps has established colonoscopy as the preferred means of colorectal cancer screening and surveillance, and has enabled it to prevent colorectal cancer. Polypectomy snares are available in a variety of shapes, sizes, and materials. Specialty snares are designed with special features for specific performance properties. Snares may be designed and marketed as disposable or reusable. Reusable snares must be designed so they can be disassembled for cleaning and sterilization and then reassembled, and, in addition, must have properties that enable them to retain their configuration and performance through multiple uses and cleaning cycles. These constraints, in addition to the availability of inexpensive materials and controlled production costs, have promoted broad acceptance of disposable snares for colonoscopic polypectomy. Colonoscopic polypectomy snares consist of an attached or continuous wire loop housed within a flexible synthetic polymer sheath. This device is passed through the accessory channel of the colonoscope. Sheaths are typically 7.0F in diameter, for a minimal channel size of 2.8 mm, and 230 cm

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Figure 24.1 Colonoscopic polypectomy snares consist of a continuous wire loop housed within a flexible synthetic polymer sheath and affixed to a plastic operator handle. (Courtesy of Olympus America Inc., Melville, NY, USA.)

in length. The wire and sheath are affixed to a moving parts plastic handle at the operator end of the device (Figure 24.1). The handle controls opening (extension) and closing (retraction) of the wire loop from and within the outer sheath. The snare wire couples to an electrical connector within the handle, which also has a socket for connecting an active cord to an electrosurgical unit. Most snares are designed to be used with monopolar current. In a monopolar device the current flows from the snare to a distant return electrode (grounding pad), generating local thermal energy for cutting and coagulation [1]. While bipolar snares have been designed with each half of the snare loop functioning as an electrode, they have not been adopted [2]. There are no comparative trials of bipolar versus monopolar snares. Braided stainless-steel wire is the most commonly used material for polypectomy snares, owing to its strength, conduction properties, and configurational memory. The snare wire is typically 0.30–0.47 mm in diameter. Nitinol wire snares may have superior configurational memory but lack sufficient stiffness, tending to be floppier than desired. Monofilament wire snares promote transection over coagulation and

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Figure 24.2 The standard snare loop shape is oval or elliptical. (Courtesy of Olympus America Inc., Melville, NY, USA.) Figure 24.4 The multiangled snares are intended for lesions difficult to access based on their wall location with respect to the tip of the colonoscope. [Courtesy of Cook Endoscopy (formerly Wilson-Cook Medical), Winston-Salem, NC, USA.]

Figure 24.3 Alternative snare loop configurations include round, crescent, or hexagonal shaped. (Courtesy of Olympus America Inc., Melville, NY, USA.)

as such are largely limited in use for cold snare polypectomy of small polyps in patients without coagulation disorders [3]. The standard shape of the snare loop is oval or elliptical (Figure 24.2). Alternative geometries include round, crescent, or hexagonal configurations (Figure 24.3). Selection of snare configuration is based on personal preference. Experienced colonoscopists may choose specific snare shapes for the removal of specific lesions based on the lesion’s location, orientation, size, and/or configuration. There are no comparative trials to support superiority of any one snare configuration over others. In practice, the standard oval snare suffices for polypectomy in the vast majority of instances. While there is some variability among the manufacturers, standard size snare loops are typically 2.0–2.5 cm in diameter, and the length of the loop varies from 5 to 6 cm. Mini snares have loop diameters of 1.0–1.5 cm and lengths of 2–3 cm and are used for completion resection of residual adenoma following mucosectomy of a sessile lesion and for resection of smaller polyps [4].

Other specialty snares have been developed to enhance success when circumstances prove challenging to the characteristics of ordinary snares. While specialty snares may offer advantages in specific instances, most experienced colonoscopists do quite well with standard loop snares along with the occasional use of mini-snares and jumbo snares. Nonetheless, a familiarity with and limited stock of specialty snares may ensure success when faced with the occasional defiant polyp. Duck-bill® (Wilson-Cook Medical, Winston-Salem, NC, USA) and multiangled (Figure 24.4) snares are intended for lesions difficult to access based on their wall location with respect to the tip of the colonoscope. Rotatable snares can be adjusted so that the snare loop opens in the most favorable orientation for polyp entrapment (Figure 24.5). Needle- or anchor-tipped snares have a short, pointed barb at the tip of the snare (Figure 24.6). The modified tip is intended to aid in stabilizing the snare for polyp capture. By impaling the barbed tip into the bowel wall just beyond the lesion, the snare tip can be fixed in place while the loop is flexed to open over and around the polyp. A variety of snares have been developed and marketed for the removal of sessile polyps. These iterations include barbed, spiral, and “hairy” snares (Figure 24.7). Each is designed to grip the edges of low-profile sessile lesions. There are no studies to indicate superiority of modified over standard snares for the resection of sessile colon polyps. Combination devices incorporating snares with injection needles (USEndoscopy, Mentor, OH, USA) have been developed to enhance efficiency when performing submucosal injectionassisted polypectomy.

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Figure 24.7 Barbed snares have tiny barbs on the wire loop intended to grasp the leading edge of sessile polyps.

Biopsy forceps

Figure 24.5 Rotatable snares can be adjusted so that the snare loop opens in an orientation favorable to polyp entrapment. (Courtesy of US Endoscopy Group, Mentor, OH, USA.)

Biopsy forceps (see Chapter 34) are used to sample colonic mucosa and mucosal-based lesions. Colonoscopic biopsy forceps consist of a flexible, metal coil outer sheath that houses a steel cable connecting a two-piece plastic handle to opposing metal biopsy cups (Figure 24.8). Some biopsy forceps are coated with a synthetic polymer to improve passage through the colonoscope accessory channel. Single-bite cold biopsy forceps allow procurement of a single specimen at a time. Double-bite cold biopsy forceps (most commonly employed) are equipped with a needle spike between the opposing biopsy cups. The needle spike serves several purposes: the spike can be used to impale the tissue of interest, thus stabilizing the forceps cups for selected tissue sampling;

Figure 24.6 Needle- or anchor-tipped snares have a short, pointed barb at the tip of the snare intended to stabilize the snare for polyp capture. [Courtesy of Cook Endoscopy (formerly Wilson-Cook Medical), Winston-Salem, NC, USA.]

Retrieval devices An assortment of retrieval devices has been developed for the extraction of polyps and foreign objects from the colon. These include a variety of graspers, baskets, and nets [5]. Polyp retrieval is discussed in detail in Chapter 45.

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Figure 24.8 This forceps is equipped with a needle spike between the opposing biopsy cups to impale tissue. (Courtesy of Olympus America Inc., Melville, NY, USA.)

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deeper biopsies can be obtained than with nonneedle versions [6]; and the spike secures the first specimen on the device while a second specimen is obtained. Without the spike, attempts at multiple tissue sampling with single-bite forceps may result in the loss of specimens and crush artifacts. Biopsy cup jaws may be standard oval or elongated, fenestrated or nonfenestrated, and smooth or serrated. Largecapacity cup or “jumbo” biopsy forceps have become routinely employed in colonoscopy when using a therapeutic channel colonoscope. Large-capacity biopsy forceps sample a larger total volume of tissue, encompassing two to three times the surface area of that sampled with standard forceps. However, they do not reliably yield deeper specimens and they require an accessory channel ≥ 3.6 mm in diameter [7]. Multibite forceps have been developed that can obtain up to four or more specimens on a single pass. In a prospective, partially blinded, randomized trial of multibite forceps compared with conventional forceps, the multibite forceps compared equivalently for diagnostic quality [8]. Multibite forceps have the potential to contribute time saving when a large number of specimens need to be obtained, such as in surveillance of patients with ulcerative colitis; however, they have not been made widely available and as such have not been widely adopted. A variety of innovative speciality forceps have been designed to overcome challenging circumstances. “Swing jaw” forceps feature a rocking cup assembly action intended to direct the jaws of the forceps toward the tissue of interest; “rotatable” forceps are designed to rotate with variable degrees of control. “Angled” forceps assume a 90° orientation to the long access of the endoscope once the device tip is extended from the accessory channel. Monopolar hot biopsy forceps were developed for simultaneous biopsy and tissue coagulation. Thermal energy is generated when current, passed through an insulated shaft, is introduced to the tissue at the blunted edges of the forceps jaws [9]. Heat energy is regulated and determined by generator voltage and waveform, current density, and application time [1]. Bipolar hot biopsy forceps have also been developed. Bipolar forceps have insulated biopsy cups except for the cup edges that are active electrodes [1]. Tissue injury is deeper with monopolar than with bipolar hot biopsy forceps [9]. Hot biopsy became popular for biopsy resection of diminutive colonic polyps. The rationale for coagulative tissue sampling is to destroy basal neoplastic tissue, thereby preventing residual or recurrent adenoma and the potential for subsequent development of carcinoma. There are insufficient data to indicate that excisional hot biopsy forceps removal reduces the incidence of colorectal cancer or even complete eradication of neoplastic tissue treated [9–11]. Complications of hot biopsy forceps include hemorrhage, perforation, and postcoagulation (transmural burn) syndrome [9]. The relative virtues of reusable versus disposable biopsy forceps can be debated. Arguments focus on cost, operational per-

Accessories

formance, and infection control. Two prospective, randomized, pathologist-blinded trials showed no differences in quality of specimen for histologic diagnosis between a variety of commercially available reusable and disposable biopsy forceps [12,13]. Yang et al. [14] prospectively measured cost and operational performance of disposable and reusable forceps in 200 biopsy sessions. Costs were factored in acquisition and reprocessing. They found that malfunction of reusable forceps increased with the number of uses. At 15–20 uses, the costs of reusable forceps are similar to those of disposable forceps, which cost around $40. When reusable forceps are used more than 20 times, they are less expensive. However, this study showed that the performance of reusable forceps deteriorated significantly in the range of 15–20 uses. Deprez et al. [15], in a much larger study (7740 sessions) using similar design and the lowest available purchase price for disposable forceps at the time ($26.90), reported that total purchase and reprocessing costs for reusable forceps were 25% less than for disposable devices. Further, on average, 315 biopsy sessions were performed with a reusable forceps, extending their mean life to 3 years. In a third study, disposable forceps outperformed their reusable counterparts and offered a cost advantage [16]. These authors also reported a concern over residual proteinaceous material observed in reusable forceps, raising an infection control risk. This charge was countered, however, by a study by Kozarek et al. [17], who performed an ex vivo evaluation of cleaning and in vivo evaluation of function, performance, and durability of reusable forceps. Their analysis concluded that reusable biopsy forceps can be confidently sterilized and reused when accepted cleaning and sterilization protocols are followed. Sterilized reusable biopsy forceps were used a mean of 91 times, rendering the potential for significant cost saving, again depending on acquisition and reprocessing costs. All published cases of transmission of infection associated with reusable biopsy forceps have been attributed to breaches in accepted standards of device reprocessing [18]. The functional performance of reusable biopsy forceps will ultimately deteriorate with increased number of uses. The durability can be extended with care in use and reprocessing. Cost comparisons depend mainly on the cost of disposable devices. Users should also factor in the cost of medical waste disposal and the environmental impact associated with the disposal of single-use devices.

Injection needles Injection needles are devices passed through the accessory channel of the colonoscope to enable injection of a solution into tissue. Injection needles are used in colonoscopy for injection-assisted polypectomy, hemostasis (variceal, nonvariceal, and hemorrhoidal), and tattooing.

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(b)

Injection needles consist of an outer sheath (plastic, Teflon®, or stainless-steel coil) and an inner hollow core needle (21–25G) (Figure 24.9a and b) [19]. The needle tip is typically beveled. Needle tip length should be sufficient to routinely penetrate into the submucosa and not so long as to routinely penetrate through the colon serosa. The outside diameter varies from 2.3 to 2.8 mm. A metal and plastic luer lock handle controls needle extension and retraction to fixed or variable lengths. Some versions allow the needle to be preferentially locked in the extended position. Most commercially available injection needles are single-use, disposable devices. One manufacturer markets disposable needles with a reusable sheath that can be sterilized. Metal coil sheathed needles may offer advantages over their plastic sheathed counterparts in that they are less likely to kink and are more apt to remain fully functional when passed through the channel of a coiled colonoscope. This allows use even when there is excessive looping of the colonoscope or when operating with a retroflexed colonoscope position. Metal coil sheaths are also less likely to allow unintended needle puncture through the sheath with the associated risk of scope injury. However, there are no published trials comparing various injection catheters for colonoscopic applications. An injection needle has also been incorporated into a multipolar electrocautery (MPEC) device (Injection Gold Probe, Boston Scientific Corporation, Natick, MA, USA). This device allows combination injection and contact thermal hemostatic therapy for nonvariceal bleeding.

Spray catheters Spray catheters are used for performing chromoendoscopy (see Chapters 31, 35 and 36). Chromoendoscopy employs a colored dye to enhance the mucosal surface pattern in order to increase the detection or discrimination of dysplastic epithelia [20]. Chromic agents may be vital stains or contrast

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Figure 24.9 (a) Injection needles consist of an outer sheath (in this case stainless-steel coil) and an inner hollow core needle. An operating handle controls the advance and withdrawal of the needle. (b) Needle placed for injection to elevate a polyp. [(a) Courtesy of Olympus America Inc., Melville, NY, USA.]

agents. Vital stains are selectively taken up by epithelial cell cytoplasm, whereas contrast agents coat the epithelial surface, enhancing the contour relief pattern. Contrast agents are commonly employed when performing high-resolution and high-magnification colonoscopy [21]. Spray catheters are disposable, flexible, hollow plastic sheaths, with a plastic luer lock handle, and a metal spray nozzle tip (Figure 24.10a and b). Alternatives to dedicated spray catheters are injection needles, endoscopic retrograde cholangiopancreatography catheters, and simple injection through the accessory port itself. Spray catheters generally allow the most controlled, precise, and tidy application of chromoendoscopy.

Endoscopic clips The application of metallic clips via flexible endoscopes (see Chapter 25) has had considerable appeal. The most experience has been with the HX series of endoscopic clip fixing devices (Olympus Corporation, Tokyo, Japan). This device was first conceived for hemostasis of nonvariceal bleeding sources. Colonoscopic clip application has been used effectively for hemostasis of immediate and delayed bleeding from polypectomy and hot biopsy forceps sites, diverticulosis, arteriovenous malformations, colorectal variceal bleeding, and prophylaxis of postpolypectomy bleeding pre- and postsnare resection. Such mechanical hemostasis allows localized, directed, and specific therapy, while minimizing tissue injury at the treatment site. Other applications have included lesion marking (bleeding or tumor site), fixation of endoscopically placed decompression tubes, and primary closure of resection sites and perforation. The clip fixing device has evolved from its first inception to a relatively easy to use, reliable, and now rotatable delivery device [22,23]. A single-use, preloaded iteration is also available. Clips typically slough off in 3–4 weeks and pass uneventfully in the stool.

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Figure 24.10 (a) Spray catheters are disposable, flexible, hollow plastic sheaths, with a plastic luer lock handle, and a metal spray nozzle tip. (b) Dye being expelled from the catheter. [(a) Courtesy of Cook Endoscopy (formerly Wilson-Cook Medical), WinstonSalem, NC, USA.]

(a)

Figure 24.11 This disposable clip-fixing device consists of a control section and an insertion tube. The control section incorporates movable plastic parts that manipulate clip loading and deployment. The insertion tube is made up of a metal coil sheath contained within an outer plastic sheath. A metal cable moves within the coil sheath. (Courtesy of Olympus America Inc., Melville, NY, USA.)

The clip fixing device consists of a control section and an insertion tube (Figure 24.11). The control section incorporates movable plastic parts that manipulate clip loading and deployment. The insertion tube is made up of a metal coil sheath contained within an outer plastic sheath. A metal cable moves within the coil sheath. At the distal end of the cable is a hooking apparatus to which the clip is attached. The insertion tube is compatible with an endoscope accessory channel of 2.8 mm or larger. Sheath lengths are available up to 230 cm. The clips themselves are configured from a multiangled stainless-steel ribbon (Figure 24.12). Clips are available in a limited variety of lengths and configurations. Standard hemoclips (MD850) have prongs that measure 6 mm in length and 1.2 mm in width. When fully opened, the predeployment distance between the clip prongs measures 7 mm. A “clip connector” enables loading of the clip onto the hooking cable. Predeployment and actual deployment is facilitated by a cylindrical “clip pipe.” A stepwise, controlled progression of

Accessories

(b)

Figure 24.12 The clips themselves are configured of a multiangled stainless-steel ribbon. When fully opened, the predeployment distance between the clip prongs measures 7 mm. (Courtesy of Olympus America Inc., Melville, NY.)

the clip pipe over the clip promotes full opening and subsequent closure of the clip. In practice, the clip is loaded onto the hooking cable and withdrawn into the outer plastic tube sheath. This procedure is unnecessary when using the preloaded ready-to-use version. The delivery device insertion tube is then passed through the endoscope working channel. With the target lesion in view, deployment is initiated by exposing the clip from within the tube sheath. Withdrawing the cable within the tube sheath slides the pipe clip up the clip itself, fully opening the clip. With the rotatable version, a rotator disk located on the control section may be used to turn the clip to the desired orientation. The insertion tube is then advanced so that the teeth of the clip engage the target tissue, whereupon further sliding of the pipe clip closes the clip and completes deployment, detaching the clip from the clip connector. Becoming facile with loading and deployment of endoscopic clips requires practice and regular use. Clips deploy with equal

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Figure 24.13 (a) A large sessile polyp is identified in the cecum in a patient requiring anticoagulation therapy. (b) Following saline-assisted polypectomy, there is oozing from the pigmented center of the resection site. (c) Primary closure of the resection site and durable hemostasis is achieved with three clips.

reliability in en face as well as in retroflexed scope positions. The most recent models (HX-5LR-1, HX-5QR-1, HX-6UR-1) are equipped with a rotating wheel that works surprisingly well. The clip can usually be rotated to the desired orientation. The rotator feature and improved durability are clear advantages over earlier clip designs. An unlimited number of clips can be placed during a single session. Mechanical cleaning followed by gas sterilization can reprocess the reusable model delivery device. Endoscopic mucosal clips are effective for hemostasis of polypectomy and mucosectomy sites and for primary or secondary hemostasis of postpolypectomy bleeding [24,25]. Endoscopic hemoclips promote durable hemostasis and do not incur additive tissue injury as is the case with thermal or injection techniques. Among 72 cases of colonoscopic immediate postpolypectomy (n = 45), delayed postpolypectomy (n = 18), and postbiopsy (n = 9) bleeding, effective and durable clip hemostasis was achieved in all but one case [26]. There were no episodes of recurrent bleeding or any need for surgery related to bleeding. However, randomized studies of clip application after polypectomy of colon polyps have found no benefit [27]. Marking with clips is effective for lesions benefiting from precise localization preoperatively including tumors and bleeding sites (e.g., diverticulum) [28]. Clips can readily be palpated or located with fluoroscopy at the time of surgery. Clips may be used for the fixation of colonic decompression tubes to prevent tube migration. Lastly, endoscopic mucosal clips have been used to achieve transient tissue remodeling to oppose surrounding tissue at a resection site or luminal defect (Figure 24.13a–c) [29]. The latter application should be limited for use in highly selected instances. A threepronged clip is available (TriClip) from Cook Endoscopy (formerly Wilson-Cook Medical Inc.). Boston Scientific Inc. has marketed the “Resolution® Clip”, which can be opened and

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closed repeatedly to assure precise application before final deployment of the clip.

Detachable loops Detachable loop snares (see Chapter 25) have been developed for the prevention and management of bleeding from polypectomy sites. Such bleeding is reported to occur in 2% of all polypectomies. Bleeding occurs more frequently with the removal of large polyps with thick stalks and in patients who have underlying coagulopathies, or in those taking anticoagulation therapy or nonsteroidal anti-inflammatory drugs. The detachable loop snare ligature was developed a little more than a decade ago for primary or secondary prophylactic therapy for postpolypectomy bleeding, or as primary or secondary treatment of active or recent postpolypectomy hemorrhage [30–33]. The detachable snare or “endoloop” (Olympus HX20Q, Olympus Corporation, Tokyo, Japan) is composed of an operating apparatus (MH-489) and an attachable loop of nylon thread (MH-477) (Figure 24.14). The operating apparatus consists of a Teflon sheath that is 2.5 mm in diameter and 1950 mm in working length, a stainless-steel coil sheath 1.9 mm in diameter, a hook wire, and the handle. The nylon loop is nonconductive and consists of a heat-treated circular or elliptically shaped nylon thread and a silicon rubber stopper that maintains the tightness of the loop. The optimal application of this device for prevention and management of polypectomy bleeding is yet to be determined. When used for primary prophylaxis, the flexibility of the loop makes it difficult to encircle the large polyps where its use would be most desirable. Entanglement of the subsequent electrocautery snare with the previously placed nylon loop may be a source of frustration. Unintentional transection of the polyp stalk with the detachable loop snare resulting in

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Figure 24.14 The detachable snare or “endoloop” (Olympus HX-20Q, Olympus Corporation, Tokyo, Japan). The nylon loop is nonconductive and consists of a heat-treated circular or elliptically shaped nylon thread and a silicon rubber stopper that maintains the tightness of the loop. (Courtesy of Olympus America Inc, Melville, NY, USA.)

a hemorrhage is a potential risk in the hands of an inexperienced assistant. When used as secondary prophylaxis against postpolypectomy bleeding, the loop is placed over the residual pedicle immediately post polypectomy (Figure 24.15a and b). This, too, can be challenging in all but the most prominent of residual stalks. Matsushita et al. [34] summarized their experience. They reported primary prophylactic use of a detachable snare for colonoscopic polypectomy of 20 large polyps in 18 patients, and secondary prophylactic placement following conventional polypectomy of five polyps in five patients. Four of the 20 polyps were semipedunculated and the loop slipped off after polypectomy in three of the four. Among the 16 pedunculated polyps, bleeding occurred in four cases, due to transection by the loop of the stalk before polypectomy in one, slipping off of the loop in another, and insufficient tightening of the loop in two. Among the five patients in whom the loop placement was attempted following conventional polypectomy, the residual stalk could not be ligated in three of the five lesions because of flattening. These authors concluded that the detachable snare is difficult to apply and subject to

Figure 24.15 Following snare resection of the large pedunculated polyp (a), a detachable loop was applied (b) to prevent delayed bleeding.

(a)

Accessories

operator-dependent error. For the treatment of active bleeding from a polypectomy site, once again the loop was only effective when there was a sufficient pedicle to allow ensnarement. Iishi et al. [35] report a more favorable experience. Secondary loop ligation for treatment of postpolypectomy hemorrhage is most apt to occur in the immediate postpolypectomy setting before the stalk has had a chance to flatten. In most instances of delayed postpolypectomy hemorrhage, bleeding or adherent clot obscures the view. Initial attempts at hemostasis with injection of epinephrine or alcohol solution may achieve partial hemostasis and improve visualization. If a sufficient residual stalk is present, loops may be applied; however, alternatives include additional electrocautery, placement of endoscopic hemostatic clips, or even the placement of a variceal rubber band ligator.

Contact and noncontact thermal devices Thermal devices (see Chapter 26) are used for coagulative hemostasis and ablation. Contact thermal devices include the heater probe (Olympus America, Melville, NY, USA) and MPEC probes [36]. Noncontact thermal devices include laser fibers and argon plasma or beam coagulators [36]. The heater probe consists of a Teflon-coated hollow aluminum cylinder with an inner heating coil at the tip of a flexible shaft. A thermocoupling device at the tip of the probe allows maintenance of a predetermined and constant temperature once the pulse has been initiated, for a predetermined duration. The mechanism of tissue coagulation is heat transfer. Water for irrigation and cleansing the target tissue passes through a central port. A foot pedal controls coagulation and irrigation. MPEC probes deliver thermal energy by completion of an electrical circuit between two or more electrodes on a probe at the tip of a flexible shaft [37]. The electrodes may be arrayed linearly or in a spiral fashion (Figure 24.16a and b). The circuit is completed locally and ceases with loss of

(b)

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conductivity as tissue desiccates, limiting maximum temperature (100°C) and depth and breadth of tissue injury. There is a central port for irrigation of water. Foot pedal control is standard. A variety of MPEC probes in colonoscopic lengths are available from endoscope device manufacturers with similar specifications but varied characteristics. One device combines an injection needle with the MPEC probe. Both the heater and MPEC probes can be used tangentially and en face. Laser fibers transmit collimated highly energized light energy, emitting a focused monochromatic beam [38]. They are flexible glass fibers with coated shafts. The laser light, delivered from a focal distance of ∼ 10 mm from the tissue, results in coagulation or vaporization. The argon plasma beam coagulator is a noncontact electrocoagulation device [39]. Monopolar current is conducted to the target tissue through an ionized argon gas (argon plasma). As it is monopolar current, a grounding pad is required to complete the circuit. Electrical energy flows through the plasma from the probe tip to the target tissue. Coagulation occurs at the plasma–tissue surface interface. As the target tissue desiccates, the plasma steam shifts to adjacent, nondesiccated tissue. The probes consist of a flexible Teflon tube as a shaft, with a tungsten electrode contained in a ceramic nozzle at its distal tip [40]. The operative distance of the probe from the target tissue is 2–8 mm. While mode-specific probes are available, the arc of energized argon plasma to the tissue enables en face or tangential coagulation/ ablation with the standard probe. An argon plasma beam coagulation unit (ERBE USA, Marietta, GA, USA; ConMed Electrosurgery, Englewood, CO, USA) includes a high-frequency electrosurgical generator, source of argon gas, gas flow meter, flexible delivery catheter, grounding pad, and foot switch to activate both gas and energy. Argon plasma coagulation of suspected residual adenoma after polypectomy has been shown to significantly reduce [41,42] or have no effect [43] on the rate of persistent adenoma at follow-up examination.

314

Figure 24.16 (a) Multipolar electrocautery probes and an angiodysplastic lesion. (b) Tissue after cautery application.

Contact and noncontact thermal devices are used for hemostasis of colonic bleeding attributed to immediate and recent polypectomy, arteriovenous malformations, radiation proctopathy, and diverticulosis [36]. The coagulation grasping forceps (Olympus Corporation, Tokyo, Japan) is a modified bipolar forceps used for directed tissue grasping and coagulation, which is employed as primary and prophylactic therapy during and after the performance of endoscopic mucosal resection (EMR) and submucosal dissection techniques. Contact and noncontact thermal devices are also used to ablate residual adenomatous-appearing mucosa at the margins of snare resection of sessile polyps, and for ablation of lesions not amenable to colonoscopic or surgical resection [44–46]. Noncontact thermal devices have been used to ablate obstructing colorectal cancer to achieve recannulation of the colonic lumen and for hemostasis of inoperable colorectal cancers.

Transparent cap Plastic transparent caps that affix to and overhang the tip of the endoscope may be used to enhance colonic visualization and facilitate EMR [47]. These caps are modifications of devices initially used for endoscopic band ligation therapy. The cap consists of a hollow cylinder of fixed or flexible plastic and a snug-fitting adaptor that slides over and is affixed to the tip of the colonoscope (Figure 24.17) [48]. Those devised for cap-assisted EMR may have a built-in rim to house a predeployed specially designed snare. A commonly used cap size is 16 mm in outer diameter with 2-mm wall thickness, and 15 mm in length. However, they are available in a variety of sizes and configurations, including straight- or oblique-angled opening, depending on the intended purpose and colonoscope being used. For cap-assisted EMR, submucosal injection of saline or other sterile solution is performed to “lift” the mucosa-based

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Figure 24.17 Plastic transparent cap to enhance colonic visualization and to facilitate endoscopic mucosal resection.

lesion on a submucosal cushion. The scope tip with the attached cap is then placed over the lesion. By applying suction, the cap cylinder becomes a vacuum chamber, drawing the target tissue into a pseudopolyp within. The predeployed snare is then closed and standard electrocautery excision is performed. This technique has been described for lesions throughout the colon and is safe and effective in experienced hands [49]. Cap-assisted EMR may also be used for completion resection of flat rectal or submucosal lesions unamenable to other mucosectomy techniques [50]. Such may be the case for very distal rectal lesions and for rectal lesions in which prior electrocautery has been introduced that prevents submucosal injection techniques alone due to “nonlifting.” Because of the potential to draw in deeper layers of the colonic wall, cap-assisted EMR is generally restricted to lesions below the retroperitoneal reflection. The transparent cap may also be used to enhance mucosal imaging during colonoscope withdrawal. Using this technique, the semilunar folds can be flattened out for improved inspection. In two series, use of the cap did not interfere with colonoscope insertion or terminal ileal intubation, and enabled identification of small polyps not seen on standard colonoscopy [51,52].

Overtubes Colonoscopic overtubes have been developed, intended to ease initial colonoscope insertion and facilitate subsequent colonoscope withdrawals and reinsertion. The SG-1 ShapeLock endoscopic guide (USGI Medical, San Clemente, CA, USA) is a novel overtube device with a unique “lockable feature on demand” designed to resist loop formation and to facilitate colonoscopy to the cecum [53]. The ShapeLock consists of a reusable, multilink, flexible overtube with a squeeze-activated handle and a disposable, sterile sheath with a smooth external skin, a hydrophic inner liner, and an atraumatic tip. The flex-

Accessories

ible link component can be “locked” in configuration to create a rigid channel for advancing the endoscope. The assembly has a 60-cm insertable length, with an outer diameter of 21 mm and inner diameter of 14 mm. Colonoscopes with an outer diameter of up to 13.5 mm can be inserted through the device. Endo-Ease (Spirus Medical Inc., Stoughton, MA, USA) is another overtube-type colonoscopy assist device, utilizing a “rotate to advance” technology [54]. This device has a raised helix on the distal end of the overtube, which when rotated is intended to follow the lumen of the colon. Once the sigmoid colon has been traversed, the Endo-Ease device is advanced, so as to “stabilize” the sigmoid colon. Thereafter, the colonoscope is independently advanced through the remainder of the colon. The EndoGuide (Syntheon LLC, Miami, FL, USA) is an overtube designed to fit over a pediatric colonoscope and be converted from a flexible to a rigid configuration, on demand, using a vacuum source. Investigators state that the EndoGuide will conform to the anatomy it is in, even when stiffened to the rigid configuration [55]. It consists of an outer jacket and an inner liner. Between these inner and outer layers is a body tube supported by rings and longitudinal rods. The body tube is responsible for the column strength exhibited by the entire device. A sliding switch controls the application of suction to stiffen the overtube into a rigid configuration.

Summary An extensive array of accessory devices have been developed and adopted for diagnostic and therapeutic colonoscopy. These innovations and adaptations have enabled the expansion of minimally invasive colonoscopic therapies for benign and neoplastic diseases of the colorectum. Countless lives have been saved, surgical procedures avoided, and societal benefits accrued as a result of the development and dissemination of colonoscopic accessories and the techniques they enable. We are indebted to the legions of physician endoscopists and their industry counterparts who have contributed to device development and evaluation. Continuous creative innovation is required to ensure the further advancement of these tools and techniques.

References 1 Carr-Locke DL, Al-Kawas FH, Branch MS, et al. Technology assessment status evaluation: bipolar and multipolar accessories. Gastroenterol Nurs 1998; 21: 187– 9. 2 Forde KA, Treat MR, Tsai JL. Initial clinical experience with a bipolar snare for colon polypectomy. Surg Endosc 1993; 7: 427–8. 3 Tappero G, Gaia E, De Giuli P, et al. Cold snare excision of small colorectal polyps. Gastrointest Endosc 1992; 38: 310–13.

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4 McAfee JH, Katon RM. Tiny snares prove safe and effective for removal of diminutive polyps. Gastrointest Endosc 1994; 40: 301–3. 5 Nelson DB, Bosco JJ, Curtis WD, et al. ASGE technology status evaluation report. Endoscopic retrieval devices. Gastrointest Endosc 1999; 50: 932– 4. 6 Bernstein DE, Barkin JS, Reiner DK, Lubin J, Phillips RS, Grauer L. Standard biopsy forceps versus large-capacity forceps with and without needle. Gastrointest Endosc 1995; 41: 573– 6. 7 Barkun AN, Liu J, Carpenter S, et al. Update on endoscopic tissue sampling. Gastrointest Endosc 2006; 66: 743–7. 8 Fantin AC, Neuweiler J, Binek JS, Suter WR, Meyenberger C. Diagnostic quality of biopsy forceps specimens: comparison between a conventional biopsy forceps and multibite forceps. Gastrointest Endosc 2001; 54: 600– 4. 9 Gilbert DA, DiMarino AJ, Jensen DM, et al. Status evaluation: hot biopsy forceps. Gastrointest Endosc 1992; 38: 753– 6. 10 Vanagunas A, Pothen J, Nimcsh V. Adequacy of “hot biopsy” for the treatment of diminutive polyps: a randomized trial. Am J Gastroenterol 1989; 84: 383– 5. 11 Peluso F, Golodner F. Follow-up of hot biopsy forceps treatment of diminutive colonic polyps. Gastrointest Endosc 1991; 37: 604–6. 12 Yang R, Naritoku W, Laine L. Prospective, randomized comparison of disposable and reusable forceps in gastrointestinal endoscopy. Gastrointest Endosc 1994; 40: 671–4. 13 Woods KL, Anand BS, Cole RA, et al. Influence of endoscopic biopsy forceps characteristics on tissue specimens: results of a prospective randomized study. Gastrointest Endosc 1999; 49: 177– 83. 14 Yang R, Ng S, Nichol M, Laine L. A cost and performance evaluation of disposable and reusable biopsy forceps in GI endoscopy. Gastrointest Endosc 2000; 51: 266–70. 15 Deprez PH, Horsmans Y, Van Hassel M, Hoang P, Piessevaux H, Geubel A. Disposable versus reusable biopsy forceps: a prospective cost evaluation. Gastrointest Endosc 2000; 51: 262–5. 16 Rizzo J, Bernstein D, Gress F. A performance, safety and cost comparison of reusable and disposable endoscopic biopsy forceps: a prospective, randomized trial. Gastrointest Endosc 2000; 51: 257–61. 17 Kozarek RA, Attia FM, Sumida SE, et al. Reusable biopsy forceps: a prospective evaluation of cleaning, function, adequacy of tissue specimen, and durability. Gastrointest Endosc 2001; 53: 747–50. 18 Bronowicki J-P, Venard V, Botté C, et al. Patient-to-patient transmission of hepatitis C virus during colonoscopy. N Engl J Med 1997; 337: 237– 40. 19 Nelson DB, Bosco JJ, Curtis WD, et al. Injection needles. Gastrointest Endosc 1999; 50: 928–31. 20 Brooker JC, Saunders BP, Shah SG, et al. Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial. Gastrointest Endosc 2002; 56: 333– 8. 21 Fleischer DE. Chromendoscopy and magnification endoscopy in the colon. Gastrointest Endosc 1999; 49: S45– 9. 22 Hachisu T. Evaluation of endoscopic hemostasis using an improved clipping apparatus. Surg Endosc 1988; 2: 13–17. 23 Hachisu T, Yamada H, Satoh S, Kouzu T. Endoscopic clipping with a new rotatable clip-device and a long clip. Dig Endosc 1996; 8: 127–33. 24 Cipolletta L, Bianco MA, Rotonano Gcatalano M, Prisco A, De Simone T. Endoclip-assisted resection of large pedunculated colon polyps. Gastrointest Endosc 1999; 50: 405– 6.

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25 Uno Y, Satoh K, Tuji K, et al. Endoscopic ligation by means of clip and detachable snare for management of colonic postpolypectomy hemorrhage. Gastrointest Endosc 1999; 49: 113–15. 26 Parra-Blanco A, Kaminaga N, Kojima T, et al. Hemoclipping for postpolypectomy and postbiopsy bleeding. Gastrointest Endosc 2000; 51: 37–41. 27 Shioji K, Suzuki Y, Kobayashi M, et al. Prophylactic clip application does not decrease delayed bleeding after colonoscopic polypectomy. Gastrointest Endosc 2003; 57: 691–4. 28 Chuttani R, Barkun A, Carpenter S, et al. Endoscopic clip application devices. Gastrointest Endosc 2006; 63: 746–50. 29 Yoshikane H, Hidano H, Sakakibara A, et al. Endoscopic repair by clipping of iatrogenic colonic perforation. Gastrointest Endosc 1997; 46: 464– 6. 30 Pontecorvo C, Pesce G. The “Safety Snare”aa ligature placing snare to prevent hemorrhage after transection of large pedunculated polyps. Endoscopy 1986; 18: 55–6. 31 Hachisu T. A new detachable snare for hemostasis in the removal of large polyps or other elevated lesions. Surg Endosc 1991; 5: 70–4. 32 Uno Y, Satoh K, Tuji K, et al. Endoscopic ligation by means of clip and detachable snare for management of colonic post polypectomy hemorrhage. Gastrointest Endosc 1999; 41: 113–15. 33 Rey JF, Marek DA, Cotton P. Endoloop in the prevention of post polypectomy bleeding; preliminary results. Gastrointest Endosc 1997; 46: 387– 9. 34 Matsushita M, Hajiro K, Takakuwa H, et al. Ineffective use of detachable snare for colonoscopic polypectomy of large polyps. Gastrointest Endosc 1998; 47: 496– 9. 35 Iishi H, Tatsuta M, Narahara H, Iseki K, Sakai N. Endoscopic resection of large pedunculated colorectal polyps using detachable snare. Gastrointest Endosc 1996; 44: 594– 7. 36 Nelson DB, Barkun AN, Block KP, et al. Endoscopic hemostatic devices. Gastrointest Endosc 2001; 54: 833– 40. 37 Laine L. Bipolar/multipolar electrocoagulation. Gastrointest Endosc 1990; 36(Suppl.): S38–S41. 38 Carr-Locke DL, Conn MI, Faigel DO, et al. Developments in laser technology. Gastrointest Endosc 1998; 48: 711–16. 39 Ginsberg GG, Barkun AN, Bosco JJ, et al. The argon plasma coagulator. Gastrointest Endosc 2002; 55: 807–10. 40 Cipolletta L, Bianco MA, Rotondano G, Piscopo R, Prisco A, Garofano ML. Prospective comparison of argon plasma coagulator and heater probe in the endoscopic treatment of major peptic ulcer bleeding. Gastrointest Endosc 1998; 48: 191–5. 41 Brooker J, Saunders B, Shah S, et al. Treatment with argon plasma coagulation reduces recurrence after piecemeal resection of large sessile colonic polyps: a randomized trial and recommendations. Gastrointest Endosc 2002; 55: 371–5. 42 Zlatanic J, Waye JD, Kim PS, et al. Large sessile colonic adenomas: use of argon plasma coagulator to supplement piecemeal snare polypectomy. Gastrointest Endosc 1999; 49: 731–5. 43 Regula J, Wronska E, Polkowski M, et al. Argon plasma coagulation after piecemeal polypectomy of sessile colorectal adenomas: long-term follow-up study. Endoscopy 2003; 35: 212–18. 44 Zlatanic J, Waye JD, Kim PS, Baiocco PJ, Gleim GW. Large sessile colonic adenomas: use of argon plasma coagulator to supplement piecemeal snare polypectomy. Gastrointest Endosc 1999; 49: 731–5. 45 Brooker JC, Saunders BP, Shah SG, Thapar CJ, Suzuki N, Williams CB. Treatment with argon plasma coagulation reduces recurrence after piecemeal resection of large sessile colonic polyps:

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47

48

49

50

a randomized trial and recommendations. Gastrointest Endosc 2002; 55: 371–5. Low DE, Kozarek RA. Snare debridement prior to Nd:YAG photoablation improves treatment efficiency of broad-based adenomas of the colorectum. Gastrointest Endosc 1989; 35: 288– 91. Tada M, Inoue H, Yabata E, Okabe S, Endo M. Feasibility of the transparent cap-fitted colonoscope for screening and mucosal resection. Dis Colon Rectum 1997; 40: 618–21. Nelson DB, Block KP, Bosco JJ, et al. Technology status report evaluation. Endoscopic mucosal resection. Gastrointest Endosc 2000; 52: 860–3. Tada M, Inoue H, Yabata E, Okabe S, Endo M. Colonic mucosal resection using a transparent cap-fitted endoscope. Gastrointest Endosc 1996; 44: 63–5. Oshitani N, Hamasaki N, Sawa Y, et al. Endoscopic resection of small rectal carcinoid tumours using an aspiration method with a transparent overcap. J Int Med Res 2000; 28: 241–6.

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51 Matsushita M, Hajiro K, Okazaki K, Takakuwa H, Tominaga M. Efficacy of total colonoscopy with a transparent cap in comparison with colonoscopy without the cap. Endoscopy 1998; 30: 444–7. 52 Dafnis GM. Technical considerations and patient comfort in total colonoscopy with and without a transparent cap: initial experiences from a pilot study. Endoscopy 2000; 32: 381–4. 53 Raju GS, Pasricha PJ. ShapeLock: a rapid access port for redeployment of a colonoscope into the proximal colon to facilitate multiple polypectomies in a single session. Gastrointest Endosc 2005; 61: 768–70. 54 Cantero D, Monier C, Toor A, et al. Spirus EndoEase: Multi-Center Experience with a New Colonoscopy Assist Device. Gastrointest Endosc 2007; 65: AB126. 55 Rothstein RI, Cimis R, Palmer M, Abelleira J, Smith K. Syntheon Endoguide: a novel overtube to assist colonoscopy. Gastrointest Endosc 2007; 65: AB343.

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Clips, Loops, and Bands: Applications in the Colon Michael J. Bourke & Stephen J. Williams Westmead Hospital, Sydney, Australia

Introduction Throughout the gastrointestinal tract, clips and loops have varied endoscopic applications; however, within the colon they are primarily used as hemostatic tools. As therapeutic intervention assumes a larger role in routine endoscopic practice, these modalities are increasingly seen as a core component of a standard endoscopy service. In general, however, their use is reserved for relatively uncommon therapeutic challenges. They can be employed in either a prophylactic setting, such as ligation of a large polyp stalk prior to electrosurgical transection, or an emergency setting to arrest bleeding (e.g., postpolypectomy hemorrhage). Endoscopic band ligation can also be used in this latter situation. These techniques form a discrete subclass within the endoscopic hemostatic therapies, namely “mechanical hemostasis,” which is both conceptually appealing and theoretically advantageous when compared with other techniques. The ability to arrest hemorrhage is due to direct mechanical ligation of the responsible vessel. The captured tissue usually includes not only the vessel walls, but also the surrounding tissue. The more conventional hemostatic techniques, such as injection therapy, contact thermal electrocoagulation (bipolar, heater probe), or noncontact thermal electrocoagulation (laser, argon plasma coagulation), rely on some degree of tissue destruction, coagulation, transient tamponade, or vasoconstriction to achieve the hemostatic effect. Rebleeding may ensue due to treatment-induced ulceration, coagulopathy, large vessel size, or poor tissue quality. Within the thin-walled colon, the risk of perforation with tissue destructive techniques, such as electrothermal devices, is also a major consideration. Clips and loops have a number of additional reported or potential applications within the lower gastrointestinal tract. These are summarized in Table 25.1. Each of these modalities is discussed in turn.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Table 25.1 Potential or reported applications of clips and loops within the lower gastrointestinal tract. Clips Endoscopic hemostasis: post polypectomy, Dieulafoy, diverticular, variceal bleeding Prophylactic stalk clipping before large pedunculated polypectomy Intraluminal marking device for fluoroscopic procedures (e.g., angiographic embolization) Closure of recognized perforation following polypectomy Loops Prophylactic stalk snaring before large pedunculated polypectomy Temporary mechanical hemostasis for large broad-based lesions before surgery (e.g., bleeding leiomyoma/lipoma) Bands Stalk bleeding post polypectomy Colonic variceal or Dieulafoy hemorrhage Aid to sessile polypectomy particularly left colon Rectal mucosal prolapse

Clips Technical considerations Metallic clips are routinely used in both open and laparoscopic abdominal surgery. The clip is made of stainless steel and does not induce a tissue reaction [1]. The result is analogous to the application of a surgical ligature; successful deployment of the clip for hemostasis is self-evident, with immediate and complete cessation of bleeding. One potential disadvantage of the clip in hemostasis is that precise targeting is required, in contrast to epinephrine injection, where an injection in the general region will often suffice. In a major hemorrhage when brisk bleeding may obscure the view, preinjection with epinephrine will usually slow bleeding sufficiently to allow accurate clip deployment. The inability to wash the bleeding point and treat with the same device, as can be done with thermal probes, is a potential disadvantage. The advent of endoscopes with water pump attachments has largely eliminated this problem. An endoscope with a working channel

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(a)

Figure 25.1 Clips for flexible endoscopy. Left to right: Triclip, Resolution® Clip, QuickClip, EZ Clip. Opening width is similar across the various devices, and ranges from 11 to 15 mm.

(b)

of 3.7 or 4.2 mm is preferred to allow both suctioning of secretions and blood alongside the device and free movement of the device within the channel, which is particularly important where acute angulation of the endoscope tip is required to target lesions (e.g., retroflexion in the rectum or cardia of the stomach). Several endoscopic clips are currently available (Figure 25.1). The opening width is similar across the various devices, and ranges between 11 and 15 mm: • TriClip [Cook Endoscopy (formerly Wilson-Cook Medical Inc.), Winston-Salem, NC, USA]; • Resolution® Clip (Microvasive Endoscopy, Boston Scientific Inc., Natick, MA, USA); • QuickClip2 and EZ Clip (Olympus Medical, Tokyo, Japan). Refinements in device design over recent years have made the procedure of endoscopic clipping much easier and, in particular, external loading of the clip is no longer required. An exception is the EZ Clip which is primarily marketed in Japan and parts of Asia; it has the advantage of a reloadable deployment device so that several clips of varying arm length of between 5.0 and 8.5 mm, and distal angles of either 90° or 135° can be used in a single setting with the same applicator. Other refinements include the ability to open and close the clip multiple times to ensure correct tissue capture before final deployment (Resolution Clip) and the ability to predictably rotate the clip, thus improving its orientation to the target tissue (Resolution Clip, QuickClip, and EZ Clip). If a standard polypectomy snare can be considered as a “two-layered” system, comprising an inner stainless-steel snare and the covering plastic sheath, then, in general, endoscopic clipping devices are “three-layered” systems (Figure 25.2). They are composed of an outer plastic sheath, an inner metal coil sheath, and a central cable with a hook at its tip to which

(c) Figure 25.2 (a) Clip and the “three-layered” clipping device. (b) Clip attached to hook. (c) Clip partially drawn into the plastic sheath.

the clip is attached. The clip is juxtaposed against the end of the metal coil sheath which is used to deploy it at the correct moment. Earlier clipping devices require the staff to attach the clip to this hook, but now all of the available systems come preassembled, although manual attachment is an option. The articulated clip and metal coil sheath complex is drawn back into the plastic sheath, ready for insertion into the working channel of the endoscope. The handle consists of two sliding components; moving these components toward one another will project the clip forward from the plastic sheath. Partial closure of the handle will allow the prongs of the clip to fully open, or, in the case of the Resolution Clip, opening the handle will achieve this. The clip is then applied firmly to the target, and with complete closure of the handle the mechanism fires with a “click,” indicating detachment of the clip from the hook. The result is that the clip has been closed and attached to the target.

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The technique of clipping is heavily dependent on the topographic features, location, and nature of the lesion. The working channel of most endoscopes exits the instrument between the 5 and 7 o’clock positions so that alignment of the target in this position greatly enhances successful clip placement. In cases of gastrointestinal bleeding, the endoscopist should endeavor to capture not only the responsible vessel but also a substantial portion of the surrounding tissue, which results in more secure anchoring of the clip. Applying suction at the critical moment just prior to clip closure can facilitate this. A tangential approach facilitates maximum tissue capture. If this cannot be achieved despite repositioning of the scope and if en face application is necessary, then usually a second clip can be placed beneath the first tangentially since the first clip tents the lesion upwards. Another option is to apply suction using a large mucosal resection aspiration cap (the larger cap allows the clip to open completely) prior to deploying the clip. Several clips may be necessary to adequately treat a large polyp stalk or an actively bleeding vessel. We prefer to avoid epinephrine injection, unless there is massive hemorrhage and the target cannot be discerned. Its use may provide temporary cessation of bleeding and thus the success of subsequent clip placement cannot be accurately assessed.

Clinical experience The metallic clip as a means of endoscopic hemostasis was first introduced by Hayashi, in Japan, in 1975 [2]. Initial experience was disappointing due to the complex method of deployment and low clip retention rates. Subsequent improvements in the design of both the delivery system and the clips have led to an expanding literature reporting applications throughout the gastrointestinal tract.

Bleeding In gastrointestinal bleeding, most of the published experience has been accumulated in the upper digestive tract, predominantly in peptic ulcer hemorrhage and primarily with clips manufactured by Olympus. When compared with the estab-

lished techniques of endoscopic hemostasis in ulcer bleeding, namely injection or contact thermal probe, outcomes after the use of endoscopic clips in either isolation or combination with injection show equivalent or superior results in the majority of the nine published randomized controlled trials [3–11]. The results for primary hemostasis across the various trials were essentially equivalent; however, the use of clips was associated with a reduced risk of rebleeding in most trials [3,4,7,10,11]. This benefit in reduced rebleeding may be due to the absence of any tissue destructive effect when clips are used to achieve hemostasis and, hence, there is limited propensity for treatment-induced ulceration and thus further bleeding. Similarly, the use of clips with actively bleeding Mallory–Weiss tears in two small randomized studies has shown equivalence or superiority for primary hemostasis and rebleeding rates when compared with injection alone [12,13]. Clips are ideally suited for the treatment of Mallory–Weiss bleeding tears as their sequential placement along the length of the tear will close the mucosal defect and arrest bleeding. Clips have also been used successfully to treat bleeding related to Dieulafoy lesions and duodenal diverticula [14–18]. Table 25.2 summarizes the experience with the use of clips in acute hemorrhage in the lower digestive tract. Parra-Blanco et al. [19] reported their experience in 72 patients with lower gastrointestinal bleeding derived from a consecutive series of 9555 colonoscopies accumulated over a 3-year period. Postpolypectomy bleeding occurred in 63 patients (45 immediate, 18 delayed), while nine others had postbiopsy bleeding. Initial hemostasis was successful (Figure 25.3) in all but one patient, who later stopped with conservative management. There were no complications in this series. Binmoeller et al. [20] report a similar experience in 45 patients, 27 of whom had spurting hemorrhage. Postpolypectomy bleeding accounted for the majority, with one case of each of solitary rectal ulcer bleeding, hemorrhoid bleeding, and diverticular bleeding. Initial hemostasis was successful in all 45 patients, with a mean of 2.9 clips per patient, and there was only one episode of rebleeding, which was managed with further clip placement

Table 25.2 Experience with acute hemorrhage in the lower digestive tract. Reference

Number of patients

Source

Active bleeding

Initial control

Rebleeding

Parra-Blanco et al. [10]

72

Immediate post polypectomy (45) Delayed post polypectomy (18) Post biopsy (9)

58/72 (81%)

71/72 (99%)

0

Binmoeller et al. [11]

45

Post polypectomy (42) Diverticula (1) Solitary rectal ulcer (1) Hemorrhoids (1)

100%

100%

1/45

7

Post polypectomy (5) Colonic diverticula (2)

100%

100%

0

Hachisu et al. [12]

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Figure 25.3 Two examples of spurting postpolypectomy bleeding controlled with one and two clips respectively.

without sequelae. Patients with spurting arterial bleeding required more clips to achieve hemostasis than those with an oozing bleed. In the authors’ experience, any given episode of endoscopic hemostasis invariably requires two or more clips to achieve a satisfactory result. Clips may also be used to prevent delayed postpolypectomy bleeding (Figure 25.4). The data are at present inconclusive. The use of clips to close mucosal defects after endoscopic mucosal resection (EMR) is theoretically appealing, but for large defects where resection has involved lesions beyond 30 mm this still represents a substantial technical challenge (Figure 25.5). In a randomized trial of 413 average-risk patients undergoing EMR for sessile colonic polyps, closing the mucosal defect with clips did not result in a reduction in delayed bleeding, perhaps because of the low event rate of less than 1% in either arm [21]. A retrospective study of 41 patients on long-term anticoagulation treated with immediate postpolypectomy clip application after the removal of small polyps between 3 and 10 mm in size revealed no episodes of postpolypectomy bleeding [22]. A more formal evaluation of the potential role of empiric clip therapy in patients at high risk of rebleeding, such as those on long-term anticoagulation or antiplatelet agents, particularly patients with drugeluting coronary stents, in whom antiplatelet therapy cannot be readily stopped, is warranted. In cases of failed endoscopic hemostasis, clips can serve as excellent radiographic markers to facilitate subsequent angiographic embolization [23,24].

Figure 25.4 A large polyp rendered ischemic as evidenced by blue discoloration after clip application and prior to snare resection.

Active colonic diverticular hemorrhage can also be treated successfully with clip application [25,26].

Perforation Iatrogenic perforations following polypectomy can be sealed using the clip, although direct published experience with this

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Figure 25.5 3-cm sessile sigmoid polyp removed by endoscopic mucosal resection and mucosal defect closed with six clips (two cannot be seen as they are beyond the fold).

Figure 25.6 Pinhole perforation after endoscopic mucosal resection of a 20-mm sessile polyp. Defect completely closed with three clips. The patient was able to be managed conservatively with gut rest and broad-spectrum antibiotics.

technique is limited (Figure 25.6). Binmoeller et al. [27] published the first successful description of this technique to repair a 5-mm perforation complicating snare resection of a pedunculated gastric leiomyoma. Clips have also been used successfully to close perforations elsewhere in the gastrointestinal tract, including postsurgical esophagogastric anastomotic leaks, duodenal perforations secondary to biliary stents, EMR or sphincterotomy, and esophageal perforation complicating a variety of situations including therapeutic intervention, such as EMR or pneumatic dilation for achalasia [28–35]. In the colon, the advent of more aggressive mucosal resection techniques in the form of both wide-field EMR and endoscopic submucosal dissection (ESD) has necessitated an improved ability to deal with iatrogenic complications including perforation. Nonoperative management of recognized perforations that are immediately repaired during the same procedure has become the standard of care in tertiary referral centers that specialize in these resection techniques, particularly in Japan [36,37]. In a prospective study from the National Cancer Center in Tokyo, ESD was performed for 200 lesions with a successful en bloc rate of 84% and mean resected specimen size of 38 mm. There were 10 perforations (5%), with only one patient requiring surgery; the remainder were managed conservatively after successful endoscopic clipping of the defect. Another report describes the management of

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iatrogenic perforation after 5413 diagnostic and 2176 therapeutic colonoscopies resulting in 3 and 27 perforations respectively. Out of the 30 patients with colonic perforation, 27 underwent acute treatment with endoscopic clip application. Twenty-five of these could be treated nonoperatively, while five patients underwent operative management. The mean postoperative length of hospitalization for surgical patients was 12.2 days, compared with 3.5 days for patients treated conservatively [38]. Although the incidence of perforation in the therapeutic group appears excessive, the majority could still be managed conservatively. Several caveats exist. Endoscopic clip closure of full-thickness defects should be attempted only by those who are experienced in and conversant with the techniques of clip application. Timing is critical. In the colon, a nonoperative course of management can be reasonably considered only if the perforation is identified at the time of the index endoscopy (recognized perforation). Rapid and effective closure of the defect to prevent contamination of the peritoneal cavity is required. Broad-spectrum antibiotics are indicated, but if clinical evidence of diffuse peritonitis develops, laparotomy and surgical repair should not be delayed. Recent animal experiments in predominantly porcine models have confirmed the efficacy of endoscopic clipping as a means of closing even large colonic perforations [39]. The

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advent of natural orifice transluminal endoscopic surgery will likely further drive innovations in endoscopic clipping for perforation and the development of other tools for mural defect closure, such as endoscopic suturing devices [40].

Loops Technical considerations Detachable snares or loops are currently available in 20 and 30 mm diameters (MAJ-340 and MAJ-254, Olympus Medical, Tokyo, Japan). They are composed of nylon with a sliding plastic collar at the base and, along with the reusable delivery system and handle, are fully autoclavable and in this format are referred to as endoloops. A single-use, preassembled system available in the same loop sizes is also marketed by the same company as the Polyloop. The loop delivery device, like the clipping device, is a three-layered system composed of an outer plastic sheath and a metal coil around a central cable with hook (Figure 25.7). The detachable nylon loop can be fixed to the hook and closed until the metal coil sheath comes to rest against the plastic collar on the base of the loop. The loop/metal coil with loop complex is then drawn back into the plastic sheath. The system is now ready for insertion into the working channel of the endoscope. An instrument with a minimum working channel of 2.8 mm diameter is required, and those with larger channels are preferred. The target lesion should be positioned between the 5 and 7 o’clock positions to facilitate successful loop placement. The loop is expressed by withdrawing the plastic sheath backward and is then placed over the target lesion. Placement is rehearsed by closing the plastic sheath over the loop without advancing the plastic collar along the loop (i.e., the handle of the device is not closed). If the endoscopist is satisfied with the positioning of the loop, it can be deployed by simultaneously withdrawing the outer plastic sheath and closing the handle of the device. This latter movement will slide the plastic collar over the loop and close it. The loop can now be released from the device by opening the handle. A cutting device (FS-5 L/Q/U-1) is available to transect the residual end of the loop after ligation has been performed, but this is rarely necessary. In contrast to a conventional metal snare, loops have limited expansile force because of their nylon composition and thus can be challenging to place in circumstances in which there is limited room for opening fully, as a result of either the large size of the target lesion or the narrow luminal diameter. This is rarely a problem in the right colon but can create significant technical difficulty in the left one, particularly within severely stenotic diverticular disease or acute angulations. The use of a double-channel instrument could potentially overcome this problem. Akahoshi et al. [41] have described a technique using grasping forceps and a doublechannel instrument in 10 patients with pedunculated polyps with heads 1 cm or greater. The grasping forceps are passed

(a)

(b)

(c) Figure 25.7 (a) Loop delivery device. (b) Detachable nylon loop attached to the hook of the loop delivery device. (c) Loop partially drawn into the plastic sheath.

down one working channel and the endoloop device down the other. Once both devices have exited the end of the instrument and are in place, the grasping forceps are inserted through the detachable snare loop. The polyp head is then grasped and pulled through the loop, which is then closed on the stalk as described above and standard polypectomy is undertaken. This technique was successful in all cases. An alternative strategy for large pedunculated lesions is the application of one or several clips to the base of the polyp stalk. Clipping may also be preferred for thin-stalked lesions (< 5 mm) as the endoloop tends to transect rather than ligate these. In general, it is not necessary to pretreat such pedicles unless another risk factor (e.g., coagulopathy) or obligatory antiplatelet therapy (e.g., clopidogrel) exist.

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Figure 25.8 Large 6-cm pedunculated sigmoid polyp rendered ischemic by endoloop ligation and then resected.

Clinical experience Loops are generally used in the prophylaxis of postpolypectomy hemorrhage. The stalk or base of the polyp is first ligated as close to the mucosal surface as possible. Firm closure of the plastic sheath on the polyp base renders the polyp head relatively ischemic, indicated by a bluish discoloration of the polyp head (Figure 25.8). The tissue above the ligature is snared and removed in the conventional way, leaving the loop in place. Although anecdotal evidence suggests that the use of the endoloop is relatively widespread within specialist therapeutic endoscopy units [42], there are surprisingly few published reports describing this experience [43–49]. Iishi et al. [43] performed a randomized trial involving 89 patients with pedunculated colonic polyps ≥ 1 cm in diameter. No bleeding occurred during or after polypectomy in the 47 patients who were assigned to the detachable snare group. Of the 42 patients who did not have a detachable snare applied, five (12%) sustained postpolypectomy bleeding. In a prospective randomized trial of epinephrine injection alone versus combination epinephrine injection and detachable snare ligation in 84 patients with large colonic polyps (> 2 cm), the use of ligation resulted in a significant reduction in early postpolypectomy bleeding (1% vs. 9%, P = 0.02) [49]. A significant advantage of prior loop ligation of a large polyp stalk or abnormally thick pedicle (e.g., colonic lipoma; see Figure 25.7a–c) is the ability to use greater electrosurgical generator power, including cutting or blended current, during polypectomy without fear of precipitating hemorrhage.

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Loops may also be used to facilitate resection of large or potentially serious submucosal lesions such as colonic lipomas [50,51] or rectal carcinoids [52] when clinically indicated (Figure 25.9). With large submucosal protuberant or pedunculated lesions there is a risk that the deeper layers of the bowel wall have been invaginated into the pedicle or are closely adherent to the pathology being resected. Thus, even in cases of transmural thermal injury the use of a loop may provide a secure ligature just below the transection and prevent free perforation [50]. Detachable snares have also been used to achieve hemostasis in actively bleeding gastric and esophageal varices [53–55]. In theory, this device could be similarly employed in colonic variceal hemorrhage. An endoloop has been used to remove a migrated selfexpanding esophageal metal stent from the upper gastrointestinal tract [56]. The loop was closed over the leading aspect of the stent to reduce the diameter and then the stent was drawn back onto the tip of the endoscope and removed. A similar technique could be used for migrated stents in the lower gastrointestinal tract.

Bands Band ligation has been proven to be the endoscopic therapy of choice in acute esophageal variceal hemorrhage [57] and is ideal for the treatment of bleeding rectal varices (Figure 25.10).

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(a)

Clips, Loops, and Bands: Applications in the Colon

(b)

(c)

Figure 25.9 (a) Colonic lipoma. (b) Loop in place around the base with snare secured above. Note the bluish discoloration of the looped tissue. (c) Lipoma removed leaving the loop in situ.

Dieulafoy lesions, Mallory–Weiss tears, and postpolypectomy bleeding. Two cases of delayed postpolypectomy hemorrhage following removal of pedunculated sigmoid colon polyps were managed by band ligation. The band was applied to the residual stalk, with immediate and permanent cessation of bleeding. The appeal of this modality is due to the rapid “single-shot” mechanism of hemostasis, analogous to the application of a surgical ligature. Published experience with this technique is limited, although it merits consideration in most forms of postpolypectomy hemorrhage in which a residual pedicle is evident [59,60]. It can also be safely used in the rectum and left colon for small (≤ 10 mm) bleeding cautery ulcers following polypectomy, when the entire lesion is aspirated into the device, the band applied, and hemostasis secured. In the right colon, the risk of capture of the full thickness of the colonic wall, with subsequent necrosis and delayed perforation, generally precludes the use of this technique for nonelevated lesions. The need to “carry” the ligation apparatus, which limits the endoscopic view, to the bleeding source adds complexity to the treatment of lesions in the right colon. Multipleband ligation has also been used to treat rectal mucosal prolapse [61] and certainly merits further study as a minimally invasive therapy for this disorder.

Summary

Figure 25.10 Top: Rectal variceal active bleeding (arrow) treated with band ligation. Bottom: Following immediate cessation of bleeding, the bleeding point is seen at the apex of the banded varix (arrow).

It is a viable therapeutic strategy in certain cases of lower gastrointestinal hemorrhage. Our group first reported this application for nonvariceal, nonulcer hemorrhage throughout the gastrointestinal tract [58]. In this series of 18 patients, abnormalities treated included arteriovenous malformations,

Technological advances in the design of the clipping, looping, and banding devices have made the use of these devices in the colon relatively user-friendly and they should be part of the available accessories in all endoscopy units undertaking colonoscopy. Their application is mainly in the prevention and treatment of complications such as postpolypectomy hemorrhage. As more aggressive endoscopic resection techniques, such as wide-field EMR and ESD, evolve and allow the safe removal of ever larger lesions, these technologies and their successors will assume an even greater role in treating the associated iatrogenic complications. Appropriate use in the current climate allows safer and more effective colonoscopic therapy.

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References 1 Soehendra N, Sriam PVJ, Ponchon T, Chung SCS. Hemostatic clip in gastrointestinal bleeding. Endoscopy 2001; 33: 172– 80. 2 Hayashi I, Yonezawa TM, Kuwabara T, Kudoh I. The study on staunch clip for the treatment of endoscopy. Gastroenterology 1975; 17: 92–101. 3 Chung IK, Ham JS, Kim HS, Park SH, Lee MH, Kim SJ. Comparison of the hemostatic efficacy of the endoscopic hemoclip method with hypertonic saline–epinephrine injection and a combination of the two for the management of bleeding peptic ulcers. Gastrointest Endosc 1999; 49: 13–18. 4 Cipolletta L, Bianco MA, Marmo R, et al. Endoclips versus heater probe in preventing early recurrent bleeding from peptic ulcer: a prospective and randomised trial. Gastrointest Endosc 2001; 53: 147–51. 5 Lin HJ, Hsieh YH, Tseng GY, et al. A prospective randomized trial of endoscopic hemoclip versus heater probe thermocoagulation for peptic ulcer bleeding. Am J Gastroenterol 2002; 97: 2250– 4. 6 Gevers AM, De Goede E, Simoens M, et al. A randomized trial comparing injection therapy with hemoclip and with injection combined with hemoclip for bleeding ulcers. Gastrointest Endosc 2002; 55: 466– 9. 7 Chou Y-C, Hsu P-I, Lai K-H, et al. A prospective randomized trial of endoscopic hemoclip placement and distilled water injection for treatment of high-risk bleeding ulcers. Gastrointest Endosc 2003; 57: 324–8. 8 Shimoda R, Iwakiri R, Sakata H, et al. Evaluation of endoscopic hemostasis with metallic haemoclips for bleeding gastric ulcer: comparison with endoscopic injection of absolute ethanol in a prospective randomized study. Am J Gastroenterol 2003; 98: 2198–202. 9 Chua TS, Fock KM, Ng TM, et al. Epinephrine injection therapy versus a combination of epinephrine injection and endoscopic hemoclip in the treatment of bleeding ulcers. World J Gastroenterol 2005; 11: 1044–7. 10 Saltzman JR, Strate LL, Di Sena V, et al. Prospective trial of endoscopic clips versus combination therapy in upper GI bleeding (PROTECCT-UGI bleeding). Am J Gastroenterol 2005; 100: 1503–8. 11 Lo CC, Hsu PI, Lo GH, et al. Comparison of hemostatic efficacy for epinephrine injection alone and injection combined with hemoclip therapy in treating high-risk bleeding ulcers. Gastrointest Endosc 2006; 63: 767–73. 12 Huang SP, Wang HP, Lee YC, et al. Endoscopic hemoclip placement and epinephrine injection for Mallory–Weiss syndrome with active bleeding. Gastrointest Endosc 2002; 55: 842– 6. 13 Chung IK, Kim EJ, Hwang KY, et al. Evaluation of endoscopic hemostasis in upper gastrointestinal bleeding related to Mallory– Weiss syndrome. Endoscopy 2002; 34: 474– 9. 14 Becker SA, Ellger R, Buyeuiz V. Hemoclip placement as definitive therapy for bleeding from a Dieulafoy lesion. Isr Med Assoc J 2002; 4: 653–4. 15 Wu NH, Wang HP, Yang CS, Wang HH, Wu MS, Lin JT. Endoscopic hemoclip therapy of a bleeding duodenal diverticulum. Gastrointest Endosc 2000; 51: 489– 91. 16 Will U, Seidel T, Bosseckert H. Endoscopic hemoclip treatment for bleeding artificially induced Mallory–Weiss tears. Endoscopy 2002; 34: 748.

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17 Yamaguchi Y, Yamato T, Katsumi N, et al. Endoscopic hemoclipping for upper GI bleeding due to Mallory–Weiss syndrome. Gastrointest Endosc 2001; 53: 427–30. 18 Raju GS, Nath S, Zhao X, et al. Duodenal diverticular hemostasis with hemoclip placement on the bleeding and feeder vessels: a case report. Gastrointest Endosc 2003; 57: 116–17. 19 Parra-Blanco A, Kaminaga N, Kojima T, et al. Hemoclipping for post-polypectomy and post-biopsy colonic bleeding. Gastrointest Endosc 2000; 51: 37–41. 20 Binmoeller KF, Thonke F, Soehendra N. Endoscopic hemoclip treatment for gastrointestinal bleeding. Endoscopy 1993; 25: 167–70. 21 Shioji K, Suzuki Y, Kobayashi M, et al. Prophylactic clip application does not decrease delayed bleeding after colonoscopic polypectomy. Gastrointest Endosc 2003; 57: 691–4. 22 Friedland S, Soetikno R. Colonoscopy with polypectomy in anticoagulated patients. Gastrointest Endosc 2006; 64: 98–100. 23 Golder S, Strotzer M, Grune S, et al. Combination of colonoscopy and clip application with angiography to mark vascular malformation in the small intestine. Endoscopy 2003; 35: 551. 24 Eriksson LG, Sundbom M, Gustavsson S, et al. Endoscopic marking with a metallic clip facilitates transcatheter arterial embolisation in upper peptic ulcer bleeding. J Vasc Interv Radiol 2006; 17: 959–64. 25 Hachisu T, Yamada H, Datoh S, Kouzu T. Endoscopic clipping with a new rotatable clip-device and a long clip. Dig Endosc 1996; 8: 127–33. 26 Rino Y, Imada T, Iwasaki H, et al. Hemostasis of colonic diverticular bleeding with hemoclips under endoscopic control: report of a case. Hepatogastroenterology 1999; 46: 1733–5. 27 Binmoeller KF, Grimm H, Soehendra N. Endoscopic closure of a perforation using metallic clips after snare excision of a gastric leiomyoma. Gastrointest Endosc 1993; 39: 172– 4. 28 Rodella L, Laterza E, De Manzoni G, et al. Endoscopic clipping of anastomotic leakages in esophagogastric surgery. Endoscopy 1998; 30: 453– 6. 29 Roses LL, Ramirez AG, Seco AL, et al. Clip closure of a duodenal perforation secondary to a biliary stent. Gastrointest Endosc 2000; 51: 487– 9. 30 Kaneko T, Akamatsu T, Shimodairo K, et al. Non-surgical treatment of duodenal perforation by endoscopic repair using a clipping device. Gastrointest Endosc 1999; 50: 410–14. 31 Baron TH, Gostout CJ, Herman L. Hemoclip repair of a sphincterotomy-induced duodenal perforation. Gastrointest Endosc 2000; 52: 566– 8. 32 Shimamoto C, Hirata I, Umegaki E, Katsu K. Closure of an esophageal perforation due to fishbone ingestion by endoscopic clip application. Gastrointest Endosc 2000; 51: 736–9. 33 Wewalka FW, Clodi PH, Haidinger D. Endoscopic clipping of esophageal perforation after pneumatic dilation for achalasia. Endoscopy 1995; 27: 608–11. 34 Cipolletta L, Bianco MA, Rotondano G, Piscopo R, Meucci C. Endoscopic clipping of perforation following pneumatic dilation of esophagojejunal anastomotic stricture. Endoscopy 2000; 32: 720– 2. 35 Qadeer MA, Dumot JA, Vargo JJ, Lopez AR, Rice TW. Endoscopic clips for closing esophageal perforations: case report and pooled analysis. Gastrointest Endosc 2007; 66: 605–11. 36 Saito Y, Uraoka T, Matsuda T, et al. Endoscopic treatment of large superficial colorectal tumours: a case series of 200 submucosal dissections. Gastrointest Endosc 2007; 66: 966–73.

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37 Tamegai Y, Saito Y, Masaki N, et al. Endoscopic submucosal dissection (ESD)–a safe technique for colorectal tumours. Endoscopy 2007; 39: 418–22. 38 Magdeburg R, Collet P, Post S, Kaehler G. Endoclipping of iatrogenic colonic perforation to avoid surgery. Surg Endosc 2008; 22: 1500– 4. 39 Raju GS, Ahmed I, Brining D, et al. Endoluminal closure of large perforations of the colon with clips in a porcine model (with video). Gastrointest Endosc 2006; 64: 640– 6. 40 Pham BV, Raju GS, Ahmed I, et al. Immediate endoscopic closure of colon perforation by using a prototype endoscopic suturing device: feasibility and outcome in a porcine model (with video). Gastrointest Endosc 2006; 64: 113–19. 41 Akahoshi K, Kojima H, Fujimaru T, et al. Grasping forceps assisted endoscopic resection of large pedunculated gastrointestinal polypoid lesions. Gastrointest Endosc 1999; 50: 95–8. 42 Waye JD. New methods of polypectomy. Gastrointest Endosc Clin North Am 1997; 7: 413– 22. 43 Iishi H, Tatsuta M, Narahara H, Iseki K, Sakai N. Endoscopic resection of large pedunculated colo-rectal polyps using a detachable snare. Gastrointest Endosc 1996; 44: 594– 7. 44 Matsushita M, Hajiro K, Okazaki K, Takakuwa H, Nishio A. A large juvenile polyp in a 1 year old child safely removed by colonoscopic polypectomy with a detachable snare. Gastrointest Endosc 2000; 52: 118–20. 45 Pietropaolo V, Bogliolo G, Lande A, et al. Endoscopic ligation in the prevention of hemorrhage after polypectomy: our experience. G Chir 1999; 20: 51–2. 46 Pai KP, Morgan RH. Endoloop: a helpful new device for transanal rectal polypectomy. Br J Surg 1995; 82: 748. 47 Fowler CL. New application of endoloop for rectal polypectomy. J Pediatr Surg 1996; 31: 1685. 48 Dell’Abate P, Del Rio P, Soliani P, Sianesi M. Endoscopic polypectomy with the use of endoloop in giant gastric polyp: a case report. Acta Biomed Ateneo Parmense 2001; 72: 105– 8. 49 Paspatis GA, Paraskeva K, Theodoropoulou A, et al. A prospective randomized comparison of adrenaline injection in combination with detachable snare versus adrenaline injection alone in the

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prevention of postpolypectomy bleeding in large colonic polyps. Am J Gastroenterol 2006; 101: 2805. Murray MA, Kwan V, Williams SJ, et al. Detachable nylon loop assisted removal of large clinically significant colonic lipomas. Gastrointest Endosc 2005; 61: 756– 9. Vardas EM, Theodoropoulou AP, Zois ES, Paspatis GA, et al. Detachable snare in the removal of large colonic lipomas. Gastrointest Endosc 2005; 62: 648– 9. Moon JH, Kim JH, Park CH, et al. Endoscopic submucosal resection with double ligation technique for treatment of small rectal carcinoid tumors. Endoscopy 2006; 38: 511–14. Cipolletta L, Bianco MA, Rotondano G, Piscopo R, Prisco A, Garofano ML. Emergency endoscopic ligation of actively bleeding gastric varices with a detachable snare. Gastrointest Endosc 1998; 47: 400–3. Shim CS, Cho JY, Park YJ, et al. Mini-detachable snare ligation for the treatment of esophageal varices. Gastrointest Endosc 1999; 50: 673– 6. Yoshida T, Hayashi N, Suzumi N, et al. Endoscopic ligation of gastric varices using a detachable snare. Endoscopy 1994; 26: 502–5. De Ronde T, Martinet JP, Melange M. Easy removal of migrated self expanding esophageal metal stent using an endoloop device. Gastrointest Endosc 2000; 52: 125–7. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995; 123: 280–7. Abi-Hanna D, Williams SJ, Gillespie PE, Bourke MJ. Endoscopic band ligation for non-variceal non-ulcer gastrointestinal hemorrhage. Gastrointest Endosc 1998; 48: 510–14. Slivka A, Parsons WG, Carr-Locke DL. Endoscopic band ligation for treatment of post-polypectomy hemorrhage. Gastrointest Endosc 1994; 40: 230– 2. Smith RE, Doull J. Treatment of colonic post-polypectomy bleeding site by endoscopic band ligation. Gastrointest Endosc 1994; 40: 499–500. Kleinubing H Jr., Pinho MS, Ferreira LC. Longitudinal multiple rubber band ligation: an alternative method to treat mucosal prolapse of the anterior rectal wall. Dis Colon Rectum 2006; 49: 876–8.

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Principles of Electrosurgery, Laser, and Argon Plasma Coagulation with Particular Regard to Colonoscopy G. Farin1 & K.E. Grund2 1

Center for Medical Research, Experimental Endoscopy, Tübingen, Germany University Hospital, Tübingen, Germany

2

Introduction Hemostasis and the ablation of pathologic tissues are the most important indications for thermal techniques in colonoscopy. However, because the wall of gastrointestinal organs, especially the colon, is thin, it is very important to know how heat affects biological tissue, and also how to apply electric or electromagnetic energy to both cause intentional heat sink and avoid unintentional thermal effects in adjacent tissue. The colon, in particular, is not the ideal organ for the application of thermal techniques. The thickness of the three layers of the colon wall, comprising the mucosa, submucosa, and muscularis propria, varies from 1.5 to 3.0 mm (Figure 26.1) throughout the length of the large intestine. After insufflation, the wall can be even thinner. Since damage to the muscularis propria of the colon should be avoided during endoscopic interventions, thermal injury should not extend beyond the submucosa in order to avoid complications such as perforation. As a consequence, only about half of the 1.5–3.0 mm constituting the thin wall of the colon is accessible to the endoscopist for thermal interventions. The necessity that endoscopically applied thermal techniques should not damage the muscularis propria of the colon makes their application within the colon difficult, especially when the lesion to be treated is large. The endoscopist must have sufficient training to master the available endoscopes, instruments, and peripheral equipment in order to effectively and safely apply electrosurgery during colonoscopy. This article deals with the theoretical principles concerning the application of thermal techniques, especially in the colon.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Relevant thermal effects in biological tissues All thermal effects in and on biological tissuesawhether intentional or unintentionaladepend on the level (intensity) and duration of temperature in the tissue (Figure 26.2), almost regardless of the way in which this temperature is reached. Thermal treatment is among the oldest therapeutic techniques. Although high-frequency surgery was introduced about 100 years ago and laser surgery about 30 years ago, the terminology uses words that are centuries old, and some of it does still not accurately describe the various types of thermal effects in biological tissue and/or the intentional purpose for which the different thermal effects are used. As an example, coagulation is the only term in current use to describe thermal hemostasis, even though different thermal effects and techniques are used for this purpose. The term “coagulation” actually encompasses many different tissue effects such as devitalization, coagulation, and desiccation. One hundred years after introducing electrosurgery, and with particular regard to its established as well as future indications for thermal techniques in flexible endoscopy, we should define and use relevant terms more precisely and consistently.

Thermal devitalization Thermal devitalization is defined as an irreversible death of biological tissue. More precisely, devitalization of a target biological tissue means irreversible as well as complete death of this tissue and its cellular structure. Biological tissue becomes devitalized if its temperature reaches 41.5°C. The higher the temperature, the faster the devitalization. Unfortunately, devitalization is not a visible phenomenon and hence is difficult to control; thus, it is not used for destruction of pathologic tissue. Even if thermal devitalization is not employed intentionally, some degree of tissue devitalization (death) occurs outside the border of the coagulation zone, intentional or not. The depth of the invisible thermal

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5 mm

10 mm 5 mm

10 mm

20 mm 30 mm < – 3 mm < – 1.5 mm x10

20 mm

x10

0 0 1 1

mm

Figure 26.1 Diagram of the wall of the right and left colon with scale representation of thickness as well as small, medium, and large adenomas.

2

mm 2

3 3

UHF > 200 Vp Above 500º C Vaporization Can be used for tissue ablation or tissue cutting Can also create smoke and explosive gases (CO) Risk of fire, explosion, perforation Above 200º C Carbonization* No useful effect But can increase absorption of laser dramatically so the temperature rises above 500º C

Thermal effects localized Vaporization Carbonization Desiccation Coagulation Devitalization Hyperthermia

Monopolar active electrode

Polypectomy snare etc.

Vapor

(* No carbonization occurs if inert (CO2) or noble (Argon) gas surrounds the tissue).

High-temperature effects

UHF < 200 Vp 100º C Fast desiccation Final contraction of water-containing tissue can be used for hemostasis of bigger vessels because of glue effect of desiccated glucose Can be used for reduction of size of tumors Can also cause sticking of coagulation probes

Thermal effects widespread Desiccation Coagulation Devitalization Hyperthermia

Above 60º C Coagulation and moderate desiccation Can cause moderate contraction of collagen Can be used for hemostasis of small vessels Can also form derivates of glucose, which become adhesive after desiccation Above 41.5º C Devitalization Can be used for tumor destruction (but also causes unintended tissue destruction)

Low-temperature effects

Figure 26.2 Thermal effects in biological tissue resulting from application of high or low (peak) voltage.

Monopolar active electrode Polypectomy snare etc.

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devitalization zone depends on many different parameters, and it should be assumed for the sake of safety that it occurs in direct proportion to the visible coagulation effect, as described in more detail below.

Thermal coagulation Thermal coagulation is defined as conversion of colloidal systems from sol to gel state (e.g., boiling an egg). Biological tissue becomes coagulated thermally if its temperature increases to approximately 60°C. When this temperature is exceeded, the structure of the cell changes, causing the following effects: • change in color of the tissue; • formation of derivatives of collagen; • contraction of collagen-containing tissue. The change in color of the tissue can be used for visual control of intended and unintended coagulation. Unfortunately, color changes can be seen only on the surface of but not within the tissue. Because thermal devitalization of biological tissue cannot become controlled visually, the change in color caused by the coagulation effect can be used as an indicator of controlled devitalization. It should be noted that an invisible thermal devitalization zone of variable depth is unavoidable outside the border of the coagulation zone. The formation of derivatives of collagen can result in a glue effect, sealing tissue to each other and to accessory instruments. The contraction of collagen can result in some narrowing of the lumen of blood vessels and hence result in hemostasis. Although the term “coagulation” is used as a synonym for thermal hemostasis, thermal coagulation alone is efficient for hemostasis only of very small vessels. Larger vessels (> 0.5 mm) can become closed thermally by desiccation of the vessel and/or adjacent tissue, as described in more detail below. Big vessels must be compressed mechanically during thermal coagulation or desiccation to achieve hemostasis.

Thermal desiccation Thermal desiccation is defined as heat-induced dehydration of tissue. If the temperature of tissue is equal to the boiling temperature of intra- or extracellular water (about 100°C), the desiccation effect can quickly dehydrate the tissue. Thermal desiccation can cause: • (contraction and) shrinkage of tissue, by dehydration; • an adhesive effect; • a dry layer that acts to insulate tissue electrically. Thermal desiccation causes significant shrinkage by drying and contraction of vessels and/or adjacent tissue, resulting in hemostasis of small vessels. Larger vessels must be mechanically compressed during thermal coagulation or desiccation to achieve hemostasis. Desiccation of derivates of collagen results in a glue effect, which in turn causes sticking of desiccated tissue to (coagula-

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tion) high-frequency surgery electrodes, heater probes, the distal end of laser fibers, and also to polypectomy snares as well as papillotomes, sphincterotomes, etc. Desiccated tissue has a relatively high specific electric resistance. A layer of desiccated tissue functions like an electric isolating layer. This can cause a problem during polypectomy, papillotomy, sphincterotomy, etc. if the adjacent tissue becomes desiccated. When this occurs, there is no cutting effect and the snare or cutting electrode can get stuck within the desiccated tissue of the polyp and cannot be moved forward or backward. During use of the argon plasma coagulator, the desiccated and hence electrically isolating layer automatically limits the (maximum) penetration depth of the thermal effects, described in more detail below.

Thermal carbonization Thermal carbonization is defined as partial oxidation of tissue hydrocarbon compounds if the temperature exceeds 200°C and the tissue is within an oxygen-containing atmosphere. Because the temperature of tissue, which contains water, does not exceed approximately 100°C, only desiccated tissue can become heated above 100°C and carbonized. Dry tissue will achieve temperatures above 100°C only by the application of sparking (electric arcs), or laser. If the temperature of desiccated tissue increases above 200°C in the presence of oxygen or oxygen containing gas (e.g., room air), it becomes carbonized after desiccation. However, if the target tissue is bathed in a noble gas such as argon, the tissue does not become carbonized. Although carbonization of tissue is not a goal in therapeutic colonoscopy, it is relevant during tissue vaporization by laser, because the absorption of light increases when the tissue becomes carbonized and black. Carbonization of tissue can cause smoke which can interfere with visibility during colonoscopy. Smoke can contain inflammable gases like carbon monoxide, which can cause fire or explosion when it is mixed with oxygen and becomes ignited by electric sparks or laser.

Thermal vaporization Thermal vaporization is defined as the combustion of desiccated and/or carbonized tissue. Tissue becomes vaporized during or after desiccation and carbonization when the temperature increases to approximately 500°C and it is within gas containing oxygen (e.g., air). If the target tissue is within inert gas (e.g., CO2) or noble gas (e.g., argon), the tissue does not become vaporized (see Argon plasma coagulation). Thermal vaporization can be used directly for the ablation of pathologic tissues as well as indirectly for tissue cutting. In colonoscopy only the laser, especially Nd:YAG laser, is used for tissue ablation by vaporization, and only high-frequency surgery is used for thermal cutting of tissue.

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Exogenous heat source Heater probe

Endogenous heat source Electro surgery

IHF

IHF

(a)

h h h

h h h

h h h (b)

Exogenous heat source Laser surgery

Exogenous heat sink

HS

Laser Flow in vessel h

h h h

h h

(c)

(a)

(b)

(d)

Figure 26.3 Modalities of heat surgery. (a) Heat (h) from a heat source flows into the tissue. (b) Electric current IHF becomes converted to heat (h) within the tissue. (c) Heat (h) from the tissue flows into a heat sink (HS) such as a blood vessel. (d) Laser becomes converted to heat (h) within the tissue.

Generation of high temperature in thermal tissue (c)

Various energy forms, and their sources, applicators, and application techniques are available for thermal intervention in the colon (Figure 26.3). A description of these possibilities and their relevance for endoscopic applications in the colon follows. The temperature of tissue can be increased either exogenously (e.g., by means of a heater probe) or endogenously (e.g., by means of electric current or laser); it can also be increased by a combination of both, as in high-frequency surgical cutting, when endogenous heat is caused by electric current and exogenous heat is caused by electric arcs between the active electrode and tissue. A combination of these two types contributes to the increase in temperature when using argon plasma coagulation (APC). For thermal interventions in the colon it is important that the temperature required for an intended thermal effect is delivered only into the target tissue. Unintentional thermal damage to adjacent tissues must be avoided. This stipulation is difficult to achieve since it is not possible to heat part of a tissue to a desired temperature without at the same time heating adjacent tissue. Although it is not possible to avoid heat transfer, it may be possible to keep thermal damage of adjacent tissues to a minimum. Where feasible, the distance between the target and deeper surrounding tissue can be increased for the purpose of limiting thermal damage by submucosal injection with physiological saline or other solutions (Figure 26.4).

Figure 26.4 (a–c) Injection of fluid into the submucosa will increase the distance between a target tissue which is to be heated and adjacent tissue which should not be heated.

Some coagulation and/or desiccation effect to adjacent tissue may be desired in some cases, especially during cutting of vascularized biological tissue, such as during polypectomy or mucosectomy. During cutting, the tissue becomes vaporized in front of a cutting electrode and heat spreads to the adjacent tissue, the cut edges. However, thermal devitalization outside the cut edges should or must be avoided. These aspects should be taken into account when choosing the primary energy form, its source, applicators, and application techniques for thermal intervention in the gastrointestinal tract, particularly in the colon. As mentioned previously, in the wall of the colon the distance is very small between the mucosa which is the target for thermal interventions and the muscularis propria where thermal damage must be avoided. As a consequence, the diffusion of heat within the (surrounding) collateral tissue has to be taken into account. Heat flows from tissues with a higher temperature into tissues with a lower temperature (Figure 26.5). (This diffusion effect is not used for therapeutic purposes in colonoscopy, and can be limited by heating the target tissue for the shortest amount of time necessary for the intended purpose.)

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Active electrode

IHF

UHF

h h h h

h (a) i

Neutral electrode

Figure 26.5 Heat flow (h) within the tissue must be taken into account during use of electrosurgery. IHF, high-frequency current; UHF, highfrequency voltage.

In order to avoid unintentional damage to the tissue adjacent to the target tissue, it is necessary to know the maximum depth of the tissue injury and how to control the effect produced by the various thermal techniques.

Heater probe Heater probes belong to the family of cautery instruments, which have a very long history. In principle, cautery instruments consist of a handle with a distal tip, which can be heated to a temperature that is able to cause one of the specific thermal effects found in biological tissue. The heater probe consists of a catheter with a special heat-generating device built into the tip, which converts electric energy to heat energy [1]. The heat generated outside the tissue (exogenously) can be applied to a target tissue by touching it with the hot tip. The temperature of modern heater probes for flexible endoscopy is adjustable and automatically controlled. Modern heater probes are provided with irrigation from a nozzle on the tip, which can be used to clear blood from the site to facilitate a clear view and accurate positioning. A special coating on the tip prevents it from sticking to desiccated tissue. Because heater probes can be pressed against the target tissue during heat application, even bleeding from mediumsized vessels can be treated by simultaneously compressing and coagulating the vessel (Figure 26.6a). However, this should be done very carefully to avoid thermal damage to the muscularis propria (Figure 26.6b).

High-frequency surgery General principles of high-frequency electrical devices High frequency is a thermal technique in which the required temperature in the target tissue is reached by the conversion

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h (b)

Figure 26.6 (a) Heater probe can be used to compress and coagulate medium-sized vessels. (b) Thermal damage to the muscularis propria may result from several factors such as temperature, pressure, and duration. h, heat flow.

of electric energy into heat energy within the target tissue (i.e., endogenously) or within electric arcs between an active electrode and target tissue (i.e., exogenously). High-frequency alternating current with frequencies greater than 300 kHz (ICE 6001-2-2) is well suited for the heating of vital biological tissues because it does not stimulate either nerves or muscles. The electric energy (E) in tissue caused by the high-frequency current becomes converted (→) endogenously into heat energy (Q). The amount of heat energy (Q), measured in watt-seconds (W s), which is produced in the tissue is a function ( f ) of the electric resistance (R) and the square of the averaged value (I 2av) and the effective duration (Δt) of the high-frequency current (Iav). E → Q = f(R, I 2av, Δt)(W s) If electric arcs exist between the active electrode and target tissue, which is the case during cutting (this is the function of the cutting effect), the electric energy becomes converted into thermal energy partially within the electric arcs and partially within the target tissue; hence the target tissue becomes heated exogenously as well as endogenously (see Principles of high-frequency surgical cutting).

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The temperature of a biological tissue increases in proportion to the amount of heat and in inverse proportion to the specific heat capacity of the tissue in question. As mentioned above, a requisite for the application of thermal techniques in the gastrointestinal tract, especially in the colon, is that the temperature required for an intentioned purpose is reached and becomes effective only at the target tissue, and unintentional thermal damage to adjacent or collateral tissues must be avoided. In high-frequency surgery, this objective is achieved via the current density ( j) and the current flow duration (Δt) in the target tissue. The current density ( j) is a function ( f ) of the amount of current (i), measured in amperes (A), that flows through a defined area (A) measured in square centimeters (cm2) at a certain point in time (t) or averaged over a defined time interval (Δt). j = f(i/A)(A/cm2) The partial amount of heat (q) generated endogenously through electric current either partially or at an arbitrary point within the tissue is proportional to the specific electrical resistance ( ρ), the square of the current density ( j2), and the effective current flow duration (Δt) at that point of the tissue. q = f(ρ, j2, Δt)(W s) Conduction of an electric current through a target tissue requires that both poles of the electric current source be con-

nected to the target tissue in an electrically conductive manner. Each of the two poles must directly or indirectly touch the target tissue. The electrodes at the target tissue are called active electrodes. The electrode through which the electric current is conducted away from the tissue back to the source of electric current, without any thermal damage to the tissue at this electrode, is called the neutral electrode. Applications which use an active and a distant neutral electrode are called monopolar applications, and the instruments used for these applications are called monopolar instruments (Figure 26.7a). Applications which use both electrodes closely spaced are called bipolar applications, and the instruments used for these applications are called bipolar instruments. As a rule, both active and neutral electrodes of bipolar instruments are located close by on the same instrument (Figure 26.7b). The density of current within the target tissue varies in proportion to the size and shape of the contact surfaces of the active electrodes of high-frequency surgical instruments. Most active electrodes used in flexible endoscopy are in the shape of a needle, loop, or ball electrode (Figure 26.7c). Apart from the shape, the size of the contact surface plays an important role as regards the current density and its distribution both in the target tissue and in adjacent tissue. A smaller contact surface results in a steep reduction in the current density and the temperature profiles in the tissue, independent of the distance from the contact surface (Figure 26.8). High-frequency current can flow through biological tissue only when the tissue contains water and electrolytes. As a IHF

IHF IHF

Figure 26.7 Application techniques of electrosurgery: (a) monopolar; (b) bipolar; and (c) quasi-bipolar. IHF, high-frequency current.

(a)

(b)

IHF

IHF

IHF

IHF

(c)

IHF

h

Figure 26.8 Current density and the resulting penetration depth of thermal effect in the tissue is dependent on the size of the contact surface. IHF, high-frequency current.

Small electrode

Large electrode

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consequence, the temperature of tissue containing water cannot rise above the boiling point of water (c. 100°C). Tissues that contain less water and/or electrolytes (are drier) have a lower electric conductivity and less high-frequency current can flow through them if the voltage does not increase simultaneously. Completely dry biological tissue is an electric insulator; hence no electric current can flow through it and the temperature cannot rise (see Figure 26.2a). This fact is of importance during the use of APC.

Electric arcs Electric arcs are ignited between an active electrode and tissues when the peak value of the high-frequency voltage is equal to or greater than 200 V, which is typical if the active electrode consists of metal and the tissue contains water (see Figure 26.2b). Since these electric arcs reach temperatures far above 300°C, they generate exogenous heat, which raises the temperature of desiccated, and hence dry, tissue above 100°C, thus causing carbonization and vaporization of dry tissue as described above. In colonoscopy, carbonization and vaporization of tissue caused by electric arcs is not only unnecessary but also annoying, as it generates smoke, which impedes vision. Because the depth of heat penetration cannot be controlled during electric arcing, it is not used as a therapeutic tool in endoscopy. Even if the vaporization effect caused by electric arcs is not used directly in colonoscopy, it is useful indirectly for cutting tissue (see Principles of high-frequency surgical cutting).

Principles of high-frequency surgical coagulation In general, as mentioned above, the term “coagulation” is used as a synonym for thermal hemostasis including the effects of devitalization, coagulation, and desiccation. In colonoscopy, high-frequency surgical coagulation can be used for thermal devitalization of pathologic tissue and for hemostasis. Thermal devitalization of pathologic tissue is performed by APC or laser and is described in more detail below. Thermal hemostasis can be used to stop spontaneous bleeding as well as to prevent iatrogenic bleeding, for example, during resection of pathologic mucosae such as polyps. The spectrum of indications for thermal hemostasis is very wide. Equally wide is the spectrum of the techniques and instruments available for thermal hemostasis, some of which have been developed or designed especially for application in flexible endoscopy. Because the wall of the gastrointestinal tract, in particular the colon, is relatively thin, thermal hemostasis applied directly on the colon wall is a compromise between efficiency and thermal wall damage. The method and instrument of thermal hemostasis is dependent on the size of the vessels causing bleeding. In small vessels, hemostasis can be achieved by thermal coagulation

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or desiccation alone. Control of bleeding from larger vessels requires mechanical compression during heat application. This principle is also applicable for hemostasis during polypectomy.

Monopolar coagulation instruments In their simplest form, monopolar coagulation instruments for flexible endoscopy consist of a catheter at the distal end of which is an electrode, often ball shaped. Because this electrode can be pushed against the target tissue, this instrument is useful for hemostasis not only of small but also of larger vessels. Especially in the colon, the risk of deep thermal wall damage has to be taken into consideration. During hemostasis, coagulated or desiccated tissue can stick to the electrode, so that the source of bleeding can be reopened when the electrode is pulled off the site. This problem was addressed by the development of the electro-hydro-thermo probe and the addition of an antistick coating.

Electro-hydro-thermo probes Electro-hydro-thermo probes for flexible endoscopy (Figure 26.9) consist of a catheter with an electrode at the distal end (usually ball shaped). On this electrode is a hole through which water or physiological sodium chloride solution can be instilled between the electrode and target tissue. When the electric current is applied, the contact surface between electrode and tissue does not become dry and the electrode does not stick to the coagulated tissue. The instillation of fluid can also be applied for the irrigation of bleeding sources. When applying electro-hydro-thermo probes, the depth of the thermal effect cannot be well controlled. This problem has been addressed with the development of bipolar coagulation probes for flexible endoscopy.

IHF

H2O

Coagulation

H2O

i

i i

i i

Figure 26.9 Schematic of electro-hydro-thermo probes. H2O, water; i, current; IHF, high-frequency current.

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Figure 26.10 Schematic depiction of the current flow of bipolar coagulation probes.

Bipolar coagulation instruments In their simplest form, bipolar coagulation instruments for flexible endoscopy consist of a catheter, at the distal end of which are at least two closely placed electrodes (Figure 26.10). The high-frequency current flows through the tissue only between these two electrodes. They can be applied either axially or laterally. The depth of the thermal effects which can be reached is relatively small, decreasing the risk of penetration; however, the efficacy is also limited (i.e., the instruments are useful only for small or very small lesions). Bipolar instruments often have irrigation capacity and some have integrated injection needles.

Principles of high-frequency surgical cutting Biological tissue can be incised electrosurgically when the high-frequency voltage between an electrode and tissue is sufficiently high to produce tiny electric arcs between the

cutting electrode and the tissue; this concentrates the highfrequency current at specific points of the tissue (Figure 26.11a). The temperature produced at the interface where the electric arcs contact the tissue (like microscopic flashes of lightning) is so high that the tissue is immediately evaporated or burned away. As the active cutting electrode passes through the tissue, electric arcs are produced wherever the distance between the cutting electrode and the tissue is sufficiently small, producing electric arcs and hence the cut (Figure 26.11b). As mentioned previously, a minimum peak voltage (Up) of 200 V is required in order to produce electric arcs between a metal electrode and biological tissue containing water. The intensity of the electric arcs increases in proportion to the peak voltage. Experience has shown that the depth of thermal coagulation along the cut edges increases with increasing peak voltage (Figure 26.12). In the system of high-frequency surgical cutting, an increase of the voltage increases the electric power (P) by the square of the voltage [P = f(U2)], so it is necessary to modulate the amplitude of the voltage (turn it down) to compensate for the strong influence provided by the mathematical power of the square multiplier. The higher the peak voltage (Up) and the degree of amplitude modulation, the deeper the thermal coagulation of the cut edges. If the voltage is not modulated and its peak value is low, the coagulation depth at the cut edges is minor or nil, it is called “cut mode,” and the high-frequency current caused by this voltage is called “cutting current.” If the voltage is strongly modulated and its peak value is high, resulting in deep coagulation of the cut edges, it is called “coagulation mode,” and the high-frequency current caused by this voltage is called “coagulation current.” One reason for this confusing terminology is the fact that conventional high-frequency

IHF

IHF

UHF Active electrode

Spark

Figure 26.11 Schematic of the electrosurgical cut effect. (a) Electric sparks ignite between an electrode and tissue if the high-frequency voltage (UHF) is sufficiently high. i, current; IHF, high-frequency current. (b) The high temperature of the electric sparks evaporates the tissue adjacent to the electrode which will cause a cut if moved through tissue.

i

i i

i i

(a)

i

i

(b)

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F

UHF 100 200 300 400

Vp

600 700 800 900 500

1000

k

k = f(Up)

(a)

considered, in particular in colonoscopy. It can be dangerous if the coagulation and/or devitalization occur outside the desired zone of thermal devitalization. If deep thermal damage occurs, tissue histology may be interfered with. A useful aspect is that coagulation of the cut edge of the colon wall can cause hemostasis, which can be used advantageously. Hence, in colonoscopy, coagulation of the cut edges is always a compromise between these three aspects. Another problem with regard to the adjustability, reproducibility, and constancy of the depth of coagulation common to all conventional high-frequency surgical generators is the internal generator impedance Ri, making the high-frequency output voltage U0 dependent on the high-frequency output current I0. The greater the generator impedance Ri, the more the high-frequency output voltage U0 depends on the highfrequency output current I0. Conventional high-frequency surgical generators have a generator impedance of between 200 and 1000 ohms. Ua = U0 − (Ri × I0)

(b) Figure 26.12 Electrosurgical effects on tissue. The cut edges become devitalized, coagulated (k), and carbonized in proportion to the peak voltage (UHF) and the intensity of the electric sparks (F). (a) Graphic depiction. (b) Photograph of the effect on tissue with low and high voltage.

surgical generators do not have the capacity for setting the output voltage, only the output power. Setting of the output power of high-frequency generators is not a good option for polypectomy, mucosectomy, etc., but it is still standard in some high-frequency generators. The depth of thermal coagulation and also the possibility of thermal devitalization outside the coagulation zone must be

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The output voltage U0, and hence also the intensity of the electric arcs and ultimately the depth of coagulation, vary considerably, since the load resistance R0 and current I0 vary from one cut to the next and also during each cutting process. During polypectomy, for example, the load resistance R0, which is the electric resistance between a polypectomy snare and a polyp, depends on the size of the polyp and increases during closing of the snare because the contact between the snare and tissue becomes smaller and smaller. Another special problem of high-frequency surgical resection of polyps is that high-frequency surgical cutting can be carried out with minor mechanical force, as long as the highfrequency voltage between the polypectomy snare and the tissue to be cut is above 200 V. Because the speed of the snare while cutting through the polyp has a major influence on the degree of hemostasis of the cut edges, the speed should be appropriate to the size of the polyp’s attachment as well as be controlled. Control of closure speed can be very difficult or impossible if there is mechanical friction between the polypectomy snare and catheter or between the slider and the slider bar of the handle of the instrument (Figure 26.13). Mechanical friction can cause uncontrolled speed of the snare and hence uncontrolled or insufficient hemostasis, especially if the snare zips through the polyp. Most of the mechanical force on the polypectomy snare is caused by friction during closing the snare.

Technical aspects of polypectomy Polypectomy is one of the most important applications of high-frequency surgery in the colon, and hemostasis is one of the main therapeutic goals in polyp resection. If the problem

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Force F2

Friction

Force F1

Friction

Friction

Figure 26.13 Depiction of mechanical friction at different parts of the polypectomy snare.

of bleeding caused by resection did not exist, it would be possible to resect polyps or adenomas in a purely mechanical fashion with a thin wire snare in the absence of heat. This would have the advantage that neither the resected specimen (with regard to the histology) nor the wall of the colon (with regard to the risk of perforation) would be thermally damaged. This is possible for tiny polyps, but the endoscopist must find the path between application of sufficient heat for hemostasis and avoidance of deep thermal damage. For safe polypectomy, the endoscopy team should be familiar with the equipment available for polypectomy.

High-frequency generators There are many different conventional as well as highly sophisticated high-frequency generators on the market which can be used for polypectomy. Some high-frequency generators do not provide special capabilities for polypectomy but are very simple to use, while others provide special capabilities for polypectomy but can be difficult or too complex to use. For efficient and safe polypectomy the endoscopy team must be completely familiar with the high-frequency generator in their unit, a position that is valid for all high-frequency generators. Conventional high-frequency generators provide cut modes with minimum penetration depth of coagulation (pure cut) or with more penetration depth of coagulation (blend or pure coagulation) for thermal hemostasis during activation. Some generators offer different coagulation modes, such as “soft” and “forced” coagulation, mainly for thermal hemostasis before or after transection of blood vessels. The selection of a cut or coagulation mode depends mainly on the personal experience and resection strategy of the endoscopist, but also on the size, shape, location, etc. of the polyp. Some endoscopists prefer using a coagulation current for cutting, some use only pure cut, some use a combined mode (blend) or use both alternatively (e.g., in form of short intervals by intermittently pressing the coagulation or cut footswitch), and many may not know what they should select in special cases. Highly sophisticated high-frequency generators provide many different cut and coagulation modes to be used for polypectomy. Additionally, some, such as “EndoCut,” have special cut modes, with many variable parameters and auto-

matically alternating coagulation, cut, and pause intervals for polypectomy. None of these different modes (including “EndoCut”) or different strategies and techniques for polypectomy is standardized nationally or internationally. Therefore, the reproducibility of effects from one generator to another and from one endoscopist to another is low or nonexistent. Each transection of a polyp consists of two phases: the precut phase and the effective cut phase. The precut phase is the time between activation of the high-frequency generator and start of the effective cut, the so-called “cut delay”. During this cut delay (Figure 26.14a–d), the tissue adjacent to the snare becomes heated until the water in this tissue reaches boiling temperature and the steam from this thermal effect insulates the snare from tissue. The heat produced during this cut delay causes thermal damage of the colon (Figure 26.14d) and could result in perforation. Thus, the cut delay must be as short as possible. The higher the amount of high-frequency current per centimeter length of snare wire around the polyp, the shorter the cut delay. High-frequency generators, which generate 200–400 W of maximum output power can deliver 1.5–3 A and, hence, polyps with a diameter of 1–2 cm can be transected in toto with an acceptable short cut delay. In contrast, the effective cut phase (Figure 26.14d) needs only about 0.1–0.2 A per centimeter length of snare wire, but a minimum voltage of 200 V. The higher the voltage, the deeper the thermal coagulation of the cut edgesaan advantage regarding hemostasis but also a disadvantage regarding histopathology. Whereas the cut delay and the proportional risk of perforation are mainly functions of the amount of high-frequency current per centimeter length of the polypectomy snare in contact with the polyp, the depth of coagulation of the cut edges and the proportional hemostasis is a function not only of the amplitude of the high-frequency voltage but also of the modulation of its amplitude and, last but not least, of the cutting speed. Unfortunately, all these important physical parameters are not directly adjustable on any high-frequency generator but are dependent on the brand of the generator model, each of which has specific power settings, blended current settings, effect settings, “EndoCut” parameter settings, etc. As a consequence of this, endoscopists should become familiar

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Adenoma

Adenoma

NaCI injected s.m.

NaCI injected s.m. Snare wire

IHF IHF

IHF

(a)

Snare wire

(b)

Adenoma

CZ NaCI injected s.m. Snare wire

IHF IHF

(c)

IHF

(d)

Figure 26.14 Each transection of a polyp consists of a precut phase (a) and an effective cutting phase (b). If the precut phase (also called the cut delay) is too long, the muscularis as well as the serosa can be devitalized or coagulated as in the diagram (d) where the red line represents the serosa and the red area above it is the muscularis propria. Both may be injured if the actual cutting phase is delayed. (c) Photograph of the depth of coagulation zone (CZ) around a 0.5-mm snare. The devitalization zone is not visible, and is outside the coagulation zone.

with the different settings on their own high-frequency generator by performing “polypectomy” on artificial polyps of different shapes and sizes on preparations of chicken or meat. NB: in vitro testing is the only way for the whole team to achieve safety and knowledge during use of any electrosurgical generator. It is very difficult or impossible to make a recommendation for polypectomy settings that is valid for all of the highfrequency generators, but the following considerations should be taken into account for selection or adjustment of any high-frequency generator:

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• The more tissue within the snare, the closer the distance between the snare to the colon wall, and/or the longer the cut delay, the higher the risk of thermal damage and the possibility for perforation of the colon wall. • The lower the high-frequency voltage and/or the faster the cut speed, the higher the risk of bleeding. • Perforation is mainly due to excessive cut delay and not excessive cut speed. • Bleeding is caused mainly by excessive cut speed and is independent of cut delay.

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Polypectomy snares The ideal polypectomy snares should cut perfectly, and should not coagulate the cut edge of the polyp in order to permit adequate histological examination. In addition, the ideal snare should coagulate the cut edge on the colon wall to guarantee safe hemostasis, should not coagulate through the muscularis propria, and should be applied easily and safely. Unfortunately, this ideal polypectomy snare is not available, as a number of problems must be addressed. For a perfect cut and minor thermal coagulation of the cut edge on the polyp margin, the snare wire should be as thin as possible. For effective coagulation of the cut edge on the wall of the colon, the snare wire should be as thick as possible. For easy and safe application on all different polyps, the snare should be both flexible as well as stiff and should assume the optimal size for small as well as big polyps. In reality, the available polypectomy snares offer only a limited compromise of all of these features. A special problem can be caused by the nose at the distal end of polypectomy snares. If this nose is too long, because it is out of endoscopic view, it can touch the wall behind the polyp without the operator’s knowledge and cause inadvertent damage, even perforation, when electrically activated.

Polypectomy snare handles Polypectomy snare handles should be designed ergonomically for both male and female hands, and should have minor friction between the slider bar and the slider. This is important in providing smooth loop closure, allowing a consistent cut quality and even coagulation. The friction of polypectomy handles can be tested by moving the slider forward and backward on the slider bar.

Polypectomy snare catheters Polypectomy snare catheters should be flexible enough for passing through working channels of twisted and looped endoscopes, and have sufficient stiffness to prevent shortening when removing large polyps. Polypectomy catheters should transmit force to the snare from the handle with minimum friction.

reversion of synchronous to asynchronous pacing or possibly pacemaker inhibition. During polypectomy, the head of a big or stalked polyp should not touch the colon wall in a continuous fashion because high-frequency current can flow through this contact resulting in uncontrolled thermal effects (Figure 26.15a). If an endoloop is used for preventing bleeding and is placed on the stalk of a polyp between the colon wall and the site of the polypectomy snare, the high-frequency current density in the smaller diameter pedicle compressed by the endoloop can be much higher than the high-frequency current density at the polypectomy snare; this will cause the narrowest part to become heated (within the endoloop) instead of the tissue within the polypectomy snare (Figure 26.15b and c). Thus, the cut will be located at the site of the endoloop and not at the site of the snare! If metallic hemoclips are used for hemostasis, the snare must not touch the clips as high-frequency current will be conducted through them and can cause perforation. Caution: high-frequency surgery must not be used within the colon before combustible or explosive gas is eliminated. Electrosurgical devices allow the endoscopist to adjust the setting to provide pure coagulation current, cutting current, or a blend of the two. Coagulation current is usually used at low power settings of 15–20 W. In theory, low-power coagulation current should provide better desiccation and sealing of blood vessels, but has the potential for deeper injury. Cutting current should provide less desiccation and sealing of vessels, but reduce the risk of deep injury. Clinical trials support this, because in nonrandomized trials coagulation current has been associated with more delayed bleeding [2] (presumably related to injury to deeper arteries in the submucosa, which begin bleeding during remodeling of the eschar), while blended and cutting current is associated with more immediate bleeding. A survey of gastroenterologists [3] found that an identical number use pure low-power coagulation current (46%) and blended current (46%) with very few using pure cutting current (3%).

Argon plasma coagulation Safety aspects of high-frequency surgery The principle of argon plasma coagulation High-frequency surgery can cause unintended thermal effects outside the target tissue during monopolar applications. This can happen in tissue directly adjacent to, or remote from, the target tissue when the high-frequency current density is higher outside the target tissue. To prevent thermal damage to the patient’s skin, the neutral electrode must be fixed firmly in contact with the skin, as recommended in the instruction manual of the specific highfrequency surgery generator. High-frequency surgery can cause interference in other electronic devices such as a pacemaker, where it can cause

The principle of APC is relatively simple [4,5]. When an electrode is placed at a distance from the surface of a tissue, and a high-frequency voltage (UHF) is applied between the electrode and the tissue, the gas between the electrode and the tissue becomes ionized and hence electrically conductive when the electric field strength exceeds a critical level. If the gas between the electrode and the tissue is a noble gas (argon, helium, etc.), an electric field strength of only 500 V/mm is needed for ionization. Argon is preferred because of its relatively low cost. The ionized argon forms argon plasma beams between the electrode and the tissue,

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Snare

(a)

HF current

Snare

Argon

Endoloop

(b)

APC probe

Ar

Ar

HF generator

Electrode

UHF

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(c) Figure 26.15 Unintended thermal effects. (a) If part of a polyp touches the colon wall during polypectomy high-frequency current can flow through this contact point into the colon wall. The closer the snare to this point, the higher the flow of high-frequency current through it. (b) If an endoloop is placed around the polyp, the high-frequency current must flow through the strangulated part of the polyp and heat will increase at the point of constriction because of the higher current density. (c) Photographic demonstration of (b) with increased heat damage at the point of narrowing (arrows).

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Shrinkage zone caused by desiccation Desiccation Coagulation Devitalization

IHF IHF

IHF

IHF Neutral electrode

Figure 26.16 The principle of argon plasma coagulation (APC). Ar, argon; HF, high-frequency; IHF, high-frequency current; UHF, high-frequency voltage.

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Pin

Pout

Ar

HF current source

Argon Source

IHF

APC probe

Neutral electrode

Figure 26.17 Equipment for argon plasma coagulation (APC): argon tank, flow valves, probe, and electrosurgical generator. Ar, argon; IHF, high-frequency current; P, pressure.

tissue becomes desiccated and hence loses its electric conductivity, the beams automatically move from desiccated to nondesiccated tissue until a large area of the target tissue is desiccated. As a result of the loss of electric conductivity at a treated site, the depth of desiccation, coagulation, and devitalization is limited.

Equipment for argon plasma coagulation The argon source is an argon cylinder with a pressure-reducing valve (Figure 26.17). For safety reasons, the argon source must have automatically controlled flow rates and limitation of the pressure. The high-frequency current source must provide both sufficiently high high-frequency voltage for the ionization of argon as well as sufficiently high high-frequency current to generate adequate heat within the target tissue. An APC probe for flexible endoscopy mostly consists of a nonconductive flexible tube (Figure 26.18) through which argon flows. An electrode within the distal end is connected to the high-frequency generator by a wire through the lumen of this tube. For safety reasons, the electrode is recessed from the distal end of the tube so that it cannot come into contact with tissue. As shown in Figure 26.19, the depth of coagulation depends on power setting and application time. In addition, the application technique has a significant influence on the depth. Movement of the activated probe tip will result in a shallower depth of thermal effect than is produced by directing the tip at one point. When the activated probe is held at one site for between about 3 and 10 s, the depth of thermal coagulation is up to about 2 mm. Above 10 s the depth increases slowly to its maximum of about 3– 4 mm.

Figure 26.18 An argon plasma coagulation probe and its distal end.

Touching the foot pedal activates the flow of argon gas and simultaneously starts the flow of electric current. The time that the foot pedal is depressed may not be the same as the activation time, which refers to the interval when the argon plasma sparks actually touch the target tissue. Ignition or the production of intermittent sparks may not occur if the distance between the probe and the tissue is too great. Figure 26.20 shows that the shape of an argon gas beam consists of a zone of laminar argon flow, a zone of divergent argon flow, and a zone where the flow becomes turbulent. Argon plasma beams can reach the target tissue only when there is argon gas between the distal end of the APC probe and the target tissue. This is the case when the argon gas beam is directed to the target tissue, as shown in Figure 26.21a (axial

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intensity and can cause carbonization as well as vaporization of tissue, hence causing deep damage and perforation of organs. Endoscopists typically use air plasma beams when using the tip of the snare wire to “spark” a polypectomy site to stop bleeding or destroy residual polyp fragments. As air plasma beams, consisting of ionized air, only travel over short distances and are completely uncontrollable, their application should be avoided.

Safety aspects of argon plasma coagulation

Ar

Ar Zone of divergent argon flow

Figure 26.19 The depth of argon plasma coagulation depends on the application time and power setting. HF, high-frequency.

Zone of laminar argon flow

Air

Figure 26.20 The profile of argon gas flow from an argon plasma coagulation probe. Ar, argon.

As in any monopolar electrosurgical procedure, the neutral electrode must be applied to the skin surface. Because argon gas is insufflated into the colon during APC, extensive distension of the colon can occur. The distal end of the APC probe must never be pressed against the mucosa or perforation can occur. If the superficial mucosal layer is destroyed by the activated argon beam as the probe tip touches the colon wall, the flow of argon gas will create instantaneous submucosal emphysema. Caution: APC must not be used within the colon before combustible and potentially explosive gas is eliminated.

Laser APC probe) and Figure 26.21b (lateral APC probe). APC probes can be used laterally as well, but the lumen must be filled with argon. The ignited spark will direct itself to the nearest tissue (Figure 26.21c and d). If the target tissue is not within the argon gas beam or within an argon-filled lumen the argon plasma beams will not ignite, or plasma beams of air will ignite instead. Air plasma beams do not look very different from argon plasma beams; however, unlike argon plasma beams, air plasma beams are of uncontrolled depth and

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Principle of Nd:YAG laser Light amplification by stimulated emission of radiation (laser), first described theoretically by Einstein in 1917, and put into practice by Maiman 5 years after Einstein’s death, made possible the generation of electromagnetic radiation in the range of optical wavelengths (light) with an extremely high power density. For about 50 years, the high energy of the laser has been used in medicine. The endoscopic application

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Specific characteristics of Nd:YAG lasers in flexible endoscopy

Ar Air Argon gas flow

Ar

i i i

Ar Argon plasma beam Air Ar

Air

Argon plasma beam

Argon gas flow

Ar

Ar

i

i

i

Air Argon gas flow Ar

Air plasma beam Carbonized tissue

Air

i

i

i i

i

i

Figure 26.21 The effects of forward- and side-firing argon plasma coagulation probe application. Ar, argon; i, current.

of laser began in 1975 [6], following the successful development of a flexible light conductor. Of all the different laser sources, only the argon laser (wavelength λ = 488/515 nm, Pmax = 20 W) and the Nd:YAG (neodymium-doped yttrium– aluminum–garnet) laser (wavelength λ = 1064 nm, Pmax = 100 W) can be used endoscopically, because their wavelengths

With an adjustable power of up to approximately 100 W, Nd:YAG laser sources are able to generate light with a wavelength of 1064 nm, which is located in the infrared range and is thus invisible to the human eye. With a flexible bundle of 0.6 mm in diameter, this probe can be introduced through the instrumentation channel of a flexible endoscope. The laser light emanates from the light guide in an axial direction with a divergence of approximately 10°. The invisible Nd:YAG laser is combined with a “pilot light” in the visible range in order to see where the beam is directed. The thermal effects within the tissue are primarily dependent on the density of light (W/mm2), absorption of light within the tissue (W/mm3), and the duration of application (Δt). The absorption is dependent on several variables: the distance (x) of the distal end of the light guide from tissue (Figure 26.22), the angle with which the light radiates onto the surface, and the absorption and reflection characteristics of the tissue. The parameters may change rapidly due to coagulation, desiccation, or even carbonization. The last can cause a dramatic increase in absorption or a decrease in reflection, leading to intentional or unintentional vaporization of tissue or even a perforation of the colon. For intentional vaporization of larger tumor masses, the distal end of the light guide has to be placed close to the target tissue and the power of the laser has to be set sufficiently high. When using lasers for thermal hemostasis, the experience of the operator is most important; if the light guide is too far away, the density of power could be too low for hemostasis, and if too close, the source of bleeding could be enhanced by vaporization rather than stopped by coagulation (Figure 26.23). The introduction of APC into flexible endoscopy has almost eliminated the need for lasers in endoscopy.

Safety aspects of Nd:YAG lasers in flexible endoscopy During applications the laser can cause unintended thermal effects outside the target tissue. During Nd:YAG laser applications all persons, including the patient, must protect their eyes, even when the distal end of the laser fiber is within the colon, because the light guide can break outside the endoscope. As the Nd:YAG laser is invisible, a break of the laser fiber can damage the retina of unprotected eyes. A number of additional safety precautions also have to be in place.

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P2

P1

Nd: YAG

P1

1 2 3 4 5 6

Devitalization Coagulation Desiccation Shrinkage Carbonization Vaporization

ø=10º x

x y = 1/2 x

1 2 3

ø=10º

Figure 26.22 The influence of power as well as the distance between the distal end of the laser fiber and tissue, where P2 > P1 or x > y.

5 6

Figure 26.23 Tissue effect is related to the distance between the distal end of the laser fiber and the tissue [superficial coagulation (a) versus deep hole (b,c)]. (a)

(b)

(c)

Summary

Table 26.1 Optimum treatment required by indication. Treatment required

All the different thermal modalities described in this chapter have their special advantages and disadvantages. None of the methods or equipment can yet be regarded as ideal for all cases. A modern endoscopy facility should have adequate equipment to provide optimum treatment for each case as listed in Table 26.1. But endoscopists should not only have the equipment available, they should also be familiar with the physical background as well as with the advantages and disadvantages of all modalities which are available in the endoscopy suite. This, combined with practical skill and experience, and competent assistance, is the prerequisite for obtaining successful results.

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Thermal ablation of pathologic tissue by resection by devitalization by vaporization (only in the rectum, not in the colon) Thermal hemostasis by coagulation (desiccation) (applicable for small vessels only) by coagulation and mechanical compression (applicable for bleeding of larger vessels) Polypectomy

Thermal method

HF APC Laser

HF, APC, HP, laser HF, HP, BICAP HF

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The physical background of thermal methods urgently needs to come into the consciousness and minds of endoscopists in order to enhance effectiveness and safety and reduce complications. Knowledge of thermal methods used for treatment in endoscopy must be learned and recalled each time electric energy is used during the course of a colonoscopic examination.

References 1 Protell RL, Rubin CE, Auth DC, et al. The heater probe: a new endoscopic method for stopping massive gastrointestinal bleeding. Gastroenterology 1978; 74: 257– 62.

2 Van Gossum A, Cozzoli A, Adler M, Taton G, Cremer M. Colonoscopic snare polypectomy: analysis of 1485 resections comparing two types of current. Gastrointest Endosc 1992; 38: 472–5. 3 Singh N, Harrison M, Rex DK. A survey of colonoscopic polypectomy practices among clinical gastroenterologists. Gastrointest Endosc 2004; 60: 414–18. 4 Farin G, Grund KE. Technology of argon plasma coagulation with particular regard to endoscopic applications. Endosc Surg Allied Technol 1994; 2: 71–7. 5 Grund KE. Argon plasma coagulation: ballyhoo or breakthrough? Endoscopy 1997; 29: 196–8. 6 Nath G, Gorisch W, Kiefhaber P. First laser endoscopy via a fiberoptic transmission system. Endoscopy 1973; 5: 208.

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Polyp Biology C. Richard Boland & Ajay Goel Baylor University Medical Center, Dallas, TX, USA

Introduction This chapter reviews the genetics, molecular biology, and familial aspects of adenomatous polyp development in the colon. Readers will be directed to other chapters for reviews of the epidemiology, pathology, prevalence and incidence rates, and growth characteristics of colonic polyps. The term “polyp” always refers to the adenoma, as this is clinically the most important lesion in the colon. Non-neoplastic polyps, including juvenile polyps, inflammatory polyps, and hamartomas, do not confer an increased risk for cancer unless adenomatous (neoplastic) tissue evolves within these lesions. Moreover, many of the paradigms developed for tumor development in general have been understood in the context of colorectal neoplasia, making this a cornerstone for understanding tumor biology.

[1–3]. However, most of these mutations are not necessary for tumor development but rather reflect the hypermutability underlying the tumor [4]. One estimate of the number of mutations present in a tumor based upon direct sequencing of the DNA indicates that there is about one point mutation for every million nucleotides (megabase, Mb) within coding sequences, which would predict a total of about 3000 mutations in the tumor [5]. However, only about 80 of these mutations lead to an altered amino acid in a typical colon cancer, and even fewer would be likely to have a significant impact on cellular behavior [6,7]. Recent data suggest that most of these 80 mutations in an individual tumor are harmless, and the number of mutations that are essential for the development of most sporadic tumors may be relatively smaller, perhaps fewer than 15. Only three genes are found to be mutated commonly (i.e., > 50%) in colorectal cancers: APC, K-ras, and p53 [7].

Clonality

Tumor genetics Neoplasia is altered growth mediated by mutated genes. Nearly all the mutations that mediate tumor development are acquired somatic mutations. Somatic mutations are found within the tumor but are not present in the underlying mucosa from which the neoplasm has arisen. Germline mutations are present in every cell of an organism, and can be involved in conferring an increased risk for cancer. Germline mutations have been important in understanding carcinogenesis but are not commonly present in the general population of patients who develop colorectal neoplasms.

How many mutations are involved? The number of mutations in a tumor is highly variable. Because of “genomic instability,” some tumors may have several thousand, and perhaps tens of thousands of, unique mutations

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Neoplasia is best understood in the context of clonality. Colonic epithelial cells have the same genes found in every other cell of the body. However, only a portion of these are expressed in colonic cells, giving rise to the differentiated phenotype of the epithelium. In fact, it is nearly impossible to grow normal colonic epithelial cells in culture because of the expression of genes that inhibit cell growth after terminal differentiation. A neoplasm begins rather inconspicuously when a genetic alteration occurs that permits a single cell to ignore the constraints on growth and to continue to replicate after it has migrated into the differentiated zone of colonic epithelium, in the upper portion of the crypt. Once cells develop selective growth advantages, they can overgrow neighboring cells and undergo clonal expansion. Unless additional genetic alterations occur, clonal expansion might be of no clinical importance to the host. However, if additional mutations occur that permit behaviors such as invasion or the complex features involved in tumor metastasis, the tumor can spread and kill the host.

Genes involved in carcinogenesis Genes are encoded in less than 2% of the entire human genome, and most cells express only a proportion of the

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20 000–25 000 genes [8,9]. A minority of expressed genes are involved in regulating cell growth. Alterations in most genes will be of no benefit to the growth of a cell. Mutated genes that are critical for tumor development can be placed into two broad conceptual classes: oncogenes and tumorsuppressor genes (TSGs). Oncogenes are altered versions of normal genes (protooncogenes) that encode proteins that participate in the regulation of cell growth. Specific mutations in protooncogenes typically lead to the overexpression, or excessive enzymatic activity, of the protein, which accelerates cell growth. The best example of an oncogene in the context of colorectal neoplasia is the K-ras protooncogene. This gene ordinarily serves in a signal transduction pathway required for ordinary cell proliferation. The ras oncogene family encodes proteins that are homologous to G proteins, which bind guanosine triphosphate (GTP) and catalyze its hydrolysis to guanosine diphosphate (GDP). Ras is active when bound to GTP, and specific mutations in the ras gene alter the ability of the ras protein to hydrolyze the GTP, which results in an unremitting stimulus for proliferation. This alteration leads to a cascade of events that accelerates cell growth and proliferation. Mutations in K-ras can be found in approximately half of all colorectal cancers; they are rarely found in tiny adenomatous polyps but mutations are detectable in proportion to the size of the adenoma [10,11]. Other oncogenes may be mutated in colorectal polyps, but none has been studied as extensively as ras. A more important set of genes regulating cellular growth are the TSGs, whose expression leads to the restraint of cell proliferation. These genes are typically silent in stem cell populations and are expressed during terminal differentiation. The best example of a TSG in the context of the colorectal adenoma is the adenomatous polyposis coli (APC) gene, which is not expressed in the proliferative zone of the colonic crypt but is uniformly expressed in the upper portion of the colonic crypt. Mutational inactivation of APC permits colonic epithelial cells to grow and ignore signals to stop growing. Oncogenes are activated typically by point mutations or by other rearrangements that lead to their overexpression. On the other hand, TSGs participate in carcinogenesis by inactivation. Given that we have two copies of every somatic gene, biallelic inactivation of a TSG is required. In fact, inactivation of only one copy of a TSG usually has no effect on cell behavior. Inactivation of a TSG therefore requires “two hits”, and, usually, the mechanisms involved in the inactivation of the two alleles are different. The requirement to inactivate both alleles of a TSG tends to make tumor development a relatively uncommon event during the lifetime of a host.

Causes of mutation A number of different mechanisms can cause mutation; in fact, there is homeostatic balance between mutational damage to DNA and its repair. The balance can be pushed toward a higher number of mutations by either increasing the mutational

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rate or reducing the rate of repair. Examples of both mechanisms can be found in animal models of cancer. For example, by administering overwhelming doses of a chemical carcinogen to a rodent, one can develop a model in which colon cancer develops in nearly every animal. Likewise, by inactivation of certain DNA repair mechanisms, one can achieve a similar outcome. The human disease xeroderma pigmentosum is an example where excessive tumor development occurs in response to a failed repair mechanism. Patients with xeroderma pigmentosum lack nucleotide excision repair activity and cannot repair the damage to DNA caused by sunlight. As a result, after exposure to sunlight, patients with xeroderma pigmentosum develop excessive skin injury and most will have multiple skin cancers by their early teenage years. Xeroderma pigmentosum is a recessive disease caused by homozygous inactivation of one of the nucleotide excision repair genes, so every cell in the body is incapable of repairing specific types of DNA damage. The skin is the target of tumors because of sunlight. Similarly, Lynch syndrome or hereditary nonpolyposis colorectal cancer is an inherited disease in which one allele of a DNA mismatch repair (MMR) gene is inactivated by mutation. However, each cell in the body still has one functioning allele and, therefore, intact DNA MMR activity. A second, somatic mutation to the wild-type (i.e., normal) allele will lead to loss of the DNA MMR activity in a cell and permit a very large number of mutations to occur at specific genetic sequences, with the colon being at very high risk for cancer.

Types of mutation There are several classes of mutations that can be found in tumors. One common variety is point mutation, in which one nucleotide (i.e., T, A, C, or G) is converted to another. This can be caused by several different mechanisms, including ordinary decay of DNA, as well as chemical carcinogenesis caused by some constituents of the diet. The DNA encodes for amino acids based on a triplet code of three consecutive bases. As there are four bases, there are 64 possible triplet combinations. Since only 20 amino acids are encoded by the triplet code, there is redundancy; several different triplets can therefore encode the same amino acids. Thus, not all mutations will necessarily change the amino acid encoded, and there can be silent sequence variations without functional importance. However, many point mutations will alter the coding sequence and encode another amino acid (missense mutation), which may or may not alter the function of the protein, depending on the nature of the coding alteration and its effect on protein folding and the ability of the protein to interact with other constituents in the cell. The most severe type of mutation is one that results in a premature “stop” codon, which terminates protein synthesis from mRNA. Another class of mutations that occurs particularly at repetitive sequences is one involving insertion or deletion. This

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Figure 27.1 The chromosomal instability pathway was initially proposed by Fearon and Vogelstein [12], who concluded that sequential alterations in genes mediated tumor progression in the colon. This pathway identified the APC gene as the “gatekeeper” for adenoma formation and later the p53 gene as the “gatekeeper” for malignant conversion.

5q (APC) alterations*

Ras mutations

Polyp Biology

17p ( p53) alterations* 18q alterations

Normal

Adenoma

Colonic epithelium

Benign

Advanced adenoma

Carcinoma Malignant

* (alterations can include point mutations that alter gene function, LOH events that delete the genes, or promoter methylation, which silences the gene)

results in a frameshift of the triplet reading sequence, which almost always produces a nonsense codon downstream.

Chromosomal instability One of the most common aberrations seen in colorectal cancers is aneuploidy, in which the integrity of chromosomal replication is altered. This can result in duplicated chromosomes, deleted chromosomes, and chromosomal rearrangements. This type of global nuclear aberration is referred to as chromosomal instability (CIN). This pathway is illustrated in Figure 27.1. Chromosomal deletions and rearrangements can lead to loss of TSGs, which is referred to as loss of heterozygosity [13]. The mechanism for this is unknown, although it has been proposed that infection with JC (John Cunningham) virus (a DNA virus that encodes a transforming gene called T antigen) is capable of inducing CIN [14,15]. JC virus DNA sequences can be found in the majority of normal gastrointestinal tissues including the colon [14,16–18], stomach [19,20], and esophagus [21]. However, T-antigen protein expression is never observed in normal epithelial tissues, but is exclusively present in the cancer cells, suggesting the oncogenic role JC virus may play in gastrointestinal tumorigenesis [17–19].

Silencing gene expression by promoter methylation Another mechanism for loss of TSGs is their silencing by promoter methylation. About half of human genes have clusters of cytosine–guanine (CpG) sequences in their promoters. An enzyme called DNA methyltransferase can covalently transfer methyl groups to the cytosine residues. When a critical number of cytosines in the CpG “island” of a promoter are methylated, the gene is permanently silenced. The methylation of cytosines is stably passed on to subsequent generations of that cell. In certain tumors, there is excessive widespread methylation of gene promoters. Such tumors are said to have the CpG island methylator phenotype (CIMP) [22]. The mechanism for this is unknown, although there is some evidence that JC virus may also be involved in aberrant methylation of critical genes in colon cancer [18]. If the small proportion of hereditary colon cancers are excluded (3–5%), it is believed that most sporadic colonic tumors develop through either CIN or CIMP pathways [23]. It is not yet clear what proportion of

tumors develop via the CIMP pathway, but CIMP is considered very common, and as many as half of all colon cancers may demonstrate signatures for this type of epigenetic instability [23,24].

Mutational signatures Colorectal neoplasia is the result of a heterogeneous accumulation of genetic abnormalities that leads to abnormal cell growth. One can characterize neoplasms based upon the predominant form of mutation found in the tumor, the “mutational signature.” Tumors with CIN are typically aneuploid, with a wide variety of chromosomal abnormalities. Some tumors show minimal degrees of CIN but are characterized by either promoter methylation (CIMP) or a large number of point mutations and insertions/deletions at short repetitive sequences called microsatellites [1]. Tumors with the latter form of mutational signature have microsatellite instability (MSI), which is caused by inactivation of the DNA MMR system. It remains to be seen how knowledge of the mutational signatures in a neoplasm can be used to direct treatment strategies in patients with polyps. However, it appears that many patients whose tumors have the CIMP phenotype have suffered inactivation of one of the DNA MMR genes (hMLH1) via promoter methylation, which then leads to MSI [25]. Thus, there can be overlap between the types of genomic instability (Figure 27.2). Although additional evidence is required to confirm this, it appears that neoplasms with MSI develop more rapidly and may convert from tiny adenomas to carcinomas in a time frame of a few months, rather than several years.

Familial colon cancer Although familial colon cancer accounts for less than 5% of all colorectal neoplasms, it plays an important role in identifying elevated risks for cancer, and these diseases have been particularly helpful in gaining an understanding of polyp biology [26].

Familial adenomatous polyposis Familial adenomatous polyposis (FAP), accounting for < 1% of all colorectal cancers, is caused by a germline mutation in

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hMLH1 silenced

Microsatellite mutations MSI TGFβ RII, BAX, IGF2R, MSH3, MSH6, β -catenin etc.

Type C methylation of tumor suppressor genes (CIMP) APC silenced

Rapid tumor progression

Other promoters methylated Adenoma

Carcinoma HIC-1, p16, p14, PTEN, RARβ TIMP-3, MGMT, etc.

Figure 27.2 Genomic instability is a feature common to all colorectal cancers. The current concept is that most colon cancers develop through one of the following three pathways of genomic instability: chromosomal instability (CIN)bin which tumor-suppressor genes are typically lost due to large chromosomal rearrangements or deletions; microsatellite instability (MSI)bin which tumors acquire mutations at repetitive microsatellite sequences; or the cytosine–guanine island methylator phenotype (CIMP)bwhere genes are epigenetically

inactivated through methylation-induced silencing of their promoter regions. Although the majority of tumors evolve predominantly through one of these mechanisms, there is some overlap, in which certain tumors may progress via multiple pathways. For instance, almost all sporadic MSI tumors arise as a consequence of methylation of the MLH1 gene, suggesting a strong overlap between MSI and CIMP mechanisms. Similarly, a weaker overlap exists between a smaller proportion of MSI and CIN neoplasms.

the APC gene, which predisposes the carrier to develop a very large number of adenomas (> 100 in number) at a young age. The APC gene has been termed a “gatekeeper gene” [27]. Inactivation of APC appears to be sufficient to permit the colonic epithelial cell to ignore signals from its environment to stop proliferating, which leads to clonal expansion. Ongoing proliferation of colonic epithelial cells at the top of the colonic crypt is the essence of the adenomatous polyp, as an early adenoma is a collection of colonic epithelial cells that do not properly differentiate and stop growing. If nothing more were to occur in these cells, they might be nothing more than trivial colonic excrescences which would occasionally become so large that they would obstruct the gut. However, because a very large number of adenomatous polyps develop in FAP, and because additional mutations may accrue in this expanding clone, these patients eventually develop cancer. The gatekeeper concept implies that loss of the APC gene opens the gate for ongoing proliferation. Adenomatous polyps occurring in FAP are fundamentally the same as adenomas that develop in the sporadic situation. In both instances, individual genetic lesions occur in both APC alleles, and these occur sequentially in time. Patients with FAP are born with one inactivated APC allele in every colorectal epithelial cell, which increases the likelihood of adenoma developing at an early age. Of interest, spontaneous regression of (small) colorectal adenomas has been observed in FAP, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and celecoxib can induce regression of adenomas in this disease [28]. It is not yet clear how these drugs can be

used in patients with sporadic adenomatous polyps, but there is very strong evidence that the use of aspirin and other NSAIDs can reduce mortality due to colorectal cancer [28,30].

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Attenuated familial adenomatous polyposis Attenuated familial adenomatous polyposis (AFAP) is a variant form of FAP in which the inherited predisposition to colorectal cancer is characterized by fewer than 100 adenomatous polyps in the colon and rectum. It is referred to as “attenuated” because there are fewer polyps than in classic FAP; moreover, the polyps and cancers tend to occur 10–20 years later than in the classic disease. The proximal colon tends to be involved first in AFAP, and rectal involvement is less common. AFAP is transmitted in an autosomal dominant manner. People with AFAP may come from families that also have members with classic FAP. Many patients with AFAP harbor germline mutations in the 5′ (codons 78–167) and 3′ (codons 1581–2843) regions, as well as exon 9 of the APC gene [31,32]. Within AFAP families, polyp numbers may be highly variable, with some mutation carriers developing hundreds of polyps and others having < 10, even with the same germline mutation.

Lynch syndrome Lynch syndrome caused by a germline mutation in one of the DNA MMR genes, usually hMSH2, hMLH1, hMSH6, or hPMS2 [33,34]. The DNA MMR system plays a “caretaker” function [27]. The presence of the one intact (wild-type) MMR allele permits normal MMR activity in the cell [35,36]. Loss of the

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remaining wild-type allele from a colonic epithelial cell in Lynch syndrome causes loss of DNA MMR activity and permits accelerated accumulation of point mutations and insertion/deletion mutations in simple repetitive sequences such as An or (CA)n, which are present > 100 000 times throughout the genome [1]. Therefore, Lynch syndrome is mechanistically different from FAP, since FAP involves germline inactivation of a structural gene that restrains cell proliferation, whereas Lynch syndrome is caused by mutational inactivation of a gene required to maintain genomic integrity, which then permits mutations at “target genes” that actually regulate cell growth [37,38]. The genetic lesions that cause familial colorectal cancer are of clinical importance: loss of the APC gatekeeper in the colon gives rise to a very large number of adenomas in FAP; inactivation of the DNA MMR caretaker in Lynch syndrome permits accelerated progression of the adenoma to carcinoma sequence, and provides an explanation of the necessity for shorter colonoscopic screening intervals in this situation [39].

MYH-associated polyposis MYH-associated polyposis (MAP) is a hereditary colorectal cancer condition which is caused by germline mutations in the base excision repair MYH gene. MAP patients often appear clinically to have mild and late-onset FAP, and this disease is inherited in an autosomal recessive manner. Approximately 1–2% of Caucasians are asymptomatic carriers of MYH mutations. As a result of recessive inheritance, the disease may look like a de novo mutation, since neither parent will have polyposis. Biallelic mutations in MYH were first associated with polyposis by evaluating siblings with multiple adenomatous polyps, but without other parental history suggesting FAP [40,41]. When the polyps were evaluated for genetic abnormalities, each polyp had a different mutation in APC but the mutational pattern suggested a defect in the base excision repair system, of which MYH is a member. Due to the similarity between MAP and AFAP, particularly without a vertical family history of FAP, when an APC mutation is not identified in an individual with FAP (or AFAP), genetic testing of MYH should be performed [32].

Hamartomatous polyposis Germline mutations in the PTEN, SMAD4, and BMPR1 genes can lead to the development of hamartomatous polyps (typically juvenile polyps). Germline mutations in these three genes account for 30–40% of patients with juvenile polyposis syndrome. Recent evidence suggests that, in addition to point mutations, large genomic deletions in SMAD4 and BMPR1 may also occur in ∼ 10–15% of juvenile polyposis syndrome patients [42,43]. The histological features of these polyps suggest that an alteration in the lamina propria or other supportive tissues is the underlying lesion that leads to polyp growth. Thus, one can think of the development of these lesions as a result of a defect in the environment in which the

Polyp Biology

epithelial cells grow, and these genes have been tentatively termed “landscaper genes.”

Multistep carcinogenesis and sporadic polyps Sporadic adenomatous polyps Sporadic adenomatous polyps are not homogeneous lesions. Some are initiated by loss of the APC gene [44], followed by the sequential mutation of oncogenes and inactivating mutations at TSGs. In a classic series of papers, Vogelstein and colleagues [12,45] outlined the sequence of events by which this takes place. They found that allelic losses in the vicinity of the APC gene (on chromosome 5q) in a proportion of adenomatous polyps were present in a similar ratio, regardless of whether polyps were small, large, or malignant. Thus, it was concluded that inactivation of the APC gene was sufficient to permit formation of the adenoma, but APC loss did not directly participate in progression to a more advanced lesion. Mutations in the K-ras oncogene were almost never found in tiny adenomas and were present in half of larger adenomas and in about 90% of very large villous adenomas [10–12]. In this instance, it was concluded that ras mutations mediated accelerated growth of the adenomas but were not sufficient to initiate the adenoma. Thus, K-ras mutations were assigned as a “second” step in the multistep process. It was subsequently found that biallelic inactivation of the p53 gene mediated the adenoma to carcinoma transition [46]. Thus, two genes were given specific temporal locations in the tumor development scheme, in which APC inactivation marked the initiation of the adenoma and p53 inactivation marked the conversion to carcinoma [47].

Alternative pathways for neoplastic evolution Once the APC gene was identified as the gatekeeper for the initiation of the adenoma, detailed studies revealed additional key concepts (Figure 27.3). First, not all polyps have the same mutations. Alternate mutational mechanisms that inactivate APC were found in different adenomas. For example, some polyps have point mutations that create premature stop codons in APC; about half of tumors have loss of heterozygosity events that delete APC; other adenomas have the APC gene silenced by promoter methylation [48]. Varying combinations of these alterations can be found in any polyp, as both APC alleles must be inactivated in the adenoma. It is our opinion that all colorectal neoplasms begin as benign lesions, incapable of invasion or metastasis, and that progressive malignant behavior “evolves” from this by the chance occurrence of additional mutations (abetted by genomic instability). This is followed by “natural selection” of those new clones that have gained additional advantages in growth (e.g., an activating K-ras mutation) or survival (e.g., inactivating mutations in p53 or BAX).

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JC virus or other mechanism

CIN

Lynch syndrome

TSGs lost by LOH: APC, p53, 18q genes

Loss of DNA MMR gene MSI Methylation of hMLH1 Mutations at target genes with microsatellites CIMP

Cancer TSGs lost by methylation: APC, PTEN, HIC-1, p16, MGMT, etc.

A serrated pathway in colorectal cancer In contrast to the original pathway of multistep carcinogenesis for colorectal cancer, an alternative pathway involving serrated polyps as precursors for colorectal cancer has been proposed [49,50]. This pathway is referred to as the “serrated pathway” because of the pathological appearance of the early lesions. This pathway may explain 8–18% of all colon cancers, and it has been suggested that this accounts for the nonfamilial, or acquired, MSI tumors. Serrated lesions include hyperplastictype aberrant crypt foci, hyperplastic polyps, sessile serrated adenomas, admixed polyps, and serrated adenomas [51]. The histopathologic characteristics predicting the severity of cancer risk of these polyps are unknown, but serrated lesions are often associated with an activating mutation in the B-raf protooncogene, excessive CpG island methylation (or CIMP), and perhaps MSI [52]. Unlike classical adenomas, serrated adenomas are also less likely to have allelic imbalances at the APC locus, and rarely harbor K-ras mutations [53].

APC Some adenomatous polyps have one or two wild-type copies of the APC gene. This conundrum was resolved when the function of APC was more fully understood. The APC gene regulates a signal transduction pathway in which the WNT ligand stimulates cell proliferation. WNT signaling leads to the expression of the β-catenin gene, which then activates a cascade of genes involved in cell proliferation; β-catenin also participates in the intercellular adhesion complex. Together, these functions lead to an increased rate of proliferation and an enhanced ability of adenoma cells to adhere to one another, as opposed to being sloughed into the lumen. When signaled to do so, the APC protein is produced in the developing colonic cell, which leads to degradation of β-catenin, which inhibits cell proliferation and allows the cell to die and detach from the crypt [54]. As mentioned, some colorectal adenomas have wild-type copies of APC. These polyps often have mutations in the βcatenin gene that prevent this protein from being degraded upon interaction with the APC protein. Additionally, inactiv-

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Figure 27.3 Integrating all the concepts proposed, tumors can develop via chromosomal instability (CIN), microsatellite instability (MSI), or cytosine–guanine island methylator phenotype (CIMP) pathways. MSI may develop either from Lynch syndrome (the hereditary form) or via the CIMP pathway (a presumably acquired form). Ultimately, all pathways converge pathologically as cancer.

ating mutations have been found (albeit less commonly) in other genes that are downstream in the WNT signaling cascade, such as WISP-3 [55]. Thus, although inactivation of APC is the most common way to initiate the adenoma, it is not the only way this happens. It has also been proposed that other mechanisms not requiring the WNT signaling pathway may lead to tumors [56].

K-ras Similarly, not every adenomatous polyp or colorectal cancer has a mutated copy of the K-ras gene. Some tumors progress through the adenoma stage, develop p53 mutations, and convert to cancers without incurring K-ras mutations. Colorectal neoplasms with K-ras mutations tend to be exophytic or pedunculated, while those without this mutation tend to be the flat adenomas and cancers [53,57,58]. The oncogenic potential of K-ras is manifested through its interaction with several effector proteins, of which the raf kinases are among the best characterized. Raf is a major proliferative and anti-apoptotic effector, and it was recently shown that B-raf, one of the raf kinases, is mutationally activated in ∼ 15% of colorectal cancers [59]. K-ras and B-raf mutations are mutually exclusive in colorectal neoplasia, and activating mutations in either of these genes may have similar consequences in tumorigenesis [60,61]. B-raf mutations are rarely found in adenomatous polyps, but frequently occur in serrated adenomas, and have been shown to be significantly correlated with the recently proposed serrated polyp–MSI pathway [52].

p53 In this context, it is not surprising that the p53 gene can be inactivated by multiple different pathways. The most common form of genetic inactivation of p53 is a point mutation of one allele followed by a loss of heterozygosity event in the other. Interestingly, the point mutations most commonly found in p53 simultaneously inactivate the functional characteristics of the p53 protein and stabilize it. Therefore, immunostaining of the adenoma may reveal excessive expression of p53, although the protein itself is inactive. In certain other experi-

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mental systems, p53 can be inactivated by the overexpression of a normal cellular protein that binds and inactivates it (MDM-2), or by the presence of a viral oncoprotein such as T antigen or other transforming genes from viruses.

Microsatellite instability and CpG island methylator phenotype As discussed earlier, some proportion of colorectal neoplasia develops via the MSI (∼ 12–15%) or the CIMP (∼ 35–50%) pathways, and these pathways overlap, because MSI in sporadic colon cancers occurs as a result of methylation-induced silencing of the MLH1 gene. In many of these tumors, one may not find alterations in the APC, K-ras, or p53 genes. It is not entirely certain how these tumors develop; however, in the presence of MSI, one frequently finds stabilizing mutations in the β-catenin gene that render it resistant to phosphorylation and inactivation in the presence of wild-type APC [54]. Neoplasms in the MSI pathway typically have mutations in microsatellite sequences that occur in a coding region of a critical gene required for cell growth. An example is the transforming growth factor-β receptor II (TGF-βRII) gene, which has an A10 sequence in an expressed exon [62]. The majority of colorectal neoplasms with MSI have a single-basepair deletion mutation in the A10 sequence that inactivates this gene. Tumors with this lesion fail to respond to the growthsuppressing effects of TGF-β. Likewise, the TSG BAX has a G8 sequence that is mutated in a proportion of colorectal neoplasms with MSI [63]. Other genes that participate in regulating cell behavior that have a microsatellite in a coding region include the insulin-like growth factor 2 receptor (IGF2R) gene [64] and, curiously, the minor DNA MMR genes MSH6 and MSH3 [65,66]. The exact order of events by which these sequences are mutated, and their impact on cell growth, is not understood as well as those neoplasms with CIN. However, experimental evidence indicates that the accumulation of mutations in microsatellite sequences may occur very rapidly. CIMP tumors evolve as a result of the inactivation of multiple tumor-suppressor genes through methylation-induced transcriptional silencing of their promoters [67,68]. Some of the genes that are targets of CIMP include MLH1, APC, p16, MGMT, RUNX3, SFRP2, and PTEN. As indicated in this brief panel of CIMP genes, although the majority of these genes are primarily silenced by aberrant methylation of their promoter regions, some of these genes may be inactivated as a result of mutations or deletions. Unfortunately, there is growing evidence that cancers are as highly heterogeneous at the genetic level as they are under the microscope[7]. However, the current concept is that there are multiple different ways to disrupt the normal restraints on cell growth, movement, and invasion. Each cancer does this with a unique combination of mutations, deletions, amplifications, or promoter methylation. We must be prepared to take this into account when we plan treatment strategies for cancer prevention, detection, and treatment.

Polyp Biology

Summary Adenomatous polyps are not homogeneous lesions, and are caused by mutations in genes that regulate cell growth and other behaviors. Colorectal neoplasia begins with the adenoma, which is usually caused by a genetic alteration that abrogates the growth-restraining function of the WNT signaling pathway. This usually, but not always, is caused by inactivation of both alleles of the APC gene. Most colorectal neoplasms are characterized by a form of genomic instability, which permits accelerated accumulation of mutations. As the adenoma grows in the context of hypermutability, more mutations may occur, permitting successive waves of clonal evolution with progressively more aggressive growth characteristics. Our current knowledge of the genes involved in this process is expanding, and we will soon begin to tailor preventive and therapeutic strategies based upon the mutational signatures of each neoplasm.

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61 Li WQ, Kawakami K, Ruszkiewicz A, Bennett G, Moore J, Iacopetta B. BRAF mutations are associated with distinctive clinical, pathological and molecular features of colorectal cancer independently of microsatellite instability status. Mol Cancer 2006; 5: 2. 62 Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995; 268: 1336– 8. 63 Rampino N, Yamamoto H, Ionov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275: 967–9. 64 Souza RF, Appel R, Yin J, et al. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet 1996; 14: 255– 7. 65 Yin J, Kong D, Wang S, et al. Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human colorectal and gastric carcinomas. Hum Mutat 1997; 10: 474–8. 66 Chang DK, Metzgar D, Wills C, Boland CR. Microsatellites in the eukaryotic DNA mismatch repair genes as modulators of evolutionary mutation rate. Genome Res 2001; 11: 1145–6. 67 Toyota M, Issa JP. CpG island methylator phenotypes in aging and cancer. Semin Cancer Biol 1999; 9: 349–57. 68 Goel A, Arnold CN, Niedzwiecki D, et al. Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res 2003; 63: 1608–14.

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Colon Polyps: Prevalence Rates, Incidence Rates, and Growth Rates Bjørn Hofstad* Ullevaal University Hospital, Oslo, Norway

Introduction The malignant potential of adenomas has been recognized for more than a century [1], but most knowledge has been collected in the last 30 years. The earliest information emerged from autopsy studies, while clinical material only appeared after the advent of fiberoptic endoscopy, in which the whole colon may be inspected without surgical intervention. Both symptomatic and asymptomatic individuals can be investigated by flexible sigmoidoscopy or colonoscopy. Other methods may include surgical material, which is highly selective and includes mostly large polyps, and radiologic studies, in which no information on histological type is available. A polyp may be defined as any protuberant lesion in the mucosa. Most of the polyps in unselected material consist of hyperplastic polyps, although about 15% of smaller polyps [2] are not histologically different from the normal mucosa and have often been termed “mucosal tags.” The evidence that adenomas are indeed precursors of most colorectal cancers (adenoma–carcinoma hypothesis) is circumstantial and based on several observations. 1 High- and low-risk areas for colorectal cancer and polyps are correlated [3–5]. 2 Polyps and cancers are located more often in the proximal and distal part of the colon than in the middle. They are both more frequent in the left side in younger persons, with a shift toward the right side of the colon at older ages [6]. 3 Malignancy increases with the size of the polyp, and with increasing dysplasia and villous structure of the adenoma [7–9]. 4 Remnants of adenomatous tissue are found in a high proportion of colorectal cancers limited to the submucosa

*Chapter from the first edition updated by the editors.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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(60–85%), whereas this is found in only 7% of cases with extension beyond the serosa [7,9,10]. This has been interpreted to indicate that cancers arise in adenomas, which are destroyed as the cancer grows. 5 Nearly 100% of patients with familial adenomatous polyposis (FAP) develop cancer if not treated surgically [7].

Prevalence The results from autopsy and endoscopy studies differ in their reported prevalence rates for various reasons. More small and proximal adenomas will be detected if a pathologist can scrutinize a dissected colon in an unstressed situation, opening up folds and crevices, straightening bends for concealed lesions, or applying a magnifying lens [11–14]. The factors that lead to a postmortem examination for a deceased person vary for the different populations within a country, and change over time. Prior to 1970, autopsy rates for most academic centers in the USA were around 40% [15]. Since then, autopsy rates have declined in many countries and are at present around 5% in the USA. This increases the selection factors so that studies from more recent times must be viewed with skepticism. Autopsies on younger individuals may overrepresent those with conditions that negatively affect the probability of having colorectal neoplasia. The persons included in colonoscopy studies are usually symptomatic patients and will also present a selection bias. Moreover, persons who voluntarily submit to colonoscopy are likely to be more health conscious.

Autopsy studies The first autopsy study in the USA was published in 1947 but first appeared in Europe in the late 1920s. Table 28.1 presents the prevalence of colorectal adenomas in several autopsy studies in relation to the cancer risk of the area. These studies are old, and for many of these countries the cancer risk has increased considerably over the last decades. The yield of adenomas is very low in low-risk areas of the developing world, evident in large series from Colombia and Costa Rica; in the largest reported series, no polyps were found among

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Colon Polyps: Prevalence Rates, Incidence Rates, and Growth Rates

Table 28.1 Age- and sex-related prevalence of adenomas (%) in autopsy studies in relation to risk of cancer. Reference

Location

Risk of cancer

Males < 60 years (* < 65 years)

Males > 60 years (* > 65 years)

Stemmerman & Yatani [16] Rkkert et al. [17] Williams et al. [18] Vatn and Stalsberg [6] Clark et al. [5] Helwig [19]

Hawaii, USA

High

50–67

66–70

0–70

59–63

New Jersey, USA Liverpool, UK Oslo, Norway

High High High

22–33 20–34* 6–21

48–70 44–52* 36–53

12–42 15–20* 7–28

50–63 35–33* 19–43

Aberdeen, UK St Louis, USA, whites St Louis, USA, blacks Akita, Japan Sao Paulo, Brazil Tromso, Norway Hong Kong Kuplo, Finland Miyagi, Japan Cali, Colombia Costa Rica Bantu, South Africa

High Intermediate Intermediate Intermediate Intermediate Intermediate Intermediate Low Low Low Low Low

16–32* 4 –16 1 23 5 –14 15–17* 18–21 4–17* 4 2–7 0–6 0

44–64* 23–26 9–13 46 30 40–45* 36–49 4–16* 23 18 13 0

4–18* 9–21 2 6 8–14 21–15* 10 8–0* 5 2–10 2–4 0

40–48* 17–20 14 37 23 14–41* 14–25 22–11* 17 15 9 0

Sato et al. [20] Correa et al. [21] Clark et al. [5] Coode et al. [22] Clark et al. [5] Sato [20] Correa et al. [4] Correa et al. [21] Bremner and Ackerman [3]

14 000 autopsies of South African Bantus. Even if the prevalence may be underreported, the differences in high-risk areas are considerable, reaching more than 50% prevalence of adenomas in older males. One factor that might affect the reported prevalence figures is that not all studies used a magnifying lens, which may increase the yield by up to 100% [20]. Conversely, applying interobserver testing of the histological evaluation may reduce the prevalence by as much as one-third [5]. Apparently, there are no ethnic differences, although a lower prevalence of adenomas was found in black people than in white people in the study from St. Louis in 1947.

Endoscopy studies Most of the initial colonoscopy studies were retrospective evaluations from hospital endoscopic units [23–26], and the patients included were referred for abdominal symptoms. The majority are referred for gastrointestinal bleeding, although other symptoms such as persistent abdominal pain or change in bowel habit are frequent. The symptoms might select persons with a higher prevalence of adenomas and hence not be representative of the population in general. Several sigmoidoscopic and colonoscopic screening studies of average-risk asymptomatic persons have been published, but most of them are also subject to selection bias. All but one are nonrandomized; in the case of randomized invitations to participate, compliance is vital and response rate at invitation can be as low as 6% [27]. In general, participation in screening studies will be influenced by such factors as health conscious-

Females < 60 years (* < 65 years)

Females > 60 years (* > 65 years)

ness, friends or close family with colorectal cancer, socioeconomic status, and health insurance. Table 28.2 shows the results of sigmoidoscopy and colonoscopy screening studies of asymptomatic persons, primarily from the USA and the developed world. With the flexible sigmoidoscope, an insertion depth of close to 60 cm is expected, including the whole of the rectosigmoid colon, although very often the full depth of insertion is not obtained due to bowel cleansing, technical difficulty, patient discomfort, and the skill and determination of the examiner. Conversely, in 15–20% of the investigations, extension beyond the rectosigmoid junction is achieved. For the age group most often selected (55–65 years) most polyps will be distal, within reach of the sigmoidoscope, but around 40% will be proximal to this (Tables 28.2 and 28.3). However, if all persons with detectable distal adenomas are then referred for colonoscopy, a considerable portion of the proximally located lesions will also be revealed. Even then, 13–70% of patients with proximal adenoma have no distal “index” adenoma [27–32]. A Spanish study [33] noted that a strategy in which colonoscopy is performed solely in patients with an adenoma or sigmoidoscopy is not effective screening for the detection of advanced proximal neoplasms in an average-risk population. However, a completely opposite conclusion was reported by an Italian study which concluded that restricting colonoscopy referral to patients with high-risk distal polyps might represent a costeffective strategy in a screening context [34]. A more recent study [35] reported that if any polyp on flexible sigmoidoscopy is 5–9 mm in diameter, there is a substantial yield of

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Table 28.2 Studies of neoplasia prevalence in asymptomatic screeneesa. (Adapted from Neugut et al. [28] with permission.) Reference

Country

Flexible sigmoidoscopy studies Ujszaszy et al. (1985) Riff et al. (1990) Cauffman et al. (1992) Krevsky et al. (1992) Matter and Campbell (1992) Brady et al. (1993) Brint et al. (1993) Maule (1994) Sakamoto et al. (1994) Cannon-Albright et al. (1994) Cannon-Albright et al. (1994)

Hungary USA USA USA USA USA USA USA USA USA USA

Colonoscopy studies Johnson et al. (1990) Rex et al. (1991) DiSario et al. (1991) Lieberman and Smith (1991) Guillem et al. (1992) Rex et al. (1993) Brady et al. (1993) Thiis-Evensen et al. (1999) Thiis-Evensen et al. (1999) Lieberman et al. 2000 Schoenfeld (2005) Regula (2006)

USA USA USA USA USA USA USA Norway Norway USA USA Poland

a

Number of patients

Adenomas (%)

Group/age

3863 329 1000 202 101 162 116 2611 866 206 200

8 8 4 12 12 48 9 11 1 14 6

County hospital, > 40 years Primary care practice, > 50 years FOBT negative, > 45 years Chemical plant employees > 50 years Asymptomatic, FOBT/FH negative, > 50 years FOBT negative, > 45 years > 45 years FOBT negative and NF > 50 years FH negative, > 25 years, males FH negative, > 25 years, females

90 210 119 105 83 621 162 109 84 3121 1463 50 149

21 25 41 41 8 25 55 47 38 38 20 14

Armed forces and dependants, > 50 years Asymptomatic, average risk, 50–75 years FOBT and FH negative, 50–79 years FOBT negative, > 50 years Asymptomatic, average risk, 31–78 years Healthcare professionals/spouses, 50–75 years FOBT and FH negative, > 50 years Population randomized, males, 63–72 years Population randomized, females, 63–72 years Recruited from medical centers, > 50 years Females aged > 50 years Asymptomatic subjects aged 40–66 years

Mean age (years)

Males (%)

63 61 53 68 62 57 60 62 52 52

47 99 96 80 76 45 44 100 0

65 64 64 55 60 62 67 67 63 59 55

68 71 100 100 55 62 80 100 0 96 0 36

For details of individual studies, readers should consult ref. 28.

Table 28.3 Anatomic distribution of colorectal adenomas in autopsy studiesa. (Adapted from Neugut et al. [28] with permission.) Reference

Country

Sex/race

Number

Cecum (%)

Ascending colon (%)

Transverse colon (%)

Descending colon (%)

Sigmoid colon (%)

Rectosigmoid colon (%)

Rectum (%)

Helwig (1947) Helwig (1947) Correa et al. (1972) Stemmerman & Yatanl (1973) Sato (1974) Sato et al. (1976) Correa et al. (1977) Correa et al. (1977) Marigo et al. (1978) Marigo et al. (1978) Vatn and Stalsberg (1982) Clark et al. (1985)

USA USA Colombia USA

Male Female

139 – 35 125

10 16 46 10

14 24 – 34

18 10 – 22

8 6 – 11

31 27 10 15

19 16 – 1

19 16 – 1

89 90 146 57 52 52 148

2 4 10 7 67 51 19

41 42 44 40 – – 12

23 20 22 21 – – 25

15 18 6 6 28 39 14

13 8 12 9 – – 9

2 3 3 5 – – 12

2 3 3 5 – – 12

174

28

–

28

15

21

–

–

60 46

17 8

21 21

17 27

11 7

13 29

12 8

12 8

Coode et al. (1985) Bombl (1988)

Japan Japan USA USA Brazil Brazil Norway UK/Norway/ Finland Hong Kong Spain

Black White Male Female

* For details of individual studies, readers should consult ref. 28.

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proximal adenomas on subsequent colonoscopy [36,37]. A few reports have recommended total colonoscopy wherever any adenoma was discovered on flexible sigmoidoscopy, while a report from Japan [38] suggested that persons over 60 years old should undergo colonoscopy even if no neoplasm was present on flexible sigmoidoscopy. Data on 141 413 colonoscopies performed for a variety of clinical conditions [39] collected in the Clinical Outcome Research Initiative database were used to evaluate the “number needed to endoscope” (NNE) to identify one patient with a mass or a polyp greater than 9 mm. In the 50–59 years average-risk group, 28 women and 18 men would need to have screening colonoscopy to identify one patient with a mass or polyp larger than 9 mm. Men older than 60 years having surveillance colonoscopies and patients with irritable bowel symptoms had similar NNE to average-risk subjects. In the screening sigmoidoscopy studies presented in Table 28.2, generally low prevalence figures are quoted (1–16%), which include only the polyps found at sigmoidoscopy and not the additional ones found by follow-up colonoscopy. The exception is the study by Brady and colleagues [40], who reported a 48% yield that is largely unexplained. In this study, 45% of screenees were examined during a total colonoscopy in which the authors included only the polyps of the distal 60 cm. This estimation of sigmoidoscopy yield may include too many polyps compared with an actual sigmoidoscopy [41]. A large-scale Norwegian colorectal cancer prevention study of 12 960 individuals who underwent screening flexible sigmoidoscopy showed that nonsteroidal anti-inflammatory drug (NSAID) and/or aspirin intake was associated with decreased risk of distal low-grade adenomas (DLGAs) in men. In women, the duration of hormone replacement therapy was inversely related to the risk of DLGA. In both men and women, current smokers had an increased risk of DLGA and distal advanced neoplasia. Alcohol was associated with a positive trend for the risk of DLGA in men but not among women. While sigmoidoscopy is a rapid examination with little discomfort in general [42], total colonoscopy is more timeconsuming, resource demanding, and causes more discomfort to the patient as a result of both bowel cleansing and the endoscopic procedure. Despite these limitations, some screening colonoscopy studies have been published (see Table 28.2). Colonoscopy is becoming the screening examination of choice for the discovery and removal of adenomas [43–45]. The number of persons with adenomas in these studies is strikingly higher than the 20% increase expected from the figures found in the sigmoidoscopy studies. The prevalence ratio ranges from 21% to 55%, with the exception of one study [46] that included a smaller number of participants with a lower male proportion and lower mean age than the rest of the studies. The colonoscopy studies are generally male dominated and there might be a considerable selection bias, as the method of recruitment and the number that declined to participate is often not stated. In a study from

Norway [47] the subjects invited were randomized from the population registry and 60% attended, which is considered a high rate.

Age and sex In autopsy studies [5,6,17], adenoma prevalence increases with age in both men and women, with very low figures for persons under 50 years of age (although high prevalence was reported from Hawaii). The prevalence steadily increases for each 10-year age group to more than 50% in high-risk areas, and 15–20% in low-risk areas, for males. An exception was found in the Oslo study, where the middle age group of women had a reduced prevalence [6]. An age increase is also confirmed in the colonoscopy studies [30,31,48], with increasing prevalence from 21–28% in the age group 50–59 years to 53–58% in the age group > 70 years. As people live longer, the agerelated prevalence will have some implications for the total prevalence in a community. In some studies a correlation between increased size of adenomas and increasing age has been demonstrated [6,18], although this has not been not confirmed in other studies [17,20]. Contrary to a 1:1 sex ratio for the incidence of colorectal cancer, the prevalence of adenomas is higher among men in all age groups, approaching a 1:2 ratio in some studies [22,29], both in high-risk [18] and low-risk [21,49,50] areas. The sex difference is most consistent in the middle age group (60–69 years). The shift from male-dominated prevalence of colorectal adenomas to an equal ratio for cancer is partly explained by the finding that age-adjusted risk is higher in men than in women, but women live longer so they “catch up” in lifetime incidence rates. In addition, women are more likely than men to develop cancers through the hyperplastic polyp to serrated adenoma to cancer sequence. Serrated polyps have seldom been counted or considered significant in endoscopic or autopsy studies. Only one autopsy study showed higher proportion of large and dysplastic adenomas in women [6]. Contrary to this, in clinical studies a lower proportion of large, dysplastic, or multiple adenomas has been observed in women than in men [48]. However, increasing age has been related to more rapid transformation of advanced adenomas into cancer [51]. Since women live longer than men, this effect may contribute to women catching up with men in lifetime colorectal cancer incidence.

Subsite distribution Tables 28.3 and 28.4 present autopsy and endoscopy studies showing the anatomic distribution of adenomas in the colon. The autopsy studies generally predate the endoscopy reports and the age groups are not properly defined in many. Autopsies are more precise in defining the correct segment localization, which is often incorrectly judged during endoscopy. The existing endoscopic studies are all from symptomatic patients in hospital endoscopic units, except one [38] that is population based and randomized, although the distribution

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Table 28.4 Anatomic distribution of colorectal adenomas in endoscopy studiesa. (Adapted from Neugut et al. [28] with permission.) Reference

Study period

Country

Number

Cecum (%)

Shinya and Wolff (1979) Gillesple et al. (1979) Granqvist (1981) Fruhmorgen and Matek (1983) Webb et al. (1985) Bat et al. (1986)

1969–79

USA

6942

13

1972–79

UK

275

1969–76 Before 1983 1975–82 1980–84

Sweden Germany

1982–85

USA Israel, Ashkenazl Germany

1986–88

USA

1996

Norway

Wegener et al. (1986) O’Brien et al. (1990) Thiis-Evensen et al. (1999) a

Ascending colon (%)

Transverse colon (%)

Descending colon (%)

Sigmoid colon (%)

Rectosigmoid colon (%)

Rectum (%)

–

12

23

46

–

6

8

–

14

19

47

–

13

264 1280

20 2

– 8

36 4

– 15

44 48

– –

– 25

274 279

13 9

– –

12 21

21 52

– –

53 –

– 19

282

4

13

18

17

24

–

21

2362

8

14

10

18

43

–

8

203

6

13

19

16

18

–

28

For details of individual studies, readers should consult ref. 28.

is not essentially different from the others. Autopsy studies [6] have clearly demonstrated a marked preponderance of adenomas on the left side in the age group < 60 years, with a shift to the right side in the age group > 70 years and a more even distribution in the middle age group. This holds true for both men and women but is less evident in the latter. The middle part of the colon, represented by the transverse colon, is the area harboring the fewest adenomas. The distribution of large and villous adenomas is similar. Hyperplastic polyps show the same age shift as adenomas for men but are more evenly distributed in women in all age groups. Age differences in the material from the different studies may account for some of the variations, although a high proportion of right-sided polyps was found in the material from Colombia and Brazil [4,52], where the data are expected to include younger persons. Subjects belonging to families with high risk of colorectal cancer (hereditary nonpolyposis colorectal cancer, HNPCC) have an increased tendency to right-sided polyps (and cancer). In endoscopic studies, which usually have a higher proportion of smaller polyps, the smaller adenomas (< 5 mm) occur more often in the rectum, whereas the sigmoid colon has more middle-sized (5–9 mm) and larger (> 9 mm) adenomas [47]. The age shift in anatomic distribution of polyps has also been observed for colorectal carcinomas [53,54], as have correlated time trends [55] between the two, and this forms some of the evidence for the adenoma–carcinoma sequence hypothesis. The highest proportion of left-sided cancers are actually located in the rectum, constituting 30–40% of all colorectal cancers; however, most studies place the bulk of

362

the polyps in the sigmoid colon. If the rectosigmoid junction area were treated as a separate entity, some of this difference would be nullified.

Size, dysplasia, and villous structure The first large report to show the size, dysplasia, and villous structure of adenomas and their interrelationships was published in 1975 [7], and was later supplemented by large endoscopic studies. The work by Muto and colleagues [7] consists of material from surgery or rigid endoscopy, and would favor large polyps. To a lesser degree this is true for retrospective hospital studies. In a randomized study with average-risk persons [47], more than two-thirds of the adenomas were less than 5 mm in diameter (Table 28.5). High-grade dysplasia and villous components (tubulovillous and villous adenoma) were rare in the reported series. In addition, 46% of all polyps removed were hyperplastic and 23% were mucosal tags, so that nearly three-quarters of the polyps were non-neoplastic. The studies have demonstrated a clear relationship between the size of adenomas, villous architecture, grade of dysplasia, multiplicity, and rate of malignant transformation [7–9]. While polyps < 1 cm are hardly ever malignant, up to 50% of those > 2 cm are malignant (Table 28.6). Tubular adenomas are malignant in 4–5% of cases, while the malignancy rate for villous adenomas is 40–50% [7]. This may be partly due to the observation that 86% of the villous adenomas are more than 1 cm in diameter. The rate of malignancy increases from 6% with mild dysplasia to 35% with severe dysplasia. Moreover, malignancy appears in 8% of adenomas when these are single but in 29% of patients when they have six

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Table 28.5 Prevalence (%) of polyp characteristics. Characteristic < 5 mm 5–9 mm 10–20 mm > 20 mm Severe dysplasia Villous components More than one adenoma

UKa # $ 60 23 17 8 25 8

USAb

Germanyb

USAb

Norwayc

40 46 14 12 35 17

45 22 17 16 4 27 –

38 36

69 24

# $ 26

# $ 7

6 13 45

2 8 27

a

Surgery/rigid endoscopy material [9]. Hospital routine endoscopy material [10,11,47]. c Randomized colonoscopy screening material [40]. b

Table 28.6 Relationship between size and risk of malignancy of colorectal adenomas based on clinical and autopsy material. (Data from references 7,9,57,58.) Polyp diameter (mm)

Malignancy (%)

<5 5–9 10–20 > 20

∼0 0.9 5–10 10–50

age of patients in different parts of the world [5,6,17,18,21]. The tendency to multiplicity may be more pronounced in high-risk than in low-risk areas [16]. A higher degree of multiplicity has also been documented for males than for females. Multiple adenomas may be spread over the total colorectum; however, two studies have demonstrated a significant spatial clustering, increasing the chance for two polyps to be located in the same or a neighboring segment [63,64], although this was not true for rectal polyps.

Risk factors for adenoma prevalence adenomas [8], although multiplicity is the factor least correlated with malignant transformation compared with other polyp characteristics. The National Polyp Study clearly demonstrated the increased risk of polyps containing high-grade dysplasia in older patients, and in patients harboring medium-sized and large adenomas, while the presence of multiple adenomas was not a separate risk factor [56]. Polyps may be pedunculated or sessile in appearance. Very few small polyps are pedunculated, while 41% of large and left-sided polyps have this characteristic [59]. It is not possible to judge the histological type from the macroscopic appearance alone, except that histology is correlated with the size of the polyp [2], since small polyps (< 0.5 mm) are likely to be non-neoplastic, while only 16% of hyperplastic polyps grow beyond this size [60]. In expert hands, however, inspection of the pit pattern using high-resolution chromoendoscopy with indigo carmine dye may reliably separate neoplastic from non-neoplastic polyps [61].

Multiplicity Multiple adenomas appear to a varying degree (see Table 28.5). The larger recent studies report a frequency of 35–45% among adenoma-bearing patients [56,62]. Autopsy studies demonstrate an increased multiplicity of adenomas with increasing

Age and male gender have already been discussed as risk factors. One sigmoidoscopy study [65] and one colonoscopy study [46] have found family history of colorectal cancer as a separate predictor for adenoma prevalence, although this is not substantiated by others [27,31,47]. In case–control studies, family members of colorectal cancer patients have a relative risk of around 1.5–2.0 for prevalence of adenomas [46,65– 67]. Smoking as a risk factor has been found in most studies [68–73], although the data on alcohol are not consistent [74–76]. Regular aspirin users may have a lower prevalence of polyps [77,78]. However, a study involving over 80 000 women in the Nurse’s Health Study showed that a significant benefit of aspirin in reducing the risk of colorectal cancer does not occur until the level of intake is greater than two standard tablets (325 mg) daily for over 10 years. At that level of intake, there is a significant dose-related risk of gastrointestinal bleeding [79]. A review prepared for the US Preventive Services Task Force concludes that both cyclooxygenase-2 inhibitors and NSAIDs decrease the incidence of colonic adenomas (NSAIDs also reduce the incidence of colorectal cancer), but the balance of benefits to the risk of cardiovascular events and gastrointestinal harms does not favor the use of these agents for chemoprotection [80]. The role of dietary factors, body mass index (BMI), and physical inactivity, which have been thought to account for

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most of the difference in prevalence of colorectal cancer and adenomas between developing and industrial countries, is not well substantiated [81]. High BMI and fat intake [81– 91] has been found to be associated with increased polyp prevalence. A reduced prevalence has been found with high intake of dietary fiber [81,83,92–96], carbohydrates [82,83], vitamin A [97], vitamin B6 [92,98–100], vitamin C [92], folic acid [92,99], magnesium [92,98], zinc [92], iron [82], selenium [101–103], and calcium [104–107]. Folic acid may reduce adenoma risk but may also accelerate progression of existing adenomas through the adenoma–carcinoma sequence [108]. A questionnaire given to over 20 000 women revealed that hormone replacement therapy did protect against the development of colorectal adenomas, but its effect ceased soon after cessation of use [109]. K-ras mutation positive and negative colorectal adenomas may differ clinically and pathologically. Epidemiological literature on the effect of diet and lifestyle on colorectal K-ras mutations is inconsistent [110]. A 3-year prospective study from the US Veterans Affairs Medical Centers reported that the findings of advanced neoplasia (an adenoma of 10 mm or greater diameter, a villous adenoma, an adenoma with highgrade dysplasia or invasive carcinoma) was associated with a history of a first-degree relative with colorectal cancer, who was a current smoker and an alcohol user [111]. There was an inverse association with intake of fiber and vitamin D as well as use of NSAIDs. There is reported to be an association

between obesity, weight gain, and adenoma risk [112]. Diabetes mellitus and metabolic syndrome are each associated with an increased risk of adenomas [112,113]. Cigarette smoking is strongly associated with colorectal adenomas, advanced adenomas, and cancer [72,114]. Cigarette smoking produces an increased risk of adenomas equivalent to the risk with a family history of colorectal cancer, and long-term smokers develop colorectal cancer at a younger mean age than nonsmokers.

Incidence The term “prevalence” rather than “incidence” should be applied to the individual who has an adenoma detected for the first time, since the adenoma has been present for an unknown period of time because polyps (with the exception of some large polyps) do not cause symptoms. Knowledge of polyp incidence or new polyp formation must be collected from follow-up studies after a colon has been inspected and certified free from polyps.

Postpolypectomy incidence For more than 20 years it has been common in developed countries to perform regular endoscopic follow-up after polypectomy of adenomas, and therefore a large number of studies from initially symptomatic patients with index adenomas have been published (Table 28.7).

Table 28.7 Adenoma incidence (recurrence) in symptomatice patients after polypectomy. Reference

Country

Number of patients

Recurrence rate (%)

Mean follow-up (years)

Henry et al. [115] Waye and Braun feld [116] Morson and Bussey [117] Neugut et al. [118] Wegener et al. [119] Kronborg and Fenger [120] Holtzman et al. [121] Nava et al. [122] Olsen et al. [123] Eckardt et al. [124] McKeown-Eyssen et al. [125] Yashiro et al. [126] Woolfson et al. [127] Winawer et al. [128] Triantafyllou et al. [129] van Stolk et al. [130]

USA USA UK USA Germany Denmark USA USA USA Germany Canada Japan Canada USA Greece USA

154 133 1697 118 66 552 49 44 500 220 137 58 109 973 44 479

30 56 18 15–39 32–54 16 50 59 26 32 46 29 50 30 36 35

7 1 5 2.2 2.6 4

1 3.2 2 3

2 3

Alberts et al. [131] Bonithon-Kopp et al. [62]

USA Europe

1303 552

49 16

3 3

3 3

364

2.8 4.4 4.3 2

Follow-up period (years)

Comments

Sigmoidoscopy and barium enema Follow-up method not stated 1 to > 3 1 to > 3 4 1–4 1–10 2 0.9–1.5

Including nonneoplastic polyps? Only polyps > 1 year included Intervention with vitamins C and E Different follow-up intervals Including nonneoplastic polyps?

Intervention with antioxidants; only polyps > 1 year included Intervention: fiber supplement Intervention: calcium/fiber supplement

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However, patients with adenomas may have a higher biological potential for new polyp formation, giving a higher rate of subsequent polyps than in persons without polyps. Moreover, the risk of overlooking polyps at index colonoscopy is far greater where one or more polyps are present. The miss rate of polyps at colonoscopy is discussed in Chapter 41. When a polyp is missed at index colonoscopy, it will appear as a recurrence at follow-up examination. This will lead to an overstatement of the true incidence rate in this subpopulation. Partly to make up for this, one study [116] included a “clean colon” at the start, which entailed a colonoscopy performed 1 year after polypectomy, where no polyps were detected. Subsequent follow-up 1 year later resulted in a lower recurrence for those with baseline single polyps (13%) but not for those with multiple polyps (80%), than another group (56%) 1 year after polypectomy without an intermediate clean colon. Other studies have performed a repeat colonoscopy after 1 year, excluding those polyps as overlooked at the initial examination [124,130]. There is a wide variety of adenoma recurrence rates reported, although most surveillance studies state that the range is 30– 50% after a mean or median follow-up period of 1–4 years. Four recent large intervention studies report no effect of the intervention medication, except for a nonsignificant beneficial effect of calcium and a slight promoting effect of fiber in the European study [62]. This study reports a lower recurrence rate than most others. In some studies, the patients have undergone multiple follow-up endoscopies, and in these the first examination detects more polyps than the succeeding ones. This may imply that some polyps, detected in the first follow-up, are in fact overlooked at the index examination. In all cases the new polyps at follow-up are smaller in size and with a more benign histology than at index colonoscopy. It has been argued that if a large polyp with advanced histology is detected after a short interval, it must certainly have been overlooked at the previous examination, judging from present knowledge of polyp growth rates. Even with repeated endoscopy, there is a possibility of missing polyps, even those of a significant size. On the other hand, even if most polyps grow very slowly or hardly at all in 3 years [14], it may be that some unusual ones can evolve with an explosive growth pattern. In one study, newly developed polyps were detected in 81% of patients in the same segment as the index polyps [122], while others report a higher frequency in the proximal part of the colon than found with the index examination [14,127], a finding more in line with the known age shift of polyp distribution. More important than the recurrence of small tubular adenomas with low-grade dysplasia is the detection of significant lesions at follow-up. Significant or advanced lesions are often defined as adenomas either > 1 cm in diameter (with villous components) or with high-grade dysplasia, in addition to, of course, invasive carcinoma.

Significant lesions are not often found on follow-up colonoscopy. The National Polyp Study found pathologically advanced adenomas in 2.9% compared with 29.5% for any adenoma, but in this study villous elements were not included. Two other reports found advanced adenomas, including villous elements, in 6.6% [132] and 11.4% [129].

Incidence in polyp-free individuals Information on polyp incidence in individuals who were initially polyp free is less readily available. Table 28.8 shows seven follow-up sigmoidoscopy and four colonoscopy studies of persons without a previous history of colorectal polyps who were free of polyps at index endoscopy. The recurrence figures are consistently low in the sigmoidoscopy follow-up reports, and are remarkably different from the colonoscopy studies. It is apparent from the sigmdoscopy reports that repeated sigmoidoscopy in persons with previous negative examinations is not very cost-effective. The incidence rate for colorectal adenomas in the four studies of subjects with a polyp-free colon at enrollment varies from 24% to 36%, which is somewhat but not considerably lower than the recurrence rate after polypectomy. In one study [139], patients were involved in a tandem colonoscopy project, in which two examinations by different endoscopists were performed in the same session to evaluate the miss rate of colorectal polyps. Eleven of these patients with “clean colons” were reexamined 2 years later, when polyps were detected in four (36%). Studies such as this are of particular value as a clean colon at baseline was certified to a higher degree than in other studies. In the study by Neugut and colleagues [141], 99 patients with a prior negative colonoscopy from different clinical practices were reexamined 3 years later, finding incident polyps in 24%. In another group of 178 patients who had undergone prior polypectomy, 46% incident polyps were detected during the same follow-up period. However, this latter group was 5 years older, with a higher male proportion. In a parallel setting to the previous study, Squillace and colleagues [140] found an adenoma incidence of 41% in 29 patients. Rex and colleagues [142] reexamined a subset of colonoscopy screenees who had participated in a previous prevalence study [27]. The participants were asymptomatic, of average risk, and tested negative on occult blood, and the follow-up interval was 4–7 years (mean 5.5 years). The incidence rate in this study was 27% [142]. The largest trial to examine this issue was reported from the Lilly screening colonoscopy study in Indianapolisaamong 1256 screenees with a normal baseline colonoscopy or with only hyperplastic polyps, 16% had any adenoma and 1.3% had an advanced adenoma at a mean follow-up of 5.3 years. No cancers were found [144]. Sigmoidoscopy screenees, randomly selected from a population registry in a polyp growth study, were reexamined by colonoscopy 13 years later [143]. Only those with polyps went on to colonoscopy at baseline. A total of 178 persons with negative sigmoidoscopy at baseline had

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Table 28.8 Adenoma incidence in asymptomatic and symptomatic screenees. Reference

Country

Number of patients

Adenomas (%)

Group/age

Follow-up interval

Mean age (years)

Males (%)

64 65 58 60 54 60

45 42 99 90

63 61 66 67

98 97 47 66 46

Flexible sigmoidoscopy studies Riff et al. [133] USA Riff et al. [133] USA Brint et al. [134] USA Maule [135] USA Krevsky & Fisher [136] USA Rex et al. [137] USA Platell et al. [138] Australia

257 140 101 894 64 259 361

5 6 1 5 8 6 8

Asymptomatic, FOBT negative Asymptomatic, FOBT negative FOBT negative, > 45 years Asymptomatic, FOBT negative, > 45 years Chemical plant employees, > 40 years Asymptomatic, FOBT negative, > 45 years 60–69 years

1 year 2 years 1 year 30–53 months Mean 17 months Mean 41 months 5 years

Colonoscopy studies Hixson et al. [139] Squillace et al. [140] Neugut et al. [141] Rex et al. [142] Thiis-Evensen et al. [143]

11 29 99 158 178

36 41 24 27 33

Symptomatic patients Symptomatic patients Symptomatic patients Asymptomatic, average risk, 50–75 years Population randomized, 64–69 years, index examination sigmoidoscopy

2 years 5.7 years Mean 36 months Mean 66 months 13 years

USA USA USA USA Norway

FOBT, fecal occult blood test.

33% new adenomas, similar to the 37% in a randomly selected control group not previously examined, but less than those who had polyps detected and removed 13 years previously (63%). Schoen and colleagues [145] reported a higher incidence of advanced adenomas 3 years after a negative sigmoidoscopy in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Among 9317 patients who returned for follow-up, 3.1% had an adenoma and 78 (0.8%) had an advanced neoplasia, including six patients with cancer. This yield of incident lesions is much higher than in the smaller studies described above. Burke and colleagues [146] described 915 patients who underwent a repeat flexible sigmoidoscopy 3 years after a negative examination, and compared this group to 1231 patients who underwent repeat examination 5 years after a negative study. Neoplasia was detected in 3.2% of the 3-year and 4.3% of the 5-year groups (P = 0.17). Advanced neoplasms (including one cancer at 3 years) occurred in 0.9% and 1.1% of the groups, respectively (P = 0.67).

Risk factors for polyp incidence (post polypectomy) The risk factors for adenoma recurrence have been amply evaluated. Multiple polyps at index endoscopy is a consistent risk factor for new adenomas. It is logical to anticipate that these patients have a higher biological potential to develop polyps than those with a single polyp. However, in the case of multiple polyps, the risk of overlooking some at index examination is far greater, reducing the true risk of recurrence. Nevertheless, both probabilities make a case for closer surveillance intervals of those with multiple adenomas. Patients with one or two tubular adenomas less than 10 mm in

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diameter represent a low-risk group for follow-up examination (147). Other risk factors for polyp recurrence have been reported less consistently. Although the National Polyp Study found by multivariate analysis, in addition to multiplicity, that increased risk exists in the presence of a medium-sized or large adenoma and when patients are > 60 years of age, this has been supported by very few others [148]. Other studies [115,130,148] have found villous/tubulovillous adenomas, and high-grade dysplasia to be risk factors. The most recent recommendations [149] for polypectomy follow-up suggest longer intervals between examinations when small polyps are found (see Chapter 54). Increased recurrence of polyps after polypectomy has been found in smokers [150] and in patients with high intakes of fat and total fiber [97]. In intervention studies, vitamin C supplementation produced polyp reduction [151] or reduced polyp volume [152] in patients with familial adenomatous polyposis and ileorectal anastomosis. The same has been found with sulindac, an NSAID, in open intervention studies [153– 155]. A randomized double-blind study of 1021 patients who had an adenoma removed shows that folic acid at a dose of 1 mg daily did not reduce the colorectal adenoma recurrence risk. Another report [156] suggested that calcium and NSAIDs may act synergistically to lower the incidence of recurrent polyps. There is evidence that NSAIDs may be chemoprotective against recurrent colorectal adenomas [157,158]. This was substantiated in another study that looked at colorectal cancer risk. Over 6000 persons were evaluated in a nested case–control study which found that prolonged use of NSAIDs

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and cyclooxygenase inhibitors [159] were associated with reduced colorectal cancer risk, but that prolonged use of statins was of no benefit. In an investigation of the association between cytokine gene polymorphisms and the risk of recurrent adenomas, it has been reported that carriers of the IL-10-1082 G > A variant allele may not benefit from the chemopreventive effect of NSAIDs on adenoma recurrence [160]. A dietary intake study found no association with either fat or red meat intake and the risk of recurrent adenoma, and only a weak inverse association with fiber ingestion [161]. A Japanese study did not support the hypothesis that consumption of red meat increased colorectal cancer risk [162]. Dried bean intake may be inversely associated with recurrence of advanced adenomata, although there was no association with other fruit and vegetable consumption [163]. Of the three intervention studies examining the effect of antioxidant vitamins on sporadic polyp recurrence [125,164, 165], only one reported a significant reduction in recurrence of polyps with a combination of vitamins A, C, and E [164]. Two other adenoma recurrence intervention studies have recently been published, one of them giving supplementation with wheat bran [131] and the second giving calcium or ispaghula [62] for a period of 3 years. Only the European study found an effect of intervention, calcium being nonsignificantly protective, with a weak but significant promoting effect of fiber supplementation [62]. The National Polyp Study [128] found baseline multiplicity of polyps to be the only risk factor for advanced adenomas at follow-up. This was supported by Triantafyllou and colleagues [129], while others [130] detected little significant risk factors. Long-term follow-up of patients having colon cancer resection reported that of 412 polyps of less than 6 mm that were left in situ (having been marked by tattoo) and examined yearly by magnification chromoendoscopy over a 3-year interval, 71% showed no change in size, 15% increased, 3% decreased, and 11% could not be identified. Their conclusion was that leaving small polyps is safe, even in patients who have had colon cancer surgery. In this group, 88 of these small polyps were removed and none showed cancer or high-grade dysplasia [166].

Growth Most colorectal cancers are believed to arise in preexisting adenomas through a multistep process of genetic events, which implies that malignant transformation may occur after an accumulation of at least five significant genetic faults [167]. A small polyp may grow for a period of perhaps 10– 15 years before it is transformed into a malignant growth. Generally polyps are discovered earlier in life than cancers, by a period of at least 4 years [9,85]. The exact time from the formation of a polyp and its progression to cancer to onset of symptoms is uncertain. Polyps > 1 cm in diameter followed

by radiography show a cumulative risk of malignancy at the polyp site of 24% after 20 years [168]. The malignant potential increases with the size of the polyp (see Table 28.6) [7,9,57, 169]. This makes the growth rate of colorectal polyps an interesting issue. However, as studies on polyp growth are a cumbersome task, few studies exist. An approximate evaluation of growth rate might be estimated from the time elapsed after the detection of a clean colon by colonoscopy to the discovery of new, size-estimated, polyps. This would, however, tend to overestimate growth rate. Polyps are frequently missed at colonoscopy, and many newly discovered polyps have been previously overlooked. Besides, it is not possible to know when the actual initiation of the polyp occurred. Moreover, polyps having a regression in size will not be included. Data from the National Polyp Study were analyzed by a group from the Netherlands. They concluded that the high adenoma detection rate during surveillance and the lower cancer rate can be explained by the probability of a dynamic process of both formation as well as regression of adenomas [170]. In a study potentially related to growth rates, German investigators found that the rate of conversion of advanced adenomas to cancers increased with advancing age. Using data from the German National Screening Colonoscopy Study, the prevalence of advanced adenomas increased in linear fashion, while the increase in incidence of cancer with age was nonlinear [51]. Another indirect method of investigating dietary or chemotherapeutic effects on the growth of colorectal polyps may be to evaluate the effect on the incidence of small and large polyps. One could argue that an effect on the prevalence of large polyps, that was not seen on small polyps, is in fact affecting polyp growth. The best method for evaluation of the growth rate of polyps is to leave the polyp in situ and to measure the size of the polyp at regular intervals. This requires a reliable method for size estimation of polyps in situ. Moreover, the problems involved in such studies need to be discussed.

Estimation of polyp size Precise measurement of polyps in situ is mainly an issue when polyps are left for studies of polyp growth. Otherwise, polyps would be best measured with a ruler or caliper after polypectomy and removal. However, smaller polyps < 5 mm in diameter are often removed with hot biopsy and would tend to disintegrate if removed by snare resection, making measurement afterward impossible. In clinical practice, polyp size has mostly been stated as an educated guess based on visual estimation or by comparing the polyp with an open or closed forceps. The validity of these measurements has been tested in latex colon models with ball bearings of different sizes [171] or plastic molds of artificial polyps [172], in which there is a consistent size underestimation of 20–30% regardless of the skill and training of the endoscopist. Measurements of artificial ulcer models also

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report an average size underestimation of 42% [173]; this study used an image-processing system to correct for lens distortion and thus reduced the average underestimation to 1.8%. Applying the open forceps method in the human colon resulted in a consistent overestimation of polyp size (18% on average) compared with postpolypectomy measurements, both for smaller (< 5 mm) and for intermediate (5–10 mm) polyps [174,175]. It appears that visual estimation of polyps without object comparison is as good as, or perhaps even more accurate than, the open forceps method [176]. The reason for the consistent difference in size between artificial models and the human colon, as evaluated by the open forceps method, is speculative [174,177]. The extracted polyp, measured with a ruler or caliper, may have changed in size and shape compared with the time before polypectomy. Snare resection may shrink the tissue as a result of cauterization, especially small sessile polyps. Moreover, at the start of a snare polypectomy venous congestion is obvious, followed by vascular collapse at the final transectionaa process that could lead to an unpredictable increase or decrease in polyp volume. In addition, the polyp graspers may deform the polyp and alter the largest diameter during extraction. This would be even more exaggerated if the polyp were brought out through the biopsy channel. Polyp size is not significantly altered by formalin fixation [174,175]. Endoscopic conditions are widely different in the artificial model and the live colon. Technical endoscopic difficulties are numerous in the live situation. Insufficient bowel cleansing is probably the most important cause of missed polyps. Frequently, it is difficult to view the polyp fully when hidden behind folds, inside curvatures, or behind flexures. Contractile movements may make the situation difficult: a soft polyp changes shape during contraction. The polyp may even alter its shape somewhat if the bowel is insufflated with large amounts of air. Finally, the time spent with the polyp in full view may sometimes be too short for adequate measurement of the diameter. The endoscopic lens is wide angled to improve peripheral view. This introduces a distortion, so that the 1-mm units may be reduced by 10% at the periphery compared with the center of the view [178]. This can be corrected by image-processing methods, which will reduce measurement errors when applying the open forceps method [173]. In practice, the measuring device and polyp should be placed close to each other in the center of the picture (Figure 28.1). Moreover, it is important to place the measuring device at the same distance from the endoscope as the polyp, preferably at the middle of the polyp. In large polyps, great variation in diameter readings will occur, whether the measuring device is placed in front of or behind the polyp. The optimal in situ measurement of colorectal polyps is achieved with a linear measuring probe positioned at 90° to the direction of sight (see Figure 28.1). The scale units should be in either 1- or 2-mm divisions. One prototype (Polyprobe)

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10

5

0

5

10

15

20

Diameter in situ (mm)

Figure 28.1 Correlation between diameter measured in situ and diameter measured after removal of the polyp (larger points indicate exact overlaps); n = 36, r = 0.94. (From Hofstad et al. [177].)

[14] is 12 mm long; this is preferable to a longer one, which may be too long to rotate into proper position in the narrow sigmoid colon. Since in situ measurements of polyps are mainly needed for studies of polyp growth, 12 mm is sufficient, as follow-up of polyps larger than 10 mm cannot be accepted for ethical reasons. Moreover, it is technically more difficult, at times impossible, to maneuver larger polyps into full view, a necessity for a correct reading. The reliability of in situ measurements with a linear measuring probe supersedes other methods (see Figure 28.1) [176– 178] and is equally good for fiberoptic and video systems [178]. The correlation coefficient for comparison of diameter measured in situ and after polypectomy exceeds 0.9 (see Figure 28.1) [177,178]. Moreover, the correlation coefficient between diameter to the third power measured in situ and weight of the polyp is more than 0.9. In another study, Gopalswamy and colleagues [179] compared the three working methods for in situ polyp size evaluation with ruler measurement of the resected polyp and showed a mean difference versus the actual size of 3.4% for the linear probe, 6.4% for visual estimation, and 12.3% for the forceps. If a picture of the polyp is taken with the measuring probe in position, an alternative size evaluation to linear measurement can be made. Using computerized image analysis, the area of the polyp on the picture can be calculated. Ideally, this would provide a more sensitive growth estimation, as polyp growth is three-dimensional and a small increase in diameter may double the volume. However, this measurement was shown to correlate less well with the weight and volume of the removed polyp than the linear measurement [177,178].

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This may have been caused by problems in maneuvering the probe and polyp into the correct position. The most sensitive estimation of polyp growth would be an in situ volume or weight estimation, but no prototype has been devised. An approximate value might be calculated from measurements of the area and depth of the polyp measured with an ultrasound probe through the working channel of the endoscope.

Problems with studies of polyp growth So far, few studies on polyp growth have been published [42,180,181]. As polyps grow slowly, they need to be observed for many years. The main technical problems are associated with in situ measurement, redetection, and reidentification of polyps. This kind of study is laborious, with demand for a large number of patients with few dropouts.

In situ measurement The problems of in situ measurement have been discussed. A linear measuring probe has been shown to give a reliable size evaluation; with a picture of the polyp, computerized image analysis of the area of the polyp can be obtained.

Redetection The problems of detection and redetection of polyps is well known to all colonoscopists. Polyps may be hidden by inadequate emptying, located behind folds or on the inside of curvatures, and contractile movements may occlude the view. Judged by repeat endoscopies within 3 months, the miss rate of polyps by single endoscopy was estimated to be 25% of polyps < 5 mm and 5% of polyps > 5 mm in diameter in one study [11], and 13% for all sizes in another study [182]. This is comparable with the results of tandem colonoscopies by two alternating examiners, revealing a miss rate of 16–27% for polyps < 5 mm, 12–17% for polyps 5–9 mm, and less than 5% for polyps > 1 cm [12,13]. In a study of polyp growth, the examiner will be aware of the location (but not the size) of previously detected polyps at follow-up, and a redetection rate of 75–90% for polyps < 1 cm has been demonstrated [2,14,183]. There is a considerable difference in redetection rate of polyps situated proximal or distal to the splenic flexure. Of polyps < 5 mm, 76–89% were redetected when the polyp was located in the left colon compared with 54– 86% in the right side of the colon [2,14]. The redetection rate of polyps 5– 9 mm was 91–96% in the left side compared with 76– 90% in the right. Location of the polyp at redetection (measured as distance in centimeters from the anus with a straightened endoscope) correlates well with initial endoscopy [2,14], resulting in a mean distance difference of 0.8 cm [14].

Reidentification Between 35% and 45% of adenoma-bearing patients have multiple polyps. Multiple polyps, especially in the same seg-

ments, may cause problems in deciding which polyps are redetected and which may be new (or previously overlooked). Polyp recurrence is substantial in follow-up studies, varying from 16% to 56% after 1-year follow-up. Tattooing in the area of the follow-up polyp has been used with success [180]. The tattoo stain has been reported to last for years [184]. However, for individual polyps, it is a laborious technique, with possible hazards [185,186], and has seen limited use. In studies of polyp growth, a strategy might be to remove all but one polyp so that reidentification will be simpler. However, this will destroy information concerning the growth of different polyps within one patient, and might lead to removal of adenomas while retaining a hyperplastic polyp. More than three-quarters of polyps < 5 mm are non-neoplastic [2,187] and cannot be separated visually from adenomas [2]. Moreover, this might lead to a tendency to keep the distal polyps, which are technically easier to follow up, discarding information on the growth pattern of the proximal polyps. For the identification of polyps during follow-up, the following data should be collected at each examination: 1 distance from anus by straightened endoscope; 2 segment localization; 3 description of body and base; 4 size; 5 distance from other intraluminal structures; 6 photographs [14]. By applying these data, a full agreement between two investigations was achieved in 79% of patients [183]. As no absolute criteria can be applied to separate multiple polyps, it was of particular value to have several observations for each patient from the annual examinations [14].

Cancer risk and ethics There might be a reluctance against not removing a potentially malignant structure. Polyps > 1 cm are at considerable risk of malignancy (see Table 28.6). However, polyps < 1 cm are very rarely malignant. The reported incidence of invasive cancer in polyps 5–9 mm in diameter is 0.5–0.9% [8,9], while in several large studies no polyps < 5 mm were found to be malignant [9,58,123]. In a study in which 196 polyps < 5 mm found in 106 patients were followed up for 2 years, with a redetection rate of 74%, none of the polyps finally removed was found to be malignant or showed signs of high-grade dysplasia [2]. In another study in which 259 polyps < 1 cm found in 116 patients were left in situ for a period of 3 years, 89% were redetected in 104 of the patients [14]. During annual colonoscopy, nine polyps had to be removed before the end of the study. None of the polyps that was followed up showed signs of invasive carcinoma. Two polyps contained areas of intramucosal carcinoma, and there was high-grade dysplasia in four polyps. One patient developed an invasive carcinoma at the second year of follow-up, probably due to incomplete removal of a large polyp at enrollment without obtaining a histological examination. In a poorly characterized study of

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257 patients with rectosigmoid polyps 2–15 mm in diameter left unresected for a period of 3–5 years, with follow-up examinations every 6–12 months, polyps were removed if they attained a size of 15 mm [180]. In two patients, invasive carcinoma developed from polyps of 7 and 10 mm, respectively. The smaller polyp was removed by snare resection, with no signs of malignant tissue at the excision base. Despite limited experience, we feel that growth studies of colorectal polyps should be considered safe, provided that polyps are < 10 mm in diameter and that frequent follow-up examinations are carried out. Cytologic smears of polyps can be performed at enrollment, but as part of scientific studies we cannot recommend biopsies, as this may shrink small polyps considerably and we do not know whether this may change the growth pattern. Such follow-up of polyps left in situ must be part of a predetermined study protocol. Until better markers of malignancy are found, all polyps must be removed during routine clinical practice in order to achieve a complete histological examination.

Observational polyp growth studies In a retrospective study before the advent of colonoscopy, polyps > 1 cm in diameter on radiographs were followed up for a mean period of 7 years (range 1–19) [168]. The cumulative risk of cancer at the polyp site at 5, 10, and 20 years was 2.5%, 8%, and 24%, respectively, indicating that the interval before malignant transformation may be long and that many polyps will never turn malignant. During the period of surveillance, 37% of the polyps enlarged and 4% could not be demonstrated at later radiography. Histology was unknown, although judging from the size we can assume that with few exceptions they must have been neoplastic. Ultimately, 47% of the polyps were removed and all were neoplastic. Knoernschild [180] followed 213 patients with an unspecified number of polyps 2–15 mm in diameter for 3–5 years before removal. A small tattoo mark was placed in the mucosa near the base of the polyp. He reported that only 4% of the polyps increased significantly in size, 70% were unchanged, while 8% decreased in size and 18% disappeared entirely, with the tattoo stain giving mute evidence of previous location and existence. Hoff and colleagues [42] discovered polyps in 35% (201 polyps in 112 persons) of 400 invited men and women aged 50–60 years, randomized from the local population registry. Polyps < 5 mm were not removed. At the 2-year follow-up examination, 74% of the polyps were redetected, in addition to 44 new polyps in 30 persons. All polyps were measured with a 2-mm linear measuring probe. No polyp increased in size beyond 5 mm. Only 35 of the redetected polyps were adenomas (25%); 17 of the adenomas showed growth from a mean of 2.8– 4.1 mm, 13 remained unchanged, and five showed a mean regression of 1.2 mm. There was an overall mean increase of 0.5 mm for all the adenomas. Moreover, the hyperplastic polyps also significantly increased in size

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by a mean of 0.5 mm in diameter, while the mucosal tags remained unchanged. This compares well with another study [14], where 58% of the adenomas < 5 mm increased in size (n = 31), with a mean of 0.5 mm in 3 years. Hoff and colleagues [42] also calculated the increase in polyp mass, with a 16% mean increase in diameter of the adenomas, resulting in a 136% increase in calculated polyp mass. In an intervention study [181], 116 polyp-bearing patients were followed for 3 years with annual colonoscopic examinations, leaving all polyps < 10 mm in situ. The patients received a placebo-controlled daily mixture of β-carotene 15 mg, vitamin C 150 mg, vitamin E 75 mg, selenium 101 μg, and calcium carbonate 1.6 g, with the intention of reducing polyp growth or polyp recurrence. The surprising finding was that while adenomas or hyperplastic polyps < 5 mm showed significant growth, those 5–9 mm showed a slight net regression in size, although not significant (Figures 28.2–28.4) [14]. This was true for both the patients receiving placebo and those receiving active medication, and was also demonstrated using computerized picture analysis to estimate polyp area. This is contrary to the expected growth of adenomas 5–9 mm in diameter. It may be speculated that most polyps grow to a certain size between 5 and 10 mm, and thereafter turn into spontaneous regression. However, this “rise and fall” of the polyps is not readily explained by any biological model. However, it may partially explain the discrepancy between the prevalence of colorectal polyps and the incidence of cancer. Only few adenomas would be expected to grow to a size that increases the malignant potential. In order to test this hypothesis further, a much longer period of observation is required, and for ethical reasons polyps > 10 mm will have to be removed.

20

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Polyps (n)

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0

–3

–2

–1

0

1

2

3

4

Change in diameter (mm)

Figure 28.2 Change in diameter of 68 adenomas in 40 patients taking placebo for a period of 3 years. (From Hofstad et al. [14].)

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4

Change in diameter (mm)

3

Figure 28.3 Change in diameter of 68 adenomas in 40 patients taking placebo after an observation period of 3 years, in relation to initial size of the polyps. The scatterplot is presented as a flower diagram, in which each line emanating from a point represents an exact overlap. Nonoverlapping registrations are presented as triangles. Regression line with confidence limits are drawn. (From Hofstad et al. [14].)

2 1 0 –1 –2 –3 2

3

4

5

6

7

8

9

n.s.

n.s.

p<0.05

–

n.s. Polyp diameter <5 mm 5–9 mm

0.6

–

– Change in diameter (mm)

0.4

Figure 28.4 Mean change in diameter of the adenomas (95% confidence interval) in patients taking placebo at each annual endoscopic follow-up and from inclusion to the third-year control (0–3 years) for polyps < 5 mm (n = 27–43) and polyps 5–9 mm in diameter (n = 32–43). P-values for the differences between growth of the smaller and larger polyps are indicated on top. (From Hofstad et al. [14].)

10

Initial polyp diameter (mm)

– –

0.2

0

–0.2

–

–0.4

–

–0.6

– 0–1 year

In the same study, Hofstad and colleagues [14] observed polyps regressing (Figure 28.5), remaining unchanged, and growing (Figure 28.6) in the same patient in 22% of cases. No specific tendency to growth or regression has been seen in different colonic segments. Significant growth in adenomas in younger patients (50–59 years) has been observed, but this comprised only 10 patients. Moreover, the patients with multiple adenomas (> 2) had a significantly larger growth than those with only one polyp. There was no difference in polyp growth between the genders. Two polyps showed an intramucosal carcinoma on removal, one had regressed from 9 to 7 mm in diameter over 3 years, and another had increased from 8 to 11 mm in 1 year. Another four tubular adenomas with high-grade dysplasia changed minimally over 3 years,

1–2 year

2–3 year

0–3 year

Observation period

except one that grew from 8 to 12 mm in 2 years. The rest of the polyps showed only low-grade dysplasia.

Risk factors for polyp growth Colon carcinogenesis is a multistep process involving initiation, growth, and finally malignant transformation of the polyp. The factors influencing the different steps may not be identical. In order to identify risk and protective factors for polyp growth, some studies have regarded small and large polyps separately, with the presumption that factors influencing the prevalence of large, but not small, polyps affect polyp growth. Hoff and colleagues [68] found that dietary fat intake was higher while fiber and iron was lower in patients with polyps

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(d)

Figure 28.5 Images of a regressing tubular adenoma, from 8 to 6 mm in 3 years: (a) polyp at enrollment; (b) first-year follow-up; (c) second-year follow-up; (d) third-year completion.

Figure 28.6 Images of an adenoma increasing in diameter from 5 to 7 mm in 3 years, presented in the same sequence as in Fig. 28.5.

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> 5 mm, but not in patients with only smaller polyps. The same was found in another study for patients with small (< 5 mm), medium (5– 9 mm), and large (≥ 10 mm) polyps [81]. It was reported that patients also consumed less carbohydrates, and the women had lower intake of calcium and vitamin C than the controls. Moreover, BMI [84] and alcohol [76] were found to be promoters of adenoma growth, with no effect from tobacco [71]. In another study, adjusting for smoking, alcohol use, and BMI, a low rice consumption and high meat intake was associated with increased risk of polyps > 5 mm, while this was not found when all the polyps were smaller [188]. Finally, alcohol intake was higher in patients with polyps > 1 cm than in those with smaller adenomas [99]. Only one study analyzing the effect of nutrients on growth of polyps has been published [189]. Over a period of 2 years, the relative risk of increased mass of the polyps (5 mm or smaller), both including and excluding new polyp formation, showed a trend toward an inverse relationship for intake of dietary fiber, nonfiber carbohydrate, and cruciferous vegetables, reaching significance only for fiber in men. The relative risk of enlarged adenoma mass for men increased with higher fat intake. A small intervention study on the effect of sulindac and piroxicam on the growth of colorectal polyps showed no change in size of the polyps after 6 months [190]. In another negative study [191] in patients with polyps < 10 mm followed for 3 years, a placebo-controlled mixture of calcium, vitamins A, C, and E, and selenium had no effect on polyp growth (adenomas or hyperplastic polyps), on polyps in the different segments of the colon, for the patients with family history of cancer, nor was a gender difference found. A significant protective effect of the trial mixture was found in a small group of patients 50–60 years of age. The Scandinavian group assessed the possible effects of several genetic and protein markers on growth of small adenomas that were left in situ for 3 years. Tumor growth was greater in women than in men and was high in the presence of K-ras mutation. Some adenomas regressed in size over the 3-year follow-up interval, and none of these had K-ras mutations, compared with 20% of those that did not change or increased in size. None of the other markers studied were correlated with polyp growth [192]. A family history of colorectal cancer is a strong risk factor for adenoma growth, as demonstrated in a 3-year endoscopic follow-up study where polyps were left in situ before removal. The adenoma cases with a family history of colorectal cancer showed growth during this follow-up interval [193].

Summary At present, we have considerable knowledge about the prevalence of polyps and the incidence after polypectomy, while few studies on polyp incidence in polyp-free individuals and

on polyp growth have been conducted. In future studies on polyp growth, interest should be concentrated on the search for specific markers in medium-sized adenomas (5–9 mm) that show further growth potential. Recent years have seen the publication of large intervention studies using dietary factors, micronutrients and antioxidants, and chemotherapeutics, with polyp recurrence as primary endpoint. These give insight into the possibility of primary prevention of colorectal cancer. Research in the future should be in combination with the advancing information from molecular biology.

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newly diagnosed adenomatous polyps. The National Polyp Study Workgroup. N Engl J Med 1993; 328: 901–6. Triantafyllou K, Papatheodoridis GV, Paspatis GA, Vasilakaki TH, Elemenoglou I, Karamanolis DG. Predictors of the early development of advanced metachronous colon adenomas. Hepatogastroenterology 1997; 44: 533– 8. van Stolk RU, Beck GJ, Baron JA, Haile R, Summers R. Adenoma characteristics at first colonoscopy as predictors of adenoma recurrence and characteristics at follow-up. The Polyp Prevention Study Group. Gastroenterology 1998; 115: 13–18. Alberts DS, Martinez ME, Roe DJ, et al. Lack of effect of a highfiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians Network. N Engl J Med 2000; 342: 1156– 62. Noshirwani KC, van Stolk RU, Rybicki LA, Beck GJ. Adenoma size and number are predictive of adenoma recurrence: implications for surveillance colonoscopy. Gastrointest Endosc 2000; 51: 433–7. Riff ER, Dehaan K, Garewal GS. The role of sigmoidoscopy for asymptomatic patients. Results of three annual screening sigmoidoscopies, polypectomy, and subsequent surveillance colonoscopy in a primary-care setting. Cleve Clin J Med 1990; 57: 131–6. Brint SL, DiPalma JA, Herrera JL. Colorectal cancer screening: is one-year surveillance sigmoidoscopy necessary? Am J Gastroenterol 1993; 88: 2019– 21. Maule WF. Screening for colorectal cancer by nurse endoscopists. N Engl J Med 1994; 330: 183–7. Krevsky B, Fisher RS. Yield of rescreening for colonic polyps using flexible sigmoidoscopy Am J Gastroenterol 1994; 89: 1165–8. Rex DK, Lehman GA, Ulbright TM, Smith JJ, Hawes RH. The yield of a second screening flexible sigmoidoscopy in averagerisk persons after one negative examination. Gastroenterology 1994; 106: 593– 5. Platell CF, Philpott G, Olynyk JK. Flexible sigmoidoscopy screening for colorectal neoplasia in average-risk people: evaluation of a five-year rescreening interval. Med J Aust 2002; 176: 371–3. Hixson LJ, Fennerty MB, Sampliner RE, McGee DL, Garewal H. Two-year incidence of colon adenomas developing after tandem colonoscopy. Am J Gastroenterol 1994; 89: 687– 91. Squillace S, Berggreen P, Jaffe P, et al. A normal initial colonoscopy after age 50 does not predict a polyp-free status for life. Am J Gastroenterol 1994; 89: 1156–9. Neugut AI, Jacobson JS, Ahsan H, et al. Incidence and recurrence rates of colorectal adenomas: a prospective study. Gastroenterology 1995; 108: 402– 8. Rex DK, Cummings OW, Helper DJ, et al. 5-year incidence of adenomas after negative colonoscopy in asymptomatic averagerisk persons. Gastroenterology 1996; 111: 1178– 81. Thiis-Evensen E, Hoff GS, Sauar J, Majak BM, Vatn MH. The effect of attending a flexible sigmoidoscopic screening program on the prevalence of colorectal adenomas at 13-year follow-up. Am J Gastroenterol 2001; 96: 1901–7. Imperiale TF, Glowinski EA, Lin-Cooper C, Larkin GN, Rogge JD, Ransohoff DF. Five-year risk of colorectal neoplasia after negative screening colonoscopy. N Engl J Med 2008; 359: 1218–24. Schoen RE, Pinsky PF, Weissfeld JL, et al. Results of repeat sigmoidoscopy 3 years after a negative examination. JAMA 2003; 290: 41– 8.

146 Burke CA, Elder K, Lopez R. Screening for colorectal cancer with flexible sigmoidoscopy: is a 5-yr interval appropriate? A comparison of the detection of neoplasia 3 yr versus 5 yr after a normal examination. Am J Gastroenterol 2006; 101: 1329–32. 147 Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 2006; 130: 1872–85. 148 Kronborg O, Hage E, Adamsen S, Deichgraeber E. Follow-up after colorectal polypectomy. II. Repeated examinations of the colon every 6 months after removal of sessile adenomas and adenomas with the highest degrees of dysplasia. Scand J Gastroenterol 1983; 18: 1095– 9. 149 Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008; 134: 1570–95. 150 Jacobsen JS, Neugut AI, Murray T, et al. Cigarette smoking and other behavioral risk factors for recurrence of colorectal adenomatous polyps (New York City, NY, USA). Cancer Causes Control 1994; 5: 215–20. 151 DeCosse JJ, Adams MB, Kuzuma JF, LoGerfo P, Condon RE. Effect of ascorbic acid on rectal polyps of patients with familial polyposis. Surgery 1975; 78: 608–12. 152 Bussey HJR, DeCosse JJ, Deschner EE, et al. A randomized trial of ascorbic acid in polyposis coli. Cancer 1982; 50: 1434–9. 153 Waddell WR, Loughry RW. Sulindac for polyposis of the colon. J Surg Oncol 1983; 24: 83–7. 154 Waddell WR, Ganser GF, Cerise EJ, Loughry RW. Sulindac for polyposis of the colon. Am J Surg 1989; 157: 175–9. 155 Nugent KP, Farmer KCR, Spiegelman AD, Williams CB, Phillips RKS. Randomized controlled trial of the effect of sulindac and cell proliferation in patients with familial adenomatous polyposis. Br J Surg 1993; 80: 1618–19. 156 Grau MV, Baron JA, Barry EL, et al. Interaction of calcium supplementation and nonsteroidal anti-inflammatory drugs and the risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 2005; 14: 2353– 8. 157 Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873– 84. 158 Tangrea JA, Albert PS, Lanza E, et al. Non-steroidal antiinflammatory drug use is associated with reduction in recurrence of advanced and non-advanced colorectal adenomas (United States). Cancer Causes Control 2003; 14: 403–11. 159 Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355: 885–95. 160 Sansbury LB, Bergen AW, Wanke KL, et al. Inflammatory cytokine gene polymorphisms, nonsteroidal anti-inflammatory drug use, and risk of adenoma polyp recurrence in the polyp prevention trial. Cancer Epidemiol Biomarkers Prev 2006; 15: 494–501. 161 Robertson DJ, Sandler RS, Haile R, et al. Fat, fiber, meat and the risk of colorectal adenomas. Am J Gastroenterol 2005; 100: 2789–95. 162 Kimura Y, Kono S, Toyomura K, et al. Meat, fish and fat intake in relation to subsite-specific risk of colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Sci 2007; 98: 590–7.

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163 Lanza E, Hartman TJ, Albert PS, et al. High dry bean intake and reduced risk of advanced colorectal adenoma recurrence among participants in the polyp prevention trial. J Nutr 2006; 136: 1896–903. 164 Roncucci L, Di Donato P, Carati L, et al. Antioxidant vitamins or lactulose for the prevention of the recurrence of colorectal adenomas. Dis Colon Rectum 1993; 36: 227–34. 165 Greenberg ER, Baron JA, Tosteson TD, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 1994; 331: 141–7. 166 Togashi K, Shimura K, Konishi F, et al. Prospective observation of small adenomas in patients after colorectal cancer surgery through magnification chromocolonoscopy. Dis Colon Rectum 2008; 51: 196–201. 167 Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319: 525–32. 168 Stryker SJ, Wolff BG, Culp CE, Libbe SD, Ilstrup DM, MacCarthy RL. Natural history of untreated colonic polyps. Gastroenterology 1987; 93: 1009–13. 169 Waye JD, Lewis BS, Frankel A, Geller SA. Small colon polyps. Am J Gastroenterol 1988; 83: 120–2. 170 Loeve F, Boer R, Zauber AG, et al. National Polyp Study data: evidence for regression of adenomas. Int J Cancer 2004; 111: 633–9. 171 Margulies C, Krevsky B, Catalano MF. How accurate are endoscopic estimates of size? Gastrointest Endosc 1994; 40: 174– 7. 172 Fennerty MB, Davidson J, Emerson SS, Sampliner RE, Hixson LJ, Garewal HS. Are endoscopic measurements of colonic polyps reliable? Am J Gastroenterol 1993; 88: 496–500. 173 Vakil N, Smith W, Bourgeois K, Everbach EC, Knyrim K. Endoscopic measurement of lesion size: improved accuracy with image processing. Gastrointest Endosc 1994; 40: 178– 83. 174 Morales TG, Sampliner RE, Garewal HS, Fennerty MB, Aickin M. The difference in colon polyp size before and after removal. Gastrointest Endosc 1996; 43: 25– 8. 175 Margulies C, Schoen RE, Gerber LD, Weissfeld JL. Inaccurate polyp size estimation can affect patient management. Endoscopic estimates of polyp size should be abandoned in favor of the pathologist’s measurement. Gastrointest Endosc 1996; 43: 368. 176 Shenoy V, Chourdhry U, Gopalswamy N, et al. Is in vivo measurement of size of polyps during colonoscopy accurate? Gastrointest Endosc 1996; 43: 371. 177 Hofstad B, Vatn M, Larsen S, Osnes M. Reliability of in situ measurements of colorectal polyps. Scand J Gastroenterol 1992; 27: 59–64. 178 Hofstad B, Vatn M, Larsen S, Huitfeldt HS, Osnes M. In situ measurement of colorectal polyps to compare video and fiberoptic endoscopes. Endoscopy 1994; 26: 461–5.

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179 Gopalswamy N, Shenoy VN, Choudhry U, et al. Is in vivo measurement of size of polyps during colonoscopy accurate? Gastrointest Endosc 1997; 46: 497–502. 180 Knoernschild HE. Growth rate and malignant potential of colonic polyps: early results. Surg Forum 1963; 14: 137–8. 181 Hofstad B, Vatn M, Hoff G, Larsen S, Osnes M. Growth of colorectal polyps. Design of a prospective, randomized, placebo controlled intervention study in patients with colorectal polyps. Eur J Cancer Prev 1992; 1: 415–22. 182 Kronborg O, Hage E, Deichgraeber E. The clean colon. Scand J Gastroenterol 1981; 16: 879– 84. 183 Hofstad B, Vatn M, Larsen S, Osnes M. Growth of colorectal polyps: recovery and evaluation of unresected polyps of less than 10 MM, 1 year after detection. Scand J Gastroenterol 1994; 29: 640–5. 184 Hyman N, Waye JD. Endoscopic four quadrant tattoo for the identification of colonic lesions at surgery. Gastrointest Endosc 1991; 37: 56–8. 185 Park SI, Genta RS, Romeo DP, Weesner RE. Colonic abscess and focal peritonitis secondary to india ink tattooing of the colon. Gastrointest Endosc 1991; 37: 68–71. 186 Coman E, Brandt LJ, Brenner S, Sablay B, Bennet B. Fat necrosis and inflammatory pseudotumor due to endoscopic tattooing of the colon with india ink. Gastrointest Endosc 1991; 37: 65–8. 187 Cannon-Albright LA, Bishop T, Samowitz W, DiSario JA, Lee R, Burt RW. Colonic polyps in an unselected population: prevalence, characteristics, and associations. Am J Gastroenterol 1994; 89: 827–31. 188 Kono S, Imanishi K, Shinchi K, Yanai F. Relationship of diet to small and large adenomas of the sigmoid colon. Jpn J Cancer Res 1993; 84: 13–19. 189 Hoff G, Moen IE, Trygg K, et al. Colorectal adenoma and food. Scand J Gastroenterol 1988; 23: 1253– 8. 190 Hixson LJ, Earnest DL, Fennerty MB, Sampliner RE. NSAID effect on sporadic colon polyps. Am J Gastroenterol 1993; 88: 1652–6. 191 Hofstad B, Almendingen K, Vatn M, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998; 59: 148–56. 192 Løvig T, Thorstensen L, Hofstad B, et al. Genetic and protein markers related to in situ growth and multiplicity in small sporadic colorectal adenomas. Scand J Gastroenterol 2003; 38: 298–306. 193 Almendingen K, Hofstad B, Vatn MH. Does a family history of cancer increase the risk of occurrence, growth, and recurrence of colorectal adenomas? Gut 2003; 52: 747–51.

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Pathology of Colorectal Polyps Noam Harpaz Mount Sinai School of Medicine, New York, NY, USA

Introduction The widespread use of endoscopy has led to a dramatic increase in the numbers and varieties of colorectal polyps referred for pathologic evaluation. These range from the commonplace to the esoteric, and include neoplastic polyps of epithelial, mesenchymal, neural and mixed compositions, as well as inflammatory, mechanically induced, and other non-neoplastic lesions (Table 29.1). This chapter will review the histopathology of the more common colorectal polyps, the pathogenesis, nomenclature, and management of polyps directly implicated in the histogenesis of colorectal cancer, and technical and procedural precautions which endoscopists and pathologists should observe to assure accurate pathologic diagnoses. Although the emphasis is on sporadic polyps, much of the pathologic detail applies equally to corresponding polyposis syndromes. Accurate pathologic diagnosis of endoscopically resected colorectal polyps depends upon four main components: (i) technical factors related to specimen preservation and processing, (ii) clinical and endoscopic data provided by the clinician, (iii) interpretation of the histological findings and assessment of their clinical significance, and (iv) communication of the findings to the clinician in a complete and meaningful form.

Diagnostic accuracy There have been few systematic efforts to verify the accuracy of surgical pathologists in classifying polyps and to evaluate their specific strengths and weaknesses [1,2]. In a study of general community pathologists challenged with a small assortment of colorectal polyps, correct classification was achieved for 94% of adenomas and 75–80% of hyperplastic,

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

inflammatory, and juvenile polyps, but for only 20% of hamartomatous and prolapsing mucosal polyps, which are less commonly encountered in routine practice. Significantly, 9% of malignant polyps were misdiagnosed as benign, half were reported without indication as to tumor grade or status of the transection margins, and 22% of benign polyps with high-grade dysplasia were incorrectly interpreted as malignant [2]. Several other studies dealing with finer histological distinctions related to growth patterns and the grading of dysplasia have reported only fair to moderate levels of intraand interobserver agreement [3–6]. Additional diagnostic challenges have been posed by the recent recognition of complex serrated polyps as distinct entities, even experts in this field failing to surpass moderate levels of interobserver agreement [7,8].

Histological artifacts Tissue morphology is sensitive to various factors that affect the preservation, sampling, and orientation of the polypectomy specimen. Serious artifacts may be introduced during the polypectomy procedure itself, most commonly by thermal electrocoagulation and tissue crushing. The combined effects depend on the severity of the insults relative to the size and geometry of the polyp, and range anywhere from mild nuclear distortion to complete effacement of morphological detail. Diminutive polyps (< 5 mm in diameter) are especially vulnerable to various artifacts. A series of 119 diminutive polypectomy specimens reviewed independently by three pathologists reported an average of 16.5% of nondiagnostic specimens resulting from thermal electrocoagulation artifact. The rates of pathologist agreement decreased with diminishing polyp size, discrepancies being most apparent below 2 mm [9]. Large polyps subjected to prolonged or multiple exposures to snare electrocoagulation, such as those with thick pedicles or requiring piecemeal resection, incur tissue artifacts along the transection lines. These rarely preclude classification of the polyp, but in the case of malignant polyps can interfere with the evaluation of cancer near the transection margins.

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Table 29.1 Colorectal polyps. Benign neoplastic polyps Epithelial Adenoma Traditional serrated adenoma Sessile serrated polyp/adenoma Hyperplastic polyp Mixed adenoma–hyperplastic polyp Mixed adenoma–carcinoid Mesenchymal Leiomyoma Benign gastrointestinal stromal tumor Lipoma Hemangioma Lymphangioma Fibroblastic polyp Mast cell tumor Lymphoid polyp Neurogenic Granular cell tumor Spindle cell schwannoma Epithelioid schwannoma Plexiform schwannoma Perineurioma Neurofibroma Malignant neoplastic polyps Epithelial Adenoma with invasive carcinoma Polypoid adenocarcinoma Carcinoid tumor Metastatic carcinoma, melanoma Mesenchymal Malignant gastrointestinal stromal tumor Leiomyosarcoma Extranodal malignant lymphoma Granulocytic sarcoma Kaposi’s sarcoma Non-neoplastic polyps Inflammatory polyp Juvenile polyp Polyp of Cronkhite–Canada syndrome Inflammatory polyp Inflammatory fibroid polyp Inverted diverticulum Mucosal prolapse-associated polyp Hamartomatous (Peutz–Jeghers) polyp Myoglandular polyp Lymphoid polyp Pneumatosis coli Fibroepithelial polyp Amyloidoma Malakoplakia Endometriosis Gastric heterotopia Elastofibroma

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Adequate fixation of polyps requires immersion in a 10- to 20-fold volume of fixative for at least several hours, larger specimens requiring longer fixation. Fixation in an inadequate volume of fixative not only incurs needless processing delays but, worse, could cause serious losses of morphological detail if the polyp is inadvertently processed before fixation is complete.

Polyp orientation and sampling The transection margin is a critical landmark guiding the proper orientation of polyps during gross sectioning and paraffin embedding (Figure 29.1). It typically presents as a white patch on the surface of the polyp, but may retract spontaneously into the polyp’s core. To assure its identification, the endoscopist should routinely mark the base of the polypectomy specimen with India ink or impale it on a pin. It is the responsibility of the pathologist who oversees the laboratory to assure that protocols for the processing of polypectomy specimens into slides are established, that they are adhered to by laboratory personnel, and that all the technical aspects of slide preparation are subject to a rigorous quality assurance program. The processing of three-dimensional polyps into twodimensional slides results in variations among different planes of section. Theoretically, sampling error could be eliminated if each tissue block were sectioned exhaustively into slides; however, the costs in terms of laboratory and pathologist resources would be impractical. In practice, each pathologist or laboratory determines the thoroughness with which polyps are sectioned. Specimens small enough to be embedded intact as a single tissue block are reportedly subject to false-negative rates (i.e., no histological evidence of a polyp) of 10–32% [10–12]. Given that diminutive polyps identified at endoscopy frequently correspond to insignificant mucosal irregularities or lymphoid follicles, most laboratories understandably report their initial negative findings without ordering deeper sections of the tissue block. However, a study of polyps whose initial slides were negative reported a 23% yield of new microscopic findings in additional slides, including a 10% yield of neoplastic polyps such as adenomas, with the corresponding incremental costs being approximately $10 per case and $95 per adenoma [11]. Clearly, any suggestion by the endoscopist that a significant finding has been overlooked should elicit further sectioning of the tissue block. The potential for clinically important sampling error is greater for large adenomas, especially those that might be harboring cancer. Such polyps are initially sectioned sagittally, preferably two to three sections per centimeter diameter on either side of the midline, and each section then embedded in paraffin as a separate tissue block for processing into slides (see Figure 29.1). Some authors recommend bisecting such polyps; however, in the case of adenomas harboring cancer near the transection line, this may result in loss of the point

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Figure 29.1 (a) The transection line is identified as a pale patch before a polyp is sectioned (arrow). (b) The polyp is sectioned sagittally on either side of the midline and each section placed in a cassette for processing. Arrow denotes the transection margin.

(a)

of deepest invasion when the histotechnician trims the face of the paraffin block in preparation for sectioning. Merely sampling large polyps in lieu of total embedding is strongly discouraged, as it incurs a substantial risk of missing important pathology. A recent study based on a series of large but grossly benign-appearing polyps calculated that a “one slide per centimeter” sampling protocol would have reduced the likelihood of detecting carcinomas to unacceptably low levels in four out of five malignant polyps, and would have missed high-grade dysplasia in 7 out of 12 benign polyps [13]. The optimal number of step sections from each block of large adenomas needed to assure adequate representation of the pathology has not been studied systematically; however, a minimum of three step sections per block has been recommended on empirical grounds [14]. Parenthetically, when slides of a large or diagnostically challenging polyp are referred to another pathologist for a second opinion, all step sections should be sent together. The author has encountered instances in which different sections of a single polyp referred to different pathologists yielded discordant diagnoses due to findings that were present in some sections but not others.

Clinical–pathologic correlation As in any other consultative arrangement, pathologist access to the patient’s clinical history, endoscopic findings, and the particulars of the procedure itself can have a critical bearing on the accuracy of the interpretation. For example, the distinction between “lookalike” polyps, such as adenomas and dysplastic polyps in inflammatory bowel disease, or between certain juvenile and inflammatory polyps, may depend entirely on clinical and endoscopic context provided by the gastroenterologist. Similarly, the wording and therapeutic implications of a cancer diagnosis may be quite different if rendered on a complete polypectomy specimen or an incomplete biopsy, yet slides of the two may be indistinguishable. Accordingly, a conscientious effort by the endoscopist to provide adequate clinical and endoscopic data (e.g., by routinely sending a copy of the endoscopy report together with each specimen) is a sound investment in quality care.

Pathology of Colorectal Polyps

(b)

Adenomatous polyps Colorectal adenomas, defined as benign neoplasms of the large intestinal epithelium, account for approximately two-thirds of endoscopically detected colorectal polyps in the USA. They are the direct precursors of most colorectal cancers in the general population, each carrying a roughly 5% a priori lifetime probability of progressing to malignancy. The opportunity to abort the adenoma–cancer sequence by identifying and removing adenomatous polyps endoscopically has placed endoscopy at the front line of colorectal cancer prevention.

Classification Adenomas are subclassified pathologically based on four features: 1 size 2 gross configuration (sessile, semisessile, pedunculated, or flat/depressed) 3 architecture (tubular, tubulovillous, villous, serrated) 4 grade of dysplasia. Adenomas vary over 10 000-fold in size from single neoplastic crypts at one extreme to carpet-like growths involving entire colonic segments at the other. According to data from the US National Polyp Study (which pertain only to endoscopically resectable polyps), 38% of adenomas are ≥ 5 mm, 36% are 6–10 mm, and 26% are > 10 mm [15]. Size correlates in turn with other important pathologic and clinical parameters, such as gross configuration, architecture, grade of dysplasia, prevalence of invasive cancer, incidence of local recurrence, and incidence of synchronous and metachronous adenomas [16,17]. For example, the prevalence of invasive cancer in diminutive adenomas is less than 0.1% [18] but increases to 30% in adenomas larger than 5 cm [19]. Parenthetically, measurements of polyp size after resection are not affected by formalin fixation; however, polypectomy itself results in shrinkage of 18% on average compared with measurements made in vivo [20]. Polyp configuration is of importance in determining cancer depth if malignancy is detected, and should be stated by the endoscopist. Once resected, pedunculated and sessile

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Figure 29.3 Tubulovillous adenoma.

(b) Figure 29.2 Tubular adenomas. (a) Diminutive tubular adenoma corresponding to a collection of slightly crowded crypts occupying the upper half of the lamina propria. The dysplastic epithelium, with its crowded, elongated nuclei and reduced mucin content, stands out from the background of normal crypts. (b) Pedunculated tubular adenoma.

adenomatous polyps are not easily distinguished by the pathologist, since pedunculated polyps may be resected with little or none of the stalk and, conversely, sessile polyps may include a pseudo-pedicle formed from adjacent mucosa. Microscopically, pedunculation can sometimes be inferred microscopically from the presence of thick-walled blood vessels within the submucosa. Tubular adenomas account for 99% of diminutive adenomas and 65–87% of all resectable adenomas [15,21–24]. Microscopically, they consist of parallel, crowded, neoplastic crypts which retain the basic architecture of normal colorectal mucosa, occupying either the full height of the mucosa or its superficial portion (Figure 29.2). With increasing polyp size, the crypts grow progressively elongated and coiled and may develop villous characteristics. Tubulovillous adenomas consist of mixed tubular and villous growth patterns, each occupying 20–80% of the polyp (Figure 29.3). Although they account for 8% of adenomas overall, tubulovillous adenomas account

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for approximately half of adenomas in the 1–2 cm range and one-third of the adenomas exceeding 2 cm. Villous adenomas consist of parallel villiform processes constituting at least 80% of the polyp (Figure 29.4). They account for approximately 5% of adenomas overall, 60% of adenomas exceeding 2 cm, and virtually all large carpet-like adenomas. The villous growth pattern correlates with the presence of high-grade dysplasia and invasive carcinoma independently of other pathologic characteristics [15,23]. These data should be considered approximations, since the definitions of tubules and villi are imprecise and agreement levels among pathologists in subclassifying adenomas are only fair to moderate [6].

Adenoma–cancer sequence: molecular pathogenesis The molecular counterpart of the adenoma–cancer sequence is a process of stepwise accrual of genetic defects in the intestinal epithelium that progressively impair cellular control of functions related to the proliferation and preservation of genomic stability. The initial event involves somatic mutations of components of the Wnt signaling pathway, usually involving the APC gene. The product of this gene, through its associations with the microtubular system and with other components of the Wnt signaling pathway, plays a key role in regulating chromosomal stability and proliferation. Loss of normal APC function results in abnormal chromosomal segregation during mitosis and in the stabilization of β-catenin, which activates multiple genes involved in promoting cell proliferation and survival. Epithelial cells bearing these mutations are therefore characterized by chromosomal instability, allelic imbalance, increased proliferation, and prolonged survival. These abnormalities set the stage for additional mutations, such as activation of K-ras and silencing of tumor-suppressor

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Figure 29.5 Low-grade dysplasia (left) contrasted with normal epithelium (right). Dysplastic epithelium contains elongated, crowded, dark-staining nuclei in a so-called “picket fence” pattern. Goblet cell mucin is diminished and the absorptive and goblet cell phenotypes are indistinct. The location of the dysplastic nuclei in the basal half of each cell reflects retained cellular polarity. Normal epithelium contains small, round, pale basal nuclei and distinct goblet and absorptive cell phenotypes.

(a)

(b) Figure 29.4 Villous adenoma. (a) The polyp is broad-based and composed of long, slender villi with tapered tips. (b) Crowded, dark-staining nuclei are visible at higher magnification. Most of the cells contain mucin vacuoles, which could result in mucoid secretions.

genes on chromosome 18q21 and activation of p53, resulting in further genomic destabilization and impaired control of cell proliferation. The cancer phenotypes that ultimately emerge are therefore characterized by aneuploidy, allelic imbalance, and chromosomal translocations, gains, and losses [25].

Dysplasia The defining feature of adenomatous epithelium is dysplasia, also termed intraepithelial neoplasia in the World Health Organization and Vienna classification systems [26,27]. Dysplasia is defined as a constellation of histological changes indicating that the epithelium has undergone unequivocal neoplastic transformation, yet has remained confined within the epithelial compartment in which it originated. More specifically, these are histological changes which imply the

presence of clonal genetic derangements, poorly regulated proliferation, impaired differentiation, and a predisposition to neoplastic progression [28]. For example, unlike normal epithelium, which proliferates in the basal region of the crypt and matures as it ascends toward the luminal surface, the dysplastic epithelium in adenomas proliferates ubiquitously with little or no tendency for maturation. The nuclei are typically crowded, darkly stained, and enlarged relative to total cell volume, and the cytoplasm exhibits abnormal differentiation manifested by diminished, or less frequently increased, goblet cell mucin, blurred distinction between absorptive and goblet cell phenotypes, and inappropriate Paneth-like or endocrine differentiation. Dysplasia in adenomas is graded on a twotier scale of low and high grade based on histological criteria borrowed from the classification of dysplasia in inflammatory bowel disease [29]. The distinction between grades is based principally on retention or loss of cellular polarity and the severity of accompanying cytologic abnormalities. In low-grade dysplasia, the nuclei, albeit enlarged, elongated, and crowded, are arranged uniformly along the bases of the epithelial cells (Figure 29.5). In high-grade dysplasia, the nuclei are stratified haphazardly, with many located in the apical portions of the cells. They also tend to be larger, more heterogeneous in size and orientation, and more cytologically atypical, featuring irregular nuclear membranes, macronucleoli, or abnormal mitotic figures (Figure 29.6). As a rule, the cytoplasm in highgrade dysplasia retains less differentiation (e.g., goblet cells or Paneth-like cells) than in low-grade dysplasia. Of course, all these changes lie on a continuum. As a result, the grading of dysplasia in adenomas, as in inflammatory bowel disease, is subjective and variable among different observers [6].

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(a)

(a)

(b)

(b) Figure 29.6 (a) High-grade dysplasia featuring undifferentiated colonocytes with stratified nuclei, many occupying the apical portion of the epithelial cells. (b) High-grade dysplasia incorporates “in situ carcinoma” (arrow), corresponding to crypts with cribriform, or sieve-like, pattern. The smooth, rounded crypt outlines indicate that there is no penetration beyond the basement membrane.

High-grade dysplasia Dysplastic epithelium by definition lacks the capacity for invasion and metastasis, irrespective of grade. As a result, a diagnosis of high-grade dysplasia in a completely resected adenoma, even if extreme (formerly in situ carcinoma), has no immediate clinical significance. Rather, it is one of several factors that make up the patient’s colorectal cancer risk profile, along with individual and hereditary risk factors, and adenoma multiplicity and size, all of which should be factors in determining the nature and frequency of future endoscopic examinations [30]. Use of the term “adenoma with dysplasia” as a synonym for “adenoma with high-grade dysplasia” by some pathologists is discouraged due to its ambiguity and the erroneous implication

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Figure 29.7 Intramucosal adenocarcinoma. (a) Neoplastic glands that have penetrated beyond the basement into the lamina propria, but have not violated the muscularis mucosae (arrow). (b) The lamina propria is infiltrated by poorly differentiated neoplastic cells.

that there can exist adenomas without dysplasia. The term “in situ carcinoma” should also be avoided in favor of highgrade dysplasia, since its ominous connotations might lead to inappropriate anxiety and even unnecessary surgery.

Intramucosal carcinoma Intramucosal carcinoma in adenomas refers to the presence of neoplastic cells that have invaded the lamina propria but not the submucosa, and is classified as Tis in the TNM (tumor, node, metastases) system (Figure 29.7). Although it signifies a more advanced biological stage of neoplasia than high-grade dysplasia, and is capable of metastasis in organs other than the large intestine, follow-up studies have established that complete polypectomy is curative. The conventional rationale is that the large intestinal mucosa is nearly devoid of lymphatic channels, limiting the access of cancer cells to this route of dissemination; however, evidence suggests that

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mucosal lymphatics are more prevalent in adenomas and cancers than realized hitherto [31]. Whatever the explanation, curative outcomes after polypectomy are the rule even when the intramucosal cancer cells are poorly differentiated, despite the ominous significance of poorly differentiated carcinoma that has invaded the submucosa [32]. Given that the favorable nature of such lesions might not be familiar to many gastroenterologists and surgeons, the pathologist is advised to include an explanatory note to this effect whenever a diagnosis of intramucosal carcinoma is made. Using the term high-grade dysplasia rather than intramucosal carcinoma is often advocated (similar to the recommendation for in situ carcinoma) to reduce the risk of overtreatment. Conversely, any uncertainty regarding the presence of poorly differentiated carcinoma in the submucosa, as might occur with piecemeal or poorly oriented specimens, should be clearly stated, since conservative management might be inappropriate.

(a)

Misplaced mucosa Traumatic translocation of mucosal tissue from the head of an adenoma into the submucosa generally occurs in pedunculated adenomas greater than 1 cm in diameter and located in the rectosigmoid. Analogous changes may also occur in hyperplastic, serrated, hamartomatous, and prolapse-associated polyps. The main significance in all cases is the potential for pathologic confusion with invasive carcinoma. Microscopically, misplaced adenomatous mucosa typically presents as wellcircumscribed submucosal nests consisting of glands and investing lamina propria arranged in rounded, circumscribed lobules (Figure 29.8). The surrounding stroma may be sclerotic, and invariably contains hemosiderin deposits due to cumulative tissue hemorrhages. In addition, as a rule of thumb, the degree of dysplasia in the misplaced glands is similar to that of the epithelium in the head of the adenoma. However, distinction from invasive carcinoma may be extremely difficult if the lobulated pattern, the investing lamina propria, or the hemosiderin deposits are inconspicuous, if the surface and submucosal epithelium show high-grade dysplasia (Figure 29.8), or if there are mucin collections in the submucosa resembling those of mucinous carcinomas.

Invasive carcinoma The term “malignant polyp” in medical jargon refers to adenomas that harbor invasive adenocarcinoma (i.e., cancer cells deep to the colorectal muscularis mucosae) which is a necessary condition for metastasis to occur (Figure 29.9). Submucosal invasion is readily recognizable in most cases; however, the diagnosis may be difficult if the fibers of the muscularis mucosae are splayed, discontinuous, absent, or obscured by electrocautery artifact, or if the polyp is poorly oriented or underfixedaall commonplace features in large or piecemeal polypectomy specimens. Other evidence of submucosal invasion includes a desmoplastic stromal reaction, acute angulation of the tumor glands, a haphazard growth

(b) Figure 29.8 (a) Adenoma with well-circumscribed lobules of misplaced mucosa in the stalk. (b) Higher magnification reveals dysplastic crypts invested by lamina propria and accompanied by hemosiderin deposits (arrows).

pattern, and absence of hemosiderin deposits. The presence of complex epithelial clusters floating within mucous spaces and the absence of hemosiderin help distinguish welldifferentiated mucinous adenocarcinoma from mucin pools produced by misplaced mucosa, especially if these appear more dysplastic than the overlying mucosa. Adenomas containing early invasive cancer (i.e., cancer that invades into but not beyond the submucosa) can be segregated into low- and high-risk categories based on certain histopathologic criteria. Most authorities agree that conservative management is appropriate if the following conditions are met: 1 The cancer is well or moderately differentiated. 2 No cancer cells are present at or within 1 mm of the polypectomy margin. 3 There is no tumor invasion into venous or lymphatic channels.

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Figure 29.9 (a) Adenoma containing invasive moderately differentiated adenocarcinoma invading the upper stalk. The invasive front (arrow) is 5 mm from the cauterized margin, exceeding the 1 mm margin recommended for considering conservative management. (b) The malignant glands are angulated and surrounded by a desmoplastic

stromal reaction. (c) Another adenoma containing invasive poorly differentiated adenocarcinoma located less than 1 mm from the transection line (arrow). The high grade of the cancer and the inadequate margin each weigh independently against conservative management.

Tumors that fail to meet all of these criteria are associated with a 10–35% risk of adverse outcome (i.e., cancer recurrence or local metastasis) [33–37]. Other potentially adverse criteria include T1 invasion into the bowel submucosa proper [37], a condition met by all invasive cancers arising in sessile adenomas, and the presence of tumor cell “budding,” defined as the presence of five or more clusters of one to five poorly differentiated tumor cells at the invasive tumor front [38]. The transection margin of polypectomy specimens usually corresponds to a band of discoloration at the tissue edges resulting from thermal electrocoagulation. However, piecemeal resections that yield multiple polypoid fragments with separate electrocoagulation zones frequently preclude identification of a definitive margin unless the endoscopist has taken the precaution of submitting the polyp base as a separate specimen. The presence of cancer emboli within endothelial-lined channels is usually associated with poorly differentiated carcinomas, but occasionally with differentiated cancers that would otherwise be considered favorable candidates for conservative management. In such cases, care must be taken to avoid confusion between vascular channels and tissue retraction artifacts. Immunohistochemical staining for podoplanin or CD34 may be attempted as a means of highlighting lymphatic and vascular endothelial-lined channels, respectively.

by dysplastic mucosa that is up to twice the thickness of the adjoining mucosa. The dysplastic crypts occupy the superficial mucosa overlying normal crypts, at least at the periphery, those of flat adenomas maintaining uniform height throughout and those of depressed adenomas being shorter in the center than in the periphery. However, the histological features per se are not unique and may occur in conventional polypoid adenomas [39]. Despite reports of disproportionately high rates of high-grade dysplasia and early carcinoma [40,41], particularly in the depressed subtype [42,43], as well as distinctive patterns in the expression of certain genetic markers [44,45], the true prevalence of this entity in developed societies and its clinical significance remain unsettled [46,47].

Flat and depressed adenomas Flat and depressed adenomas are nonexophytic adenomas that are slightly elevated, may contain a central depression, and are usually less than 10 mm in diameter [23]. Although difficult to detect by routine endoscopy, they are purported to show aggressive growth characteristics and high rates of progression to cancer. Microscopically, they are characterized

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Serrated polyps “Serrated” neoplastic pathway Approximately 20% of colorectal cancers do not demonstrate chromosomal instability. These cancers usually exhibit high levels of microsatellite instability (MSI-H), genome-wide frameshift mutations, and silencing of multiple tumor-suppressor genes. Pathologically, they characteristically occur in the right colon and feature mucinous, signet ring or medullary histology, tumor-infiltrating lymphocytes, and peritumoral chronic inflammation. MSI-H colorectal cancers in the general population are usually associated with silencing of hMLH1, a DNA replication error repair gene, resulting from methylation of CpG (cytosine–guanine) dinucleotide sequences in its promoter region. This type of methylation usually corresponds to a global genetic abnormality, referred to as CIMP (CpG island methylation phenotype), in which nonrandom methylation of promoter regions throughout the genome results in altered

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Table 29.2 Serrated colorectal polyps. Nomenclature

Cytological dysplasia

Gross appearance and location

Histological and key molecular features

Proliferative compartment (Ki67 immunohistochemistry) [53]

Common molecular alterations

Hyperplastic polyp (metaplastic polyp)

No

Diminutive, domeshaped, smooth surface or mucin cap; predominantly left-sided

Overall symmetry Parallel tubular crypts Superficial serration Mitoses limited to lower and middle crypt zones Subtypes: microvesicular, goblet cell, mucin-poor K-ras or B-raf mutations CIMP (especially microvesicular type)

Increased, symmetric

K-ras or B-raf mutations CIMP MSI Prevalence rates vary with histological subtype and anatomical location (see text)

Sessile serrated polyp (sessile serrated adenoma, serrated polyp with abnormal proliferation)

No

Flat, broad-based, predominantly right-sided

Hyperserrated, dilated crypts Microvesicular and goblet cell epithelium Basal flattening and budding Mild nuclear abnormalities, occasional superficial mitoses

Irregular, asymmetric, variable

B-raf mutation CIMP

Serrated adenoma

Yes

Tall, eosinophilic cells

Decreased, limited to secondary (“ectopic”) crypts

Mixed serrated adenomatous polyp

Yes (focal)

Flat, sessile, or exophytic, predominantly left-sided

Corresponds to dominant lesion

MSI

Slender nuclei with dispersed chromatin Low mitotic rate Secondary (“ectopic”) crypts

Composite of hyperplastic polyp or sessile serrated polyp with conventional adenoma

MSI CIMP B-raf mutation K-ras+ subset with overlapping features of conventional adenoma–cancer pathway

Corresponds to dominant lesion

Corresponds to dominant lesions

CIMP, cytosine–guanine island methylator phenotype; MSI, microsatellite instability.

transcription of multiple tumor-related genes, promoting alternate pathways of colorectal carcinogenesis [48–51]. During the past decade, morphological, molecular, and clinical evidence has accrued supporting the concept that CIMP-positive colorectal cancers are preceded by a distinctive group of polyps with serrated crypt architecture that are morphologically distinct from conventional adenomas and are not necessarily even dysplastic in the conventional sense [52]. Thus, whereas all dysplastic polyps were previously classified as adenomas and all nondysplastic serrated polyps as hyperplastic polyps, the recognition of this expanded spectrum of potentially neoplastic serrated polyps (Table 29.2) has introduced new complexities in the nomenclature and classification of colorectal polyps as well as clinical uncertainties regarding their significance and the management of patients with these lesions.

Nondysplastic serrated polyps Hyperplastic polyps Hyperplastic polyps are common, typically diminutive, nondysplastic serrated polyps that are second in prevalence only to adenomas, occurring in 20–40% of adults in the USA and Western Europe. They occur throughout the colon but predominate in the left side. Approximately 80% are less than 5 mm in diameter, accounting for 40% of diminutive polyps [54], and only 1–3% exceed 1 cm [55,56]. Endoscopically, the typical hyperplastic polyp presents as a sessile, hemispherical, smooth or mucus-capped protrusion located on the crest of a colonic fold. Microscopically, hyperplastic polyps feature elongated, parallel crypts, the upper portions of which are dilated and

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lined by nondysplastic columnar epithelium with a serrated luminal profile and bland, mitotically inactive nuclei (Figure 29.10). The mid and lower portions of the crypts usually correspond to an expanded zone of proliferative, nonserrated epithelium with mildly enlarged, hyperchromatic nuclei and abundant mitotic figures. In many cases, one may observe a superficial band of glassy, eosinophilic collagen running along the surface basement membrane. “Inverted” hyperplastic polyps containing misplaced epithelium in the submucosa are thought to occur in response to trauma, analogously to misplaced mucosa in adenomas [57]. Hyperplastic polyps have been subclassified into three morphologically distinct categories: 1 microvesicular, the most common, featuring tall columnar cells with small intracytoplasmic mucin vacuoles interspersed with smaller numbers of goblet cells; 2 goblet cell, second in prevalence, consisting of distorted, minimally serrated crypts lined by goblet cells; 3 mucin poor, the least common, characterized by diminished cytoplastic mucin, enlarged nuclei, and frequent mitotic figures [58]. Although customarily classified as non-neoplastic lesions, hyperplastic polyps usually harbor genetic alterations that implicate them as neoplasms. For example, the prevalence of

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Figure 29.10 Hyperplastic polyp. (a) Endoscopic appearance of diminutive, sessile polyp with smooth surface. (b) Microscopically, the crypts are elongated and superficially dilated and serrated. (c) Higher magnification reveals scattered goblet cells and intervening columnar cells with microvesicular cytoplasm and bland nuclei. (d) Inverted hyperplastic polyp with lobules of hyperplastic mucosa in the submucosa.

CIMP, B-raf, and K-ras mutations in microvesicular hyperplastic polyps is reportedly 76%, 47%, and 13%, respectively, whereas goblet cell hyperplastic polyps are mostly CIMPnegative and have reversed ratios of B-raf and K-ras mutations [59,60]. These findings have implicated microvesicular hyperplastic polyps as one of the putative precursors of the serrated neoplastic pathway.

Sessile serrated polyps (sessile serrated adenomas) These lesions are broad-based, relatively flat polyps that predominate in the right colon. Microscopically, they resemble large hyperplastic polyps but exhibit less symmetry and contain dilated, hyperserrated crypts with frequent lateral budding at the base to produce L or inverted T shapes [58] (Figure 29.11). The serrated epithelium usually resembles that of microvesicular hyperplastic polyps. In some cases, although not invariably, the nuclei near the surface exhibit mild nuclear atypism with darker staining, more irregular membranes, and more mitotic activity than normally observed in hyperplastic polyps. B-raf mutations and CIMP are highly prevalent, implicating sessile serrated polyps as another putative precursor of CIMP-positive cancers. The development of cancer is thought to involve progressive methylation accompanied by morphological progression from nondysplastic to dysplastic

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Figure 29.11 Sessile serrated polyp (sessile serrated adenoma). (a) Endoscopic image. (b). Microscopically, one sees distended, hyperserrated crypts with lateral budding above the muscularis mucosae.

Hyperplastic polyp, microvesicular type

Sessile serrated polyp

No dysplasia

(a)

Pathology of Colorectal Polyps

(b)

Dysplastic serrated polyps Serrated adenoma or Mixed sessile serrated – adenomatous polyp

Low-grade dysplasia

CIMP-positive adenocarcinoma

High-grade dysplasia

DNA hypermethylation

Figure 29.12 The serrated neoplastic pathway leading to cytosine– guanine island methylator phenotype positive colorectal cancer.

serrated lesions such as serrated adenomas and mixed, serrated, adenomatous polyps (Figure 29.12). The pathologic distinction between hyperplastic and sessile serrated polyps is by no means straightforward, even among specialist gastrointestinal pathologists with research interest in this field, with rates of interobserver agreement in the moderate range [7,8]. However, a recent study has suggested that the two types of polyp can be distinguished based on their distinct patterns of immunohistochemical staining with Ki67, which highlights the proliferative epithelial cell compartment, hyperplastic polyps featuring regular, elongated, symmetric zones of proliferative epithelium, and sessile serrated polyps exhibiting irregular, asymmetric, variable staining [61]. The nomenclature of these polyps is unsettled. Some authors have maintained that the cumulative evidence implicating them as precursors of colorectal cancer justifies the designation “adenoma,” an assertion that also carries with it a more liberal definition of dysplasia than hitherto accepted [52,53,58]. Others have cited significant gaps in the evidence and in our understanding of the biology of these lesions, as well as the potential risks of overly aggressive management, and have advocated more neutral alternatives such as sessile serrated polyp or “serrated polyp with abnormal proliferation” [60,62,63].

Serrated adenomas Serrated adenomas are dysplastic polyps with papillary infoldings similar to those of hyperplastic polyps [26,64]. They account for 1–11% of all adenomas [65], predominate in the left colon, and present endoscopically as flat, sessile, or exophytic lesions, the flat lesions generally being larger than exophytic ones [66]. The term “traditional” serrated adenoma has been used to distinguish these polyps from dysplastic serrated lesions arising within sessile serrated polyps. Microscopically, serrated adenomas may be tubular, tubulovillous, villous, or occasionally filiform [64–68]. The lining cells are tall and eosinophilic, and contain slender, open nuclei with little or no mitotic activity (Figure 29.13). The characteristic papillary infoldings have been ascribed in part to the formation of secondary, or “ectopic,” crypts which bud inward from the lateral surfaces of the villous fronds [61]. Although most serrated adenomas feature less pronounced degrees of cytological atypia than conventional adenomas, they may exhibit the full gamut of low- and high-grade dysplasia and direct progression to adenocarcinoma [64,69]. It remains unclear whether serrated adenoma represents an obligatory stage in the serrated neoplastic pathway leading to CIMP-positive carcinomas. Several lines of evidence suggest that this may not be the case, including the dichotomous distributions of sessile serrated polyps and serrated adenomas within the right and left colon, respectively, as well as molecular similarities between serrated and conventional adenomas [70,71].

Mixed-serrated adenomatous polyps Nondysplastic serrated polyps occasionally contain discrete, overtly dysplastic foci with features of either conventional or serrated adenoma (Figure 29.14) [61]. Molecular studies have revealed overlapping alterations between their dysplastic and nondysplastic components, suggesting that the dysplasia is not an independent phenomenon but the product of neoplastic progression, and perhaps one of the obligatory stages

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(b) Figure 29.13 Traditional serrated adenoma. (a) Microscopically, the polyp features serrated architecture and dysplastic epithelium with abundant eosinophilic cytoplasm. (b) High magnification reveals slender, dark nuclei and secondary (“ectopic”) crypts budding from the lateral surfaces of the primary crypts (arrows).

in the progression from nondysplastic serrated polyps to carcinoma [72,73].

Management of serrated polyps Although it is established that patients with the syndrome of serrated adenomatous polyposis carry a high risk of developing colorectal cancer, the clinical implications of isolated sessile serrated polyps, serrated adenomas, and mixed polyps with respect to cancer risk remain uncertain, due to a lack of prospective studies, inconsistencies in the nomenclature of serrated polyps in the literature, and gaps in our understanding of the natural history and biology of these lesions [52,62]. For example, it is uncertain at what rates serrated polyps progress to carcinoma or with what frequency they recur after endoscopic resection. There is a consensus that nondysplastic sessile serrated polyps need not be regarded as being

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(b) Figure 29.14 Mixed sessile serrated polyp-serrated adenoma. (a) Serrated adenoma “piggybacked” on a sessile serrated polyp, both lifted with saline injection. (b) Serrated adenoma (right) abutting on sessile serrated polyp (right).

intrinsically rapidly progressive lesions [52]. Nevertheless, specific guidelines for the management of serrated polyps are difficult to ascertain based on the data currently available. Complete endoscopic resection is the treatment of choice whenever feasible. Some authors recommend that subsequent surveillance follow the guidelines for conventional adenomas. Patients with incompletely resectable polyps that do not contain dysplasia, which are most likely to occur in the right colon, can be managed expectantly with reexaminations at 1-year intervals, with surgical resection to be considered only in the event of progression to dysplasia [52].

Neurogenic polyps Neurogenic polyps of the large intestine are neoplastic proliferations that derive from or recapitulate elements of the

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(a)

(a)

(b)

(b) Figure 29.15 Epithelioid schwannoma. (a) Pale spindle cells arranged in short fascicles and interdigitated among the crypts. (b) Higher magnification reveals abundant light pink cytoplasm and bland, slender nuclei.

Figure 29.16 Spindle cell schwannoma. (a) Well-circumscribed spindle cell tumor with peripheral cuff of lymphoid tissue. (b) The spindle cells feature pale, eosinophilic cytoplasm and delicate, wavy nuclei.

enteric nervous system. In the sporadic setting, they are usually solitary and almost invariably have a benign clinical course. Although relatively uncommon, their true incidence rates are unknown, since they are usually asymptomatic and discovered incidentally.

Spindle cell schwannomas

Epithelioid schwannomas These lesions, also referred to as epithelioid peripheral nerve sheath tumors, are small mucosal-based polyps ranging from 0.2 to 1.0 cm in size. The overlying mucosa is generally intact. Histologically, they present as an infiltrative proliferation of ovoid or elongated epithelioid cells arranged in nests and whorls. The cells have uniform, round, or oval nuclei and abundant eosinophilic fibrillar cytoplasm (Figure 29.15). They regularly express S-100 protein immunohistochemically, assisting their distinction from smooth muscle and stromal tumors [74].

Spindle cell schwannomas tend to be larger, better circumscribed, mural-based, and symptomatic [75]. Like their soft tissue counterparts, they exhibit regions of high cellularity and nuclear palisading interspersed with regions of low cellularity with myxoid stroma. A distinctive feature of this lesion is the presence of a cuff of small lymphocytes (Figure 29.16).

Granular cell tumors These are submucosa- or mucosa-based sessile polyps that occur in all age groups, with a male predominance of 3:1, and range from 0.2 to 3.0 cm in diameter [75]. Microscopically, they consist of sheets, nests, and cords of epithelioid cells which contain abundant, coarsely granular, eosinophilic cytoplasm, and central round nuclei with nucleoli and scant mitoses (Figure 29.17). The growth pattern is either well circumscribed or infiltrative, the latter potentially mimicking

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Figure 29.17 Granular cell tumor consists of cells with abundant palepink, granular cytoplasm and centrally placed, slightly pleomoprhic nuclei arranged in nests of varying sizes and shapes.

carcinoma. Although the precise histogenesis of granular cell tumors remains unsettled, they express the neural marker S-100 protein and frequently other neural markers, and are ultrastructurally similar to neural cells. For example, the periodic acid–Schiff (PAS)-positive cytoplasmic vacuoles that confer their distinctive cytoplasmic granularity correspond ultrastructurally to lipid-rich secondary lysosomes similar to those seen in Schwann cells. Although malignant granular cell tumors have been encountered rarely in other parts of the gastrointestinal tract, none has been reported in the large intestine.

Neurofibromas Neurofibromas occur numerously in von Recklinghausen’s neurofibromatosis (NF-1) but as solitary lesions in the general population. Nonsyndromic neurofibromas account for 0.2% of colorectal polyps. They are usually encountered in middle-aged to older patients and have no sex predominance. Grossly, they range from small incidental polyps of 0.2 cm to large symptomatic masses 7 cm in size, and present as a well-circumscribed, gray–white, slightly translucent nodule. Microscopically, they consist of Schwann-like spindle cells with wavy, elongated nuclei as well as scattered mast cells and mononuclear inflammatory cells residing in a mucopolysaccharde-rich fibroconnective tissue matrix. Immunohistochemically, neurofibromas express S-100 protein and neuron-specific enolase [75].

Perineuriomas and fibroblastic polyps Perineuriomas are solitary, sessile, mucosa-based polyps with a median size of 0.4 cm. Microscopically, they consist of a solid or focally whorled infiltrate of uniform spindle cells that occupies the lamina propria and entraps the colonic crypts which, curiously, are often hyperplastic. The derivation of this lesion from perineurial cells is supported by its invariable

392

(b) Figure 29.18 Combined fibroblastic–hyperplastic polyp. (a) Spindle cell tumor expands the lamina propria and entraps the crypts. (b) Densely packed fibroblast-like spindle cells with slender nuclei are arranged in parallel. The entrapped crypts are those of a microvesicular hyperplastic polyp. Negative immunohistochemical staining for epithelial membrane antigen is required to distinguish this polyp from a perineurioma.

immunohistochemical expression of epithelial membrane antigen. Benign fibroblastic polyps [76] are histologically identical polyps which do not express epithelial membrane antigen under routine staining conditions (Figure 29.18). However, a recent report that they do stain for this antigen under modified conditions has suggested that they may correspond to the same entity [77].

Ganglioneuromas These polyps are usually encountered as multiple lesions in patients with systemic syndromes such as NF-1, multiple endocrine neoplasia type IIb, tuberous sclerosis, and Cowden’s disease, but occasionally occur as isolated sporadic lesions. The median age is 48 years and there is no sex predilection. The polyps occur predominantly in the left colon, presenting as sessile or pedunculated mucosa-based polyps which usually range from < 1 to 3 cm in size. Histologically, they consist of admixtures of ganglion cells, nerve fibers, and Schwann cells [75].

Juvenile polyps Juvenile, or retention, polyps are benign hamartomatous polyps which account for approximately 90% of intestinal polyps in the pediatric age group, although they are by no

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Figure 29.19 Juvenile polyp. (a) Pale, sessile polyp with smooth surface. (b) Microscopic view showing crypts of varied sizes and shapes, many distended with mucin secretions, surrounded by chronically inflamed, edematous stroma. (c) Serrated, regenerative crypts occur just beneath the eroded surface.

means uncommon in adults. They usually present as a single polyp, ranging from 2 mm to several centimeters in diameter, with a smooth or lobulated surface which is often eroded. Larger polyps usually have a pedicle. On section, they present an edematous fibrotic stroma containing mucus-filled cysts of varying sizes. Microscopically, the cysts are lined by cytologically bland cuboidal or columnar mucinous cells of colorectal type and contain mucus, often admixed with acute inflammatory cells or necrotic debris. The stroma usually consists of edematous fibrous tissue with scattered mononuclear inflammatory cell infiltrates and lymphoid follicles but little or no smooth muscle (Figure 29.19). In larger polyps, the stroma may be partially hyalinized, calcified, or ossified. Reactive epithelial changes occur regularly beneath the eroded surface and should not be confused with dysplasia, which is rare in sporadic lesions. Early juvenile polyps consist mostly of granulation tissue, creating the potential for confusion with inflammatory polyps of inflammatory bowel disease [78], but examination of the intervening mucosa shows it to be grossly and microscopically normal. Whereas sporadic juvenile polyps have no significant potential for development of colorectal neoplasia, the genetic syndrome of juvenile polyposis carries a high lifetime risk

Figure 29.20 Peutz–Jeghers-type hamartomatous polyp. (a) Endoscopic image. (b) Microscopically, the polyp consists of colonic epithelium on a scaffold of arborizing smooth muscle bundles.

(a)

for development of colorectal carcinoma. The sporadic and syndromic polyps are similar pathologically, although the latter have a tendency to grow larger and more irregularly lobulated and to acquire higher proportions of epithelium with a predisposition to dysplasia. Identification of a juvenile polyp, whether in a child or adult, calls for a workup for juvenile polyposis if three or more polyps are present or if there is a family history of the disease [79].

Hamartomatous (Peutz–Jeghers) polyp Hamartomatous polyps, classically associated with Peutz– Jeghers polyposis syndrome, may also occur as isolated lesions. They range from 5 mm to 3 cm in size, feature a coarsely lobulated surface, and are attached to the mucosa by short stalk or broad base. Microscopically, they consist of lobules of mature, tubular, or serrated colorectal epithelium separated by coarse bands of smooth muscle that radiate outward from the muscularis mucosae (Figure 29.20). Peutz–Jeghers polyps of the large intestine may have a less prominent smooth muscle component than their small intestinal counterparts, and consequently may be difficult to distinguish from other serrated or prolapse-associated polyps, especially on the basis of biopsies. Misplaced epithelium beneath the polyp base may mimic

(b)

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adenocarcinoma, but attention to the lack of dysplasia should suggest the correct diagnosis. Dysplasia rarely occurs outside the syndromic setting. Patients with Peutz–Jeghers syndrome face a greater than 10-fold increased risk of developing gastrointestinal, pancreatobiliary, and other cancers. The diagnosis is generally based on the detection of three or more Peutz–Jeghers polyps in a patient with no family history of the disease or physical signs, or of any polyps in a patient with a family history or characteristic mucocutaneous pigmentation. However, Burkart et al. [80] have recently cast doubt on the sporadic nature of isolated Peutz–Jeghers polyps, suggesting that they may correspond to occult cases of the syndrome or at least carry a similar risk for cancer development. (a)

Inflammatory polyp These are produced by inflammatory processes that cause undermining ulceration of mucosa, an exuberant granulation tissue reaction, or both. They occur either singly as sequelae of localized mucosal injury or more diffusely, most often as a manifestation of chronic inflammatory bowel disease, and assume diverse macroscopic appearances, including nodules, filiform excrescences, mucosal bridges, and leafy fronds. The microscopic appearances vary with the phase of the inflammation. When actively inflamed, inflammatory polyps comprise admixtures of inflamed and regenerative epithelium, edematous, chronically inflamed stroma, and granulation tissue; however, once the inflammation has subsided they may revert to normal histology (Figure 29.21). The regenerative epithelium frequently assumes a serrated appearance similar to that of hyperplastic or hamartomatous polyps. The diagnosis can generally be made at low magnification based on the disorganized arrangement and marked variations in crypt sizes and shapes, which contrasts with the relative uniformity of hyperplastic polyps and the distinctive lobulated architecture of hamartomatous polyps.

Polyps associated with mucosal prolapse Reactive polypoid lesions resulting from mucosal prolapse may occur in diverse settings, such as the solitary rectal ulcer syndrome, hemorrhoids, and colostomy sites adjacent to diverticula. They all share certain histological features, including upward growth of muscle fibers into the lamina propria, distortion of the crypt architecture, inflammation, and fibrosis. Any of these polyps may contain serrated crypts, but their overall architecture is distinct from that of hyperplastic and serrated polyps.

Polypoid prolapsing mucosal folds in diverticular disease These polyps are observed adjacent to diverticula, presenting as single or multiple discrete, sessile, reddish-brown protrusions

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(b) Figure 29.21 Inflammatory polyps consist of granulation tissue, colorectal mucosa, or both. (a) Polypoid mass of granulation tissue. (b) Relatively uninflamed mucosa with marked variations in crypt sizes and shapes resulting from previous inflammation.

with smooth surfaces, and consist of redundant mucosal folds resulting from spastic muscular contraction in diverticulosis. Microscopically, they feature elongated crypts, venous congestion, edema, inflammation, fibrosis, and hemosiderin deposits (Figure 29.22). Some of these polyps may correspond to inverted diverticular mucosa, which could lead to perforation if removed by snare resection [81–83].

Solitary rectal ulcer syndrome Solitary rectal ulcer syndrome (SRUS) results in inflammatory and reactive changes in the rectum, usually on its anterior or anterolateral aspect. These changes range from shallow ulcerations to formation of one or more polypoid, plaque-like, or villiform masses in approximately 40% of cases. Microscopically, these polyps feature elongated crypts with superficial villiform or serrated features which are invested by vertical muscular extensions from a hypertrophic muscularis

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Figure 29.22 Polypoid prolapsing mucosal folds in diverticular disease. (a) The lesion presents endoscopically as a red–brown, sessile peridiverticular mound. (b) Microscopically, the crypts are elongated crypts and surrounded by hemorrhagic lamina propria. (c) The polyp base contains occasional smooth muscle bundles extending upwards between the crypts (single arrow) and hemosiderin deposits (double arrows).

(a)

(b)

(c)

Figure 29.23 Solitary rectal ulcer syndrome. (a) Endoscopic view showing pale, sessile plaques on the anterior rectal wall. (b) Elongated crypts are enveloped by smooth muscle bundles extending upward from the muscularis mucosae. The surface is eroded and covered by pseudomembranous inflammatory exudates (arrows). (c) Angulated crypt bases are entrapped in the smooth muscle.

mucosae. Entrapment of the crypt bases within this muscle results in distinctive tapered profiles instead of the normal curved appearance (Figure 29.23). Surface erosion is heralded by a superficial band-like zone of granulation tissue, and culminates in a cap of mucosuppurative exudate resembling pseudomembranous colitis or frank ulceration and fibromuscular obliteration of the underlying lamina propria. Analogous polypoid lesions of the anorectal transition zone are referred to as inflammatory cloacogenic polyps. The gross appearances and induration of SRUS-associated polyps may suggest a clinical diagnosis of villous neoplasm or invasive cancer. This impression may be reinforced pathologically by their villiform architecture and tapered crypts, by reactive surface changes which may resemble dysplasia, and in some instances by the presence of traumatically misplaced mucosa within the muscularis propria, referred to as proctitis cystica profunda, which can mimic invasive cancer. Avoiding such errors requires awareness of the syndrome and its pathologic features, including the histological distinctions between reactive and dysplastic epithelium [84].

Inflammatory cap polyp This is an uncommon reactive polyp that usually occurs singly or multiply in the distal colon, and consists of expanded mucosa covered by a “cap” of inflammatory exudate. Patients may be men or women of any age who present with mucoid diarrhea, rectal bleeding, constipation, straining at stool, tenesmus, or, in a few reports, protein losing enteropathy [85–88]. Endoscopically, cap polyps are typically sessile or semisessile, hemorrhagic lesions locted on the crests of the mucosal folds, and are surrounded by normal mucosa. Microscopically, they feature elongated crypts lined by abundant goblet cells, mixed mononuclear inflammatory cell infiltrates, upward growth of smooth muscle fibers, and an eroded surface covered by thick mucosuppurative exudates (Figure 29.24). The etiology and pathogenesis of cap polyps are uncertain. Some authors regard them as manifestations of mucosal prolapse resulting from straining during defecation wherein mechanical forces produce ischemic changes on the apices of the colonic folds. Cases of clinical resolution in response to reduction of straining have been reported, and the mucosal

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(a) Figure 29.24 Inflammatory cap polyp. Expanded lamina propria features elongated crypts and dense mononuclear inflammatory cells and is covered by an acute inflammatory exudate.

extensions of smooth muscle fibers reinforce the analogy to SRUS. Therapy usually includes polypectomy or segmental resection, depending on the number and extent of polyps and severity of symptoms. Anti-inflammatory therapies have yielded mixed success. Curiously, several patients with gastritis have reportedly experienced resolution of cap polyps following eradication of Helicobacter pylori with antibiotics [89,90].

Lymphoid polyps and polypoid lymphomas Benign lymphoid polyps occur singly or multiply, usually in the lower rectum, and range from tiny papules to pedunculated polyps up to several centimeters in diameter [91,92]. Their incidence is unknown since they are clinically innocuous and rarely reported. On section, they are tan and fleshy. Histologically, they consist of a circumscribed collection of well-formed, clearly separate lymphoid follicles with prominent germinal centers. The depth of infiltration of the rectal wall is usually limited to the submucosa; however, penetration into the muscularis propria is not a criterion of malignancy [93]. Local excision is curative. Primary lymphomas present infrequently as one or multiple colorectal polyps. Most correspond to B cell lymphomas, specifically marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type or mantle cell lymphoma; however, rare cases of polypoid follicular lymphoma, adult T cell lymphoma, Burkitt lymphoma, and other types have been reported. Mantle cell lymphoma, a relatively aggressive entity, typically presents diffusely as multiple lymphomatous polyposis, but similar appearances have been ascribed to other entities [94,95]. Histologically, marginal zone B cell lymphoma of MALT type is characterized by a heterogeneous population of predominantly small to medium-sized lymphocytes, including follicular center-like cells with irregular nuclear contours and

396

(b) Figure 29.25 Marginal zone lymphoma of mucosa-associated lymphoid tissue type. (a) Dense lymphocytic infiltration of the lamina propria and submucosa. A residual germinal center is present (arrow). (b) The lamina propria is infiltrated by mostly small lymphoid cells with irregular nuclear contours. An immunohistochemical profile of CD20+, CD79a+, CD43+, CD3−, and CD5− helped confirm the diagnosis.

abundant cytoplasm, similar cells with monocytoid features, small round lymphoid cells, interspersed blast cells with vesicular nuclei and prominent nucleoli, and sometimes plasmacytoid cells. The infiltrate often surrounds germinal centers and invades the crypt epithelium, forming lymphoepithelial lesions (Figure 29.25). Mantle cell lymphoma, by contrast, is characterized by a monomorphous infiltrate of small to medium-sized B cells with irregular nuclear contours, frequently interspersed with macrophages to produce a “starry sky” pattern. There is no association with germinal centers or formation of lymphoepithelial lesions [96]. Both MALT and mantle cell lymphomas express surface IgM (immunoglobulin M) and are positive for pan-B-cell markers CD20 and CD79a and negative for pan-T-cell marker CD3.

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MALT lymphomas are negative for CD5, variably positive for CD43, and do not overexpress cyclin D1, whereas mantle cell lymphomas are positive for CD5 and CD43 and overexpress cyclin D1. Negative staining for CD10 is useful in distinguishing both from follicular lymphoma. In addition to benign lymphoid polyps, lymphoma must be distinguished from reactive lymphoid hyperplasia, small cell carcinoma, granulocytic sarcoma, and other leukemic infiltrates.

Carcinoid tumors Approximately 90% of large intestinal carcinoid tumors occur in the rectum, most presenting as solitary sessile polyps less than 1 cm in size and running a benign course [97–99]. Microscopically, the tumor cells are arranged as ribbons, solid nests, tubules, or mixed patterns, and contain round, uniformly spaced nuclei with speckled or clumped chromatin (Figure 29.26). Mitotic figures generally number < 1 per 10

Pathology of Colorectal Polyps

high-power fields. A background of hyalinized stroma accounts for the firm consistency. A substantial minority of cases do not react with stains used to diagnose carcinoids elsewhere, such as silver-based stains and immunohistochemical stains for neuroendocrine markers. The main criteria of malignancy are muscularis propria invasion, size, and lymphatic invasion [97,100–103]. Tumors that invade the muscularis propria are regarded as potentially malignant regardless of size [104]. Metastasis occurs in 2–3% of tumors < 1 cm, 5–15% of those 1–2 cm, and 60% of larger tumors [97,99,105]. Carcinoids < 1 cm in diameter that spare the muscularis propria are generally considered adequately treated by polypectomy or local excision; however, there is a low rate of unpredictable adverse outcomes [106]. Low mitotic rates, DNA diploidy, and low cell proliferation indices do not assure benign behavior in the presence of other adverse features [97,98,104] Colonic carcinoids are histologically similar to rectal carcinoids, but as a group are larger, averaging 5 cm in diameter, and more aggressive. Composite adenoma–carcinoid tumors are quite rare. Although some seem to be fortuitous collision tumors, there are case reports describing intimate intermingling of the adenomatous and carcinoid components, supporting origin from a common stem cell [107–109], as well as microcarcinoids arising at the base of otherwise conventional adenomas [109].

Summary The clinical approach to the postpolypectomy patient is based largely on the histopathologic features of the recovered tissue. There are a vast number of pathologic entities that comprise the overall category of “polyps,” some of which may require further patient evaluation and treatment, depending on the histology. Resected polyps must be adequately examined microscopically following prescribed quality control laboratory procedures, and diagnostic reporting should employ standardized nomenclature. The dialogue between the clinician and pathologist is an important communication that can provide a more accurate consultation, leading to a better informed clinical decision for the patient.

(a)

References

(b) Figure 29.26 (a) Rectal carcinoid tumor consists of complex cribriform glandular structures arranged in lobules and nests. (b) Higher magnification reveals evenly spaced, round-to-ovoid nuclei with clumped chromatin.

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Management of Malignant Polyps Sidney J. Winawer1 & Michael J. O’Brien2 1

Sloan-Kettering Cancer Center, New York, NY, USA Boston University School of Medicine, Boston, MA, USA

2

Introduction “Malignant polyp” is a term used when a polyp removed by colonoscopy appears grossly benign but has adenocarcinoma identified histologically (Figure 30.1). The clinical issues in this setting are more difficult than in a patient who has had a surgical resection because of a large sessile polyp or suspected malignancy, where a surgical specimen and adjacent lymph nodes are available for staging. The management of patients with malignant polyps has assumed increased importance in recent years as a result of more widespread screening in the general population, and especially with the introduction of colonoscopy as a screening option [1,2]. A decision must be made in each of these patients whether to consider the colonoscopic polypectomy curative or refer the patient for surgery. This decision is compounded when an asymptomatic person has been induced to have a screening test that uncovers the unsuspected pathology. Management decisions require an assessment of the pathology, risk of adverse outcome, risk of surgery and colonoscopic follow-up, and the available surgical options. There are additional considerations in high-risk patients [e.g., those with a family history suggesting hereditary nonpolyposis colorectal cancer (HNPCC), long-standing inflammatory bowel disease, and familial polyposis]. This chapter deals primarily with the average-risk patient.

Pathology Malignant polyps are adenomas with adenocarcinoma that has invaded beyond the muscularis mucosa (Figure 30.2). The cancer cells have thus gained access to the submucosa, which contains lymphatics and blood vessels that can permit spread to adjacent lymph nodes and less commonly to distant organs. Spread to the deeper layers of the colonic wall can

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Figure 30.1 Endoscopic photo of a large benign-appearing sessile polyp in the ascending colon that had early invasive cancer histologically.

also occur by direct extension. In pedunculated adenomas, the submucosa is in continuity with the core of the stalk and head of the polyp. In sessile adenomas, invasive carcinoma is directly into the submucosa of the bowel wall. “Intramucosal carcinoma” is a term used to describe invasion of cells through the basement membrane of the crypts into the lamina propria of the surrounding mucosa but with no penetration into or through the muscularis mucosa into the submucosa. There is therefore no opportunity for regional or distant spread and there is no clinical significance regarding the initial management of the patient. The older term “carcinoma in situ” has now been replaced by the term “high-grade dysplasia,” which also includes severe dysplasia. The pathologic diagnosis of high-grade dysplasia also has no clinical significance in terms of the initial management of the patient. All adenomatous polyps have at least low-grade dysplasia, which incorporates mild and moderate dysplasia [1,2]. Accurate assessment of the resected polyp is required for rational clinical decision-making. Every effort must be made to retrieve the entire specimen for examination and classification. This is easier for pedunculated polyps than for large sessile polyps that are removed in piecemeal fashion. Saline injection

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Adenocarcinoma, invasive Adenomatous mucosa Normal mucosa Muscularis mucosae Submucosa Muscularis propria Subserosa (a)

(b)

(c)

Figure 30.2 Malignant polyp variants. (a) Pedunculated malignant polyp with invasion in the submucosa of the polypoid adenoma head. (b) Adenocarcinoma arising in a flat adenoma and invading the submucosa. (c) Sessile malignant polyp with adenocarcinoma invading the submucosa.

resected site difficult. To avoid this, sessile polyps can be placed flat on a piece of cardboard or thick paper, on absorbable gelatin sponge (Gelfoam), or on a frosted glass slide before insertion into fixative. Histological sections are made from stepwise sagittal blocks of the entire polyp, taking care to represent the stalk and polyp resection margin. When invasive adenocarcinoma is identified, the report should include the grade of differentiation of the carcinoma, lymphatic or vascular space invasion, volume of polyp replaced by carcinoma, depth of invasion, and proximity to resection margin. Pseudoinvasion with adenoma misplaced into the stalk or submucosa should be distinguished from true invasion (Figure 30.3). Reporting should include whether or not there is adenomatous tissue at the resection margin and if there is cancer at the margin to indicate the completeness of the removal histologically.

Risk factors for malignant polyps

Figure 30.3 Pedunculated polyp showing pseudoinvasion of stalk. Glands are present in the submucosa of the polyp head and stalk deep to the muscularis mucosae. The glands are associated with stroma identical to adenoma mucosal stroma, and distinct from the fibrous stroma characteristic of invasive adenocarcinoma. The dysplasia of the glandular elements in the stalk in pseudoinvasion may be low or high grade (in this case, low grade). Other features that suggest pseudoinvasion include hemosiderin deposits and pools of acellular mucin. Pseudoinvasion is likely to represent a manifestation of polyp prolapse and is seldom, if ever, encountered in sessile or flat adenomas.

to provide a cushion of normal submucosa under a sessile polyp can greatly aid in the completeness of removal. An attempt should be made to identify the base of the polyp. Contraction of the muscularis mucosa after resection may cause a specimen to curl into a ball, making subsequent identification of the

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The frequency of finding malignant polyps was 1.5% in the National Polyp Study, a multicenter study with a database of approximately 5000 polyps removed in 2000 patients (Figure 30.4) [3]. These patients were mostly average-risk men and women. In recently reported screening colonoscopy studies, approximately 10% of asymptomatic average-risk people had advanced neoplasia including 1% with malignant polyps [4]. The vast majority of adenomas removed in these studies were benign. It has been estimated that only 0.25% of adenomas will demonstrate conversion to malignancy each year [5]. Analysis of the National Polyp Study database has confirmed that polyp size is a major determinant of the likelihood that high-grade dysplasia will be found in a colorectal adenoma. The amount of villous growth in the adenoma is also an independent determinant of this risk, with an effect of comparable magnitude to that of size. Furthermore, the effects of size and villous component have been found to be multiplicative (i.e., their combined effect is greater than the sum of their individual effects). Frequency of high-grade dysplasia in adenomas is unrelated to gender of the patient, according to the National Polyp Study data analysis, but logically appears to increase significantly with advancing age. When a patient

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92.5% Adenomas with high-grade dysplasia Adenomas with invasive cancer Adenomas without high-grade dysplasia or invasive cancer

Figure 30.4 Relative frequency of a finding of high-grade dysplasia or invasive carcinoma in an adenoma resected at colonoscopy.

6%

has multiple adenomas, which will be the case in almost 50% of the adenoma-bearing population, the patient’s risk of harboring an adenoma with high-grade dysplasia is proportionately increased, although this increased risk from multiplicity appears to be dependent on the associated factors of size and villous component [3].

1.5%

Increased polyp size, villous histology, and severe dysplasia are all associated with an increased risk of cancer in adenoma (Figure 30.5). Reports from the pathology laboratory, in the years before colonoscopic polypectomy was introduced, also demonstrated (in surgically resected specimens) the relation of lesion size and dysplasia grade to the probability of

Adenoma–carcinoma sequence

Serrated polyp pathway

Normal colon

Normal colon

BRAF

APC

Sessile serrated adenoma (nondysplastic serrated polyp)

Small adenoma

COX2

CIMP Serrated adenoma (dysplastic serrated polyp)

Large adenoma

K-ras Large adenoma with high-grade dysplasia

p53 Large adenoma with invasive carcinoma

hMLH1 inactivation

TGF-β RII

18q LOH

BAX

5q LOH

IGF-IIR

CSI

MSI

Figure 30.5 Adenoma–carcinoma sequence compared with the serrated polyp pathway. This schema summarizes the key molecular genetic events associated with the genesis of conventional adenoma and its progression to invasive carcinoma. The key initiating event is a mutation of the APC gene. Mutation of the K-ras oncogene occurs in a proportion of cases and is associated with villous morphology. The subsequent molecular changes in the adenoma carcinoma sequence are related to chromosomal instability and loss of heterozygosity (LOH) resulting in inactivation of key

Serrated adenoma with high-grade dysplasia

Serrated adenoma with invasive carcinoma

tumor-suppressor genes. The alternative pathway, the serrated polyp pathway, which may account for up to 15% of colorectal cancers, is attributed to an activating B-raf mutation leading to the formation of a nondysplastic serrated polyp (hyperplastic polyp). This progresses via an atypical hyperplastic polyp (sessile serrated adenoma) and eventually to a dysplastic serrated polyp (serrated adenoma). A proportion of the latter progress to invasive carcinomas that frequently exhibit microsatellite instability.

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malignancy [6– 8]. The reported incidence of cancer in polypoid lesions before and after the colonoscopy era is not comparable. The incidence of cancer in colonoscopically resected polyps reflects the histopathologic finding in lesions that the endoscopist considered to be endoscopically resectable (and likely benign) as opposed to surgically resected lesions usually discovered on the barium enema. Molecular changes parallel the histopathologic progression of the adenoma–carcinoma sequence. The adenoma–carcinoma sequence may not always evolve within a polypoid lesion. Small flat invasive cancers have been described that are thought likely to have developed within a preceding flat adenoma [9,10]. Flat adenomas, originally described by Muto and colleagues [11], have been reported to have greater propensity to develop into cancer and invade the submucosa than polypoid adenomas. An association between small flat adenomas and cancer has been reported in HNPCC. While these associations are controversial, it is accepted that cancer may develop in flat nonpolypoid adenomas and present particular problems for diagnosis and resection. These tumors may be difficult to identify endoscopically. Dye spraying with either topical spray of 0.2% indigo carmine on the colonic surface or by oral ingestion of dye during the preparation phase prior to colonoscopy may aid in their endoscopic visualization. Small flat adenomas, some of which contain invasive carcinoma, have been resected and cured by the submucosal injection of saline followed by removal with an endoscopic snare. Fewer reports of flat adenomas in the English literature led to speculation that they are not recognized and therefore “missed” during colonoscopy, or that they are seen and removed but not separately categorized by western endoscopists. Rigorous follow-up of patients by the National Polyp Study has demonstrated an extremely low incidence of subsequent cancer in colons from which all adenomas were removed by National Polyp Study endoscopists [12]. The latter of these two explanations would appear to be the “best fit” to available data because, when specifically sought, flat adenomas are found in North Americans. O’Brien and colleagues [13] reclassified as flat or polypoid all nonpedunculated adenomas detected at the initial colonoscopy in the National Polyp Study. Flat adenomas did not have an increased presence of high-grade dysplasia. In addition, patients with flat adenomas did not have an increased risk of subsequent advanced adenomas.

Initial endoscopic evaluation and treatment The endoscopic appearance of a polyp may suggest a malignant component, although most malignant polyps have a benign appearance at endoscopy (see Figure 30.1). Gross features of malignancy include an irregular surface contour, ulceration, firm (or hard) consistency when the head is

404

Figure 30.6 Pedunculated polyp with irregularity of surface and nodularity of the stalk indicating the presence of deeply invasive cancer, which was demonstrated histologically.

pushed with a snare or forceps, and broadening of the stalk [1,2,14–18] (Figure 30.6). Although polyps with these features are not invariably malignant, the endoscopist should pay special attention to any lesion with malignant characteristics, since it may be desirable to resect these somewhat differently than the routine adenoma. If cancer is suspected by any of the above criteria, the snare should be placed more toward the wall when resecting a pedunculated polyp than toward the head, as is the usual practice. Special care must be directed to recovering all of the fragments for histopathologic evaluation and to precisely localizing the polyp’s position in the colon should subsequent surgery be a consideration of the endoscopist at the time of the polypectomy. The initial evaluation by the endoscopist may be of great significance, since the morphology of the lesion may be difficult to assess accurately once the resection is completed. Following resection, it may not be possible to ascertain whether a polyp was sessile or pedunculated, because a short pedicle may retract completely into the polyp head. Polyps tend to curl up in formalin, and the site of attachment of sessile polyps may not be recognizable in the pathology laboratory [19,20]. The endoscopist can usually tell, with some confidence, whether or not a complete polypectomy has been performed when the polyp is pedunculated, since the stalk is readily identified and the absence of residual adenoma is easily discerned. The determination is more difficult when a sessile polyp is resected, although a clean base without adjacent, evaluated, reddened tissue usually indicates completeness of resection. This assurance may be difficult to achieve when a polyp has been removed in piecemeal fashion, because fragments at the base could equally prove to be nonviable coagulum or residual adenomatous tissue.

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Figure 30.7 India ink “tattoo” at time of polypectomy to localize polypectomy site because invasive cancer was strongly suspected.

Precise localization of the polypectomy site may be desirable even if surgery is not to be performed and the patient is to be followed endoscopically. Reliance on the distance of colonoscopy insertion (in centimeters) is unreliable, as are intraluminal landmarks. The best method for localizing the polypectomy site is by injection of a surgical marker such as India ink or a suspension of pure carbon particles, whereby a dilute suspension of sterile black carbon particles is injected at the site (Figure 30.7). The area is stained forever and can be readily detected by the surgeon or the endoscopist on repeat examination. The injection, or tattoo, should be made circumferentially around the polypectomy site using 10 mL of solution in 2- to 3-mL fractions. Precise localization of the polypectomy site is critical since a resection may be carried out by laparoscopic technique.

Evidence for surgery versus endoscopic follow-up Pedunculated adenomas The pedunculated malignant polyp has by long convention been placed in a different category from the sessile malignant polyp by many clinicians. When polyps are pedunculated, the submucosa of the polyp is separated from the submucosa of the colon wall by a thin tubular segment of submucosa; whereas, in sessile polyps the submucosa of the polyp is directly contiguous with the submucosa of the colon wall. The literature on malignant polyps is inconsistent, with several authors using their own classification system for depth of invasion, rendering it difficult to compare the extent of tumor invasion and its significance from one paper to another. Some reports mix the results from surgically resected specimens with those removed colonoscopically, which tends to skew

Management of Malignant Polyps

the outcomes unfavorably by including cases that would not have been considered for endoscopic resection. However, guidelines for endoscopic polypectomy are fairly well accepted when discussing pedunculated polyps. When certain favorable clinical and histological criteria are met following removal of pedunculated malignant polyps, it is the general consensus of the literature on this subject that surgery should not be performed since the risk of having residual cancer at the site or nodal metastasis is extremely low and less than the mortality from surgical resection. These favorable criteria are that the tumor be well or moderately differentiated, the resection margin be clear of malignant cells, and the cancer not invade lymphatic channels or vascular spaces within the polyp (Figure 30.8). Poorly differentiated carcinoma is rare in malignant polyps but is seen in 15% of surgical resection specimens for colorectal carcinoma [21]. Poor differentiation appears to be a feature that can be correlated with tumor mass and with vascular space invasion. Its presence in malignant polyps is an ominous prognostic sign and mandates surgical resection if the patient’s clinical condition does not preclude it (Figure 30.9). Invasion of lymphatics or veins within the submucosa of the polyp head or stalk is also a relatively rare phenomenon and is thought to be a poor prognostic sign, although there have not been enough cases reported to constitute a series that would bear a statistical analysis of its impact, independent of other negative factors. A recent report indicates that this type of vessel invasion is found more frequently if a combination of hematoxylin/eosin and elastin stains is used [22]. The acceptable distance from invasive carcinoma to the endoscopic diathermy burn is variable among many reports in the literature. Some authors insist that the margin must be “healthy,” while others permit a minimum of a 1-mm, 2-mm, or 3-mm margin [15,16,23,24]. Lipper and colleagues [25] state that the presence of malignant cells at the resection margin is the only criterion that reliably predicts a poor outcome. Day and Morson [26] have found good long-standing results in cases with a tumor at the resection margin that was deemed to be safe because the endoscopist considered that all abnormal tissue had been removed during colonoscopy. They felt that in such cases the diathermy burn caused sufficient cell necrosis to eradicate all residual malignant cells at the margin of the tumor.

Sessile adenomas Sessile malignant polyps are often considered separately by both clinicians and pathologists. The concern is that malignant cells that cross the muscularis mucosa of a sessile polyp are actually invading the portion of the submucosa that is directly contiguous with the rest of the bowel wall submucosa, and are not protected by a “buffer zone” of submucosa as in pedunculated polyps. Many authors feel, however, that there is no sound basis for this assertion and that sessile malignant polyps

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(b)

Figure 30.8 Pedunculated adenoma with favorable histological features. This pedunculated tubulovillous adenoma has focal well-differentiated adenocarcinoma in the head of the polyp. The short pedicle is free of tumor. The appearance of the polyp head at endoscopy (b) suggests slight surface erosion but is otherwise unremarkable. The invasive component (c) shows characteristic fibrous stroma.

(a) (c)

(b)

(a) (c)

406

Figure 30.9 Malignant pedunculated polyp with unfavorable histological features. The head of this pedunculated villous adenoma is extensively replaced by poorly differentiated adenocarcinoma (a, b). In addition, invasion of lymphatics in the pedicle by invasive adenocarcinoma is present (detail in c).

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(a)

Figure 30.10 Sessile malignant polyp with favorable histological features. This sessile tubulovillous adenoma shows a focus of well to moderately differentiated adenocarcinoma that superficially infiltrates the submucosa, barely extending beyond the boundary muscularis mucosae. (a & c) The invasive edge is 2 mm from the resection cautery margin, indicating an adequate excision (b).

(c)

(b)

should not be considered any differently from those that are pedunculated [15,25–27]. A review of the literature in 1988 [23] drew the conclusion that sessile and pedunculated malignant polyps did not differ in their risk for residual or metastatic disease if favorable criteria were applicable (Figures 30.10 and 30.11). However, a paper on decision analysis and the therapeutic options in malignant polyps concluded that all sessile malignant polyps should have an operative resection if the patient is a good-risk candidate [28]. Other authors have also expressed the view that sessile malignant polyps should be treated by further surgical resection [29–32]. In one report [33], sessile malignant polyps had a high frequency of residual or nodal cancer, but all eight of the cases in this series found to have residual disease also had positive resection margins. It has been suggested that only sessile malignant polyps resected in a piecemeal fashion should be subjected to surgery because

Figure 30.11 (right) Malignant sessile polyp with unfavorable histological features. This sessile polyp is totally replaced by invasive moderately differentiated adenocarcinoma, which is partially mucinous (polypoid carcinoma). (a) The carcinoma extends to the cautery margin. (b) A segmental resection which was performed revealed no residual carcinoma at the excision site but metastatic adenocarcinoma was present in several of the regional lymph nodes.

(a)

(b)

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of the possibility of error in orienting tissue received by the pathologist [27].

New concepts and risk parameters Malignant polyps and the serrated polyp pathway Approximately 15% of colorectal carcinomas are thought to evolve in the serrated polyp pathway, an alternative molecular and histological pathway to the adenoma–carcinoma sequence (see Figure 30.5) [34]. The immediate precursors of the endpoint carcinomas of this pathway are serrated adenomas, and these can present as malignant polyps removed at colonoscopy (Figure 30.12). Most serrated adenomas are found to have an activating mutation of the oncogene B-raf, which is also a marker for a nondysplastic precursor of serrated adenoma, an atypical hyperplastic polyp, by current convention referred to as a “sessile serrated adenoma” [35]. B-raf-mutated serrated adenomas (dysplastic serrated polyps) have a mainly proximal distribution in the colon, and like their precursor hyperplastic polyp variant, sessile serrated adenomas, are often flat or sessile; they have the potential to progress to adenocarcinomas that may be histologically well differentiated with glands that have a serrated appearance; or they may show mucinous differentiation, or be undifferentiated; frequently, carcinoma of serrated pathway histogenesis is polymorphous and shows more than one or all of the above patterns [36]. At the molecular genetic level malignant serrated polyps and cancers often (but not invariably) exhibit microsatellite instability due to inactivation of the mismatch repair gene hMLH1 [35,36]. This high level of microsatellite instability has been shown to be acquired late in the progression of this type

(b)

(a)

408

(c)

of serrated adenoma and appears to correlate with the development of high-grade dysplasia and early invasive carcinoma [35]. There is no evidence as yet to support the speculation that serrated adenomas progress to high-grade dysplasia and cancer more rapidly than conventional adenomas. B-rafmutated serrated carcinomas show inactivation of mutator and suppressor genes by an epigenetic process called CpG (cytosine–guanine) island methylation. Assays for this phenomenon in B-raf-mutated serrated carcinomas and serrated adenoma precursors reveal high levels of CpG island methylation or a so-called CpG island methylation phenotype (CIMP). CIMP appears to be the engine of progression of B-raf-mutated serrated adenomas to malignancy, whereas the equivalent driving force of the conventional adenoma–carcinoma sequence is chromosomal instability and loss of heterozygosity of suppressor genes [36]. Serrated adenomas in the distal colon are less likely to show B-raf mutations and frequently have K-ras mutations instead. In contrast to the B-raf-mutated variant, K-ras-mutated serrated adenomas, although they lack an instigating APC mutation, appear to follow a molecular genetic pathway similar to that of conventional adenomas; early cancers of this pathway frequently show extensive loss of heterozygosity and chromosomal instability, and do not exhibit high levels of microsatellite instability [37]. This “fusion” version of the serrated polyp pathway has been less studied than the B-rafmutated serrated polyp pathway. To date there is no evidence to suggest that the qualitative and quantitative characteristics of the invasive carcinoma that determine approach to management of malignant serrated polyps are different from those for conventional malignant polyps. While as a group, sporadic microsatellite instability cancers are thought to have a somewhat better prognosis than

Figure 30.12 Malignant serrated polyp. This is a serrated adenoma (dysplastic serrated polyp) resected endoscopically from the proximal colon. It appears to have arisen in a sessile serrated adenoma (nondysplastic serrated polyp; synonyms: atypical hyperplastic polyp; sessile serrated polyp; serrated polyp with abnormal proliferation). Inset (b) shows an area of the serrated adenoma that exhibits high-grade dysplasia and a focus of poorly differentiated adenocarcinoma [detail in (c)] invading through the muscularis mucosae into the superficial submucosa. This serrated polyp was found to have a B-raf (V600E) mutation. Immunohistochemical staining of the lesion and laser microdissection followed by polymerase chain reaction for microsatellite instability of the extracted DNA showed loss of hMLH1 and MSI restricted to area of highgrade dysplasia and invasive carcinoma (c).

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conventional pathway cancers, those serrated cancers that are B-raf mutated and microsatellite stable frequently show poorly differentiated histology and, according to Samowitz et al. [38], poor survival.

New histological measures of risk Tumor budding is a recently recognized histological variable in colorectal carcinoma, distinct from tumor grade, that appears to have promise as an independent predictor of prognosis and a potentially valuable measure of risk for regional lymph node metastases in malignant colorectal polyps [39]. The term refers to loss of cohesion and disassociation of tumor cells at the advancing edge of a carcinoma indicated by the presence of single cells or small groups of cells that appear dedifferentiated and appear to merge with contiguous fibrous stromal cells. This histological finding has been linked to the phenomenon of epithelial–mesenchymal transition that basic science studies have shown to be an important mechanism of cancer cell invasion and metastasis [39]. One limitation in evaluating tumor budding is the lack of agreement on how it should be measured. Ueno et al. [40] used as a measure of positivity the presence of five or more isolated cells or small groups of fewer than five cells in one medium-power field (20× objective). Their study found tumor budding by this measure to be predictive of nodal metastases in a large series of T1 colorectal carcinomas, independent of tumor grade and vascular invasion; the finding was present in 15% of 251 early cancers and malignant polyps evaluated. Measured depth of invasion into the submucosa is also being used increasingly as a criterion to assess risk for local recurrence and lymph node dissemination. Recent studies have noted that in malignant polyps and early carcinomas, frequency of lymph node metastases can be linked to depth of invasion of carcinoma into the submucosa and the risk for lymph node metastases may be low with up to 2-mm depth of submucosal invasion if no other adverse features are present [40,41].

Role of the clinician There is a consensus that if no unfavorable criteria are present in pedunculated malignant polyps, there is a low or nonexistent risk of residual tumor or lymph node metastases and therefore surgery is not indicated [16,18,42,43]. Many also contend that this equally applies even if the polyp is sessile, but it is reasonable to consider a resection in these patients if their surgical risk is low [26,27,44]. Some authors have attempted to add other risk factors to these criteria, such as deep stalk invasion [44] or extensive tumor invasion of over one-third of the polyp’s submucosa [16]. After colonoscopic removal of a malignant polyp with favorable risk criteria, a follow-up colonoscopy is generally performed in about 3– 6 months to assess the polypectomy

Management of Malignant Polyps

site for completeness of removal, particularly if the polyp was sessile [1,2]. If residual cancer is found, the individual is referred for surgical resection, providing that the patient is a good surgical candidate. If there is no residual cancer, a 1-year follow-up colonoscopy may be performed, and if this examination is negative it may be repeated again in 3 years. Additional clinical follow-up with computed tomography and other tests such as carcinoembryonic antigen may be appropriate in select patients. Endoscopic ultrasound is usually not helpful after polypectomy because of the inflammatory reaction at the polypectomy site and possible reactive changes in regional lymph nodes [45,46]. In order to achieve the best outcome, the decision to operate on a patient who has had an endoscopically resected malignant polyp involves balancing the risk of residual cancer at the excision site and regional lymph node metastases against that of mortality from abdominal surgery. In general, the risk of death from elective colonic surgery varies from 0.2% to 2.0%, with the patient below age 50 years being at lowest risk [47,48]. A summary analysis of the recent literature yields an estimate of the risk of residual tumor or nodal cancer in colonoscopically resected pedunculated malignant polyps with favorable criteria as 0.3%, and for sessile malignant polyps as 1.5% (Table 30.1) [2]. Patients of any age with favorable resection criteria who have pedunculated malignant polyps resected endoscopically should not have a subsequent surgical resection, nor normally should patients over 50 years of age with sessile malignant polyps with favorable resection criteria [49]. Among healthy patients under 50 years old with sessile malignant polyps with favorable criteria, the risk of residual tumor or nodal disease is similar to or slightly higher than the risk of death from surgery, and the argument can be made that this group of patients should have surgical resection of that segment of bowel. Subsequent cancer surgery with bowel resection and node dissection will result in a cure of residual cancer in only about 50% of the patients with nodal metastases. Malignant polyps in the distal rectum require special consideration because permanent colostomy is an issue. Malignant polyps in this location are also unique in that they are amenable to proctologic surgical techniques that permit deep excisions, which are not applicable in the colon. In patients who have a positive margin at colonoscopic polypectomy, a transanal surgical excision may reverse the situation

Table 30.1 Adverse outcome (residual cancer in colon or nodes) in malignant adenomas with favorable pathologya. Pedunculated adenomas Sessile adenomas a

0.3% 1.5%

Well differentiated, no vascular or lymphatic invasion, clear margins.

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to a favorable margin-free tumor. A low anterior or abdominoperianal resection can thus be avoided. If the decision is made to refer the patient for surgery, the endoscopist should perform another endoscopy as soon as possible and tattoo the polypectomy site if this had not been done previously. This is critical because often there is a delay in the final decision until multiple consultations have been sought by the patient, and the precise polypectomy site may not be identifiable. Patients who have a family history of HNPCC should be considered separately from the above considerations. The presence of a malignant polyp regardless of “safe” margins or other adverse pathology mandates a surgical resection. They may have an accelerated adenoma–carcinoma progression and have a high synchronous and metachronous rate of additional adenomas. For these reasons, surgery in these patients should be a subtotal colectomy [50].

4

5 6

7 8

9

10

Summary The clinician’s role is to take into account the many factors relevant to each patient with a malignant polyp. The first step is to examine the histological slides with the pathologist in order to gain an accurate understanding of the pathologic characteristics of the cancer. Other factors that need to be considered by the clinician include the completeness of the polypectomy, ease or difficulties of the colonoscopy, anatomic location of the polyp, its configuration, and the patient’s comorbidity. If a decision is made to refer the patient for surgery, there should be a discussion with the surgeon regarding the above factors as well as the surgical options, including transanal excision, and standard resection versus subtotal colectomy. The surgery needs to be a cancer operation that will include an adequate number of regional lymph nodes as well as adequate lateral and deep margins, and the clinician needs to assist the surgeon by placing a tattoo at the polypectomy site. Effective management of patients with malignant polyps therefore requires a team approach that involves the pathologist, the clinician, and possibly the surgeon. Following this, the final decision must be made jointly with the patient, who because of comorbidity, age, personal philosophy, and other reasons will influence the final decision and ultimate outcome.

11

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13

14

15

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17 18 19 20

References 21 1 Waye JD, O’Brien MJ. Cancer in polyps. In: A Cohen, S Winawer (eds). Cancer of the Colon, Rectum and Anus. New York: McGrawHill, 1994: 465–76. 2 O’Brien MJ, Winawer SJ, Waye JD. Colorectal polyps. In: S Winawer (ed.). Management of Gastrointestinal Diseases. New York: Gower, 1992. 3 O’Brien MJ, Winawer SJ, Zauber AG, et al. The National Polyp Study: patient and polyp characteristics associated with high-grade

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dysplasia in colorectal adenomas. Gastroenterology 1990; 98: 371–9. Lieberman DA, Weiss DG, Bond JH, et al. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. N Engl J Med 2000; 343: 162– 8. Eide TJ. Risk of colorectal cancer in adenoma-bearing individuals within a defined population. Int J Cancer 1986; 38: 173–6. Williams AR, Balasooriya BAW, Day DW. Polyps and cancer of the large bowel: a necropsy study in Liverpool. Gut 1982; 23: 835– 42. Muto T, Bussy HJR, Morson BC. The evolution of cancer of the colon and rectum. Cancer 1975; 36: 2251–70. Day DW, Morson BC. The adenoma–carcinoma sequence. In: BC Morson (ed.). The Pathogenesis of Colorectal Cancer. Philadelphia: WB Saunders, 1978: 58–71. Rembacken BJ, Fujii T, Cairns A, et al. Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 2000; 355: 1211–14. Kudo S. Endoscopic mucosal resection of the flat and depressed types of early colorectal cancer. Endoscopy 1993; 25: 455–61. Muto T, Kamiya J, Sawada T, et al. Small “flat adenoma” of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985; 28: 847–51. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993; 329: 1977–81. O’Brien MJ, Winawer SJ, Zauber AG, et al. Blinded assessment of the flat adenoma in the National Polyp Study (NPS) does not demonstrate an excess risk for high-grade dysplasia initially or for advanced adenomas at surveillance. Gastroenterology 2001; 120: A96. Cranley JP, Petras RE, Carey WD, et al. When is endoscopic polypectomy adequate therapy for colonic polyps containing invasive carcinoma? Gastroenterology 1987; 91: 419–27. Rossini FP, Ferrari A, Coverlizza S et al. Large bowel adenomas containing carcinoma: a diagnostic and therapeutic approach. Int J Colorectal Dis 1988; 3: 47–52. Sugihara K, Muto T, Morioka Y. Management of patients with invasive carcinoma removed by colonoscopic polypectomy. Dis Colon Rectum 1989; 32: 829–34. Williams CB, Whiteway JE, Jass JR. Practical aspects of endoscopic management of malignant polyps. Endoscopy 1987; 19: 31–7. Christie JP. Polypectomy or colectomy? Management of 106 consecutively encountered colorectal polyps. Am Surg 1988; 54: 93–9. Rosseland AR, Bakka A, Reierstein O. Endoscopic treatment of colorectal carcinoma. Scand J Gastroenterol Suppl 1988; 149: 102–5. Russell JB, Chu DZ, Russell MP, et al. When is polypectomy sufficient treatment for colorectal cancer in a polyp? Am J Surg 1990; 160: 665– 8. Morson BC, Whiteway JE, Jones EA, Macrae FA, Williams CB. Histopathology and prognosis of malignant colorectal polyps treated by endoscopic polypectomy. Gut 1984; 25: 437–44. Muller S, Chesner IM, Egan MJ, et al. Significance of venous and lymphatic invasion in malignant polyps of the colon and rectum. Gut 1989; 30: 1385– 91. Ephrinpreis MN, Kinzie JL, Jaszewski R, Peleman RL. Management of the malignant polyp. Gastroenterol Clin North Am 1988; 1: 837–50.

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24 Cranley JP, Petras RE, Carey WD, et al. When is endoscopic polypectomy adequate therapy for colonic polyps containing invasive carcinoma? Gastroenterology 1986; 91: 419–27. 25 Lipper S, Kahn LB, Ackerman LV. The significance of microscopic invasive cancer in endoscopically removed polyps of the large bowel. A clinicopathologic study of five cases. Cancer 1983; 52: 1691– 9. 26 Day DW, Morson BC. The pathogenesis of colorectal cancer. In: Major Problems in Pathology, 10th edn. Philadelphia: WB Saunders, 1978: 58– 71. 27 Langer JC, Cohen A, Taylor BR, Stafford S, Jeejeebhoy KN, Cullen JB. Management of patients with polyps containing malignancy removed by colonoscopic polypectomy. Dis Colon Rectum 1984; 27: 6– 9. 28 Wilcox GM, Beck JR. Early invasive cancer in adenomatous colonic polyps (“malignant polyps”). Evaluation of the therapeutic options by decision analysis. Gastroenterology 1987; 92: 1159– 68. 29 Cohen LB, Waye JD. Treatment of colonic polyps: practical considerations. Clin Gastroenterol 1986; 15: 359–76. 30 Riddell RH. Hands off “cancerous” large bowel polyps. Gastroenterology 1985; 89: 432–5. 31 Fried GM, Hreno A, Duguid WP, Hampson LG. Rational management of malignant colon polyps based on long-term follow-up. Surgery 1984; 96: 815–21. 32 Haggitt RC, Glotzbach RE, Soffer EE, Wruble LD. Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy. Gastroenterology 1985; 89: 328–36. 33 Cooper HS. Surgical pathology of endoscopically removed malignant polyps of the colon and rectum. Am J Surg Pathol 1983; 7: 613–23. 34 Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50: 113– 30. 35 O’Brien MJ, Yang S, Mack C, et al. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol 2006; 30: 1491–501.

Management of Malignant Polyps

36 O’Brien MJ. Hyperplastic and serrated polyps of the colorectum. Gastroenterol Clin N Am 2007; 36: 947– 68. 37 Jass JR, Baker K, Zlobec I, et al. Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer. Histopathology 2006; 49: 121–31. 38 Samowitz WS, Sweeney C, Herrick J, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 2005; 65: 6063–9. 39 Prall F. Tumour budding in colorectal carcinoma. Histopathology 2007; 50: 151– 62. 40 Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma Gastroenterol 2004; 127: 385– 94. 41 Cooper HS. Pathology of the endoscopically removed malignant colorectal polyp. Curr Diagn Pathol 2007; 13: 423–37. 42 Eckardt VF, Fuchs M, Kanzler G, Remmele W, Steinen U. Followup of patients with colonic polyps containing severe atypia and invasive carcinoma. Cancer 1988; 61: 2552–7. 43 Richards WO, Webb WA, Morris SJ, et al. Patient management after endoscopic removal of the cancerous colon adenoma. Ann Surg 1987; 205: 665–72. 44 Greenburg AG, Saik RP, Coyle JJ, Peskin GW. Mortality and gastrointestinal surgery in the aged. Arch Surg 1981; 116: 788–91. 45 Niederhuber JE. Colon and rectum cancer: patterns of spread and implications for workup. Cancer 1993; 71: 4187–92. 46 Roseau G, Palazzo L, Paolaggi JA. Endoscopic ultrasonography in colorectal diseases. Biomed Pharmacother 1992; 46: 133–8. 47 Hermanek P, Gall FP. Early (microinvasive) colorectal carcinoma: pathology, diagnosis, surgical treatment. Int J Colorectal Dis 1986; 1: 79–84. 48 Wilcox GM, Beck JR. Early invasive cancer in adenomatous colonic polyps: evaluation of the therapeutic options by decision analysis. Gastroenterology 1987; 92: 1159–68. 49 Bond JH. Polyp Guideline: diagnosis, treatment, and surveillance for patients with nonfamilial colorectal polyps. Ann Intern Med 1993; 119: 836– 46. 50 Karita M, Tada M, Okita K et al. Endoscopic therapy for early colon cancer: the strip biopsy resection technique. Gastrointest Endosc 1991; 37: 128–32.

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Magnifying Colonoscopy, Depressed Colorectal Cancer, and Flat Adenomas Hiroshi Kashida & Shin-ei Kudo Showa University, Yokohama, Japan

Introduction Magnifying or zoom colonoscopes became commercially available in 1993 [1] and are now being used throughout the world. Zoom colonoscopes have all the basic functions of conventional colonoscopes and therefore can be used during routine examinations with a standard view. The magnified view can be obtained instantaneously by rotating the magnification knob of the scope or stepping on the foot controller. The image may be magnified up to 75- or 100-fold by focusing the lens mechanisms in the tip. Identification of the surface mucosal pattern is achieved by a combination of the magnified image and its enhancement by application of various colored dyes when an abnormal finding is identified. Chromoendoscopy is useful for determining the lateral extent of small colorectal lesions for and revealing their gross configuration, especially the presence or absence of a depression within them [2]. Two methods for chromoendoscopy are popular at present. The contrast method involves using the dye to enhance visualization of the surface topography and the staining method uses different colored chemical compounds that stain the surface cells through the process of absorption (see Chapter 35). In the contrast method, dye accumulates in concave areas and clarifies unevenness of the colon wall. Usually 0.2% indigo carmine solution is employed, although several compounds are available. Dye is retained in depressed portions, which makes unevenness of the lesion conspicuous. Some lesions that appear through gross visual inspection to have a flat surface are often minimally depressed and/or elevated when the irregularity is augmented by dye, which fills crevices and runs off the higher elevation. The staining method relies on the capability of colonic surface cells to absorb fluid. A common dye is 0.05% crystal violet solution, which stains the absorbent epithelium of the

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large bowel. The orifices of the crypts themselves are not stained. This technique is critical in evaluating the pit pattern with magnifying scopes. Frequently, indigo carmine and crystal violet are used consecutively to achieve differential effects which are amplified by using magnification endoscopy. The first dye should be washed away before the other dye is sprayed.

Procedure When a lesion or an abnormal area is encountered, feces or mucus over that portion should be washed away before the dye is applied. Water is a good flushing agent, but the addition of dimethicone (polydimethylsiloxare) and/or pronase may help to remove bubbles and mucus adhering to the surface of the lesion. Contrast dye such as indigo carmine can be injected through the forceps channel with a syringe. A staining dye such as crystal violet is usually injected through a catheter. The catheter permits precise application just over the lesion. A large volume of contrast dye should be avoided because it will result in excessive darkening of the image. Any excess must be removed by suction or washed with water before observation. It takes a minute for crystal violet to stain the mucosa after spraying. The combination of chromoscopy and magnifying colonoscopy is useful for the differential diagnosis of a colorectal lesion, and for predicting the depth of a cancer, because it enables observation of the microanatomy of the lesion.

Gross appearance Classification of the gross appearance of colorectal adenomas and early carcinomas has been proposed by the Japanese Research Society for Cancer of the Colon and Rectum, but it is fairly complicated. We use a more simplified classification which divides all lesions into three categories: protruded, flat elevated, and depressed (Figure 31.1) [3]. Recognition of depression is very important, because depressed lesions often harbor invasive cancer despite a small diameter (even when

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Protruded

Flat elevated

Laterally spreading tumor (LST)

Figure 31.1 Classification of gross appearance of early colorectal carcinoma and adenoma.

less than 10 mm in size) (Table 31.1). In some cases a depression can be seen in a lesion that is actually elevated above the surface as a result of submucosal invasion and proliferation of the tumor cells. Such lesions must not be mistaken for ordinary elevated neoplasms, as they are quite different in biologic behavior. Chromoendoscopy is particularly essential for diagnosing these lesions, as it is possible to overlook the depressed area in the midst of a diffusely elevated polyp. Japanese and other experts gathered and discussed the gross appearances of superficial colorectal neoplasms at the International Conference on Endoscopic Classification of Superficial Neoplastic Lesions held in Paris, November 30 to December 1, 2002. The results of the meeting were reported in the journal Gastrointestinal Endoscopy [4]; the adopted classification (so-called Paris classification) of gross appearance of early colorectal neoplasia was basically in accordance with the Japanese classification schema.

Surface structures of the colon The surface microstructure of colorectal epithelium was first analyzed using dissecting microscopes on resected specimens in the 1970s. The normal surface mucosal morphology was

described by Bank et al. [5], and subsequent investigators have detailed the structural alterations in colorectal epithelial neoplasms. In the early 1980s, Nishizawa et al. [6] reported on the characteristic surface structural difference between normal colonic mucosae, adenomas, and adenocarcinomas. Studies on the surface microstructure had been started on stomach diseases earlier, but these were not pursued at that time because the stomach mucosa is often too damaged by the erosive effect of gastric acid and/or the inflammatory changes induced by Helicobacter pylori infection to obtain a clear magnified image. On the other hand, a normal colon is usually free of superficial inflammatory change, thus rendering the large bowel mucosa suitable for magnifying observation. The development of magnifying fiber colonoscopes enabled visualization of the microstructure of the mucosa and various colorectal lesions in vivo, instead of in vitro [7]. The advent of commercially available magnifying video colonoscopes with high-power resolution in the 1990s accelerated the study of the microanatomy of colonic lesions [8]. The combination of chromoscopy and magnifying colonoscopy is useful for detecting small localized lesions for their differential diagnosis, and for determining not only their lateral extent but also their depth [9]. Some investigators have also reported on analysis of the diffuse mucosal changes or localized neoplastic changes in inflammatory bowel diseases using magnifying colonoscopies [10–13].

Pit pattern classification In the dye-enhanced visualization of the colon surface, the openings of the colonic crypts are referred to as “pits,” and the specific arrangement of the openings of the glands in normal mucosae and in various kinds of lesions is called the “pit pattern.” These can be seen with high-definition colonoscopes to some extent, but are usually observed with magnifying scopes. Although there have been a variety of different classifications [6,7], the most frequently used at present is our description [2,8], which divides the pit patterns into six groups: types I, II, IIIL, IIIS, IV, and V. These specific pit patterns can be used to predict the histological structure of a lesion. The pits of normal mucosae (Kudo’s type I) are round and regular in both size and arrangement. The pits of hyperplastic polyps (type II) are larger than normal pits, and instead of round are star shaped or onion-like, but are

Table 31.1 Rate of submucosal (T1) cancer in colorectal neoplasms (excluding advanced cancers). Size (mm)

Depressed type Flat type Protruded type Total

Total

≤5

6–10

11–15

16–20

≥ 21

22/263 (8.4%) 2/7583 (0.03%) 0/7046 (0%) 24/14 892 (0.16%)

75/172 (43.6%) 5/1436 (0.35%) 72/5582 (1.3%) 152/7190 (2.1%)

64/93 (68.8%) 21/658 (3.2%) 105/1360 (7.7%) 190/2111 (9.0%)

29/34 (85.3%) 29/271 (10.7%) 87/503 (17.3%) 145/808 (17.9%)

20/23 (87.0%) 81/415 (19.5%) 94/323 (29.1%) 195/761 (25.6%)

210/585 (35.9%) 138/10363 (1.3%) 358/14814 (2.4%) 706/25 762 (2.7%)

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Table 31.2 Gross appearance and pit patterns. IIIL

Depressed Flat elevated Protruded Total

70 7453 (88.7%) 10 208 (72.5%) 17 731

IV

1 551 (6.6%) 3236 (23.0%) 3788

IIIS

V

257 (46.0%) 78 17 352

regularly arranged. Types I and II pit patterns are characteristic of non-neoplastic lesions. Identification of these pit patterns is aided by the use of magnification instruments. Lesions which show compactly arranged pits that are smaller than normal (type IIIS; “s” stands for “short” or “small”) are characteristically depressed. Lesions with small, compact crypts are not frequently found but are considered to be precursors of de novo advanced cancers. The small pits reflect the crowding of cells in these precursor lesions. In polypoid adenomas, the pits often appear elongated (type IIIL; “L” stands for “long” or “large”) and sometimes appear branched (type IV). Types IIIS, IIIL, and IV are adenomatous pit patterns. The type V pit pattern is seen in cancers, and subdivided into two groups. In deeply invasive or advanced cancers the surface of the lesion is rough and often ulcerated; therefore, it is almost devoid of pits and looks unstructured. Such a pit pattern is named VN (“N” stands for “nonstructural”). In contrast to the findings in advanced cancers is the more structured pit pattern of severely dysplastic adenomas or submucosally invasive carcinomas, in which the pits are in a somewhat irregular array but not in a completely chaotic arrangement. Such an irregular pattern has been named type VI (“I” stands for “irregular”). Many studies using magnifying colonoscopes show that the observed pit pattern corresponds well to those seen with dissecting microscopes.

Surface pit pattern and the structure of colonic glands There have been several attempts to evaluate and further understand the three-dimensional structure of localized colonic

I

N

53 (9.5%) 245 511 809

178 (31.8%) 78 112 112

IIIS IIIL IV

414

Adenoma (dysplasia) Low grade

High grade

251 (86.0%) 12 709 (95.3%) 2604 (76.3%)

31 (10.6%) 631 (4.7%) 695 (20.4%)

559 (100%) 8405 (100%) 14 084 (100%) 14 084 (100%)

lesions. Kudo et al. [8] compared the pit pattern at colonoscopy or stereomicroscopy with histological sections taken in the horizontal axis (parallel to the mucosal surface). Precise calibration with microscopy permits measurement of the width of individual pits of types I, II, IIIS, IIIL, and IV. These widths were 70 ± 20 μm, 90 ± 20 μm, 30 ± 10 μm, 220 ± 90 μm, and 930 ± 320 μm, respectively [2]. Similar results were reported recently by Tamura et al. [14], who studied the colonic glands using scanning electron microscopy. The first studies concerning the analysis of pit patterns using scanning electron microscopy were reported by a few researchers [15–17]. This method, using much higher magnifications than those achieved during endoscopy, is costly and time-consuming. Nevertheless, scanning electron microscopy studies are of considerable academic importance for the understanding of the three-dimensional structure of colonic polyps and cancers. Rubio and colleagues [1,16] attempted to plot out a planimetric three-dimensional histological pattern incorporating the surface profile from biopsy specimens, using scanned images of serial tissue sections manipulated with computer software.

Gross appearance of colorectal neoplasms and their pit pattern Considerable interest has developed in endoscopic evaluation of the surface pit pattern in both normal and pathologic conditions. There are definite correlations between the gross appearance and the pit pattern of a colorectal lesion (Table 31.2 and Figures 31.3–31.7). Depressed lesions present with either type IIIS or V pit pattern; the latter implies that the lesion is cancerous. Almost all flat and protruded

Table 31.3 Pit patterns and histology of lesions. Pit pattern

Total

Submucosal cancer (T1)

Total

10 0 115

292 13 340 3414

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Table 31.4 Type V pit pattern and depth of submucosal cancer. Pit pattern

VI Low grade High grade VN Total

Submucosal invasion Slight

Massive

29 (82.9%) 12 0 41

6 68 (85.0%) 63 (100%) 137

Total

35 80 63 178

neoplasms have pit patterns that correspond to type IIIL or IV pits.

Pit pattern and histology The pit pattern closely correlates with the histology of the lesion. Lesions which present only with type II pit pattern are considered non-neoplastic, and are seldom removed. Once this pattern is identified, the overall accuracy of pit pattern analysis is 95.5% for differentiating between neoplastic and non-neoplastic colorectal polyps [18– 22]. In neoplastic lesions, pit pattern analysis is useful for distinguishing between adenomas, early signs of cancer, and invasive cancers (Table 31.3). The majority of polyps that have only type IIIS, IIIL, or IV pits are low-grade adenomas. The tumors of type VI encompass a variety of lesions from benign adenoma to invasive carcinoma. These lesions with

type VI pit pattern are removed endoscopically, and additional treatment consisting of surgical colectomy and lymph node dissection is considered after histological analysis of the resected specimen. The majority of lesions with type VN pit pattern are invasive cancers (Table 31.4), which means that these lesions are not resected endoscopically but treated surgically from the time of first diagnosis [18]. It cannot be denied that there are some limitations to the pit pattern diagnosis, as pit patterns reflect the changes on the surface of lesions but are not necessarily indicative of what lies deep beneath the visible portion of the lesion. However, investigators agree that changes in the deeper layers are also reflected on the surface to some extent; thus, pit patterns can be used as surrogate markers reflecting abnormal cellular proliferation at the basal layers of the colonic crypts. Pit pattern analysis is beginning to be widely understood and is becoming widely embraced throughout the world [20,23].

So-called flat adenoma and depressed lesion There is some confusion about depressed and flat lesions among colonoscopists from the developed world. It is possible that part of the difficulty in acceptance of this concept is that “flat” adenomas are not absolutely flat, but are often slightly elevated. The terminology “flat adenoma” was coined by Muto et al. [24] in 1985. It referred to a type of neoplastic lesion which was slightly elevated and plateau-like, with a reddish surface and sometimes a central depression. The definition of “flat” requires that the thickness of the adenomatous

Figure 31.2 Pit pattern classification.

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component is not more than twice that of the adjacent nonneoplastic mucosa. In addition to the flat-surfaced lesion, a depressed variety of flat adenoma was described, which started the confusion regarding depressed lesions and flat elevated adenomas. Some benign adenomas appear to have a depression and resemble depressed-type early cancers [3,25]; however, the depression in a “depressed lesion” is rather extensive and clearly demarcated. By contrast, the “depression” in flat elevated benign adenomas is actually a shallow concavity or an ill-defined pseudodepression. Flat elevated adenomas with a pseudodepression should be differentiated from truly depressed lesions, because the former are almost invariably benign. A critical part of the understanding of this distinc-

(a)

(b)

(c)

(d)

(e)

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(f)

tion is that depressed lesions are not to be considered as flat adenomas, but should be regarded as a different entity. Confusion over this concept has been compounded because many authors discuss flat adenomas and depressed lesions together [26–36]. Their natures should be discussed separately. Comprehensive terms such as “nonpolypoid” or “superficial” may also be misleading and the use of these descriptions should be chosen carefully. Laterally spreading tumors are flat elevated adenomas that spread extensively along the colonic wall and are, by definition, very short in height [2] (Figures 31.6 and 31.7). These lesions are sometimes malignant, but not as advanced as one would expect when compared with their large diameter.

Figure 31.3 A depressed lesion in the sigmoid colon, 4 mm in diameter. (a) Ordinary colonoscopic view. (b) Chromoendoscopy with indigo carmine. (c) Chromoendoscopy with crystal violet and medium-power magnification. (d) Highly magnified view showing small, compactly arranged, type IIIs pits. (e) The lesion was endoscopically removed. (f) High-power microscopic view of the histological specimen. It was shown to be intramucosal cancer according to the Japanese rule or high-grade adenoma according to the Western rule.

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Characteristics of flat elevated adenomas and depressed lesions When Muto et al. [24] reported on 33 “flat adenomas,” they pointed out that more than 40% of such lesions contained focal carcinomas or severely dysplastic tubules. In the series of Wolber and Owen [37], which reported on 29 flat adenomas, the proportion of these with high-grade dysplasia was virtually identical to that in the study of Muto et al. [24].

Figure 31.4 A depressed lesion with marginal elevation (type IIc + IIa) in the transverse colon, 9 mm in diameter. (a) Ordinary colonoscopic view. (b) Chromoendoscopy with indigo carmine. (c) Magnified view of narrow-band image showing network pattern. (d) Chromoendoscopy with crystal violet and high-power magnification showing slightly irregular pit pattern (type Vi-low). (e and f) The lesion was endoscopically removed. (g) Highpower microscopic view of the desmin-stained specimen. The lesion was diagnosed as slightly invasive submucosal cancer.

Because of our deep interest and with the use of chromoendoscopy and magnification colonoscopy, we have encountered many cases of flat elevated adenomas (see Table 31.1). Invasive carcinoma is present in 0.08% of flat adenomas less than 10 mm in diameter and present in 5.4% of those 11–20 mm. The rate of invasive cancer is slightly lower than, but not remarkably different from, that in protruded polyps (see Table 31.1). Therefore, our findings are that flat lesions are

(a)

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(d)

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(f )

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usually benign or only focally malignant and grow very slowly, and do not become invasive cancer until they are rather large. By contrast, the rate of invasive carcinoma in depressed lesions is 22.3% when the lesion does not exceed 10 mm and 73.2% in those of 11–20 mm. Cancer in depressed lesions grows rather rapidly, advancing at an early stage [38,39]. Muto et al. [24] were right in pointing out that lesions “with a central depression” were more malignant than others, but their original description did not emphasize the differentiation between truly depressed lesions and flat elevated adenomas with a pseudodepression.

Diagnosis of flat elevated adenomas and depressed lesions Whether depressed or not, there have been relatively few cases of nonpolypoid early colon cancers reported by researchers. We think the cause is that candidate lesions are overlooked as a result of a misunderstanding of the concept or because proper diagnostic methods are not used [26–36]. A review of pathology specimens obtained during the National Polyp Study in the US found that many flat adenomas had been removed during colonoscopy but had not been reported in a separate category, and were referred to in the endoscopy reports only as polyps [40]. High-magnification colonoscopy and chromoscopy clearly improve the detection of nonpolypoid neoplastic lesions.

418

Figure 31.5 A case of an elevated lesion with depression (type IIa + IIc) in the ascending colon, 14 mm in diameter. (a) Ordinary colonoscopic view. (b) Chromoendoscopy with indigo carmine. (c) Chromoendoscopy with crystal violet and high-power magnification showing highly irregular pit pattern (type Vihigh). (d) The lesion was treated surgically, and was shown to be deeply invasive (sm2; depth 2700 mm) cancer with lymphatic invasion.

Despite the term “flat,” there are few adenomas that are perfectly flat, and the majority of small adenomas are slightly elevated [25]. Detecting a tiny area with a slight color change is important; some lesions are slightly reddish while others may appear pale or discolored [2,18]. Bleeding spots, interruption of the capillary network pattern, or slight deformation of the colonic wall may suggest the existence of a neoplastic lesion. Some flat elevated adenomas appear to have a depression at first sight, but it may not be a true depression [25]. When a topical spray of dye is applied over a depressed lesion, a true depression appears rather extensive and has a roundish shape, while the “depression” of the flat adenomas is ill defined and has only a thorny or groove-like appearance. The depressed type of colorectal cancer can be either absolutely depressed or accompanied by a slightly elevated margin (see Figures 31.2–31.4). The periphery is usually covered with normal mucosa and is elevated because of compression by the carcinoma or because of submucosal proliferation of tumor cells. It is worth noting that the elevated margin does not usually consist of adenomatous tissue. The transition from carcinoma to the adjacent normal colonic mucosa is usually abrupt without lateral spread of adenoma. There can occasionally be a few glands adjacent to the cancer that show adenoma-like changes, but these could be reactive to the tumor and not related to carcinogenesis.

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Figure 31.6 LST in the cecum, 50 mm in diameter. (a) Ordinary colonoscopic view. (b) Chromoendoscopy with indigo carmine delineates the boundary of the lesion. (c) The lesion spread partially into the ileocecal valve. (d) Chromoendoscopy with crystal violet and magnification showing type IV pit pattern. (e) The lesion was treated by piecemeal endoscopic mucosal resection. (f) The histological specimen of the lesion. (g) Highpower magnification of the histology showing that the lesion was low-grade adenoma.

Magnifying Colonoscopy, Depressed Colorectal Cancer, and Flat Adenomas

(a)

(b)

(c)

(d)

(f )

(e)

Magnifying colonoscopy and chromoscopy enable the examiner to see the microstructure of the mucosal surface of any lesions. There are definite correlations between the gross appearance and the pit pattern of a colorectal lesion. Depressed lesions present with type IIIS or type V pit pattern. Almost all flat elevated adenomas consist of type IIIL or IV pits. The pit pattern analysis facilitates the differentiation between flat elevated adenoma and depressed lesions by magnifying colonoscopy and chromoendoscopy.

(g)

New modalities for observing the surface microstructure The surface microvasculature of the gastrointestinal tract is visualized with a narrow-band imaging system, which is known to be especially useful for the diagnosis of small esophageal cancer. This system is now also being assessed in the colorectum [41–43]. We classified colonic microvascular patterns into six types: normal, faint, network, dense, irregular, and sparse [44]. The vascular pattern of hyperplastic polyps

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is almost always faint pattern, whereas that of protruded or flat adenomas is usually either network or dense pattern. The sparse pattern is characteristic for depressed cancers, and irregular pattern is mainly seen in protruded or flat-elevated cancers. If we assume that patterns, except faint, are diagnostic for neoplasia, we should be able to differentiate between neoplastic and non-neoplastic lesions with high accuracy. The narrow-band imaging system also enables us to see the pit pattern indirectly because each pit is usually surrounded by vessels. Chromocolonoscopy might be replaced by narrow-band imaging for the purpose of distinguishing

420

Figure 31.7 LST in the rectum, 72 mm in diameter. (a) Ordinary colonoscopic view. (b) Chromoendoscopy with indigo carmine delineated the boundary of the lesion. (c) Chromoendoscopy with crystal violet and high-power magnification showing nonstructural pit pattern (type VN). (d) The lesion was treated surgically. (e and f) The lesion was deeply invasive submucosal cancer with vessel invasion and nodal metastasis.

neoplastic from non-neoplastic lesions. Narrow-band imaging and other image enhancement systems are sometimes referred to as “optical choromoscopy.” Assuming that either irregular or sparse pattern in narrow-band imaging represents cancers, the rate of accurate diagnosis will be around 85%. Thus, narrow-band imaging with magnification may also be useful for distinguishing between cancers and adenomas, but the accuracy rate should be higher (> 90%) in the chromoendoscopy with magnification [43,44]. Some ultra-high magnifying scopes with a magnification power of nearly ×500 have been developed. The basic

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mechanism for these are a laser confocal microscopy system (endomicroscopy) [45,46] and a contact endoscopy system (endocytoscopy) [47– 49]. Their usefulness in the diagnosis of early colorectal cancers is being assessed.

Summary Chromoendoscopy and magnification colonoscopy are useful for an accurate diagnosis of colorectal neoplastic lesions, especially depressed and flat elevated types. They also help to predict the histology, and therefore are useful in determining the treatment options: endoscopic or surgical. Endoscopists should have further training in the use and findings of these combined techniques [50].

References 1 Kudo S, Rubio CA, Teixeira CR, Kashida H. Pit pattern in colorectal neoplasia: endoscopic magnifying view. Endoscopy 2001; 33: 367– 73. 2 Kudo S. Early Colorectal Cancer. Detection of Depressed Types of Colorectal Carcinoma. Tokyo: Igaku–Shoin, 1996. 3 Kudo S, Kashida H, Tamura T, et al. Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer. World J Surg 2000; 24: 1081–90. 4 Lambert R, Lightdale CJ. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointest Endosc 2003; 58: S1–50, 5 Bank S, Cobb JS, Burns DG, Marks IN. Dissecting microscopy of rectal mucosa. Lancet 1970; 1: 64–5. 6 Nishizawa M, Okada T, Sato F, Kariya A, Mayama S, Nakamura K. A clinicopathological study of minute polypoid lesions of the colon based on magnifying fiber-colonoscopy and dissecting microscopy. Endoscopy 1980; 12: 124– 9. 7 Tada M, Kawai K. Research with the endoscope: new techniques using magnification and chromoscopy. Clin Gasroenterol 1986; 15: 417–37. 8 Kudo S, Hirota S, Nakajima T, et al. Colorectal tumours and pit pattern. J Clin Pathol 1994; 47: 880–5. 9 Kashida H, Kudo S. Early colorectal cancer: concept, diagnosis, and management. Int J Clin Oncol 2006; 11: 1– 8. 10 Matsumoto T, Kuroi F, Mizuno M, Nakamura S, Iida M. Application of magnifying chromoscopy for the assessment of severity in patients with mild to moderate ulcerative colitis. Gastrointest Endosc 1997; 46: 400–5. 11 Kiesslich R, Fritsch J, Holtman M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Endoscopy 2003; 124: 880– 8. 12 Hata K, Watanabe T, Motoi T, et al. Value Pitfalls of pit pattern diagnosis in ulcerative colitis-associated dysplasia. Gastroenterology 2004; 126: 374– 6. 13 Sada M, Igarashi M, Yoshizawa S, et al. Dye spraying and magnifying endoscopy for dysplasia and cancer surveillance in ulcerative colitis. Dis Colon Rectum 2004; 47: 1816– 23.

14 Tamura S, Firuya Y, Tadokoro T, et al. Pit pattern and threedimensional configuration of isolated crypts from the patients with colorectal neoplasm. J Gastroenterol 2002; 37: 798–806. 15 Shields H, Bates MI, Goldman H, et al. Scanning electron microscopic appearance of chronic ulcerative colitis with and without dysplasia. Gastroenterology 1985; 89: 62–72. 16 Rubio CA, May I, Slezak P. Ulcerative colitis in protracted remission: a quantitative scanning electron microscopical study. Dis Colon Rectum 1988; 31: 939– 44. 17 Sano Y, Fujimori T, Ichikawa K, et al. Comparative studies of the surface structure of colorectal tumor with its histological features [in Japanese with English abstract]. Stomach Intestine 1996; 31: 1327–40. 18 Kudo S, Kashida H, Tamura T, et al. Colonoscopic diagnosis and management of nonpolypoid ECC (early colorectal cancer). World J Surg 1999; 23: 694–701. 19 Togashi K, Konishi F, Ishizuka T, et al. Efficacy of magnifying endoscopy in the differential diagnosis of neoplastic and nonneoplastic polyps of the large bowel. Dis Colon Rectum 1999; 42: 1602– 8. 20 Kiesslich R, von Bergh M, Hahn M, Hermann G, Jung M. Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon. Endoscopy 2002; 33: 1001–6. 21 Konishi K, Kaneko K, Kurahashi T, et al. A comparison of magnifying and nonmagnifying colonoscopy for diagnosis of colorectal polyp: a prospective study. Gastrointest Endosc 2003; 57: 48–53. 22 Fu KI, Sano Y, Kato S, et al. Chromoendoscopy using indigo carmine dye spraying with magnifying observation is the most reliable method for differential diagnosis between non-neoplastic colorectal lesions: a prospective study. Endoscopy 2004; 36: 1089–93. 23 Lambert R, Rey JF. Colonoscopy: an increased detection yield? Endoscopy 2002; 33: 1031–5. 24 Muto T, Kamiya J, Sawada T. Small “flat adenoma” of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985; 28: 847–51. 25 Kudo S, Kashida H, Tamura S, Nakajima T. The problem of “flat” colonic adenoma. Gastrointest Endosc Clin N Am 1997; 7: 87– 98. 26 Hirata I, Tanaka M, Sugimoto K. Clinicopathological study on flat and depressed minute colorectal carcinomas. Dig Endosc 1991; 3: 526–35. 27 Iishi H, Tatsuta M, Tsutsui S, et al. Early depressed adenocarcinomas of the large intestine. Cancer 1992; 69: 2406–10. 28 Hunt DR, Cherian M. Endoscopic diagnosis of small flat carcinoma of the colon. Dis Colon Rectum 1990; 33: 143–7. 29 Mion F, Desseigne F, Napoleon B. Failure of endoscopic detection of a de novo carcinoma of the colon in a patient with adenomatous polyps. Gastrointest Endosc 1992; 38: 703–6. 30 Stolte M, Bethke B. Colorectal mini-de novo carcinoma: a reality in Germany too. Endoscopy 1995; 27: 286–90. 31 Kobayashi K, Sivak MV Jr. Flat adenoma: are Western colonoscopists careful enough? Endoscopy 1998; 30: 487–9. 32 Fujii T, Rembacken BJ, Dixon MF, et al. Flat adenomas in the United Kingdom: are treatable cancers being missed? Endoscopy 1998; 30: 437– 43. 33 Hart AR, Kudo S, Mackay EH, et al. Flat adenomas exist in asymptomatic people: important implications for colorectal cancer screening programs. Gut 1998; 43: 229–31.

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34 Saitoh Y, Waxman I, West AB, et al. Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology 2001; 120: 1657– 65. 35 Hurlstone DP, Cross SS, Adam I, et al. Efficacy of high magnification chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum comparison: a prospective analysis. Gut 2004; 53: 284– 90. 36 Soetikno RM, Friedland S, Kaltenbach T, et al. Nonpolypoid (flat and depressed) colorectal neoplasmas. Gastroenterology 2006; 130: 588–9. 37 Wolber RA, Owen DA. Flat adenomas of the colon. Hum Pathol 1991; 22: 70– 4. 38 Kudo S, Kashida H. Flat and depressed lesions of the colorectum. Clin Gastroenterol Hepatol 2005; 3: S33– 6. 39 Kashida H, Kudo S, Takeuch T, Ohtsuka K. The importance of depressed lesions in the development of colorectal cancer. In: Fujita R, Jass J, Kaminishi M, Schlemper RJ (eds.). Early Cancer of the Gastrointestinal Tract. Tokyo: Springer-Verlag, 2005: 243–7. 40 O’Brien MJ, Winawer SJ, Zauber AG, et al. Flat adenomas in the National Polyp Study: is there increased risk for high-grade dysplasia initially or during surveillance? Clin Gastroenterol Hepatol 2004; 2: 905–11. 41 Tanaka S, Kaltenbach T, Chayama K, Soetikno R. Highmagnification colonoscopy (with videos). Gastrointest Endosc 2006; 64: 604–13. 42 Machida H, Sano Y, Hamamoto Y, et al. Narrow-band imaging in the diagnosis colorectal mucosal lesions: a pilot study. Endoscopy 2004; 36: 1094– 8.

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43 Tischendorf JJ, Wasmuth HE, Koch A, et al. Value of magnifying chromoendoscopy and narrow band imaging (NBI) in classifying colorectal polyps: a prospective controlled study. Endoscopy 2007; 39: 1092– 6. 44 Wada Y, Kashida H, Ikehara N, et al. The surface microvasculature of colorectal lesions observed by magnifying scope with narrow band imaging (NBI) system. Gut 2007; 56: A370. 45 Kiesslich R, Burg J, Vieth M, et al. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gatroenterology 2004; 127: 706–13. 46 Polglase AL, McLaren WJ, Skinner SA, et al. A fluorescence confocal endomicroscope for in vivo microscopy of the upperand the lower-GI tract. Gastrointest Endosc 2005; 62: 686–95. 47 Inoue H, Kazawa T, Sato Y, et al. In vivo observation of living cancer cells in the esophagus, stomach, and colon using cathetertype contact endoscope, “Endo-Cytoscopy system”. Gastrointest Endosc Clin N Am 2004; 14: 589– 94. 48 Sakashita M, Inoue H, Kashida H, et al. Virtual histology of colorectal lesions using laser-scanning confocal microscopy. Endoscopy 2003; 35: 1033– 8. 49 Sasajima K, Kudo S, Inoue H, et al. Realitime in vivo virtual histology of colorectal lesions when using the endocytoscopy system. Gastrointest Endosc 2006; 63: 1010–17. 50 Hurlstone DP, George R, Brown S. Novel clinical in vivo roles for indigo carmine: high-magnification chromoscopic colonoscopy. Biotech Histochem 2007; 82: 57–71.

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Flat and Depressed Colorectal Neoplasia in the Western Countries Roy Soetikno & Pankaj J. Pasricha Stanford University School of Medicine, Palo Alto, CA, USA

Introduction Recent reports showing that nonpolypoid colorectal neoplasms (NP-CRNs) are relatively common lesions diagnosed during routine colonoscopy in Western countries have challenged the traditional paradigm that colorectal cancers arise primarily through polypoid growth of adenoma over time. The need to shift the paradigm is critical as NP-CRNs are more likely to contain high-grade dysplasia or submucosal invasive carcinoma than are polypoid colorectal neoplasms, irrespective of size. With the importance of NP-CRNs being scientifically proven, as shown by the Flat Lesion Study [1] and other studies [2–7], this can thus lead to all neoplasms (polypoid or not) being carefully looked for during every colonoscopy. In this chapter, we will review the literature on NP-CRNs in Western countries with emphasis on its detection, diagnosis, and treatment.

Polypoid type

Pedunculated

Sessile

Nonpolypoid type

Superficial elevated

or

Flat

Depressed

Definitions NP-CRNs can be defined endoscopically and pathologically, although in practice most lesions are classified during endoscopy. The classification system of the Japanese Society for Cancer of the Colon and Rectum [8] (Figure 32.1) is practical for describing colorectal lesions endoscopically, and is widely used in clinical studies. This classification has recently been slightly modified and is known as the Paris classification [9]. The use of either classification is important as it allows a common descriptor to be used by the gastroenterologist, pathologist, surgeon, and radiologist in clinical and research settings. Colorectal neoplasms are divided into two types: superficial and invasive [8,9]. Superficial neoplasms are lesions

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Larger superficial elevated

or

Figure 32.1 A macroscopic classification of superficial colorectal neoplasms. Superficial colorectal neoplasms are limited to the mucosal and submucosal layers. Invasive neoplasms are cancers that have invaded the muscularis propria. Superficial neoplasms are divided into two types: polypoid (pedunculated/semi-pedunculated and sessile shape) and nonpolypoid (superficial elevated, completely flat, and depressed shape).

limited to the mucosal and submucosal layers. Superficial neoplasms are divided into two: polypoid (protruding) and nonpolypoid (nonprotruding) (Figure 32.2). In turn, the polypoid type is either pedunculated or semipedunculated and consists of sessile morphology. The nonpolypoid type consists of superficial elevated, completely flat, and depressed morphology. It should be noted that advanced colorectal neoplasms are not classified as NP-CRNs, although they may appear to be flat or depressed. In the colon and rectum, the term “flat” is used to describe the superficial elevated lesions, i.e., the lesions that appear flat like a pancake. The description of superficial elevated lesions as “flat” lesions in the colon

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Figure 32.2 A variety of small nonpolypoid colorectal neoplasms before and after image enhancement using diluted indigo carmine detected in our unit in Palo Alto. The lesions range from 6 mm (top images) to about 13 mm (bottom images), respectively, with the pathology range from tubular adenoma to high-grade dysplasia.

occurs because of its ease of use, and completely flat lesions are quite rare. Endoscopically, a lesion is defined as flat when its height is less than half its diameter. This definition can, however, be difficult to apply to a small lesion and perhaps has

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contributed to the variation in the prevalence of NP-CRNs reported in the different studies (see Table 32.1). The Paris classification defines a flat lesion by comparing the height of the lesion to that of the height of the closed cups of biopsy

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forceps (2.5 mm). Lesions protruding above the level of the closed jaws of the biopsy forceps are classified as protruded, whereas those whose elevation is below this level are classified as flat. Pathologic definition relies on measurement of the height of the mucosa: the height of the neoplastic mucosa of a flat lesion is no more than twice that of the adjacent normal. Some flat colorectal neoplasms have smooth surfaces, while others may have granulated surfacesathese are called the nongranular and granular flat lesions, respectively. In the Japanese literature, large flat neoplasms (diameter ≥ 10 mm) are often called laterally spreading tumors [10], while in the Western literature they are called carpet lesions. We suggest refraining from using these terms as they do not provide additional information and, more importantly, it is not possible to describe the growth pattern of a lesion based on a single colonoscopy examination. Depressed lesions are lesions with the base of the depression lower than the adjacent normal mucosa. Although depressed lesions are quite rare, they are very important because they are associated with the highest risk of containing malignancy at the time of diagnosis [11–14]. The depressed part of a lesion may be accentuated by air insufflation and deflation, and by the use of techniques in image-enhanced endoscopy [15], in particular the use of dye-based image-enhanced endoscopy using diluted indigo carmine (see Chapters 31, 36, and 38). The depression in the depressed lesion is distinct and circular and must be differentiated from pseudodepression, which is a simple groove that can be seen in many flat lesions. The presence of pseudodepression does not confer an increased risk for malignancy [9].

Epidemiology Data are available to show that both Western and Asian populations may develop NP-CRNs. We will concentrate on data collected from studies in the Western hemisphere. To the best of our knowledge, at the time of writing, NP-CRNs have been reported from the following countries: Australia, Brazil [16], Canada [17], France [18], Germany [19,20], Korea, Israel, Japan, Singapore, Spain [21], Sweden [2,6], the UK [4,7,22], and the US [1,5,23]. We herein describe the highlights of some of these studies.

North America The Flat Lesion Study provides the strongest and most recent evidence of the importance of NP-CRNs in Western patients [1]. The study involved 1819 predominantly male veterans in California who received outpatient colonoscopy for screening, surveillance, and symptoms. This was a cross-sectional study designed to determine the prevalence of NP-CRNs in a veterans hospital population and to characterize their association with colorectal cancer. The study was conducted by a group of American endoscopists who developed the expertise

to diagnose NP-CRNs through an exchange program with Japanese endoscopists and also through self-study using digital recordings of NP-CRN cases. Over time, these efforts led them to seek automatically characteristic findings of NP-CRNs using standard high-resolution colonoscopy. The patients studied consisted of predominantly white men with an average age of 64 years. Patients were prescribed 4 L of polyethylene glycol solution and an additional 296-mL bottle of magnesium citrate. Image-enhanced endoscopy using diluted indigo carmine solution was used only after an area suspected of containing NP-CRN was detected. In this group of veterans, the overall prevalence of NP-CRNs was 9.35% [95% confidence interval (CI) 8.05–10.78%]. The prevalence of the subpopulations is shown in Table 32.1. The overall prevalence of high-grade dysplasia or submucosal invasive carcinoma was 0.82% (95% CI 0.46–1.36%); in the screening population, the prevalence was 0.32% (95% CI 0.04–1.17%). Most importantly, in this study, the NP-CRNs were shown to be more likely to contain high-grade dysplasia or submucosal invasive carcinoma (odds ratio 9.78; 95% CI 3.93–24.4%), irrespective of size. To be specific, the odds ratio for an NP-CRN to contain high-grade dysplasia compared with a polypoid neoplasm was 19.36 (95% CI 5.49–68.2%). Similarly, the risk of containing submucosally invasive carcinoma was higher for an NP-CRN than for a polypoid neoplasm (odds ratio 3.32; 95% CI 0.94–11.7%). Depressed lesions confer the highest risk of containing high-grade dysplasia or submucosal invasive carcinoma (33%). Finally, the study showed that NP-CRNs containing high-grade dysplasia or submucosal invasive carcinoma were smaller in diameter than the polypoid ones (mean diameter 15.9 mm vs. 19.2 mm, respectively). Other studies have been reported from centers in North America. A visiting Japanese colonoscopist and colleagues [5] reported the prevalence of NP-CRNs in Galveston, Texas. NP-CRNs were detected in 48 of the 211 patients enrolled (22.7%), which was 41% of adenomas found. In that study, 62% of NP-CRNs were seen only after the use of indigo carmine solution. Similar to the results of the Flat Lesion Study, flat and depressed lesions were more likely than polypoid lesions to be adenomatous; NP-CRNs more often contained invasive carcinoma. Although it would be difficult to classify retrospectively the macroscopic appearance of the lesions as seen during colonoscopy, two other studies have relied on surgical pathology data. Reexamination of the pathology specimen of lesions removed during the National Polyp Study found that 27% of all adenomas removed could have been classified as flat [24]. The incidence of high-grade dysplasia was low and not higher than that in polypoid lesions. In a review of surgical pathology data of 340 adenomas in Vancouver, Canada, 8.5% were classified as flat, equating to 8.6% of patients [17]. In that study, the frequency of high-grade dysplasia was 10-fold higher in NP-CRNs than in analogous polypoid adenomas with an equivalent spherical diameter. A smaller study from Nebraska has also been reported [23].

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Table 32.1 aSelected prospective routine colonoscopy studies of nonpolypoid colorectal neoplasm (NP-CRN) prevalence in the West.b Authors (country), n

Study, population (%), n (%)

Prevalence of NP-CRN, n (%)

NP-CRN/CRN, n (%)

NP-CRN with HGD/NP-CRN, n (%)

NP-CRN with SI/NP-CRN, n (%)

NP-CRN with HGD or SI/all HGD or SI, n (%)

Soetikno et al. [1] (US), 1819

Mixed Screening, 616 (34) Surveillance, 654 (36) Symptomatic, 549 (30) Mixedc Mixedc Mixedc Mixedc Mixedc Mixedc

170 (9.4) 36 (5.8) 101 (15.4) 33 (6.0) 55 (23.7) 28 (13.3) 123 (12.3) 48 (22.7) 52 (6.0) 254 (25.4)

227/1535 (14.8) 52/527 (9.9) 131/709 (18.5) 44/299 (14.7) 109/261 (41.7) 28/68 (38.2) 119/327 (36.4) 57/139 (41.0) 66/973 (6.8) 254/628 (40.4)

11/227 (4.8) 1/52 (1.9) 10/131 (7.6) 0/44 (0) 12/109 (11.0) 1/28 (3.5) 16/123 (13.0) Not stated 11/66 (16.7) 43/254 (16.9)

4/227 (1.8) 1/52 (1.9) 3/131 (2.3) 0/44 (0) 3/109 (2.7) 2/28 (7.1) 4/123 (3.2) 3/57 (5.2) 5/66 (7.5) 16/254 (6.3)

15/28 (53.6) 2/8 (25.0) 13/15 (86.7) 0/5 (0) 3/17 (1.8) 2/3 (66.7) 4/6 (66.7) 3/3 (100) 5/16 (31.3) 16/22 (72.7)

Jaramillo et al. [2] (Sweden), 232 Fujii et al. [3] (UK), 210 Rembacken et al. [4] (UK), 1000 Saitoh et al. [5] (US), 211d Tsuda et al. [6] (Sweden), 866 Hurlstone et al. [7] (UK), 850

HGD, high-grade dysplasia; SI, invasive submucosa. a Modified from Table 1 in Soetikno et al. [1]. b Studies that were reported in a non-English language, contained fewer than 200 patients, were based on pathologically determined morphology, or were retrospective were not included. c Mixed population did not include average-risk colorectal cancer screening patients. d Two flat with depression lesions with invasion to the muscularis propria or beyond (i.e., advanced cancer) were excluded from the Table data.

UK Data from Leeds also provide strong evidence of the existence and importance of NP-CRNs among Western patients. After training alongside a Japanese visiting endoscopist, a British colonoscopist prospectively studied the prevalence of NP-CRNs in 1000 patients undergoing outpatient colonoscopy [4]. Contrast colonoscopy using diluted indigo carmine was used to highlight areas suspicious for neoplasm. He found 321 adenomas and six Dukes’ A cancers in 231 patients, of which 117 (36%) were flat, two (0.6%) were depressed, and 202 (63%) were polypoid. Of the 31 adenomas with severe dysplasia, 15 were flat and one was depressed. Of the Dukes’ A cancers, two were flat, two were depressed, and two were polypoid. The risk of a lesion containing early cancer was twice as high for flat lesions larger than 10 mm in size as for polypoid lesions. In the UK study, similar to other studies, depressed lesions had a high risk of containing cancer (75%). A subsequent study by Hurlstone et al. [7] in 850 patients undergoing routine colonoscopy showed a high prevalence of NP-CRNs (25.4%) and similar associations between NPCRN and advanced pathology.

appearance, 27 showed 178 lesions after staining (176 flat, two depressed) with a mean size of 3 mm. On histological investigation, 210 lesions showed hyperplastic or inflammatory changes, 67 were adenomas, and six were cancers.

Sweden Jaramillo et al. [2] studied 232 patients in Sweden between 1992 and 1993 after excluding inflammatory bowel disease and hereditary colorectal polyposis syndromes. Using highresolution video endoscopy and indigo carmine chromoendoscopy, these investigators found 109 colorectal flat neoplastic lesions in 55 patients (about 24%). These lesions were generally seen in patients over 60 years of age (78%) but not in patients less than 40 years of age, and they were twice as common in men as in women. Most (71%) were 0.5 cm or less, 21% were 0.6–1.0 cm, and 8% were larger than 1.0 cm. Low-grade dysplasia was seen in 86% and high-grade dysplasia in 12% of flat lesions. Adenocarcinoma was diagnosed in 3% of flat lesions. Flat lesions with a central depression showed high-grade dysplasia more often than those without central depression (43% vs. 7%). Another study from Sweden further corroborated the results of this study.

Germany Kiesslich et al. [20] studied 100 consecutive patients in Germany during routine colonoscopy. If macroscopic examination was unremarkable, all visible lesions, including those in the rectum, were stained with indigo carmine solution (0.4%, 1–10 mL). A total of 52 patients had 105 visible lesions (89 polypoid, 14 flat, two depressed). The mean size of the lesions was 1.4 cm. Among the 48 patients with mucosae of normal

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Detection and diagnosis of nonpolypoid colorectal neoplasms The detection of NP-CRNs begins with good patient preparation. Well-trained colonoscopists equipped with an appropriate, yet simple, armamentarium of endoscopes and accessories

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Table 32.2 The equipment we typically use in the management of nonpolypoid colorectal neoplasms. Colonoscope with water jet Diagnostic: adult colonoscope with high-resolution or high-definition system; pediatric colonoscope with high-resolution image for small patients Therapeutic: adult colonoscope (right-sided lesion) or therapeutic upper (left-sided lesion) Carbon dioxide regulator Diluted simethicone in 60-mL syringe Diluted indigo carmine (0.2%) in 60-mL syringe Injection needle (preloaded with 10-mL saline for submucosal injection or Spot India ink for marking) Snare with standard generator (blend current 35–40 W) Stiff snare: two types (Olympus SD 230 and SD 210, for large and small snares, respectively) Biopsy forceps (cold and hot, of standard cup size) Endoscopic clips (naked Resolution® and Endoclip) Endoscopic loop Argon plasma coagulator with straight catheter Roth net and multichannel suction trap

are needed (Table 32.2). The staff of the endoscopy unitathe most difficult component to develop in any unitais indispensable in providing care to detect, diagnose, and treat NPCRNs efficaciously and safely. Intravenous Buscopan® can be given to reduce colonic contractions during the procedure. In the US, glucagon in 0.5-mg aliquots can be used. Dye-based image-enhanced endoscopy using 0.2–0.4% diluted indigo carmine is typically employed after a suspected area has been identified. A newer method using narrow-band imaging to determine if a lesion is present has the potential to be more practical but has not been formally studied. The characteristic findings of NP-CRNs include a slightly red appearance, altered or absent vascular network, friability, and wall deformity [25,26]. At present, these findings are best sought through standard white-light endoscopy using at least a high-resolution and, if available, high-definition endoscope. Image enhancement of a suspected area using dye-based [27] or equipment-based image-enhanced endoscopy technique can be deployed to rule in or out the presence of NPCRN. The use of fluorescence is currently under investigation [28]. The presence or absence of the innominate grooves is the most practical second step to determine if a lesion is present. Evaluation of the border of the lesion and its surface topography is then performed to estimate the size and assess the likely pathology. In the case of NP-CRNs, this step is important in the determination of the degree of invasiveness, as NP-CRNs include only superficial lesions. At the conclusion of the evaluation of an NP-CRN, the colonoscopist should be able to have a good understanding of the location, size, likely pathology, and depth of invasion, and have a plan of the potential treatment (Figure 32.3).

Colorectal lesion Standard + imageenhanced endoscopy

Endoscopic Hyperplastic diagnosis

Serrated

Adenoma/ villous adenoma

Early cancer (HGD+ TI)

Advanced cancer

No radiotherapy

Polypectomy for polypoid EMR/ESD for nonpolypoid

Treatment

Bx Surgery Chemo XRT

Endoscopy

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Figure 32.3 An endoscopic road map for diagnosis and treatment of a colorectal lesion. Understanding the most likely pathology at the time of endoscopy facilitates a directed treatment approach. The use of standard high-resolution (if available high-definition) colonoscopy is necessary.

Treatment technique Endoscopic mucosal resection (EMR) using the inject and cut method is the preferred treatment method for large flat adenomas, high-grade dysplasia, or mucosal carcinomas (see Chapters 43 and 44) [29,30]. Otherwise, when EMR is not available and the patient is to be referred to an expert endoscopist, cold biopsy can be performed once or twice. Repeated cold biopsy of the flat lesion for sampling, repeated hot biopsy for removal, and partial resection of the flat lesion are not recommended because they can lead to a significant scar formation, which can prevent future endoscopic removal of the residual lesion. EMR is preferred over standard polypectomy because flat lesions are usually difficult to capture and, without submucosal injection, the underlying muscularis propria may be inadvertently coagulated excessively or even inadvertently resected. Because the resection plane of EMR is in the submucosa, EMR, rather than polypectomy, of flat lesions also allows the depth of the lesion to be evaluated appropriately. Thus, the risks of lymph node metastasis can be assessed and patients can be triaged accordingly. Depressed lesions smaller than 10 mm may be removed by mucosal resection as well, if possible en bloc. It is better for depressed lesions larger than 10 mm to be removed by surgery once the pathology is proven to be high-grade dysplasia or submucosal invasive carcinoma because the risk of submucosal invasive carcinomas is too high. It is emphasized that accurate pathologic evaluation of the depth of neoplasm is a critical component of EMR and can be achieved only when the specimen is appropriately oriented.

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Tanaka et al. [10] reported on the safety and efficacy of EMR inject and cut for removing large (> 20 mm) flat colorectal neoplasms. EMR was successful in approximately two-thirds of these lesionsaen bloc resection was successful in 78% for lesions 20–29 mm in diameter, 29% for lesions 30–39 mm, and 17% for those larger than 40 mm. Thirteen patients (16%) had bleeding that was controlled by application of clips or sclerosant, the majority of which (10 patients) occurred during the procedure, two within 24 h, and one delayed. Microperforation was recorded in one patient (1.2%) and was treated conservatively. Residual or recurrent lesions at the resection site were found in six (7.7%) within 1–13 months after EMR; all were adenomas and were treated endoscopically. Using a standardized approach that included lesion assessment, classification, inject and cut EMR technique, reassessment, and treatment of residual tissue, we had studied the short- and long-term mucosectomy outcomes of 125 nonpolypoid lesions in 100 patients [31]. The mean lesion size was 16.7 ± 7 mm (range 10–50 mm) with histology including five submucosal invasive cancers, five with high-grade dysplasia, and 91 adenomas. No major complications of severe bleeding or perforation occurred (95% CI 0–2.5%). Two patients with minor bleeding (1.8%; 95% CI 0.2–6.2%) were treated by mechanical hemostasis with endoscopic clipping within 24 h of the EMR. Eight lesions had local recurrence on surveillance. Complete resection was achieved in 100% of the 62 patients (77 lesions) who underwent between one and three surveillance colonoscopies. No patient studied developed colorectal cancer or metastasis on clinical follow-up (mean ± standard deviation = 4.5 ± 1.4 years). Others have reported the use of the endoscopic submucosal dissection (see Chapter 44) technique to remove large NP-CRNs en bloc, although currently the perforation rate of submucosal dissection in the colon (> 2%) is still too high [32].

Biology In the Japanese literature, many submucosal invasive colorectal carcinomas [33] were diagnosed without findings of accompanying adenomas [14,34,35]. Stolte and Bethke [36] have reported a similar finding from cases in the West. They stated that about 40% of submucosal invasive cancers without evidence of adenoma were NP-CRNs. This finding and others raised the possibility that some flat carcinomas either arise “de novo” [37] or, once formed, quickly replace the small adenomatous cells from which they have arisen [38]. Although molecular biology studies of NP-CRNs are incomplete, they suggest that NP-CRNs have their own unique molecular signature (which may have implications for carcinogenesis as well as natural history) and NP-CRN is not biologically homogeneous, but rather appears to arise and progress through a number of genetic and signaling pathways.

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The classic multistep genetic model for colorectal carcinogenesis proposed by Vogelstein et al. [39] suggests mutations in the adenomatous polyposis coli (APC) gene (and the associated loss of heterozygosity of chromosome 5q) as a very early, if not initial, step in genesis of the majority of tumorsaeven those of very small size. This is followed by changes in the ras–raf signaling pathway, allowing progress to larger more dysplastic tumors. Later, p53 mutations may be important in the transformation to cancer. Recent studies have indicated that small (< 10 mm) NP-CRNs may develop through a different pathway. APC mutations were nearly twice as common in polypoid adenomas with high-grade dysplasia than in their nonpolypoid counterparts (44% vs. 25%) [40]. Further, when the nonpolypoid group was analyzed, this difference appeared to be contributed to entirely by the depressed lesions, only 13% of which showed an APC mutation. K-ras mutations are also uncommon and indeed may be absent in diminutive NP-CRN lesions, particularly in those with a predominant depressive feature (see above discussion) [14,41–47]. By contrast, several studies have shown that p53 mutations are similar in polypoid and nonpolypoid tumors [48–50] or lower in the latter [5,51]. The pattern of chromosomal instability in these lesions is similar to that of polypoid adenomas and carcinomas, characterized by a high prevalence of 18q loss and 20q gain [52]. On the other hand, microsatellite instability seems to be low in sporadic NP-CRNs, suggesting a lesser role for dysfunction of DNA repair machinery [53]. Flat lesions that are larger than 10 mm may represent a different morphological variant than smaller flat or depressed lesionsahaving several distinct molecular associations and potentially a distinct pathway to carcinoma. They have an increased frequency of K-ras mutations, COX-2, and gastrin expression [54–57]. An increase in cytosine–guanine island methylation, particularly in the proximal colon, has also been noted [56]. On the other hand, methylation of methyl–guanine methyltransferase, CDKN2A (p16), and MLH1 was found to be less common in these tumors, suggesting that epigenetic changes may not be as important in NP-CRN carcinogenesis [58]. Abnormalities of the β-catenin gene have also been reported [57]. APC mutations result in increased β-catenin signaling and upregulation of genes such as c-myc, cyclin D1, and the gene encoding matrix metalloproteinase 7 (MMP7). Genome-wide expression analysis has also revealed upregulation of several other genes, including MMP7, CDH3 (coding for cadherin 3), S100P, and DUOX2 (coding for dual oxidase 2) as well as differences between right- and left-sided laterally spreading tumors [59].

Conclusions It is now clear that NP-CRNs can be found in Western populations [60]. The best method of detecting and diagnosing NP-CRNs is by colonoscopy. The detection and removal of

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NP-CRNs may require additional techniques, such as image enhancement using a dye- or equipment-based method, and mucosal resection. Many questions remain to be answered, as it is currently unclear if NP-CRN is biologically distinct from the polypoid neoplasms and if patients with NP-CRNs require more intensive colonoscopic surveillance.

References 1 Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008; 299: 1027–35. 2 Jaramillo E, Watanabe M, Slezak P, Rubio C. Flat neoplastic lesions of the colon and rectum detected by high-resolution video endoscopy and chromoscopy. Gastrointest Endosc 1995; 42: 114– 22. 3 Fujii T, Rembacken BJ, Dixon MF, Yoshida S, Axon AT. Flat adenomas in the United Kingdom: are treatable cancers being missed? Endoscopy 1998; 30: 437– 43. 4 Rembacken BJ, Fujii T, Cairns A, et al. Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 2000; 355: 1211–14. 5 Saitoh Y, Waxman I, West AB, et al. Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology 2001; 120: 1657–65. 6 Tsuda S, Veress B, Toth E, Fork FT. Flat and depressed colorectal tumours in a southern Swedish population: a prospective chromoendoscopic and histopathological study. Gut 2002; 51: 550– 5. 7 Hurlstone DP, Cross SS, Adam I, et al. A prospective clinicopathological and endoscopic evaluation of flat and depressed colorectal lesions in the United Kingdom. Am J Gastroenterol 2003; 98: 2543– 9. 8 Yasutomi M, Baba S, Hojo K, et al. Japanese Classification of Colorectal Carcinoma. Tokyo: Kanehara & Co., 1997. 9 The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach and colon. Gastrointest Endosc 2003; 58(Suppl. 6): S3– 43. 10 Tanaka S, Haruma K, Oka S, et al. Clinicopathologic features and endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 MM. Gastrointest Endosc 2001; 54: 62–6. 11 Kudo S. Early Colorectal Cancer. Tokyo: Igaku-Shoin, 1996. 12 Kudo S, Kashida H, Tamura T, et al. Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer. World J Surg 2000; 24: 1081– 90. 13 Kudo S, Kashida H, Nakajima T, Tamura S, Nakajo K. Endoscopic diagnosis and treatment of early colorectal cancer. World J Surg 1997; 21: 694–701. 14 Sakashita M, Aoyama N, Maekawa S, et al. Flat-elevated and depressed, subtypes of flat early colorectal cancers, should be distinguished by their pathological features. Int J Colorectal Dis 2000; 15: 275– 81. 15 Kaltenbach T, Sano Y, Friedland S, Soetikno R. American Gastroenterological Association (AGA) Institute technology assessment on image-enhanced endoscopy. Gastroenterology 2008; 134: 327– 40. 16 Teixiera C. Current status of depressed colorectal neoplasia in Latin America. Early Colorectal Cancer 2004: 57–60.

17 Wolber RA, Owen DA. Flat adenomas of the colon. Hum Pathol 1991; 22: 70–4. 18 Samalin E, Diebold M-D, Merle C, et al. Prevalence of colonic flat neoplasia in a French series. Gastroenterology 2002; 122(Suppl.): W1224. 19 Stolte M, Bethke B. Colorectal mini-de novo carcinoma: a reality in Germany too. Endoscopy 1995; 27: 286–90. 20 Kiesslich R, von Bergh M, Hahn M, Hermann G, Jung M. Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon. Endoscopy 2001; 33: 1001–6. 21 Parra-Blanco A, Gimeno-Garcia AZ, Nicolas-Perez D, et al. Risk for high-grade dysplasia or invasive carcinoma in colorectal flat adenomas in a Spanish population. Gastroenterol Hepatol 2006; 29: 602– 9. 22 Hart AR, Kudo S, Mackay EH, Mayberry JF, Atkin WS. Flat adenomas exist in asymptomatic people: important implications for colorectal cancer screening programmes. Gut 1998; 43: 229–31. 23 Lanspa SJ, Rouse J, Smyrk T, Watson P, Jenkins JX, Lynch HT. Epidemiologic characteristics of the flat adenoma of Muto. A prospective study. Dis Colon Rectum 1992; 35: 543–6. 24 Zauber AG, O’Brien MJ, Winawer SJ. On finding flat adenomas: is the search worth the gain? Gastroenterology 2002; 122: 839–40. 25 Soetikno RM, Fujii T, Friedland S, Barro J, Matsui S, Rouse RV. Diagnosis of Flat and Depressed Colorectal Neoplasmsaan Educational DVD. Chicago, IL: American Society Gastrointestinal Endoscopy, 2004. 26 Sano Y, Tanaka S, Teixeira CR, Aoyama N. Endoscopic detection and diagnosis of 0-IIc neoplastic colorectal lesions. Endoscopy 2005; 37: 261–7. 27 Fujii T, Hasegawa RT, Saitoh Y, et al. Chromoscopy during colonoscopy. Endoscopy 2001; 33: 1036–41. 28 Hsiung PL, Hardy J, Friedland S, et al. Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nat Med 2008; 14: 454– 8. 29 Hurlstone DP, Cross SS, Drew K, et al. An evaluation of colorectal endoscopic mucosal resection using high-magnification chromoscopic colonoscopy: a prospective study of 1000 colonoscopies. Endoscopy 2004; 36: 491– 8. 30 Soetikno RM, Gotoda T, Nakanishi Y, Soehendra N. Endoscopic mucosal resection. Gastrointest Endosc 2003; 57: 567–79. 31 Kaltenbach T, Friedland S, Maheshwari A, et al. Short- and longterm outcomes of standardized EMR of nonpolypoid (flat and depressed) colorectal lesions > or = 1 CM (with video). Gastrointest Endosc 2007; 65: 857– 65. 32 Saito Y, Uraoka T, Matsuda T, et al. Endoscopic treatment of large superficial colorectal tumors: a case series of 200 endoscopic submucosal dissections (with video). Gastrointest Endosc 2007; 66: 966–73. 33 Muto T. Superficial colorectal neoplasms: how to detect them in routine colonoscopy? Jpn J Clin Oncol 1998; 28: 533. 34 Kuramoto S, Oohara T. Flat early cancers of the large intestine. Cancer 1989; 64: 950–5. 35 Kuramoto S, Oohara T. How do colorectal cancers develop? Cancer 1995; 75: 1534– 8. 36 Stolte M, Bethke B. Colorectal mini-de novo carcinoma: a reality in Germany too. Endoscopy 1995; 27: 286–90. 37 Kuramoto S, Oohara T. How do colorectal cancers develop? Cancer 1995; 75: 1534– 8.

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38 Minamato T, Sawaguchi K, Ohta T, Itoh T, Mai M. Superficial-type adenomas and adenocarcinomas of the colon and rectum: a comparative morphological study. Gastroenterology 1994; 106: 1436–43. 39 Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319: 525–32. 40 Yagi OK, Akiyama Y, Ohkura Y, et al. Analyses of the APC and TGF-beta type II receptor genes, and microsatellite instability in mucosal colorectal carcinomas. Jpn J Cancer Res 1997; 88: 718–24. 41 Morita T, Tomita N, Ohue M, et al. Molecular analysis of diminutive, flat, depressed colorectal lesions: are they precursors of polypoid adenoma or early stage carcinoma? Gastrointest Endosc 2002; 56: 663–71. 42 Yamagata S, Muto T, Uchida Y, et al. Lower incidence of K-ras codon 12 mutation in flat colorectal adenomas than in polypoid adenomas. Jpn J Cancer Res 1994; 85: 147–51. 43 Soh K, Yanagisawa A, Hiratsuka H, Sugano H, Kato Y. Variation in K-ras codon 12 point mutation rate with histological atypia within individual colorectal tumors. Jpn J Cancer Res 1993; 84: 388–93. 44 Minamoto T, Sawaguchi K, Mai M, Yamashita N, Sugimura T, Esumi H. Infrequent K-ras activation in superficial-type (flat) colorectal adenomas and adenocarcinomas. Cancer Res 1994; 54: 2841–4. 45 Kaneko K, Kurahashi T, Makino R, Konishi K, Mitamura K. Growth patterns of superficially elevated neoplasia in the large intestine. Gastrointest Endosc 2000; 51: 443–50. 46 Kurahashi T, Kaneko K, Makino R, Mitamura K. Colorectal carcinoma with special reference to growth pattern classifications: clinicopathologic characteristics and genetic changes. J Gastroenterol 2002; 37: 354– 62. 47 Olschwang S, Slezak P, Roze M, et al. Somatically acquired genetic alterations in flat colorectal neoplasias. Int J Cancer 1998; 77: 366–9. 48 Yamamura-Idei Y, Satonaka K, Fujimori T, Maeda S, Chiba T. p53 mutations in flat- and polypoid-type colorectal tumors detected by temperature-gradient gel electrophoresis. Dig Dis Sci 1994; 39: 2043–8.

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49 Yukawa M, Fujimori T, Maeda S, Tabuchi M, Nagasako K. Comparative clinicopathological and immunohistochemical study of ras and p53 in flat and polypoid type colorectal tumours. Gut 1994; 35: 1258– 61. 50 Aoki T, Takeda S, Yanagisawa A, et al. APC and p53 mutations in de novo colorectal adenocarcinomas. Hum Mutat 1994; 3: 342–6. 51 Rubio CA, Rodensjo M. Mutation of p53 tumor suppressor gene in flat neoplastic lesions of the colorectal mucosa. Dis Colon Rectum 1996; 39: 143–7. 52 Postma C, Hermsen MA, Coffa J, et al. Chromosomal instability in flat adenomas and carcinomas of the colon. J Pathol 2005; 205: 514– 21. 53 Kinney TP, Merel N, Hart J, Joseph L, Waxman I. Microsatellite analysis of sporadic flat and depressed lesions of the colon. Dig Dis Sci 2005; 50: 327–30. 54 Mukawa K, Fujii S, Takeda J, et al. Analysis of K-ras mutations and expression of cyclooxygenase-2 and gastrin protein in laterally spreading tumors. J Gastroenterol Hepatol 2005; 20: 1584– 90. 55 Yamashita K, Arimura Y, Shimizu H, et al. Increased cyclooxygenase-2 expression in large flat colorectal tumors (laterally spreading tumors). J Gastroenterol 2003; 38: 69–73. 56 Hiraoka S, Kato J, Tatsukawa M, et al. Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations. Gastroenterology 2006; 131: 379–89. 57 Mikami M, Nosho K, Yamamoto H, et al. Mutational analysis of beta-catenin and the RAS-RAF signalling pathway in early flattype colorectal tumours. Eur J Cancer 2006; 42: 3065–72. 58 Takahashi T, Nosho K, Yamamoto H, et al. Flat-type colorectal advanced adenomas (laterally spreading tumors) have different genetic and epigenetic alterations from protruded-type advanced adenomas. Mod Pathol 2007; 20: 139– 47. 59 Kita H, Hikichi Y, Hikami K, et al. Differential gene expression between flat adenoma and normal mucosa in the colon in a microarray analysis. J Gastroenterol 2006; 41: 1053–63. 60 Soetikno R, Friedland S, Kaltenbach T, Chayama K, Tanaka S. Nonpolypoid (flat and depressed) colorectal neoplasms. Gastroenterology 2006; 130: 566–76; quiz 588–9.

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Hereditary Colorectal Cancer Randall W. Burt Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

Introduction Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the US, with approximately 150 000 new cases and 55 000 deaths every year. The lifetime risk for CRC is about 6% in both males and females [1]. The causes of CRC are multifactorial and include environmental and heritable factors. The majority of cancers occur in individuals with no obvious family history. These are categorized as sporadic cases, although lifestyle and environmental factors appear to be important. Approximately one-third of colon cancers arise from heritable factors and 1–3% belong to one of the well-characterized inherited syndromes. The genetic and molecular mechanisms of these syndromes are well defined and have contributed significantly to the understanding of colon cancer pathogenesis. This understanding has in turn provided genetic testing for diagnosis of the syndromes and will likely lead to better preventive and therapeutic approaches. An understanding of the familial and heritable factors in colon cancer is clinically important for both defining risk and determining appropriate screening and surveillance. Most health policy organizations now include family history as part of colon cancer screening guidelines (CA, A Cancer Journal for Physicians, 2008, 58: 130–60). Particularly aggressive colon screening is needed for the inherited syndromes in view of the extreme cancer risk. A number of extracolonic cancers are also common in these syndromes, further outlining the importance of syndrome identification and management. Continuing study of the more common but less penetrant familial colon cancer category has clarified risk levels and indicated screening strategies. Genes involved in this type of familial risk are being sought. Identification of such genes will further add to the basic understanding of cancer pathogenesis and will allow more specific risk identification and

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

screening strategies in this larger group of patients with a family history.

Common familial colon cancer A family history of colon cancer is a significant risk factor for the subsequent development of this malignancy [2–6]. With a family history risk is elevated, occurrence is at a younger age, and clusterings of cases within families occur frequently. The risk of CRC for a first-degree relative of a person with this cancer is the same at the age of 40 years as the risk for a person in the general population at the age of 50 years [7]. The risk for CRC is also increased two- to threefold if a first-degree relative is affected [3]. This risk is threefold or higher if the first-degree relative is diagnosed under the age of 50 years or if two or more first-degree relatives are affected. The risk of colorectal cancer is also increased if a relative has colonic adenomatous polyps and is even higher if the adenomas are “advanced” [8–10]. A large twin study demonstrated that approximately onethird of colon cancer was familial [4]. Shared environment factors accounted for less than 10% of familial cases. There seems little doubt that colon cancer etiology is heterogeneous, with both inherited and environmental factors often interacting to give rise to this malignancy. Complex genetics, involving gene–gene and gene–environment interactions, also appear likely in view of ongoing genetic investigations that have also identified a number of candidate susceptibility genes [4,11–16]. Screening approaches for persons with familial risk of colon cancer have been given by a number of health policy organizations, and these are outlined in Table 33.1 (CA, A Cancer Journal for Clinicians, 2008, 58: 130–60) [2,17–20]. Recommendations for CRC screening in the setting of familial colon cancer are primarily empiric, based on known risk and the known effectiveness of screening modalities. For persons with at least two first-degree relatives with CRC, or with a single first-degree relative with CRC or adenomatous polyps diagnosed before the age of 60 years, colonoscopy every 5 years is suggested, starting at the age of 40 years or 10 years

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Table 33.1 Colon cancer screening recommendations for persons with familial risk. Familial risk category

Recommendation

Second- or third-degree relative with colorectal cancer

Same as average risk

First-degree relative with colon cancer or adenomatous polyps diagnosed at age ≥ 60 years

Same as average risk, but begin at age 40 years

Two or more first-degree relatives with colon cancer, or a single first-degree relative with colon cancer or adenomatous polyps diagnosed at an age < 60 years

Colonoscopy every 5 yearsa, beginning at age 40 years or 10 years younger than the earliest diagnosis in the family, whichever comes earlier

a

An interval of 3 years may be appropriate in some families with very strong family history.

younger than the earliest case in the family (whichever comes first). If a first-degree relative is diagnosed with CRC or adenomatous polyps at age 60 years or older, the screening recommendations are the same as for average-risk persons, but beginning at the age of 40 years. This is also the recommendation for those with two second-degree relatives affected with CRC.

Inherited syndromes of colon cancer Inherited syndromes of colon cancer account for 1–3% of CRC cases and include the adenomatous polyp syndromes of familial adenomatous polyposis (FAP), MYH gene-associated polyposis (MAP), and hereditary nonpolyposis colorectal cancer (HNPCC); and the hamartoma syndromes of Peutz– Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and Cowden’s syndrome. Hyperplastic polyposis syndrome is only rarely inherited but will also be discussed. Genetic etiologies for these syndromes (except hyperplastic polyposis) have been determined, genetic testing is available for diagnosis, and colon cancer risk is extreme. Other specific cancers and benign manifestations are also known for each syndrome, and diagnostic and surveillance approaches have been developed for each. It is important that the syndromes are identified because cancer can usually be prevented with proper surveillance.

Familial adenomatous polyposis Epidemiology Familial adenomatous polyposis is an autosomal dominantly inherited condition characterized by hundreds to thousands of colonic adenomatous polyps with the inevitable occurrence of CRC without colectomy. The prevalence of FAP is approximately 1 in 10 000 persons, with both genders affected equally. Historically, FAP accounted for about 0.5% of all CRC cases, although currently this number is likely to be substantially lower due to improved recognition, screening, and CRC prevention. Variants of FAP include Gardner’s syn-

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drome, about two-thirds of Turcot’s syndrome families, and attenuated FAP.

Etiology Familial adenomatous polyposis occurs in families as an autosomal dominant condition, arising from mutations in the adenomatous polyposis coli (APC) gene [21–23]. About onethird of newly diagnosed cases not belonging to a known FAP family represent spontaneous or new APC mutations [24] although mosaicism in a parent may also cause an apparent de novo case [25,26]. The location of the mutation within the APC gene has a bearing on the phenotype of the disease. The most frequent mutation in FAP involves codon 1309. Persons with mutations at this location tend to present at an average age of 20 years, or approximately 10 years earlier than those with mutations between codons 168 and 1580 (excluding 1309) [27]. Mutations in the “mutation cluster region,” which includes exon 1309, exhibit a high density of colonic polyps, often over 5000, while mutations proximal and distal to this region result in intermediate polyp numbers, averaging 1000 [28,29]. In attenuated FAP, mutations are found in the extreme 5′ end of the gene, in certain areas of exon 9, or in the far 3′ end. An average of 30 adenomas is present in this variant [30]. Extracolonic manifestations also associate to some degree with the mutation location [28]. Congenital hypertrophy of the retinal pigment epithelium is observed with mutations between codons 463 and 1387, while it tends to be absent when the mutation is between codons 1444 and 1578. Thyroid cancer is associated with mutations in the 5′ end of exon 15. Studies have also found desmoid tumors and osteoma to be more common with mutations in the distal end of the APC gene.

Clinical presentation Gastrointestinal manifestations Currently, most patients with FAP are diagnosed at an asymptomatic stage of their disease due to screening efforts. If symptoms do develop, 66% of patients already have cancer.

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Figure 33.1 Colonic adenomatous polyps in a patient with familial adenomatous polyposis. (Courtesy of James DiSario, MD.)

Typical symptoms are nonspecific and include rectal bleeding, diarrhea, weight loss, and abdominal pain. The average age at diagnosis among patients who present with symptoms is approximately 36 years. A clinical diagnosis of FAP can be made when a patient has 100 or more colonic adenomatous polyps, or fewer than 100 if the patient has an immediate relative with FAP or in the case of attenuated FAP. In early disease development and attenuated FAP, the polyp number can be significantly lower. Polyps usually begin to appear in the second or third decade of life, with an average age of polyp occurrence at 15.9 years (range 8–34 years) in typical FAP patients [9,21–23]. The adenomatous polyps in FAP are small. In fully developed cases, only 5% of polyps are larger than 5 mm, and only 1% are larger than 1 cm. Polyps can carpet the entire colonic mucosa (Figure 33.1) but may also occur as more distinct, larger lesions. Polyps are distributed throughout the colon with a slight distal predominance. Histopathologic examination of polyps is indistinguishable from sporadic adenomas. There can be villous and tubulovillous architecture, but this is seen far less commonly than simple tubular adenomas. A unique feature of FAP that is not seen in the general population is the finding of adenomatous epithelial cells in a single crypt, called microadenomas. These are often found in the biopsy specimens of normal-appearing, flat mucosa. Budding of dysplastic epithelium is also seen as well as aberrant crypt foci, which are identified by staining the colonic wall with methylene blue. Untreated FAP will inevitably progress to adenocarcinoma of the colon. The average age at CRC diagnosis is 39 years. Eighty-seven percent of affected persons will develop cancer by the age of 45 years, and 93% by the age of 50 years. Although uncommon before adolescence, CRC has been described in children with FAP as young as 9 years of age. Synchronous (41%) and metachronous (7%) tumors occur often. The risk for CRC correlates to some degree with polyp burden. The risk of CRC in patients with over 1000 polyps at the time of diagnosis is twice that of those with fewer than 1000 polyps.

Hereditary Colorectal Cancer

Figure 33.2 Fundic gland polyps in the stomach of a patient with familial adenomatous polyposis. (Courtesy of James DiSario, MD.)

Polyps also develop in other parts of the gastrointestinal tract. Gastric polyps occur in 23–100% of FAP patients and are usually non-neoplastic fundic gland polyps [31] (Figure 33.2). They can be so numerous that they cover the entire gastric body and fundus. Dysplasia is frequently observed on the surface of these polyps, although it rarely progresses to malignancy. About 10% of FAP patients develop adenomatous polyps in the stomach, typically in the antrum and less so in the body and fundus. There is some increased risk of gastric malignancy, although the lifetime risk appears to be less than 1%. Duodenal polyps, including ampullary polyps (Figure 33.3), are clinically more significant than gastric polyps [32–34]. About 50–90% of FAP patients will develop adenomatous polyps in the duodenum [35], which are often small (1–5 mm), numerous, and located throughout the duodenum, although most commonly in the periampullary area. Like colon polyps, duodenal polyps show an adenoma–carcinoma progression and can have villous architecture and high-grade dysplasia. Duodenal cancer usually occurs in the periampullary region, with lifetime incidence of 3–5% and an average age at diagnosis of 45–52 years (range 17–81 years). It is one of the leading causes of death in FAP patients who have undergone a prophylactic colectomy.

Figure 33.3 Duodenal polyps in a patient with familial adenomatous polyposis.

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Small bowel adenomas can also occur and are found predominantly in the proximal jejunum (50% of cases) or distal ileum (20% of cases) [36]. Patients can also develop adenomas in the distal ileum after colectomy. Small bowel cancer is uncommon. Although the frequency is unknown, adenomas and cancer can develop in the gallbladder, biliary tree, and pancreas.

Extraintestinal manifestations Familial adenomatous polyposis is associated with several extraintestinal manifestations. Osteomas are found in approximately 20% of FAP patients [37,38]. They are benign growths of bone that often occur in the skull and mandible. The lesions appear as radiopaque lucencies on plain radiographs and are of little clinical importance, except for occasional cosmetic concerns. Osteomas can appear in children before the development of polyposis, but can occur later in life as well. Several dental abnormalities have also been described in FAP, including supernumerary teeth, unerupted teeth, dentigerous cysts, and odontomas [23]. These may precede the development of polyposis. The incidence of these dental abnormalities in FAP patients is 17%, compared with 1–2% in the general population. Desmoid tumors are benign fibrous growths with an incidence in FAP of 3.6– 20.0% [39]. The relative risk of desmoid tumors in FAP patients compared with the general population is 825, and these tumors occur at an average age of 28–31 years. They may be the first manifestation of disease and, in some families, may be the only finding of FAP. Other than the location of the APC mutation, risk factors include a family history of desmoids, female gender, and osteomas [29]. Although considered benign, desmoid tumors are a significant cause of morbidity and mortality [40]. Mortality from the tumors in patients who have them is 10–50% with a 10-year survival rate of 63%; they are a common cause of death in those who have undergone prophylactic colectomy. Desmoid tumors in FAP consist of monoclonal growths of hyperproliferative fibroblastic cells. Tumors are most common in the abdomen, both intra-abdominally and within the abdominal wall. The most common symptom is abdominal pain, though only a third of tumors cause pain. They do not metastasize, but can grow and compress structures, such as nerves, blood vessels, and hollow organs, and can erode into bones. Surgery can stimulate the development and growth of desmoid tumors. Congenital hypertrophy of the retinal pigment epithelium manifests as dark round areas of pigment of the retina, ranging in size from 0.1 to 1.0 disk diameters [41]. They are best seen on slit lamp examination. Bilateral or multiple (≥ 4) lesions are relatively specific for FAP (94–100%), but have a sensitivity of only 58– 84%. Congenital hypertrophy of the retinal pigment epithelium can be the earliest clinical manifestation of FAP. Adrenal adenomas are also more common in FAP patients than in the general population, with incidence of 7% and

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13% in two studies [42]. Functioning adenomas and adenocarcinoma have both been reported, although the association with FAP is unclear. Management is identical to that in the general population. Cutaneous lesions in FAP consist of epidermoid cysts, sebaceous cysts, lipomas, fibromas, and pilomatricomas. Epidermoid cysts often occur before puberty and may precede the development of polyposis. Nasal angiofibromas have also been reported in FAP patients.

Extragastrointestinal malignancies Several malignancies not affecting the gastrointestinal tract have been associated with FAP. Hepatoblastoma is an important malignancy in children with FAP. The risk is 800-fold higher than that of the general population, but the occurrence is 1.5% and almost always in the first 5 years. Thyroid cancer affects 2% of FAP patients, with a relative risk of 7.6 compared with the general population [43]. The average age at diagnosis is 28 years (12–62 years) and there is a female predominance. The characteristic histology is papillary cancer. Pancreatic cancer has also been found to be higher in the FAP population, with a relative risk of 4.46 and overall incidence of 2%.

Variants of familial adenomatous polyposis Attenuated familial adenomatous polyposis As the name implies, less polyp burden and later onset of disease characterize attenuated familial adenomatous polyposis [30,44–46]. There is an average of 30 colonic polyps, although the number can vary widely. In some persons, polyp burden can be minimalamaking the diagnosis difficult without genetic testingabut in others, the number can approach those in typical FAP, but never more than hundreds. Polyps have a more proximal distribution in the colon. CRC develops, on average, at age 54 years with a lifetime risk of 70–80%. Unlike colonic polyps, upper gastrointestinal polyps are often not attenuated.

Gardner’s syndrome The term Gardner’s syndrome is mostly of historic interest, although it is still commonly used. Gardner’s syndrome is characterized by typical FAP, but with a high propensity to develop extracolonic growths, especially osteomas, fibromas, and epidermoid cysts. With the discovery of the APC gene, it was realized that FAP and Gardner’s syndrome both resulted from mutations of that gene. The location of the mutation in the APC gene correlates with development of extracolonic growths. Turcot’s syndrome Approximately two-thirds of Turcot’s syndrome patients have germline mutations in the APC gene, giving rise to polyposis as well as central nervous system tumors [23]. The other third arise from germline mutations in the DNA

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mismatch repair genes and are a variant of HNPCC. The central nervous system tumors in patients with germline APC mutations are typically medulloblastoma-type, anaplastic astrocytomas, or ependymoma. By contrast, in patients with germline DNA mismatch repair gene mutations, the tumors are usually glioblastoma multiforme. The relative risk of central nervous system tumors in FAP is 92-fold, the absolute risk 1.5%, and 40% of families with central nervous system malignancy have more than one family member with tumors.

Genetic testing Genetic testing for hereditary syndromes allows a precise diagnosis and identification of affected family members. Informed consent is an essential component of genetic testing, and the patient or his or her representative must understand the rationale, meaning, and limitations of testing, including implications for screening and treatment. Genetic counseling both before and after testing should be available. Laboratories offering genetic testing can be found at the website, www.genetests.org. Genetic testing for FAP should be utilized in two specific situations: 1 to confirm the diagnosis in an individual clinically suspected of having the disease; 2 to make diagnoses in at-risk family members. An affected person should be tested first to identify the mutation [47]. The disease-causing mutation can be found in up to 90% in such individuals. Other family members can then be tested for the presence or absence of that mutation with near 100% accuracy. When no mutation can be identified in the index case, all family members must be considered high risk. Genetic testing is usually delayed until age 10–12 years, when colon screening would start in mutation carriers, although it may be needed earlier to determine which infants should have screening for hepatoblastoma.

Hereditary Colorectal Cancer

Cancer screening Appropriate management of FAP patients includes surveillance not only for colon polyps and CRC, but also for other potential malignancies as well as timely referral for prophylactic colectomy [21,23]. Several studies have shown the benefit of screening and subsequent colectomy in FAP patients. In relatives screened for FAP, the mortality from colon cancer is 1.9% compared with 44% in FAP patients who present with symptoms. Screening should be offered to anyone with a genetic diagnosis of FAP or to relatives of those with FAP when genetic testing is inconclusive or not available. Annual sigmoidoscopy should be carried out, beginning at age 10–12 years (Table 33.2). The interval can be increased each decade and changed to that for the general population at age 50 if no polyposis is found. If screening begins at a later age, then colonoscopy is the preferred modality for the first examination. Likewise, if surgery is delayed for more than a year after polyposis develops, then annual colonoscopy should be instituted. In attenuated FAP, polyps are predominantly proximal and, thus, colonoscopy should always be used. In this condition, screening can be delayed until the late teens or mid-20s. After surgery, adenomas and cancers may develop in the rectum if a subtotal colectomy with ileorectal anastomosis is performed, or in the ileal pouch if a total colectomy with ileoanal pull-through is done. Screening the rectum or ileal pouch should occur within 2 years after surgery and then every 6 months to 3 years, depending on the polyp burden. Because of the higher incidence of duodenal cancer and, to a lesser degree, gastric cancer, the upper gastrointestinal tract should also undergo periodic examination [32–34,48]. Although routine screening has never been shown to improve outcome, the theoretical advantage makes this recommendation reasonable. The general recommendation is to begin screening at age 20–25 years, or prior to surgery. It should be repeated every 1–3 years, depending on polyp burden. Upper

Table 33.2 Colon screening recommendations for persons with hereditary syndromes. Hereditary syndrome

Recommendation

Familial adenomatous polyposisa

Sigmoidoscopy or colonoscopy annually, beginning at age 10–12 yearsb

Hereditary nonpolyposis colorectal cancerc

Colonoscopy, every 1–2 years, beginning at age 20–25 years

Peutz–Jeghers syndrome

Colonoscopy, beginning with symptoms or in late teens if no symptoms occur Interval determined by number of polyps but at least every 3 years

Juvenile polyposis syndrome

Colonoscopy, beginning with symptoms or in late teens if no symptoms occur Interval determined by number of polyps but at least every 3 years

Cowden’s syndrome

Uncertain, but interval colonoscopy every three years after polyps emerge would seem appropriate in view of newer reports of adenoma and cancer risk

a

Includes the all adenomatous polyposis coli gene-related syndromes. In attenuated familial adenomatous polyposis, colonoscopy should always be used because of the preponderance of proximal colonic adenomas, and screening should begin in the late teens or early twenties. c Includes Muir–Torre syndrome. b

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Table 33.3 Risks and screening recommendations for extracolonic cancers in the inherited syndromes of colon cancer. Syndrome, cancer risk Familial adenomatous polyposis Duodenal or periampullary cancer, 5% Pancreatic cancer, 2% Thyroid cancer, 2% Gastric cancer, 0.5% Central nervous system cancer, usually cerebellar medulloblastoma (Turcot’s syndrome), 1.5% Hepatoblastoma

Hereditary nonpolyposis colorectal cancer Endometrial cancer, 40% Ovarian cancer, 10% Gastric cancer, 10–20% Urinary tract cancer, 10% Renal cell adenocarcinoma, < 5% Biliary tract and gallbladder cancer, 15% Central nervous system (usually glioblastoma), < 5% Duodenal and small bowel cancer, 1–2% Peutz–Jeghers syndrome Stomach, duodenum, 25% Small bowel, duodenum, 10–15% Breast cancer, 50% Pancreatic cancer, 35% Lung cancer, 15% Uterine cancer, 10% Ovarian cancer, 20% Adenoma malignum (cervix), 10% Sertoli cell tumor (male), 10%

Juvenile polyposis syndrome Gastric and duodenal cancer, 10%

Cowden’s syndrome Thyroid cancer, 3–10% Breast cancer, 25–50% Uterine and ovarian cancer, some increased

Screening recommendations

Upper gastrointestinal endoscopy (including side-viewing examination) every 1–3 years, depending on the severity of polyposis, starting at age 20–25 years Possibly periodic abdominal ultrasound or abdominal CT after age 20 years Annual thyroid examination and ultrasound, starting at age 10–12 years Same as for duodenal cancer Annual physical examination, possibly periodic head CT in families where central nervous system cancer has already occurred, or with any symptoms Liver palpation, hepatic ultrasound, and a-fetoprotein blood test, every 3 months, during the first decade of life

Pelvic examination, transvaginal ultrasound, and/or endometrial aspirate every 1–2 years, starting at age 25–35 years Same as for endometrial cancer Upper gastrointestinal endoscopy every 1–2 years, starting at age 30–35 years Ultrasound and urinalysis with cytology every 1–2 years, starting at age 30–35 years Same as for urinary tract cancer Annual liver function tests and possible periodic abdominal ultrasound Annual physical examination, and if any symptoms occur, head MRI Upper gastrointestinal endoscopy as for gastric cancer, no recommendations for small bowel

Upper gastrointestinal endoscopy every 2 years, starting at age 10 years Annual hemoglobin, small bowel X-ray every 2 years, both staring at age 10 yearsa Annual breast examination and mammography every 2–3 years, both starting at age 25 years Endoscopic or abdominal ultrasound every 1–2 years, starting at age 30 years No recommendations given Annual pelvic examination with Pap smear and pelvic ultrasound, both starting at age 20 years Same as for uterine cancer SCTAT tumors (female), in almost all women with Peutz–Jeghers syndrome, same as for uterine, add Pap smear Annual testicular examination, starting at age 10 years; testicular ultrasound if feminizing features occur

Upper gastrointestinal endoscopy every 3 years, starting in early teens (mainly to avoid complications of benign polyps)

Annual thyroid examination and ultrasound, starting in teens Annual breast examination and mammography, starting at age 25–30 years No recommendations given

SCTAT, sex cord tumor with annular tubules. a Interval may be lengthened if polyps not found, to avoid excess irradiation.

endoscopy should include side-viewing examination of the duodenal papilla. Screening for other malignancies includes annual thyroid examination beginning at age 10–12 years and possibly annual ultrasound [43], periodic head computed tomography (CT) or magnetic resonance imaging (MRI) in patients with a family history of central nervous system tumors, α-fetoprotein blood test every 3 months, liver ultrasound and

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liver palpation in the pediatric patient at risk, and periodic examination of the small bowel (enteroclysis or CT with oral contrast), especially if extensive duodenal polyposis is found. Consideration should be given to abdominal CT every 3 years to examine the pancreas, small bowel, and adrenals. Table 33.3 summarizes extracolonic screening recommendations. Except for the colon, the screening recommendations are empirical, based on risk.

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Treatment Colectomy is the definitive treatment for patients with FAP to prevent CRC, and should be considered once polyps emerge [23,49–51]. Most centers defer surgery until after high school if the polyp burden is minimal. Surgical options include subtotal colectomy with ileorectal anastomosis; total colectomy with mucosal proctectomy, ileal pouch construction, and ileoanal pull through; and restorative proctocolectomy. Subtotal colectomy, which is a single-stage procedure and is associated with less morbidity, is an option for those with attenuated FAP or those with a low rectal polyps burden. Nonsteroidal anti-inflammatory drugs and cyclooxygenase2 inhibitors have some utility in the management of FAP [52]. Several studies have shown regression of colonic adenomas with the nonsteroidal anti-inflammatory drug sulindac, and less so with the cyclooxygenase-2 inhibitor celecoxib. The latter has approval from the Food and Drug Administration for use in rectal adenoma regression in those patients who have undergone a subtotal colectomy. A recent study suggested that sulindac may have a role in regression of polyps in the remaining rectal segment in patients who had undergone subtotal colectomy, making further endoscopic management and resection of polyps easier. However, the use of sulindac as primary prevention in the development of adenomatous polyps in patients with FAP has not been shown to be effective. Duodenal adenomas may also require management and definitive therapy [32–34,48]. Removal of duodenal polyps should be considered when they are large (≥ 2 cm) or exhibit advanced histologyavillous architecture or high-grade dysplasia. Options for treatment include endoscopic ablation or polypectomy, surgical polypectomy, duodenectomy, or the Whipple procedure. Endoscopic papillectomy for ampullary adenomas should be performed for advanced histology or when obstructive symptoms occur. Multiple sessions are sometimes required, and the recurrence rate is substantial. Desmoid tumors are a particular therapeutic challenge in FAP [53–56]. Surgery is usually indicated for extra-abdominal and abdominal wall tumors secondary to symptoms, cosmetic issues, or risk to adjacent structures. Less than half will recur with this approach. However, for intra-abdominal desmoid tumors, surgery is often difficult or impossible. Medical therapies include sulindac and tamoxifen, an antiestrogen, chemotherapy, radiation therapy, or a combination of these.

MYH gene-associated polyposis MAP is a newly described syndrome of colonic adenomatous polyposis that is phenotypically similar to attenuated FAP [57–60]. It arises from biallelic mutations of the MYH gene and is therefore inherited in a recessive manner. Over 80% of MAP cases in the US are accounted for by two specific mutations, making genetic diagnosis of this condition considerably technically easier than the other genetic syndromes presented in this chapter.

Hereditary Colorectal Cancer

MAP appears to be fairly common in several situations. A reported 0.4% of colon cancer patients in one populationbased series exhibited germline biallelic MYH mutations, compared with 0.8% of patients under 55 years old [61–63]. One-third of these colon cancer patients had no colonic adenomatous polyps, but the remainder had 3–100 adenomas. Approximately 10% of clinically diagnosed FAP families in which an APC mutation was not found have been determined to have MAP, and 10–40% of patients with 15–100 adenomas and no germline APC mutation have also been found to have MAP [57–59,64]. Hundreds but not thousands of colonic adenomas have been found in MAP [58,65]. Upper gastrointestinal polyps and other extraintestinal manifestations of FAP have been reported in MAP, but their frequency and absolute association remain to be determined [65]. The risk for CRC in MAP is substantially elevated compared with average risk [61,63]. The age at polyp and cancer onset has not been determined, nor have specific screening and surveillance guidelines. Until more information is available, MAP should be managed in a similar way to attenuated FAP, with colonoscopy frequency and possible surgical decisions based on polyp number. One study did recommend colonoscopy beginning at 18 years in biallelic carriers [60]. Genetic testing should be considered when any patient is found with 15 or more adenomas [66], or with fewer and a suggestive history, such as colon cancer onset at younger than age 50 years and no other apparent syndrome. Genetic testing should usually begin with evaluation of the APC gene for mutations. If none is apparent, then testing for MYH gene mutations should be carried out. MYH mutations can be first sought if the family history is autosomal recessive. Genetic testing has also been recommended specifically for MAP in persons with a colon cancer history typical of HNPCC (but no apparent HNPCC syndrome present) [59].

Hereditary nonpolyposis colorectal cancer Epidemiology HNPCC, or Lynch’s syndrome, is an autosomal dominantly inherited syndrome with a very high risk of CRC but few colonic adenomas. HNPCC accounts for 1–3% of colon cancer cases [21]. However, in a recent population-based study from Utah and California, HNPCC accounted for only 0.86% of CRC cases, based on identification of germline mutations of DNA mismatch repair genes [67]. A number of other cancers are also observed in this condition, including endometrial and others (see Clinical presentation).

Etiology HNPCC is an autosomal dominantly inherited disease caused by a germline mutation in any one of the four DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 [47,68]. Over 90% of affected families involve mutations of MLH1 or MSH2, while 6% of families arise from MSH6 gene mutations and 1% or less from PMS2 gene mutations. One mutant allele is inherited.

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With time, the remaining wild-type allele may become inactivated through somatic mutation, called loss of heterozygosity, resulting in gene dysfunction. In the general population, germline mutations in the DNA mismatch repair genes are not common but account for 1–3% of colorectal cancers that occur as part of the HNPCC syndrome [67]. The role of mismatch repair proteins is to repair DNA replication errors that commonly occur prior to cell division. When mutations exist in the mismatch repair genes, these replication errors persist and accumulate through repeated cell divisions. This is manifested by microsatellite instability (MSI) in colon and other cancers that harbor mismatch repair gene mutations. DNA microsatellites are segments of repeating DNA bases found throughout the human genome. MSI exists when there are errors in two or more of six commonly examined microsatellites [69]. MSI is typical of almost all CRCs arising in the setting of HNPCC, but about 15% of sporadic colon cancers also exhibit MSI [70]. In sporadic cases, MSI usually occurs by a different mechanism, usually hypermethylation and resultant inactivation of the MLH1 promoter region. MSI testing can be performed on colon cancer tissue in an individual suspected of having HNPCC. If MSI is found, genetic testing should be carried out to determine if germline mismatch repair gene mutations are present, thus making the diagnosis of HNPCC. If mismatch repair gene mutations are not found, then MSI has likely arisen secondary to acquired mismatch repair mutations, which is the case in up to 15% of sporadic colon cancers. Immunohistochemistry testing for expression of the mismatch repair proteins in the cancer tissue is an approach similar to MSI. If any of the proteins are not expressed, gene sequencing from peripheral blood DNA can be performed to test for germline mutations of that gene.

Clinical presentation The lifetime risk of developing CRC in HNPCC is about 80%, with an average age of 44 years at diagnosis [21], although recent studies suggest that the risk might be slightly lower and the average age at cancer diagnosis higher [71]. Patients exhibit few adenomatous polyps. The distribution of both polyps and cancers favors a proximal location in the colon,

with about 60–80% of polyps and cancers developing proximal to the splenic flexure. Up to 45% of persons with HNPCC will have synchronous CRC, or metachronous CRC within 10 years of resection. In comparison with sporadic polyps, polyps in the setting of HNPCC develop at a younger age, are larger than in age-matched control subjects, and tend to exhibit a more advanced histology [72,73]. The cancerous tissue has a peritumoral lymphocytic response or a Crohn’slike pattern [74]. Stage for stage, HNPCC patients with CRC have better survival than sporadic cases [21]. Persons with HNPCC exhibit an increased risk for cancers of the genitourinary system, biliary system, central nervous system, small bowel, and stomach [21]. The highest extracolonic cancer risks are endometrial cancer (43–60% lifetime risk), gastric cancer (13–19% lifetime risk), and ovarian cancer (9–12%). Endometrial cancer is more common when etiologic mutations occur in the MSH6 gene. “Amsterdam criteria” define HNPCC in the clinical setting: • at least three relatives with CRC, two being first-degree relatives of the first; • at least two generations should be affected; • at least one CRC should be diagnosed before the age of 50 [75]. FAP should be excluded and tumors should be verified by pathologic examination. As approximately 50% of families will be missed if only these criteria are applied, Amsterdam II criteria were developed, which are similar except that any malignancy or combination of malignancies associated with the syndrome can be used to fulfill the criteria. As many families will be missed by applying either of these criteria, “Bethesda Guidelines” were developed to determine which patients with colon cancer should undergo MSI testing of the colon cancer [74–77] (Table 33.4). If MSI is present, then germline genetic testing is indicated to find which tumors with MSI actually arise from HNPCC. Using this last approach is even more sensitive, with approximately 90% of HNPCC families being detected. Tumor immunohistochemistry to look for expression of mismatch repair proteins can be used instead of MSI. Genetic testing is indicated if one of the mismatch repair proteins is not expressed (see Genetic testing).

Table 33.4 Modified Bethesda criteria for microsatellite instability testing in colorectal cancer. 1 Individuals with cancer in families that meet the Amsterdam criteria 2 Individuals with two hereditary nonpolyposis colorectal cancer related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers 3 Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or hereditary nonpolyposis colorectal cancer related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at age < 45 years, and the adenoma diagnosed at age < 40 years 4 Individuals with colorectal cancer or endometrial cancer diagnosed at age < 45 years 5 Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribriform) on histology diagnosed at age < 45 years 6 Individuals with signet-ring-cell-type colorectal cancer diagnosed at age < 45 years 7 Individuals with adenomas diagnosed at age < 40 years

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Families meeting the Amsterdam criteria but lacking MSI in tumors and mismatch repair gene defects have been designated as having family colon cancer syndrome X. The genetic basis of syndrome X is unknown, but the risk of extracolonic tumors is lower than with HNPCC, and the optimal intervals for colonoscopy are uncertain.

Variants of hereditary nonpolyposis colorectal cancer Muir–Torre syndrome Muir–Torre syndrome is characterized by several different cutaneous manifestations in addition to the malignancies of HNPCC [78]. These include sebaceous adenomas and epitheliomas, basal cell epitheliomas, keratoacanthomas, and sebaceous carcinomas. The last are usually found on the eyelid.

Turcot’s syndrome As already mentioned under FAP, about one-third of Turcot’s syndrome cases arise from mutations in the mismatch repair genes [79,80]. These patients usually will manifest typical findings of HNPCC together with CNS glioblastomas. Interestingly, the 5-year survival rates for members of these families with glioblastomas appear to be higher than those for patients with sporadic glioblastomas. Genetic testing As HNPCC lacks a specific premalignant phenotype, genetic testing can be particularly helpful in affected families [9,47,68]. When a family meets the Amsterdam criteria (I or II), genetic testing is indicated. The person most likely to have the mutation should be tested first. Typically, this would be the youngest person with colon cancer in a family that meets the Amsterdam criteria. There is an approximately 50–70% likelihood of finding a mismatch repair gene mutation in the index case. If the mutation is identified in this index case then other family members can be tested for the presence or absence of the mutation with near 100% accuracy. Aggressive surveillance need be applied only to those with the disease mutation. When a mutation is not found in the index case, the family usually does not have HNPCC. There is nonetheless a significant risk of CRC, but usually not the other associated cancers [81]. Genetic testing should commence in at-risk individuals at age 20–25 years. A family with a strong family history of CRC but who do not meet Amsterdam criteria should have the Bethesda guidelines applied (see above). If any of these are met, tumor testing for MSI or immunohistochemical staining for lack of expression of one of the mismatch repair genes should be undertaken. If either is abnormal, then genetic testing of peripheral blood DNA for germline mutations to identify HNPCC is indicated [68]. As Amsterdam criteria and Bethesda guidelines are not consistently applied in the clinical setting, an alternative

Hereditary Colorectal Cancer

approach is gaining favor. This approach involves testing all CRC tumors for expression of the mismatch repair proteins by immunohistochemistry [68,82]. This can be done in any pathology laboratory and is relatively inexpensive. If one of the mismatch repair proteins is not expressed, then peripheral DNA of that gene is sequenced to examine for germline mutations. As this would involve testing 10–15% of persons with CRC to find the 1–3% who have HNPCC, a further intermediate step is incorporated. Most sporadic CRCs with mismatch repair dysfunction arise from methylation of the promoter region of the MLH1 gene in tumor tissue. A good test for determining increased methylation in colon cancer tissue involves examining for a specific mutation in the B-raf gene [68,70]. If present, the tumor can be considered to be sporadic. This test will eliminate half of those who will need germline genetic testing, leaving 5% or 6% of CRC patients who will need germline DNA testing. Many centers are now incorporating this approach, which relieves the burden of extensive family history assessment and application of the somewhat complex Bethesda guidelines. An ethical issue with this approach arises because lack of expression of the MSH2 protein by immunohistochemistry most likely indicates a germline mutation and thus the diagnosis of HNPCC. One might therefore ask if testing all CRC tumors by immunohistochemistry to examine mismatch repair protein expression is a form of genetic testing without proper informed consent. However, even in this instance, the diagnosis with immunohistochemistry tumor testing for mismatch repair gene expression is not absolute, and subsequent genetic testing is always needed to establish firmly the syndrome diagnosis. Nonetheless, it is important that appropriate infrastructure and processes are in place before comprehensive tumor testing is undertaken. This primarily involves the presence of genetic counselors and physicians who are familiar with this condition and genetic testing for cancer predisposition. All immunohistochemistry results need to be systematically reviewed by these individuals, and genetic counseling should be undertaken when suggestive results are determined. Finally, the benefit to individuals and families so outweighs any risk of problematic issues arising that this approach appears very reasonable. Recent national legislation which prohibits by law genetic discrimination by health insurance agencies and employers further protects individuals and families and allows proper medical use of genetic information.

Cancer screening Screening for syndrome cancers should be offered to persons found to have a genetic mutation consistent with HNPCC [20,21,83]. Because of the incidence of proximal colonic tumors, colonoscopy screening should begin at age 20–25 years, or 10 years earlier than the age of occurrence of the youngest case in the family, whichever is first. Screening should be repeated every 1–2 years as the polyp–cancer

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progression occurs much faster than in the sporadic setting [73,84]. Screening other potential sites of cancer development is recommended but, except for endometrial cancer, is not based on clinical trials. Recommendations for gastric cancer screening are upper gastrointestinal endoscopy every 1–2 years beginning at age 30–35 years. For uterine cancer screening, pelvic examination, transvaginal ultrasound, and/or uterine aspirate should be performed every 1–2 years starting at the age of 25–35 years. Recommendations for screening for urinary tract cancers suggest beginning at age 30–35 years and entail annual ultrasound, urinalysis, and urine cytology. Other cancer screening guidelines are even less well established. Tables 33.2 and 33.3 summarize the screening recommendations for malignancies in HNPCC.

Treatment Surgical intervention, specifically subtotal colectomy, is indicated when either a patient develops colon cancer or an advanced adenoma is diagnosed that cannot adequately be removed with endoscopic techniques [21,85]. If colonoscopy surveillance every 1–2 years can be assured, standard segmental cancer surgery rather than colectomy is considered a reasonable approach by many colorectal surgeons. Prophylactic colectomy in patients with known mismatch repair mutations is not clearly indicated but remains a matter of debate. Hysterectomy with ovarectomy has been demonstrated to decrease malignancy in those organs and should thus be considered after childbearing is finished [86].

Peutz–Jeghers syndrome Epidemiology PJS is a syndrome that includes characteristic hamartomatous polyps in the gastrointestinal tract and distinctive mucocutaneous pigmentation [87– 89]. There is an associated risk of both gastrointestinal and nongastrointestinal malignancies. About 1 in 120 000 live births is afflicted with PJS.

Etiology PJS is an autosomal dominant genetic condition, and is known to arise from a mutation in the STK11 gene (also called LKB1), which is located on chromosome 19p [87]. The gene codes for a serine–threonine kinase that is involved in the p53 apoptosis pathway [90]. Several types of mutations can occur in the STK11 gene, including frameshift mutations and deletions, but all of them lead to loss of activity. About 50% of cases are familial, and the rest are presumed to be isolated cases representing new mutations. Mutations in the STK11 gene are found in about 60% of apparent inherited cases and in 50% of isolated cases [91].

Clinical presentation The most distinct manifestation of PJS is pigmented mucocutaneous lesions, found in over 95% of patients [87,92]. These are melanin pigment spots, and occur on the lips or

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Figure 33.4 Duodenal polyps in a patient with Peutz–Jeghers syndrome.

buccal mucosa but may be found on other cutaneous surfaces. Pigmented spots on the lips usually cross the vermilion border, and are darker and more clustered than the common freckle. Lesions appear in infancy and begin to fade at puberty except on the buccal mucosa, where they often persist into adult life. Clinical diagnosis is made by the presence of the mucocutaneous lesions together with characteristic gastrointestinal polyps (Figure 33.4). The average age at diagnosis is 22 years in men and 26 years in women [91], though about a third of patients present within the first decade of life. Typically, symptoms result from complications of gastrointestinal polyps, which occur in 88–100% of patients. Polyps are found throughout the gastrointestinal tract with a frequency of 96% in the small bowel, 27% in the colon, and 24% in the stomach and rectum, [91]. They begin to grow in the first decade of life and usually become symptomatic in the second or third decade. Polyps range from 0.1 to 3.0 cm in size and can be sessile or pedunculated. Endoscopically, the polyps have a lobulated appearance. Histologically, they are nondysplastic with a normal-appearing surface mucosa appropriate for the gastrointestinal area in which the polyp is found. The muscularis mucosa extends as branching fronds in the polyp, giving an arborizing pattern that is sometimes described as “pseudoinvasion.” Adenomatous and subsequently cancerous changes may occur in PJS polyps, and are related to the cancer risk in various sections of the gastrointestinal tract. Polyps can ulcerate, infarct, bleed, or cause intussusception with intestinal obstruction and cause much of the morbidity and surgical intervention of PJS. After the age of 30 years, malignant complications become the major concern. By the age of 65, over 90% of PJS patients will have some kind of malignancy, either intestinal or extraintestinal [88,93]. The most common gastrointestinal cancers include colon, with a lifetime risk of 39% and presenting at an average age of 46 years, and pancreatic, with a lifetime risk of 36% and presenting at an average age of 41 years. Gastric and small bowel cancers occur less frequently. Nongastrointestinal malignancies include breast (54% lifetime incid-

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ence), ovarian (21% lifetime incidence), Sertoli cell tumors (9% lifetime incidence, with 10– 20% becoming malignant), and lung (15% lifetime incidence).

Genetic testing Genetic testing is available for patients suspected of having PJS based on family history or clinical presentation. However, only about 50% of families with clinical PJS will have an STK11 germline mutation [47,80,94], suggesting other possible genetic etiologies.

Screening Colon screening should begin in the late teens if symptoms have not already occurred, and should include colonoscopy every 3 years. For pancreatic cancer, either endoscopic ultrasound or transabdominal ultrasound should be performed every 1–2 years starting at age 30 years. Radiography of the small bowel should commence at age 10 years and be repeated every 2 years. Because of the high risk of breast and ovarian cancer, mammography every 2–3 years and annual breast examinations should begin at age 25, and annual pelvic examinations with or without uterine washings should start at age 20 years. For males, testicular examinations should begin at age 10 years. Cancer screening recommendations are outlined in Tables 33.2 and 33.3. All of the screening in PJS is empirical and based on risk, but nonetheless provides a rational approach.

Treatment Treatment focuses on preventing both benign and malignant complications of gastrointestinal polyps and extraintestinal cancers. Removal of polyps is indicated when they are greater than 0.5–1.0 cm in size, or if symptoms occur. Surgery is often necessary to remove large polyps in the small bowel. Colectomy may be necessary if polyps are too large or numerous to be managed safely and effectively by endoscopy.

Juvenile polyposis syndrome Epidemiology About 1 in 100 000 individuals are affected with juvenile polyposis, a syndrome characterized by multiple juvenile polyps of the gastrointestinal tract with associated colon cancer risk as well as cancer risk in other gastrointestinal and nongastrointestinal sites [87,89]. Juvenile polyps are found in about 2% of children, and must be distinguished from JPS because of the clinical significance of the latter.

Etiology JPS is an autosomal dominantly inherited disease. Genes involved in the etiology of JPS include SMAD4 (also called the DPC4), BMPR1A, and ENG [87,89,95,96]. Mutations in one of these genes are found in about 50% of affected families. The SMAD4 protein is involved in the transforming growth factor beta (TGF-β) signaling pathway, and the BMPR1A gene pro-

Figure 33.5 Colonic juvenile polyps in a patient with juvenile polyposis syndrome.

duct is a serine–threonine kinase type 1 receptor, which also belongs to the TGF-β receptor superfamily.

Clinical presentation The clinical criteria for the diagnosis of JPS include: • at least five juvenile polyps in the colorectum; • juvenile polyps throughout the gastrointestinal tract; • any number of juvenile polyps in a person from a family with known JPS [87,89]. The average age at diagnosis based on symptoms is 18.5 years. Juvenile polyps are most common in the colon, although they can occur anywhere in the gastrointestinal tract. The size of polyps ranges from small, sessile lesions to large (> 3 cm), pedunculated ones. Endoscopically, polyps are usually round, reddish, and smooth (Figure 33.5), although larger polyps can appear multilobulated. Often, they have a white exudate on their surface. Histologically, the polyps contain cystic spaces filled with mucin, and the surface mucosa is nondysplastic with abundant lamina propria. Characteristically, there are elongated, benign, cystically dilated glands that lack a smooth muscle core. Polyps usually appear in the first decade of life and can number anywhere from dozens to several hundred. Most patients will become symptomatic within the first two decades of life, presenting with rectal bleeding, abdominal pain, passage of tissue per rectum, and intussusception. Colon cancer incidence ranges from 9% to 68%, although the latter figure is probably more accurate, based on recent studies [87,89]. The average age at cancer diagnosis is 34 years (range 15–68 years). Cancers are thought to arise from adenomatous tissue within the juvenile polyp. Other cancers include malignancies of the stomach, duodenum, biliary tree, and pancreas [97]. Benign manifestations of JPS have also been found and include congenital abnormalities of the heart, gastrointestinal tract, genitourinary system, and central nervous system [97].

Genetic testing, screening, and treatment Once the mutation is determined in a family, genetic testing for JPS should be performed in family members or when

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symptoms occur. Cancer screening should include both upper gastroontestinal endoscopy and colonoscopy beginning in the late teens [47,87,89,95,96,98]. The screening interval can be 3 years if no polyps are found, but annually once polyps are found (see Tables 33.2 and 33.3). Colectomy should be considered when polyps are difficult to control endoscopically or when advanced histology is found. Likewise, partial or complete gastrectomy may be necessary for large or advanced gastric neoplasia, usually associated with SMAD4 mutations [99].

Cowden’s syndrome Cowden’s syndrome is autosomal dominantly inherited and includes hamartomatous polyps that may occur throughout the gastrointestinal tract. There is some colon cancer risk in this syndrome and adenomatous changes of polyps may also be observed. Cowden’s syndrome arises from mutations of the PTEN gene, a tumor-suppressor gene [87,100,101]. Up to 80% of patients fulfilling clinical criteria of Cowden’s syndrome will be found to have a mutation of the PTEN gene. A variant of Cowden’s syndrome, Bannayan–Riley–Ruvalcaba syndrome (BRR), also arises from mutations in PTEN, but only 50–60% of patients with BRR are found to have a PTEN mutation [80]. Clinical manifestations include multiple gastrointestinal hamartomas with the following occurrences: stomach, 75%; esophagus, 66%; colon, 66%; and duodenum, 37% [87,102]. In the esophagus, the polyps are actually glycogenic acanthosis, which are white, flat elevations [103]. In the remainder of the gastrointestinal tract, the hamartomas are of several different types, including the most common, juvenile polyps, but also lipomas, inflammatory polyps, ganglioneuromas, and lymphoid hyperplasia. A characteristic feature of the juvenile polyps in Cowden’s syndrome is the neural elements contained in the polyps. Colon cancer risk is elevated compared with the general population but not as much as in the other hamartoma syndromes [104,105]. One study suggested a 9% CRC risk, but the precise risk remains to be determined. Patients are at risk for extraintestinal malignancies including thyroid cancer (10% lifetime risk, usually follicular but sometimes papillary), breast cancer (25–50% risk in females with reports of cases in males), endometrial cancer (2–5% risk), and also some cancers of the kidney, ovary, lung, and retina [87]. Gliomas and melanomas have also been reported. Multiple facial trichilemmomas are pathognomonic of Cowden’s syndrome [87,101]. Other lesions include verrucous skin lesions of the face and limbs and cobblestone-like hyperkeratotic papules of the gingiva and buccal mucosa. By the third decade of life, 99% of patients will have mucocutaneous features of the disease. Congenital defects have also been described, including hypoplastic mandible, a prominent forehead, a high-arched palate, macrocephaly, and mental retardation. Many patients (50%) will develop thyroid goiters, and some will develop early uterine leiomyomas, heman-

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giomas, lipomas, lymphangiomas, meningiomas, and neurofibromas. Diagnostic criteria for Cowden’s syndrome have been established [100,101]. Intestinal arteriovenous malformations also appear to be a feature of this condition [106]. BRR is a variant of Cowden’s syndrome that includes typical Cowden’s syndrome as well as macrocephaly, delayed psychomotor development, lipomatosis, hemangiomatosis, and pigmented macules of the glans penis [87,100]. Lhermitte– Duclos disease is a condition with benign hamartomatous overgrowth of ganglion cells in the cerebellum. Nearly all cases of this disease occur in the setting of Cowden’s syndrome [107,108]. No specific screening recommendations exist for gastrointestinal malignancy in Cowden’s syndrome, although at least average-risk screening should be performed, probably starting at age 40 years. Annual thyroid examinations should start at age 18 years and annual breast examinations at age 25 years, with annual mammography at 30 years. Annual skin examinations for melanoma and annual urinalysis for renal cell carcinomas should also be performed, as well as annual suction biopsies of the uterus, commencing at age 35 years (Table 33.3).

Hyperplastic polyposis syndrome Hyperplastic polyposis syndrome (HPS) is defined as the occurrence of hyperplastic polyps that are larger (> 1 cm) or more numerous (> 30) than those seen in the general population. HPS does not appear to be an inherited condition, with the exception of several reported families. Other polyp types are also frequently observed in HPS including adenomas, serrated adenomas, and admixed hyperplastic/adenomatous polyps [109–111]. There appears to be an increased risk of colon cancer in HPS [112,113]. Whether this risk is due to the presence of adenomas or arises from the hyperplastic polyps themselves is still under investigation [109,110,114]. The World Health Organization’s international classification of HPS is defined as one of the following: 1 at least five histologically diagnosed hyperplastic polyps proximal to the sigmoid colon, of which two are greater than 10 mm in diameter; 2 any number of hyperplastic polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with HPS; 3 more than 30 hyperplastic polyps but distributed throughout the colon [115]. HPS appears confined to the colon without associated cancers except colon cancer. A genetic etiology is not yet known. Reports have defined rare families that appear to have an autosomal dominant segregation of HPS in the family, and there is at least one reported case of what appears to be autosomal recessive HPS [109]. Colorectal screening for individuals with HPS should include colonoscopy every 1–3 years, depending on the severity of the polyposis, and beginning with disease diagnosis [111]. Colectomy may be necessary when polyps cannot be

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managed by colonoscopy or when one or more polyps begin to exhibit severe dysplasia.

Summary Up to one-third of CRC cases occur in the setting of familial risk. A small fraction of cases represent single gene inherited syndromes with extreme colon cancer risks. The majority of familial cases exhibit sufficient risk to deserve more aggressive screening than that for average-risk persons, but genetic testing is not yet available for this group. Genetic testing and special screening, often starting at young ages, are necessary for the inherited syndromes. Family history is important to identify those with moderate risk as well as those with inherited syndromes of colon cancer. Genetic testing should be carried out when certain clinical phenotypes are present or the familial risk is particularly strong. Laboratory methods are now available to identify the large majority of persons with HNPCC, by examining the colon cancer tissue for expression of mismatch repair proteins and then moving to genetic testing if one of those proteins is not expressed. Both the primary care provider and the gastroenterologist are important in identifying the patient groups at increased familial and inherited risk of CRC. With knowledge of the etiology, clinical presentations, cancer screening, and treatment options, clinicians can prevent most familial and syndromic colon cancers and thus have a significant impact on morbidity and mortality.

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Colonoscopic Biopsy Wilfred M. Weinstein UCLA Centre for Health Sciences, Los Angeles, CA, USA

Biopsy instruments “Large cup” versus conventional-sized biopsy forceps The term “large cup” rather than the more familiar “jumbo” will be used throughout this chapter. This forceps has been available for more than 30 years but has not been used by most endoscopists, mainly because more than 85% of endoscopes sold in the US are the “diagnostic” type, with channels that cannot accommodate the larger forceps, which requires a 3.7-mm channel. As a result, until recently, the standard, almost since the advent of flexible endoscopy, has been a 2.8-mm channel forceps. However, that has now changed and there is a larger capacity forceps that passes through conventional channel forceps and is not restricted to a “therapeutic” endoscope (Figure 34.1). The biopsies are superior in size and quality, so there is no longer any reason to use traditional smaller forceps. The rationale for taking larger biopsies than with conventional-sized forceps is not that more mucosa is sampled. These biopsies have a two- to threefold larger surface area, but they are not deeper; their main benefit is that the histotechnologist can see the biopsy sufficiently to orient it properly. Orientation for embedding in paraffin is the key to maximizing the diagnostic yield from mucosal biopsies. Biopsies taken with large cup forceps contain proportionately less crush artifact, permit more precise evaluation of architecture, and are more likely to histologically detect smaller focal lesions when these are targeted. Some fear a higher complication rate with a large cup forceps, but that is not borne out by analysis of complication rates with these forceps in large numbers of biopsies [1].

Figure 34.1 Comparison of the open span of biopsy forceps (endoscope channel size); right to left: large cup (“jumbo” 3.5-mm channel); conventional sized (2.8-mm channel); pediatric sized (2.2-mm channel).

Hot biopsy forceps Hot biopsy refers to a coagulation current passed through the jaws of an insulated pinch biopsy forceps. The belief has been that hot biopsy leaves behind a burn that takes care of any residual adenoma not biopsied off. This view of complete obliteration has been challenged in one study [2]. The cautery artifact induced by hot biopsy often makes the tissue histologically uninterpretable. Therefore, if it is used to remove a cluster of small polyps, a few should be biopsied off with conventional forceps to obtain better-quality histology. Hot biopsy appears to be safe in experienced hands [3], but when it is used in the right colon caution should be exercised [4]. For diminutive polyps, “cold” pinch biopsy forceps removal is more commonly used.

Suction biopsy Suction biopsies are sometimes used for biopsy in children, especially in the diagnosis of Hirschprung’s disease. They provide easier measurement of biopsy distance from the anal verge and, more commonly, they contain submucosae, which are critical for the assessment of ganglion cell presence [5].

Grasp biopsies Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Grasp biopsies are taken through a rigid sigmoidoscope using an alligator-jaw cutting forceps. These instruments are rarely used except, on occasion, in biopsy of rock-hard, immobile rectal tumors.

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Discarding inadequate biopsies

Improving the quality of handling of tissue specimens in the endoscopy unit There is widespread disorganization and apparent antipathy in the approach to surveillance for dysplasia in ulcerative colitis and Crohn’s disease [6,7]. This is graphically illustrated by what might be termed “endoscopic detumescence.” In ulcerative colitis biopsy surveillance, the work should really begin when the cecum is reached. Yet there is commonly a rush to exit and, on the way out, minimize the number of biopsy sites, and this leads to a failure to take a sufficient number of biopsies.

Retrieval of biopsy from the forceps and insertion into fixative The best way to remove a biopsy from the forceps is to use a blunt dental probe or dissecting needle and scoop it out from the bottom of the opened forceps cups. If one approaches the biopsy from the top of the opened forceps and pushes it sideways into fixative there is more likely to be trauma to the surface epithelium with denudation or squashing of the whole mucosa. A common practice is to shake the opened biopsy forceps in the formalin fixative solution until it floats out. This may cause detachment of the surface epithelium. Orientation of biopsies makes it easier for the histotechnologist to embed them perfectly, but biopsies are rarely oriented in the endoscopy unit, mucosal side up on support materials. However, it requires training and ongoing quality control to avoid biopsy crush in the process of the orientation. The quality of biopsies can be markedly improved, with: • the acquisition of larger biopsies; • by empowering the endoscopy assistants to report a biopsy as tiny, shallow (transparent), or containing only blood or mucus. If the endoscopist returns to the site and obtains a higher quality biopsy in those circumstances, the proportion of uninterpretable biopsies (size, malorientation, just blood or mucus) approaches zero.

(a)

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(b)

Tiny biopsies, or pieces of mucus and blood that come back in the forceps in place of a biopsy, must be discarded rather than put in with the good-quality biopsies, because variable-sized biopsies make it hard to have all of the inadequate ones oriented for embedding. Also, the variable size, from tiny to adequate-sized biopsies in the paraffin block, makes it more difficult to avoid “chatter” (multiple uneven cuts on the specimen) from uneven sectioning.

Never place more than four biopsies into a fixative bottle All the biopsies that are put into a fixative bottle are embedded by the histotechnologist into a single tissue block. It is a rare histotechnologist who can line up more than four biopsies in a tissue block during embedding and section them so that they are all predictably represented with optimal orientation for interpretation. Those endoscopists who cram multiple biopsies (10–15) into one specimen container argue that doing so reduces pathology charges, effectively reducing multiple sites to one composite site, all in one tissue slide. No one tells us (the “silence of the pathologists,” discussed subsequently) that half or fewer of these 10–15 specimens may actually be fully interpretable (Figure 34.2).

Handling polyps and endoscopic resection specimens The central focus of this chapter is biopsy, but a few comments regarding the tissue handling of polypectomy and endoscopic resection specimens are relevant to the general handling of tissue specimens in the endoscopy unit.

Identifying the stalk region in pedunculated polyps To diagnose early cancer invasion in pedunculated polyps requires the oriented stalk zone to be represented in the histological sections. This is crucial. In the freshly snared

Figure 34.2 Quality issues. (a) Multiple biopsies were put into one fixative bottle, then were processed in one tissue block. Many of the pieces are tiny and should not have been put into the fixative with the adequate sized specimens. Having multiple biopsies in one tissue block makes it impossible to orient many of the biopsies for the accurate assessment of dysplasia, inflammatory bowel disease type, or severity. (b) Totally tangential section. There are no oriented test tube-shaped crypts, just doughnut circles representing cross cut crypts.

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polyp, the snared stalk zone looks distinct; however, in the formalin fixative, it shrinks and is difficult to find. Identifying the stalk region makes it possible for the histotechnologist to predictably provide sections right through the stalk zone. There are two ways to identify the stalk zone. One is to insert a thin short needle (e.g., 25G) into the line of resection, with the needle point emerging at the most convex part of the tip of the polyp. An alternative technique, without the use of needles, is to ink the polyp stalk. After a few hours of fixation the tissue hardens, and then the polyp can be bisected with a scalpel or razor blade through the stalk zone. Each of the two bisected halves is embedded in a separate block, face down; in this way, the first sections obtained are those that show the stalk region in its best orientation [8].

Endoscopic resection Endoscopic resection is a more accurate term than the more commonly used endoscopic mucosal resection, because the objective is to uniformly obtain submucosa, and in some cases extend endoscopic submucosal dissection to the muscularis propria. Thus, the term endoscopic resection will be used throughout this chapter instead of endoscopic mucosal resection. Specimens of endoscopic biopsy tissue should be handled identically to any surgical resection for cancer or dysplasia. The principle of endoscopic resection is the same as that of oncologic surgery. The specimen should be removed in one piece, and the cut side identified with ink. The best results are obtained when the resected specimen is sent fresh to the pathologist, who pins it out and takes sections from one end to the other [9]. The accurate diagnosis of cancer hinges on the ability to ascertain that the muscularis mucosae and upper submucosa are visualized. Adenomatous change of any grade that penetrates the muscularis mucosae through to the submucosa is invasive cancer. If piecemeal removal (shave biopsy) is unavoidable, then the specimens need to be submitted with the cut sides inked. Piecemeal resection may often seriously compromise the accuracy of the histological diagnosis regarding whether or not cancer is present and regardless of how much it invades.

Pinch biopsy techniques to improve quality and efficiency Less force against the wall More gentle indentation of the opened forceps against the wall results in higher-quality biopsies. Partial deflation beforehand helps to grasp the tissues. The main principle is to indent the wall gently with the opened forceps, apply several staccato bursts of suction to help pull the mucosa in, and snap the forceps closed. One distinctive biopsy urge needs to be suppressed: to make a second push on the wall after the first, as if for good measure, before closing the forceps. This stretches

Colonoscopic Biopsy

Table 34.1 Indications for colonic biopsy. Biopsy removal of polyps Biopsy of larger neoplasms for diagnosis Undiagnosed diarrhea with either normal or abnormal colonic mucosa In ulcerative colitis or Crohn’s disease Differential diagnosis Assessing disease extent and activity Established case but atypical course to rule out other contributor, e.g., cytomegalovirus Surveillance biopsy in inflammatory bowel disease for dysplasia or carcinoma Lumps and bumps in inflammatory bowel disease Biopsy of focal lesions with no apparent cause Hirschprung’s disease Biopsy of the colon in generalized gastrointestinal disease or in systemic disease; examples include amyloidosis, graft-versus-host disease, vasculitis

the wall, and may result in shallower biopsies than the preferred one indent maneuver.

The tenting maneuver After the forceps is closed around the tissue, it should be snapped back quickly and withdrawn. Tenting causes crush artifact. In earlier days, some advocated pulling the forceps back slightly to tent the specimen and thus avoid getting too much submucosa in the specimen. This is only rarely possible, as with any size of biopsy forceps it is difficult to obtain submucosa on a routine basis. This becomes key in biopsies for amyloid or Hirschprung’s disease, or in a hunt for vasculitis (Table 34.1).

Double bites Double bites refers to taking two biopsies from two different locations with a single pass of the biopsy forceps. This can actually be done successfully in the colon and the small bowel by using large cup forceps. Double bites with the conventional forceps for the “diagnostic” scopes yield inadequate-sized biopsies. In the small bowel and the colon, after the first biopsy is obtained, the closed forceps is then placed with slight pressure on the wall where the next biopsy is to be taken and the forceps is opened against minimal pressure to help prevent the first biopsy from falling out into the lumen. After opening the forceps, a few staccato bursts of suction are applied and the forceps is quickly closed to obtain the second biopsy. Average success in obtaining a high-quality second biopsy varies. Three out of four times a good yield occurs. The double-bite technique works poorly in the esophagus and stomach. In the esophagus, it is difficult because of the need for angulation and the fact that the esophagus remains the last frontier for routinely obtaining adequate-sized biopsies

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with the lamina propria. In the stomach, the biopsy size is so generous with the first biopsy that there is scant room for a second.

Reducing the time taken to obtain multiple biopsies In surveillance biopsy in colitis, or random sampling for the diagnosis of endoscopy-normal diarrhea, it is not necessary to be up close, nor to have a pristine clean site. Focal lesions are biopsied first and thereafter it is unnecessary to advance the endoscope each time to within a few centimeters, or wash the site chosen for biopsyathey just add time to the performance of the biopsies. If colonoscopy is carried out for the diagnosis or differential diagnosis of inflammatory bowel disease (IBD) and it is impossible to get into the terminal ileum (a scenario suggested tremulously in the company of the distinguished contributors to this book), blind biopsy may work. A forceps can sometimes be advanced in the closed position through the ileocecal valve, with biopsies taken at the point at which resistance is met. This should be done gingerly so as not to press too hard on the nonvisualized ileum. Blind biopsy of the terminal ileum should not be performed if there is ileocecal valve deformity or marked inflammatory swelling. A second assistant in the room when the biopsies are taken helps prevent biopsy antipathy and fatigue. One assistant watches the patient and handles the forceps while the second assistant handles the biopsies, putting them into fixative and recording biopsy sites and appearances.

Dialogue with the pathologist Colonic biopsy to rule out IBD requires more correlative information between the endoscopist and pathologist than biopsies anywhere else in the gastrointestinal tract [10–12]. IBD encompasses a variety of inflammatory conditions including a variety of IBDs, ischemia, infections, and ulcerative colitis and Crohn’s disease. When the endoscopist asks to “rule out IBD” the pathologist needs to know if that endoscopist means just ulcerative colitis and Crohn’s disease or if the question refers to any inflammatory disease. When biopsies are taken in the workup of diarrhea to rule out IBD, the way to get a focused or differential diagnosis is to provide the pathologist with relevant clinical information: 1 important historical points; 2 what was seen, not what we think it represents; 3 labeling of biopsy sites as normal or abnormal; 4 question(s) for the pathologist. Different biopsy sites commonly have different questions. A pathologist sufficiently versed in the range of benign colonic diseases can come up with a meaningful differential diagnosis when provided with adequate information from the endoscopist. A diagnosis does not need to be attached to every question. When a focal or unusual diffuse endoscopic

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abnormality is encountered, the question can and should simply be “What is the histology of this?”

What information should we give to the pathologist? In the US, it is likely that more than 85% of biopsy cases are submitted to the pathologist with no clinical lesion appearances, location information, clinical information, or questions for the pathologistathe silence of the endoscopists. During each of the past three years, I have polled 100–110 pathologists attending a 1-week national gastrointestinal pathology course and asked for the information listed in the preceding section. No more than 10% of pathologists each year indicated that they obtained this information. Information on the requisition commonly comes though as: 1 Crohn’s disease 2 random colon biopsies 3 no questions for the pathologist. That this degree of dysfunctional communication has continued since the advent of flexible endoscopy nearly 40 years ago, is astounding. Noncommunication from the endoscopist can be solved by using standardized biopsy requisitions that incorporate the key information given in Tables 34.2 and 34.3. This maximizes the potential for biopsy to aid in patient management. In regards to biopsy location, the surrounding terrain may also be important, especially for biopsies taken in the region of diverticula. Diverticula may be associated with a localized mucosal inflammation, sometimes obvious or sometimes endoscopically occult. The pathologist should be made aware when biopsies are taken in the vicinity of diverticula for whatever reason [13–15].

The history The history should be brief and relevant, ending with questions for the pathologist (Table 34.3). For example, information on the duration of diarrhea and whether or not it is bloody helps the pathologist avoid rushing into a premature diagnosis of chronic IBD (ulcerative colitis, Crohn’s disease). If the pathologist knows that there has been longstanding nonbloody diarrhea, that in itself makes ulcerative colitis highly unlikely. Pathologists should be given information that will spare them needless time with a given case. For example, if, after biopsies are taken, an infectious colitis is diagnosed, tell them. This will avert irrelevant differential diagnoses.

What medication does the patient take? Table 34.3 outlines the information regarding drug or other therapy that can impact biopsy diagnosis in any part of the gut and some that is more site relevant. For chemotherapy and radiotherapy, it is essential to know when these were last administered because the early effects differ histologically from the delayed effects.

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Table 34.2 Standardized reporting of biopsy and lesion locations, modified from ref. 11. Locations

Comment

Cecum and ascending colon

The cecum and ascending colon look histologically inflamed relative to the left colon Separate these biopsies from the rest of the biopsies

Hepatic flexure regiona Transverse colon

If multiple sites are biopsied then designate as proximal, mid, or distal

Splenic flexure regiona Descending and sigmoid colon Rectum

a

Note biopsy location as “descending,” and sigmoid as distance in centimeters from anal verge Describe simply as rectum, but for important focal rectal disease, in centimeters from anal verge.

This can also include biopsies just distal and proximal to the flexure.

Table 34.3 Lesion descriptions, relevant medications, history, and questions for the pathologist. Lesion description Use simple language to describe mucosal abnormalities: thick folds rather than hypertrophy; define friability if used, i.e., bleeding or oozing Describe what was seen rather than use an interpretive term such as colitis Biopsy instrument Detail type of instrument if different from a pinch biopsy forceps (e.g., hot biopsy forceps, electrocautery snare) For polyps Give size, whether sessile or pedunculated, and instrument used (e.g., biopsy forceps, hot biopsy forceps, or electrocautery snare) Key drugs Colon: type of preparation: enemas or oral, and type of oral; 5-aminosalicylate compounds or other inflammatory bowel disease drugs For all sites in the gastrointestinal tract: any immunosuppressives, chemotherapy, radiotherapy (and when last treatment with same), or current or recent nonsteroidal anti-inflammatory drugs History Brief usually suffices; in patients with diarrhea state duration of diarrhea and whether bloody or nonbloody Question for the pathologist Be as specific as possiblebsee Table 34.4, which lists good and bad questions

Nonsteroidal anti-inflammatory drugs (NSAIDs) are important to document, especially if unusual lesions are found virtually anywhere in the gut; a link between cause and effect in such instances is difficult to prove, but at least NSAIDs can be put into the differential diagnosis [16–18]. It is not necessary to list all drugs that a patient takes, just the ones that can potentially harm the gut. The importance of some of the drugs taken by a patient may become apparent only after review of the biopsies. For example, if ischemic colitis is suspected on the basis of the endoscopic and/or biopsy findings, then the drug histology should include cocaine, methamphetamines, and oral contraceptives. Revisiting the drug history (including supplements) becomes paramount. In addition to drugs, some com-

mon infections caused by Campylobacter, Salmonella, Shigella, and, uncommonly, Escherichia coli OH:157 may produce a picture of ischemia. The list of drugs capable of producing colitis in general, including ischemic colitis, grows every year [17,19–22]. For both drug- and infection-associated ischemic colitis the apparent increased incidence may reflect the aging of a population. A healthy septuagenarian may be more vulnerable to colonic ischemia solely because of a more limited ability to respond to an insult to the gut, such as transient hypotension, infectious colitis, or drug injury. This patient’s vascular system may be normal at an age-adjusted level but the vascular changes that accompany even healthy aging may be more vulnerable. As

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Table 34.4 Examples of good and bad questions. Biopsy site

Bad question

Good question

Biopsy of large tumor scheduled for surgery Biopsy of apparent ulcerative colitis

Rule out cancer Is it compatible with ulcerative colitis?

Biopsy of suspect Crohn’s disease Biopsy of normal mucosa in a patient with diarrhea

Is it compatible with Crohn’s disease? Is there mild colitis?

Rule out adenomatous change Looks like ulcerative colitisbis there anything to suggest another cause? Rule out focal inflammation, granulomas Almost any other question is better (see text)

endoscopists, we need to be aware of these scenarios and consider a wider group of potential culprits than in the past [23,24].

Questions for the pathologist Table 34.4 gives examples of some good and bad questions that are discussed in this section. When a tumor destined for surgical resection is biopsied, instead of asking if it is cancer, it is better to ask if the biopsy shows adenomatous change and indicate that the tumor is slated for resection in the near future. The objective in biopsying likely adenocarcinomas that are destined for resection is to make sure that no major surprises, such as lymphoma, are found. Narrowing the question to whether or not there is an adenomatous change avoids having the pathologist feel compelled in some circumstances to state that cancer could not be confirmed and thus recommending rebiopsy. In the colon, the main unreasonable expectation is that the pathologist should provide a specific diagnosis of ulcerative colitis or Crohn’s disease, in both of which biopsy by itself only rarely provides a diagnosis of the type of IBD at the outset or even after long-term symptoms. The correlation of the clinical information, imaging studies, and other tests often permits a putative biopsy diagnosis. Indeterminate colitis can be made more determinate by integrating all the clinical and investigative information [12,25]. The most unrealistic and potentially damaging (to the patient) expectation results from asking “Is this Crohn’s or compatible with Crohn’s?” Too often there is a “yes” answer, usually hedged, but on the record nevertheless. Virtually any mucosal abnormality can be seen in Crohn’s disease. If Crohn’s is suspected it is better to ask whether or not granulomas or multifocal inflammation are present. Of course, neither of these findings confirms the diagnosis of Crohn’s disease, but the question alerts the pathologist that we are looking for more solid evidence to suggest Crohn’s disease, without the expectation that he or she must make that diagnosis. In the case of granulomas, pathologists recognize, and we must also, that there may be tiny crypt granulomas in the region of crypt breakdown (e.g., from crypt abscesses) that may be seen frequently in ulcerative colitis. These are different than the freestanding granulomas of Crohn’s disease.

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A rush to judgment with a premature diagnosis of ulcerative colitis or Crohn’s disease can be damaging in a number of ways: worry about cancer and other complications, difficulty, and/or the increased cost of life and health insurance. In ulcerative colitis, biopsy helps most when it does not fit. The best question is “It looks like ulcerative colitis but might I be wrong?” That alerts the pathologist to look for disorders that can mimic ulcerative colitis, such as infections, or multifocal noncrypt-associated granulomas that would suggest Crohn’s disease. In endoscopically normal mucosa in a patient with chronic diarrhea, one obvious question “Is is there microscopic colitis?” In a person at risk, the presence of amyloid might also be queried. If we use the redundant but established term “microscopic colitis,” we need to ensure that everyone understands that it refers to either lymphocytic or collagenous colitis.

What can the pathologists do? Better-quality processing Unfortunately, processing of gastrointestinal biopsies is often technically poor, especially because of malorientation in tissue sectionsathe doughnuts. These refer to the histological appearance of a series of doughnuts or circles piled on each other, rather than the vertical array of test tube-shaped crypts of colonic mucosa. The colonic crypts should look like linedup test tubes and not cross-cut circles, which indicate that the mucosa was sectioned horizontally at some level. The same appearance reflects cross-cut mucosal structures in the crypts of the small intestine, the foveolae (pits) of the stomach, and the papillae of the esophagus (Figures 34.2 and 34.3). Tangentially cut sections seriously compromise the ability to diagnose and differentially diagnose inflammatory conditions and dysplasia in the colon. In both settings, crypt architectural distortion is a key finding: 1 To indicate chronicity in inflammatory disorders, cross-cut crypts make it impossible to assess the degree and location of inflammation in the lamina propria. 2 In dysplasia, architectural distortion is one of the two criteria for the diagnosis of dysplasia, the other is cellular changes of neoplasia.

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Figure 34.3 High-grade dysplasia. (a) There are two criteria: architectural disarray of intestinal crypts and abnormal nuclear cytology. (Courtesy of the late Rodger Haggitt, MD.) (b) This biopsy is mostly tangentially sectioned. Only the small part within the square shows a few oriented colonic crypts, the rest shows doughnut-type circles, which eliminate the use of architectural change as a diagnostic criterion for dysplasia. (a)

Sending difficult cases with poorly processed biopsies for a second opinion is not a good alternative. Biopsy interpretation remains seriously compromised, irrespective of the expertise of the pathologist.

Know the truth and consequences Pathologists must know the consequences of their diagnoses, especially false-positive diagnoses (Barrett’s esophagus), rash judgments of Crohn’s disease and ulcerative colitis, and frequent diagnoses of mild chronic inflammation.

Stop the worldwide pandemic of “mild chronic inflammation” This pandemic diagnosis is commonly affixed to biopsies that are normal. When healthy, the gut, from the esophagus to the rectum, has some mild chronic inflammation, the sole exception in the animal kingdom being germ-free animals. Thus, it is best to ignore the diagnosis entirely. In the colon, the attendant risk is that some cases of lymphocytic colitis might be overlooked. The alternative is to believe the diagnosis and potentially subject patients to needless and expensive therapy and tests. So, be wary of the pathologist’s report of “mild chronic inflammation.” The Internet brings a new urgency to banish this terminological disease. An increasing number of patients ask to receive copies of their pathology and endoscopy reports, usually for interest rather than litigation. If they come across a broad differential diagnosis of mild chronic inflammation, not infrequently they may return with concern about the long-term consequences of this putative chronic inflammatory disorder. If we reassure them that it is nothing and usually means that everything is normal, then their confidence in us and our colleagues in pathology may be shaken. Some ask for the slides to be reviewed elsewhere.

Colonoscopic Biopsy

(b)

The solution in a high-inflammation-rate pathology department is to discuss it with the pathologists. If that fails to change the sign-out practice, one option is to request the biopsies be sent for primary sign-outs to a center with expertise in gastrointestinal pathology. Two reasons above all no doubt account for this practice of reporting “mild chronic inflammation:” 1 Insecurity with what is normal; in clinical medicine we also use hedge terms at times (e.g., “grossly normal”). 2 Some pathologists and endoscopists believe that the endoscopist will get into trouble if too many biopsies are signed out as normal. That is a false belief. Accrediting agencies look not at the proportion of normal biopsies, but rather whether or not the indications for biopsy are appropriate.

Use modern accepted terminology The pathologist should not use terms for which there is no action plan. The best example is moderate dysplasia, a grade that does not exist in the modern classifications of dysplasia in ulcerative colitis, Crohn’s disease, or Barrett’s esophagus. Hackneyed terminology is of no value. Nonspecific is the most hackneyed. It is very commonly used as a descriptor for any abnormality in the gut (e.g., nonspecific inflammation, nonspecific reactive changes in crypts). This descriptor is nonactionable. In benign disease of the gut, almost all patterns of injury are nonspecific, or, at best, provide a focused differential diagnosis. Examples of specific pathologic diagnoses are infections such as cytomegalovirus colitis and syphilitic proctitis. Eosinophilic colitis is an example of a pattern of inflammation that narrows the differential diagnosis to only a few entities. Clinical correlation recommended is another nonactionable term. It is intended by some pathologists to transmit some

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concern to the clinician. Others just build it into many of their reports. Of course, clinicians establish clinical correlation every day with all tests: biopsies, blood tests, and imaging studies.

Feedback Pathologists rarely, if ever, tell us that many of our biopsies are uninterpretable (the silence of the pathologists), and that we should separate biopsies into groups by site or any other rationale and not put them all into one bottle (see Figure 34.2). They also rarely take the initiative and tell us that they will separate the biopsies into smaller groups in the pathology laboratory, prior to embedding in paraffin. The pathologists and our patients continue to be victims of the absence of clinical information on pathology requisitions. The initiative for clinicians to supply more information must come from the pathologist. Endoscopists might have stopped some of their practices (discussed earlier) decades ago if the rules of engagement were open, blunt, and proactive dialogue.

When and where to biopsy the colon, and special circumstances in diagnosis Table 34.1 gives broad indications for colonic biopsy. In the biopsy removal of sessile polyps, a diagnosis of the margins are clear is misleading. The only way to clear the margins is to section the dome-shaped sessile lesion entirely from front to back. Most of the sessile lesions removed with biopsy are small and can be judged as removed by the endoscopist. The issues with larger lesions removed with endoscopic resection and with pedunculated polyps were discussed previously. In biopsies for amyloidosis and Hirschprung’s disease, submucosa must be present in the biopsy in order to visualize submucosal vessels (amyloidosis) or determine the presence or absence ganglion cells in suspected Hirschprung’s disease. When amyloid is suspected but the biopsies are negative and the pathologist recognizes that, the report should indicate something to the effect negative for amyloid, little submucosa present to rule it out definitively. When biopsies are taken for graft-versus-host disease, other concomitant findings should be sought, the main one being cytomegalovirus [26]. The rectosigmoid is the best place to biopsy for graft-versus-host disease [27], but sometimes the stomach and/or small intestine may show changes of greater severity than would the colonic mucosa [28,29]. If the patient is neutropenic, inflammatory change both endoscopically and histologically may be rather mild in the face of advanced lesions with diffuse crypt dropout. In the transplantation setting, drugs which the patient is taking may have a bearing on the histological findings. The main drug is mycophenolate, which can sometimes produce graft-versus-host disease-like changes [30].

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Newer imaging modalities Major advances in endoscopic imaging have been highresolution endoscopy with magnification potential and highdefinition television monitors. Those, combined with a simple highlighter dye such as indigo carmine, provided very good three-dimensional definition. A variety of novel superimposable modalities include narrow-band imaging, confocal endomicroscopy, and computed virtual chromoendoscopy [31–34]. The objective is to detect dysplasia and early neoplasia more easily and to provide a way to make biopsy targeting in surveillance more specific and less random. The clinical value of these techniques needs to be defined [31].

Diarrhea and a normal endoscopy In patients with chronic diarrhea (assuming that infection is ruled out) and a normal endoscopic appearance, important colonic disorders to exclude are collagenous and lymphocytic colitis [35–37]. In collagenous colitis, random biopsies, especially in the rectosigmoid, may miss the subepithelial collagen deposits and reveal only lymphocytic colitis [38]. Other potential findings in diarrhea with a normal endoscopy include amyloidosis and melanosis coli. Melanosis coli is commonly unassociated with any endoscopic clues. When found unexpectedly, it raises the question of a prior or recent history of laxative use or abuse. However, in many patients, the melanosis is unexplained. Figure 34.4 shows the technique used at UCLA (University of California, Los Angeles): two biopsies per site, six sites. Four biopsies are grouped per fixative bottle and hence will be placed together in one tissue block: the cecum and ascending colon together; transverse and proximal descending colon; and the other two left-sided sites together. Because the cecum and ascending colon look inflamed in health relative to the left colon (Figure 34.5), biopsies from those sites should be kept separate from all others [39]. With a second assistant present when biopsies are taken, the biopsy “mapping” (see Figure 34.4) can be carried out in 10–15 min. The scheme shown in Figure 34.4 is also used in the biopsy of abnormal mucosa, such as in ulcerative colitis, to map the severity and extent. Focal lesions would be biopsied in addition, as would the terminal ileum if relevant to the patient’s disorder.

Diarrhea and an abnormal endoscopy Figure 34.6 highlights some issues related to biopsy in the wide range of IBDs for diagnosis and differential diagnosis, and for focal lesions throughout the gastrointestinal tract. Ileal biopsies are added if required for differential diagnosis.

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Figure 34.4 Scheme for biopsy of the colon in diarrhea where endoscopy is normal or there is pancolitis or left-sided colitis, seen for the first time, to define extent. Two biopsies per site. Three groupings of four biopsies each, in separate fixative bottles: cecum and ascending colon; transverse colon and proximal descending; and sigmoid and rectum (see text).

In severely ill patients with colitis at first presentation, the first endoscopic examination might be an unprepped examination with a colonoscope advancing proximally as far as safety permits. The main task at the outset is to assess severity, obtain biopsies for differential diagnosis, and rule out infections, especially cytomegalovirus or amebiasis. The full colonoscopy can be performed later, after the patient has improved. Ileal biopsies are added if required for the differential diagnosis.

(a)

(b)

Figure 34.5 In health, the normal cecal mucosa (top) looks more cellular and inflamed than the normal sigmoid colon mucosa (bottom). If the sigmoid colon biopsy looked like the cecal biopsy, it would be considered abnormal.

(c)

Figure 34.6 Some principles of where to biopsy in inflammatory bowel disease diagnosis. For ulcerative proctitis (a), one biopsy within the inflamed zone and one approximately 10 cm away (see text). For any focal lesion (b), biopsy the adjacent mucosa. For diffuse inflammation (c) at flexible sigmoidoscopy, biopsy the descending colon, sigmoid colon, and rectum. This helps resolve whether or not the histology is patchy, verifies apparent diffuseness, and additional biopsies may help find a specific diagnosis.

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Ulcerative proctitis refers to inflammatory change like that of ulcerative colitis but confined to the rectum. It should not be diagnosed solely on the basis of one biopsy from the abnormal rectum. A second biopsy about 10 cm proximal to the upper margin of inflammation should be taken. Not uncommonly, there is unequivocal histological inflammatory change in the proximal biopsy from normal-appearing mucosa. That finding converts putative ulcerative proctitis to left-sided ulcerative colitis. Subsequent colonoscopic biopsies to the cecum will determine if there is inflammation even closer. If the 10-cm biopsy is normal then the patient can be informed that the diagnosis is ulcerative proctitis; and that includes the fact that in 90% of these cases the disease does not migrate proximally, and thus the risk of cancer is lower or nonexistent. The conversion rates from ulcerative proctitis to ulcerative colitis cannot be assessed from the literature because virtually no studies establish a gold standard by excluding endoscopically invisible inflammation 10 cm proximally [40,41]. Some of the reported cases that progressed probably had endoscopically occult proctosigmoiditis. The role of biopsy in the putative diagnosis of ulcerative proctitis is also to rule out other causes, where potentially applicable: trauma from repeated enemas or receptive anal intercourse, ischemia, sexually transmitted infectious proctitis, radiation proctitis, and proctitis from instillation of a variety of compounds into the rectum [42–45]. In the case of workups

for sexually transmitted disease and proctitis in the immunosuppressed or immunocompetent, the endoscopy unit should keep a list of the kinds of samples besides biopsy to send to the laboratory. In these clinical settings, the endoscopist is also a conduit to the laboratory. The endoscopy unit personnel should periodically (every year at least) review the procedures for obtaining biopsies, smears, and the transport media required by the staff in microbiology and virology. Figure 34.6 also illustrates an important principle in biopsies throughout the gut. Namely, if a focal lesion is seen and biopsied, one or two biopsies about 1 cm away should be taken. The reasons for this recommendation include: • Frequently, what appears focal is not. • Sometimes the adjacent mucosa is more revealing than the target lesion (e.g., in ischemia or cytomegalovirus); in these instances, among others, the target lesion may show only necrosis or ulceration. The adjacent mucosa may provide the clue that cytomegalovirus is present or that there is isolated crypt necrosis indicating ischemic disease. Figure 34.7 illustrates the approach to a large unclassifiedtype ulcer of the colon and its biopsy sites where the surrounding mucosa provides the diagnosis.

Biopsies at the outset of, or in, established ulcerative colitis or Crohn’s disease Diagnosis at presentation and the assessment of extent and disease activity The principles of biopsy are those given in the previous section. Some endoscopists biopsy the ileum at first presentation of every case of colitis; I do also. If the terminal ileum is biopsied for differential diagnosis it should be noted that the finding of moderate to marked inflammation when the ileum appears normal is not common. In other words, there appear to be fewer histological surprises in the terminal ileum than in the colon. In centers with large experience of IBDs and where the endoscopists and pathologists communicate well [12,46,47], the numbers of cases of indeterminate colitis are only a tiny fraction of the whole IBD population. This presupposes that the category of indeterminate colitis is based upon all the methods of evaluation in a given patient, after at least 1 year and with at least one colonoscopic rebiopsy session.

Established ulcerative colitis or Crohn’s disease but atypical course Figure 34.7 Suggested biopsy scheme for a colonic ulcer of unknown cause. Focusing only on the center (1) might yield only nonspecific exudate and granulation tissue and not yield a clue to causation. The edges (2) are often high yield for specific processes associated with overlying exudate [e.g., infections (cytomegalovirus), lymphoma]. Biopsy sites (3) and (4) within 1 cm may be the ones that are diagnostic, as in cytomegalovirus or ischemia, with focal crypt dropout.

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When the patient fails to respond to the same therapy that was previously successful for flare-ups or maintenance, stool studies to rule out infection are needed. If those are negative, repeat the colonoscopy and biopsy. The objective is to rule out a concomitant cause of poor responsiveness, such as more severe disease, coinfection with cytomegalovirus, or development of ischemic colitis [48,49]. Cytomegalovirus

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Figure 34.8 Biopsy sites in surveillance for dysplasia and cancer in ulcerative colitis and Crohn’s disease. Nine sites with four biopsies per site. Landmarks are used rather than the “every 10 cm rule.”

may in some cases be a hanger-on, and be found in those who pursue a more usual clinical course [50].

Surveillance for cancer The conventional recommendation has been to biopsy four quadrants every 10 cm. However, most patients do not have a featureless colon where 10 cm at a time is meaningful or accurate on withdrawal, without springing back. Therefore, focusing on anatomic landmarks is preferred, at least in the descending colon, where the measurement technique is more successful because of minimal springback upon withdrawal (Figure 34.8). Thirty to forty random biopsies should be taken per surveillance examination and also biopsies of lesions such as bumps or ulcers [51]. The management of polyps in ulcerative colitis and Crohn’s has attracted considerable attention and is discussed in detail in the next section.

Lumps and bumps in ulcerative colitis and Crohn’s disease Biopsy surveillance in ulcerative colitis and Crohn’s disease is directed to the finding of dysplasia. Dysplasia is graded as indefinite, low grade, and high grade.

Colonoscopic Biopsy

“high-grade dysplasia.” In some countries, the term adenoma is used for endoscopically normal mucosa and for dysplasia on biopsy. Normally, dysplasia without a visible bump or other endoscopic abnormality (not a polyp or bump) is just dysplasia, whereas a visible collection of dysplastic (adenomatous) tissue is referred to as an adenoma. For this discussion, the conceptual focus will be on pedunculated adenomas, sporadic-type sessile adenomas that look benign, irrespective of whether they occur within or outside the colitis zone, and dysplasia-associated lesions or masses (DALMs), which are sessile, larger, and may have other worrisome endoscopic appearances, such as an irregular surface and a broad base [52]. Excluded from this discussion is the consideration of giant (filiform) pseudopolyps (inflammatory polyps), which have to be differentiated from carcinoma when localized or confluent [53]. Giant filiform pseudopolyps often look like worms and may bridge the lumen or occur in groups as discrete lesions. Also excluded is the question of dysplasia in patients with ileoanal pouches. It is not clear how and when to carry out surveillance of the ileal pouch and the anal transition zone [54,55]. Pathologists’ interobserver agreement in dysplasia grading in Barrett’s esophagus or ulcerative colitis indicates that it is in the range of 70% or less at the low end of the spectrum (low grade, indefinite, no dysplasia), and for high-grade dysplasia agreement is up to 85% [56–58]. The Vienna classification was introduced in 2000 [59] and appears to be used much more in Europe than in the US. Intraepithelial neoplasia is the start-off term and is then qualified as indefinite, or low- or high-grade dysplasia. Two other categories go beyond the usual dysplasia classification. One is high-grade alone or suspicious for carcinoma. The second higher level is invasive carcinoma with either an intramucosal or a submucosal pattern [59]. One of the “hottest” areas of discussion in ulcerative colitis surveillance is the handling of lumps and bumps. The concern is whether or not a given raised lesion in ulcerative colitis represents a carcinoma. Is it an ALM (adenoma-like mass), i.e., like a sporadic adenoma or a DALM. For this discussion, the conceptual focus will be on pedunculated adenomas, sporadic-type sessile adenomas that look benign (ALM) irrespective of whether they occur within or outside the colitis zone, and DALMs that are sessile, larger, and may have other worrisome endoscopic appearances.

The dysplasia-associated lesion or mass What is dysplasia? Dysplasia is a neoplastic change of the lining epithelial cells that does not extend into the lamina propria of the mucosa, or deeper, and with no potential for metastasis. If the dysplastic cells break through into the lamina propria, the diagnosis is intramucosal cancer, but most pathologists use the term

The coining of this term served a very useful purpose for clinicians [60]. It alerted us to the fact that a sessile lesion with any grade of dysplasia could represent a carcinoma, be it with or without ulcerative colitis or Crohn’s disease. If the dysplastic lesion (low or high grade) penetrates the muscularis mucosae into the submucosa then there is invasive cancer.

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DALMs at colectomy were found to be carcinomas in 47% of cases in one systematic review [61].

large ALMs that develop exclusively in the left colon are of greater concern because that is where more cancers occur in ulcerative colitis.

The adenoma-like mass lesion The initial judgment that the endoscopist must make is whether a polypoid lesion in IBD is a sporadic adenoma, i.e. ALM, [62] or the more dreaded mass or lesion which may represent a cancer at the outsetathe DALM. In practical terms, if a sessile lesion looks like a common sporadic adenoma, and is removed in toto, without evidence of invasive cancer, then it is considered to be an ALM (sporadic adenoma). If it looks worrisome for cancer, bumpy surface, raised, hard, and/or fixated to underlying tissue [52], then it should be considered a DALM and colectomy recommended. If one is not sure, then endoscopic resection will be a staging technique in a sense. If invasive cancer into submucosa is present, then a colectomy is required. If, with endoscopic resection, an adenomatous lesion is superficial, is confined to the mucosa, and the specimen is removed intact with a clear submucosa, then the lesion could be considered an ALM. As indicated previously, if an adenoma is removed completely, its grade of dysplasia should not change the mode of follow-up. Even in sporadic adenomas in non-IBD patients, some smaller lesions may show high-grade dysplasia. Removal of an ALM in ulcerative colitis requires that biopsies taken within 1 cm (four quadrants) and throughout the colon have no evidence of dysplasia elsewhere. If dysplasia is present elsewhere, a colectomy should be performed. There is one other important factor in the patient with IBD and an ALM: age. A 30-year-old in whom ALMs start to grow should give cause for concern, with consideration of colectomy [63]. If, for some reason, continued surveillance is chosen, then the patient should be reviewed 6 months after the endoscopy that revealed the ALM to see if any lesions were missed, then every year thereafter, irrespective of how many years he or she has had ulcerative colitis. Studies have shown that when ALMs are removed with polypectomy the outcome is good, providing there is no dysplasia elsewhere [52,64]. The lesions are usually small, with one series reporting that the mean size of adenoma was 5.4 mm (range 2–12 mm) [52]. In another study, Paris grade 0-II accounted for 61% of all lesions, and median size was 8 mm (range 2–24 mm) [65]. Paris grade I adenoma accounted for 31% of the total and the median size was 15 mm (range 4–38 mm). All manner of removal techniques were used: biopsy, endoscopic resection, snare polypectomy, and endoscopic submucosal resection. The original thinking was that ALMs were sessile lesions that resemble ordinary adenomas, but if they occurred outside of the colitis zone they were less ominous. That distinction is not worth making in a patient with ulcerative colitis. At any given time we do not know the extent of the histological inflammation in the recent or more remote past. Small or

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Potentially confusing terminology 1 The term ALM–DALM is sometimes used instead of just ALM. 2 Some publications use the term “flat” neoplasia [65]. These lesions are not totally flat. They are endoscopically visible as raised lesions of one of two patterns: a like a coin on the mucosa, elevated, but with flat topography and not a discrete little bump; b like flat adenomas in non-IBD patients, in which case lesions are commonly raised at the edges with nonneoplastic crypts but the centers are depressed and contain the dysplastic (adenomatous) epithelium [66]. 3 Some have used flat dysplasia to refer to endoscopically invisible dysplasia. If the term “flat” is to be used, it should not refer to endoscopically invisible dysplasia.

Management and implications of lumps and bumps in ulcerative colitis and Crohn’s disease Pseudopolyps There is nothing “pseudo” about pseudopolyps. They are visible bumps and as such are polyps, but they are “pseudoadenomatous” polyps which occur from the inflammatory colitic process. When these become confluent over several centimeters or more, it is difficult to reliably exclude cancer or DALMs. Pseudopolyps that look nearly transparent and pale are more readily recognized as postinflammatory polyps. When pseudopolyps are confluent and extend over more than a few centimeters, it is important to inform the patient that a relative blind zone (for surveillance) is now present and to consider whether surveillance as usual will continue, or whether this should be used as a factor in the decision for colectomy [61]. Clearly, the clinician should make a recommendation for management after summarizing the options. In surveillance biopsy of pseudopolyp clusters, the aim is to look for lesions that stand out especially because of differences in color or shape.

How many isolated totally benign-appearing pale pseudopolyps should be biopsied at the time of colonoscopic biopsy surveillance in colitis? It is hard to resist biopsying a few, but if they are all isolated, pale, or semitranslucent without any “shape alerts” (irregular, nodular, depressed surface), then one should focus on the flat mucosa nearby, rather than on these lesions themselves, in the hunt for dysplasia.

Pedunculated adenomas Typical “balloon-on-a-string” adenomatous polyps in colitis either inside or outside of the inflammation zone can generally be regarded as sporadic adenomas. As for any adenoma

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in ulcerative colitis or Crohn’s disease, the surrounding mucosa should be biopsied, within a 1-cm zone (four quadrants) to see if there is associated endoscopically invisible dysplasia. The remainder of the examination should include the standard sites and biopsy numbers for dysplasia. The purpose is to be sure that an innocuous-looking polyp is not occurring in a dysplastic soil.

Dysplasia-associated lesions or masses Because cancer may already be present in 40–50% of these patients [61], it is accepted that the only way to reliably rule out cancer is with colectomy. Colectomy has been the standard when DALMs were found. The decision is clear-cut when, for example, a dysplastic adenomatous lesion is > 2 cm in diameter with irregular margins and a bumpy surface. Some endoscopists have performed endoscopic resection on large DALMs rather than recommend colectomy. In these cases, the area should be re-examined after 3 months to rebiopsy the site and near the site. One has to consider that removal of a DALM in the size range of ≥ 1 cm may actually be removing cancer [52]. We will need 5-year follow-up data to prove that endoscopic resection of DALMs is not associated with recurrences at or near the resection site, nor is it a harbinger of ALMs, DALMs, or cancer in the future.

Ink the polypectomy site Any worrisome lesions slated for removal should have the site marked with a surgical marker (injection of carbon particles into the submucosaasee Chapter 43) so that the area can be identified at the next endoscopy.

Summary If endoscopically invisible dysplasia (low or high grade) is found in association with an ALM, colectomy should be advised. Those who prefer to continue heightened surveillance for low-grade dysplasia should provide the patients with the data regarding cancer risk when low-grade dysplasia is found in colitis [61,67]. Colectomy is the treatment for DALMs. Anyone who undertakes to remove putative DALMs with endoscopic mucosal or submucosal resection is performing the equivalent of a cancer operation. This means that the specimen should come out in one piece otherwise the pathologist cannot rule out submucosal invasion. The rest of the colon and the mucosa within 1 cm of the resected lesion (four quadrant biopsies) should be negative for dysplasia. Excision of DALMs irrespective of the grade of dysplasia requires frequent surveillance. An adenoma occurring in a young patient (e.g., age 30 years) with IBD, should raise greater suspicion of colitis-related adenoma than a sporadic one. If this younger patient keeps producing small benign adenomas or is found to have concomitant dysplasia at any time, he or she should undergo

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colectomy. If the patient has a family history of colon adenomas or cancer then concern should also be heightened [68,69]. In conclusion, patients benefit when endoscopists understand how to maximize the yield from mucosal biopsies for patient management, from anywhere in the gut. I hope the next generation of endoscopists will come to be ardent believers in the “joy of biopsy,” will find great pathologists to partner and communicate with, and will be less timid and minimalist when it comes to biopsy, which after all is a highpowered extension of our eyes.

Acknowledgments I am indebted to the ongoing excellence of the gastrointestinal endoscopy unit nurses and technologists for guarding the quality of the biopsies and of the biopsy requisitions. Zhang Da and Li Hui run the gastrointestinal biopsy laboratory at the UCLA Center for Health Sciences. They consistently produce world-class biopsy sections for interpretation, thousands of gastrointestinal biopsies year after year. I am also grateful to Dr. Adrian Lunn, the co-coordinator of our weekly UCLA Gastrointestinal Pathology and its Clinical Implications conference. He enriches it with his verve, his knowledge, and his challenge of conventional wisdom when it is needed. And, finally, my gratitude is extended to Marilyn Weinstein, a software applications expert, who keeps me up to date with the latest techniques for reference databases, preparing photographs from the endoscope and microscope, and advice on minimalist slides.

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Colonoscopic Chromoendoscopy David P. Hurlstone Barnsley NHS Foundation Trust, Barnsley, UK

Introduction In the 1960s, colonoscopy was introduced as a means of directly visualizing the colon, and the development of its therapeutic capabilities soon followed. Technological advancements and a greater understanding of the pathogenesis of colorectal diseases have allowed colonoscopy to evolve into the “gold standard” colorectal imaging modality with the endoluminal resection of early neoplastic lesions now possible [1]. It is pivotal to colorectal screening programs aimed at the secondary prevention of colorectal cancer (CRC) [2–5]. In essence, the early detection of precancerous lesions: • facilitates targeted surveillance of an at-risk population; • permits early resection of neoplastic lesions, therefore decreasing the incidence of CRC; • allows less radical resection procedures to be performed, resulting in decreased morbidity compared with conventional surgery; • is cost-effective in the long-term management of an “at-risk” population. The clinical objective at colonoscopy is to detect and definitively treat potential neoplastic lesions and provide a valid “risk assessment” of the individual’s lifetime progression to CRC [6,7]. Hence, further surveillance colonoscopic procedures may serve to reduce the overall lifetime risk of CRC in an individual [6,8]. However, prior to discussing the apparent benefits and limitations of adjunctive endoscopic techniques such as chromoendoscopy, it is important to appreciate the current limitations associated with conventional white-light imaging in addition to the morphological and histopathologic distinct lesions where these techniques have proven to be of benefit.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Evidence to suggest failure in secondary colorectal cancer prevention using conventional “white-light” colonoscopy: the need to reappraise techniques Until recently, colorectal screening was based on Morson’s hypothesis that CRC develops from polypoid adenoma [9]. It is also known that the likelihood of malignant change is in direct correlation with the size of a polyp [10]. This morphological adenoma–carcinoma sequence is mirrored by genetic changes in the polypoid tissues [11]. These morphological premises, combined with histological findings, form the rationale behind the management and subsequent surveillance of patients with colorectal polyps. It has been shown, however, that colonoscopic polypectomy of exophytic lesions (Paris type 0-Ip/s) [12] alone results in a higher than expected incidence of CRC [6,13,14]. The National Polyp Study reported on the 6-year follow-up of 1418 patients after repeated colonoscopy to clear all polyps [13]. While this study did not incorporate a true control arm, the background age- and sex-specific incidence of CRC was used as a control group. These data led to the conclusion that the removal of all observed polyps prevented the development of 75% of carcinomas. The Veterans Affairs Study found that only 50% of CRCs were prevented, but not all patients underwent total colonoscopy [14]. These data suggest that the inability to prevent all subsequent CRC could potentially be attributable to flat (Paris 0-II) and depressed (Paris 0-IIc/III) colorectal lesions that were not detected or were inadequately treated in these studies. Because this “flat adenoma” concept has not found widespread acceptance in the Western hemisphere, there is a discrepancy in published data addressing the issues of the morphological and clinicopathologic features of atypical polyps and validation of new colonoscopic technologies and therapeutics in Western cohorts. Though well established in Japan, the concept of flat adenomas and early progression to cancer has so far failed to make a major impact on colonoscopic practice in the UK, Europe, and the US [3,15]. However, on reviewing the material from the National Polyp Study, it was found that, although one-third of all removed adenomas could be

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classified as “flat,” they were capable of total ablation and their presence did not affect the 90% reduction in the expected incidence of CRC [16]. Recently, however, studies performed in Western cohorts have corroborated many Japanese findings regarding the prevalence, anatomical location, and histopathologic characteristics of Paris type 0-II lesions, thereby stressing the requirement for adjunctive endoscopic techniques such as chromoscopy, which facilitates the in vivo detection and characterization of such lesions [17–28]. The Sheffield group in the UK reported a prospective study addressing the prevalence and clinicopathologic characteristics of flat and depressed colorectal lesions in a patient cohort at high risk of developing colorectal neoplasm [22]. Thirty-eight percent of all detected adenomas were flat lesions. This prevalence was similar to that reported by Rembacken et al. [27], but was higher than that reported by Saito et al. [17] and Wolber and Owen [28] in the US and Canada, respectively. Factors which may account for these differences include case mix, interobserver variation, endoscopic detection techniques (the use of high-magnification and chromoscopic colonoscopy), and variation in histopathologic reporting [29]. It was also shown that flat lesions exhibited a predilection for the development of high-grade dysplasia (HGD). Twenty-five percent of flat lesions in the UK series contained HGD or worse [22,27]. For lesions greater than 8 mm in diameter, a twofold increase in the presence of HGD as compared with exophytic adenomatous lesions of the same size was observed [27]. In addition, these data demonstrated a significant prevalence of early invasive carcinoma in lesions smaller than conventional exophytic lesions, corroborating the observation of many Japanese groups [30,31]. For example, in a study of 15 flat rectal cancer cases, Tada and colleagues [32] found that, despite all the tumors being less than 2 cm in diameter, nine of them had invaded the submucosa. However, the metastatic risk of flat and depressed lesions remains controversial. Shimoda and colleagues [33], in a single-center prospective cohort analysis, showed that, despite exophytic carcinomas being larger (mean 55 mm) than flat (Paris 0-II) carcinomas (mean 43 mm), the rate of lymphovenous infiltration was 32% vs. 77%, respectively. Furthermore, in this study, Paris type 0-II lesions were more likely to invade the submucosa [33]. As CRC survival rates depend on the extent of local invasion and on the presence or absence of metastatic disease [34–36], detection of malignancy at an earlier stage in CRC can significantly improve the prognosis ain early colon cancer a 5-year survival rate in excess of 97% has been reported [37].

Basic principles and practice of chromoendoscopy Chromoendoscopy is the use of dyes that may facilitate the improved detection and characterization of suspected gas-

Colonoscopic Chromoendoscopy

trointestinal lesions and is used as an adjunctive tool with high-magnification and confocal laser scanning endomicroscopic imaging [7,38–42]. This technique has been applied throughout all gastrointestinal segments that are accessible via the endoscope [12]. Although dyes have been used to stain the gastrointestinal mucosa for over 40 years, interest has been renewed by the rapid improvement of endoscopic image resolution [40]. Using high-magnification colonoscopy and colonic chromoscopy, it is now possible to resolve the mucosal topography and colonic crypt architecture previously described by using ex vivo stereomicroscopy (Table 35.1) [43]. Furthermore, there is a high correlation between in vivo highmagnification chromoscopic colonoscopy and ex vivo stereomicroscopy [23,34,43–45]. This technology, and Kudo’s modified crypt pattern classification [43] can provide an in vivo optical biopsy that can be used at the time of ongoing video colonoscopy to enhance diagnostic precision and facilitate subsequent therapeutic strategiesathe “optical biopsy” hypothesis [23,42,46,47]. Magnification colonoscopy is described in further detail in Chapter 31.

Stains used in chromoendoscopy Several stains are used in chromoendoscopy; they are categorized as either absorptive (vital) or contrast (reactive) [40]. It is essential that the endoscopist appreciates the differences between the two groups in order to utilize them most effectively. Indigo carmine is the chromoscopy agent used predominantly for identifying flat (Paris 0-II) colorectal lesions. It is a nontoxic, inexpensive agent, normally used at a concentration of 0.5%, although concentrations in the published literature vary from 0.2% to 2.0% [39,40]. To achieve optimal results, the mucosa must be cleaned with a normal saline or water lavage and, if required, a mucolytic employed to remove any adherent mucoid debris that can distort detailed endoscopic imaging. Subsequently, 3–5 mL of indigo carmine solution is “drawn up” in a 20-mL syringe, along with 20 mL of room air. The air and liquid mixture is “pushed” through the biopsy channel of the scope to create a spray effect on the colonic mucosa. Indigo carmine does not stain the colonic crypt dynamically, but pools in abnormal mucosal areas, delineating the detailed morphological anatomy. It provides an immediate result, contrasting mucosal irregularities and contour. However, disadvantages of using this method are that the dye can easily be displaced by lavage or diluted by intestinal secretions [48]. Dyes used in the vital or absorptive method stain the circumferential convex portions but not the grooves of the colonic mucosa [48]. Substances such as crystal violet and methylene blue stain the mucosa by being actively absorbed into the intestinal crypts [42]. The absorptive chromoscopy method provides enhanced imaging of the glandular crypt openings. Its advantage is that it is hard to remove the stain

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Table 35.1 The modified Kudo criteria for the in vivo assessment of colorectal crypt architecture. Pit type

Characteristics

Appearance using HMCC

I

Normal round pits

0.07 ± 0.02 mm

II

Stellar or papillary

0.09 ± 0.02 mm

IIIS

Tubular/round Smaller than pit type I

0.03 ± 0.01 mm

IIIL

Tubular/large

0.22 ± 0.09 mm

IV

Sulcus/gyrus

0.93 ± 0.32 mm

V(A)

Irregular arrangement and sizes of type IIIL, IIIS, and IV pit patterns

N/A

Pit size (mm)

HMCC, high-magnification and chromoscopic colonoscopy.

once it has been applied, so there is no realistic limitation in time parameter required to gain optimal imaging [42]. Prior to the application of crystal violet or methylene blue with a nontraumatic steel-tipped catheter, often used for the detailed magnification analysis of the types V and IIIS crypt patterns [1,49], the lesion requires preparation with a proteinase solution (N-acetylcysteine 2 mg/mL) to remove adherent mucus [7]. A “fixing” phase of between 2 and 3 min should then be observed, followed by a final saline mucosal wash prior to high-magnification views being obtained.

Chromoscopic techniques and the morphological classification of lesions Chromoscopy facilitates the detailed morphological assessment of suspected lesions at colonoscopy in addition to improving lesion detection [50]. The Paris workshop consensus guidelines now provide an endoscopic morphological reporting “framework,” which reduces ambiguity in reporting [12] (Table 35.1). Detailed morphological assessment requires

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the localized application of a contrast chromoscopic agent [51]. In the colorectum, this agent is usually indigo carmine 0.1–0.5% solution or methylene blue 0.1% locally applied to the lesion using the syringe push technique or via a transportal diffusion catheter [1]. Importantly, at this stage in morphological grading the macroscopic classification is made only from the gross chromoscopic appearance and should not be influenced by adjunctive clinical information or supplementary histopathologic findings (i.e., a lesion demonstrating type 0 morphology may subsequently be “upgraded” to an advanced neoplasm at histopathology using the postoperative tumor–node–metastasis (TNM) classification, or indeed “downgraded”) [12]. Hence, in most Japanese studies, superficial lesions are classified according to subtypes of type 0 morphology that can be grouped into three distinct types (0-I, polypoid; 0-II, nonpolypoid and nonexcavated; 0-III, nonpolypoid with a frank ulcer). Group I can again be segmentalized to include type 0-Ip (pedunculated) and 0-Is (sessile). Also, type 0-II lesions include three distinct subgroups (0-IIa, elevated; 0-IIb, completely flat with the mucosa; 0-IIc, slight depression without an ulcer crater). A

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depressed lesion with central elevation is classified as type 0-IIc + IIa, in contrast to a primary elevated lesion with a central depression at its apex (0-IIa + IIc), in the latter class the relative depression as a rule does not extend below the level of the adjacent normal mucosa. Such morphological differentiation, although complex, is clinically of the utmost importance, as type 0-IIa + IIc lesions have a poor prognosis with an increased risk of deep submucosal invasion and hence lymph node metastasis and associated lymphovenous involvement, and mucinous or poorly differentiated histopathologic features [34,36]. Detailed chromoscopic morphological assessment at index management can be further complemented by high-magnification chromoscopic colonocopy crypt architecture analysis or confocal endomicroscopy [1,52].

Pancolonic chromoendoscopy Orally administered indigo carmine capsules taken with bowel preparation have been studied and found to be suboptimal due to differential mucosal coverage of the right colon, with inadequate left-hemicolonic and rectal application [53]. Some groups advocate total colonic mucosal chromoendoscopy, in which the lumen of the colon is sprayed in a segmental fashion with indigo carmine delivered by a specially designed chromoscopy diffusion catheter (Olympus PW-5V1) [42,54]. After allowing the dye to settle for a few seconds, excess pools of indigo carmine are suctioned and the mucosa is inspected. Hurlstone and colleagues [55] and Brooker and colleagues [54] conducted the initial published randomized controlled trials of panmucosal chromoscopy for the detection of sporadic neoplastic lesions of the colorectum [54,55]. They were able to show a significant increase in the detection of diminutive neoplastic lesions. Panchromoscopy using indigo carmine also identified more patients with multiple adenomas. Predictably, the time taken for chromoscopy was twice that for conventional colonoscopy; however, in the study by Hurlstone and colleagues [55], the potential bias effects of lavage and differential extubation time were controlled. These studies and the evidence base for panchromoscopic colonoscopy are discussed in detail later in the chapter. Further evidence for the use of pancolonic chromoscopic colonoscopy in patients assuming a high lifetime risk of CRC has been demonstrated by Hurlstone and colleagues using a “back-to-back” conventional versus pancolonic chromoscopic study design [56]. In this study of 25 patients fulfilling modified Amsterdam criteria for hereditary nonpolyposis colorectal cancer screening, panchromoscopy identified significantly more adenomas than were found by conventional colonoscopy after dye (P = 0.001), and also detected a significantly higher number of right-hemicolonic flat adenomas (P = 0.004), suggesting that panchromoscopy is the endoscopist’s tool of choice in this patient cohort [56].

Colonoscopic Chromoendoscopy

Selective or “targeted” chromoendoscopy Using this technique, lesions are initially identified using conventional colonoscopic views, which enable polypoid lesions to be more easily recognized [57]. However, identifying flat lesions (Paris 0-II) is dependent on the endoscopist detecting subtle mucosal change such as paleness, loss of mucosal vascular net pattern, mucosal deformity, or mucosal erythema [58]. If suspicious mucosal changes are identified, the area should be washed with normal saline solution or water to clean the surface of any fecal residue or mucus, then the chromoscopic stain applied. Indigo carmine is used initially to delineate the contour and morphology of the lesion [59]. Enhanced views of a lesion’s pit pattern then require application of an absorptive stain such as crystal violet [39]. Crystal violet is the chromoscopic agent of choice for delineating the invasive (Kudo type V) crypt pattern, which suggests invasive submucosal disease [30,60]. In this group, lymph node metastasis occur in 15–30% of patients [20,36,61,62]. Direct surgical referral rather than attempted endoscopic resection is indicated in this group.

Level of evidence in support of routine chromoscopic colonoscopy: results from a systematic review Recently, a systematic evidence-based review has examined the potential benefit of chromoendoscopy for the detection of intraepithelial neoplastic lesions of the colorectum [50]. Studies in which participants were prospectively randomized to either chromoscopic or conventional endoscopic examination of the colorectum were incorporated. Four trials that randomized patients to conventional versus chromoscopic colonoscopy were included, equating to a total of 1009 participants. All trials examined the effect of chromoscopy on polyp detection.

Data analysis All the studies examined demonstrated a significant difference in favor of chromoscopy rather than conventional “white-light” imaging for all lesion detection outcomes [50]. The number of lesions (neoplastic and non-neoplastic) detected using chromoscopy as significantly greater for all studies, with a highly significant greater effect when the studies were combined [weighted mean difference (fixed) 0.77 confidence interval (CI) 0.52–1.01] [54,55,63,64].

Systematic data analysis: the evidence base for chromoendoscopy in clinical practice Despite the variability in design between these studies, there appears to be strong evidence that chromoscopy enhances the detection of neoplastic polyps in the colorectum [49]. The number of patients with at least one neoplastic lesion was increased by over 50% [54,55,63–66]. In addition, the number

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of patients with three or more lesions was more than doubled [50]. Although none of the studies carried out prospective follow-up of the participants, it can be extrapolated from other studies that these patients, particularly those with multiple neoplastic lesions, are at increased risk of developing CRC if these lesions are left in situ. The lesions that would be missed with conventional colonoscopy could therefore contribute to the interval cancer numbers on any polyp surveillance program [50]. However, the increase in neoplasms detected was sometimes confined to diminutive adenomas with low-grade dysplasia [54]. Since these lesions have limited clinical significance, the use of routine pancolonic chromoendoscopy has not become widely accepted.

In vivo staging of neoplastic colorectal lesions using chromoscopy and morphological analysis: expanding the role of chromoscopy beyond lesion detection alone Accurate in vivo staging is essential at colonoscopy, because Paris type 0-II CRCs which are limited to the submucosal (sm) layer 1 can be managed by endoscopic mucosal resection as the risk of lymphovenous invasion and lymph node metastases is < 5% [67–70]. Lesions with deeper vertical invasion (Paris criterion > 1000 μm) (i.e., stage T2 disease) are associated with an increased risk of lymph node metastases (10–15%) [36,71]. Endoscopic mucosal resection in this group is therefore undesirable due to a higher risk of perforation, noncurative excision, and untreated nodal disease [36]. Surgical excision is recommended in this group. The use of chromoscopic colonoscopy as an in vivo staging tool has been reported by Saitoh and colleagues [72]. In their analysis of Paris 0-IIc CRCs, combined video endoscopy and chromoscopy was used to characterize the essential endoscopic features favored by lesions with submucosal layer 1 and 2 invasion, which at the time of endoscopy may be used as a tool to guide the colonoscopists’ management [72]. Using specific criteria (expansion appearance, present; surface depression, deep; irregularity of depressed surface, uneven; and converging folds toward the tumor), Saitoh and colleagues [72] demonstrated that the sensitivity and specificity for determining submucosal layer 2 disease were both 90%. However, when 21 lesions showing intramucosal carcinoma were excluded from the analysis, specificity fell to 70% [72]. A recent prospective analysis of endoscopic morphological anticipation of submucosal invasion in Paris type 0-II lesions [34] using the Nagata subtype [73] analysis of the Kudo type V pit pattern [43] showed that a kappa coefficient of agreement between pit type V and histologically confirmed sm2 (deep submucosal) invasion was 0.51 (95% CI). Using pit types VN(B) and VN(C) as clinical indicators of invasive dis-

466

(a)

(b)

(c)

(d)

Figure 35.1 (a) High-definition white-light images of a proximal ascending colonic lesion. The lesion highlighted is distinguished by focal erythema and loss of vascular net architecture. (b) High-definition indigo carmine 0.4% targeted chromoscopy imaging of the lesion. The lesion is now clearly circumscribed and can be classified as a Paris 0-IIa (flat elevated) lesion in the absence of a fixed type 0-IIc component (central depression). (c) Postendoscopic mucosal resection en bloc resection image. The muscularis mucosa can be clearly visualized with no evident neoplastic crypt architecture at the horizontal or vertical resection margins. The lesion has been completely resected (R0 anticipated endoscopically). (d) High-magnification (100×) image shows a normal Kudo type I crypt pattern adjacent to the lesion with a predominant Kudo type IIIL pit pattern at the lesion’s apex, i.e., intraepithelial neoplasia positive. Endoscopic excision is indicated.

ease, 97% of lesions were correctly anticipated to have sm2+ invasion; however, specificity was low, at 50% (overall accuracy 78%) [34]. The clinical implication of these data is that these lesions tend to be overstaged, which may deprive some patients of the opportunity of curative local excision with endoscopic mucosal resection [67]. Similar problems have been encountered using the 7.5-MHz ultrasound probe in the staging of rectal carcinoma, with reported accuracy rates of 60–79% according to the T-stage system [74]. Highfrequency “mini-probe” ultrasound has been reported to have a high overall accuracy when used to determine submucosal invasion of Paris type 0-II lesions [44,75–77]. However, ultrasound imaging requires further training, is very expensive, and may prolong the procedure [44]. Clinical examples are shown in Figures 35.1–35.4.

Chromoscopy in the detection of intraepithelial neoplasia and colitis-associated cancer The management and clinical interpretation of dysplasia in the context of chronic ulcerative colitis is radically different

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(a)

(b)

(c)

Figure 35.2 (a) Conventional high-definition white-light views of a lateral-spreading tumour (granular type) positioned at the rectosigmoid junction. (b) Indigo carmine 0.4% chromoscopy has been applied to the rectosigmoid segment. The peripheral neoplastic pit pattern can now be fully defined and the circumfrential margins of the lesion identified. (c): High magnification (100×) image of the largest nodule (highlighted) shows a Kudo type IV crypt pattern.

to that of sporadic dysplastic lesions in the “normal” population [78,79]. In addition to the detection of sporadic neoplastic lesions of the colorectum, chromoscopic colonoscopy has now been described for the detection of intraepithelial neoplasia in chronic ulcerative colitis [42,80,81]. Either targeted chromoscopy or panchromoscopy using either methylene blue or indigo carmine is used to improve the diagnostic yield of intraepithelial neoplasia, i.e., to “unmask” circumscribed lesions during ongoing colonoscopy and enhance targeted biopsy accuracy or guide subsequent endoluminal resection strategy [51].

Chromoscopic intraepithelial neoplasia detection and characterization in chronic ulcerative colitis: current evidence-based practice As intraepithelial neoplasia and colitis-associated cancer can occur in macroscopically normal mucosa, random biopsies at 10-cm intervals throughout the colorectum are currently recommended during screening colonoscopy [82]. Historic-

(a)

(b)

Figure 35.3 (a) Endoscopic mucosal resection of the lesion shown in Fig. 35.2 is indicated (neoplastic noninvasive pit pattern). The lesion has been raised using a submucosal injection of 50% dextrose solution. The lesion has lifted in a symmetrical fashion with no tethering suggestive of submucosal deep invasion. (b) The postendoscopic mucosal resection appearance demonstrates visible muscularis mucosa. There are some

Colonoscopic Chromoendoscopy

ally, the probability of detecting neoplastic change was thought to be correlated with the numbers of biopsies taken [83–86]. However, recent data suggest that panchromoscopy using methylene blue with targeting of biopsies can improve the detection of Paris type 0-II and diminutive neoplastic lesions in chronic ulcerative colitis compared with conventional colonoscopic screening protocols alone [80,81,87,88]. Kiesslich and colleagues [42] showed that chromoscopy permitted a more accurate diagnosis of extent and inflammatory activity in chronic ulcerative colitis but also enhanced the detection of intraepithelial neoplasia and CRC in colitis (P = 0.0002 and P = 0.003, respectively), a finding subsequently validated by a further UK-based prospective single cohort trial [89]. In that randomized controlled study, intraepithelial neoplasia detection was increased more than threefold in the chromoendoscopy group than for patients undergoing “white-light” video endoscopy and conventional biopsy protocols (32 vs. 10 intraepithelial neoplasias). Hurlstone and colleagues [80,89,90] again validated these data using a selective indigo carmine chromoscopic technique. In this prospective study, 162 patients with long-standing established pancolitis (≥ 8 years) underwent colonoscopy using indigo carmine chromoscopy and were compared with a control group consisting of 162 disease-, age-, and sex-matched control subjects undergoing conventional screening colonoscopy. Targeted chromoscopy, rather than pancolorectal methylene blue chromoendoscopy, was used after detection of subtle changes in mucosal architecture such as fold convergence, air-induced deformation, innominate groove interruption, or focal color change prior to targeted intravital staining with indigo carmine and subsequent magnification imaging. In this study, chromoendoscopy with magnification assistance significantly increased the diagnostic yield for intraepithelial neoplasia compared with control subjects (more than fourfold). Intraepithelial neoplasia in flat mucosal change was observed in 37 lesions, of which only 31 were detected using chromoendoscopy and high-magnification and chromoscopic colonoscopy [80].

(c) prominent vessels shown in the vertical dissection plane which have been prophylactically coagulated using argon plasma. (c) Hematoxylin and eosin-stained fixed pathological specimen at high power. Features shown are of a high-grade villous adenoma without submucosal invasive characteristics. Curative resection was achieved endoscopically in this case.

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(a)

(b)

(c)

(d)

(e)

(f)

(a)

(b)

(c)

Rutter and colleagues [91] also found a strong trend that dysplasia detection was greatly increased following indigo carmine pancolorectal chromoscopy (P = 0.06), with a targeted biopsy protocol detecting dysplastic change in significantly more patients than a nontargeted protocol (P = 0.02). Furthermore, no dysplasia was detected in 2904 nontargeted biopsies, but a targeted biopsy protocol utilizing pancolonic indigo carmine chromoendoscopy [91] required fewer biopsies (157) yet detected nine dysplastic lesions, seven of which were visible only after indigo carmine application [91]. Clinical examples are shown in Figures 35.5–35.8. The largest prospective data set using chromoscopy and targeted biopsies has recently been published by the Sheffield group [80]. In this series, a total of 350 patients with longstanding pancolitis (≥ 8 years’ duration) underwent surveillance colonoscopy with quadratic biopsies taken at 10-cm incremental extubation intervals (in accordance British Society of Gastroenterology and American Society for Gastrointestinal Endoscopy protocols), but with the addition of targeted indigo carmine dye spray and biopsies of abnormal mucosal areas

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Figure 35.4 (a) Conventional high-definition white-light image of a descending colonic Paris class 0-Isp (subpendunculated) lesion. (b) Conventional nonmagnified image of the same lesion following application of 0.4% indigo carmine chromoscopy. The highlighted areas show the lesion segments at high magnification (100×). (c) High magnification (100×) image of the highlighted segment shows a Kudo type II pit pattern (non-neoplastic non-invasive crypt), (d) The basal polyp segment highlighted (top left) is shown at 100× magnification using 0.4% indigo carmine chromoscopy. The pit pattern is neoplastic, noninvasive (Kudo type IIIL). (e) High magnification (100×) image of the highlighted segment shows a tortous vascular net architecture in combination with a IIL crypt pattern (f) highly suggestive of a serrated adenoma component. Postendoscopic mucosal resection showed complete excision (R0) of a “collision” lesion, i.e., villous, tubular, serrated, and hyperplastic component polyp.

Figure 35.5 (a) Conventional white-light views of the distal descending colon in a patient with longstanding ulcerative colitis. There is focal erythema and subtle change in vascular net architecture compared with the surrounding mucosa. (b) Methylene blue 0.1% chromoscopy reveals an irregular raised nodule adjacent to a depressed mucosal area. (c) The adjacent mucosal depression is highlighted by a blue arrow.

following a saline flush of the area. These data were then compared with 350 historical control subjects matched for disease, duration, and extent, and who had undergone conventional colonoscopic surveillance. Importantly, more intraepithelial neoplasia lesions were detected in the chromoscopy group than in the control group [69 vs. 24 (P < 0.0001)]. Furthermore, the number of Paris type 0-II lesions detected with intraepithelial neoplasia was higher in the chromoscopy group than in the control group (P < 0.001). Twenty intraepithelial neoplasia lesions were detected in 12 950 biopsies taken using conventional colonoscopy (0.15%), compared with 49 detected in 622 biopsies (8%) in the chromoscopytargeted group; furthermore, of all the biopsies taken in the control group, only 18 (0.14%) yielded intraepithelial neoplasia. However, from the targeted biopsy group without chromoscopic imaging, the yield was modestly improved at 1.6% (6 out of 369). The total procedure time was significantly longer in the magnification chromoscopic group than in the control group (P < 0.02). These data suggest that chromoscopic colonoscopy is a valid tool for the detection

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(a)

(b)

Figure 35.6 (a and c) Confocal laser scanning endomicroscopic images using intravenous 10% fluorescence of the adjacent lesional mucosa. At 20 mm (a) and 80 mm (b) in the z-axis there is clear crypt architectural distortion suggesting adjacent flat dysplasia. Mucin depletion, gross loss in regular crypt architecture, and ridge-lined epithelium are present. (b) The circumscribed lesion has been imaged at 50 mm in the z-axis

Colonoscopic Chromoendoscopy

(c) usining confocal endomicroscopy. There is gross extravasation of fluorophore (whiteout field) with a central dilated, tortous capillary with red cells “stacked up,” i.e., the red cell stack sign of neoplasia. The lesion can be characterized in vivo as a Dysplasia-Associated Lesional Mass. Urgent referral for panproctocolectomy should be considered in this clinical scenario.

Figure 35.7 (a and c) High-power hematoxylin and eosin-stained image of the background mucosa shows abnormal crypt architecture compatible with chronic inflammatory bowel disease in addition to dysplastic crypt architecture (b) High-power hematoxylin and eosin-stained image of the circumscribed lesion shows high-grade dysplastic features with an invasive component. Histopathology confirms this lesion to be a dysplasia associated lesion mass and colectomy should be considered as the management of choice.

(a)

(b)

(c)

Figure 35.8 (a) High-definition white-light image of the distal sigmoid colon in a patient with chronic panulcerative colitis. There are florid neovascular changes but also a focus of focal pallor. (b) Narrow-band image of the segment shows the vascular architecture as brown tortuous streaks. The lesion is clearly defined as highlighted. (c) Indigo carmine 0.4% chromoscopy delineated the circumferential margin of the lesion. The lesion was a flat, de novo, intraepithelial neoplastic lesion (Paris class 0-IIb).

(a)

(b)

(c)

and in vivo classification of intraepithelial neoplasia in chronic ulcerative colitis. Chromoendoscopy has now been incorporated into the guidelines for chronic ulcerative colitis surveillance in the US (Crohn’s and Colitis Foundation of America Colon Cancer in IBD Study Group) and may prompt changes to the current screening guidelines endorsed by the British Society of Gastroenterology [82], which are labor-intensive, time-consuming, and have a low diagnostic yield.

Conclusion In this chapter, we have discussed the clinical applicability of chromoendoscopy for the detection, morphological assessment, and surface analysis of both sporadic intraepithelial neoplasia and CRC complicating chronic ulcerative colitis. We have shown that chromoscopy is a valid adjunctive

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tool to the endoscopist which, when utilized in centers with appropriate training and skill acquisition, can potentially improve the clinical outcome in selected patient cohorts undergoing colonoscopy. The technique is simple and likely to be cost-effective. However, ongoing training and education are mandatory prior to the clinical implementation of this technique in routine clinical practice.

Acknowledgments I would like to thank all the staff at Barnsley NHS Foundation Trust who made completion of this chapter possible. I would like to especially thank David and Cath for their extraordinary support, for which I am indebted.

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14 Muller AD, Sonnenberg A. Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case–control study of 32,702 veterans. Ann Intern Med 1995; 123: 904–10. 15 Bond JH. Small flat adenomas appear to have little clinical importance in Western countries. Gastrointest Endosc 1995; 42: 184– 7. 16 O’Brien MJ, Winawer SJ, Zauber AG, et al. Flat adenomas in the National Polyp Study: is there increased risk for high-grade dysplasia initially or during surveillance? Clin Gastroenterol Hepatol 2004; 2: 905–11. 17 Saito Y, Waxman I, West AB, et al. Prevalence and distinctive biological features of flat colorectal adenomas in a North American population. Gastroenterology 2001; 120: 1657– 65. 18 Kiesslich R, von Bergh M, Hahn M, Hermann G, Jung M. Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon. Endoscopy 2001; 33: 1001–6. 19 Colton CG, Sivak MVJ. Flat adenomas and cancers. Gastrointest Endosc 1995; 42: 182– 4. 20 Adachi M, Okinaga K, Muto T. Flat adenoma of the large bowel: re-evaluation with special reference to central depression. Dis Colon Rectum 2000; 43: 782–7. 21 Fujii T, Rembacken BJ, Dixon MF. Flat adenomas in the United Kingdom: are treatable cancers being missed? Endoscopy 1998; 30: 437– 43. 22 Hurlstone DP, Cross SS, Adam I, et al. A prospective clinicopathological and endoscopic evaluation of flat and depressed colorectal lesions in the UK. Am J Gastroenterol 2003; 98: 2543–9. 23 Hurlstone DP, Cross SS, Adam I, et al. Efficacy of high magnification chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum: a prospective analysis. Gut 2004; 53: 284– 90. 24 Jaramillo E, Watanabe M, Slezak P, Rubio C. Flat neoplastic lesions of the colon and rectum detected by high-resolution video endoscopy and chromoscopy. Gastrointest Endosc 1995; 42: 114– 22. 25 Kato S, Fujii T, Koba I, et al. Assessment of colorectal lesions using magnifying colonoscopy and mucosal dye spraying: can significant lesions be distinguished? Endoscopy 2001; 33: 306–10. 26 Lanspa SJ, Rouse J, Smyrk T, Watson P, Jenkins JX, Lynch HT. Epidemiologic characteristics of the flat adenoma of Muto. A prospective study. Dis Colon Rectum 1992; 35: 543–6. 27 Rembacken BJ, Fujii T, Cairns A, et al. Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 2000; 355: 1211–14. 28 Wolber RA, Owen DA. Flat adenoma of the colon. Hum Pathol 1991; 22: 70–4. 29 Willis J, Riddell RH. Biology versus terminology: East meets West in surgical pathology. Gastrointest Endosc 2003; 57: 369–76. 30 Kudo S, Hayashi S, Miura K, Takano M, Saito M, Kubuta Y. The clinicopathological features of flat and depressed type of early colorectal cancer [in Japanese with English abstract]. Stomach and Intestine 1989; 24: 317–29. 31 Matsumoto T, Iida M, Yao T, Fujishima M. Role of nonpolypoid neoplastic lesions in the pathogenesis of colorectal cancer. Dis Colon Rectum 1994; 37: 450– 5. 32 Tada S, Iida M, Matsumoto T, et al. Small flat cancer of the rectum: clinicopathological and endoscopic features. Gastrointest Endosc 1995; 42: 109–13.

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33 Shimoda T, Ikegami M, Fujisaki J, Matsui T, Aizawa S, Ishikawa E. Early colorectal carcinoma with special reference to its development de novo. Cancer 1989; 64: 1138– 46. 34 Hurlstone DP, Cross SS, Adam I, et al. Endoscopic morphological anticipation of submucosal invasion in flat and depressed colorectal lesions: clinical implications and subtype analysis of the Kudo type V pit pattern using high-magnification-chromoscopic colonoscopy. Colorectal Dis 2004; 6: 369–75. 35 NHS Executive. Guidance on Commisioning Cancer Services. Improving Outcomes in Colorectal Cancer. Wetherby ,UK: NHS Executive, 1997. 36 Kikuchi R, Takano M, Takagi K, et al. Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines. Dis Colon Rectum 1995; 38: 1286–95. 37 Moreaux J, Catala M. Carcinoma of the colon: long-term survival and prognosis after surgical treatment in a series of 798 patients. World J Surg 1987; 11: 804– 9. 38 Kudo S, Kashida H, Tamura T, et al. Colonoscopic diagnosis and management of nonpolypoid early colorectal cancer. World J Surg 2000; 24: 1081– 90. 39 Kudo S, Kashida H, Nakajima T, Tamura S, Nakajo K. Endoscopic diagnosis and treatment of early colorectal cancer. World J Surg 1997; 21: 694–701. 40 Kiesslich R, Jung M, DiSario JA, Galle PR, Neurath MF. Perspectives of chromo and magnifying endoscopy: how, how much, when, and whom should we stain? J Clin Gastroenterol 2004; 38: 7–13. 41 Hurlstone DP, Baraza W, Brown S, Thomson M, Tiffin N, Cross SS. In vivo real-time confocal laser scanning endomicroscopic colonoscopy for the detection and characterization of colorectal neoplasia. Br J Surg 2008; 95: 636– 45. 42 Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepitheial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003; 124: 880– 8. 43 Kudo S, Rubio CA, Teixeira CR, Kashida H, Kogure E. Pit pattern in colorectal neoplasia: endoscopic magnifying view. Endoscopy 2001; 33: 367–73. 44 Hurlstone DP, Brown S, Cross SS, Shorthouse AJ, Sanders DS. High magnification chromoscopic colonoscopy or high frequency 20 MHz mini probe endoscopic ultrasound staging for early colorectal neoplasia: a comparative prospective analysis. Gut 2005; 54: 1585– 9. 45 Fu KI, Sano Y, Kato S, et al. Chromoendoscopy using indigo carmine dye spraying with magnifying observation is the most reliable method for differential diagnosis between non-neoplastic and neoplastic colorectal lesions: a prospective study. Endoscopy 2004; 36: 1089– 93. 46 Tung SY, Wu CS, Su MY. Magnifying colonoscopy in differentiating neoplastic from nonneoplastic colorectal lesions. Am J Gastroenterol 2001; 96: 2628– 32. 47 Togashi K, Konishi F, Ishizuka T, Sato T, Senba S, Kanazawa K. Efficacy of magnifying endoscopy in the differential diagnosis of neoplastic and non-neoplastic polyps of the large bowel. Dis Colon Rectum 1999; 42: 1602– 8. 48 Hurlstone DP, Brown S, Cross SS. The role of flat and depressed colorectal lesions in colorectal carcinogenesis: new insights from clinicopathological findings in high-magnification chromoscopic colonoscopy. Histopathology 2003; 43: 413– 26.

Colonoscopic Chromoendoscopy

49 Fujii T, Nagata K, Saito Y. The correspondence of magnifying endoscopic diagnosis and pathological diagnosis. Stomach and Intestine 1999; 34: 1653– 64. 50 Brown SR, Baraza W, Hurlstone P. Chromoscopy versus conventional endoscopy for the detection of polyps in the colon and rectum. Cochrane Database Syst Rev 2007: CD006439. 51 Kiesslich R, Hoffman A, Neurath MF. Colonoscopy, tumors, and inflammatory bowel diseaseanew diagnostic methods. Endoscopy 2006; 38: 5–10. 52 Inoue H, Cho JY, Satodata H, et al. Development of virtual histology and virtual biopsy using laser-scanning confocal microscopy. Scand J Gastroenterol 2003; 237: 37– 9. 53 Mitooka H, Fujimori T, Ohno S, et al. Chromoscopy of the colon using indigo carmine dye with electrolyte lavage solution. Gastrointest Endosc 1992; 38: 373– 4. 54 Brooker JC, Saunders BP, Shah SG, et al. Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial. Gastrointest Endosc 2002; 56: 333– 8. 55 Hurlstone DP, Cross SS, Slater R, Sanders DS, Brown S. Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy. Gut 2004; 53: 376– 80. 56 Hurlstone DP, Karajeh M, Cross SS, et al. The role of highmagnification-chromoscopic-colonoscopy in hereditary nonpolyposis colorectal cancer screening: a prospective “back-to-back” endoscopic study. Am J Gastroenterol 2005; 100: 2167–73. 57 Hurlstone DP, Fujii T. Practical uses of chromoscopic colonoscopy. Gastrointest Clin N Am 2005; 15: 687–702. 58 Keisslich R, von Bergh M, Hahn M, Hermann G, Jung M. Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon. Endoscopy 2001; 33: 1001–3. 59 Kiesslich R, Jung M. Magnification endoscopy: does it improve mucosal surface analysis for the diagnosis of gastrointestinal neoplasias? Endoscopy 2002; 34: 819–22. 60 Kudo S, Tamure S, Nakajima T, et al. Depressed type of colorectal cancer. Endoscopy 1995; 27: 54–7. 61 Kudo S, Tamura S, Hirota S, et al. The problem of de novo colorectal carcinoma. Eur J Cancer 1995; 31: 1118–20. 62 Hurlstone DP, Brown SR, Cross SS, Shorthouse AJ, Sanders DS. High-magnification-chromoscopic-colonoscopy or high-frequency 20 MHz mini-probe endoscopic ultrasound staging for early colorectal neoplasia: a comparative prospective analysis. Gut 2005; 54: 1585– 89. 63 Lapalus MG, Helbert T, Napoleon B, Rey JF, Houcke P, Ponchon T. Does chromoendoscopy with structure enhancement improve the colonoscopic adenoma detection rate? Endoscopy 2006; 38: 444– 8. 64 Le Rhun M, Coron E, Parlier D, et al. High resolution colonoscopy with chromoscopy versus standard colonoscopy for the detection of colonic neoplasia: a randomized study. Clin Gastroenterol Hepatol 2006; 4: 349–54. 65 Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112: 24–8. 66 Hixson LJ, Fennerty MB, Sampliner RE, Garewal HS. Prospective blinded trial of the colonoscopic miss-rate of large colorectal polyps. Gastrointest Endosc 1991; 37: 125–7.

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67 Rembacken BJ, Gotoda T, Fujii T, Axon AT. Endoscopic mucosal resection. Endoscopy 2001; 33: 709–18. 68 Rembacken BJ, Fujii T, Kondo H. The recognition and endoscopic treatment of early gastric and colonic cancer. Best Pract Res Clin Gastroenterol 2001; 15: 317–36. 69 Riddell RH. Management of colonic dysplasia and adenomas. Monogr Pathol 1990: 356–75. 70 Sawada T, Hojo K, Moriya Y. Colonoscopic management of focal and early colorectal carcinoma. Baillieres Clin Gastroenterol 1989; 3: 627–45. 71 Tanaka S, Haruma K, Teixeira CR, et al. Endoscopic treatment of submucosal invasive colorectal carcinoma with special reference to risk factors for lymph node metastasis. J Gastroenterol 1995; 30: 710–17. 72 Saitoh Y, Obara T, Watari J, et al. Invasion depth diagnosis of depressed type early colorectal cancers by combined use of videoendoscopy and chromoendoscopy. Gastrointest Endosc 1998; 48: 362–70. 73 Nagata S, Tanaka S, Haruma K, et al. Pit pattern diagnosis of early colorectal carcinoma by magnifying colonoscopy: clinical and histological implications. Int J Oncol 2000; 16: 927– 34. 74 Hunerbein M, Schlag PM. 3D-endosonography for staging of rectal cancer. Ann Surg 1997; 225: 432– 38. 75 Hunerbein M, Totkas S, Bijan M, Ghadimi BM, Schlag PM. Preoperative evaluation of colorectal neoplasms by colonoscopic miniprobe ultrasonography. Ann Surg 2000; 232: 46–50. 76 Hunerbein M, Handke T, Ulmer C, Schlag PM. Impact of miniprobe ultrasonography on planning of minimal invasive surgery for gastric and colonic tumours. Surg Endosc 2004; 17: 615–19. 77 Hurlstone DP, Brown S, Cross SS, Shorthouse AJ, Sanders DS. Endoscopic ultrasound miniprobe staging of colorectal cancer: can management be modified? Endoscopy 2005; 37: 710–14. 78 Brostrom MO, Lofberg R, Ost A. Cancer surveillance of patients with longstanding ulcerative colitis: a clinical and endoscopical and histological study. Gut 1986; 27: 1408–13. 79 Goldmann H. Significance and detection of dysplasia in chronic colitis. Cancer 1996; 78: 2261–3. 80 Hurlstone DP, Sanders DS, Lobo AJ, McAlindon ME, Cross SS. Indigo carmine-assisted high-magnification chromoscopic colo-

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noscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy 2005; 37: 1186– 92. Hurlstone DP, McAlindon ME, Sanders DS, Koegh R, Lobo AJ, Cross SS. Further validation of high-magnification chromoscopiccolonoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2004; 126: 376– 8. Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004; 53(Suppl. 5): V1–16. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001; 48: 526–35. Lynch DA, Lobo AJ, Sobala GM, Dixon MF, Axon AT. Failure of colonoscopic surveillance in ulcerative colitis. Gut 1993; 34: 1075–80. Matheny R, Symmonds RE. The incidence of colon carcinoma complicating ulcerative colitis. Surg Clin North Am 1986; 66: 801–6. Morson BC. Dysplasia in ulcerative colitis. Scand J Gastroenterol Suppl 1983; 88(Suppl.): 36–8. Hurlstone DP, Sanders DS, Hunter MD, et al. Endoscopic mucosal resection for flat neoplasia in chronic ulcerative colitis: can we change the endoscopic management paradigm? Gut 2006; 56: 838– 46. Kiesslich R, Gotz M, Lammersdorf K. Chromoscopy guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis with reduced number of biopsies. Gastroenterology 2007; 132: 874– 82. Hurlstone D, Sanders D, McAlindon M, Thomson M, Cross S. High-magnification chromoscopic colonoscopy in ulcerative colitis: a valid tool for the in vivo optical biopsy and assessment of disease extent. Endoscopy 2006; 38: 1213–17. Hurlstone DP, Cross SS. Role of aberrant crypt foci detected using high-magnification chromoscopic colonoscopy in human colorectal carcinogenesis. J Gastroenterol Hepatol 2005; 20: 173– 81. Rutter MD, Saunders BP, Schofield G, Forbes A, Price AB, Talbot IC. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004; 53: 256–60.

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Optical Techniques for the Endoscopic Detection of Early Dysplastic Colonic Lesions Ralph S. DaCosta1, Brian C. Wilson1 & Norman E. Marcon2 1

Ontario Cancer Institute, University Health Network, Toronto, Canada St. Michael’s Hospital, Toronto, Canada

2

Introduction Colon cancer is associated with high morbidity and mortality rates as well as tremendous emotional and economic costs in the developed world. It is well accepted that most malignant colonic lesions arise in pre-existing adenomatous polyps. Japanese authors such as Kudo et al. [1] have theorized that some cancers arise de novo and present as small flat depressed lesions with high-grade dysplasia and indeed even in lesions ≤ 1 cm with invasion into the submucosa. Commonly, when patients present with clinical symptoms, malignant lesions are large enough to be detected by conventional endoscopic methods [i.e., white-light endoscopy (WLE) accompanied with multiple random biopsies] or even barium contrast radiology. However, at this point of detection, large and symptomatic tumors have typically reached an advanced stage, resulting in poor prognosis and significantly reduced possibility of cure. Because prognosis and ultimate survival are related to lesion size and stage (i.e., mural invasiveness and positive node status), the ideal scenario would be to detect lesions in their earliest premalignant form, before they have reached the point of incurability. The presumption in this is that outcomes such as survival and quality of life would be significantly enhanced by administering treatment while the lesion is still localized to the mucosa. Despite the reduction in the incidence of colon cancer in screened populations as a result of WLE plus polypectomy [2,3], the clinical effectiveness of this method remains suboptimal. Why is this? Removal of readily visible lesions that are adenomatous has been shown to reduce the incidence of colon cancer. The question arises whether small subtle

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

lesions (i.e., flat adenomas, flat-depressed adenomas) are missed because of inadequate preparation and/or lack of visual recognition by endoscopists who are not searching for these lesions carefully. Additionally, unless visibly obvious alterations in tissue topography (i.e., nodules, raised plaques, or changes in surface texture and color) are present, premalignant lesions may go undetected during routine endoscopic surveillance. In addition, using back-to-back colonoscopies, Hixon et al. [4] and Rex et al. [5] reported that even an experienced endoscopist could miss 15–24% of neoplastic polyps (< 1 cm), and up to 6% of larger polyps were overlooked at the time of colonoscopy. Bensen et al. [6] confirmed this significant colonoscopic miss rate for neoplastic and hyperplastic polyps. Possible explanations for the miss rate of lesions greater than 1 cm are multifactorial, including bowel preparation, anatomic situations (e.g., extensive diverticular disease), sharp angulated flexures, and prominent colonic folds (ribbing). Development of adjunctive endoscopic technology may reduce the inherent miss rate of lesions less than 1 cm in diameter which is associated with conventional WLE, and thereby reduce the long-term rates of occult colon cancer in this group of patients. Normal tissues undergo changes in phenotype and genotype as they progress through various distinct pathologic stages of dysplasia, toward invasive cancer [7]. Typically in the West, endoscopic surveillance is targeted at groups with premalignant disorders and associated higher risks for cancer, including those with Barrett’s esophagus, long-standing chronic ulcerative colitis, and familial adenomatous polyposis. These various high-risk groups are often subjected to poorly defined surveillance algorithms. The detection of small dysplastic lesions is largely dependent on the experience of the endoscopist and on the identification of subtle changes in mucosal topography. In the absence of these changes, the endoscopist detects dysplasia by relying upon strict protocols for multiple random biopsies (as in surveillance of Barrett’s and chronic ulcerative colitis). In addition, the extent and precise

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assessment of depth of invasion of the dysplastic lesion in the tissue is often not effectively determined with WLE [8]. An area of recent controversy has been the low reported incidence in the Western hemisphere of flat adenomas and small depressed carcinomas of the colon. Japanese authors have been describing these lesions for several years [9–12]. Some Western endoscopists suggest that this is a Japanese phenomenon. However, recent studies by Japanese endoscopists examining European and North American patients reported an incidence comparable with Japanese patients [13]. Why is this so? It would seem that an important factor is careful and thorough examination by an experienced endoscopist using chromoendoscopy in an adequately prepared bowel. The adjuvant use of dye spraying and magnification endoscopy can improve detection and differentiation, but tends to be time-consuming, labor-intensive, and not commonly used outside Japan [14]. It now seems to be accepted in most centers in the Western hemisphere that dye spraying with high-magnification colonoscopes improves the detection of diminutive lesions and their statuses (hyperplastic or adenomatous) [15]. However, a report by Le Rhun et al. [16] on a French cohort of patients did not confirm an overall increase in the detection of colonic adenomas in a population at increased risk of neoplasia. An area of intense interest and study has been the search for an optical technology that would facilitate the rapid scanning of wide areas of colonic mucosa, which highlights diminutive and potentially occult lesions. To have reliable technology that could avoid the use of dye spraying and yet allow accurate interrogation of the mucosal surface would be a great benefit. Currently, the two technologies that are best suited to this are autofluorescence and narrow-band imaging (NBI). Although these may seem to be competitive methodologies, it is only a matter of time, engineering costs, and commercial competitiveness until all these technologies coalesce into a single endoscopic platformathe “superscope.” For a thorough review of NBI, the reader is referred to Chapter 38. Recent large-scale studies in both the UK and the US have begun to point clearly at an increased detection rate of small, flat adenomas in the colon. Tweedle et al. [17] found that the prevalence of small, flat cancers in 1763 surgically resected colorectal cancer specimens in the UK concurs with that of Japanese studies. Furthermore, in a landmark publication of a cross-sectional study involving 1819 patients undergoing elective colonoscopy, Soetikno et al. [18] determined that nonpolypoid (flat and depressed) colorectal neoplasms were relatively common lesions diagnosed during routine colonoscopy and had a greater association with carcinoma than did polypoid neoplasms, irrespective of size. Several such studies highlight a critical urgency to detect these dangerous flat lesions, with growing evidence to support the theory of accelerated carcinogenesis in flat cancers [17–19]. Nevertheless, detection of flat adenomas with white-light imaging alone can be difficult. Distinguishing between hyper-

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plastic and adenomatous polyps is often not possible. The ability to detect and identify dysplasia within fields of transformed mucosa remains another major clinical problem. For example, identifying flat dysplastic lesions and which polyps are dysplastic in the background of long-standing chronic inactive ulcerative colitis is highly problematic. Furthermore, for in vivo differential diagnosis between benign hyperplastic polyps and adenomatous polyps of the same size and shape, diagnosis continues to be challenging. For instance, if there is a high degree of confidence that the polyp is adenomatous and less than 5 mm, it must be removed. On the other hand, lesions shown to be hyperplastic can be left behind, therefore saving time and processing costs. However, recent controversy has arisen in the speculation that a small subset of hyperplastic polyps undergoes transformation to a form of atypical hyperplastic polyp (termed sessile serrated adenoma) then to a dysplastic serrated polyp and, ultimately, to a serrated carcinoma [20]. In recent years, the sessile serrated adenoma has become recognized as the precursor lesion to a group of sporadic colorectal carcinomas characterized by morphologic and molecular features distinct from conventional adenomas. Such findings have challenged the long-held paradigm that all colorectal carcinomas arise through the traditional adenoma–carcinoma sequence. These lesions present a major challenge for the early detection and management of colorectal cancer, which is no longer regarded as a homogeneous entity [21,22]. Such clinical issues provide strong motivation to develop and evaluate alternative but complementary endoscopic systems with higher sensitivities and specificities for detection and definition of diminutive or occult lesions in the colon. The search for such alternative diagnostic techniques has led to the evaluation of several optically based methods with the potential to revolutionize modern endoscopy. This chapter will provide a basic overview of the most developed emerging optical technologies, which offer a promising means of improving the endoscopic detection and identification of early dysplastic lesions. They include fluorescence spectroscopy and imaging, Raman spectroscopy, light scattering spectroscopy, optical coherence tomography, and immunophotodetection. The reader is directed to Chapter 39 for a thorough and up-to-date assessment of the clinical use of confocal fluorescence microendoscopic technologies in the colon.

Basic tissue optics Tissues are a complex mixture of biomolecules. The interaction of light in tissue can be described by two fundamental properties by which photons and these biomolecules interact: scattering and absorption (Figure 36.1). When light of a particular wavelength illuminates the tissue surface, some of the light is specularly reflected from the surface. The remainder enters the tissue and can be either scattered by tissue

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Blue (430 nm) excitation Specular Reflectance

Mucosa

longer wavelengths penetrate deeper into tissue. In biological tissues, scattering dominates absorption.

Wavelength Incident Light

Diffuse Reflectance

Red (630 nm) emission

Fluorescence Emission

Scattering

Absorption Fluorophore Chromophore Submucosa

Muscularis propria

Figure 36.1 Schematic illustrating the light interaction with tissue.

microstructures or absorbed by tissue molecules. These photons are scattered diffusely throughout the tissue. Those scattered close to the tissue surface can be re-emitted from the surface, without a change in wavelength (diffuse reflectance). A small number of excitation photons are scattered several times and escape from the tissue surface, while a smaller number escape the surface after only a single scattering event. Conventional white-light endoscopic images are composed of light which is both specularly and diffusely reflected by tissues. Most photons are scattered deep into the tissue and are eventually absorbed by tissue components. Photons can be absorbed by chromophores and fluorophores. The former comprise molecules that do not emit photons once an excitation photon is absorbed, while the latter will emit a photon of longer wavelength, producing fluorescence (see Tissue autofluorescence). The depth of penetration of incident light is dependent on wavelength, because wavelength-dependent tissue absorption and scattering determine the extent to which light will be attenuated. The probability of a photon being absorbed per unit distance through tissue for a given wavelength can be described as the absorption coefficient (μa). This value is determined by the concentration and absorption crosssection of the various chromophores in the tissue. In tissue, the dominant absorber is hemoglobin, which exhibits characteristic absorption peaks at 420, 540, and 580 nm. Tissue scattering is dependent on the wavelength of the incident light and on the size and relative index of refraction of the scattering particles. Scattering for a particular wavelength can be characterized by the scattering coefficient (μs), which describes the probability of a scattering event per unit path length traveled by the photon in the tissue. Longer wavelengths are scattered less than shorter ones; therefore,

Tissue autofluorescence Illumination of tissue with ultraviolet or short wavelength visible light from a laser source or a filtered lamp results in the emission of fluorescence light of a longer wavelength by endogenous tissue molecules (fluorophores). This “autofluorescence” arises mainly from: • components of connective tissues (i.e., collagen, elastin); • cellular metabolism-related co-enzymes (i.e., reduced nicotinamide adenine dinucleotide, flavin adenine dinucleotide, flavin mononucleotide); • aromatic amino acids (i.e., tryptophan, tyrosine, phenylalanine); • by-products of heme biosynthesis (i.e., porphyrins); • lipopigments (i.e., lipofuscin, ceroids). Different excitation wavelengths activate different groups of fluorophores, each of which emits at a range of different wavelengths (Table 36.1). Tissues also contain molecules (chromophores) that absorb light without re-emission of fluorescence. The absorption is strongly wavelength dependent and may significantly modify the in vivo fluorescence spectrum observed at the tissue surface. The main chromophore in gastrointestinal tissues in the visible wavelength range is hemoglobin. While each fluorophore has a distinct fluorescence spectrum, tissues have a mixture of several fluorophores that occur in different concentrations and at different depths. Thus, the mucosa, submucosa, and muscularis propria have distinct fluorophore compositions, so that the fluorescence measured at the luminal surface consists of contributions from the fluorophores in the various layers. Given that the excitation and fluorescence emission bands are often broad, relatively featureless, and overlap with one another, identifying individual fluorophores in a given tissue spectrum is difficult. Changes in the intrinsic fluorescence of the tissue layers with disease are due to alterations in their biochemical composition (metabolic state, microenvironment). In addition, changes in the layer thicknesses or in the blood content contribute to the differences seen between normal and diseased tissues. Thus, the use of autofluorescence to detect early cancers or premalignant colonic lesions is dependent on changes in one or more of the following factors: 1 the tissue architecture (mucosal thickening or loss of layered structures); 2 the light absorption and scattering properties of each layer, particularly hemoglobin in the capillary networks; 3 the distribution and concentration of fluorophores in the different layers; 4 the biochemical microenvironment of the tissue which may alter the fluorescence yield or spectral shape;

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Table 36.1 Some known endogenous fluorophores and wavelengths of the excitation and emission maxima. Tissue fluorophore

Biological source

Wavelength of maximum fluorescence excitation (nm)

Wavelength of maximum fluorescence emission (nm)

Collagen Elastin Tryptophan NADH FAD Porphyrins

Connective tissues Connective tissues Amino acids Metabolic cofactor Metabolic cofactor By-product of heme biosynthesis; bacterial flora Lipopigment granules; age related; lipid oxidation products

330 350 280 340 450 405

390 420 350 450 515 635

340–395

430–460, 540–640

Ceroid, lipofuscin

FAD, flavin adenine dinucleotide; NADH, nicotinamide adenine dinucleotide.

5 the metabolic status of the tissue (e.g., changes in nicotinamide adenine dinucleotide fluorescence have been used to differentiate normal from dysplastic tissues) [23]. Therefore, tissue autofluorescence is sensitive to alterations in tissue morphology and biochemistry resulting from malignant transformation, although the details are complex. The degree to which disease changes in vivo fluorescence measurements is significantly wavelength dependent, as the excitation and emission wavelengths that are used determine the dominant fluorophores involved. For example, tissue proteins, composed of amino acids, are autofluorescent only when excited by ultraviolet wavelengths, while all other fluorophores (mentioned above) are excited by visible wavelengths. In general, as the wavelength increases, so too does the penetration depth of the excitation light. Thus, there may be one or more optimal excitation or emission wavelength bands, depending on the anatomic site or application. Unfortunately, for each type of tissue the optimal excitation and emission wavelengths are not known a priori, and must be determined from ex vivo tissue samples. This has the advantage of providing detailed fluorescence spectroscopy and microscopy, but the accuracy of the results must be considered carefully as the measured spectra may be altered by loss of blood or metabolic changes [24]. The measurement of excitation and emission matrices of known and suspected biological fluorophores in solution may also help identify the optimal excitation and emission wavelength bands for tissue autofluorescence spectroscopy (see Figure 36.3) [25]. In general, the macroscopic autofluorescence features of colonic tissue are well characterized. In contrast, the autofluorescence characteristics of colonic epithelial cells have only recently been investigated in detail by our group [26]. Because preneoplastic lesions usually develop intramucosally

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and are thought to be of epithelial origin [7], understanding the contribution of epithelial cells to in vivo autofluorescence is important. We used short-term primary cell cultures from endoscopic biopsies to investigate autofluorescence at the glandular (crypt) and cellular levels. The differences between normal, hyperplastic, and adenomatous epithelial cells were attributable in part to differences in the intrinsic numbers of mitochondria and lysosomes. The detection of colonic epithelial fluorescence alone might be sufficient to differentiate benign (hyperplastic) from preneoplastic and neoplastic (adenomatous) colonic intramucosal lesions during in vivo fluorescence endoscopy. Importantly, highly orange/red autofluorescent intracellular granules found only in dysplastic epithelial cells may serve as a potential biomarker [26].

Clinical evaluation of fluorescence endoscopy The field of fluorescence diagnostics in gastrointestinal endoscopy is about 15 years old, and in vivo fluorescence imaging has only begun to appear within the last 10 years. Wagnieres et al. [27] presented a critical status report on the detection and characterization of premalignant or malignant lesions using in vivo fluorescence spectroscopy and imaging. AnderssonEngels et al. [28] described the current use of in vivo fluorescence imaging, while Bigio et al. [29] discussed point fluorescence measurements. DuVall et al. [30] reviewed tissue autofluorescence in the gastrointestinal tract and showed the first preliminary endoscopic images using an in vivo prototype fluorescence imaging system. DaCosta et al. [31] reviewed both clinical and mechanistic features of autofluorescence imaging and spectroscopy in the gastrointestinal tract. Stepp

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Figure 36.3 Example of in vivo fluorescence spectra of normal colon, hyperplastic and dysplastic polyps, and colon adenocarcinoma. Note the significant differences in fluorescence intensity and spectral line shapes between normal and abnormal tissue types. Normal human colon A

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et al. [32] studied the basic principles, techniques, and clinical experience of fluorescence endoscopy in gastrointestinal diseases, while Bohorfoush [33] presented various spectroscopic techniques being investigated in the gastrointestinal tract. Richards-Kortum and Sevick-Muraca [34] described, from a more quantitative perspective, several optical spectroscopies, including fluorescence. Two primary endoscopic methods (point spectroscopy and imaging) have been developed to investigate tissue fluorescence in vivo. Fluorescence point spectroscopy involves the use of an optical fiber probe, typically 0.5–1 mm in diameter, passed down the accessory channel of the endoscope and placed in gentle contact with the mucosa (Figure 36.2). The majority of such probes are multifibered; typically a central delivery fiber illuminates the tissue while a surrounding circular array of sensor fibers collects the emitted fluorescence. Optical filters block the detection of scattered excitation light. The fluorescence light is separated into component colors by a spectrograph, and displayed as a fluorescence intensity versus wavelength line curve (Figure 36.3). Various mathematical procedures can be applied to these spectra to extract diagnostic information, such as taking the ratio of two or more fluorescence emission wavelength bands [4,35–38]. However, the effectiveness of some diagnostic algorithms in distinguishing dysplastic from normal tissue can be significantly altered by background inflammation, such as in Barrett’s esophagus and chronic long-standing ulcerative colitis. Thus, different algorithms may have to be evaluated for different segments of the gastrointestinal tract. During endoscopy, fluorescence point measurements must be guided by white-light viewing of the luminal surface. However, the actual spectral measurement must be performed with the white light temporarily turned off to minimize background saturation. Fluorescence point spectroscopy was the first approach used for tissue autofluorescence diagnosis in the gastrointestinal tract. The majority of the initial studies involved tissue analysis ex vivo, particularly in the colon. In 1990, Kapadia et al. [39] used 325 nm excitation on excised human colon tissues, applying multivariate linear regression analysis of the fluorescence emission band (350–600 nm), and demon-

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Figure 36.4 Examples of average autofluorescence excitation and emission matrices: three-dimensional plots of ex vivo tissues from normal human colon and adenomatous polyps collected using a surface contact fiberoptic probe. Fluorescence intensity is represented by a color scale bar. Both tissue excitation and emission matrices were measured using an optical fiber probe with a central illumination fiber and several radially displaced collection fibers, placed in contact with the tissue surface. Comparison of regions A and C show significant increase in ultraviolet-excited endogenous fluorophores (i.e., amino acids) appearing as red color in the adenomatous polyp (attributed to increased cellular proliferation rate), while comparison of regions B and D show increased visible light-induced fluorescence, appearing as a green color, from connective tissues (i.e., collagen, elastin) in the normal tissue.

strated accuracies of 100%, 94%, and 100% for identifying normal, hyperplastic, and adenomatous tissues, respectively. Richards-Kortum et al. [40] measured excitation and emission matrices in ex vivo colon polyps, using a range of excitation and emission wavelengths (Figure 36.4). The optimal excitation wavelengths for discrimination of normal colon from adenomatous polyps were around 330, 370, and 430 nm.

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Subsequently, they showed that adenomas could be accurately identified against normal colon using 370 nm excitation light and emission wavelengths of 404, 480, and 680 nm. Schomacker et al. [41] confirmed that fluorescence spectroscopy could be used to differentiate between non-neoplastic and neoplastic colon tissues with a sensitivity of 80% and a specificity of 92%. In the first in vivo study reported by Cothren et al. [42], using 370 nm excitation and a two-dimensional scatterplot of fluorescence intensities at two emission wavelengths (460 and 680 nm), allowed differentiation of adenomas and nonadenomatous colon tissue in 97% of cases. The first blinded study of in vivo fluorescence spectroscopy of the colon reported by this group identified the correct tissue type in 88% of cases, with a sensitivity of 90% and a specificity of 95% [43]. To date, several algorithms have been developed in order to exploit spectral differences in autofluorescence intensities and line shapes between normal and premalignant lesions [41,43–45]. Determining the contribution of specific fluorophores and the degree of light absorption due to hemoglobin has also been attempted [34,39,41,44,46,47]. However, these studies were performed mostly using ultraviolet excitation, with limited success reported for visible excitation wavelengths. Most of the in vivo point spectroscopy studies to date have involved steady-state fluorescence measurements. An alternative approach based on time-resolved autofluorescence spectroscopy was demonstrated when Mycek et al. [48] reported the in vivo results of 17 patients with 24 polyps (13 adenomatous, 11 nonadenomatous). Time-resolved fluorescence spectra represent the decay of fluorescence intensity at a given emission wavelength as a function of time after a brief pulse of excitation light (∼ 10 ns). The decay time of colonic adenomas was shorter than that of nonadenomas, yielding an 85% differential sensitivity, 91% specificity, 92% positive predictive value, and 83% negative predictive value. Further evaluations are required to confirm the clinical effectiveness of this technique in other anatomic sites. To date, all point spectroscopy-based studies in the colon have involved readily visible polypoid lesions, and no occult lesions have been described. Although there is a high degree of accuracy in differentiating nondysplastic from dysplastic obvious lesions, this technology is not likely to be efficient or useful in the screening of mucosal abnormalities in largecapacity organs such as the colon and the stomach. Despite the potential benefits and relative technical simplicity of fluorescence point spectroscopy, a major drawback is the sampling of only a small volume of tissue (∼ 1–3 mm3) immediately beneath the probe tip (Figure 36.5). The technique is, therefore, dependent on placing the probe in the right spot (as for biopsy). Targeted sampling is possible only with visible lesions [49]. This inherently limits the sensitivity and specificity. In addition, unlike imaging, the information lacks the contextual information that is often needed to distinguish abnormal

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Figure 36.5 Schematic diagram illustrating relative depths of interrogation into tissue for various optical techniques used in point spectroscopy and imaging modes.

from surrounding normal tissues. Instruments that can produce real-time high-resolution fluorescence images have become available [30,37,50], enabling in vivo light-induced fluorescence endoscopy (LIFE) imaging to evaluate large areas of the mucosal surface in parallel with WLE examinations. WLE images are images of diffuse reflectance, which occur when the different wavelength components of a broad-band (white) light source are multiply scattered and absorbed into tissue. In WLE, the applied and reflected light photons have the same wavelength, as opposed to fluorescence, in which the emitted fluorescence photons are longer in wavelength than the (near) monochromatic excitation light. Since the scattering and, in particular, absorption are wavelength dependent, the different wavelengths effectively interrogate the tissue to different depths (red being the most and blue the least penetrating). The resultant image provides the endoscopist with visual clues to the tissue surface topography and underlying patterns of vasculature.

Light-induced fluorescence endoscopy LIFE images are formed using only selected emission wavelength bands. There are various ways in which this can be achieved [27]. For example, the emission bands can be selected using special optical filters, and then detected by separate cameras to form the final displayed fluorescence image. Thus, real-time false color fluorescence images of the tissue can be viewed, with switching between this and WLE. Such a system for LIFE imaging has been demonstrated successfully for the bronchus [51,52] as a screening tool for dysplasia and carcinoma in high-risk patients, leading to a commercial system (LIFE-Lung®, Xillix Technologies Corporation, Richmond, Canada). This instrument uses blue light excitation, with separate red and green fluorescence imaging channels. Detection rates of moderate- or high-grade bronchial dysplasia increased by 171% using LIFE in combination with WLE in

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Figure 36.6 Schematic block diagram of a typical in vivo fluorescence endoscopic imaging system.

comparison with white-light bronchoscopy alone, with only a 22% decrease in specificity. Currently, prototype imaging systems derived from the original Xillix LIFE-Lung device are being evaluated for gastrointestinal endoscopy, and initial clinical feasibility studies have been reported by ourselves and other collaborating groups [37,38,50,53]. The most recent prototype, the Xillix LIFE-GI imaging system, uses a detachable camera module, which connects to the optical head of a conventional fiberoptic endoscope. The module contains two individual light-sensitive cameras, one for the green (490–530 nm) and one for the red (590–700 nm) fluorescence. The digital images are combined to produce a real-time false color image, in which normal tissue generally appears green and abnormal tissue appears red (Figure 36.6). The ratio of red to green fluorescence is standardized over normal mucosa. The current system can be rapidly switched (∼ 4 s) between WLE and LIFE, allowing surveyance of wide areas of the mucosa. Sensitivity and specificity values are determined by correlating the positive (“red” fluorescence) and negative (“green” fluorescence) images with histological diagnosis of corresponding biopsy samples. In a preliminary study, we demonstrated detection of atypia or higher-grade lesions in the colon, with a sensitivity and specificity of 87% and 79%, respectively. In the noninflamed colon, we have not had any false negatives [30]. False-positive lesions have been seen with acute colitis (Figure 36.7a), both infective and idiopathic. Other investigators have also observed this in both animal and human studies [54]. Large pedunculated polyps of the colon are usually easily detected on WLE. However, distinguishing between growths of the same gross size and shape (e.g., an adenomatous polyp and a submucosal lipoma) may be difficult. Figure 36.7b shows an example of a submucosal lipoma which was (true) negative on fluorescence, and this can be compared with Figure 36.7c which shows another large pedunculated polyp which was (true) positive under fluorescence and was adenomatous. Diminutive polyps are extremely common and,

because the endoscopist cannot usually determine whether they are hyperplastic or adenomatous, these polyps are removed or fulgurated. This can be labor-intensive. The LIFE imaging system can potentially differentiate between hyperplastic polyps, which have no known malignant potential, and adenomatous polyps, which should be removed. Figure 36.7d shows a true-negative LIFE image of a hyperplastic polyp, while Figure 36.7e shows a similar appearing diminutive lesion with positive fluorescence, which is shown histologically to be an adenoma. While these lesions were detected as nodules by WLE, the real challenge would be to detect dysplastic lesions not recognized by obvious topographic irregularity. For screening, there is considerable interest in the detection of flat diminutive adenomas with dye spraying, using either conventional WLE or magnification. According to Saitoh et al. [55], dye spraying with conventional endoscopy increased the yield of flat adenomas by 66%. For comparison, we detected ∼ 60% of the flat dysplastic lesions that were occult to WLE, without the use of dye spraying. This is an area that requires careful study with multicenter trials [56]. However, the design of future comparative trials will be difficult because the use of dye spraying interferes with the simultaneous detection of fluorescence. Figure 36.7f demonstrates the fluorescence detection of a WLE-occult area of high-grade dysplasia in a 34-year-old woman with a strong family history of colon, breast, and ovarian cancer. This lesion was not seen on WLE. Detection of lesions of this type would be the ultimate goal of any effective screening program and would have a significant impact on survival. One target group for cancer screening is patients with longstanding ulcerative colitis and Crohn’s disease. An example of a dysplasia-associated lesion or mass (DALM) is shown in Figure 36.7g: the lesion can be seen as a “brick-red” color against a blue–green normal background. Villous adenomas are often sessile and can cover several square centimeters of colonic mucosa. Their removal usually involves the submucosal injection of saline prior to polypectomy. Complete removal is sometimes problematic, and recurrence is sometimes difficult to identify with WLE in the area of the scar. However, fluorescence endoscopy facilitates this satisfactorily. Figure 36.7h shows an example of a recurrence (red area) in a postpolypectomy scar.

Factors involved in fluorescence imaging systems Despite progress in the clinical evaluation of prototype fluorescence imaging systems, understanding of the microscopic, biochemical, and molecular origins of tissue autofluorescence and its variation with anatomic site and disease stage remains incomplete. Such understanding contributes to optimum design of clinical instruments and development of more accurate algorithms for image analysis and display. Many factors are involved. The excitation wavelength determines which endogenous fluorophores are excited in the tissue, while the content and

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Figure 36.7 Examples of white-light endoscopy, in vivo light-induced fluorescence endoscopy (LIFE) imaging, and corresponding histology of a variety of colonic lesions: (a) ulcerative colitis; (b) submucosal lipoma; (c) pedunculated adenomatous polyp; (d) hyperplastic polyp; (e) adenomatous polyp; (f) high-grade dysplasia occult to white-light endoscopy in patient with a strong familial cancer history; (g) dysplastic-associated lesion or mass; and (h) postpolypectomy recurrence (dysplasia).

distribution of these fluorophores and of absorbing chromophores vary with anatomic site, depth in tissue, and disease stage. The illumination and fluorescence detection geometry are also relevant (e.g., with wide-beam illumination, used for imaging, the detected fluorescence light has greater contribution from tissues at greater depth than with point spectroscopy). Figure 36.8 shows the difference between the measured in vivo spectra of gastrointestinal tissues with narrow (point geometry) and wide-beam imaging (illumination). In the latter, the dips in the spectra are due to differential light absorption by blood in the submucosal capillary network. This effect is lacking in the shallow depth “sampling” of contact point spectroscopy.

Neoplasia and fluorescence imaging In terms of the optimal excitation wavelengths, a number of different values have been used for in vivo point spectroscopy:

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325 nm [39], 370 nm [42,43], 410 nm [57,58], and 437 nm [30]. The data indicate some advantages of using ultraviolet wavelengths for separating normal and abnormal colon tissues according to their intrinsic fluorescence spectra, but there is concern for possible mutagenic effects associated with ultraviolet light. The tissue optical absorption properties are also strongly wavelength dependent, so that differences in tissue composition and architecture (i.e., squamous versus Barrett’s mucosa, and normal colonic mucosa versus adenomatous mucosa) mean that the effectiveness of any one excitation wavelength may vary with anatomic site. To date, there have been a number of ex vivo studies, particularly in the colon, attempting to characterize and explain the effects of neoplastic changes on clinical measurements [24,35,39,41,44,46,47,59–61]. Most studies have been with ultraviolet excitation. Currently, it is believed that gross changes in tissue morphology and changes in mucosal blood content

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Currently, there is an intense effort to investigate the in vivo characterization of normal and dysplastic gastrointestinal tissues using fluorescence imaging and point spectroscopy devices adjunctively to WLE. Which system will prove to be the most clinically suitable remains to be determined, as each is associated with certain pros and cons. In general, for a given excitation wavelength, point spectroscopy allows the collection of a fluorescence spectrum, with a wide emission bandwidth, which may be repeated for other excitation wavelengths. A major disadvantage of WLE-guided fluorescence point spectroscopy as a diagnostic tool in the gastrointestinal tract is the necessity to perform many “point” measurements over a large tissue area. This not only is time-consuming, but also has the potential of missing lesions occult to WLE. Fluorescence imaging techniques usually allow large areas of tissue to be examined “instantaneously” but with limited spectral information. The effectiveness of these techniques is dependent on whether a localized measurement is interpretable alone, or whether surrounding tissue is required for contextual comparison to detect and localize a lesion [27]. Point spectroscopy has aided the design of fluorescence imaging devices and helped identify the optimal excitation and emission wavelengths. Imaging systems have been able to detect unknown lesions over large tissue surfaces, to perform lesion localization and margin identification quickly, and to monitor therapy. Additionally, fluorescence imaging has been used in conjunction with nonfluorescent pharmacologic agents to improve lesion visualization. For example, Namihisa et al. [63] investigated the use of noradrenaline (20 mL of 0.02%) sprayed onto

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thickening and are topographically similar to surrounding mucosa. This suggests that there are important tissue changes other than, or in addition to, changes in gross morphology. These have been shown to include alterations in the local blood volume, tissue metabolic activity, and relative fluorophore concentrations [24,46,59,60]. Detailed studies of the composition, organization, and content of colonic tissue fluorophores and chromophores at different stages of malignant transformation have been performed [62]. Most mechanistic studies to date have concentrated on distinguishing normal from adenomatous polyps in the colon, yet the important question of differentiating between hyperplastic and dysplastic lesions has only been touched upon [62]. In addition, until recently, mechanistic studies have been limited to characterizing the macroscopic autofluorescence features of ex vivo (frozen and unstained) tissue sections from biopsy or resection (Figure 36.9). Additionally, high-resolution confocal fluorescence microscopy with special immunohistological staining and transmission electron microscopy were used in combination to characterize the cellular origins of whole living colonic crypts, and isolated living colonic epithelial cells derived from primary cell cultures of normal, premalignant, and malignant gastrointestinal tissues [26].

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Figure 36.8 The effect of blood absorption on measured in vivo autofluorescence spectra (with 442 nm excitation). Spectra corresponding to normal colon, hyperplastic, dysplastic, and adenocarcinoma tissues were measured in (a) point geometry (central delivery and surrounding collection fibers in contact with the tissue surface); and (b) imaging geometry (with wide field illumination of the tissue surface and the spectral measurement made at the central point). Note the significant differences in spectral fluorescence intensity and line shapes between point and imaging geometries.

are significant contributors to the differences in fluorescence intensity and spectral shape seen between normal and adenomatous polyps [24,41,44,46,47,59,61]. For example, thickening of the mucosa leads to an overall decrease in the fluorescence intensity and a loss of green fluorescence relative to red. These changes are due primarily to reduction of the excitation light intensity reaching the submucosa and preferential absorption of the shorter wavelength components of the emitted fluorescence, respectively. However, LIFE imaging in vivo has also been able to differentiate between hyperplastic and adenomatous polyps of the same gross size and shape, and to detect flat adenomas that have no marked mucosal

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the gastric lesions of seven patients with gastric cancer, who were imaged with conventional WLE and LIFE-GI imaging before and after spraying. They concluded that this method improved the visualization of the lesion boundary with LIFE-GI imaging because the normal mucosa became paler than the tumor after spraying noradrenaline. Whether this method is applicable to colonic imaging is a subject of current investigation. Early experience with clinical fluorescence imaging systems showed that autofluorescence from endogenous porphyrins in fecal bacteria and bile salts interfered with image interpretation. For example, porphyrin fluorescence appeared a bright “scarlet” red against the deeper “brick-red” color of an adenomatous polyp (Figure 36.10). This issue has now been resolved with the modification of camera systems.

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In the setting of acute colitis or long-standing chronic inflammatory bowel disease, the presence of inflamed mucosa results in nondysplastic fluorescence (i.e., false positives) (Figure 36.7a). However, this is also a problem that is encountered in the interpretation of random biopsies read by experienced gastrointestinal pathologists attempting to diagnose dysplasia against the background of inflammation. Owing to background inflammation, which can be confounding even to the pathologist, it is recommended that patients with longstanding chronic inflammatory bowel disease undergo their surveillance colonoscopy when the disease is quiescent and inactive. Under these circumstances it is possible to identify dysplastic lesions with the LIFE imaging system. See Figure 36.7g, which shows a classic sessile DALM lesion that appears brick-red against the blue–green background.

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Figure 36.10 Example of in vivo white-light endoscopy and light-induced fluorescence endoscopy (autofluorescence) images of an adenomatous polyp. Note the “brick-red” fluorescence of the polyp against a cyancolored normal background, and the bright areas of endogenous porphyrin (arrow) fluorescence caused by residual feces at the edge of the polyp.

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In a recent prospective study by our group, we used the latest clinical prototype fluorescence imaging device called Onco-LIFE® (Xillix Technologies Corporation, Richmond, Canada) to examine 63 patients for whom colonoscopy was indicated for colon cancer screening or surveillance [64]. Segmental examination of the colon during withdrawal was carried out using white light followed by fluorescence light colonoscopy. Lesions missed at white-light examination were recorded as false negatives. White-light colonoscopy was able to detect 101 positive lesions, and 18 additional adenomas were identified only at fluorescence examination. The addition of fluorescence imaging resulted in an increased adenoma detection rate of 17.8% (18 out of 101), which included diminutive and flat adenomatous lesions. The accuracy of endoscopic diagnosis for dysplastic lesions improved from 58% to 72%, and for hyperplastic lesions from 62% to 73%, with the use of white light plus fluorescence. The sensitivity (detection and correct endoscopic diagnosis) using white light plus fluorescence was 80.7% compared with 58.0% (or approximately 20%) for white light only, yielding a relative sensitivity of 1.39. In the noninflamed colon, we had no false negatives. False-positive lesions have been seen with acute colitis, both infective and idiopathic. A more recent publication reported the use of autofluorescence endoscopy for detection of colonic dysplastic polyps. McCallum et al. [65] reported a study of 107 patients in which each patient was assessed by autofluorescence and whitelight colonoscopy. An autofluorescence intensity ratio was calculated for each polyp to background for a total of 75 polyps (54 adenomatous and 21 hyperplastic). Colorectal adenomas had a significantly higher intensity ratio than hyperplastic polyps: adenoma (3.54, 2.54–5.00) versus hyperplastic (1.60, 1.30–2.24) (P = 0.0001). When using an intensity ratio cut-off value of 2.3, autofluorescence endoscopy had a sensitivity of 85% and a specificity of 81% for distinguishing adenomatous from hyperplastic polyps. Diminutive polyps are extremely common and, because the endoscopist cannot usually determine whether these are hyperplastic or adenomatous, are removed or fulgurated. This can be labor-intensive. The OncoLIFE imaging system was able to differentiate between hyperplastic polyps, which have no known malignant potential, and adenomatous polyps, which should be removed. Detection of lesions of this type is the ultimate goal of any effective screening program and could have a significant impact on survival. These studies support the increased accuracy and usefulness of autofluorescence in improved detection and enhanced visual distinction between hyperplastic and adenomatous polyps. However, it should be noted that both these studies used fiberoptic-based fluorescence technology. New prototype systems with higher resolution using video endoscopes are currently being developed, and should soon be commercially available (e.g., the XCF-Q240FAI, Olympus Medical Systems).

Exogenous photosensitizer-induced fluorescence Exogenous fluorescent drugs, or prodrugs that induce fluorescence, offer an alternative for fluorescence diagnosis, and to date clinical studies have largely exploited the selective localization in neoplastic tissue of photosensitizers used in photodynamic therapy, many of which are also inherently fluorescent. Examples include hematoporphyrin derivative, tetra(m-hydroxyphenyl)chlorin, chlorine e6, phthalocyanines, benzoporphyrin derivative, Photofrin II, and tin etiopurpurin. There are several advantages to using drug-induced fluorescence: 1 The fluorescent signal is strong compared with autofluorescence, resulting in simpler and cheaper instrumentation. 2 The optimum excitation and emission wavelengths are known a priori, which allows for subtraction of the “background” tissue autofluorescence. However, diagnostic effectiveness of drug-induced fluorescence is dependent on the degree of selective localization of the drug within premalignant lesions, and the procedures must be performed at the optimum time for the drug pharmacokinetics, which may vary from patient to patient and from tissue to tissue. The use of fluorescent drugs also involves extra costs and regulatory issues and, although much lower drug doses are needed for diagnosis than are typically used therapeutically, another concern may be cutaneous photosensitization. The compound 5-aminolevulinic acid (ALA) has shown promise in obtaining good fluorescence contrast between normal and neoplastic tissues. It is well established in many in vitro and in vivo systems that administering ALA to excess results in elevated endogenous synthesis of protoporphyrin IX (PpIX) via the heme biosynthesis pathway [66,67]. PpIX is a fluorescent photosensitizer which has a distinct red fluorescence emission between 625 and 725 nm. Since the PpIX is endogenously generated, there is often a high degree of tissue specificity, with particular localization in the mucosal layer of internal hollow organs, such as the lung [68], bladder [69], and gastrointestinal tract [70]. Although not well understood, in general, PpIX appears to accumulate preferentially or be generated in malignant tissues. However, contradictory results have been reported in in vitro studies of the differential synthesis of ALA-induced PpIX in tumor and normal epithelial cells [71]. Moreover, in vivo results have demonstrated significant variation in PpIX fluorescence from lesion to lesion in the same patient [67] and a strong dependence on the anatomic site [72]. Imbalances in concentrations of endogenous iron, porphobilinogen deaminase, or in ferrochelatase, an enzyme involved in conversion of PpIX to heme, are considered possible reasons for increased tumor cell production of PpIX [73]. ALA has shown rapid metabolic

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breakdown [74], with few side-effects, and a short duration of skin photosensitivity [75]. Chemical modification of ALA (e.g., ALA esters) has shown some promise in increasing tissue penetration [76]. Additionally, administration of exogenous compounds such as desferrioxamine [36], an iron chelator that inhibits conversion of PpIX to heme by ferrochelatase, may enhance PpIX accumulation, thereby allowing lower ALA doses. However, the optimal ALA dose and time delay before fluorescence detection remains an issue [77]. ALA-induced PpIX fluorescence can be detected in vivo using both point spectroscopy and fluorescence imaging, although imaging is the preferred method. In a study by Eker et al. [78] in 41 patients, the spectra from 32 adenomas, 68 normal sites, and 14 hyperplastic polyps were obtained with a fluorescence point spectroscopy system. Twenty-one of the patients had been given a low dose of ALA before the examination. Light of 337, 405, or 436 nm wavelength was used as excitation. This group found that 337 nm excitation, 100% sensitivity, and 96% specificity were obtained between normal mucosa and adenomas, while 77% of the hyperplastic polyps were classified as non-neoplastic. Interestingly, when exciting with 405 and 436 nm, the possibility of distinguishing different types of tissue was considerably better in the ALA patients than in the non-ALA ones. Messmann et al. [77], using the D-Light system (Stortz, Germany), previously used to image drug-induced fluorescence in the bladder, lung, and esophagus, studied six patients with colonic disease, one with ulcerative colitis, and two with rectal polyps. This nonlaser light source is based on a 300-W xenon short arc lamp, which delivers high-intensity light into a fiberoptic light guide. The system is capable of delivering broad-spectrum white light as well as filtered blue light (380– 440 nm) for excitation of PpIX in tissues. The endoscopist can switch between either mode using a footswitch or a camera-mounted button. Fluorescence is detected by a charge-coupled device camera with special fluorescence filters which reduce interference from reflected blue excitation light. With this instrument, Messmann et al. [77] also demonstrated that active inflammation was associated with a high false-positive rate related to background inflammation.

Clinical evaluation of exogenous fluorescenceinducing drugs To date, several key reports have been published on the clinical effectiveness of prodrugs, such as ALA, in detecting preneoplastic gastrointestinal lesions. The majority of these reports have been on Barrett’s esophagus, for which the results of its ability to detect dysplasia are controversial. The number of reports on the in vivo use of subtherapeutic doses of ALA in the colon are limited. Messmann et al. [54] reported an experimental ulcerative colitis rat model in which ALA–PpIX fluorescence (ultraviolet excitation; intravenous administration of ALA at 25–200 mg/kg body weight; visualization 1– 4 h later) was used to enhance the detection

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of low-grade dysplastic lesions. The best results were obtained with 75 mg/kg ALA, for which dysplasia (low grade and high grade) was detected with a sensitivity of 92%, although the specificity was disappointing at 35%. Focal lesions as small as five abnormal crypts were observed in ex vivo tissue samples, which is a significant finding, as aberrant crypts are thought to be the earliest precursors to dysplastic lesions in the colon [14,79]. The major limitation of this study was that ulcerative colitis also showed appreciable concentrations of PpIX, resulting in high false-positive rates, although identification of low-grade dysplasia against an active colitis background may be difficult even for the skilled pathologist using biopsied tissues [80]. Lowering the ALA dose increased the specificity, with a notable decrease in the false-positive rate, although at the price of reduced sensitivity, which may have been due, in part, to the use of the unaided eye for detecting the fluorescence. Messman et al. [77] suggested improving the technique by topical administration of the ALA, by optimizing the time period between drug administration and fluorescence observation, and by attempting to detect high-grade dysplasia in quiescent colitis. An alternative may be to keep the ALA dose low and increase the detection sensitivity (e.g., using a highsensitivity imaging system; see below) [81]. Regarding the use of exogenous photosensitizers, such as ALA, the detection of dysplasia in a background of chronic ulcerative colitis is fraught with methodological issues related to background inflammation, which is associated with high sensitivity and low specificity. The role of these agents in the detection of subtle areas of dysplasia which are occult to WLE in routine colonoscopic screening has not been evaluated, but will likely be hampered by issues of methodologies, expense, and potential toxicity [77]. For use in the colon, local administration of ALA has been investigated in animal models for tumor detection [82]. The aim of this study was to detect cancer in the rat colon before macroscopic visibility. Multifocal colon carcinomas were induced by carcinogen. Local photosensitization with ALA was performed by lavage. Using green (514 nm) excitation light, red fluorescence (635 nm) was detected with the naked eye using a filter (< 515 nm) to block the reflected excitation light. A total of 99 macroscopically visible carcinomas and four macroscopically visible dysplasias were examined, and fluorescence diagnosis detected 16 additional carcinomas and 41 additional dysplasias. The first study to examine colon PpIX distributions microscopically was reported by Regula et al. [83], who evaluated 18 patients with colorectal, duodenal, and esophageal tumors after oral administration of 30–60 mg/kg ALA for photodynamic therapy. Biopsies of tumor and adjacent normal mucosa were taken over a 1- to 72-h interval. These specimens were examined by quantitative fluorescence microscopy for assessment of sensitization with PpIX, and showed glandular localization of ALA-induced PpIX. Additionally, 10 patients were given a second dose of ALA a few weeks later and their tumors were treated with red

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(628 nm) excitation light. With 30 mg/kg ALA, the highest fluorescence values were detected in the duodenum and esophagus, and the lowest in the large bowel. Doubling the ALA dose in patients with colorectal tumors improved the PpIX sensitization ratio in tumor and normal mucosa. Furthermore, treated patients showed superficial mucosal necrosis in the areas exposed to laser light. This study also documented two patients with mild skin photosensitivity reactions and five with mild nausea and vomiting. Furthermore, the optimal mode of ALA administration (oral versus systemic) and the associated pharmacokinetics were studied by van den Boogert et al. [84]. In this study, after 200 mg/kg ALA administration, either orally or intravenously, the ALA-induced PpIX production and biodistribution was examined in ex vivo tissue and serum samples in 21 rats (six control rats). At 1, 2, 3, 4, 6, 12, and 24 h after ALA administration, ALA and porphyrin concentrations were measured in 18 tissues and fluids. This study showed that in situ synthesis of porphyrins rather than enterohepatic circulation contributes to the PpIX accumulation, while confocal laser scanning microscopy shows selective porphyrin fluorescence in epithelial layers. Moreover, peak levels and total production of porphyrins were found to be equal after oral and intravenous ALA administration. The conclusions of this study were that administration of 200 mg/kg ALA resulted in accumulation of PpIX 1– 6 h after administration in all tissues except muscle, fat, skin, and brain, and that understanding the time–concentration relationship would be helpful in selecting dosages, routes of administration, and timing of ALA photodynamic therapy. Is there a future for the use of this technique in colonic disease? Currently, the literature does not support the view that ALA will be useful in the colon; however, new ongoing research into modified versions of ALA may change this. Chemical modification of ALA into its more lipophilic esters seems to be promising to overcome these problems [85]. ALA–PpIX fluorescence has also been studied in a variety of other organs, such as Barrett’s esophagus [77], the bladder [76], the oral cavity [87], and the brain [88]. Peng et al. [71] have reviewed the use of ALA for photodynamic therapy, while Marcus et al. [89] have summarized both the clinical and the preclinical development of ALA as a fluorescence diagnostic agent. Recently, Mayinger et al. [90] published a pilot study in which they combined the use of fluorescence video endoscopy with a tissue-localizing photosensitizer precursor called hexaminolevulinate in 12 patients with colorectal lesions. Hexaminolevulinate was applied locally by enema in two concentrations (0.8 and 1.6 mmol/L). The examination was conducted either 30 or 60 min after rectal administration of the sensitizer, using a special light source capable of delivering either white or blue excitation light. Blue-light illumination of the tissue surface produced red fluorescence, which was detected via a prototype fluorescence video colonoscope.

Biopsies were taken from suspicious areas found with white or blue light. Using histological findings as the gold standard, 52 out of 53 of the premalignant/malignant lesions showed red fluorescence under the photodynamic diagnosis examination, while 38 out of 53 were detected with WLE alone. Thus, fluorescence imaging with hexaminolevulinate showed 28% more polyps than did WLE imaging. The greatest fluorescence intensity in precancerous lesions was found with retention for 60 min of 500 mL of 1.6 mmol of hexaminolevulinate. To date, the use of exogenous prodrugs, such as ALA and hexaminolevulinate, has had no clinical impact on the colon. However, groups continue to explore the use of such agents to improve detection and differentiation of dysplastic lesions. Further studies will continue to investigate the complementary aspects of exogenous fluorescent compounds and fluorescent imaging systems with conventional endoscopy. Their use in everyday endoscopic practice will be influenced by extra costs, regulatory approval, possible drug-related toxicities, and overall cost-effectiveness as part of a screening program.

Raman spectroscopy The Raman effect is the inelastic scattering of light by molecules. It is named after Chandrasekar Raman, who discovered it and, indeed, won the Nobel Prize for physics in 1930. Raman spectroscopy has been evaluated as a means of obtaining detailed information about the molecular composition of tissue. Unlike fluorescence and reflectance spectra, Raman spectra are “molecule specific” and offer much narrower spectral features from signals obtained as deep as 500 μm from the tissue surface. However, because the Raman effect comprises a very small fraction (about 1 in 107) of the incident photons, it is more difficult to implement than fluorescence. Raman signals are much weaker than autofluorescence, and they can be masked by the broad-band fluorescence background. In addition, specially designed optical fiber probes are required to minimize the fluorescence and Raman signals generated in the probe itself. Most light photons are scattered in tissue without a change in energy or wavelength (elastic scattering, which is responsible for diffuse reflectance) in WLE. The Raman effect is an inelastic process in which the scattered photon’s energy is changed, and this Raman scattering light is shifted to a lower frequency, i.e., longer wavelength. The molecular information contained in the Raman emission spectrum can be extracted by using a spectral analyzer, yielding a fingerprintlike signature for the tissue sample. Since molecular bonds possess a unique pattern of Raman spectral peaks, the molecular composition of a tissue sample can be determined. Raman spectroscopy is sensitive to a wide range of specific biomolecules such as proteins, lipids, and nucleic acids. As the onset of cancer is accompanied by changes in biochemical

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composition, Raman scattering offers a potentially powerful diagnostic technique. Generally, near-infrared light (∼ 700–1300 nm) has been used for in vivo Raman spectroscopy; it penetrates deeply into tissue, and near-infrared excitation minimizes tissue fluorescence compared with visible light. It is also possible to use ultraviolet light to induce Raman spectra. This has the advantage of producing tissue autofluorescence that is well separated from the detected Raman spectral bands. By using optical filters, unwanted background fluorescence can be reduced. Also, in ultraviolet resonance Raman spectroscopy, certain Raman spectral bands can be appreciably amplified using excitation light corresponding to a particular absorption band. However, compared with near infrared, ultraviolet light does not penetrate deeply into tissues and is potentially mutagenic, thereby limiting its use clinically. In a paper by Shim et al. [91], potential artifacts in Raman spectroscopy were determined due to handling of ex vivo tissue samples collected from biopsy. It was concluded that tissue samples should be immediately frozen and, prior to Raman spectroscopy, the tissue should be acclimatized at room temperature in phosphate-buffered saline and immersed in it during spectroscopic examination. This study demonstrated that Raman spectroscopy and microscopy could be performed on biopsied tissues. Using a specially designed optical probe, ex vivo spectra were able to differentiate dysplasia from intestinalized dysplasia in esophageal biopsies with a sensitivity of 77% and a specificity of 93%. More recently, Chowdary et al. [92] reported the use of Raman spectroscopy with 785 nm excitation light to discriminate between ex vivo normal and malignant colonic tissues. Spectral data were analyzed by principal components analysis and revealed the presence of specific biomolecules in malignant tissues such as protein (stronger amide III and I), lipids [1100, 1300 cm−1], and DNA [1340, 1470 cm−1] versus those seen in normal tissue. This method produced an unambiguous objective discrimination for rapid and objective decision-making for biopsy.

in contact with the tissue surface. Background signals were suppressed and the light collection efficiency was optimized [95]. Spectra were obtained with good signal-to-noise ratio in ∼ 5 s. The effects on the spectra of varying the pressure of the probe tip on the tissue and the probe–tissue angle were insignificant. The spectra from normal and diseased tissues revealed only subtle differences. For example, initial ex vivo studies on Barrett’s esophagus samples (207 nondysplastic, 53 dysplastic) demonstrated slight differences in spectral line shapes in the 1100–1800/cm range, but no specific prominent changes in peak intensity or position. Sophisticated computational techniques such as principal component analysis and artificial neural networks are being investigated that have the advantage of analyzing the full Raman spectrum and, hence, the full diagnostic content, in order to distinguish subtle spectral differences among these spectra. One type of neural network analysis differentiated esophageal dysplasia from metaplasia with a sensitivity of 77% and a specificity of 93%. These diagnostic algorithms are being refined to improve upon these results and, furthermore, to give the best discriminating power in classifying the various dysplastic grades (low versus high). Once optimized, these algorithms can be used in a prospective fashion to assess the potential of Raman spectroscopy for Barrett’s tissue differentiation. Moreover, the recent demonstration of the feasibility of obtaining in vivo Raman spectra of the gastrointestinal tract (Figure 36.11) is a critical step in initiating systematic clinical trials to determine the diagnostic accuracy of Raman spectroscopy in Barrett’s esophagus. With respect to studies in the colon, Molckovsky et al. [96] have reported studies on the use of Raman spectroscopy for differentiation between normal colon and hyperplastic and adenomatous polyps. Here, in vivo Raman spectra, collected with specially designed Raman probes, have been subjected to a variety of spectral analysis algorithms (i.e., artificial neural networks and principal component analysis) to determine the optimal diagnostic values. Furthermore, this group has begun work on characterizing the microdistribution of Raman

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CH2 twist Amide I

d{CH2}

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Intensity (a.u.)

Several investigators have used different configurations to acquire in vivo Raman spectra, but there are few reports for the gastrointestinal tract [93]. Moreover, the majority of studies to date have evaluated in vivo Raman spectroscopy in Barrett’s esophagus, with a very limited number of reports on Raman spectroscopy of the colon. Recently, Shim and Wilson [94] designed and built a near-infrared fiberoptic device for in vivo Raman spectroscopy measurements, and reported the first in vivo Raman spectra of human gastrointestinal tissues measured during routine clinical endoscopy with acceptable signal-to-noise ratio and short collection times. This was achieved by using an optically filtered fiberoptic probe (∼ 2-mm diameter), capable of “beam steering,” which was passed through the endoscope instrument channel and placed

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Figure 36.11 Typical example of Raman spectra collected in vivo from normal colon. Note the peak assignment of specific molecular bonds. (Data courtesy of Dr. Louis Michel Wong Kee Song, Mayo Clinic, Rochester, MN, USA.)

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emitting sources in colonic tissues using ex vivo-based Raman microscopy. Similarly, Widjaja et al. [97] reported the use of near-infrared Raman spectroscopy of ex vivo colonic tissues (105 colonic tissue specimens from 59 patients comprising 41 normal, 18 hyperplastic polyps, and 46 adenocarcinomas) combined with a powerful support vector machine technique (a supervised learning algorithm) as a potential means of providing an effective and accurate diagnostic schema for cancer diagnosis in the colon. Such important studies may contribute to a better understanding of the mechanisms involved in determining which Raman scattering differentiates normal from abnormal gastrointestinal tissues. Although Raman microscopic imaging can be performed ex vivo, the weakness of the endogenous tissue signals may never allow real-time endoscopic in vivo Raman imaging. However, exciting new work is emerging in the use of novel biocompatible and nontoxic nanoparticles for in vivo tumor targeting and detection based on pegylated gold nanoparticles and surface-enhanced Raman scattering. For example, such probes have been found to amplify the efficiency of Raman scattering by 15– 20 orders of magnitude. Qian et al. [98] showed large optical enhancements can be achieved under in vivo conditions for tumor detection in live animals. This group also reported the use of small-molecule Raman reporters such as organic dyes that were combined with colloidal gold nanoparticles and conjugated to tumor-targeting ligands for considerable enhancement of the Raman signal for cancer detection. However, despite such innovative developments, the potential to detect very early biochemical changes in vivo in tissues associated with neoplastic transformation either using endogenous or surface-enhanced Raman scattering based spectroscopy or imaging, remains a daunting challenge. To date, there have been no correlative mechanistic studies to identify “pathologic stage-specific” molecular Raman biomarkers. Such mechanistic as well as clinical studies remain overdue.

Light scattering spectroscopy Light scattering spectroscopy (LSS) is based on white-light reflectance, in which photons incident on tissue are backscattered without a change in their wavelength, and provides structural information about tissue in situ. LSS measurements are performed with visible light (400–700 nm) using fiberoptic probes placed at the tissue surface through the endoscope, and detect the relative intensity of back-scattered photons. These measurements have been shown to be sensitive to both endogenous tissue scatterers (i.e., cell nuclei and mitochondria) and tissue absorbers (i.e., hemoglobin). Since the optical probe detects scattered photons from as deep as the submucosa, information about the mucosal layer must be obtained by separating the contribution of multiply scattered light from deep in the tissue. Methods to do this include spec-

tral subtraction or the use of cross-polarization to remove the contribution of multiply scattered “deeper” photons from the detected signal. In this way, singly scattered photons originating primarily from the mucosa can be obtained. Tissue transformation is associated with changes in the density and/or size of endogenous scatterers within the mucosal layer. These can be measured from the fine structure in the spectra and correlated with histopathology. One of the hallmarks of dysplastic change is that nuclei enlarge and become crowded, and LSS is able to measure the size distributions of epithelial cell nuclei. In this way, direct quantitative measurement of nuclear enlargement, crowding, hyperchromaticity, and amount of chromatin is provided, which aids in clinical diagnosis. LSS is a noninvasive method that does not require expensive laser light sources, but instead is performed with white light, which yields a strong signal in real time (< 1 s for a spectroscopic reading) [33,99,100]. More recently, Yu et al. [101] reported the use of azimuthal LSS (phi/LSS) as a novel technique for assessing epithelial cell nuclear morphology in ex vivo normal and cancerous colonic tissues. Here, the difference between the LSS spectra was measured at azimuthal angles φ = 0° and φ = 90°, and this preferentially isolated the single back-scattering contribution due to large (∼ 10 μm) structures such as epithelial cell nuclei by discriminating against scattering from smaller organelles and diffusive background. This technique demonstrated that spectra from cancerous colon tissue exhibited significantly greater azimuthal asymmetry than those from normal colonic tissue. However, despite its diagnostic potential, this technology has the same disadvantage as other point spectroscopy devices in that they all sample only a minute surface and tissue volume, and are not likely to convince the vast majority of endoscopists of their clinical usefulness.

Clinical evaluation of light scattering spectroscopy To date, the potential of using LSS in vivo to detect epithelial nuclear crowding and enlargement in human colon has not been reported. The capability of detecting changes in nuclear size and density could potentially be useful in identifying dysplastic lesions in the colon, despite the limited sampling volume. Roy et al. [102] used enhanced back-scattering spectroscopy for quantitative, depth selective analysis of the epithelial micro- or nanoscale architecture in ex vivo preneoplastic colon tissues from 63 patients undergoing screening colonoscopy to predict risk of colon carcinogenesis. However, unlike for its use in identifying dysplasia in Barrett’s esophagus [99,103], clinical studies of LSS for detection of dysplastic lesions in the colon are awaited.

Optical coherence tomography Optical coherence tomography (OCT) is a novel biomedical imaging technique which is based on the principle of

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low-coherence interferometry and enables cross-sectional imaging in near real time with high spatial resolution (∼ 10–20 μm). OCT is analogous to B-scan ultrasonography, but, while B-scan detects back-scattered sound waves, OCT images are formed by detecting light that is back-reflected from subsurface tissue microstructures. Low-coherence infrared light is split by a 50/50 beam splitter, with half of the light directed toward the tissue and the other half toward a moveable mirror whose exact location is known. Light reflected from the mirror and tissue is recombined with the beam splitter and directed to a sensitive detector. Using a light source with limited coherence length, an interference signal is produced only when the light that returns from the tissue travels the same distance as the light returning from the mirror. The amplitude of interference signal depends on the magnitude of the back-reflected light intensity from tissue microstructures at that particular depth. By using an interferometric technique, the distance of the mirror is varied to allow scanning at varying depths of the tissue to produce an axial scan (A-scan). The optical probe can be scanned across the tissue surface to repeat the A-scan measurements at different lateral positions, resulting in a two-dimensional image (B-scan) (Figure 36.12). OCT will provide a real-time histological image of high clarity, similar to a standard hematoxylin and eosin-stained biopsy sample, without the need for tissue extraction. Current endoscopic OCT prototypes have an axial (depth) resolution of about 10 μm, which is determined by the coherence length of the light source, whereas the lateral resolution of these is about 25 μm and is determined by the focusing beam optics. Compared

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Figure 36.12 Typical example of an optical coherence tomography image collected from ex vivo colonic tissue samples showing normal mucosa on the left and a moderately differentiated tubulovillous adenocarcinoma on the right. Note the crypt structures in the normal mucosa. (Data courtesy of Dr. Alex Vitkin, Department of Medical Biophysics, University of Toronto, Canada.)

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with high-frequency endoscopic ultrasound with resolutions of ∼ 100 μm, current OCT systems have resolutions of ∼ 4–20 μm, thereby permitting identification of microscopic features such as villi, glands, crypts, lymphatic aggregates, and blood vessels. Despite this high resolution, OCT has a limited imaging depth (∼ 2 mm) compared with endoscopic ultrasound (∼ 5 cm). OCT will provide a real-time histological image of high clarity similar to a standard hematoxylin and eosin-stained biopsy sample without the need for tissue extraction. OCT should be the ideal optical biopsy in that it offers high-resolution images similar to what might be expected with confocal fluorescence microendoscopy, with the added bonus of depth-specific scanning (approximately 5–10 times greater depth penetration than confocal microendoscopic technologies). Thus, OCT would be a true optical biopsy. We define “optical biopsy” as a means of obtaining tissue diagnosis based on real-time in situ optical measurements, which would eliminate the need for tissue removal in vivo. Similar to endoscopic ultrasound catheter probes, current in vivo endoscopic OCT probes typically have a diameter ranging between 2.0 and 2.4 mm, and with varying designs allow either end-on scanning, linear scanning (along the longitudinal axis of the esophagus), or 360° radial scanning. Working distances less than 1 mm from the tissue surface provide adequate focus, and some compression artifacts may be seen with probe tissue contact. Although OCT images can be obtained as quickly as four frames per second, avoiding motion blurring, in principle, real-time OCT imaging is possible and development is in progress. The majority of publications about OCT in the gastrointestinal tract have involved ex vivo tissue studies. Tearney et al. [104] investigated the capability of OCT to differentiate ex vivo the architectural morphology of normal and diseased gastrointestinal tissues, including the esophagus and colon, collected post mortem. Images were compared with corresponding histology to confirm tissue identity and suggest the possible mechanisms that produce tissue contrast. This group reported that microstructure was delineated in different tissues at a resolution of 16 ± 1 μm, higher than any clinically available cross-sectional imaging technology available. They determined that differentiation of tissue layers, such as the mucosa, submucosa, and muscularis, was achieved because of their different optical properties. In a similar ex vivo study, Kobayashi et al. [105] also used OCT to examine human gastrointestinal tissues from surgical resection and autopsy. Specimens were imaged within 5 h of resection or snap frozen in liquid nitrogen. When compared with histology, OCT images demonstrated clear delineation of the mucosa and submucosa in most specimens, and clearly showed microscopic structures such as crypts, microvasculature, or esophageal glands in the submucosa and lymphatic nodules. Sivak et al. [106] evaluated a prototype OCT system by imaging ex vivo tissues from varied segments of the gastro-

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intestinal tract from 38 patients. Here, the 2.4-mm-diameter OCT probe was inserted through an endoscope (tissue contact is not required) and provided a 360° radial scan. Images were collected at 6.7 frames per second and displayed on a television monitor. The probe-to-tissue distance was varied in this study. At ∼ 1 mm above the mucosal surface, the OCT probe produced images consisting of mucosal structures such as colonic crypts, gastric pits, and duodenal villi. However, when held against the wall, the OCT image revealed several layers interpreted as mucosa, muscularis mucosae, and submucosa (and blood vessels were evident in the submucosa). This study concluded that OCT imaging provided interpretable high-resolution images of mucosa and submucosa, and thereby would be diagnostically useful. Recently, ultra-high-resolution OCT has been reported for the detection of colonic cancers. Hariri et al. [107] used ultrahigh-resolution OCT to serially image the lower colon of azoxymethane-treated A/J mouse models of colorectal cancer in order to monitor the progression of neoplastic transformations and determine whether OCT is capable of identifying early disease. Using a 2.0-mm-diameter ultra-high-resolution OCT endoscopic system with 3.2 μm axial and 4.4 μm lateral resolution, this group correctly diagnosed 95% of adenomas and 23% of gastrointestinal neoplasias (38% protruding and 9% nonprotruding). The panel identified 68% of disease foci (95% adenoma, 76% protruding gastrointestinal neoplasias, and 13% nonprotruding gastrointestinal neoplasias). This demonstrated a nondestructive optical means of visualizing colon cancer progression in an animal model. As a further development, ultra-high-resolution OCT probes have recently been developed which are capable of imaging resolutions near the cellular level, leading to a potential capability of identifying abnormal crypt formation and dysplastic cellular organization in vivo [108]. Doppler OCT is a recent extension of OCT that acquires a morphological image of the tissue as well as local blood flow velocities in vivo [109,110]. Reflectivity within the tissue provides contrast for the morphological image, while blood velocity maps the distribution of moving scatterers. Doppler OCT provides noninvasive functional imaging of microcirculation in tissue blood vessels that are too small to be imaged by conventional Doppler ultrasound and are sensitive to voxel blood volumes of ∼ 10 μm3 and on-axis blood velocities of ∼ 30 μm/s. A recent publication reported an animal study in which OCT was combined with fluorescence and confocal microendoscopy as a multimodal approach for detecting colon cancer in APC(Min/+) (APC, adenomatous polyposis coli; Min, multiple intestinal neoplasia) mice [111]. It was found that OCT and confocal microendoscopic images provided complementary structural information about the tissue, while the measured autofluorescence signal provided biochemical information. This study introduces us to the future potential of an integrated endoscopic probe capable of obtaining an “optical biopsy.”

Clinical evaluation of optical coherence tomography Pitris et al. [112] examined the feasibility of OCT for highresolution imaging of gastrointestinal malignancies with ex vivo imaging of normal squamous esophagus, Barrett’s esophagus, squamous carcinoma, ulcerative colitis, normal colon, and colonic adenocarcinoma. The columnar epithelial morphology as well as other mucosal structures in normal colon were also distinct. In contrast, disorganization of the normal mucosal layers and ulcerative lesions were identified in ulcerative colitis and colon adenocarcinomas. The ability of OCT to image tissue microstructure at high resolutions showed that it may be useful for minimally invasive assessment of the gastrointestinal tract and evaluation of early neoplastic changes. Das et al. [113] reported an in vivo comparative study between OCT and catheter probe endoscopic ultrasound to determine their potential clinical roles. These techniques were used to evaluate normal-appearing portions of the gastrointestinal tract at the same sites (44 histologically confirmed normal sites in 27 patients). Catheter probe endoscopic ultrasound was performed with either a 20-MHz or a new 30-MHz catheter probe. Mucosa and muscularis mucosa were clearly seen at all sites with OCT. Except in the stomach, OCT demonstrated the submucosa in all sites. The penetration depth of OCT ranged from 0.7 to 0.9 mm. Microscopic structures such as esophageal glands, intestinal villi, colonic crypts, and microvasculature were easily identified. Catheter probe endoscopic ultrasound penetration ranged from 10 to 20 mm, and five to seven distinct layers were discernible. However, both mucosa and submucosa were seen as thin layers without microscopic detail. This important study demonstrated that OCT resolution is superior to high-frequency catheter probe endoscopic ultrasound, but depth of penetration is limited to mucosa and submucosa. In addition, OCT images major structural components of the mucosa and submucosa, whereas catheter probe endoscopic ultrasound does not. Potentially, OCT and high-frequency catheter probe endoscopic ultrasound may be complementary for clinical imaging. In its current form and resolution, OCT will likely localize areas displaying architectural distortion for biopsy, but will be limited to staging dysplasia. However, one can speculate that OCT may determine tumor invasion through the muscularis mucosa into the submucosa better than conventional endoscopic ultrasound, and hence improve upon the Tstaging for selecting patients for endoscopic cure. OCT may have some role in the immediate postendoscopic mucosal resection as to real-time histological evaluation of the basal margins. Improvements in both axial and lateral resolutions are expected, with the development of better light sources and focusing beam optics, respectively. Currently, these sources are cumbersome and expensive, but are a starting point for the development of high-power, compact, and affordable lasers. Newer prototype designs may improve the axial resolution to

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subcellular levels (< 5 μm), which may allow dysplastic cells to be resolved. One drawback of the linear scanning OCT technique is its small sampling area and limited depth, similar to point spectroscopy. The placement of the OCT probe at a specific site amid peristaltic motion also appears challenging, so that contact with tissue (with potential compression artifacts) may be necessary. OCT is not likely to soon replace biopsy and histopathology in the gastrointestinal tract because of its current lack of histology-equivalent image resolution. However, it has the potential to merge the disciplines of endoscopy and pathology into a single entity. The future “OCT endoscopist” must be an expert in “surface” features of endoscopy as well as in micropathology.

Immunophotodiagnostics Conventional immunohistochemistry permits microscopic imaging of biopsied tissues on a “molecular” level by routinely combining chromogenic and fluorescent dyes with the specificity of monoclonal antibodies and directing them against tumor-related or tumor-specific antigens. Recently, this idea has been extended to in vivo endoscopic imaging as a means of enhancing the contrast between tumors and the surrounding normal tissue by targeting tumors with monoclonal antibodies. For the past 20 years, radiopharmacology has relied on the highly specific reactivity of the antigen–antibody complex. For example, radiotherapeutic agents are commonly conjugated to monoclonal antibodies directed against tumorassociated antigens. These are used to selectively target tumor cells for destruction, based on the inherent overexpression of a particular tumor-associated antigen relative to normal tissues [114]. Adapting this principle for fluorescence endoscopy involves the conjugation of a fluorophore dye to a monoclonal antibody or other tumor-targeting moiety, thereby producing a “fluorescent contrast agent.” Typically, these dyes are excited in the red range (> 600–700 nm), and emit near-infrared fluorescence efficiently. They have adequate stability for labeling in vivo and produce fluorescence that is detectable through millimeter thicknesses of tissues [115]. Recent improvements in monoclonal antibodies and their derivatives (i.e., fragments), the development and commercial availability of near-infrared-emitting fluorophores, and the availability of high-sensitivity digital cameras in this spectral region have made tumor localization using fluorescence contrast agents practical and attractive. Optimal fluorescent dyes can be selected based on their photophysical and spectral properties, independent of their tumor-localizing properties [116]. Recent animal studies have demonstrated that fluorophore labeling of monoclonal antibodies produces adequate sensitivity and improved image contrast. In separate studies,

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far-red-emitting cyanine-based dyes were conjugated to the tumor-targeting monoclonal antibodies, anti-carcinoembryonic antigen, and monoclonal antibody E48 directed against squamous cell carcinoma. These were injected into nude mice bearing xenografted human tumors that overexpressed the antigen [117,118]. Specific tumor localization was achieved at 24 h post injection, and clearly detectable red fluorescence contrasted the tumors with the minimal to nonfluorescent normal tissues. No detectable red fluorescence was observed in control mice injected with conjugated irrelevant antibodies or free dye. In a study by Gutowski et al. [119], monoclonal antibody– dye conjugates were prepared using the monoclonal antibody against carcinoembryonic antigen (35A7) labeled with indocyanine and 125I. Time- and dose-dependent biodistribution studies were performed in nude mice bearing an LS174T peritoneal carcinomatosis, demonstrating high tumor uptake at 48 h post injection. Forty-eight hours after intravenous injection of 40 mg of the 125I-labeled monoclonal antibody 35A7–indocyanine conjugate, the fluorescent status of 333 biopsies was compared with histology. Sensitivity was 90.7%, specificity was 97.2%, the positive predictive value was 94.7%, and the negative predictive value was 94.9%. A few false positives were found in lymph nodes and biopsies with inflammation. This study demonstrated the detection of very small nodules (< 1 mm in diameter), but noted a sensitivity decrease with decreasing tumor mass (100% for nodules > 10 mg vs. 78% for nodules ≤ 1 mg). Tumor nodules occult to the naked eye were also detected, and very low conjugate quantities (< 1 ng) were sufficient for tumor nodule visualization. However, the authors also noted false-negative findings with some deep small tumor nodules producing very weak fluorescence, which was not detected due to tissue scattering and absorption and the relative insensitivity of their detection camera. To determine the binding of such fluorescently labeled contrast agents in vivo, Kusaka et al. [120] used Balb/cA nude mice grafted with human gastric cancer (St-40) and colorectal cancer (COL-4-JCK) cell lines, and the unconjugated anti-human anti-MUC1 mucin antibody to show that specific tumor labeling can be achieved in live mice at the tumor surface, thereby demonstrating that in vivo administration of a fluorescence-labeled monoclonal antibody for fluorescence detection was possible. However, many difficulties remain with this approach. Until recently, most monoclonal antibodies were raised in nonhuman hosts (i.e., mice), resulting in a host immune response against them when used in patients. This not only causes the antibodies to be quickly eliminated, but also forms immune complexes that cause damage to the kidneys [121]. However, “humanized” monoclonal antibodies have become available recently. In addition, whole antibodies bound in human tumors do not exceed 10 −5 of the administered dose per gram of tumor, hence requiring large amounts of injected conjugated monoclonal antibody, long

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exposure times, and high sensitivity to achieve adequate tumor brightness and contrast. This limitation is due to the pharmacokinetic properties of conjugated whole antibodies. The production of antibody fragments, smaller than the whole antibody, has resulted in some improvements in pharmacokinetics and tissue labeling. In a mouse xenograft model, Ramjiawan et al. [122] conjugated an near-infrared-emitting dye (Cy5.5) of a fragment of antihuman antibody with broad cancer specificity, to demonstrate specific binding. Here, the peak fluorescence intensity was detected with a highsensitivity charge-coupled device camera 2 h post injection. The presence and distribution of the conjugated fragment revealed that about 16% and 73% were located in the tumor and the kidneys, respectively. Use of smaller antibody fragments produced rapid tumor uptake, better penetration (at the expense of reduced circulation time), more homogeneous tumor penetration, and reduced immunogenicity [123]. Recently, Kostenich et al. [124] demonstrated the use of a synthetic somatostatin analog-targeted fluorescent probe for endoscopic detection (using a fiberoptic confocal microendoscope) of HT29 colon cancers in a mouse xenograft model. Using a relatively low dose of 6 mg/kg of body weight enabled targeting and five- to eightfold increase in the contrast between malignant and normal tissues for the detection of small (∼ 1–5 mm in diameter) tumors with high sensitivity and selectivity. Furthermore, toxicity studies at dosages up to 1000 mg per kg body weight did not reveal any drug-related abnormalities. Fluorescent dyes can also be targeted to tumor tissues by means other than monoclonal antibodies. For example, molecular beacons or “smart” probes offer a highly specific means of detecting tumor-associated enzymes or mRNA in vivo. Molecular beacons are target activatible probes that use the fluorescent resonance energy transfer principle to control their fluorescence emission in response to specific biological stimuli. They are useful tools for cancer imaging because of their potential for improving imaging specificity (activation through tumor-specific enzymes or mRNAs) and sensitivity (signal amplification from nonfluorescent to highly fluorescent) as well as their ability to interrogate a wide range of molecular abnormalities. Weissleder et al. [125] coupled a near-infrared fluorophore to a biocompatible polymer which was taken up by tumor cells via pinocytosis. The intracellular release of the fluorophore in tumor-bearing mice by the protease cathepsin D in the tumor resulted in a fluorescence signal detected in vivo in subnanomolar quantities and at depths sufficient for clinical imaging. They demonstrated that specific enzyme activity in a tumor could be imaged by fluorescence contrast agents in vivo. In addition, Marten et al. [126] studied the expression of the protease cathepsin B in dysplastic adenomatous polyps using an APC(Min/+) mouse experimental model for familial adenomatous polyposis. Here, a cathepsin B-sensing near-infrared fluorescence imaging probe was used in vivo. Cathepsin B was consistently over-

expressed in adenomatous polyps. When mice were injected intravenously with the reporter probe, intestinal adenomas became highly fluorescent, which indicated high cathepsin B enzyme activity. Even microscopic adenomas undetected by white-light imaging were readily detected by fluorescence, with the smallest lesion being ∼ 50 μm in diameter. Control animals were either not injected or injected with a nonspecific near-infrared fluorescent probe (indocyanine green), and these adenomas were only barely detectable above the background. This impressive study demonstrated the potential of using such fluorescently labeled enzyme-sensing probes to detect such gastrointestinal lesions against adjacent normal mucosa. Recently, Alencar et al. [127] described the intravenous administration of cathepsin B-sensing near-infrared beacon (nanomolar concentration) for microcatheter-based confocal detection in an orthotopic mouse CT26 tumor model that resulted in a 30-fold greater fluorescence intensity in a tumor than in the adjacent normal colon. An additional method of targeting fluorescent contrast agents to colonic neoplastic lesions is the use of peptide sequences derived from phage display libraries. Phage libraries permit the screening and recovery of bacterioviral clones expressing peptides that bind to unique antigens on a given tissue or cell. The small size of the peptides allows them to diffuse into neoplastic colonic mucosa and to bind to markers specific for early cancer or disease. Also, a peptide sequence of this length is able to generate a much higher degree of complexity than typical monoclonal antibodies. Briefly, the inserted peptides are randomly generated, resulting in a library of millions of phage clones, each with a different peptide. This library can be screened for only those clones whose peptides bind specifically to a given target, which may range from purified molecules to whole tissues (i.e., dysplasia in colon). Recovery of phages that bind to a given tissue permits subsequent synthesis of the peptide for linking to a fluorescent molecule, such as indocyanine green, Cy 7, or AlexaFluor 750, for endoscopic imaging in the colon or elsewhere in the body. For example, Kelly and Jones [128] reported the isolation of a nine-amino-acid, disulfide-constrained peptide, CPIEDRPMC (RPMrel), that targeted HT29 colon carcinoma cells without binding to normal colonic tissues. More recently, Zhang et al. [129] reported the discovery of a peptide CP15 (VHLGYAT) that was demonstrated to be most effective in targeting colonic tumor cells (SW480 and HT29) and tumor tissues, but not the normal human intestinal epithelial cells and control colon tissue. These studies suggested that peptide CP15 might be a promising lead candidate in the development of a useful colon tumor diagnostic and targeted drug delivery agent. The utility of such peptide-based probes for optical detection of colonic lesions was reported by Kelly et al. [130]. In this important in vivo animal study, the researchers demonstrated the use of a peptide sequence (CPIEDRPMC) conjugated to the nearinfrared fluorescent dye Cy 5.5 for detecting colonic HT29 tumors using a fiberoptic confocal microendoscope.

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Currently, work in our laboratory is assessing the utility of colonic mucins as a possible target for colonic adenomas and adenocarcinomas. Nude mice were xenografted with human colonic adenocarcinoma LS174T cells. The monoclonal antibody CC49, which recognizes a tumor-associated glycoprotein antigen, was conjugated to a commercial fluorescent dye (Alexa Fluor®647, Molecular Probes®, Invitrogen Corporation, Carlsbad, CA, USA) at a molar ratio of 6 mol of dye to 1 mol of antibody, as was an irrelevant monoclonal antibody (against M195, an anti-CD33 monoclonal antibody). The conjugated relevant and irrelevant antibodies and free dye of equivalent concentration were administered intravenously, each at a dose of ∼ 30 μg per mouse. Using 630 nm excitation, and a high-sensitivity charge-coupled device camera with a fluorescence bandpass filter (670 ± 10 nm), preliminary results demonstrated distinct contrast enhancement of the tumor compared with surrounding normal tissues using the labeled CC49, further compared with control autofluorescence images. Tumor visualization was apparent as early as 2 h with the fluorescence-conjugated CC49 probe, and the maximum contrast was at 48 h post injection (Figure 36.13). Conjugated irrelevant antibody and free dye did not produce detectable fluorescence contrast at the tumor site. Hence, this demonstrated the selective in vivo targeting of fluorescence dye to tumor-associated mucins, resulting in the enhanced fluorescence detection of small (∼ 4–5 mm in diameter) xenografted human colonic tumors [131]. The recent identification of gastrointestinal tumor-associated biomarkers, especially for the colon [132,133], offers the potential for improving the efficacy of fluorescence endoscopy. The

White-light image

Fluorescence image

Figure 36.13 Example of in vivo tumor targeting with a fluorescence contrast agent. This was achieved by administering a fluorescence-conjugated antibody directed against a tumor-associated glycoprotein (TAG72) in a xenograft nude mouse model of human colon cancer. (a) White-light image of dorsal side of mouse indicating tumor site (arrow). (b) Whole-body fluorescence image shows significant enhancement of tumor to normal contrast, thereby allowing the tumor to be detected easily with fluorescence at 48 h post administration of the tumor-targeted fluorescence probe.

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availability of monoclonal antibodies that target gastrointestinal tumor-associated antigens could enable detection of the very earliest onset of dysplasia in vivo, before lesions become visible. Ideally, in order to improve sensitivity and specificity, several distinct agents would be used simultaneously to target multiple early cancer stage-specific markers. For instance, multiplexed fluorescent bioconjugates each selectively recognizing normal colonic mucins [134], modified colonic mucins (tumor-associated glycoproteins) [135] expressed in early adenomas, and carcinoembryonic antigen in colon adenocarcinomas [136] may help differentiate between normal tissue and early- and late-stage colon cancer. Unfortunately, a significant limitation in “multiplexing” with organic dyes is their broad and overlapping fluorescence emission spectra. This has led to an interest in exploring the potential of a new nanotechnology, quantum dots. Quantum dots are semiconductor nanoparticles (∼ 1–20 nm in diameter) which have unique optical properties [137]. Specifically: 1 They have very high brightness (∼ 20× organic fluorophores), which allows low concentrations (lower cost of antibodies, toxicity) and/or less expensive imaging detectors. 2 Their emission spectra are very narrow (∼ 20 nm) and size dependent, so that multiplexing is much easier (theoretically, a set of ∼ 80 spectrally unique nanocrystals can be synthesized in the emission range of 300–1900 nm). 3 Their excitation spectra are very broad, allowing excitation of multiple quantum dots with a single light source, again facilitating multiplexing and simplifying the instrumentation. 4 They have very low photobleaching, which enhances the advantage of high brightness. The main potential for quantum dots is as topically applied fluorescence contrast-enhancing agents which target and bind to specific biomarkers in vivo. Although this approach has not yet reached the clinic, recent exploratory research in our laboratory has been leading the effort to explore this novel technology in preclinical studies for application in endoscopic detection of dysplasia in the colon and in Barrett’s esophagus. Examples of this work include the evaluation of quantum dot agents in vitro in established gastrointestinal tumor cell lines (Figure 36.14) and in vivo in relevant animal models of colonic adenomas (Figure 36.15), as well as in Barrett’s esophagus (Figure 36.16). Overall, the long-term goal for tumor-targeting fluorescence contrast agents is to translate their use from preclinical animal cancer models to the clinical environment. Currently, regulatory restraints prevent/restrict the testing of such agents in humans without careful studies confirming that such exogenous diagnostic agents are effective, nontoxic, and safe. Furthermore, potential toxicology studies are still awaited and such probes are currently costly to use, but the basic methodology of using such molecularly specific contrast agents continues to be investigated at the preclinical proof of concept stage. It is envisaged that once optimized and validated in prospective clinical trials, these modalities are likely to be used

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Clinical evaluation of immunophotodiagnostics

Figure 36.14 Example of the in vitro use of fluorescent quantum dots conjugated to detect the cell surface receptor (tumor-associated antigen72) overexpressed in LS174T human adenocarcinoma cells. Bright-red fluorescence from the quantum dot probes is observed on the cell surface of the colon tumor cells (which also emit a weak green autofluorescence) indicating specific targeting (458 nm excitation; emission wavelength: green channel = 500–530 nm, red channel = 650–710 nm).

by the endoscopist as guiding tools for targeted biopsies, and to more accurately assess lesion margins and the adequacy of endoscopic treatment. It is conceivable that optimal detection will require a combination of techniques (multimodal diagnosis). A suspicious area could be identified initially by a wide-field imaging modality, such as fluorescence endoscopy or NBI, and then further characterized (or graded) by spectroscopy or by a high-resolution technique, such as confocal fluorescence microendoscopy (see Chapter 39). Furthermore, such optical probes may not only detect superficially localized lesions, but also determine the extent of local tumor infiltration

Figure 36.15 Example of in vivo targeting of carcinoembryonic antigen (CEA) in colonic adenomas developing in a mouse mode. (a) Transmitted white-light image of resected mouse colon showing dysplastic lesions (arrows), and (b) corresponding fluorescence image of the bright green-emitting quantum dots conjugated to a monoclonal antibody recognizing CEA, which is overexpressed in dysplastic lesions. Note the intense green fluorescence of the adenomas, indicating selective targeting of the agent and significant enhancement of the tumor to normal contrast.

(a)

Preliminary in vivo evaluation of fluorescence contrast agents in patients has been reported in a very limited number of studies. Early vascular changes were assessed in Crohn’s disease in a prospective endoscopic study of 10 asymptomatic patients using unconjugated 10% sodium fluorescein [138]. Fluorescence endoscopy was used to evaluate the mucosal microcirculation of the neoterminal ileum in relation to endoscopic recurrence in patients who had undergone ileocolonic resection for Crohn’s disease. The fluorescence observed may reflect vasodilation associated with inflammation, or genuine microvascular lesions. Correlation with histology suggested that these early vascular lesions were secondary to the inflammatory process [138]. In another study with ex vivo human tissues, Bando et al. [139] developed a near-infrared-excited fluorescent dye, indocyanine green (ICG)-sulfo-OSu, conjugated to anti-sulfomucin and anti-MUC1 antibodies in paraffinized tissue sections from 10 patients with esophageal cancer, 30 patients with gastric cancer, and 20 patients with colorectal cancer. They found that antibody staining patterns varied depending on the organs, and the histological types and depths of the cancers. Generally, staining on the mucosal surface of cancer tissues was retained and images of cancer cells were obtained by infrared fluorescence observation using the labeled anti-MUC1 antibody. These authors noted the difficulty of adapting this staining method to in vivo, in which the antibody agent would be administered to the luminal surface, because of such problems as surface mucus and pH. Hayashi et al. [140] performed similar studies of immunostaining of indocyanine greenconjugated antiepithelial membrane antigen antibodies on nonfixed freshly excised tissue samples by eliminating these

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Figure 36.16 Example of in vivo targeted labeling of quantum dots in BE rat model. (a) White-light image of resected rat esophagus, (b) ex vivo tissue section stained immunohistochemically for villin (brush border protein) expression, and (c) fluorescence image of the luminal surface of the esophagus, with topical application of a conjugate comprising 660 nm emitting quantum dots conjugated to an antibody targeted to villin, which is overexpressed in BE tissue. BE, Barrett’s esophagus; SE; squamous esophageal mucosa.

factors under various conditions. Specimens were stained immunohistochemically, and incubated with antiepithelial membrane antigen antibodies at 37°C for 10 and 30 min (esophagus), and for 60 and 120 min (stomach). The results suggested that vital immunohistochemical staining is possible under optimized conditions. Ito et al. [141], in a small number of patients (n = 3), confirmed that such immunofluorescent staining using indocyanine green derivative (ICG-sulfo-OSu) conjugated to anti-carcinoembryonic antigen antibodies could be performed in vivo to detect small gastric cancers. Tatsuta et al. [142] labeled anti-carcinoembryonic antigen monoclonal antibodies with fluorescein isothiocyanate to study ex vivo human gastric lesions. Fluorescein isothiocyanate has high fluorescence efficiency, and high excitation and detection wavelengths (∼ 488 nm excitation, ∼ 520 nm emission). In vitro fluorescent images of 42 gastric lesions were obtained, including 20 early carcinomas and 10 advanced cancers. The con-

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jugated antibody was applied topically. Twenty-seven out of 30 tumors (90%) showed positive fluorescence after 60 min with no false positives, whereas only two out of five cancers (40%) could be detected earlier than 60 min. To remove gastric mucus and improve the binding of the tumor with the labeled antibody, pretreatment with a mixture of proteinases, sodium bicarbonate, and dimethyl polysiloxane was used. In vivo, this would add another 90 min to the endoscopic examination. Computer-assisted processing was used to enhance the fluorescence images. No significant relationship between positive fluorescence and tumor type or stage was found. However, positive fluorescence could also not be demonstrated in benign gastric lesions. In 1998, Keller et al. [143] coined the term “immunoscopy” in a report on the detection of colorectal carcinomas and villous adenomas in surgically resected tissue samples. Fluorescence from a fluorescein isothiocyanate-labeled anticarcinoembryonic antigen antibody was detected using a sensitive filtered photographic camera in 27 out of 28 cancers and in one out of two adenomas, as well as in 6 out of 18 normal controls, giving a sensitivity of 93% and a specificity of 67%. To date, there are two published reports of fluorescenceconjugated monoclonal antibodies used in humans in vivo. The first study used a monoclonal fluoresceinated anti-carcinoembryonic antigen conjugate to detect human colon carcinoma [144]. Following intravenous administration of the mouse–human chimeric anti-carcinoembryonic antigen monoclonal antibody, ex vivo photodetection of the tumors was accomplished in a limited set of six patients, and in vivo fluorescence rectosigmoidoscopic imaging in one patient. Upon laser irradiation, clearly detectable heterogeneous green fluorescence from the dye–antibody conjugate was visually observed on all six tumors; minimal fluorescence was detectable on normal mucosa. Tissue autofluorescence, from both tumor and normal mucosa, was subtracted by real-time image processing. In the second in vivo study of 27 patients with colonic polypoid lesions, Keller et al. [145] used a locally administered fluorescein-labeled anti-carcinoembryonic antigen monoclonal antibody for in vivo fluorescence endoscopic detection of colorectal dysplasia and carcinoma. During conventional WLE colonoscopy, the conjugated monoclonal antibody was applied directly to the mucosal surface. After an incubation time of 10 min, and using 490 nm light to illuminate the tissue surface, specific fluorescence was visualized with a conventional fiber endoscope modified for fluorescence imaging with fluorescence bandpass filters (520 nm). Here, fluorescence was present in 19 out of 25 carcinomas and in three out of eight adenomas. Interestingly, the technique failed in the presence of mucosal ulceration or bleeding. One fluorescence-positive villous adenoma showed high-grade dysplasia, and another fluorescence-positive polypoid lesion was diagnosed as carcinoma in adenoma. Normal-appearing mucosa was fluorescence negative in all cases. In all cases

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(without ulceration or bleeding), the specificity of fluorescence endoscopy was 100%, the sensitivity was 78.6%, and the accuracy was 89.3%. Subsequent immunohistochemistry on biopsied tissues revealed that endoscopic fluorescence significantly correlated with the carcinoembryonic antigen expression of luminal epithelial cells. Larger trials to demonstrate the value of this technique for differential diagnosis are currently under way. In a breakthrough study, Hsiung et al. [146] published the first clinical trial using a fluorescently labeled heptapeptide (peptide containing seven amino acids) in patients undergoing colonoscopy. To create the targeting optical probe, they screened phage display peptide libraries against fresh human colonic adenomas for high-affinity ligands with preferential binding to premalignant tissue, and identified a specific heptapeptide sequence (VRPMPLQ). The fluorescein-conjugated peptide was administered topically and imaged in patients by fluorescence confocal microendoscope delivered through the instrument channel of a standard colonoscope. The fluorescent peptide probe bound more strongly to dysplastic colonocytes than to adjacent normal cells with 81% sensitivity and 82% specificity. Despite the limited number of patients, this study demonstrated that novel molecularly based probes can meet regulatory requirements and represent a promising diagnostic imaging approach for the early detection of colorectal cancer and potentially of other epithelial malignancies. However, despite these encouraging initial results, several important issues must be resolved. What are the best tumor-associated targets (i.e., monoclonal antibodies, peptides, enzymes) is not clear, and the possibilities are seemingly endless. For example, antigens expressed on the cell surface, such as growth factor receptors, mucins, and cell adhesion molecules, can be targeted by their corresponding fluorescence-conjugated antibodies, as can intracellular markers such as enzymes [132,147]. Biomarker studies continue to be reported in the literature for each segment of the gastrointestinal tract, in which a variety of molecular markers are evaluated in large tissue archives for their potential as diagnostic and/or prognostic indicators (i.e., carcinoembryonic antigen, mucin epitopes, etc.). It is possible that each segment of the gastrointestinal tract will have its own specific diagnostically relevant markers. Additionally, simultaneous localization of multiple reagents is made possible by labeling multiple near-infrared fluorophores; thus, background subtraction and differential labeling of multiple tumor-associated components can be performed. Difficulties in using the fluorophore labels are mainly related to light scattering and absorption in tissues, but detection of small tumors at depths of several millimeters should be feasible. Given the limitations in current fluorescence endoscopic imaging in detecting very early gastrointestinal lesions or preventing false positives due to confounding concurrent conditions (i.e., inflammation), these developments significantly complement existing fluorescence endoscopy.

Summary Several new optically based techniques are being evaluated to enhance the diagnosis of dysplasia in the colon. The ideal system should function in real time and combine excellent diagnostic accuracy with wide mucosal area surveillance. It is our impression that autofluorescence is a very important technology for the detection and evaluation of neoplastic disease in the colon, primarily allowing wide-area surveillance of the mucosa. NBI is another technology that also seems to have a role in the wide scanning of the colon. A number of studies have reported on the use of NBI for the detection and classification of diminutive colonic lesions, more than with autofluorescence. However, to our knowledge, there has not been a direct comparison between the two methods for these types of important lesions. A major issue is how the detection of dysplasia and intramucosal cancer will ultimately fit into the treatment algorithm; for example, who and/or what should be treated with endoscopic ablation, chemoprevention, or resective surgery? Treatment will be markedly affected by accurate staging of lesions, via super-high-resolution ultrasound or OCT. Short of replacing conventional biopsy, such technologies should provide guidance in locating optimal sites for targeted biopsy and be able to monitor ablative therapies such as photodynamic therapy. In this regard, fluorescence endoscopic imaging, with its wide field of view, has already identified early lesions, detected occult recurrence in postpolypectomy scars, and demonstrated reliability in differentiating hyperplastic and adenomatous polyps in vivo, and so appears most appealing and practical for screening. Additionally, fluorescence endoscopy does not require dye spraying and is relatively fast. However, many issues, such as optimal excitation and emission wavelengths, confounding background fluorescence from inflammation (false positives), and artifacts due to motility and fecal contaminants, remain unresolved. Additionally, it is not clear if exogenous fluorophores, such as prodrugs like ALA, will be necessary to achieve clinically useful sensitivity and specificity. Despite its very high molecular specificity, Raman spectroscopy suffers from the same weakness as all point spectroscopies, in that its clinical use is limited by practicality. This is also the case for LSS, which has shown promise in differentiating dysplasia (low grade and high grade) from Barrett’s esophagus for example, based on nuclear size and density. However, used adjunctively with imaging techniques that survey large tissue surfaces for targeting suspicious lesions, the molecular specificity of Raman spectroscopy or the sensitivity to subcellular scattering features of LSS may be useful for in situ diagnosis. These combinations are yet to be attempted. The main clinical role of OCT will be to provide a mucosal “optical biopsy.” Possible applications include:

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the identification of occult dysplastic lesions in longstanding field defects such as ulcerative colitis; 2 the immediate assessment of diminutive polyps as hyperplastic, adenomatous, or, even more challenging, serrated adenomas; 3 the determination of residual disease in postpolypectomy circumferential margins as well as basal submucosal margins. OCT should be able to reproduce the high sensitivity and specificity of confocal microendoscopy, with the added advantage of exceeding the depth limitations of the latter. Despite these optimistic speculations, the technology must improve its degree of resolution and quality of histological images to equal, at the very least, those of hematoxylin and eosin staining. Furthermore, Doppler OCT may offer an additional endoscopic capability for imaging blood flow in mucosal and submucosal microvasculature, and may be of use in assessing changes in microcirculation resulting from in situ therapies. All point spectroscopic techniques are inherently limited by the small tissue area that they sample. However, they contain more detailed “biomolecular” information about tissue than any imaging system, which may translate into more accurate tissue differentiation. Rather than competing with an imaging system, the “best” instrument for surveillance may combine imaging and spectroscopy. For instance, a lesion could be detected by fluorescence imaging or NBI, and its dysplastic nature characterized by Raman spectroscopy, confocal fluorescence microendoscopy, and OCT. However, in this era of cost containment, such an approach may be prohibitive. Moreover, all of these expensive optical modalities will need to be compared against cheaper and equally promising alternatives such as chromoendoscopy. By far the least reported method to date is the use of immunorelated fluorescence contrast agents. A limited number of ex vivo studies have demonstrated relative selectivity in gastrointestinal tumors with fluorescence-conjugated antibodies to well-known tumor-associated biomarkers. Such contrast agents have also been evaluated in a very limited number of patients with encouraging enhancement of tumor contrast. There are important technical issues to be resolved, for example finding the optimum “site- and pathology-specific” biomarkers, conjugate design, and false positives associated with inflammatory conditions, and optimizing the relative tumor uptake, cost, and toxicity. However, we are advancing in our understanding of cancer biology, tumor-associated colon cancer biomarkers, conjugation biochemistry, safety assessments, and development of fluorescence imaging hardware and software continues. This technology also offers the means of aiding our fundamental understanding of disease processes in the colon on a molecular level. It is conceivable that, in the future, molecularly targeted fluorescence endoscopic imaging will allow earlier detection and characterization of colonic disease, and may offer in vivo noninvasive monitoring of the functions of a variety of overexpressed tumor-associated proteins as well as assessment of treatment response. 1

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Conventional endoscopy has strongly relied on the detection of subtle topographic and morphological changes associated with the evolution of dysplasia through to invasive cancer, which may become apparent only at an advanced stage. However, the future of diagnostic endoscopy will certainly involve “molecular imaging,” whether fluorescence, Raman, or by immunophotodetection. This may translate into a truly “early detection” of preneoplastic changes, when therapeutic intervention can result in cure. The above-mentioned optical techniques are striving toward this goal, but none is likely to replace conventional biopsy and histopathologic interpretation in the near future. Future implementation of these optically based methods for endoscopic detection of colonic neoplastic disease will likely involve a combination of more than one technology. The concept of a “superscope,” an endoscope that integrates several different optical technologies into the same platform, is attractive and grabs our imagination. However, whether such a device will ever reach the marketplace will be determined by a number of theoretic and practical considerations, such as engineering limitations, clinical effectiveness, physician learning curve, the cost-to-benefit ratio, and industrial commercial competitiveness. Although this “ideal” device offers the potential for improved diagnosis and resulting treatment, its realization requires significant future technological refinement and large-scale clinical trials to assess its utility and limitations.

Acknowledgments The authors wish to thank the following individuals for their contributions to this book chapter: Dr. Lothar Lilge, Dr. Robert Weersink, Maria Cirocco, Nancy Bassett, Dr. Louis Michel Wong Kee Song, Dr. Andrea Molckovsky, Dr. Alex Vitkin, Dr. Warren Chan, Dr. Victor Yang, Dr. Maggie Gordon, and Dr. Shou Tang. We wish to acknowledge the support of the following organizations for work at our institution in these endoscopic developments: LIFE and immunophotodiagnostics studies received support by Xillix Technologies Corporation and the Ontario Research and Development Challenge Fund. Work on OCT is supported by Photonics Research Ontario and the National Sciences and Engineering Research Council of Canada.

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Optical Techniques for the Endoscopic Detection of Early Dysplastic Colonic Lesions

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Endoscopic Ultrasonography and Colonoscopy Joris W. Stubbe1 & Paul Fockens2 1

Az Sint-Jan, Ostend-Bruges, Belgium University of Amsterdam, Amsterdam, The Netherlands

2

History Imaging of colon, rectum, and surrounding tissues remains a difficult task. Colonoscopy, conventional barium studies, as well as computed tomography all offer only limited information about the local staging of rectal, perirectal, and colonic neoplasms, although the introduction of multidetector-row helical computed tomography demonstrated better results in the detection and staging of colorectal neoplasms. Magnetic resonance imaging (MRI) has proven its value in the staging of rectal cancer, and the role of MRI and endoscopic ultrasonography (EUS) seems rather complementary. EUS was developed in the early 1980s to overcome the deficiencies of standard transabdominal ultrasound, whose use is limited due to interposed structures (e.g., air). With EUS it is possible to visualize the individual layers of the rectal and colonic wall and to detect adjacent lymph nodes. Using frequencies between 5 and 20 MHz provides an optimal resolution of around 0.1 mm and adequate penetration (> 5 cm for 5 MHz, 1 cm for 20 MHz). Early in its development, EUS was limited to imaging rectal lesions, given that only rigid probes were available. However, since the introduction of flexible (both mechanical and electronic) echoendoscopes and through-the-scope ultrasound catheter probes, numerous studies have been published about indications for colonic EUS proximal to the rectum. The first report of (rigid) endorectal endosonography came from Wild and Reid in 1956, when they were able to diagnose a recurrence of rectal cancer after previous surgery [1]. However, it was not until 1983 that the first studies were published on endosonography of rectal cancer with the new flexible instruments [2– 4]. This chapter discusses indications, achievements, and shortcomings of colorectal EUS as performed with flexible

instruments using either through-the-scope or dedicated echoendoscopes. We will not discuss the important role endosonography performs in imaging the pelvic floor (including gynecological abnormalities extending to the gastrointestinal tract, as in endometriosis) and its musculature in fecal incontinence nor the perirectal complications of inflammatory bowel disease.

Instruments Dedicated echoendoscopes Dedicated echoendoscopes are flexible instruments equipped with dual imaging modalities: endoscopy and ultrasonography. About 15 years ago a special instrument was developed for use in the colon (CF-UM3/CF-UM20; Olympus Optical Company, Tokyo, Japan). It was a forward-viewing 160-cm-long echocolonoscope with a frequency of 7.5 or 12.0 MHz. It was not a completely 360° radial scanning instrument as the fiber bundles necessary for endoscopy blocked about 60° of the ultrasonographic image; this endoscope is no longer in production. The current dedicated electronic array echoendoscopes, developed for the upper gastrointestinal tract, are also used in the lower gastrointestinal tract. One of the endoscopes is the 45° oblique-viewing electronic radial instrument from Olympus (GF-UE160-AL5, Olympus Medical Systems, Tokyo, Japan), equipped with four ultrasound frequencies (5.0, 6.0, 7.5, and 10.0 MHz). Extreme caution is warranted with these oblique-viewing instruments in the colon because of its multiple bends and the frequent presence of diverticulosis [5,6]. The forward-viewing electronic radial echoendoscope from Pentax (EG-3630UR; Pentax Precision Instruments, Tokyo, Japan) seems to be preferable when lesions above the rectum need to be investigated.

Miniprobes

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

High-frequency ultrasonography (HFUS) generally uses through-the-scope catheter probes that can be advanced through the biopsy channel of a standard colonoscope. At the tip of these miniprobes, a small single-crystal transducer is rotating at 10 cycles per second. This gives a 360° image with

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depth of penetration dependent on the frequency chosen (up to 2 cm for 12 MHz, diminishing to less than 1 cm for frequencies of 20 MHz or higher). The miniprobes are quite durable and can provide at least 50 examinations without loss of function. The miniprobes are manufactured by the Fuji and Olympus companies.

Patient preparation For rectal lesions, an enema is adequate preparation. Higher up in the colon a complete standard bowel preparation is necessary. The patient is usually examined in the left lateral decubitus position. After endoscopic inspection of the lesion, water can be instilled in the rectum using a syringe or pump to submerse the lesion and achieve acoustic coupling, although complete filling of the rectum is not needed. Changing the position of the patient is of paramount importance in order to obtain an EUS image of an acceptable quality. If submersing the lesion is successful, the rest of the EUS examination is usually relatively easy, providing a real-time image of the lesion (with the exception of three-dimensional imaging). If the lesion cannot be submersed, a balloon around the miniprobe or echoendoscope may be used. When examining a narrow segment of the colon, extreme caution is necessary when using a side- or oblique-viewing instrument. Advancing the probe blindly across a stenotic tumor may disturb interpretation of the lesion by distorting the shape of the tumor as well as causing pain and possible perforation. A standard transrectal ultrasound examination is best performed with 360° radial scanning transducers and starts just above the rectosigmoid junction in order to look for enlarged

Figure 37.1 Monitor image during miniprobe endoscopic ultrasound examination of rectal polyp using the picture-in-picture function.

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lymph nodes near the iliac vessels. Additional information about suspicious lymph nodes can be obtained by using a linear array probe, in which the imaging plane is parallel to the rectal axis instead of perpendicular. Flexible instruments are preferred for this type of investigation, allowing fineneedle aspiration (FNA) biopsy under direct EUS guidance. When using HFUS miniprobes, a colonoscope provides a visual evaluation and description of the lesion. The colon is then filled with 200–300 mL of deaerated water and the miniprobe is inserted through the working channel of the colonoscope. Using the “picture in picture” modality, the lesion can be evaluated under direct endoscopic guidance to permit corrections in positioning (Figure 37.1). Sedation for rectal EUS application is generally not necessary. For colonic evaluation by miniprobe, the same sedation is employed as for colonoscopy, i.e., intravenous short-acting benzodiazepine (midazolam), with or without pethidine, or propofol. Standard patient monitoring is mandatory.

Anatomy Endosonographic images of the colorectal wall are a composite of surface reflections and actual layers of the wall. Typically a five-layer pattern is described, although higher ultrasound transducer frequencies allow more layers to be discriminated. Each layer is represented by either a hypoechoic (dark or echo-poor) or hyperechoic (bright or echo-rich) band. Crucial to accurate staging is the identification of the muscularis propria, the fourth (hypoechoic) layer. Controversy still exists as to the anatomic correlation of each layer of the imaged rectal wall. The first model, described by Hildebrandt and Feifel [7], states that the three hyperechoic lines correspond to interfaces, while the two hypoechoic lines represent actual anatomic layers. The first white line is the interface between the balloon and the mucosa, followed by the second interface between the submucosa and muscularis propria, and finally the interface between the muscularis propria and the perirectal fat. The first hypoechoic layer in this theory corresponds to the mucosa and submucosa, making differentiation between a mucosal and a submucosal tumor impossible. In contrast, in the model depicted by Beynon and colleagues [8], the middle three lines correspond to the specific layers of the rectal wall: • first (hyperechoic) layer: the interface between the water/ balloon and the mucosal surface; • second (hypoechoic) layer: combined image produced by the mucosa and muscularis mucosae; • third (hyperechoic) layer: the submucosa; • fourth (hypoechoic) layer: the muscularis propria; • fifth (hyperechoic) layer: the interface between the muscularis propria and perirectal fat. The sonographic layers of the normal colonic wall are similar to those described for the rectal wall, taking into account that

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the colonic wall is surrounded not by hyperechoic perirectal fat, but by a serosal layer. Some authors have further subdivided the fourth (hypoechoic) layer into three layers: two hypoechoic layers representing inner circular and outer longitudinal muscle layers and a thin hyperechoic layer that represents the connective tissue between the two muscle layers [7,9–14]. Using HFUS probes, it is possible to image the colorectal wall as a structure of nine layers, in which the first three echo layers are considered to correspond to the mucosa, the fourth (hypoechoic) layer to the muscularis mucosae, the fifth (hyperechoic) layer to the submucosa, the sixth (hypoechoic) layer to the inner circular muscle, the seventh (hyperechoic) layer to the intermuscularis propria layer, the eighth (hypoechoic) layer to the outer longitudinal muscle layer, and the ninth (hyperechoic) layer to the subserosa and serosa (or perirectal fat). These categories are not absolute, as shown in a study using a 20-MHz ultrasound probe in which imaging the normal colorectal wall as a nine-layered structure succeeded in only half the cases [15].

Colorectal adenocarcinoma The preoperative staging of colorectal malignancies is one of the most important indications for EUS. Because less invasive treatments have been developed for early stages and because neoadjuvant therapy is widely accepted for more advanced stages, the findings of colorectal EUS influence treatment, i.e., endoscopic versus surgical treatment (transrectal local excision, laparoscopic surgery, terminal sphincter-sparing procedures, neoadjuvant chemotherapy, and/or radiotherapy). EUS has been shown to alter clinical decision-making in up to one-third of patients with advanced T-stage [16,17], and in one-half of the cases when taking into account every stage of disease, often leading to a less complicated approach [18]. In colonic cancer proximal to the rectum, preoperative T and N determination, although helpful for prognosis, is not

Figure 37.2 (a) Endoscopic and (b) endosonographic images of a flat villous adenoma in the distal rectum imaged with a dedicated echoendoscope at 12 MHz. The endosonographic image shows a normal five-layer wall pattern at the bottom of the image (5–7 o’clock) and thickening of the second (hypoechoic) layer between 2 and 5 o’clock. The area between 12 and 5 o’clock is not completely in focus. The ultrasound image is compatible with a mucosal lesion; no infiltration in deeper layers is detected.

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of major significance in view of the fact that surgical resection is the major treatment modality.

Endoscopic ultrasound assessment of T-stage Colorectal carcinoma is seen by EUS as an intraluminal or transmural mass altering parts of the wall structure. Most of the time, the tumor is a mainly hypoechoic mass with different types of penetration according to its T-status. Irregular thickening of a layer with a hypoechoic mass is interpreted as the presence of invasion into that corresponding layer. Disruption of a layer by a hypoechoic mass is interpreted as invasion through that corresponding layer. Therefore, the destruction or disappearance of one or more of the normal layers is a reliable indication of depth of tumor invasion, although it is possible for normal hyperechoic layers to disappear because of inflammatory infiltration around a tumor mass [19–23]. The infiltration depth of a colorectal malignancy is based on the tumor–node–metastasis (TNM) classification, with the prefix “u” added, indicating endosonographic staging [7] (Figures 37.2 to 37.6). uT1 is diagnosed when the lesion is limited to either the second or third layer. Complete disruption of the middle echogenic layer, with invasion of the lesion into the fourth hypoechoic layer (representing the muscularis propria), is interpreted as uT2; uT3 is diagnosed when the lesion infiltrates through the muscularis propria. In this case the border between the outer hypoechoic layer and the outer hyperechoic layer (interpreted as serosa or perirectal fat) is irregular or serrated with some pseudopodia. Continuity between the hypoechoic tumor and adjacent structures or organs is indicative of a uT4 tumor. Because of the difficulty in differentiating between a uT2 and uT3 tumor, an alternative criterion has been postulated, whereby an irregular outer border of the muscularis propria is still interpreted as representing a T2 tumor as long as the outer hyperechoic layer (interface between muscle layer and perirectal fat) is not disrupted. Only complete disruption of this hyperechoic layer is in concordance with a T3 tumor. Although this view leads to

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Figure 37.3 (a) Endoscopic and (b) endosonographic images of a slightly more elevated lesion imaged with a miniprobe with 20 MHz frequency. The ultrasound image shows the lesion as a thickened second layer with intact submucosa and muscularis propria. No infiltration can be detected.

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Figure 37.4 (a) Endoscopic and (b) endosonographic images of a polypoid tubulovillous adenoma of the rectum. The examination is done with a 12-MHz miniprobe and the probe is maneuvered close to the edge of the lesion in order to delineate the transition between the normal wall and the lesion, which is limited to the second (hypoechoic) layer.

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Figure 37.5 Substenosing rectal tumor uT3 at 10 MHz with broad extension of the hypoechoic mass through the muscularis propria. No invasion of surrounding organs.

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Figure 37.6 (a) Endoscopic and (b) endosonographic images of a ulcerated unilateral rectal tumor (10 MHz), causing difficulties in interpretation due to air interposition in this uT3 lesion.

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less overstaging of T2 tumors, it does understage some T3 tumors, which can lead to undertreatment [19,24,25]. Several reports and reviews have shown EUS to be superior to digital rectal examination, computed tomography (CT), and MRI in staging rectal cancer, although use of endorectal coil MRI shows a similar accuracy rate to endorectal EUS in T-staging as it is also capable of evaluating the depth of wall invasion [8,26–30]. Even with the use of an endorectal coil, it remains difficult to differentiate between a T1 and T2 lesion. The accuracy level reported for standard CT and MRI ranges between 33% and 77% for CT and between 59% and 95% for MRI [31]. It has to be stated that most patients included in studies using CT had advanced disease, and only few studies classified wall penetration according to TNM classification. In addition, the number of patients included in studies using MRI was very limited, usually fewer than 40 patients. Most of the initial studies in endosonography were performed with blind rigid probes, but more recent data using echoendoscopes showed similar results [32]. The use of the endorectal coil has been abandoned due to the development of high-resolution phased-array surface coil systems, but there are no new studies comparing its efficacy in rectal cancer staging. Moreover, this evolution made it possible to clearly identify the mesorectal fascia and its relation to the edges of the tumor, which is the anatomic landmark for subsequent total mesorectal excision and a major determinant of local recurrence [33,34]. Exact depiction of the mesorectal fascia is mostly not possible with EUS, demonstrating the complementary importance of MRI. Phased-array MRI seems more accurate and reliable in predicting the circumferential resection margin than it is in predicting T-stage [35]. Owing to the importance attributed to the circumferential resection margin as a prognostic factor, EUS can provide additional prognostic information by making a discrimination between T3 tumors that can easily be resected with a wide resection clearance and T3 tumors with more advanced disease [36–38]. In comparing the ability of all imaging modalities for Tstaging accuracy there is a large variability, ranging between 52% and 100%. Pooled data show accuracy for determining wall penetration of 79% for CT, 82% for MRI, and 84% for MRI with endorectal coil. The pooled sensitivity, specificity, and accuracy for colorectal EUS are 93%, 78%, and 87% respectively. A large review of 40 studies showed a similar accuracy of 85.2% [39]. Accuracy is affected by T-stage, with accuracies of 80%, 68%, 94%, and 89% for stages T1–T4, respectively [26,28,40,41]. Three recent large (n > 400) studies showed a lower accuracy of between 69% and 64%, which might be due to the exclusion of advanced tumors because of preoperative radiotherapy, and possibly from lack of experience in the German study [42–44], indicating a learning curve, with, it has been postulated, as many as 50–100 cases having to be performed before consistent accuracy is reached [45]. A recent review showed higher accuracy rates in older studies than in more recent publications, which is common with the

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introduction of new techniques, and an inverse relationship between study size and reported EUS accuracy, both suggesting publication bias, although the inverse relationship can also be explained by a learning curve [39]. In general, in most series overstaging is twice as common as understaging, a particular problem with T2 tumors. This is caused by peritumorous inflammation (inflammatory infiltrate or even abscesses), which cannot be distinguished from malignant tissue, desmoplastic changes, or hypervascularity. Understaging is caused by microscopic invasion beyond the resolution of EUS, or tumor location close to the anal canal or on the valves of Houston. Less accurate staging in the lower rectum is caused by difficulty in reaching an optimal (perpendicular) imaging of all sites of the ampulla recti, especially with a rigid probe, a problem solved by the use of a flexible instrument. Interpretative errors can also affect accuracy, especially the tendency to overestimate a malignant lesion because of concern for undertreatment [16,46–51]. Staging postpolypectomy and postbiopsy also seems to affect accuracy, mainly due to focal edema and/or postpolypectomy hematoma, especially in smaller lesions [23,52–57]. In larger sessile adenomas the incidence of malignancy is postulated to be 20%. Given that endoscopic mucosal resection techniques or surgical transanal excision have enabled the removal of superficial colorectal neoplasms, much attention has been directed to the depth of invasion of these lesions. On the other hand, discrimination between T1 and T2 lesions with MRI remains difficult. Overstaging of adenomas is more likely in the evaluation of villous lesions than nonvillous lesions, especially when large (≥ 20 mm) lesions are taken into account. It was suggested by Mosnier and colleagues [58] that overstaging of villous tumors is due to the difficulty showing the interface between mucosa and submucosa using lowfrequency endosonography [14,22,59]. Understaging in early rectal cancer seems to be even a greater problem, as it might lead to undertreatment. In one series, up to 20% of investigated mucosal lesions showed invasion to the submucosa or deeper. It can be concluded that the resolution of conventional EUS is not always sufficient to provide absolute accuracy in order to determine the appropriate treatment [60,61]. Therefore, the use of high-frequency endosonography is indicated, in which a disruption or irregularity of the submucosal layer is diagnostic for a T1 lesion [62–64]. After endoscopic removal of a malignant polyp, an EUS within the month following polypectomy is recommended by some authors [65]. In locally advanced rectal cancer, preoperative irradiation has resulted in a reduction in local recurrence rate and an increase in disease-free survival. Preoperative radiotherapy also causes changes in echogenicity of the ultrasound image (tumor as well as rectal wall), due to inflammation and/or fibrosis, resulting in a significant decrease in accuracy, ranging from 29% to 75% [66–71]. After irradiation, the rectal wall is thickened and becomes more hypoechoic, allowing a less clear visualization of the different layers, especially the outer

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limit of the rectal wall, as a result of fibrosis. The tumor itself might reveal three different echo features post radiotherapy: 1 a hypoechoic pattern as observed before radiation, with possible changes in both morphology and size; 2 a more hyperechoic and nonhomogeneous pattern; 3 the reappearance of the typical five-layer structure (although thickened) at the site of the tumor, which might correlate with a complete sterilization of the lesion [72]. Owing to its lower accuracy, EUS is considered to be unsatisfactory for predicting treatment response [73].

Endoscopic ultrasound assessment of N-stage In colorectal cancer, not only the depth of penetration but also the involvement of peritumoral lymph nodes are major determinants of prognosis, giving an indication of the risk of disseminated disease. Moreover, identification of metastatic lymph nodes plays an important role in decision-making, and the absence of lymph node involvement in T1 and T2 disease means that this stage of disease is suitable for local resection. However, no single imaging modality shows sufficient accuracy to allow confident determination of metastatic involvement. Determination of lymph node involvement is less accurate than T-staging [13,27,74]. The accuracy of EUS ranges between 44% and 87%. Pooled data show an accuracy of 66% for CT, 74% for EUS, 74% for MRI, and 82% for MRI with endorectal coil [41,75]. A recent review of 27 publications showed a similar N-staging accuracy of 75% [39]. Although CT does not allow discrimination between involved and noninvolved nodes, because the internal structure of the nodes cannot be depicted, a diameter of 1 cm is considered the cut-off value for differentiating between metastatic and inflammatory nodes [76,77]. In a recent study, malignant iliac lymph nodes were more likely to be detected by EUS than by CT, demonstrating a substantial change in management and suggesting the inadequacy of rigid EUS probes in the staging of rectal cancer [78]. The delineation of the mesorectal fascia by MRI in N-staging is also of pivotal importance as the involvement of lymph nodes in the vicinity of the mesorectal fascia is associated with a higher risk of local recurrence. The introduction of ultra-small supermagnetic

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iron oxide particles has shown some promising results, but the particles are not yet clinically available [34]. Overstaging is mainly due to the difficulty of discriminating between inflammatory and metastatic lymph nodes. In contrast to T-staging, in which Doppler ultrasonography has no proven benefit, Doppler has been suggested as useful in differentiating hypoechoic lymph nodes from blood vessels, especially when the vessel is running perpendicular to the scanning plane, in which case a normal vessel is difficult to assess [79,80]. Understaging is due to the presence of metastasis in extramesorectal nodes (out of reach of the endosonographic probe), micrometastasis in small nodes, lymph nodes too small to be visible, and inadequacy of criteria for involved nodes [81]. The normal criteria used elsewhere in the gastrointestinal tract (round in shape, hypoechoic with a distinct border and size) cannot be applied in N-staging for colorectal cancer [82,83]. Initially, suspicious lymph nodes were described as rounded, echo-poor, and with a short-axis diameter greater than 5 mm [28,48] (Figure 37.7). Most of the normal lymph nodes cannot be seen, as they are isoechoic with perirectal fat. Lymph nodes are found by EUS in less than 50–66% of patients [74, 84,85]. Detection increases with their size, and invasive cancer is associated with larger diameters of nodes. Node size itself is a bad indicator of metastatic disease. Although lymph nodes that harbor malignant deposits are usually larger than nonmalignant ones, size alone cannot distinguish reactive hyperplasia from metastatic involvement. Lymph nodes smaller than 3 mm are beyond the resolution of EUS, and up to 20% of lymph node metastases in rectal cancer are smaller than 3 mm. In one series, up to 50% of the positive nodes were smaller than 5 mm [20,86–88]. EUS features of metastatic lymph nodes include a shortaxis diameter ≥ 9 mm (99% specificity), a degree of heterogeneity, and the presence or absence of a hilar reflection, although large interobserver variability makes accurate evaluation difficult. Echogenicity itself is not an objective criterion and depends on the tissue structure of the node, transducer frequency, gain, distance between lymph node and transducer, attenuation due to the overlying tumor, and

Figure 37.7 Suspicious perirectal lymph node in the vicinity of a uT3 lesion with rounded and echopoor characteristics.

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choice of the reference tissue [89–91]. The potential value of EUS elastography in the staging of rectal cancer and the selection of nodes for puncture has not yet been established [92]. The addition of linear EUS and FNA to a radial examination is suggested to increase the accuracy of staging lymph nodes [93,94]. Nevertheless, FNA is not frequently used because of the difficulty of gaining access to a lymph node without transgressing the primary tumor. In several series, FNA led to a change in management in a relatively small percentage of patients, due to the close agreement between the T- and N-stage, and the fact that the visualization alone of perirectal lymph nodes has a much higher predictive value for perirectal lymph node metastasis than for nodes elsewhere in the gastrointestinal tract [17,95]. Other series showed that, in a substantial proportion of patients, management changed as a result of the addition of FNA of perirectal lymph nodes [96]. The addition of hypermethylation gene promoter analysis to the conventional histological evaluation of EUS–FNA samples can detect occult neoplastic cells. The role of digital image analysis and fluorescence in situ hybridization in EUS– FNA samples has not been investigated in rectal cancer [97,98].

Endoscopic ultrasound detection of local recurrence Local recurrence after curative surgery represents a significant problem in 15–25% of patients, with most of the recurrences appearing within the first 2 years after resection, a rate that has declined since the introduction of preoperative radiotherapy and new surgical techniques (total mesorectal excision). Although the percentage of local recurrence is still high, with huge implications for survival and quality of life (and with most patients asymptomatic at the time of diagnosis), early detection is warranted to allow curative reintervention or at least palliative prevention of tumor compression symptoms [99–101]. In addition to MRI, CT has been shown to be very useful in detecting local recurrence, although it has several limitations. For CT to be effective, lesions have to be at least 2 cm in diameter for accurate diagnosis, and the distinction between local recurrence and postoperative alterations remains difficult [102]. MRI gives better results for tumor characterization, with reported accuracy ranging from 75% to 93% [103]. Both CT and MRI have to be repeated frequently in order to permit early detection, which leads to high cost and (for CT) radiation exposure. Because growth of local tumor recurrence is predominantly extraluminal, implying that it is undetectable in follow-up screening by colonoscopy, EUS can be used as the diagnostic method of choice. In one series, local recurrences of up to 3 mm could be detected. Because it is relatively cheap, well tolerated, readily accessible, and does not involve X-ray exposure, EUS appears to be an ideal technique for repeated use in the postoperative monitoring of (colo)rectal cancer. Although postoperative EUS incorporated in a follow-up program has not been proven to influence patient survival,

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some authors propose performing EUS every 6 months during the first 2 postoperative years [104,105]. The reported accuracy rate ranges from 80% to 85%, increasing to more than 90% using FNA. Improving accuracy by EUS-guided biopsy can prevent overtreatment of patients with suspicious lesions [100,104,106,107]. A baseline EUS is suggested by some authors within 3 months after surgery to facilitate the interpretation of later examinations. Because this interval after primary resection is relatively short, any hypoechoic mass must be differentiated from a pelvic floor abscess, a hematoma, or fluid collection [99,102, 108]. A normal anastomosis is visualized as an echo-mixed symmetric interruption of the typical five-layer structure. In the case of stapling, small localized bright echoes appear in the anastomotic wall, without creating a shadow. An extramural recurrence is identified as an oval or circular echo-poor lesion in the perirectal area. An anastomotic recurrence is often seen as a hypoechoic, irregularly shaped area in the anastomotic region that may infiltrate the perirectal fat. Sometimes, it is visualized as an echo-mixed or hyperechoic lesion, especially after radiotherapy. Peritoneal carcinomatosis is diagnosed when EUS shows small hypoechoic nodules (usually < 1 cm) surrounding the colonic serosa, and a heterogeneous mass is detected in the omentum, or can be suspected if ascites is present [103,105,109–111].

High-frequency ultrasound As mentioned earlier, no accurate differentiation is possible between adenomas and uT1 carcinomas because both manifest as a broadening of the second (hypoechoic) layer. Lesions that expand the second layer with invasion into the third (submucosa) have to be considered uT1 lesions [42]. Since the introduction of HFUS probes, due to their higher resolution, accurate staging of more superficially located lesions became possible. An HFUS probe can be introduced through the working channel of a colonoscope, permitting its use in the same session for diagnostic colonoscopy and evaluation of stenotic lesions. It is suggested that HFUS could be the first choice for narrow strictures, early cancer, and submucosal lesions due to its higher resolution, as well as for staging of proximally located lesions [112–115]. According to the Japanese Cancer Society Classification, the submucosa can be divided into three layers: 1 sm1atumor limited to the upper third of the submucosa; 2 sm2atumor limited to the middle third; 3 sm3atumor involving the deep portion of the submucosa. The risk for positive lymph nodes is considered to be 0–3% in T1m and T1sm1, whereas the possibility of lymph node metastasis in T1sm2 and T1sm3 is suggested to be as high as 22%, therefore necessitating surgical therapy [116–120]. To improve accuracy, a new technique called “enhanced EUS” has been created, in which deaerated saline solution is injected into the submucosa to lift the tumor. The saline-infiltrated submucosa is then visualized as a thickened hypoechoic layer,

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whereas an additional echoic layer is seen between the mucosa and submucosa, allowing better distinction of invasion into the submucosa using HFUS [121]. The accuracy rate of HFUS in evaluating colorectal T-staging has been reported to be in the range of 80– 96%. There seems to be no significant difference in staging between colonic and rectal lesions. Accuracy for staging lymph nodes varies between 63% and 87% [15,60,122–124]. Accuracy as low as 24% has been reported in a small number of patients [125]. Accuracy for T-staging is relatively less discriminate in T4 staging, due to the limited depth of penetration, but accuracy is also related to tumor size (accuracy decreases as tumor size increases) and shape (lesser accuracy with protruded lesions). To enhance accuracy, it has been suggested that lower frequencies are used in elevated or large polypoid lesions [15,126–128]. Also, because of attenuation with limited depth of HFUS, deep lymph nodes cannot be detected, although the ability to detect lymph nodes is higher in rectal cancer because rectal lymph nodes are located closer to the rectal wall. Preliminary data show that HFUS performs better than magnifying colonoscopy in predicting invasion depth in early colorectal cancer. Optical coherence tomography offers a better resolution of mucosa and submucosa and could be more accurate in evaluating superficial lesions confined to mucosa and submucosa. This technique seems promising but is still in its experimental stage [125,129]. The fact that in the past few years no large-scale clinical studies with optical coherence tomography have been published makes us believe that an important clinical role in the future is unlikely.

Benign mucosal and submucosal tumors Because EUS is able to evaluate the five-layered structure of the bowel wall, it can be used to differentiate submucosal growth from extraluminal compression in cases in which endoscopy shows only bulging of the normal wall without visible mucosal defects. HFUS can also be used to define accurately the extent of the submucosal lesion before endoscopic mucosal resection [112,130]. Lipomas appear on EUS as hyperechoic lesions with regular borders in the third layer. EUS can be used to determine any extension into the muscularis propria before injectionassisted polypectomy of symptomatic lipomas [131]. Gastrointestinal stromal tumors (formerly designated as leiomyoma, leiomyoblastoma, and leiomyosarcoma) are the most frequent nonepithelial submucosal tumors in the gastrointestinal wall. Gastrointestinal stromal tumors are visualized as hypoechoic masses in continuum with the fourth (muscularis propria) layer, seldom deriving from the muscularis mucosae. Because of its uncertain nature, several criteria have been proposed for distinguishing malignant from more benign forms, recognizing that a definitive diagnosis can be made only by immunohistochemistry. A mass of 40 mm or more in diameter,

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with irregular borders, cystic spaces (> 3 mm), and echogenic foci is depicted as a suspicious lesion. Echogenic foci might be due to fibrosis or cystic degeneration, or may be caused by cellular necrosis. Two or more features are present in most cases of malignant disease. Interpretation is difficult and is strongly dependent on interobserver variability. The accuracy of EUS for the diagnosis of malignant gastrointestinal stromal tumors has been reported to be 78%; the accuracy of EUS– FNA, with the addition of the Ki-67 labeling index, for the diagnosis of malignant gastrointestinal stromal tumors is stated to be 100% [132–135]. Carcinoid tumors are mainly located in the third layer, although they may also appear in the second layer. They are visualized as oval or round lesions, generally slightly hypoechoic and homogeneous. EUS is indicated for evaluation of the size and estimation of the depth of invasion before endoscopic removal. EUS is also useful in determining the presence of local metastasis and lymph nodes [136,137]. A lymphangioma is visualized as a cystic lesion with septal structures in the third layer. Lymphomas are mostly seen as hypoechoic inhomogeneous masses, located in the second to fourth layer [138]. Rectal linitis plastica is characterized by diffuse circumferential thickening of the wall, especially in the submucosa and muscularis propria; extension into the perirectal fat may be visualized. In rare cases, a complete disappearance of the normal five-layer structure can be seen. No distinction is possible between primary and secondary rectal linitis plastica by EUS alone, although EUS–FNA can provide the diagnosis. EUS can be used in follow-up by measuring reduction of rectal wall thickening [139,140]. In portal hypertension, rectal varices appear as rounded, oval, or longitudinal echo-free structures, mainly in the submucosa or outside the wall. Rectal varices often have a diameter greater than 2 mm [141]. Endometriosis, which is predominantly located in the distal colon, may appear as either extrinsic compression or an irregular hypoechoic mass mainly in the fourth layer, in continuity with the fifth layer. Metastases appear as hypoechoic, heterogeneous masses and can potentially be encountered in all layers. Cysts are seen as anechoic, rounded, or ovoid lesions and must be differentiated from pneumatosis cystoides intestinalis and colitis cystica profunda [134,142].

Inflammatory bowel disease Apart from the evaluation of perianal abscesses and fistulae in inflammatory bowel disease, EUS is also useful in the evaluation of colorectal wall involvement, although the impact of EUS on medical therapy is not yet clearly defined [109, 143]. Several parameters have been proposed for evaluation but no reliable criteria are available to make a clear distinction between Crohn’s disease and ulcerative colitis. Involvement of the colorectal wall in Crohn’s disease is characterized by

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thickening, mostly with hypoechoic changes of the submucosa or the whole wall, often with disappearance of the normal five-layer structure, with deep ulcerations and fibrosis of the serosa, correlating well with anatomopathologic findings. Thickening can be present in the absence of mucosal lesions [144,145]. Discontinuity of lesions on EUS suggests Crohn’s disease, as in colonoscopy [22]. In ulcerative colitis there is mostly a thickening of the first three layers, with preservation of the five-layer structure, although involvement of the entire wall has been reported [146,147]. EUS has been used to assess the severity of inflammation and to predict relapse in ulcerative colitis due to persistent wall thickening during remission [148–150]. In collagenous colitis, a broadening of the second layer, consistent with subepithelial collagen bands, and of the fourth layer is observed [151].

Conclusion During the past decade, EUS has proven its reliability and accuracy in colorectal cancer staging, making it an essential and indispensable tool in the preoperative staging and follow-up of colorectal cancer. Although there are limitations, especially in assessment of nodal disease, there is no better, relatively inexpensive alternative available. With the development of HFUS, a better selection of less invasive treatments in patients with early cancer became possible. EUS is clearly the best modality for the evaluation of submucosal lesions, particularly with the addition of FNA. In inflammatory bowel disease, the value of EUS seems rather limited apart from its diagnostic capabilities in perianal disease.

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Narrow-band Imaging Yasushi Sano,1 Fabian Emura2 & Hiroaki Ikematsu3 1

Sano Hospital, Kobe, Japan Emura Foundation for the Promotion of Cancer Research, Bogotá, Colombia 3 National Cancer Center Hospital East, Chiba, Japan 2

Rationale for narrow-band imaging application

Historical background of narrow-band imaging

In 1971, Folkman proposed the hypothesis that all tumor growth is angiogenesis dependent. This founded the field of angiogenesis research, and opened investigations now pursued by scientists in many fields worldwide. New blood vessel development stimulates tumor growth by bringing oxygen and nutrients, thus promoting the transition from hyperplasia to neoplasia, i.e., the passage from a state of cellular multiplication to a state of uncontrolled proliferation characteristic of tumor cells [1,2]. In the colon, studies on the adenoma–carcinoma sequence have demonstrated a gradual increment of microvessel density and a reduction of the apoptosis process during the progression from low-grade to high-grade dysplasia and cancer [3]. Since angiogenesis performs a critical role in the development of solid tumors, an in vivo approach to visualize microvascular anatomy or microvessels’ morphologic changes in superficial neoplasia might constitute a promising method for early diagnosis of epithelial tumors. Narrow-band imaging (NBI) is an innovative optical technology that has the potential to provide detailed characterization of lesions based on changes in the pattern and size of microvessels when tissue becomes hyperplastic, dysplastic, and malignant. These changes are easily observed during endoscopy and are helpful to differentiate abnormal from normal mucosa [4]. The NBI physical principle is based on spectral modifications of conventional white light into shorter wavelengths. The rationale for NBI application is that the shortwavelength light is within the hemoglobin absorption band, so the contrast of the capillary pattern in the superficial mucosal layer is markedly improved and, thus, clear visualization of vascular structures is achieved during endoscopy [5].

Efforts to achieve optical spectral differentiation between normal and abnormal gastrointestinal mucosa were initiated in 1994 as part of the Japanese second-term comprehensive 10-year strategy for cancer control [6]. Conception of the NBI system began in the end of the twentieth century when Japanese investigators used a multispectrum high-powered light camera to study the contrast difference between the vascular pattern of human tongue mucosa by narrow- and broad-band illumination [7]. Also in this study, observations on the reflectance spectra of the gastrointestinal mucosa using an endoscopic spectroscopy system revealed clear differences in spectral data between early cancer and normal tissue [8,9]. These results led to the first clinical application of NBI, reported by Sano et al. [10] in 2001. In 2004, the first NBI study in the colorectum reported better visualization of the vascular pattern than with conventional colonoscopy for the diagnosis of colorectal polyps [11]. In December 2005, the NBI system manufactured by Olympus Corporation became commercially available, opening the field of equipment-based optical image-enhanced endoscopy [4] to the diagnosis of premalignant and malignant epithelial lesions. Currently, multiple studies not only in the colorectum but also in the oropharynx [12], esophagus [13], stomach [14], bronchus [15], and ampulla of Vater [16] have reported the feasibility and efficacy of the NBI system and are revalidating its clinical significance worldwide.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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The blue light physical principle Video endoscopes use white light from a xenon source for illumination. To understand the reflectance spectrum of any tissue, both the scattering process and absorption should be considered. Several investigations into the mechanism of scattering from tissue structures have reported that the depth to which light penetrates depends on the wavelength (Figure 38.1), based on the Monte Carlo simulation (Figure 38.2). In

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Figure 38.1 The endoscopic spectrophotometer system. (a) Reflectance spectral data of early colon cancer using an endoscopic spectroscopy system. The difference in spectral features is apparent in the short wavelength region (white asterisk). (b) The fiber probe of the endoscopic spectroscopy system is inserted through the endoscope channel, and the spectral signal is measured by proximity of the surface. Reflected light from a halogen lamp is sent to the spectrophotometer through an optical fiber which serves as a light guide.

Narrow-band Imaging

Figure 38.2 The Monte Carlo simulation. The center wavelength and the bandwidth have an effect on the penetration depth. The difference in penetration depth between the narrow filters (F4–8) was larger than that between the broadband filters (F1–3). The spectral specifications of the broadband filters (F1–3) were similar to those of the filters used in a conventional illumination unit.

this study, multiple narrow- and broad-band filters were used to evaluate spectral differences in tissues. The contrast difference was apparent in the blue short-wavelength light, and two trichromatic optical filters were selected for the new systemaNBI [7,8]. The filters in the processor cut all illumination wavelengths, except two narrow bands. The central wavelengths of each band are 415 and 540 nm. During endoscopy, the wavelength of 415–30 nm provides the most information on the capillary and pit patterns of the super-

ficial mucosa and the wavelength of 540–30 nm provides information on thicker capillaries in the slightly deeper tissue (Figure 38.3). Standard white-light endoscopy uses the full visible red– green–blue wavelength range (400–800 nm). In contrast, the NBI system modifies both the center wavelengths and the bandwidths of the light spectrum (Figure 38.4), producing a final illumination color emerging from endoscopes as not white but blue (Figure 38.5). This blue short-wavelength light is within the hemoglobin absorption band, resulting in clear visualization of blood vessels.

Figure 38.3 Narrow-band images and fusion images (filter combinations) showing anterior mucosa of the human tongue. On narrow-band images (a–g), the appearance of blood vessels depended on the center wavelength and thickness of the blood vessels. The thick blood vessel marked by a white arrow in (c) could not be seen well in (a). (a) NBI using 415–30 nm (center wavelengthbbandwidth of filters), (b) NBI using 540–30 nm, (c) NBI using

600–20 nm, (d) fusion image of (a–c), (e) NBI using 415–30 nm, (f) NBI using 445–30 nm, (g) NBI using 500–30 nm, (h) fusion image of (e–g). The color image in (d) looks more natural than that in (h). However, the capillary pattern was clearer in (h). Therefore, three sets consisting of 415–30 nm, 445–30 nm, and 500–30 nm were selected as the trichromatic optical filters of NBI. NBI, narrow-band imaging.

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(a)

400 (nm)

500 (nm)

600 (nm)

400 (nm)

500 (nm)

600 (nm)

(b)

Figure 38.4 Filters and illumination. (a) Spectral data of standard red, green, and blue filters in comparison with narrow-band imaging filters (b). The filter decreases the illumination of all wavelengths, except two narrow wavelengths. The central wavelengths of each band are 415 nm and 540 nm.

Difference between conventional chromoendoscopy and narrow-band imaging Although in Japan chromocolonoscopy has demonstrated effectiveness in the identification of adenomatous from hyperplastic polyps and in differentiating superficial from deep

(a)

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submucosal early lesions [17], in the West it is considered inconvenient and difficult to reproduce [18]. Indigo carmine dye spraying is inexpensive and in practice differs from the NBI system in that it does not target the superficial vascular patterns but accentuates the contours of the lesion and highlights the pit pattern of the colonic crypts [19]. Interestingly, spraying of indigo carmine is not recommended before NBI as it may obscure blood vessel visualization. NBI defines clearly the borders of a lesion without the need for dye spraying and is helpful for pit pattern identification, but it also provides accurate definition of vascular capillary vessels of the colonic mucosa. As for lesions with adherent mucus, assessment of the pit pattern by magnifying chromoendoscopy is difficult. In contrast, the NBI method does not require dye, therefore the assessment of the pit pattern is possible even with adherent mucus [20]. In addition, NBI optical image-enhanced endoscopy seems to be more appealing to Western endoscopists, who generally have not embraced the use of chromoendoscopy in the colon [21]. However, the diagnostic accuracy of NBI may be affected by the learning curve associated with this new technique [22], and extra time might be needed to acquire proficiency in diagnosis.

Using the narrow-band imaging system at the endoscopy unit In early prototypes, the NBI system was activated by an assistant, who pushed a button within the video processor unit, making the procedure impractical and time-consuming. Currently, the NBI system is incorporated into the Olympus Luxera or Exera II video processors but activated from a onetouch button located at the control head of the endoscope (Figure 38.6). The left forefinger can activate the NBI system and keep the lesion in view, providing a fast and electronic alternative to chromoendoscopy. Once the NBI system is activated, meshed capillary vessels are seen as green–brown in color and the surrounding normal colonic mucosa as yellowish (Figure 38.7).

Figure 38.5 Final illumination using standard filters (a) and using narrow-band imaging filters (b).

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Figure 38.6 Narrow-band imaging activation button. The narrow-band imaging system is activated through a single operator-controlled switch based on “push the button (red arrow) and the system will do the rest.”

The hue of non-neoplastic lesions is very similar to that of the normal epithelial layer, whereas the majority of neoplastic lesions appear brownish. On the other hand, feces and intestinal liquids have a reddish color, being sometimes misinterpreted as small polyps (Figure 38.8) [23].

Narrow-band imaging for screening colonoscopy Several back-to-back studies on detection of adenomatous polyps in the proximal colon have demonstrated that chromoendoscopy with indigo carmine significantly improves the detection rate of significant neoplastic lesions in the setting of

Figure 38.7 Standard light and NBI images. (a) Conventional colonoscopy findings of blood vessels in a normal sigmoid colon. Thick veins and capillaries are seen. (b) In NBI colonoscopy, in addition to thick veins and capillaries, fine capillaries are seen and network mucosal vessels are well visualized in much finer detail than in conventional colonoscopy. NBI, narrow-band imaging.

(a)

Narrow-band Imaging

hereditary nonpolyposis colorectal cancer (HNPCC) screening [24,25]. Although, in theory, NBI “optical chromoendoscopy” is supposed to have at least the same impact on screening colonoscopy as conventional chromoendoscopy, further validation studies are needed. Results of randomized prospective studies report on the number of lesions detected during colonoscopy and may vary according to the type of patients (HNPCC or non-HNPCC relatives). East et al. [26] in a backto-back study of 62 patients from HNPCC families demonstrated that the second pass with NBI detected significantly more adenomas than the first pass with white-light colonoscopy (P = 0.004). In addition, the proportion of flat adenomas detected with NBI, 9/21 (45%), was higher than in the white-light pass, 3/25 (12%), (P = 0.03). On the other hand, other studies with non-HNPCC patients have reported different results. Adler et al. [27], in a prospective randomized study, stated that, although adenomas were detected more frequently in the NBI group (23%) than in the control group (17%), the difference was not statistically significant (P = 0.129). Rex et al. [28], using high-definition colonoscopes with either white light or NBI, reported that NBI did not result in a high adenoma detection rate. Recent pilot and single-center studies, however, have reported a higher overall number of neoplastic lesions and of flat and diminutive lesions using NBI than using white-light colonoscopy [29–31].

Narrow-band imaging for non-neoplastic and neoplastic lesions Although the general consensus is to remove adenomas > 10 mm [32–33], no consensus exists for polyps < 10 mm. Different management strategies include resection, biopsy only, or no treatment. Recently, an increasing rate of colorectal cancers < 10 mm has been reported [34–36], which suggests that colorectal polyps should not be treated only on the basis of their size, but also on the basis of the underlying

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histological characteristics observed during high-resolution colonoscopy [37]. Taking into account lesions < 10 mm, it is accepted that hyperplastic polyps and other non-neoplastic colorectal lesions do not require endoscopic treatment because they are benign and do not have malignant potential [38,39]. In contrast, adenomatous polyps should be removed to prevent the progression of the adenoma–carcinoma sequence [40,41]. Although not comparable with biopsy, magnifying chromocolonoscopy is highly effective for in vivo selective management of colorectal polyps [33,42]. The most widely used intravital staining technique for observation of pit pattern [43] is indigo carmine application. An early study with a prototype NBI system examined 34 patients with 43 lesions and reported better visualization of the mucosal vascular network and of the color of lesions than with conventional endoscopy. Both chromocolonoscopy and NBI had a sensitivity of 100% and a specificity of 75% [11]. Subsequently, differences between conventional colonoscopy, chromoendoscopy, and NBI for distinguishing neoplastic and non-neoplastic colonic polyps were assessed by Su et al. [44] in 78 patients with 110 lesions. No significant differences between the NBI system and chromoendoscopy were detected. The sensitivity, specificity, and accuracy of conventional colonoscopy were significantly lower (82.9%, 80.0%, and 81.8%, respectively)

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Figure 38.8 Frequent NBI images during colonoscopy. (a) In NBI colonoscopy, intestinal contents have a reddish color similar to blood seen with conventional white light. (b) Intestinal fluids with standard colonoscopy. (c) In NBI colonoscopy, feces appear to be reddish similar to a polyp. (d) Feces under standard colonoscopy. NBI, narrow-band imaging.

than that of both chromoendoscopy and the NBI system (95.7%, 87.5%, and 92.7%, respectively). The usefulness of NBI for pit pattern diagnosis of colorectal neoplasia was also demonstrated in 148 colorectal lesions observed first under NBI magnification without chromoendoscopy and then under standard magnification with chromoendoscopy. The two systems were of equal diagnostic value [20].

Meshed capillary vessels by narrow-band imaging Most hyperplastic polyps are seen as light brown lesions without a vascular network on NBI colonoscopy. Adenomatous polyps, on the other hand, including flat and depressed types, are seen as dark-brown vascular lesions which are easily detected during endoscope withdrawal without the application of any dye solution (Figure 38.9) [45]. The usefulness of NBI in demonstrating meshed capillary vessels for differential diagnosis of colorectal small polyps has been shown to have an overall diagnostic accuracy, sensitivity, and specificity for distinction between neoplastic and non-neoplastic lesions or 95.3% (143/150), 96.4% (107/111), and 92.3% (36/39), respectively (P < 0.0001) [46,47]. This

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Figure 38.9 Meshed capillary vessels by NBI (a) Hyperplastic polyp: Kudo’s type II pit pattern seen by magnifying observation using NBI without any dye solution; meshed brown capillary vessels are not seen. (b) Adenomatous polyp: Kudo’s type IIIL pit pattern demarcated by meshed brown capillary vessels are seen by magnifying observation using NBI without application of dye solution. NBI, narrow-band imaging.

Meshed capillary vessel (a)

prospective study demonstrated that simple visualization of the surface meshed capillary pattern using magnifying NBI is effective in differentiating colorectal polyps < 10 mm without the application of any dye solution.

Benefit of in vivo diagnosis of small colorectal polyps Previous studies of patients undergoing colonoscopy have found that small polyps are identified during more than 50% of such examinations [48]. More than half of these small polyps are adenomas [49]. Therefore, a key clinical decision in patients with small polyps may depend on determination of the histology. The Paris endoscopic classification of superficial neoplastic lesions recommends avoiding resection of colorectal non-neoplastic lesions by performing biopsy before resection [50]. In addition, it has been stated that every effort should be made during colonoscopy to obtain a tissue diagnosis when encountering polyps, masses, lesions, or colonic strictures [51]. However, if lesions could be accurately recognized as non-neoplastic or neoplastic at colonoscopy, then biopsies or resection would be unnecessary. This approach might save time and minimize the risk for unnecessary interventions [37]. Therefore, in addition to making technical changes to decrease polypectomy complications rates, efforts to reduce the number of unnecessary biopsies or polypectomies in patients with non-neoplastic polyps would also be beneficial. Magnifying chromoendoscopy has clearly shown the detail and pattern recognition to identify neoplastic lesions. With this technology, the number of biopsies can be decreased because only relevant lesions need to be biopsied or removed. In spite of its advantages, chromoendoscopy has not been widely used because of concerns that it is time-consuming, a messy technology, not well standardized, and that interpretation of the visible surface detail is too difficult [52]. NBI addresses all the deficiencies of chromoscopy, as simple visualization of the surface meshed capillary pattern is easy to reproduce and is simpler and faster than conventional chromocolonoscopy.

(-)

Narrow-band Imaging

Meshed capillary vessel

(+)

(b)

Furthermore, meshed capillary vessel evaluation is highly effective in differentiating colorectal polyps. Global application of NBI for in vivo distinction of non-neoplastic and neoplastic lesions has the potential to greatly increase the efficiency of colonoscopic procedures in terms of reducing resources, the number of biopsies, the total procedure time, and complications from unnecessary polypectomies (Figure 38.10) [23,39].

Nonmagnifying narrow-band imaging system Since 2001, Japanese studies have routinely used magnifying NBI endoscopes to evaluate colorectal polyps with excellent results. Although utilization of NBI technology has been increasing, the lack of magnifying NBI endoscopes in many Western countries has in part limited the reproducibility of the Japanese results. Recently, however, studies from the Western hemisphere have reported the advantages of nonmagnifying NBI (Olympus Exera II system) over conventional white light during screening colonoscopy. Rastogi et al. [29], using nonmagnifying NBI after an initial screening with white light, observed five different surface/vascular patterns, and reported a sensitivity, specificity, and overall accuracy of 86%, 96%, and 92%, respectively, in the diagnosis of hyperplastic polyps and of 96%, 86%, and 92%, respectively, in the diagnosis of adenomatous polyps. It has not been shown whether NBI without magnification is as accurate as the system used in Japan for the estimation of the depth of invasion of early colorectal cancer. Prospective validation studies using nonmagnifying endoscopes are needed.

Narrow-band imaging for noninvasive and invasive colorectal cancer Evidence supports the theory that lesions with submucosal invasion limited to < 1000 μm (sm1) with neither

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lymphovascular invasion nor a poorly differentiated component do not have lymph node metastases [50]. In Japan, the analysis of the pit patterns proposed by Kudo (see Chapter 31) has proven effective in allowing accurate prediction of the level of submucosal invasion. In practice, there are limitations of white-light visualization of the VI pit pattern to discriminate between m–sm1 and submucosal deep invasion (sm2) [18,53]. The pattern observed under magnifying chromocolonoscopy proposed by Fujii et al. (distorted and irregular crypts, and a specific demarcated area) has been reported to be effective in predicting sm2 invasion [54– 56]. One of the promising fields of the NBI system is the possibility of accurate depth estimation of early colorectal cancer. Hirata et al. [20] reported a high concordance between the analysis of pit pattern by NBI and by chromoendoscopy. However, in early carcinoma the concordance in the evaluation of VI pit pattern between magnifying chromocolonoscopy and NBI was only 78%. Two other promising studies on the prediction of the depth of invasion of early colorectal cancer by analyzing the microvascular architecture have been reported. Using NBI with magnification, Fukuzawa et al. [57] observed several characteristics of the microvascular architecture in early colorectal lesions (m–sm1 and sm2–3). The univariate analysis showed that wide caliber, irregular caliber, tortuosity, irregularity, short length, and nondense arrangement were significantly more frequent in sm2–3 cancers than in m–sm1 cancers

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Figure 38.10 Chromoendoscopy and NBI images. (a) Standard colonoscopy shows a lesion type 0-IIA, 4 mm in size located in the rectum. (b) Under NBI, the lesion is seen to have a dark brown surface (like a brown disk-shaped blob) (c) Magnifying NBI shows a Kudo type IIIL pit pattern demarcated by meshed brown capillary vessels. (d) Magnification white-light image observation after spraying with indigo carmine dye shows a Kudo type IIIL pit pattern similar to that in NBI colonoscopy. NBI, narrowband imaging.

(P < 0.001). In the multivariate analysis, only irregularity remained as an independent factor (odds ratio = 22.9, P = 0.019). Horimatsu et al. [58] analyzed the presence of “meshed brown capillary vessels” in colorectal lesions (m, sm1, and sm2) by NBI colonoscopy with magnification. The overall diagnostic accuracy, sensitivity, and specificity of microvessel density and of lack of uniformity of microvessel diameter for distinction between sm1 and sm2 lesions were 82.4%, 93.3%, and 75.0% respectively.

Vessel diameter measured by immunohistochemistry Experimental studies, which were performed by scanning electron microscopy of benign and malignant human colonic tumors using microvascular casting techniques, gave early evidence for the existence of qualitative and quantitative differences in the vascular architecture of normal colonic mucosa, adenomas, and carcinomas. Specifically, an increased and progressive vascular density was observed in the progression from normal to benign and malignant tumors, suggesting that tumor progression correlates with active neovascularization [59,60]. A study of the microvascular proliferation and vessel diameter by immunostaining of endothelial cell with anti-human

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Figure 38.11 Immunostaining of microcapillary vessels in different colonic tissues. Anti-CD31 (clone JC/70A, DAKO, dilution 1:20) staining of endothelial cells. Original magnification ×100. (a) The superficial portion of normal colonic mucosa: many microcapillary vessels measuring approximately 10 mm are seen in the stromal tissue. (b) The superficial portion of hyperplastic polyps: many microcapillary vessels measuring approximately 10 mm are seen in the stromal tissue as with normal mucosa. (c) The superficial portion of adenomatous polyps: thicker capillaries are seen surrounding the adenomatous glands. (d) The superficial portion of well-differentiated adenocarcinoma: thicker capillaries are seen surrounding the cancerous glands.

(a)

(b)

(c)

(d)

monoclonal CD-31 antibody in specimens of normal colonic mucosa, hyperplastic polyps, adenomas, and carcinomas [60], showed clear differences in vessel diameter between the samples. Meshed capillary vessels measuring less than 12 μm were seen in the stroma at the surface of normal colonic mucosa and hyperplastic polyps. In contrast to hyperplastic polyps, an increased number of vessels per high-power field as well as thicker capillary vessels (20–30 mm) surrounding glands just under the basal membrane were seen in adenomatous polyps and cancerous lesions. These immunohistochemical findings further validated earlier experimental observations, and in addition suggest that meshed capillary vessels at the surface of adenomatous polyps and cancerous lesions, but not hyperplastic polyps, are increased in number and diameter (Figure 38.11).

Rationale for differences in size of meshed capillary vessels in colorectal polypscthe Toppan test Even with magnifying colonoscopy, meshed capillary vessels in normal colonic mucosa and hyperplastic polyps are invisible or faintly visible, and those on the surface of adenomatous polyps and cancer lesions are clearly visible. Studies with optical standardization techniques (Toppan test chart No. 1, Toppan Printing Company, Tokyo, Japan) have suggested that

Narrow-band Imaging

capillary vessels < 12 μm (normally present) are not visible by magnifying endoscopes due to limitations of the endoscope system resolution (Figure 38.12) [61].

The Sano–Emura narrow-band imaging classification of the capillary pattern Using magnifying NBI, the meshed capillary network, normally arranged in a honeycomb pattern around the mucosal glands, is classified into four types: capillary pattern types I, II, IIIA, and IIIB [23,61].

Normal colonic mucosa (capillary pattern type I) The vascular network of the mucosa is visualized in much finer detail with NBI than with standard colonoscopy. Thick veins and fine capillaries appear brown. However, meshed capillary vessels (diameter < 12 μm) arranged in a honeycomb pattern around the mucosal glands are invisible or faintly visible under NBI because the endoscopic resolution is not high enough to visualize the network.

Hyperplastic polyps (capillary pattern type I) Most hyperplastic polyps can be seen as light brown lesions without neovasculature. Kudo’s type II pit pattern can be seen with magnifying observation using NBI without a dye solution. In many cases, the mucosal capillary meshwork

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MC (-), MVP: type I

MC (+), MVP: type II

(usually < 10 μm) is invisible or faintly visible. However, meshed capillary vessels are recognized in some polyps such as large hyperplastic polyps [62,63] and hyperplastic polyps with serrated adenomatous change [19].

Adenomatous lesions (capillary pattern type II) Adenomatous lesions including the flat and depressed types can be seen as dark-brown neovascular lesions (brownish area) on NBI colonoscopy without magnification, and are easily detected during withdrawal of the colonoscope. Kudo’s type IIIL or IV pit pattern, indicated by the appearance of meshed capillary vessels, can be seen without the application of a dye solution. Meshed capillary vessels are clearly visible because these capillaries are elongated and have larger diameters (12–18 μm) than hyperplastic polyps. In general, lesions diagnosed as capillary pattern type II should be resected by hot biopsy, snare polypectomy, or endoscopic mucosal resection.

Intramucosal and superficial submucosal cancer (capillary pattern type IIIA) The meshed capillary vessels are clearly visible and appear more uneven and thicker (diameter > 18 μm) than those in adenomatous polyps, often with branching and irregularity. Meshed capillary vessels of intramucosal and superficial submucosal cancer (sm1) are characterized by a lack of uniformity (blind ending, branching) and an increased density of microvessels. Therapeutically, lesions diagnosed as capillary

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Figure 38.12 Benchmark study with the Toppan test. (a) Magnifying observation of a 3-mm2 plate (Toppan test chart No. 1). The highlighted area relates to 8- to 12-mm bars, which are not clearly visible or distinguishable, owing to the endoscope resolution. (b) Magnifying observation of a hyperplastic polyp 3 mm in size, meshed capillary (-), capillary pattern type I. At this magnification, it is not possible to identify 8- to 12-mm-diameter meshed capillary vessels as shown in Figure 38.6a. (c) Magnifying observation of a 3-mm2 squared plate (Toppan test chart No. 1). The highlighted area relates to the 14- to 20-mm bars, which are clearly visible at this magnification. (d) Magnifying observation of an adenomatous polyp, 3 mm in size, meshed capillary (+), capillary pattern type II. Observation of meshed capillary vessels in the range of 14–20 mm are evident as shown in Figure 38.6c.

pattern type IIIA should be removed by snare polypectomy, endoscopic mucosal resection, or endoscopic submucosal dissection.

Deep submucosal invasive cancer (capillary pattern type IIIB) Microvascular observation of colorectal cancer lesions with magnifying NBI has demonstrated that, in addition to the characteristics shown by capillary pattern type III lesions, there are also findings highly associated with deep submucosal invasion or beyond [57,58]. In addition to a lesion showing a clear distinction between normal/cancerous mucosa on the surface they have a nearly avascular or loose microvascular area in the stromal tissue due to histological desmoplastic changes. Therapeutically, lesions diagnosed as capillary pattern type IIIB should be removed surgically. Microvessel architecture and capillary diameters are summarized in the Sano–Emura classification of capillary pattern patterns (Figure 38.13). Representative images of lesions corresponding to capillary pattern types I and IIIB are shown in Table 38.1. Recently, Katagiri et al. [64] reported that capillary patterns observed by NBI with magnification provided high accuracy for distinction between low-grade dysplasia (capillary pattern type II) and high-grade dysplasia/invasive cancer (capillary pattern type III). Sensitivity and specificity were 90.3% and 97.1%, respectively. The overall accuracy was 95.5%.

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I

II

IIIA

Narrow-band Imaging IIIB

Endoscopic findings

Meshed capillary vessels (–)

Histology

Normal mucosa Hyperplastic polyp

Treatment

No treatment

Meshed capillary vessels characterized by branching, curtailed irregularity and blind ending

Meshed capillary vessels (+) Capillary vessel surrounds mucosal glands

Lack of uniformity High density of capillary vessels

Adenoma *m cancer and **Sm-superficial cancer

Endoscopic treatment (polypectomy or EMR)

Nearly avascular or loose microcapillary vessels

#Sm-deep Cancer

Surgical treatment

Figure 38.13 Endoscopic characteristics of lesions and clinical application of Sano’s modified classification of the capillary pattern of colorectal lesions. *Intramucosal cancer. **Sm superficial cancer (< 1000 mm). #Sm deep invasion (≥ 1000 mm).

Detection of dysplastic areas in ulcerative colitis Patients with long-standing ulcerative colitis are at increased risk of developing colorectal cancer. However, endoscopic detection of early neoplasia is difficult because these lesions can be subtle or even macroscopically invisible. A laborious protocol of not only target biopsies from suspicious lesions but also two to four random biopsies taken every 10 cm of colon has been proposed [65,61]. Currently, magnifying chromocolonoscopy has emerged as the best available method for identifying dysplastic lesions in the setting of bowel inflammatory disease [66,67]. In a study of patients with long-standing ulcerative colitis, the sensitivity of NBI for the detection of patients with neoplasia was similar to that of conventional colonoscopy, although more suspicious lesions were found during NBI colonoscopy [68]. Because NBI shows fine superficial blood vessels whose diameter and density are greater in neoplastic lesions than in normal mucosa, studies with a third-generation prototype have demonstrated that dysplastic lesions seen with NBI have

a stronger (blacker) capillary vascular pattern than normal mucosa [69].

Future perspective The basic foundations for proficiency in NBI diagnosis of colorectal lesions are interpretation of the pit pattern proposed by Kudo and knowledge of magnifying colonoscopy. Training general endoscopists with the principles of optical endoscopy applied in Japan such as stereomicroscopy, conventional chromoendoscopy, magnifying colonoscopy, and pit pattern analysis [70–73] is becoming a priority in Western countries. In practice, the new technical developments provided by new-generation NBI prototypes seem to have clear advantages over conventional chromocolonoscopy. However, further studies are still needed to validate the effectiveness of NBI for screening colonoscopy, for detection of adenomatous polyps, in estimating the depth of invasion of early colorectal cancer, and in the detection of dysplastic lesions in the setting of inflammatory bowel disease.

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Table 38.1 Schematic microvessel architecture and capillary diameters of colorectal lesions by magnifying narrow-band imaging (Sano–Emura classification). Capillary characteristics

Vessel diameter (mm) (minimum–maximum)

Visibility using narrow-band imaging (capillary pattern classification)

Normal mucosa

Mucosal capillary network (meshwork) arranged in a honeycomb pattern around the mucosal glands

8.6 ± 1.8 to 12.4 ± 1 .9 (6.4–20.9)

MC vessel: invisible or faintly visible (capillary pattern type I)

Hyperplastic

Mucosal capillary network (meshwork) arranged in a honeycomb pattern around the mucosal glands

< 10

MC vessel: invisible or faintly visible (capillary pattern type I)

Adenoma

Vascular casts showed that the microvasculature have a similar organization to the normal colon. However, capillaries are elongated and have increased diameters compared to normal

13.1 + 3.3

MC vessel: clearly visible, slightly thicker capillaries; capillary density: loose (capillary pattern type II)

Carcinoma

Vascular casts of colonic carcinoma is characterized by a disorganized structure and increased density of microvessels. The increased number and density of microvessels results in formation of nodular clusters of capillaries

18.3 ± 0.1 to 19.8 ± 7.6 (2.2–84.5)

MC vessel: clearly visible, thicker capillaries, unevenly sized with branching and curtailed irregularity (capillary pattern type IIIA)

Schematic microvessel architecture

MC vessel: presence of a nearly avascular or loose microvascular area due to histological desmoplastic changes in the stromal tissue (capillary pattern type IIIB) MC, mucosal capillary.

At present, evidence suggests that NBI constitutes an electronic alternative for chromocolonoscopy and is a reliable tool for in vivo visualization of vascular structures. Hopefully, in the future NBI will become an increasingly reliable tool with scientific evidence to support its clinical applications.

Manabu Muto, Kazuhiro Kaneko, Atsushi Ohtsu, and Shigeaki Yoshida (National Cancer Center East Hospital, Chiba, Japan) for invaluable advice in developing the NBI system.

References Acknowledgments We are grateful to Kazuhiro Gono, Kenji Yamazaki, Masao Sambongi, Makoto Igarashi, and Nobuyuki Douguchi, Olympus Medical Systems Company, who helped with the engineering and development of the NBI mechanism. We also thank Dr. Hisao Tajiri (Jikei University School of Medicine, Tokyo, Japan) and Drs. Masahito Kotaka, Masanori Toyoda, Hirohisa Machida, Yasuo Hamamoto, Takahiro Horimatsu, Kuang-I Fu,

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5 Muto M, Katada C, Sano Y, et al. Narrow band imaging: a new diagnostic approach to visualize angiogenesis in superficial neoplasia. Clin Gastroenterol Hepatol 2005; 3: S16–20. 6 Yoshida S. Narrowband imaging: historical background and basis for its development. In: Cohen J (ed.). Advanced Digestive Endoscopy: Comprehensive Atlas of High Resolution Endoscopy and Narrowband Imaging. Oxford: Blackwell Publishing, 2007: 4–5. 7 Gono K, Obi T, Yamaguchi M, et al. Appearance of enhanced tissue features in narrow-band endoscopic imaging. J Biomed Opt 2004; 9: 568–77. 8 Gono K, Yamazaki K, Doguchi N, et al. Endoscopic observation of tissue by narrowband illumination. Optical Rev 2003; 10: 211–15. 9 Sanbongi M, Igarashi M, Obi T, et al. Analysis of spectral reflectance using normalization method from endoscopic spectroscopy system. Opt Rev 2002; 9: 238– 43. 10 Sano Y, Kobayashi M, Hamamoto Y, et al. New diagnostic method based on color imaging using narrow-band imaging (NBI) system for gastrointestinal tract [abstract]. Gastrointest Endosc 2001; 53: 125. 11 Machida H, Sano Y, Hamamoto Y, et al. Narrow-band imaging in the diagnosis of colorectal mucosal lesions: a pilot study. Endoscopy 2004; 36: 1094– 8. 12 Muto M, Nakane M, Katada C, et al. Squamous cell carcinoma in situ at oropharyngeal and hypopharyngeal mucosal sites. Cancer 2004; 101: 1375– 81. 13 Yoshida T, Inoue H, Usui S, Satodate H, Fukami N, Kudo SE. Narrow-band imaging system, with magnifying endoscopy for superficial esophageal lesions. Gastrointest Endosc 2004; 59: 288– 95. 14 Nakayoshi T, Tajiri H, Matsuda K, Kaise M, Ikegami M, Sasaki H. Magnifying endoscopy combined with narrow band imaging system for early gastric cancer: correlation of vascular pattern with histopathology (including video). Endoscopy 2004; 36: 1080– 4. 15 Shibuya K, Hoshino H, Chiyo M, et al. High magnification bronchovideoscopy combined with narrow-band imaging could detect capillary loops of angiogenic squamous dysplasia in heavy smokers at high risk for lung cancer. Thorax 2003; 58: 989– 95. 16 Uchiyama Y, Imazu H, Kakutani H, et al. New approach to diagnosing ampullary tumors by magnifying endoscopy combined with a narrow-band imaging system. J Gastroenterol 2006; 41: 483– 90. 17 Gross SA, Wallace MB. Hold on Picasso, narrow band imaging is here. Am J Gastroenterol 2006; 101: 2717–18. 18 Kato S, Fujii T, Koba I, et al. Assessment of colorectal lesions using magnifying colonoscopy and mucosal dye-spraying: can significant lesions be distinguished? Endoscopy 2001; 33: 306–10. 19 Sano Y, Saito Y, Fu KI, et al. Efficacy of magnifying chromoendoscopy for the differential diagnosis of colorectal lesions. Dig Endosc 2005; 17: 105–16. 20 Hirata M, Tanaka S, Oka S, et al. Magnifying endoscopy with narrow band imaging for diagnosis of colorectal tumors. Gastrointest Endosc 2007; 65: 988– 95. 21 East JE, Saunders BP. Look, remove, and discard: can narrowband imaging replace histopathology for small colorectal polyps? It is time to push the button! Gastrointest Endosc 2007; 66: 953– 6. 22 Sharma P, Bansal A, Mathur S, et al. The utility of a novel narrow band imaging endoscopy system in patients with Barrett’s esophagus. Gastrointest Endosc 2006; 64: 167–75. 23 Sano Y, Yoshida S. Optical chromoendoscopy using NBI during screening colonoscopy: usefulness and application. In: Cohen J

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41 Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993; 329: 1977– 81. 42 Fu KI, Sano Y, Kato S, et al. Chromoendoscopy using indigo carmine dye spraying with magnifying observation is the most reliable method for differential diagnosis between non-neoplastic and neoplastic colorectal lesions: a prospective study. Endoscopy 2004; 36: 1089– 93. 43 Kudo S, Tamura S, Nakajima T, Yamano H, Kusaka H, Watanabe H. Diagnosis of colorectal tumorous lesions by magnifying endoscopy. Gastrointest Endosc 1996; 44: 8–14. 44 Su MY, Hsu CM, Ho YP, Chen PC, Lin CJ, Chiu CT. Comparative study of conventional colonoscopy, chromoendoscopy, and narrow-band imaging systems in differential diagnosis of neoplastic and nonneoplastic colonic polyps. Am J Gastroenterol 2006; 101: 2711–16. 45 Sano Y, Muto M, Tajiri H, Ohtsu A, Yoshida S. Optical/digital chromoendoscopy during colonoscopy using narrow band imaging system. Digest Endosc 2005; 17: S60–5. 46 Sano Y, Horimatsu T, Fu KI, Katagiri A, Muto M, Tajiri H, Yoshida S. Magnified observation of microvascular architecture using narrow band imaging (NBI) for the differential diagnosis between non-neoplastic and neoplastic colorectal lesion. A prospective study [abstract]. Gastrointest Endosc 2006; 63: 102. 47 Sano Y, Ikematsu H, Fu KI, et al. Meshed capillary vessels using narrow band imaging for differential diagnosis of small colorectal polyps. Gastrointest Endosc 2008; epub ahead of print. 48 Weston AP, Campbell DR. Diminutive colonic polyps: histopathology, spatial distribution, concomitant significant lesions, and treatment complications. Am J Gastroenterol 1995; 90: 24–8. 49 Waye JD, Lewis BS, Frankel A, Geller SA. Small colon polyps. Am J Gastroenterol 1988; 83: 120–2. 50 The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003; 58: S3– 43. 51 Davila RE, Rajan E, Adler D, et al. ASGE guideline: the role of endoscopy in the diagnosis, staging, and management of colorectal cancer. Gastrointest Endosc 2005; 61: 1–7. 52 Kiesslich R, Neurath MF. Magnifying chromoendoscopy: effective diagnostic tool for screening colonoscopy. J Gastroenterol Hepatol 2007; 22: 1700–1. 53 Kudo S, Rubio CA, Teixeira CR, Kashida H, Koruge E. Pit pattern in colorectal neoplasia: endoscopic magnifying view. Endoscopy 2001; 33: 367–73. 54 Saito Y, Emura F, Matsuda T, Saito D, Fujii T. Invasive pattern is an indication for surgical treatment. Gut online 2004. Available at: gut.bmjjournals.com/cgi/eletters/53/2/284 (accessed March 4, 2005). 55 Saito Y, Uraoka T, Matsuda T, et al. Endoscopic treatment of large superficial colorectal tumors: a case series of 200 endoscopic submucosal dissections (with video). Gastrointest Endosc 2007; 66: 966–73. 56 Emura F, Saito Y, Matsuda T, et al. How to diagnose early rectal adenocarcinoma? Endoscopic features and predictors of submucosal invasion at National Cancer Center Tokyo [abstract]. Gastrointest Endosc 2005; 61: 249. 57 Fukuzawa M, Saito Y, Matsuda T, et al. The efficiency of narrow band imaging with magnification for the estimation of invasion

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Endomicroscopy for in vivo Diagnosis of Colorectal Cancer Ralf Kiesslich & Markus F. Neurath Johannes Gutenberg University of Mainz, Mainz, Germany

Introduction

Principle of confocal microscopy

The prognosis of patients with colonic malignancies is dependent on early detection of neoplastic tissue, because only intraepithelial neoplasia and early colorectal cancer can be cured by endoscopic resection [1]. Histological analysis of biopsy material is the gold standard for the final diagnosis of colorectal lesions. However, the time delay between the colonoscopy and the histopathologic diagnosis limits the ability of the endoscopist to immediately determine the need for resection during ongoing colonoscopy. Furthermore, overtreatment (resection of non-neoplastic lesions) or undertreatment (biopsy instead of resection for neoplastic tissue) can lead to unnecessary risks for the patient. Recently, colonoscopy has seen major technical improvements. Magnifying, high-resolution, or high-definition endoscopy techniques, often in conjunction with chromoendoscopy, enable detailed surface analysis and help define areas of interest in the gut [2]. Chromoendoscopy, known for decades, and providing good results for cancer screening and surveillance in the colon, is now facing electronic competition from altered bandwidths of light that emulate the dye spray technique. Filters such as narrow-band imaging or postprocessing techniques may at least partially mimic chromoendoscopy by enhancing surface vessel architecture [3]. All of these techniques unmask a plethora of new, visible details that need immediate interpretation in order to target biopsies to suspicious surface architecture. In spite of advances in endoscopic imaging, the final diagnosis relies on the pathologist microscopically examining the tissue. Recent advances in endoscopic technology have placed a microscope on the tip of an endoscope that enables in vivo histology of the mucosal layer at subcellular resolution during ongoing endoscopy [4]. This joining together of an endoscope and a microscope is called confocal laser endomicroscopy (CLE).

Confocal microscopy permits a better spatial resolution than conventional fluorescence microscopy, because images are not contaminated by light scattering from other focal planes. A low-power laser is focused through a lens at a single point in a defined microscopic field of view, and the same lens is used as both a condenser and an objective folding optical path [5]. Thus, the point of illumination coincides with the point of detection within the tissue. Light emanating from that point is focused through a pinhole to a detector, and light scattering from outside the illuminated spot is rejected. Both illumination and detection systems are at the same focal plane and are termed as “confocal.” All detected signals from the illuminated spot are captured and measured. The created grayscale image is an optical section representing one focal plane within the examined specimen [6]. The image of a scanned region can be constructed and digitized by measuring light returning to the detector from successive points at various depth levels. A series of confocal images within successive planes can be used to observe fine (sub)cellular structures, and, in addition, three-dimensional structures from multiple scanned sections can be created. Confocal microscopy is now a standard method for molecular imaging in basic research in conjunction with fluorescence labeling techniques, thereby permitting the localization of specific proteins at distinct cellular locations [7]. However, up to the present endoscopic developments, confocal microscopy has been mainly performed on a microscope stage at the bench rather than the bedside.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Endoscopic confocal microscopy Endoscopic confocal microscopy is an outgrowth of conventional laboratory confocal microscopy. Miniaturization of confocal imaging systems began in the mid-1990s [8], and clinical applications of confocal systems were first reported in the early 2000s [9–12]. Currently, two confocal imaging systems for in vivo detection of gastrointestinal diseases are

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available: confocal imaging relying on tissue reflectance and confocal imaging based on tissue fluorescence.

Reflectance confocal imaging Reflectance confocal imaging was first reported by Sakashita et al. [13], who investigated the ability of a laser scanning confocal microscopy probe (Endo-Microscopy system, Prototype, Olympus, Tokyo, Japan) to identify and characterize neoplasia in tissue specimens. The flexible catheter probe had a 3.4 mm outer diameter and a 250 cm longitudinal length, and could pass through any endoscope with an instrument channel larger than 3.4 mm. A miniaturized sensor which acquires a digitized image was mounted on the distal end of the probe which measured the intensity of the reflective light from an integrated laser beam [14,15]. The light source used was a 405-nm-wavelength diode laser beam, and the spatial resolution was around 1 μm. Using reflectance technology, no vital staining process is needed for imaging. However, image quality is unsatisfactory to date. More recently, another series of reflectance confocal imaging systems has been developed by Mauna Kea Technologies, France, which are equipped with a semiconductor laser that oscillates at 685 nm [16]. The original probe was 6.9 mm in diameter (which made it impossible to apply through a regular endoscope working channel) and 250 mm long. The scanning field was 30 000 pixels provided by bundle technology, and the frame rate 12 images per second. The fixed focus was 30 μm from the objective lens. In a study by Yoshida et al. [14] using this system, confocal ex vivo imaging was correlated with conventional histology. The prototype used in this study allowed confocal imaging but was of insufficient quality for in vivo diagnosis. Nuclei and cell membranes could not be visualized in all cases and the fixed imaging plane depth did not permit scanning at various levels within the mucosal layer. However, the authors were able to demonstrate that an irregular nuclear architecture identified gastric cancer. Currently, the system has been further developed using cresyl violet-based confocal microscopy, and a miniaturized probe (outer diameter 2.5 mm) can now be placed through the working channel of a standard endoscope onto the mucosal surface (lateral resolution 3.5 μm, axial resolution 15 μm; field of view of 600 × 500 μm). Preliminary feasibility data show that probe-based endomicroscopy permits differentiation of neoplastic from non-neoplastic tissue. Accuracy values in a blinded study were 92.4% for suitable images and 81.5% in the intention to diagnose analysis [16,17].

Fluorescence confocal imaging The first publication about an integrated confocal fluorescence microscope into the distal tip of a conventional colonoscope

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(Pentax EC 3830FK, Tokyo, Japan) was released in 2004 [4]. This methodology demonstrated that in vivo microscopy at subcellular resolution (0.7 μm) could be achieved through an endoscope that could simultaneously display a standard white-light endoscopy image. A high degree of accuracy (99.2%) could be achieved when these images were compared with conventional histology. This approach, designated CLE, permitted immediate diagnosis of colorectal intraepithelial neoplasia using fluorescein or acriflavine as contrast agents.

Components of the confocal laser endoscope The distal tip of the newly developed colonoscope for CLE contains the components of the confocal laser microscope, an air and water jet nozzle, two light guides, an auxiliary water jet channel (used for topical application of the contrast agent), and a 2.8-mm working channel adjacent to the confocal imaging window, allowing endomicroscopically guided biopsies (Figure 39.1). The diameters of the distal tip and the insertion tube are 13.4 mm and 12.8 mm, respectively. During laser endoscopy a solid-state laser delivers an excitation wavelength of 488 nm with a maximum laser power output of ≤ 1 MW at the tissue surface. Confocal image data are then collected at a scan rate of either 0.8 frames/s (1024 × 1024 pixels) or 1.6 frames/s (1024 × 512 pixels). The optical slice thickness is 7 μm with a lateral resolution of 0.7 μm (field of view 475 × 475 μm). The range of the z-axis (depth) is 0–250 μm below the surface layer. The confocal endoscope is handled in a similar fashion to a standard endoscope. Imaging is collected as the distal tip of the endoscope is placed in gentle contact with the mucosa, allowing targeted endomicroscopic imaging. The position of the focal plane within the specimen is adjusted by using two additional buttons on the endoscope control body. Successive images from the surface to the deeper parts of the mucosal layer can be obtained, and images of interest can be stored digitally on the hard drive using a footactivated switch [18,19].

Contrast agents Confocal imaging at high resolution requires a contrast agent to enhance the differentiation of subcellular structures. This is made possible with the Pentax device using an exogenous fluorescence technique. Potentially suitable agents are fluorescein, acriflavine, or cresyl violet. The most common contrast agents are acriflavine hydrochloride (0.05% in saline; topical use only) or fluorescein sodium (5–10 mL of a 10% solution; intravenous application). Confocal imaging following staining with acriflavine hydrochloride and fluorescein sodium reveals the characteristic morphology of mucosal tissue. Whereas topically used acriflavine hydrochloride strongly

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Endomicroscopy for in vivo Diagnosis of Colorectal Cancer

Figure 39.1 Technique of confocal laser endomicroscopy. A miniaturized confocal microscope is integrated in the distal tip of a conventional endoscope (Pentax EC 3830FK, Tokyo, Japan) (A). A blue laser light is applied onto the mucosal surface (B) and to deeper parts of the mucosal layer (C). Optical horizontal grayscale images (D) are obtained using a fluorescence confocal imaging technique. Imaging plane depth ranges from 0 to 250 mm with a maximum resolution of 1024 × 1024 pixels (lateral resolution 0.7 mm).

labels the superficial epithelial cells including nuclei, intravenously administered fluorescein sodium distributes throughout the entire mucosa, providing a strong contrast within the connective tissue and the capillary network. While fluorescein binds to serum albumin, the remaining unbound dye molecules pass across systemic capillaries and enter the tissue, highlighting the extracellular matrix. Confocal images can be generated simultaneously with endoscopic images for the identification of typical histological structures within the upper and lower gastrointestinal tract. Pooled data from three centers with over 2000 examinations showed low complications rates using CLE (2.0%), which were mainly related to endoscopic interventions (e.g., polypectomy). Although all patients developed a transient discoloration of the skin after fluorescein-aided endomicroscopy [20], there was no mortality, phototoxicity, or allergy.

Endomicroscopy of the normal colon In the colon, mucin-containing goblet cells and the columnar epithelial cells can be readily identified by fluorescein-aided CLE. The luminal openings of the crypts appear in the horizontal axis as black holes projecting onto the surface of the mucosa, and each crypt is covered with a layer of epithelial cells. With change of the focal length, the microvascularization is highlighted within the lamina propria in deeper parts of the mucosal layer. The vasculature within the mucosa of the colon shows a typical honeycomb appearance, which represents a network of capillaries. Red blood cells are not labeled by fluorescein, but appear as moving black dots in the lumen of the vessels (Figure 39.2). CLE-based imaging of the terminal ileum enables visualization of intestinal villi including those of the brush border, which appear as small finger-like exten-

sions projecting from the surface. The epithelial cells covering the villi can be readily identified and single goblet cells can be detected.

Confocal imaging of colon pathology In 2003, Inoue et al. [21] reported on their initial experience with real-time confocal endoscopy on tissue specimens ex vivo. They used a prototype endomicroscope (Olympus Optical Company, Tokyo, Japan), which was passed through the working channel of an endoscope. The aim of the study was to create microscopic criteria to distinguish high-grade dysplasia and cancer from benign lesions. Inoue et al. examined 100 endoscopically or surgically resected colorectal lesions from 90 patients. Although nuclei could not be visualized in normal colonic mucosa or hyperplastic polyps, they were visible more often in neoplastic lesions. Conversely, goblet cells were visible less often in malignant or premalignant lesions. In this imaging system, individual nuclei could not be distinguished, but dark areas of irregular cells could be visualized. Importantly, however, the difference in the detection rate of nuclei (dark areas) in confocal images between non-neoplastic and neoplastic lesions was statistically significant in this study. Inoue et al. recommended, based on these results, preliminary criteria for a confocal imaging classification of high-grade intraepithelial neoplasia and cancer, in which neoplasia was characterized by the presence of structural abnormalities and clear visualization of nuclei. However, sensitivity for predicting neoplasia in the colorectum was only 60%, reflecting the limitations in resolution of this system. Sakashita et al. [13] investigated the ex vivo ability of laser scanning confocal microscopy to identify and characterize neoplasia in specimens of colonic tissue. Polyps removed

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Figure 39.2 In vivo and ex vivo histology of normal colonic mucosa. (a) Fluorescein-aided endomicroscopy of normal colonic mucosa shows several crypts with goblet cells (arrow). The crypts are arranged in a hexagonal fashion. (b) Acriflavin-aided endomicroscopy of the surface epithelium also shows normal crypt arrangement. Acriflavin stains nuclei within epithelial cells, which are displayed with bright contrast. (c) Conventional histology after hematoxylin and eosin staining shows normal colonic crypt architecture. Note that mucin of goblet cells is displayed as white inclusions in epithelial cells. The cryptal lumen is marked with an arrow. (d) Further magnification of b shows single epithelial gaps (arrow), which occur due to shedding.

during endoscopy or a surgical procedure were examined and imaged using a benchtop laser scanning confocal microscope prior to fixation. Resected specimens included adenomatous polyps, hyperplastic polyps, dysplastic polyps, and adenocarcinoma. The benchtop confocal images obtained were then compared with the hematoxylin and eosin-stained fixed histopathology specimens to determine confocal criteria. Confocal images compared favorably with histopathology. Nuclei of dysplastic mucosa were visualized with benchtop confocal imaging but were not identifiable in normal mucosa. Once familiar with the confocal microscopic images, the investigators examined the performance of the endomicroscope by examining normal colonic mucosa in vivo. Clinical utility and performance of the endomicroscope were limited by technical problems. Adequate image acquisition and resolution were critically dependent on the ability to limit motion artifacts. In addition, the glandular lumen of the crypts and the goblet cells were only marginally resolvable. However, the study by Sakashita et al. [13] made a critical contribution to the field as it was the first to characterize colonic tissue with a confocal imaging system in humans without a fluorescent agent and to compare the results with standard histopathology. Future technological improvements in imaging speed should make this device easier to use in clinical practice.

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In 2004, the first paper appeared about fluorescence-aided endomicroscopy in 42 patients with indications for screening or surveillance colonoscopy after previous polypectomy. Patients underwent total colonoscopy with in vivo endomicroscopy using the Pentax confocal laser endoscope [4]. The aim of the study was to assess in vivo histology during ongoing colonoscopy to diagnose intraepithelial neoplasias and colon cancer. Fluorescein-guided endomicroscopy of intraepithelial neoplasias and colon cancers showed tubular, villous, or irregular architecture with a reduced number of goblet cells. Furthermore, irregular vessel architecture with leakage of fluorescein characterized neoangiogenesis in neoplasms. Aberrant crypt foci, and hyperplastic and neoplastic changes, could be immediately identified during ongoing endoscopy. Often, chromoendoscopy prior to endomicroscopy was performed to define areas of interest, where subsequently chromoscopic-guided endomicroscopy could be performed (Figures 39.3–39.5). A simple confocal pattern classification (Table 39.1) based on the initial experience with confocal endomicroscopy was developed for differentiation between neoplastic and nonneoplastic tissue using CLE. Macroscopic and microscopic images were taken together to immediately predict histopathology. A total of 13 020 confocal images from 390 locations

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Figure 39.3 Colorectal adenoma. Analysis of a colonic polyp with (a) white-light endoscopy, (b) magnified chromoendoscopy, (c,d) fluorescein-based confocal endomicroscopy in different imaging depths, and (e) final histology. Chromoendoscopy highlights surface architecture with tubular staining pattern. (c) Endomicroscopy

(a)

(b)

(e)

of the surface shows characteristic tubular cellular and tissue architecture (blue arrow). (d) At about 150 mm depth, subepithelial capillaries become visible (red arrow). Final histology confirms the presence of tubular adenoma with low-grade intraepithelial neoplasia.

(c)

Figure 39.4 Colitis-associated dysplasia. (a) The rectum is inflamed and an ulceration with partially elevated borders is present (arrow). (b) The area is magnified after chromoendoscopy with methylene blue. A villous surface pattern becomes visible after staining. (c) Tubular architecture (arrow) can be seen in targeted endomicroscopy (arrow).

Figure 39.5 Colorectal cancer. (a) Ex vivo and (b) in vivo histology correspond well, showing cancerous cells and tumor desmoplasia.

(d)

(d)

(e)

(d) The cells are enlarged and a depletion of goblet cells is prominent. The overall shape and size of the crypts is irregular, which is highly suspicious for the presence of neoplastic changes. (e) Final histology proved the presence of low-grade intraepithelial neoplasia diagnosed by the nuclei arrangement (arrow).

(a)

(b)

Table 39.1 Confocal pattern classification for colorectal lesions. Grading

Vessel architecture

Crypt architecture

Normal

Hexagonal, honeycomb appearance that presents a network of capillaries outlining the stroma surrounding the luminal openings of the crypts

Regular luminal openings and distribution of the crypts covered by a homogeneous layer of epithelial cells, including goblet cells

Regeneration

Hexagonal, honeycomb appearance with no or mild increase in the number of capillaries

Star-shaped luminal crypt openings or focal aggregation of regularshaped crypts with a regular or reduced amount of goblet cells

Neoplasia

Dilated and distorted vessels with elevated leakage; irregular architecture with little or no orientation to adjunct tissue

Ridged lined irregular epithelial layer with loss of crypts and goblet cells; irregular cell architecture with little or no mucin

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were compared with the histological data from 1038 biopsies. It was possible to predict the presence of neoplastic changes using the newly developed confocal pattern classification with a sensitivity of 97.4%, specificity of 99.4%, and accuracy of 99.2%.

Ulcerative colitis It is impossible to examine the whole surface of the colon in the endomicroscopic mode. Thus, in diseases without typical macroscopic changes, additional endoscopic techniques are required to define areas of interest within the gut, where subsequently targeted endomicroscopy can be performed. It is well known that neoplastic changes occur in patients with long-standing ulcerative colitis, which manifest as flat and multifocal lesions, and are hard to recognize with white-light endoscopy. Thus, panchromoendoscopy with either methylene blue or indigo carmine was used as a new and valid diagnostic tool to improve the endoscopically visible diagnosis of intraepithelial neoplasia by using the surface guidelines [18,19,22,23]. Chromoendoscopy can be used to unmask circumscribed lesions, and chromoscope-guided CLE can then be used to diagnose intraepithelial neoplasias (see Figure 39.4). Thus, targeted biopsies of relevant lesions can be performed. Rapid confirmation of neoplastic changes by confocal laser endoscopy during colonoscopy may lead to significant improvements in the clinical management of ulcerative colitis patients. In the first randomized trial concerning the combination of panchromoendoscopy and endomicroscopy, a total of 153 patients with long-term ulcerative colitis in clinical remission (surface guidelines) were randomized at a 1:1 ratio to undergo conventional colonoscopy or panchromoendoscopy using 0.1% methylene blue in conjunction with endomicroscopy to detect intraepithelial neoplasia or colorectal cancer [24]. Circumscribed lesions (areas with defined borders) in the colonic mucosa detected by chromoendoscopy were evaluated with endomicroscopy for cellular and vascular changes according to the confocal pattern classification to predict neoplasia. Targeted biopsies of the examined areas were performed and histologically graded according to the new Vienna classification. In the standard colonoscopy group, randomized biopsies were performed every 10 cm between the anus and cecum, as were targeted biopsies of visible mucosal changes. Primary outcome analysis was the histological diagnosis of neoplasia. Using chromoendoscopy in conjunction with endomicroscopy (80 points; average examination time 42 min), significantly more intraepithelial neoplasia could be detected (19 vs. 4; P = 0.007), as with standard colonoscopy (73 points; average examination time 31 min). Endomicroscopy revealed different cellular structures (epithelial and blood cells), capillaries, and connective tissue limited to the mucosal layer; 5580 confocal images from 134 circumscribed lesions were compared

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with the histological results from 311 biopsies. The presence of neoplastic changes could be predicted with high accuracy (sensitivity 94.7%, specificity 98.3%, accuracy 97.8%) [24]. Endomicroscopic-guided biopsies led to a total number of 21.2 biopsy specimens per patient, whereas 42.2 biopsies on average were necessary when performing the usual random and targeted biopsies. This difference was statistically significant. Furthermore, if only circumscribed lesions would have been biopsied using chromoendoscopy, the total number of biopsies could have been limited to 3.9 biopsies per patient, without reducing the number of identified intraepithelial neoplasias. In addition, in theory, endomicroscopy could further decrease by fivefold the number of biopsies needed to diagnose intraepithelial neoplasia if only suspicious in vivo architecture were biopsied, i.e., to 0.78 biopsies per patient. Furthermore, endomicroscopy enables differentiation of dysplasia-associated lesions or masses (DALMs) from adenomalike mass (ALMs) [25]. The management of DALMs and ALMs in chronic ulcerative colitis differs radically: total proctocolectomy versus endoscopic resection and surveillance. It is difficult to reliably differentiate these lesions visually using conventional colonoscopy. Confocal laser scanning imaging enables in vivo surface and subsurface cellular resolution imaging during ongoing video endoscopy. Thirty-six patients with long-standing ulcerative colitis presenting 36 lesions were examined with the endomicroscopic system. The kappa coefficient of agreement between CLE and histopathologic evaluation was 0.91, and accuracy was 97% (95% confidence interval 86–99%). Endomicroscopy can also be used to guide mucosal biopsies after lesions are unmasked using chromoendoscopy. In a randomized controlled trial comparing panchromoendoscopy with panchromoendoscopy in conjunction with endomicroscopy, the latter approach was 2.5-fold more effective in diagnosing intraepithelial neoplasias in ulcerative colitis [26]. In summary, chromoendoscopy unmasks circumscript lesions, and confocal laser microscopy can be used to confirm intraepithelial neoplasias with high accuracy. Thus, biopsies can be limited to targeted biopsies of relevant lesions. In vivo histology with endomicroscopy leads to significant improvements in the clinical management of patients with ulcerative colitis in terms of both a reduced number of confirming biopsies and time gained by performing immediate therapeutic intervention instead of waiting for histopathologic confirmation of biopsy material.

Consequences of in vivo confocal microscopy In vivo microscopic imaging at subcellular resolution to differentiate nuclei, goblet cells, connective tissue, and microvasculature was a dream of endoscopists in the past. Now,

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endomicroscopy is available and will alter clinical management in the endoscopic suite by providing optical biopsies. In the near future when these novel techniques become broadly available, white-light endoscopy, interpretation of macroscopic changes, and in vivo microscopy will occur simultaneously during ongoing endoscopy. This scenario would improve patient care with major advantages leading to immediate and targeted intervention without any delay. Endomicroscopy offers the potential of in vivo cellular analysis, which can lead to precisely targeted biopsies. The pathologist will receive fewer biopsies but will find more tumor tissue, as more “smarter” tissue biopsies containing neoplastic tissue will be provided by the endomicroscopist [27]. When in vivo histology becomes widely available, random mucosal biopsies will be a procedure of the past. But, first, critical issues such as interpretation of images, reliability of images, standardized training, legal issues, and limitations of imaging of endomicroscopy have to be discussed. In vivo histology is a remarkable endoscopic advance using confocal fluorescence laser endomicroscopy. However, fluorescein-based endomicroscopy does not display nuclei in all optical sections due to the pharmacokinetic properties of fluorescein. As nuclei are of special importance in judging lowor high-grade dysplasia, the local application of acriflavine, which can strongly label nuclei, may help to overcome this problem. More importantly, the imaging plane depth of CLE is currently limited to 250 μm. This permits analysis of the deepest parts of the mucosal layer, but in many cases the submucosal layer cannot be reached. As submucosal malignant invasion defines invasive cancer in the colon for Western pathologists, CLE is currently not well suited to diagnose invasive cancer. Fluorescein-based endomicroscopy is based on pattern recognition motifs to judge the presence of potential mucosal alteration. The real challenge in endomicroscopy is the interpretation of what is seen because of the high resolution of cellular and subcellular detail. Single confocal images are so detailed that immediate in vivo diagnosis is difficult. There is a strong need for standardized image interpretation and training. In the colon, the established confocal pattern classification can be used to differentiate between normal tissue and non-neoplastic changes like inflammation and hyperplasia, and to diagnose intraepithelial neoplastic changes during ongoing endoscopy. Based on macroscopic and microscopic appearance, endoscopic treatment can be planned and immediately performed. Up to the present time, random or targeted biopsies and the pathologist’s report have offered the best diagnostic yield for gastrointestinal malignancies. However, in patients with longstanding ulcerative colitis, chromoendoscopy will unmask areas of interest (flat, circumscribed lesions), while concurrent endomicroscopy can immediately confirm the presence or absence of neoplasia and reduce the need for biopsies. With this approach, the average number of biopsies could

Endomicroscopy for in vivo Diagnosis of Colorectal Cancer

be decreased from about 40 per patient (random biopsies) to theoretically fewer than 4 (combined approach of chromoendoscopy and endomicroscopy), while still providing a significantly higher diagnostic yield for intraepithelial neoplasias than random biopsies [24]. It is tempting to speculate that endoscopes of the future will combine several new diagnostic possibilities. Using light filters (e.g., narrow-band imaging, I-Scan or optimal-band imaging) instead of chromoendoscopy to guide endomicroscopy might further decrease the examination time, and autofluorescence might emerge as a sensitive tool for highlighting areas of mucosal abnormality. The combination of various imaging techniques with endomicroscopy may significantly decrease the number of false-positive results. Taken together, several recent studies have added new energy to the fast-moving field of endomicroscopy. The modern endoscopist is challenged by many new visible details and all of the new imaging modalities will require substantial training of the endoscopist by pathologists and gastrointestinal specialists. Endomicroscopy is an emerging technology that provides a detailed microscopic analysis of the mucosal surface. Even single gaps within the epithelial layer can be imaged, which may further refine the understanding of the epithelial barrier function in inflammatory bowel disease. Endomicroscopy will significantly decrease the time for ideas, concepts, and treatment to travel from bench to bedside, because many questions from basic research can now be immediately transferred; even molecular imaging in humans is possible using CLE [28,29]. At the present time, endomicroscopy is still in its infancy, and this technology represents a highly examiner dependent technology. Substantial theoretical and hands-on training will be of crucial importance before a reliable histological diagnosis can be uniformly made. The various confocal imaging systems currently available are the beginning of a new area in endoscopy. The ability to visualize all parts of the gut and biliopancreatic system has developed over the past 50 years. It is now possible to explore the in vivo cell architecture of the mucosa at subcellular resolution, which will allow functional and molecular imaging in the future [30]. These tools currently permit the accurate real-time diagnosis of mucosal abnormalities, and may unravel the mucosal differences in various inflammatory bowel diseases while opening a visible window into the cell where direct observation of medical or biological therapy will be possible.

Summary CLE is a new endoscopic tool enabling in vivo histology at subcellular resolution during ongoing endoscopy, which permits subsurface imaging of normal and neoplastic human mucosa. This new technique unequivocally has major implications for

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the diagnosis and clinical management of patients scheduled for screening or surveillance colonoscopy for colorectal cancer. Endomicroscopy allows immediate diagnosis of colonic neoplasia, and the detection of neoplastic cells helps to target endoscopic intervention to relevant areas. Furthermore, the combination of chromoendoscopy and CLE significantly decreases the number of biopsies required for cancer surveillance in patients with ulcerative colitis, providing a fourfold higher diagnostic yield than present in white-light endoscopy with random biopsies. CLE has led endoscopy in colorectal cancer into a new imaging era; it has emerged as a crucial novel imaging technique for in vivo diagnosis of colon cancer.

References 1 Schulmann K, Reiser M, Schmiegel W. Colonic cancer and polyps. Best Pract Res Clin Gastroenterol 2002; 16: 91–114. 2 Kiesslich R, Neurath MF. Chromoendoscopy and other novel imaging techniques. Gastroenterol Clin N Am 2006; 35: 605–19. 3 Machida H, Sano Y, Hamamoto Y, et al. Narrow-band imaging in the diagnosis of colorectal mucosal lesions: a pilot study. Endoscopy 2004; 36: 1094– 8. 4 Kiesslich R, Burg J, Vieth M, et al. Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo. Gastroenterology 2004; 127: 706–13. 5 Helmchen F. Miniaturization of fluorescence microscopes using fibre optics. Exp Physiol 2002; 87: 738– 45. 6 Robinson JP. Principles of confocal microscopy. Meth Cell Biol 2000; 63: 89–106. 7 Conchello JA, Lichtman JW. Optical sectioning microscopy. Nat Meth 2005; 2: 920–31. 8 Delaney PM, King RG, Lambert JR, Harris MR. Fibre optic confocal imaging (FOCI) for subsurface microscopy of the colon in vivo. J Anat 1994; 184: 157–60. 9 Karadaglic D, Juskaitis R, Wilson T. Confocal endoscopy via structured illumination. Scanning 2002; 24: 301– 4. 10 Helmchen F. Miniaturization of fluorescence microscopes using fibre optics. Exp Physiol 2002; 87: 737– 45. 11 Evans JA, Nishioka NS. Endoscopic confocal microscopy. Curr Opin Gastroenterol 2005; 21: 578– 84. 12 Inoue H, Kudo S, Shiokawa A. Technology insight. Laser scanning confocal microscopy and endocytoscopy for cellular observation of the gastrointestinal tract. Nat Clin Pract Gastroenterol Hepatol 2005; 2: 31–7. 13 Sakashita M, Inoue H, Kashida H, et al. Virtual histology of colorectal lesions using laser-scanning confocal microscopy. Endoscopy 2003; 35: 1033– 8. 14 Yoshida S, Tanaka S, Hirata M, et al. Optical biopsy of gastrointestinal lesions by reflectance-type laser-scanning confocal microscopy. Gastrointest Endosc 2007; 66: 144– 9. 15 Kakeji Y, Yamaguchi S, Yoshida D, et al. Development and assessment of morphologic criteria for diagnosing gastric cancer using confocal endomicroscopy: an ex vivo and in vivo study. Endoscopy 2006; 38: 886–90.

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16 Becker V, Vercauteren T, von Weyhern CH, Prinz C, Schmid RM, Meining A. High-resolution miniprobe-based confocal microscopy in combination with video mosaicing. Gastrointest Endosc 2007; 66: 1001–7. 17 Meining A, Saur D, Bajbouj M, et al. In vivo histopathology for detection of gastrointestinal neoplasia with a portable, confocal miniprobe: an examiner blinded analysis. Clin Gastroenterol Hepatol 2007; 5: 1261–7. 18 Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003; 124: 880– 8. 19 Rutter MD, Saunders BP, Schofield G, et al. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004; 53: 256– 60. 20 Kiesslich R, Hurlstone DP, Dunbar KB, et al. Confocal laser endomicroscopy is an effective and safe diagnostic tool in GI endoscopy. Gastroenterology 134(Suppl. 1): A-191. 21 Inoue H, Cho JY, Satodate H, et al. Development of virtual histology and virtual biopsy using laser-scanning confocal microscopy. Scand J Gastroenterol Suppl 2003: 37–9. 22 Hurlstone DP, Sanders DS, Lobo AJ, McAlindon ME, Cross SS. Indigo carmine-assisted high-magnification chromoendoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy 2005; 12: 1186–92. 23 Kiesslich R, Neurath MF. Surveillance colonoscopy in ulcerative colitis: magnifying chromoendoscopy in the spotlight. Gut 2004; 53: 165–7. 24 Kiesslich R, Götz M, Lammersdorf K, et al. Chromoscopy guided endomicroscopy increases the diagnostic yield of intraepithelial neoplasia in ulcerative colitis with reduced number of biopsies. Gastroenterology 2007; 132: 874– 82. 25 Hurlstone DP, Thomson M, Brown S, Tiffin N, Cross SS, Hunter MD. Confocal endomicroscopy in ulcerative colitis: differentiating dysplasia-associated lesional mass and adenoma-like mass. Clin Gastroenterol Hepatol 2007; 5: 1235–41. 26 Hurlstone DP, Kiesslich R, Thomson M, Atkinson R, Cross SS. Confocal chromoscopic endomicroscopy is superior to chromoscopy alone for the detection and characterisation of intraepithelial neoplasia in chronic ulcerative colitis. Gut 2008; 57: 196–204. 27 Kiesslich R, Galle PR, Neurath MF. Endoscopic surveillance in ulcerative colitis: smart biopsies do it better. Gastroenterology 2007; 133: 742–5. 28 Hsiung P, Hardy J, Sahbaie P, Friedland S, Contag CH, Wang TD. Detection of colonic dysplasia in vivo using a targeted fluorescent septapeptide and confocal microendoscopy. Nat Med 2008; 14: 454– 8. 29 Kiesslich R, Goetz M, Angus EM, et al. Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. Gastroenterology 2007; 133: 1769–78. 30 Goetz M, Fottner C, Schirrmacher E, et al. In vivo confocal real time mini-microscopy using a rigid probe in animals with various induced inflammatory and neoplastic diseases. Endoscopy 2007; 39: 350– 6.

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Introduction There are numerous ways of managing colonoscopy; they are determined by local circumstances and endoscopist preferences as well as by the particular instrument or medication used (from no sedation to use of general anesthesia). The account given here is intended to cover the general principles and practicalities involved in successful, atraumatic intubation of this surprisingly variable organathe colon. During colonoscopy, the challenge to the endoscopist is, step by step, to crumple or convolute the thin-walled large bowel over the colonoscope with the minimum of force, using various “tricks of the trade.” Even experts may need to resort to different instruments, accessories, or endoscopic techniques to reach the cecum, but no one claims 100% “success” in all patients. While there is no single perfect recipe, some of the classic maneuvers are described. The account benefits from use of the magnetic imager (ScopeGuide®, Olympus Corporation, Tokyo, Japan), now widely used by European endoscopists, which graphically explains the basis of the various challenges and the maneuvers used empirically or intuitively by experts. To be conventional, the text refers to air insufflation, whereas some use CO2 for rapid absorption and greater comfort. The use of antispasmodics is optional.

Choice of instrumentcthe relevance of sex, symptomatology, and embryology Most endoscopy units favor the routine use of long colonoscopes (165 cm) because of the extraordinary length of some colons. However, because shorter instruments (130 cm) are a little easier to handle, they are in semiroutine use in some countries (Germany, Italy), which then creates occasional problems in reaching the proximal colon.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

The need to use a longer instrument for a particular patient can be predicted with some certainty. Female sex is found to be predictive of a longer colon and a more uncomfortable procedure. A long-term history of constipation, especially if a familial trait and associated with routine self-purgation, virtually guarantees a long and looping colon. To add to the procedural challenges that can be expected in such a patient (including the need for a longer period of dietary restriction and the possibility of extra bowel preparation), the colon as a whole is likely to be more mobile and more likely to form repeated or atypical loops; therefore, the patient requires an experienced endoscopist and the best available equipment. The likely explanation for variations in colon length and attachments starts in embryo. The fetal intestine and colon initially develop as a functionless muscle tube which lengthens into a U shape on a longitudinal mesentery (Figure 40.1a). As the embryo at this 5-week stage is only 1 cm long, the lengthening intestine and colon (Figure 40.1b) are forced out into the umbilical hernia (Figure 40.1c). By the third month of development the embryo is 4 cm long and there is room within the peritoneal cavity for first the small and then the large intestine to be returned into the abdomen. At this stage, the mesentery of the transverse colon is free, but the mesenteries of the descending and ascending colon, pushed by the fluid-filled and bulky small intestine against the peritoneum of the posterior abdominal wall, fuse with it so that the ascending and descending colon typically become retroperitoneal and fixed (Figure 40.2a), although not always (see below). If there is failure of enteric innervation of the intestinal muscle tube in early embryonic development, the atonic bulky fetal intestine and colon will be retained longer than usual outside the abdomen in the umbilical hernia, until the developing abdominal cavity is large enough to reaccommodate them. Delayed return of a large colon into the abdomen will cause it to miss the “milestone moment” when retroperitoneal fixation and fusion usually occur (10–12 weeks after conception). Endoscopically, such a colon is noted to be unusually capacious, long, and often atypically loopingabut it can also be dramatically squashed down and shortened when the colonoscope is withdrawn at the cecum (Figure 40.2b) (typically to a length of only 50–60 cm), proving the lack of

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Figure 40.1 The fetal intestine and colon start on a longitudinal mesentery (a), then rotate as the small intestine elongates (b), and from 5 weeks (1-cm embryo) to nearly 3 months (4-cm embryo), are in the umbilical hernia (c). (a)

(b)

Figure 40.2 The mesentery of the embryonic colon partially fuses retroperitoneally (a) but sometimes the “mesocolon” persists and the colon is totally mobile (b).

fixations. This is probably a genetically determined abnormality; other first-degree relatives, especially females and sometimes over several generations, may have disturbance of habit, constipation, or flatulence. If endoscoped or imaged, their colons (stomachs and small intestines also) are found to be large, long, and mobile, which explains the difficulty of colonoscopy and the need for superior equipment and skills to manage them successfully and achieve the > 99% completion rate expected of experts. Figure 40.3 Single-handed colonoscopy.

Preprocedure checks Having selected the endoscope, its functionality should be checked before starting. Ensure that insufflation is satisfactory, depressing the air/water valve to see water squirting or dripping briskly, or vigorous bubbling under water. Suboptimal insufflation is difficult to spot once the endoscope is in the colon if a connection is loose, the air/water valve misplaced, or the air outlet partially obstructed.

Instrument handlingcsingle-handed, two-handed, or two-person approach? The one-person, single-handed approach to colonoscope control is used by most skilled endoscopists (Figure 40.3),

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although a few still work successfully with the two-person method, using an assistant to manipulate the shaft, as was the original design intention for (gastro)scope handling. Current colonoscope angulation controls and control body ergonomics are identical to those of gastroscopes, designed almost half a century ago to be steered with two hands on the angulation controls. However, greater fluency is needed to traverse the colon, so “single-handed” colonoscopy uses the left hand alone to manage the angulation controls (Figure 40.4). Two fingers (the third and little finger) grip the control body, with the thumb resting on the up-/down-angulation control ready for immediate responses, leaving the middle finger free to assume a “helper” role to the thumb when needed. The first finger alone operates the air/water or suction valves. For those with reasonably large hands it is practicable for the left thumb

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Middle “helper” finger

Figure 40.4 Single-handed control: the forefinger alone activates the air/water and suction valves; the middle finger acts as “helper” to the thumb for angulation.

Figure 40.6 The instrument shaft should, whenever possible, be held delicately between the thumb and fingers.

Two-person colonoscopy uses an assistant to control the shaftaperforming the role ascribed to the right hand of the single-handed endoscopist, pushing and pulling according to spoken instructions. However, assistants tend to push excessively, causing unnecessary loops, and rarely torque appropriately. Except with an unusually skilled assistant, two-person colonoscopy therefore tends to be more clumsy. However, in occasional difficult situationsasteering through an awkward angulation or snaring a difficult polypaall endoscopists may justifiably use the help of an assistant to control the shaft. As coordination develops between right and left hands (or between endoscopist and assistant in the two-person technique), colonoscopy, from slow deliberate beginnings, gradually becomes rapid and fluent. Attention to small practical details is part of this process. Figure 40.5 The thumb can reach the lateral angulation control if the hand is correctly positioned.

Patient position to reach across from the up/down to the lateral angulation control when needed (Figure 40.5). Alternatively, some expert endoscopists never use the left thumb to operate the lateral angulation control, preferring to release the grip of the right hand on the shaft and using it to more fully turn the smaller, outer wheel. When released from right-hand control, shaft position can be maintained by leaning on it transiently, maintaining its position by trapping it between the operator’s lateral thigh and the examination table. The right hand holds the shaft 25–30 cm away from the anus, using a towel or gauze for hygiene and friction grip. This avoids the frequent hand changes and jerky intubation that results from holding it closer to the anus. The right hand feels whether the shaft moves easily (is straight) or there is resistance (due to looping). The shaft (insertion tube) of a colonoscope is made to be “torque stable,” so that twisting force applied at one end is faithfully transmitted to the bending section and tipathe basis for “torque steering.” Both feel and precise torque control are helped if the shaft is held in a finger grip (Figure 40.6), rather than more clumsily in the fist.

Most endoscopists place the patient in the left lateral position for the whole procedure, although the supine position is common in some countries, especially if anesthesia is used. Changes of position (to the back or even right side) often help when there is technical difficulty, or improve the view, whether during intubation or during examination on withdrawal.

Inserting into the anorectum Start with a digital examination to prelubricate the anal canal and relax the sphincters. Lubricate about 10 cm of the instrument tip and then insert, supporting the bending section with the forefinger and pressing in obliquely (Figure 40.7). Alternatively, the instrument may be introduced directly end-on under direct vision. The initial view of the rectum may be a “red out” if the lens has pressed against the rectal mucosa. Insufflating and pulling back will reestablish vision. Angulating and rotating

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Figure 40.8 Angulate maximally with both angulation controls, then push in with twist to retrovert in the rectum. Figure 40.7 Colonoscope insertion, with finger support of the bending section.

the endoscope helps find the lumen. Aspirate fluid or residue from the rectum at this stage to avoid leakage and soiling. Pass into the proximal rectum and beyond only when an adequate view has been obtained. Torque steering is the economic way of steering through the bends at this stage, the thumb angulating the tip up or down and the right hand corkscrewing around the haustral folds, twisting clockwise or counterclockwise to keep an adequate view during inward progress. The distal rectum is a potential blind spot which needs careful inspection at some stage of the procedure (typically before withdrawal at the end of the examination). The rectal ampulla will usually, but not always, allow tip retroversion. Choose the widest part of the distal rectum, angulate both controls fully, and push inward with a vigorous twisting movement to invert the tip toward the anal verge (Figure 40.8). Retroversion may not be possible in some narrowed rectums, and undue force should not be used. “Video anoscopy” is a useful adjunct in patients with unexplained bleeding, inserting a rigid rectoscope and using the video endoscope to illuminate, view, and document the anorectum and any hemorrhoids.

Efficient handling 1 Twisting (torquing) the shaft only affects the tip when the shaft is straight. If a loop is present, twisting affects only the loop. Providing that the shaft is straight, twisting or “torque steering” of the angulated tip is highly effective. 2 Torque steering is affected by the direction in which the tip is angulated. With the tip angulated upward, clockwise torque moves the tip to the right, but it moves to the left if angulation is down (Figure 40.9). 3 Torque steering involves first angulating up or down, then torquing (twisting, rotating) the shaft clockwise or counterclockwise. This rotation should corkscrew the tip around laterally, precisely and quickly, usually avoiding use of the lateral angulation control. Tip angulation is important because rotating a completely straight instrument does not result in lateral deviation of the tip. 4 Torque (as a maintained twist) can also be used to control spiral loops, but lateral steering may then have to be with the angulation controls. It is essential to realize that if shaft torquing force is being applied in one direction to keep the shaft straight, torque steering in the opposite direction will tend to re-form the loop. 5 Coordinate left- and right-hand activities: each hand is disciplined to fulfill only its appropriate tasks.

Up Left

Right Down

(a)

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Figure 40.9 With clockwise shaft twist: (a) an up-angulated tip moves to the right; (b) a down-angulated tip moves to the left.

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Figure 40.11 If the tip is fixed, it cannot be steered (the shaft moves instead).

Figure 40.10 Do not overangulate when pushing around flexuresbthe “walking-stick handle” effect.

Withdrawal of the shaft and removal of the tip from mucosal contact will restore the use of the angulation controls.

6 Use the lateral angulation control as little as possible. It is the least effective of the available angulating or steering actions (whether by the left thumb or right hand). 7 If maximal up/down angulation has already been applied, lateral angulation adds only a small degree of increased tip deflection. This additional angulation may nonetheless assist in locating the lumen in a tortuous sigmoid colon. Aggressive application (two-handed) of both angulation controls is rarely helpful but can damage the angulation wires. 8 Avoid overangulationaa fully angulated tip will not slide through the colon, the “walking-stick handle” phenomenon (Figure 40.10). 9 If the tip is impacted or fixed by adhesions, it cannot be steeredaattempted angulation simply moves the shaft instead (Figure 40.11). This is an unavoidable limitation of flexible endoscopes, apparent in fixed diverticular disease or tight strictures. Torque steering is more effective in such situations.

Intubating and steeringcpractical tips

Figure 40.12 (a) The sigmoid colon is an elastic tube, (b) pushing causes loops, but (c) pulling back shortens and straightens the colon.

(a)

Intubating to the cecum should be as quick as reasonably possible, because this phase is the most uncomfortable and stressful for the patient. However, trying to hurry intubation by using force usually results in looping, leading to a slower, traumatic, or failed procedure. The sigmoid colon is an elastic tube (Figure 40.12a). When inflated it becomes long and tortuous; deflated it is significantly shorter. When stretched by a colonoscope, especially if overinflated as well, the bowel forms loops and acute bends (Figure 40.12b). Shortened by pulling back and deflating, the sigmoid can usually be telescoped into a few convoluted centimeters (the 12–15 cm of rectum are relatively uncompressible) (Figure 40.12c). 1 Insufflate as little as possible. Gentle insufflation may be needed throughout the examination in order to maintain vision,

(b)

(c)

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Suction

Figure 40.14 Aim at the convergence of folds.

Air

Suction

Figure 40.13 The colonoscope air outlet is at the bottom left of the view and the suction channel opening is at the bottom rightVorientate correctly before use.

but it is counterproductive to overinflate. Bubbles caused by insufflating under water can be avoided by angulating above the fluid as far as possible. Remember that the colonoscope air outlet is below and to the left of the lens view (and the suction/instrumentation channel below and to the right) (Figure 40.13). If preparation and residual bile salts result in excessive bubbles, introducing antibubble silicone emulsion will remove them. 2 Suction air frequently. A perfect luminal view is not necessary. Whenever fully distended, it takes only a second or two to suction excess air from the colon until it starts to wrinkle and collapse slightly, so becoming shorter and easier to manipulate. 3 Suction fluid infrequently. Having evacuated fluid from the rectum, only aspirate fluid during the rest of the intubation phase when absolutely necessary to maintain vision. Aspirating each pool of retained fluid wastes time, loses the view, and requires reinflation. It is often quickest to steer over the fluid levels, leaving aspiration of any fluid or residue until withdrawal. When suctioning, orientate accurately above the surface of the fluid so that the channel dips in precisely, which avoids time-wasting air evacuation or mucosal suction “blebs.” 4 Use all visual clues. The direction of the colonic lumen should be ascertained before pushing in. The lumen when deflated or in spasm is at the center of converging folds (Figure 40.14). Aim toward the darkest area, worst illuminated because it is furthest from the instrument and nearest the lumen (Figure 40.15). Lumen direction is at the center of any convex arcs,

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Figure 40.15 Aim at the darkest area.

Figure 40.16 The bulge of a tenia coli indicates lumen direction.

which are formed by visible wrinkling of the circular muscles, haustral folds, or the highlights reflected from the mucosa over them. The slight inward bulge of one of the underlying longitudinal muscle bundles (teniae coli) is another clue to lumen direction (Figure 40.16). 5 Steering direction is predictable from the view. Because endoscopes are made torque stable, angulating “up” always moves the tip toward the top of the monitor view (similarly the rightangulation control will move the view toward the right unless the bending section is already acutely angulated). Seen in close-up, however, the surface will appear to move

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Figure 40.17 Pull back when lost, the mucosa slides away in the direction of the lumen.

in the opposite direction; thus to angulate successfully “up,” the surface vessel pattern must move down. 6 Steer slowly and exactly (rather than jerkily and erratically). A rapid steering movement in the wrong direction can simply lose the view altogether, quite unnecessarily. Each individual movement should be slow and purposeful. 7 Consider the proper steering actions before engaging the colonoscope in an acutely angled portion of the colon. Colonic bends can be acute and it is easy to become unsighted when angulating around them. 8 “Prepare” bends so that steering around them is easier. An acute bend is most easily passed if its axis is upward or downward (for easy thumb steering). Optimize mechanical efficiency by making the colonoscope shaft straight (for better push) and the bending section not overangulated (to help it slide around). 9 If there is no view, pull back at once. If lost, even for a few seconds, keep the angulation controls still or let go of them, then insufflate and gently withdraw the instrument. The mucosa will then slip slowly past the lens in a proximal direction (Figure 40.17). Follow the direction of this slippage by angulating the controls or twisting the shaft, and the lumen of the colon will come back into view. Pushing blindly, especially if there is a “red out” and total loss of view, is usually a pointless waste of time and potentially a cause of perforation. 10 Position change of the patient may help if the view is poor, especially when there is excess fluid. Let gravity reposition fluid, gas, and the colonathis will often be beneficial. 11 Keep the colonoscope as straight as possible in order to transmit inward shaft push to the tip.

(a)

Insertion Technique

(b)

Figure 40.18 (a) The sigmoid colon loops anteriorly and then (b) passes up into the left paravertebral gutter.

is important during intubation, because small lesions can be missed during the withdrawal phase. The sigmoid mesentery is very variable in length and may be affected by adhesions from previous inflammatory disease or surgery. After hysterectomy the sigmoid tends to be angulated and fixed into the area previously occupied by the uterus. The inevitable push force of colonoscope intubation may stretch the bowel to the limits of its attachments or the confines of the abdominal cavity (larger loops can occur in a protuberant belly). The shape of the pelvis, with its curved sacral hollow and forward-projecting sacral promontory, causes the colonoscope to pass anteriorly (Figure 40.18a). The shaft often loops near the anterior abdominal wall before it passes posteriorly to the descending colon (Figure 40.18b). The resulting anteroposterior loop tends often to form a spiral loop, with 90% probability of this being clockwise, rather than anticlockwise (Figure 40.19). When a sigmoid colonoscope

Sigmoid coloncendoscopic anatomy The sigmoid colon is 40–70 cm long (or more) when stretched, but will crumple to 30–35 cm (or less) once the instrument is straightened by pulling back. This crumpling makes anatomic localization by distance unpredictable and is why inspection

Figure 40.19 Sigmoid loop: anterior view (clockwise spiral).

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Figure 40.20 Hand pressure may restrict looping of the sigmoid.

Figure 40.22 The endoscope may push a fully mobile distal colon up the midline.

Figure 40.21 Acute (iatrogenic) hairpin bend at the sigmoid–descending junction.

Figure 40.23 Pre-steer before pushing into an acute bend.

loop runs anteriorly against the abdominal wall, it may be possible to affect it by hand pressure (Figure 40.20). The descending colon is normally fixed retroperitoneally in the left paravertebral gutter. Ideally the descending colon runs straight to the splenic flexure, but colonoscope stretch can create an acute or “hair pin” bend at the junction with the sigmoid colon (Figure 40.21). Mesenteric variations and mobility, occurring in at least 15% of subjects, can result in varying degrees of descending mesocolon displacement rather than the usual retroperitoneal fixation. For instance, the descending colon can run up the midline (Figure 40.22) or allow atypical (counterclockwise spiral) “reversed alpha” looping.

Navigating through the sigmoid Single-handed torque steering, as described above, is an efficient way of passing the multiple bends of the sigmoid, whereas coordination with an assistant handling the shaft can be difficult. Each of the succession of serpentine bends requires

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a conscious steering decision. Consider the best combination of angulation and rotation to steer correctly into the axis of the bend and perform the combination of advance, torque, and tip deflection as the tip engages the angulated bowel (Figure 40.23). This ensures that the tip will subsequently slide around with minimal push pressure. Occasionally, scope advance will be relatively “blind,” but this is acceptable if sliding in the predetermined direction of the lumen. Using torque steering, most of the sigmoid can be traversed with little or no use of the lateral angulation control, the angulated tip corkscrewing the shaft first one way and then the other around the succession of bendsatwisting the shaft during advance and moving the up-/down-angulation controls simultaneously. Acute and mobile bends are a particular problem in the sigmoid. Having angulated around an acute bend, if the view is poor, gently pull back the angulated/hooked tip, which should simultaneously reduce the angle, shorten the bowel distally, straighten it proximally, and disimpact the tip to improve the view (Figure 40.24). Maneuvering around a bend may cause a mobile colon to swing around on its attachments,

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Figure 40.26 At acute bends, a longitudinal bulge (tenia coli) shows the direction to follow. Figure 40.24 Pulling back flattens out an acute bend and improves the view. No

Yes

(a)

(b)

Figure 40.27 In diverticulosis, the lumen is often difficult to locate.

Figure 40.25 Rotation of vessel pattern (from a to b) indicates rotation of the colon, so the endoscopist needs to change the steering direction correspondingly.

seen in close-up as a rotation of the visible vessel pattern, which gives a clue as to which direction to follow (Figure 40.25). In a capacious colon, there may be a longitudinal fold pointing toward the correct direction of the lumen, caused by the muscle bulk of a tenia coli (Figure 40.26); following this longitudinal fold helps to avoid becoming disoriented.

Diverticular disease In severe “muscular” diverticular disease (as opposed to minor diverticulosis), there can be a narrowed lumen, pericolic adhesions, and problems in choosing the correct direction. A close-up view of a diverticulum means that the tip must be at right angles to the lumen, and major reorientation is required (Figure 40.27). The perfectly round shape of a

diverticulum contrasts with the narrowed lumen of pronounced diverticular disease, often quite difficult to locate and never circular. Fixation of the tip of the colonoscope is an inherent limiting factor of flexible endoscopes, making precise steering movements more difficult. Once the instrument has passed through, however, the “splinting” effect of the abnormally muscular diverticular segment usually prevents any sigmoid looping problems for the rest of the examination. The secret in passing significant diverticular disease is extreme patience in visualization and steering, with particular use of withdrawal, rotational, or corkscrewing movements. Using a thinner and more flexible pediatric colonoscope or gastroscope may make an apparently impassable narrow, fixed, or angulated sigmoid colon relatively easy to examine. Severe angulated sigmoid diverticular disease and a proximal colon that proves to be long and mobile is the ultimate endoscopic nightmare. “Underwater” colonoscopy, using a 50-mL syringe to instill water, may help passage in some patients with very hypertrophic musculature and redundant mucosal folds in diverticular disease, in whom it can sometimes be difficult to obtain an adequate air view. Larger volume water instillation has also been found by some to help insertion through the normal sigmoid colon if the view is poor or passage problematic.

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Be prepared to abandon or change instruments if postoperative or peridiverticular adhesions have fixed the pelvic colon so as to make passage impossible or dangerous. If there is difficulty, if the instrument tip feels fixed and cannot be moved by angulating or twisting, or if the patient complains of pain during attempts at intubation, there is a danger of perforation or instrument damage.

Sigmoid loops Some degree of upward looping always occurs as the colonoscope pushes inward. Looping around the apex of a long sigmoid, then proximally and up the descending colon is occasionally easy and may prove to be the best option (Figure 40.28). However, pushing through any loop is unacceptable if force is required or pain results. Pain indicates potential for damage to the bowel or mesentery. Similarly, pushing blindly around any bend should be limited to a few centimeters and only if “slide by” of the mucosal vascular pattern view continues smoothly toward the predetermined direction of the lumen. Stop if the mucosa blanches (indicating excessive local pressure) or the patient experiences pain (indicating undue stress on the bowel or mesentery); perforation is a possibility if excessive or unrelenting force is used. Patients with short sigmoid loops tend to be pain sensitive, and their shorter mesenteric attachments are more aggressively stretched. Long colons, with longer mesenteries, simply stretch upward and can adapt to let the colonoscope pass relatively easily into the descending colon without an acute hairpin bend (Figure 40.29). Inward push should be applied gradually, avoiding sudden shoves and limited to a tolerable duration, typically no more

(a)

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(b)

Figure 40.28 A very long sigmoid may allow the scope to push through without a hairpin bend.

than 20–30 s. The apparent “wind pain” which is caused by loop stretching, stops immediately when the instrument is withdrawn slightly. “N” looping is the “classic” loop of the scope-stretched sigmoid colon, so described originally because of its appearance on anteroposterior fluoroscopic views, although often there is a “three-dimensional spiral” component if seen laterally (as with the magnetic imager). It helps to warn the patient that “stretch pain” or “wind pain” may be felt during this brief push around the apex of the sigmoid loop. The challenge is to progress the instrument tip through the sigmoid loop without repeatedly losing the view, minimizing applied force and scope looping as far as possible. Pushing movements should therefore start slowly and gently, giving time for accurate torque steering and allowing the colonoscope to

(c)

Figure 40.29 (a) An N loop with the tip at the sigmoid–descending junction, (b) twist clockwise and withdraw, (c) keep twisting and find the lumen of the descending colon.

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slide in (rather than just buckle upward toward the diaphragm, as tends to happen with a rapid push). In contrast, pullback movements must be frequent and vigorous whenever the view is lost, in order to reduce the looping and regain the view. Hand pressure on the abdomen may help modestly during sigmoid intubation, opposing any loop that passes anteriorly, close to the abdominal wall. The assistant compresses “nonspecifically” over the lower abdomen, hoping to buffer the abdomen against the sigmoid loop, which may reduce stretch pain and help the colonoscope slide around more easily (because the loop is smaller). Assistant hand pressure is only relevant during the 20 –30 s of inward push; more prolonged effort is pointless, especially as in around 50% of patients the sigmoid loop is nowhere near the abdominal surface. A short or pain-sensitive colon is best managed by removing the loop when the tip is at the sigmoid–descending colon junction, the angulation of which gives the endoscopist a chance of obtaining leverage control to reduce or straighten the loop by a “pullback and shortening” move. Because there is so often a clockwise spiral element, “pullback with clockwise twist” is worth trying. With luck this will simultaneously shorten (pleat/accordion) the sigmoid over the colonoscope shaft and slide the tip forward into the descending colon without force or pain. Such direct passage to the descending colon is ideal, elegant, and pain free for the patient. Follow these steps: 1 Straighten the shaft by withdrawal (usually with clockwise torque) to reduce the sigmoid loop and create a more favorable angle of approach to the junction of the sigmoid and descending colon (Figure 40.30). 2 Apply abdominal pressure, the assistant pushing on the left lower abdomen, in the hope of compressing the loop or reducing the abdominal space within which it can form. 3 Deflate the colon (without losing the view) to shorten it and make it as pliable as possible.

Figure 40.31 (a) The tip is hooked into the retroperitoneal descending colon, then pulled back. (b) When the endoscope is maximally straightened the tip is redirected and (c) the endoscope pushed, with clockwise twist, into the descending colon.

(a)

(a)

Insertion Technique

(b)

Figure 40.30 (a) Pull back and deflate to keep the sigmoid short, (b) which may allow direct passage to the descending colon.

4 Angulate the controls and use torque simultaneously in approaching the bend, so the tip is coaxed into the axis of the descending colon just before the bend and so is likely to slide around more easily (see Figure 40.23). 5 Withdraw the colonoscope further and try clockwise shaft twist so that this corkscrewing force applied to the tip swings it around the bend, with no inward push pressure required (Figure 40.31a). 6 Simply pulling back can be a mistake, causing the hooked tip to impact the mucosa (Figure 40.31b), so it is essential at the same time to steer toward the lumen of the descending colon (Figure 40.31c). A wrong move at this point will lose tip hold in the retroperitoneal fixation and the instrument can fall back into the sigmoid. 7 Changing patient position may improve things at the sigmoid–descending junction (air rises, water falls), and gravity often causes the descending colon to drop down into more favorable configuration.

(b)

(c)

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Figure 40.32 An “alpha” spiral loop.

Careful close-up view, minimal insufflation, twist, delicate steering movements, and patience are all needed to pass straight up into the descending colon without the sigmoid relooping or the scope slipping back. Long, pain-insensitive colons and spiral (or “alpha”) loops suggest a “push and go” approachaproviding that no force is required, the patient is comfortable, and there is a reasonable view ahead. A spiral loop is a potential blessing for the endoscopist, because its smooth shape (Figure 40.32) should mean that there is no acute bend between the sigmoid and descending colon, allowing the descending colon and splenic flexure to be reached rapidly and relatively painlessly. So, if the instrument appears to be inserting a long way through the sigmoid, with a view ahead and no undue pain, problems, or acute angulations, a spiral loop may have formed. The classical “alpha” spiral loop was originally described (on anteroposterior views with fluoroscopy) as occurring

AP view

in 10% of patients. If lateral views are included, however (Figure 40.33a and b), spiral configuration is seen in around 60% of patients, especially those with long colons, who, conveniently, tend to be relatively pain insensitive. If, therefore, spiral loop formation is suspected, do not withdraw but carry on pushing (Figure 40.33c) to the proximal descending colon or splenic flexure (at around 90 cm) before trying any withdrawal or straightening maneuvers (Figure 40.33d). Although the patient may experience mild stretch pain, or the view into the descending colon may be poor because of fluid, push on inward (Figure 40.34). Applying normal sigmoid straightening maneuvers halfway round a spiral loop is a potential mistake, as it may lose the beneficial spiral and convert it to “N loop” configuration with an acute hairpin bend and then greater difficulty in reaching around to the descending colon. The alpha maneuver describes the intentional formation of an alpha or spiral loop. It was first used in the 1970s under fluoroscopy, as a way of avoiding acute colonic angulation at the sigmoid–descending colon junction, which could be difficult to pass with early instruments. It is likely to return to favor with the gradual introduction of magnetic imaging. The principle of maneuvering is to encourage the sigmoid into the favorable spiral shape when insertion is proving technically difficult (Figure 40.35). The imager view, if available, allows the endoscopist either to realize that an alpha or spiral loop has already formed, thus warning against pulling back and the risk of losing the beneficial configuration, or to maneuver within the sigmoid loop (or loops) until a spiral occurs. This may take a few seconds of manipulation, but then assures rapid inward intubation to the descending and splenic flexure. “Push through” is the option of last resort in a long colon. If subtlety (including withdrawals, maneuvering, position change, hand pressure, and other “tricks”) is not successful, intubation may require calculatedly vigorous “push through.”

Lateral view

=

(a)

548

(b)

(c)

(d)

Figure 40.33 Many “N” loops (a), if also seen in lateral view, are actually spiral (b), so push on toward the splenic flexure (c) before straightening back (d). AP, anteroposterior.

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90 cm

Figure 40.34 In an alpha loop, the colonoscope runs through the fluidfilled descending colon to the splenic flexure at 90 cm.

Warn the patient to expect discomfort, then a few seconds of careful “persuasive” pressure may slide the instrument tip successfully around the bend and up the descending colon, before pulling back and straightening again (to 45–50 cm). In some patients, a large spiral or alpha loop may have formed, resulting in easy passage, despite looping, while in others (see Figure 40.28) the sheer length of the sigmoid allows it to

Figure 40.35 (a) Alpha maneuver (with magnetic imager): manipulate the sigmoid by (b) rotating the loop counterclockwise to pass toward the cecum, then (c) down into an alpha and easily on up into the descending colon.

Insertion Technique

adopt a smooth “s” shape which, while transiently uncomfortable, allows rapid passage up the descending colon. Without fluoroscopy or the magnetic imager the endoscopist is usually unsure exactly what has happened. Providing that the patient has no pain and the scope progresses satisfactorily, the exact configuration does not matter as long as the loop (whichever it is) is then rapidly and fully removed. Sigmoid loop removal is essential at some point. Most of the pain or difficulty experienced while passing the proximal colon (splenic flexure, transverse colon, and hepatic flexure) stems from recurrent or persistent looping in the sigmoid. It is for this reason that, both initially and when inserting through the proximal colon, repeated “pullback” straightening of the sigmoid colon is so important. With a longer colon, complete removal of the spiral loop may be difficult until the instrument tip has reached well up the descending or is “hooked” around the angulation of the splenic flexure. This gives adequate purchase for withdrawal, using a combination of shaft twist (usually clockwise) and vigorous pullback to straighten out the loop (Figure 40.36). The feel of the shaft should indicate whether twist is being applied in the correct direction to straighten the spiral; twist in the wrong direction worsens the loop, so worsening the

(a)

(b)

(c)

90 cm

50cm

Figure 40.36 (a) To remove an alpha loop, (b) pull back and twist clockwise (c) to straighten completely.

(a)

(b)

(c)

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Counterclockwise

Clockwise

Figure 40.38 Reversed alpha loop (counterclockwise spiral) is due to a persistent descending mesocolon.

Figure 40.37 A clockwise spiral is straightened by clockwise twist. A counterclockwise twist worsens it.

feel of the shaft and controls (Figure 40.37). Withdrawing the shaft initially reduces the size of the loop, which then makes de-rotation easier. Most colonoscopists prefer to straighten the spiral loop as soon as the upper descending colon or splenic flexure is safely reached (at 90 cm) and then to pass the splenic flexure with a straightened instrument (though in a very long colon it may be possible to insert around into the transverse colon before straightening). If, during straightening, the scope starts to slip out excessively, it may be necessary to reinsert and forcibly angulate at the flexure. If straightening the loop proves difficult or the patient has more than the slight discomfort, the situation should be reassessed. Adhesions can make de-rotation difficult and occasionally impossible. Do not use force. The sigmoid spiral loop may not be a true clockwise or “alpha” loop but a “reversed alpha” (see below), which needs counterclockwise de-rotation. Occasionally, it is better to pass into the proximal transverse colon with the spiral loop in position before straightening. Atypical or multiple sigmoid loops are more likely in a very long colon. It is in such patients that withdrawal with counterclockwise twisting force may be needed to de-rotate and straighten a “reversed” loop (Figure 40.38). Sometimes there can be several spiral loops in the distal colon (typically mobile as well as long, and with no obvious separation into “sigmoid” or “descending”). Successful straightening may involve derotation first in one direction and then the other. Eventual “success” in straightening should be obvious from measurement (45–50 cm of instrument inserted) and the fully responsive feel of the instrument (one-to-one progression and precise torque control). Instrument shaft loops external to the patient occur as a result of rotating the colonoscope when straightening one or

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Figure 40.39 Shaft loops external to the patient can be transferred to the umbilical by rotating the control body.

more sigmoid loops or of applying torquing force, which may result in a loop forming in the shaft external to the patient. Such a loop makes instrument handling awkward, inhibiting torque steering and causing unnecessary control wire friction, so is best removed by rotating the control body to transfer this loop from the shaft to the umbilical (Figure 40.39). Alternatively, a dexterous endoscopist can, if the instrument is straight, torque the external shaft loop out while steering up the lumen so that the colonoscope rotates on its axis within the colon.

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air

water

Figure 40.40 Fluid levels in the left lateral position. Figure 40.41 Phrenicocolic ligamentWthe variable fixation below the splenic flexure.

Descending colon The conventional descending colon, which characteristically has a horizontal fluid level in left lateral position, is normally traversed in a few seconds (Figure 40.40). If fluid makes steering difficult, it may be quicker, rather than wasting time suctioning and reinflating, to turn the patient onto his or her back or right side in order to fill the descending colon with air. Sometimes the descending colon is not straight and the endoscopist, having struggled through a number of bends and fluid-filled areas, believes the tip to have reached the proximal colon when the colonoscope is only at the splenic flexure.

Splenic flexure The splenic flexure is the halfway point during colonoscope intubation, and an excellent place to ensure that the instrument is properly straightened (to around 50 cm) before tackling the proximal colon. A common reason for problems in the proximal colon is inadequate straightening of distal loops, so making the rest of the procedure progressively more difficult or even impossible. Anyone who frequently finds the proximal colon or hepatic flexure difficult to traverse should apply the “50-cm rule” at the splenic flexure, and is likely to find most of the problem solved. The splenic flexure is conventionally fixed because of the phrenicocolic ligament (Figure 40.41), a tethering peritoneal fold of variable length. Passage around the apex of the splenic flexure is usually obvious, because the instrument emerges from fluid into the air-filled, often triangular, transverse colon. However, while the flexible and angulated tip section of the colonoscope passes around without effort, the stiffer shaft may not follow so easily. To pass the splenic flexure without force or relooping, follow these steps: 1 Straighten the colonoscope, pulling back with the tip hooked around the flexure until the instrument is 40–50 cm from the

Figure 40.42 Control sigmoid looping by hand pressure to help pass the splenic flexure.

anus (splenic avulsions or capsular tears have been reported, so do this gently). 2 Avoid overangulation of the tip (“walking-stick handle” effect), which causes impaction in the flexure and can block intubation. Consciously de-angulate a little so that the instrument runs around the outside of the bend (see Figure 40.10), even if the view is worsened. 3 Deflate the colon slightly to shorten the flexure and make it more flexible. 4 Stiffen the scope (if it has variable stiffening facility). 5 Apply assistant hand pressure to the left lower abdomen to resist looping of the sigmoid colon (Figure 40.42). 6 Use clockwise torque on the shaft to counteract any spiral looping tendency in the sigmoid colon while pushing in (Figure 40.43). Because the tip is angulated, applying such clockwise shaft torque may affect the luminal view, so readjustment of the angulation controls may be needed to compensate and maintain vision. 7 Push in slowly. Pressure is needed to slide around the flexure but aggressive push will simply reform the sigmoid loop. While pushing in, if possible deflate again and, if necessary,

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Figure 40.45 “Reversed” splenic flexure will result in a deep transverse loop. Figure 40.43 Twist the shaft clockwise while advancing to hold the sigmoid straight.

(a)

(b)

Figure 40.44 (a) In the left lateral position the transverse colon flops down, making the splenic flexure acute. (b) In the right lateral position gravity rounds off the splenic flexure, making it easy to pass.

readjust the angulation controls so as to “wiggle” the bending section around the curve. 8 If the combination does not work, pull back and start again. Run through all the above actions again, and push in once more. It can take two or three attempts to achieve success. 9 Finally, change patient position and try again. Patient position change is the single most effective trick if the splenic flexure is hard to pass. The left lateral position, used by most endoscopists, has the undesirable effect of causing the transverse colon to flop down (Figure 40.44a), making the splenic flexure acutely angled. In the right lateral position, the transverse colon sags under gravity, pulling the splenic flexure into a smooth curve (Figure 40.44b). Supine position has an intermediate effect and is an easier move to make, so first try rotating the patient onto his or her back.

Distal colon mobility and the “reversed splenic flexure” In the absence of fixation of the descending colon, all sense of anatomy can disappear; the colonoscope may even run through

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the “sigmoid” and “descending” distal colon straight up the midline (see Figure 40.22), resulting inevitably in a “reversed” splenic flexure and consequent mechanical problems later in the examination. When counterclockwise rotation seems to help passage around the sigmoid–descending junction, the endoscopist is alerted to the probability of atypical mobility. This mobility may allow an unconventional counterclockwise spiral or “reversed alpha” loop (see Figure 40.38) and then cause the descending colon to deviate medially, rather than being fixed retroperitoneally and immobile. In 5% of patients with a long and mobile colon, the magnetic imager shows the instrument passing from medial to lateral around the splenic flexure (Figure 40.45), with the disadvantage that the transverse colon is pushed into a deep loop. This subsequently creates an unusually acute angle when approaching the hepatic flexure, making it difficult to reach the cecum and virtually impossible to steer into the ileocecal valve. De-rotation of a reversed splenic flexure loop is sometimes possible, usually after withdrawing the tip toward the splenic flexure and then twisting the shaft strongly counterclockwise (Figure 40.46a). Counterclockwise de-rotation makes the tip pivot around the phrenicocolic suspensory ligament. Maintaining this counterclockwise torque while pushing in causes the instrument to pass the transverse colon in the conventional “question mark” configuration because the descending colon is forced laterally against the abdominal wall (Figure 40.46b). This counterclockwise straightening maneuver is quite feasible by feel alone (but easier using the magnetic imager); try it whenever atypical looping is suspected in the proximal colon. However, if straightening does not work, it may be necessary simply to “push through” harder than usual (if necessary with extra sedation).

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(b)

Figure 40.48 Follow the longitudinal bulge (tenia coli) round an acute bend. (a)

Figure 40.46 (a) Counterclockwise rotation (b) swings a mobile colon back to a normal position.

Transverse colon Problems in the transverse colon are often due to the sigmoid colon re-forming an N loop, thus reducing effective transmission of inward push pressure to the colonoscope tip. The transverse colon can be pushed downward by the advancing colonoscope forming a deep loop, with greater resistance and force needed to advance the tipaoften resulting in sigmoid looping as well. A clue is given that the transverse is long and likely to be problematic when a tenia coli is seen indenting the capacious colon, although this acts as a useful pointer to followarather like the white line down the center of a road (Figure 40.47). At acute angulations, such as the mid-transverse, follow the tenia to steer or push around the bend and see the lumen beyond (Figure 40.48).

(a)

(b)

Figure 40.49 (a) If passage up the proximal transverse is difficult, (b) pull back to lift and shorten.

After the midpoint of the transverse, it may be slow and difficult to “climb the hill” up the proximal limb of the looped transverse colon (Figure 40.49a). Pull back, using the hooked tip to lift up and straighten the transverse (Figure 40.49b). The tip often advances as the shaft is withdrawn, the phenomenon known as paradoxical movement. Hand pressure can be helpful, whether over the sigmoid colon during inward push (nonspecific pressure), or in the left hypochondrium or central abdomen to try to lift up the transverse loop (specific pressure). Deflation of the colon, torquing movements, and even change of position (usually to the left lateral position, sometimes to the supine, right lateral, or even prone position) can also help. Counterclockwise torque often helps advance the last few centimeters toward the hepatic flexure, providing that the shaft has been straightened enough (so that torsional force transmits proximally).

Effect of a mobile splenic flexure Figure 40.47 The longitudinal bulge of a tenia coli shows the axis of the colon.

“Lift” withdrawal maneuvers in the transverse colon depend on the fulcrum or cantilever effect made possible by the

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40 cm

90 cm

(a)

(b)

Figure 40.50 (a) If the phrenicocolic ligament is lax, withdrawal maneuvers are ineffective but deflation may advance the tip; (b) pushing in simply reforms the loop.

phrenicocolic ligament (see Figure 40.41) fixing the splenic flexure. In some patients this attachment is lax, allowing the splenic flexure to be pulled back to 40 cm rather than the usual 50 cm (Figure 40.50a). The colon is then found to be hypermobile, the scope inserting or withdrawing massively with little of the usual cantilever effects to progress it through the transverse, and often running almost straight toward the hepatic flexure. When this happens the use of force is usually ineffectual, whereas deflation, hand pressure, and position change (usually to the right lateral position) can eventually coax the tip up to and around the hepatic flexure. The alternative tactic of simple aggression and push force reforms the transverse loop (Figure 40.50b), which is sometimes unavoidable and the quickest option.

Gamma looping of the transverse colon A gamma loop (1% of examinations) forms when the mesocolon of the transverse colon (Figure 40.51a) is so long that colonoscope pressure pushes it across the abdomen into a

Figure 40.52 “Specific” hand pressure may elevate the transverse colon.

large drooping loop, effectively a “volvulus” (Figure 40.51b). A gamma loop, once formed, is not usually removable, because of its size (which conflicts with the small intestine and other organs during attempted de-rotation) and because colon mobility makes it difficult to find any fixation point on which to angulate and stop the tip falling back during withdrawal. The cecum can be reached with a gamma loop in position, but control wire friction then makes it difficult to enter the ileocecal valve.

Hand pressure in the transverse colon The use of hand pressure to attempt control of the looping sigmoid colon has been described (see Figure 40.20). The tendency of the sigmoid to reloop at all stages of intubation means that pressure over it is worthwhile whenever the instrument is looping, described as nonspecific hand pressure. Loops can also be reduced or resisted by appropriate hand pressure, notably a drooping transverse colon, but only once the transverse loop has been pulled up and shortened as far as possible. Specific targeted hand pressure may then help push the colonoscope tip further inward (Figure 40.52). Try pushing empirically (to see if the tip can be advanced) in the: 1 left hypochondrium (to lift the loop and the tip across the abdomen toward the hepatic flexure); 2 midabdomen (to counteract the sagging transverse colon); 3 right hypochondrium (to impact directly on the hepatic flexure).

Hepatic flexure

(a)

(b)

Figure 40.51 (a) Transverse mesocolon; (b) gamma loop.

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A common problem in the transverse colon is to be able to see the hepatic flexure but not reach it without the scope relooping and falling back. If the flexure is only 2–3 cm away, with a reasonably straight colonoscope (70–80 cm), hand pressure has already been tried and perhaps counterclockwise torque also, a final combination of small actions (listed below) should ensure rapid passage around the hepatic flexure.

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Figure 40.53 (a) When around the hepatic flexure and viewing the ascending colon, (b) pull back to straighten, (c) and aspirate to collapse the colon and pass toward the cecum.

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(b)

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(c)

Passing the hepatic flexure 1 Assess from a distance the correct eventual steering direction around the flexure. 2 Aspirate air carefully from the inflated hepatic flexure in order to collapse it toward the tip. 3 Ask the patient to breathe in (and hold the breath), which lowers the diaphragm and often the flexure too. 4 It may be possible to push the scope tip toward the hepatic flexure by finding a specific pressure point on the abdomen, and then, as the assistant presses, perform the next maneuver. 5 Angulate the tip blindly in the previously determined direction around the flexure. The hepatic flexure is very acute, often a 180° hairpin bend, so it takes some confidence to angulate around with partial view (Figure 40.53a). Use both angulation controls simultaneously for full angulation (using both hands makes this major angulation easier). Adding clockwise torque may also help. 6 Withdraw the instrument substantially (up to 30–50 cm) to lift up the transverse and straighten the colonoscope (Figure 40.53b) for passage into the ascending colon. 7 Aspirate air again once the ascending colon is seen, which shortens the colon and drops the tip down toward the cecum (Figure 40.53c). 8 If steps 1–7 are ineffective, position change to right lateral or even prone (which helps compress a particularly bulging abdomen) may help coax the colonoscope tip into and around the hepatic flexure. Forceful pushing rarely pays off, because looping in the sigmoid and transverse colon can use up most of the length of the colonoscope shaft. With the instrument really straightened at the hepatic flexure, only about 70 cm of the shaft should remain in the patient, and it is at this point that the subtleties described above are likely to work. 9 Be realistic. If things are not working out at the hepatic flexure after applying these various fixes, the colonoscope may actually still be in the splenic flexure. In a long and mobile colon it is easy to be overoptimistic and become hopelessly lost. The clue to this is often that the hepatic flexure (in left lateral position) is dry or air filled, whereas the splenic flexure is likely to be fluid filled.

Ascending colon and ileocecal region The temptation to push in to the ascending colon from around the hepatic flexure should be resisted, as it usually only results in the transverse loop reforming and the tip sliding back. The secret is to deflate; the resulting collapse of the capacious hepatic flexure and ascending colon will drop the tip down toward the cecum (see Figure 40.53c). Deflation also lowers the hepatic flexure, a mechanical advantage, so that pushing inward is more effective. Repeated aspirations, steering carefully down the center of the lumen (with torque if it helps), then pushing for the last few centimeters, should reach the cecum. Passing the last few centimeters to the cecal pole can be difficult because the cecum tends to be bent anteriorly. Position change to prone (even a partial position change of 20–30° may help) or to supine should alter things enough to reach to the appendix. Retroversion is often (but not always) possible in the proximal colon, providing that the instrument has been straightened back and is fully maneuverable. It is significantly easier with pediatric instruments and in wide-diameter colons. Choose the widest place, angulate fully with both controls (lock the lateral control if necessary), and simultaneously twist the shaft forcibly clockwise or counterclockwise, which maximizes angulation. The scope tip should flip semiblind over several folds and then regain the (retroflexed) luminal view. “Complete colonoscopy” for certainty requires identification of the ileocecal valve opening and also of the slit or curve of the appendix opening at the cecal pole. The “crow’s foot” or “Mercedes-Benz” sign (Figure 40.54) where the teniae join is the classic appearance, but is actually rather uncommon. The cecum can be voluminous and confusing to examine. It is also possible to be mistaken; the ileocecal valve fold can be in spasm, being mistaken by the unwary for the appendix orifice or cecal pole. Insufflation, giving an antispasmodic, changing the patient’s position, or simply pushing in may advance the scope a few centimeters further into the cavernous cecal pole beyond.

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Figure 40.54 Cecal pole: “Mercedes-Benz” or “crow’s foot” sign of teniae fusing at the appendix.

Entering the ileocecal valve The “appendix trick” or “bow and arrow” sign is an ingenious (and usually successful) way of both finding and entering the valve: 1 Find the appendix orifice. This is usually crescentic and shaped like a bow. 2 Imagine an arrow in that bow. It will point in the direction of the ileocecal valve (Figure 40.55).

3 Angulate in that direction and withdraw so the tip (still angulated) slides back about 3–4 cm. 4 Watch for the proximal lip of the ileocecal valve as it starts to ride up over the lens. 5 When it does, stop, insufflate, and angulate gently into the ileum. The trick works when, as it does more often than not, the angulated appendix lies bent in the direction of the center of the abdomen, from which direction the ileum enters the cecum. The crescentic fold created by the angulation of the appendix acts as a directional indicator, much as an airport windsock indicates wind direction for a pilot. After appendectomy or when the cecum is mobile and the appendix is straight-on, there is no such indication. Finding the valve otherwise requires the endoscopist to pull back about 8–10 cm from the cecal pole and identify the first prominent circular haustral fold, around 5 cm back from the pole. On this “ileocecal fold” will be the tell-tale thickening or bulge of the valve. From the side, the valve may appear flattened, may bulge in (especially on deflation, when it can bubble), can show a characteristic “buttock-like” double bulge, or, less commonly, have obvious protuberant lips or a “volcano” appearance. The best the endoscopist can usually achieve is a partial, close-up, and tangential view, often only after careful maneuvering. Change of patient position may be helpful if the initial view is poor or entry proves difficult. Entering the ileocecal valve, other than by the “appendix trick” described above, is by one of three methods.

Direct entry into the ileum

Figure 40.55 The “bow” of the appendix opening shows the direction of the appendixband usually the ileum also.

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Direct entry into the ileum is almost always possible but often takes some patience. 1 Rehearse at a distance (10 cm back from the cecal pole) the easiest movements for entry. If possible, rotate the endoscope so that the valve lies at the bottom of the visual field, which allows entry with an easy down-angulation movement (single-handed lateral or oblique movements are awkward) (Figure 40.56a). 2 Pass the colonoscope tip in over the ileocecal valve fold (aspiration alone may do this) and angulate toward the valve (Figure 40.56b). Overshoot a little so that the action of angulation directs the tip into the opening, not short of it. 3 Deflate the cecum partially to make the valve supple. 4 Pull back the colonoscope, angulating toward the valve until the tip catches in its soft lips, resulting in a “red out” of transilluminated tissue (Figure 40.56c), typically with dappled reflections or granular appearance of the villi in close-up (as opposed to the pale shine of colonic mucosa). 5 On appearance of the “red out,” freeze all movement and insufflate air to open the lips (Figure 40.56d), gently twisting or angulating the endoscope a few millimeters to find the ileal lumen. 6 Injecting water lifts the villi into more obvious view.

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(a)

(b)

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(d)

Figure 40.56 (a) Locate the ileocecal valve (preferably at 6 o’clock), (b) pass in and angulate and deflate slightly, (c) pull back until “red out” is seen, and (d) insufflate to open the valve.

7 Multiple attempts may be needed to succeed in locating the valve and entering the ileum, and changing position may help greatly if there are problems. Since the scope will be “straight” around to the cecum and respond precisely, all of these maneuvers can be performed with the thumb on the up/down control wheel and the right hand on the shaft, withdrawing and torquing it simultaneously.

Entry using biopsy forceps Entry using the biopsy forceps is helpful only if a distant, partial, or uncertain view can be obtained of the ileal bulge or opening. The biopsy forceps is used to locate, and then pass into, the opening of the valve, either to obtain a blind biopsy or to act as an “anchor” (Figure 40.57). Aspiration then deflates the colon and usually allows the tip to slide into the valve.

Entry in retroversion Entry in retroversion is useful if the colon is capacious and the ileocecal valve is slit-like and invisible from above (and the colon is also capacious enough). In order to retrovert to see the ileocecal valve from below, the tip is placed at the orifice of the appendix, then maximum angulation of both

Figure 40.58 If necessary (a) retrovert to see the valve, (b) pull back to impact, and (c) insufflate and de-angulate to enter the ileum.

(a)

Figure 40.57 Biopsy forceps can be used to locate, and pass into, the ileocecal valve.

controls and forcible clockwise twist will frequently flip the tip around. The extra length of the bending section of video endoscopes (even if retroversion is possible) may preclude any view of the valve. If retroversion works and the valve slit is visible (Figure 40.58a), pull back to impact the tip within it (Figure 40.58b), then insufflate to open the lips, and deangulate and pull back further to enter the ileum, with or without use of the forceps (Figure 40.58c).

(b)

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Terminal ileum The surface characteristics of the terminal ileum are variable. The ileal surface appears granular or matt in air, but under water the villi are seen projecting. In younger patients the surface is often studded with raised lymphoid follicles resembling small polyps, or these can be aggregated into plaquelike Peyer’s patches. Sometimes the ileum is surprisingly colon-like, with a pale shiny surface and visible submucosal vascular pattern, although water filling will cause the villi to stand up and become visible. After colon resection the difference between the colon and ileum may be imperceptible because of villous atrophy, although dye spray will discriminate between the granular or “sandpaper” appearance of the ileal mucosa and the circumferential “innominate grooves” of the colonic surface. Once the colonoscope tip is in the ileum, it can often be passed inward for up to 30–50 cm with care and patience, although this length of intestine may be convoluted onto only about 20 cm of instrument. Air distension of the small intestine should be kept to a minimum as it is particularly uncomfortable and slow to clear after the procedureaa problem avoided by using CO2. Problems in finding or entering the ileocecal valve occur for a number of reasons. The endoscope may be in the hepatic flexure, not the cecum. The opening may simply be unobvious. Some valve openings are flat and slit-like, effectively invisible on the reverse side of the fold. In Crohn’s disease the valve can be strictured and impassable, although a limited view may be possible and biopsies may be taken through it. After chronic ulcerative colitis, atrophy may make the valve so large and gaping that it can be missed altogether as the scope enters the featureless ileum.

Further reading Ambardar S, Arnell TD, Whelan RL, Nihalani A, Forde KA. A preliminary prospective study of the usefulness of a magnetic endoscope locating device during colonoscopy. Surg Endosc 2005; 19: 897–901. Arcovedo R, Larsen C, Reyes HS. Patient factors associated with faster insertion of the colonoscope. Surg Endosc 2007; 21: 885– 8. Barthel J, Hinojosa T, Shah N. Colonoscope length and procedure efficiency. J Clin Gastroenterol 1995; 21: 30–2. Baumann UA. (1999). Water intubation of the sigmoid colon: water instillation speeds up left-sided colonoscopy. Endoscopy 31: 314–17. Bretthauer M, Lynge AB, Thiis-Evensen E, Hoff G, Fausa O, Aabakken L. Carbon dioxide insufflation in colonoscopy: safe and effective in sedated patients. Endoscopy 2005; 37: 706– 9. Church, JM. Ancillary colonoscope insertion techniques. An evaluation. Surg Endosc 1993; 7: 191– 3. Church, JM. Warm water irrigation for dealing with spasm during colonoscopy: simple, inexpensive, and effective. Gastrointest Endosc 2002; 56: 672– 4.

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Church J, Oakley J, Milsom J, Strong S, Hull T. Colonoscopy training: the need for patience. ANZ J Surg 2002; 72: 89– 91. Fatima H, Rex DK, Rothstein R, et al. Cecal insertion and withdrawal times with wide-angle versus standard colonoscopies: a randomized controlled trial. Clin Gastroenterol Hepatol 2008; 6: 109–14. Hamamoto N, Nakanishi Y, Morimoto N, et al. A new water instillation method for colonoscopy without sedation as performed by endoscopists-in-training. Gastrointestinal Endosc 2002; 56: 825–8. Han Y, Uno Y, Munakata A. Does flexible small-diameter colonoscope reduce insertion pain during colonoscopy? World J Gastroenterol 2000; 6: 659– 63. Harewood GC. Relationship of colonoscopy completion rates and endoscopist features. Dig Dis Sci 2005; 50: 47–51. Harewood GC, Petersen BT, Ott BJ. Prospective assessment of the impact of feedback on colonoscopy performance. Aliment Pharmacol Ther 2006; 24: 313–18. Hsieh YH, Kuo, CS, Tseng KC, Lin HJ. Factors that predict cecal insertion time during sedated colonoscopy: the role of waist circumference. J Gastroenterol Hepatol 2008; 23: 215–17. Kessler WR, Rex, DK. Impact of bending section length on insertion and retroflexion properties of pediatric and adult colonoscopies. Am J Gastroenterol 2005; 100: 1290–5. Kim WH, Cho YJ, Park JY, Min PK, Kang JK, Park IS. Factors affecting insertion time and patient discomfort during colonoscopy. Gastrointest Endosc 2000; 52: 600–5. Lee SK, Kim TI, Shin SJ, Kim BC, Kim WH. Impact of prior abdominal or pelvic surgery on colonoscopy outcomes. J Clin Gastroenterol 2006; 40: 711–16. Marshall JB, Patel M, Mahajan RJ, Early DS, King PD, Banerjee B. Benefit of intravenous antispasmodic (hyoscyamine sulfate) as premedication for colonoscopy. Gastrointest Endosc 49: 720–6. Moore KL, Persaud TVN. The Developing Human: Clinically Oriented Embryology, 8th edn. Philadelphia: WB Saunders, 2007. Mui LM, Ng EK, Chan KC, et al. Randomized, double-blinded, placebocontrolled trial of intravenously administered hyoscine N-butyl bromide in patients undergoing colonoscopy with patient-controlled sedation. Gastrointest Endosc 2004; 59: 22–7. Rex DK, Khashab M, Raju JS, Pasricha J, Kozarek R. Insertability and safety of a shape-locking device for colonoscopy. Am J Gastroenterol 2005; 100: 673– 86. Rex DK, Shawn CC, Overhiser AJ. Colonoscopy technique in consecutive patients referred for prior incomplete colonoscopy. Clin Gastroenterol Hepatol 2007; 5: 879– 83. Sakai Y. Technique of colonoscopy. In: Sivak MV (ed.). Gastroenterologic Endoscopy. Philadelphia: WB Saunders, 2000. Shah SG, Saunders BP. Aids to insertion: magnetic imaging, variable stiffness, and overtubes. Gastrointest Endosc Clin N Am 2005; 15: 673–86. Shah SG, Saunders BP, Brooker JC, Williams CB. Magnetic imaging of colonoscopy: an audit looping, accuracy and ancillary maneuvers. Gastrointest Endosc 2000; 52: 1– 8. Shaheen NJ, Robertson DJ, Crosby MA, et al. Hyoscyamine as a pharmacological adjunct in colonoscopy: a randomized, double blinded, placebo-controlled trial. Am J Gastroenterol 1999; 94: 2905–8. Sorbi D, Schleck CD, Zinsmeister AR, Gostout CJ. Clinical application of a new colonoscope with variable insertion tube rigidity: a pilot study. Gastrointest Endosc 2001; 53: 638– 42. Thomas-Gibson S, Bassett P, Suzuki N, Brown, GJ, Williams, CB, Saunders BP. Intensive training over 5 days improves colonoscopy skills long-term. Endoscopy 2007; 39: 818–24.

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Waye JD, Yessayan SA, Lewis BS, Fabry TL. The technique of abdominal pressure in total colonoscopy. Gastrointest Endosc 1991; 37: 147–51. Webb WA. Colonoscoping the “difficult” colon. Am Surg 1991; 57: 178– 82. Wehrmann K, Fruhmorgen P. Evaluation of a new three-dimensional magnetic imaging system for use during colonoscopy. Endoscopy 2002; 34: 905– 8.

Insertion Technique

Williams CB. Colonoscopy and flexible sigmoidoscopy. In: Cotton PB, Williams CB (eds.). Practical Gastrointestinal Endoscopy bthe Fundamentals, 6th edn. Oxford: Blackwell Publishing, 2008. Williams CB, Waye JD, Sakai Y. Colonoscopy: the DVD. Tokyo: Olympus Optical Co., 2002. Yoong KY, Perkin D, Portal J, Strickland I, Heymann T. Intravenous hyoscine as a premedication for colonoscopy: a randomized double blind controlled trial. Endoscopy 2004; 36: 720–2.

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Missed Neoplasms and Optimal Colonoscopic Withdrawal Technique Kyu Chan Huh1 & Douglas K. Rex2 1

Konynag University School of Medicine, Daejeon, South Korea Indiana University Medical Center, Indianapolis, IN, USA

2

Introduction The fundamental goal of colonoscopy, in most cases, and certainly in the case of screening colonoscopy, is to prevent the development of, and death from, colorectal cancer. Thus, in most cases in which colonoscopy is undertaken, effective inspection of the colon for neoplastic and preneoplastic lesions is the most important technical aspect of the procedure and is the goal of the colonoscopist. Anecdotally, most colonoscopists concentrate their inspection efforts during the withdrawal phase of colonoscopy. During the insertion phase, effort is usually focused primarily on achieving rapid, safe, and comfortable intubation of the cecum. Not until the withdrawal phase do most colonoscopists concentrate on mucosal inspection. Therefore, the withdrawal phase is arguably the most important phase of colonoscopy, although insertion is generally more technically demanding. For several decades, education and colonoscopy focused primarily on technical aspects of insertion and polypectomy. Because the withdrawal phase is less complicated from the perspective of technical maneuvering, it was largely taken for granted in older textbooks of colonoscopy [1–5] and in the teaching of colonoscopy. Only since the emergence of consistent evidence that colonoscopy misses many adenomas and some cancers, and that colonoscopists differ dramatically in their sensitivity for neoplasia, has interest in the withdrawal phase of colonoscopy developed. This chapter reviews technical issues that affect the sensitivity of colonoscopy, and discusses evidence regarding optimal time and technique for the withdrawal phase of colonoscopy. However, it bears noting that the paradigm described above of performing a rapid insertion with little or no emphasis on inspection, followed by inspection during the withdrawal phase, has not been scientifically proven to

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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be the optimal approach for achieving maximum detection of adenomas in cancer. Anecdotally, many colonoscopists are aware that a polyp seen during insertion and not removed may be very difficult to find during withdrawal. Indeed, the colon is often in a very different conformation during insertion than during withdrawal, when it has been shortened and telescoped over the colonoscope shaft. The wisdom of this paradigm deserves reconsideration, and future studies could potentially show that inspection during insertion leads to important improvements in adenoma detection.

The impact of colonoscopy on incidence and mortality from colorectal cancer The only known mechanisms by which colonoscopy can prevent incident colorectal cancers is detection of precancerous polyps and their effective resection by polypectomy. Unfortunately, the evidence regarding the magnitude of the impact of colonoscopy and polypectomy on colorectal cancer prevention is mixed (Table 41.1). Several studies suggest that the

Table 41.1 Variable levels of protection by colonoscopy against colorectal cancer. High-level protection (∼ 80%) National Polyp Study [6] Italian cohort study [7] Telemark Polyp Study [8] German case–control study [9] Intermediate-level protection (∼ 50%) US Veterans case–control study [10] Manitoba negative colonoscopy study [11] California Medicaid study [12] Low-level protection US chemoprevention trials [13] US dietary fiber trials [14,15] Funen adenoma follow-up study [16]

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reduction in incidence provided by colonoscopy and polypectomy is about 80% compared with rates expected in the general population [6– 9,17]. The most important of these, perhaps because it was the first study to examine the issue, is the US National Polyp Study. In this trial, a cohort of patients who had undergone colonoscopy and polypectomy and were followed over time incurred an incidence of colorectal cancer calculated to be 76–90% lower than expected based on reference populations [6]. Subsequent mathematical analyses of the baseline and colonoscopy studies suggested that, 10 years after the baseline examination, almost all of the incidence reduction was the result of the baseline colonoscopy rather than subsequent surveillance examinations, and even after 20 years’ follow-up, most of reduction in incidence and mortality could be attributed to the baseline clearing colonoscopy [18]. Similar levels of incidence reduction were described in an Italian adenoma cohort [7], a randomized controlled trial performed in Telemark County, Norway (in which patients were randomized to undergo flexible sigmoidoscopy with colonoscopy for any polyp detected compared with no screening) [8], and in a case–control study performed in Germany [9]. An additional study showed similar levels of cancer reduction in average-risk patients, and a lesser risk reduction than achieved by colonoscopy in patients with hereditary nonpolyposis colorectal cancer (HNPCC) [10]. Intermediate levels of protection (see Table 41.1) resulting from clearing colonoscopy, typically of the order of about 50%, were reported in a case–control study of US veterans [10], in a cohort of 35 000 symptomatic patients in Manitoba who had a negative colonoscopy in the 1990s [11], and in a study of Medicaid patients in California [12]. Interestingly, the study from Manitoba demonstrated a risk reduction of less than 50% in colorectal cancer incidence for each of the first 5 years after a negative colonoscopy, which increased to 72% by 10 years [11]. This improvement in risk reduction with time is counterintuitive and suggests that many patients with symptomatic cancers were not detected at the baseline examination but were identified because of repeat procedures performed for persistent symptoms in the first few years after the negative colonoscopy. The California Medicaid study demonstrated better protection against left-sided than against right-sided cancers and better protection against right-sided cancers in men than against right-sided cancers in women [12]. A third group of studies has found little or no protection from colonoscopy and polypectomy against colorectal cancer compared with expected rates in the general population. These studies include an analysis of three combined chemoprevention trials performed in the US [13], two dietary intervention trials undertaken in the US [14,15], and the Funen adenoma follow-up study [16]. It should be emphasized that a reduction in risk of colorectal cancer in an adenoma cohort to levels expected in the general population could be a significant achievement, because the adenoma cohort might be

expected to have cancer incidence rates substantially higher than those of the general population [16]. Overall, colonoscopy and polypectomy appear to have a substantial protective effect, but one that is clearly imperfect. Improvements in technical performance or technological aspects of the procedure are of major interest, as in the foreseeable future colonoscopy will remain the cornerstone of all colorectal cancer prevention strategies, either as a primary colonoscopy screening tool or in the evaluation of other positive screening tests.

Medicolegal risk and the impact of missing on surveillance The widely held expectation a decade ago that colonoscopy could prevent all colorectal cancers led to the unfortunate consequence in countries with poor medicolegal environments (such as the US) that an incident cancer occurring after clearing colonoscopy may be presumed to be the result of negligent technical performance of colonoscopy. The increasing literature documenting failed detection of both large and small adenomas during colonoscopy, combined with awareness of the potential medicolegal consequences of interval cancers, has contributed to unwillingness among colonoscopists to accept recommended intervals for screening and surveillance after polypectomy and cancer resection [19,20]. In fact, when colonoscopy is performed with adequate bowel preparation and employing careful inspection technique, recommended screening [21] and surveillance intervals in the US [22] are respectively either adequate or still too conservative. Systematic overuse of colonoscopy for screening and surveillance may reflect lack of knowledge of guidelines, lack of trust of guidelines, concern about interval cancers, or insufficient financial disincentives for overuse. The relative contribution of these factors to overuse of surveillance by some gastroenterologists and many surgeons [19] and family physicians [20] is uncertain. The most rational approach to emerging information about missed lesions is not overuse of screening and surveillance but rather institution of quality measures that maximize detection during baseline examinations, followed by adherence to recommended screening and surveillance intervals. Because medicolegal risk is a practical reality in some environments, certain measures are recommended [23]. The limitations of the bowel preparation should be described. Descriptors such as “excellent” or “good” are appropriate and imply that recommended screening or surveillance intervals should be followed. Descriptors such as “fair” or “poor” should lead to prompt repeating of the examination or, in the case of “fair,” should be accompanied by a descriptor that justifies a shortened interval for screening or surveillance, rather than prompt repeating. For example, the description could say, “Preparation may have prevented the detection of small

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polyps,” which could justify repeating at a shortened interval, as opposed to prompt repeat examination. Another useful descriptor scale is simply “adequate” versus “inadequate” [24]. A recent study suggested that many Israeli gastroenterologists shortened the interval for screening or surveillance when the bowel preparation was impaired, rather than promptly repeating the study [25]. Again, from the medicolegal perspective, if the interval is shortened, it may be best to specify the sorts of lesions that could have been obscured by the preparation. Obviously, the indication for the procedure and any lesions that were detected, despite a less than ideal preparation, could impact the clinician’s decision regarding when to repeat the procedure. Because interval cancers are an inherent risk of colonoscopy, the informed consent statement should list “missed lesion,” “missed cancer,” or an equivalent as risks of colonoscopy. The patient must understand that colonoscopy is not perfect even when carefully performed [23,24]. Intubation of the cecum should be documented by notation of the cecal landmarks, particularly the appendiceal orifice and the ileocecal valve [24]. Experts can recognize the cecum accurately in 100% of cases but recognition requires visualizing the landmarks [26]. The cecum is a common site of missed lesions, as is the ascending colon. A photograph of the appendiceal orifice taken far enough away to demonstrate the cecal strap fold or “crow’s foot” around the orifice documents full cecal intubation, and visualization of the medial wall of the cecum. A second photograph taken from just distal to the ileocecal valve is also useful [26] (Figures 41.1 and 41.2). In the case of interval cecal or ascending colon cancers resulting in medicolegal action, the plaintiff’s expert often opines that the ascending colon and cecum were never intubated. Documentation of the landmarks eliminates this argument as well as, in many instances, any reasonable basis for the legal case. It may be useful to add verbiage in the endoscopy report indicating that an appropriate withdrawal technique was used. The withdrawal time should be documented for purposes of

Figure 41.2 The medial wall of the cecum is best photographed from a sufficient distance so that both the appendiceal orifice and the surrounding “crow’s foot” appearance is visible.

continuous quality improvement. Guidelines regarding quality indicators for colonoscopy suggest that the withdrawal time should average more than 6 min in order to maximize adenoma detection. Given this admonition, it should be inappropriate for a plaintiff’s expert to opine that a withdrawal time less than 6 min for an individual patient is below the standard of care, but anecdotally I have already seen this happen on multiple occasions. Ultimately, the most appropriate defense against an interval cancer may be the demonstration that an individual endoscopist has an acceptable adenoma detection rate [24]. In summary, the most effective and cost-effective approach to preventing colorectal cancer and limiting malpractice risk is to use the common sense steps described above and then perform an effective, careful inspection in a well-prepared colon, followed by adherence to recommended screening and surveillance intervals.

Mechanisms of interval cancers Table 41.2 summarizes a priori mechanisms by which a patient can undergo colonoscopy and still return within the next few Table 41.2 A priori mechanisms of interval cancers. Potentially correctable now Inadequate bowel preparation Suboptimal withdrawal technique Incomplete polypectomy Potentially correctable in future Technical limitations of colonoscopy in highlighting flat lesions and exposing hidden mucosa

Figure 41.1 The most convincing still photograph for documenting cecal intubation is taken from just distal to the ileocecal valve. This view shows the valve, which may or may not appear notched or lipomatous.

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Possibly not correctable Rapid adenoma–carcinoma transformation Rapid normal mucosa–carcinoma transition

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years with cancer (an “interval” cancer). Several of the mechanisms appear to be potentially correctable by means that are relatively straightforward. Potentially correctable factors include bowel preparation, suboptimal technique, and effectiveness of polypectomy, and, on the horizon, improved technology may enhance detection. More rapid transformation through the adenoma–carcinoma sequence is a potential cause for interval cancers in patients with HNPCC, and may also occur in sporadic cancers that pass through the microsatellite instability pathway. These tumors may arise through a hyperplastic polyp to serrated adenoma to cancer sequence that is more common in the proximal colon and in elderly women [27]. It might account partially for the recent observation that colonoscopy has less protective effect in the right colon in older women [12]. The first study to measure microsatellite instability in interval cancers found that the prevalence was 30%, compared with 10% in noninterval cancers [28]. Although colonoscopy may not be able to prevent interval cancers in rapid adenoma–carcinoma scenarios, such as microsatellite instability, it is possible that the protective effect of colonoscopy in these settings could be improved through better detection of tiny adenomas and proximal colon hyperplastic polyps [29,30]. For example, chromoendoscopy in HNPCC resulted in detection of more small adenomas [29], and even tiny adenomas may be relevant in HNPCC. Other chapters in this book cover the topics of bowel preparation, polypectomy, and some of the technical advances in imaging in detail. This chapter focuses on issues related to colonoscopy technique, but other aspects of the issues as they pertain to adenoma detection are briefly mentioned in Table 41.2. Thus, impaired bowel preparation has been associated with lower detection rates of small [31,32] and large [32] adenomas. Although optimal bowel preparations with regard to efficacy, safety, and tolerability have not yet been identified, one aspect of bowel preparation that can be incorporated into sodium phosphate [33,34] or polyethylene glycol preparations [34] is “split” dosing. In this approach, the bowel preparation is divided so that half is given the night before colonoscopy and the second half is given on the morning of colonoscopy, typically several hours before the procedure. This approach complies with American Society of Anesthesiology guidelines on intake of clear liquids, which allow clear liquids up until 2 h prior to sedation [35]. Split dosing has been shown in a prospective trial to improve polyp detection for both sodium phosphate and polyethylene glycol [34]. In particular, it clears from the cecum and ascending colon chyme and mucus, which tend to accumulate and adhere to those sections of the colon when the interval between the last dose of the preparation and the colonoscopy is too long (Figure 41.2). Ineffective polypectomy has been implicated in up to a quarter of interval cancers [36,37], although the evidence is not fully convincing. Snare techniques are more effective than biopsy techniques for eradicating small polyps [38], and en bloc resection is more effective than piecemeal technique

for large sessile polyps. Large sessile polyps removed piecemeal require close follow-up because the short-term recurrence rate varies from 14% to 55% [39]. The evidence that suboptimal technique contributes to interval cancers is based on the observation of variable detection of cancers and adenomas among endoscopists. Variable detection using the same technology implies that some examiners employ methods that result in better detection. The evidence for variable performance is overwhelming, and it has been identified in virtually every study of colonoscopy [40–42] and sigmoidoscopy [43–45] that has looked for it. Evidence for variable detection of cancer has not been extended to individual endoscopists in the same manner that has been shown for adenomas. However, three large population-based studies have found that gastroenterologists have superior detection rates of cancer to nongastroenterologists [46–48], although the latter have mainly been primary care physicians. Only one study has shown superior detection of cancer by gastroenterologists than by general surgeons [46], and no study has compared gastroenterologists with colorectal surgeons. Two recent studies have extended the importance of variable detection by demonstrating that it applies not only to adenomas overall but also to large (≥ 1 cm) adenomas [40,41]. In one of the studies, high-level adenoma detectors found not only more large adenomas but also more high-risk adenoma scenarios (more than three adenomas), by substantial margins [41].

Optimal withdrawal time In 2002, the US Multisociety Task Force recommended that withdrawal time during colonoscopies that did not include biopsies or polypectomies should average at least 6–10 min [49]. In 2006, a combined task force of the American College of Gastroenterology and American Society for Gastrointestinal Endoscopy updated its recommendation to say that the withdrawal phase of these colonoscopies should last at least 6 min [24]. The initial evidence on which the 6-min recommendation was based was scant [49]. Essentially, two colonoscopists with very high adenoma detection rates had average withdrawal times of approximately 8 min [49]. Subsequently, the 6-min goal for average withdrawal times in normal colonoscopies was validated in a landmark prospective study performed by a private practice group in Rockford, Illinois [40]. Among 12 gastroenterologists in private practice, all of whom had performed at least 3000 previous colonoscopies, there was a strong correlation between withdrawal time in normal colonoscopies and adenoma detection rates. In addition, those colonoscopists with average withdrawal times over 6 min detected adenomas ≥ 1 cm in 6.4% of screenees, compared with a 2.6% prevalence in colonoscopies performed by endoscopists with withdrawal times that averaged less than 6 min.

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This dramatic difference in small and large adenoma detection with longer withdrawal time was followed up by the same group in a study demonstrating that the use of a timer in the room designed to force endoscopists to spend at least 8 min on examination time resulted in across-the-board improvements in adenoma detection [50]. The Mayo Clinic Rochester group also validated the 6-min withdrawal target as separating high from low adenoma detectors [51]. At the time of this writing, withdrawal time remains the single aspect of withdrawal technique with the best demonstrated association with adenoma detection. However, withdrawal time is not the primary measure of the quality of mucosal inspection during withdrawal. Rather, the primary measure is the measured adenoma detection rate, which should be 25% or higher in screening colonoscopies in men aged ≥ 50 years and at least 15% in women ≥ 50 years [24,49]. Although there is a powerful statistical association between withdrawal time and adenoma detection, individual examiners with long withdrawal times and low adenoma detection, as well as the opposite instance of examiners with short withdrawal times and high adenoma detection rates, have been described [51,52]. Further, individual examiners have been able to achieve comparable adenoma detection rates using 170° angle of view instruments with shorter withdrawal times than when using 140° angle of view instruments. Thus, acceptable average withdrawal times may need modification for certain examiners using wide-angle colonoscopes [52–54]. The medicolegal implications of withdrawal time were mentioned previously. However, the authors emphasize again here that it is inappropriate for plaintiff’s experts to opine that a withdrawal time in an individual patient of less than 6 min is negligent. The length of the colon and its number of twists and turns are quite variable from one individual to another. For example, in some colons the colonoscope can be inserted to the cecum in less than 1–2 min. These same colons are likely to be effectively examined during the withdrawal phase in less than 6 min. In addition, withdrawal time includes time for suctioning material and washing the colon walls, which can also be variable depending on the quality of the preparation. Therefore, withdrawal time is best used as a parameter in the continuous quality improvement process rather than used to evaluate an individual colonoscopy.

Examination technique In this section, the authors give their perception of optimal colonoscopic withdrawal technique, based on both available evidence and the authors’ experience. Clearly, optimal detection of lesions requires spending an adequate amount of time. The mean time spent on withdrawal by examiners with known low miss rates suggests that mean examination time during withdrawal in normal persons with intact colons should be at

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least 6 min [24,49]. To document this, it is best to record the time of colonoscope insertion into the anus, the moment of cecal intubation, and the moment of colonoscope withdrawal. At our hospital, nurses record these data on the nursing record. Electronic report generating systems may allow electronic recording of this data. An endoscopist who photographs the cecum and the rectum in retroflexion may unknowingly be recording the withdrawal time if the clock time is recorded on those photographs. Because experienced colonoscopists insert the colonoscope in many cases in only a few minutes, this means that total examination time can, in some cases of adequate performance, be as little as 8–14 min. Furthermore, colons in which cecal intubation is very fast (1–2 min) may be relatively short and less redundant, so that adequate examination can be performed at the lower range of the recommended time scale. This can contribute to the occasional occurrence of a normal colonoscopy performed in a total time of less than 10 min and yet with adequate withdrawal technique. The optimal duration of examination is not yet settled, and the recommendation that mean withdrawal times should be at least 6 min is based on available evidence [24,49]. However, no study has adequately addressed the issue of what the optimal length of withdrawal should be. Withdrawal technique fundamentally involves methodology to carefully and meticulously examine the proximal sides of the ileocecal valve, all flexures, all haustral folds, and the rectal valves. Thus, a “straight pullback” technique, in which the examiner slowly pulls the colonoscope back with the tip in the center of the lumen, is suboptimal. Rather, as each fold, flexure, and turn is passed, an assessment must be made of how far that fold projects into the lumen and therefore how much the projection obscures mucosa on the proximal side of that structure. In general, good technique involves constant use of torque on the examining shaft with the right hand, essentially prying apart the space between haustral folds. During withdrawal, the experienced examiner can sense whether the next haustral fold will appear in the up, down, right, or left endoscopic fields by knowing whether the colonoscope tip is flexed up or down via the position of the left thumb on the up/down wheel and by the feel of the instrument shaft with the right hand. Thus, when the scope tip is flexed up and the right hand senses some resistance as a fold on the up endoscopic field resists withdrawal of the up deflected colonoscope tip, the examiner can anticipate that the next fold will appear in the up direction (Figure 41.3). By continuing or further exaggerating upward deflection, the examiner can see the mucosa on the proximal aspect of that fold as the shaft is withdrawn and the tip pulls on the fold. Whenever a fold or flexure is passed at a rate that does not allow careful examination of the proximal aspect of a fold, reinsertion to a point proximal to that fold, flexion in the direction of the fold, and rewithdrawal are necessary. Deflection in the direction of the hidden mucosa should be forceful enough to virtually flatten the obscuring fold, followed

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Figure 41.3 In (a), the endoscope tip is deflected in the up direction during withdrawal. The examiner can anticipate, therefore, that the next fold will appear in the upper aspect of the visual field (b). This anticipation facilitates rapid downward deflection to maintain the lumen in the center of the visual field (c).

Missed Neoplasms and Optimal Colonoscopic Withdrawal Technique

(a)

by pulling back on the instrument shaft until the flattened fold reappears. In some cases, slight deflation of the lumen will allow the examiner to maintain the colonoscope tip on the proximal aspect of a fold or flexure for an adequate period of time to achieve inspection. Our own preference is to rely on instrument torque with the right hand in order to achieve adequate right/left movement and to use the thumb to control up/down movement from the large angulation control. Some examiners use their left thumb to also control the right/left movement, using the wheel on the control head, but we find that maneuver to be ergodynamically stressful. Slow and careful attention to the hidden portions of mucosa is the essential ingredient of careful withdrawal technique. Occasionally, particularly in the sigmoid, an angulation is so sharp that a “red out” occurs during withdrawal, and the examiner has the sense that a substantial portion of the mucosa proximal to the angulation cannot be seen. In this case, the entire turn can generally be visualized by reinsertion and viewing during insertion. The bend in the instrument shaft that develops during insertion changes the contour of the colon and exposes the lumen of the angulated colon. The issue of distension is also important. Some experts have advocated suctioning air as withdrawal is performed. However, if examinations are performed primarily during withdrawal, then suctioning air in order to improve patient comfort can interfere with adequate examination. When colonic mucosa collapses onto another section of mucosa because of deflation, the opposing portions can hide lesions; therefore, adequate distension is critical. Our practice is to maintain adequate distension by air insufflation as necessary

(b)

(c)

during withdrawal. If a section of colon is difficult to distend on withdrawal, it usually means that it is dependent, and rolling the patient even slightly into a different position may allow distension of that section. After withdrawal, we typically palpate the abdomen and if it seems distended, quickly run the colonoscope back up to the proximal colon and then deflate and withdraw rapidly, continuing deflation. The use of carbon dioxide for insufflation obviates the need to reinsert the scope for deflation and allows the examiner to distend adequately, without fear of postprocedural pain and distension [55]. All pools of fluid material should be suctioned. Adding water to the lumen, followed by suctioning, is appropriate when semisolid debris occludes the view. The experienced examiner develops a sense of when adherent mucus is sufficiently tenacious that it cannot be washed clear, even with repeated washing, and when it can be readily washed free and removed. Appropriate preprocedure attention to patient instructions regarding preparation is an essential element of efficient and accurate colonoscopic examination. If areas are insufficiently prepped to allow adequate examination, photo documentation is appropriate to assist in the justification of a repeat procedure. In areas where solid stool is present, rolling the patient from one side to another can expose the underlying mucosa and is a very reasonable undertaking if there are only one or a few small areas of retained solid debris. During appropriate insertion technique, the colon often becomes telescoped over the instrument shaft. Overly rapid withdrawal can be associated with slippage of a section of colon off the tip of the instrument at a rate that does not

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Figure 41.4 Typical endoscopic appearance of the retroflexed rectum.

allow adequate examination. In this instance, reinsertion and reexamination is essential. During withdrawal, slight deflation and/or jiggling of the instrument with the right hand can facilitate more gradual slippage of the colon off the colonoscope tip and ensure adequate time for examination. In some instances, retroflexion in the colon may be appropriate in order to achieve adequate examination. Retroflexion in the rectum is performed routinely by most experts [56] (Figure 41.4). The practice is to examine the entire rectum, in the forward view. The proximal sides of the rectal valves are often examined a second time (Figure 41.5). After examining the entire rectum adequately in the forward view, the retroflexion maneuver is performed. The instrument shaft is positioned with most or all of the bending section just inside the

Valves of Houston

Tumor behind valve Ampulla

Figure 41.5 The careful examiner looks behind haustral folds and rectal valves (as shown here).

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Figure 41.6 Technique for retroflexion. With the tip deflected in the maximum up and left direction, advance and apply counterclockwise torque (left), resulting in a retroflexed view of the anus (right).

anus. The instrument tip will achieve maximum retroflexion by flexing in both an up or down direction and a right or left direction simultaneously. Our practice is to flex the instrument up and to the left maximally. The right hand is then placed under the instrument shaft with the palm facing up, and the instrument is torqued to the left or in a counterclockwise direction and inserted (Figure 41.6). The instrument tip should not be deflected when resistance to tip deflection is apparent, nor should the shaft be pushed in when resistance to advancement and torque is felt. Retroflexion (particularly with standard scopes) may not be feasible and is not required if the rectal lumen is very narrow, as may occur in ulcerative colitis or following radiotherapy. The utility of rectal retroflexion has been both substantiated [57] and questioned [58]. When retroflexion is required but cannot be achieved with a colonoscope, it is facilitated by the use of upper endoscopes, which have a shorter and more compact turning radius when maximally deflected in the up and left or right direction. Thin upper endoscopes will usually allow retroflexion within the sigmoid colon and can be used to perform it in the proximal colon, although in some instances they have insufficient length to reach the cecum [59]. Retroflexion in the right colon can be readily achieved using pediatric or standard colonoscopes (Figure 41.7) and is sometimes achievable within the cecum, allowing a retroflexed view of the ileocecal valve (Figure 41.8). The senior author has experience with an Olympus prototype pediatric colonoscope with a shortened bending section (Figure 41.9), which allows retroflexion in the cecal tip in nearly all patients [60]. Neither the safety nor any benefit of

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Figure 41.7 Typical appearance of the right colon during retroflexion, demonstrating two polyps on the proximal side of a haustral fold. Only the tip of one polyp had been visible on forward view.

Figure 41.9 Photographs of a standard “adult” Olympus colonoscope (left), a pediatric colonoscope (center), and an Olympus prototype pediatric colonoscope with short bending section (right), all displayed in full retroflexion. Note the narrow diameter of the bending section with the retroflexed prototype.

2 Polyps can be hidden on the proximal sides of folds and flexures. Technologies to overcome these problems must be both effective in improving lesion detection and be practical to use. Table 41.3 summarizes these technologies and whether or not they meet the criteria of being both effective and practical. Chromoendoscopy, narrow-band imaging (NBI), and autofluorescence are all covered in detail elsewhere in this text (Chapters 31, 35, and 36). Chromoendoscopy is established as the most effective but also the least practical, because it

Table 41.3 Technologies to enhance neoplasia detection at colonoscopy. Figure 41.8 Retroflexed view of the ileocecal valve, obtained with the prototype pediatric instrument shown in Figure 41.9. The instrument has a short bending section which facilitates retroflexion.

routine right colon retroflexion has been demonstrated, and routine use of the maneuver cannot be recommended. Examination of difficult to access areas has also been achieved with prototype oblique viewing instruments [61] and anecdotally has been achieved with side-viewing instruments.

Technologies to improve detection of flat lesions Colon polyps are missed during the examination for two reasons: 1 The lesion may be so subtle, i.e., flat or depressed, that some form of enhancement is needed to visualize it.

Effective

Practical

For detection of flat lesions Chromoendoscopy Narrow-band imaging High definition Autofluorescence

Yes Yesa Unknown Yes

No Yesb Yes Unknownc

For exposure of hidden mucosa Cap-fitted Third Eye® retroscope Wide-angle optics

Yes Unknown No

Yes Unknown Yes

a Appears effective as a learning tool but not effective for high-level white-light adenoma detectors. b More difficult than white light in large luminal diameter sections and when preparation is poor. c Limited number of studies; not currently adaptable to colorchip charge-coupled device systems.

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often takes several minutes to apply dye to the colon surface, although a single flush of dye may quickly delineate the size and edges of a vaguely defined lesion. Chromoendoscopy has been effective primarily in the detection of very small adenomas, at the cost of removing many nonadenomatous polyps. Its use in routine cases to improve detection of adenomas is unlikely to develop [62]. NBI can highlight adenomas because the color contrast between adenomas and the surrounding normal mucosa is greater in NBI than in white light. However, NBI is ineffective in improving adenoma detection when utilized by highlevel white-light adenoma detectors [30]. Experienced users find that when an adenoma is detected in NBI and the light is converted to white light, the adenoma is almost invariably still evident. A multicenter trial in Europe found that NBI could serve as a useful training technique to improve flat adenoma detection by low-level adenoma detectors [63]. Autofluorescence is not yet commercially available in the US, but early Japanese studies have suggested that it is both effective and practical [64]. Some endoscope processors have integral autofluorescence capability, available by pressing a button in the instrument head. In a randomized controlled trial, the use of high-definition endoscopes, processors and monitors using either white light or NBI resulted in the highest adenoma detection rates that have yet been reported [30], but high-definition colonoscopy has not itself been directly tested for its effect on adenoma detection.

Technologies to increase mucosal exposure One technique for improving exposure of hidden mucosa is cap-fitted colonoscopy (Figure 41.10). The technique appears to be both effective and practical, although North American studies have not been performed. The transparent hood on the end of the scope does not impede insertion, and the

Figure 41.10 A disposable hood or cap on the end of a pediatric colonoscope. The tip is flexed against haustral folds, flattening the folds and exposing the mucosa on the proximal side.

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soft tip is safe. The cap is used during withdrawal to flex against haustral folds and flatten them out, thereby increasing exposure. Wide-angle colonoscopy has been tested in both tandem studies [53,54] and a two-center randomized controlled trial in the US [52]. The studies have not identified improved overall adenoma detection using wide-angle scopes, but individual examiners are able to improve adenoma detection or perform withdrawal faster with no reduction in adenoma detection [52–54]. However, the apparent benefit is operator dependent. In all likelihood, a highly effective withdrawal technique using 140° angle of view instruments can achieve the same level of mucosal exposure with 170° scopes. A computer model based on computed tomographic colonography suggested that the gain in mucosal exposure from 170° to 140° was minimal using even “straight pullback technique” (pulling the instrument straight back without working the instrument tip to inspect between folds) [65]. Like many effects in endoscopy, the benefits of wide-angle colonoscopy depend on the individual examiner, suggesting the need for training endoscopists concerning the differences between the 170° and 140° image and how to alter technique with the wider angle of view to speed withdrawal. Essentially, this involves recognizing that the 170° angle of view allows faster inspection of the proximal sides of colorectal folds, particularly in straighter sections of the colon. The newest development to improve detection with polyps on the proximal sides of folds is the Third Eye® retroscope (Avantis Medical Systems, Sunnyvale, CA, USA). The device is an endoscopic catheter passed through the instrument channel of an adult colonoscopy, which automatically retroflexes after exiting the instrument tip [66] (Figures 41.11). A multicenter trial is currently in progress in the US to determine if adenoma detection is improved by viewing the colon mucosa simultaneously during standard forward-viewing colonoscopy while also seeing and illuminating the proximal portions behind folds with the device. Initial technical problems with the retroscope include difficulty keeping the lens clean (particularly in a poorly prepped colon), difficulty keeping

Figure 41.11 The left panel shows the forward view from the colonoscope with the Third Eye retroscope projecting from the colonoscope instrument channel. The right-hand polyp shows a small polyp on the proximal side of a fold seen only with the retroscope.

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the two systems aligned during withdrawal, the need to watch two images side by side rather than just one, and less than ideal image resolution. It is necessary to remove the retroscope when a polyp is discovered, followed by polypectomy, followed by reinsertion of the device for additional inspection. Further studies are needed to determine if the device is both effective and practical.

Summary Missing lesions is one of the most important adverse outcomes of colonoscopy. The detection of lesions is enhanced by spending adequate time during withdrawal and by a colonoscopic technique that emphasizes careful evaluation of the proximal aspects of folds, flexures, and valves, as well as adequate distension and cleaning of fecal debris. Colonoscopists should obtain informed consent for the possibility of missing lesions, document their withdrawal time, document cecal landmarks in the colonoscopy report, and obtain photo documentation of cecal intubation. Because there is an inherent miss rate for colonoscopy, even with optimal performance, methods that reduce miss rates could have a significant impact on the effectiveness and cost-effectiveness of colonoscopy.

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population-based flexible sigmoidoscopy screening. Gastrointest Endosc 2002; 55: AB214. Atkin W, Rogers P, Cardwell C, et al. Wide variation in adenoma detection rates at screening flexible sigmoidoscopy. Gastroenterology 2004; 126: 1247–56. Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997; 112: 17–23. Bressler B, Paszat LF, Chen Z, Rothwell DM, Vinden C, Rabeneck L. Rates of new or missed colorectal cancers after colonoscopy and their risk factors: a population-based analysis. Gastroenterology 2007; 132: 96–102. Singh H, Turner D, Xue L, Targownik LE, Bernstein CN. Colorectal cancers after a negative colonoscopy. Gastroenterology 2007; 132: A149. Rex DK, Bond JH, Winawer S, et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: recommendations of the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2002; 97: 1296–308. Barclay R, Vicari JJ, Johanson JF, Greenlaw RI. Effect of a prespecified minimum colonoscopic withdrawal time on adenoma detection rates during screening colonoscopy. Gastrointest Endosc 2006; 63: AB83. Simmons DT, Harewood GC, Baron TH, et al. Impact of endoscopist withdrawal speed on polyp yield: implications for optimal colonoscopy withdrawal time. Aliment Pharmacol Ther 2006; 24: 965–71. Fatima H, Rex DK, Rothstein R, et al. Cecal insertion and withdrawal times with wide-angle versus standard colonoscopes: a randomized controlled trial. Clin Gastroenterol Hepatol 2008; 6: 109–14. Rex DK, Chadalawada V, Helper DJ. Wide angle colonoscopy with a prototype instrument: impact on miss rates and efficiency as determined by back-to-back colonoscopies. Am J Gastroenterol 2003; 98: 2000–5. Deenadayalu VP, Chadalawada V, Rex DK. 170 degrees wide-angle colonoscope: effect on efficiency and miss rates. Am J Gastroenterol 2004; 99: 2138– 42. Sumanac K, Zealley I, Fox BM, et al. Minimizing postcolonoscopy abdominal pain by using CO2 insufflation: a prospective, randomized, double blind, controlled trial evaluating a new commercially available CO2 delivery system. Gastrointest Endosc 2002; 56: 190–4. Waye, JD. What constitutes a total colonoscopy? Am J Gastroenterol 1999; 94: 1429–30. Grobe JL, Kozarek RA, Sanowski RA. Colonoscopic retroflexion in the evaluation of rectal disease. Am J Gastroenterol 1982; 77: 856– 8. Cutler A, Pop A. Fifteen years later: colonoscopic retroflexion revisited. Am J Gastroenterol 1999; 94: 1537– 8. Rex DK, Chen SC, Overhiser AJ. Colonoscopy technique in consecutive patients referred for prior incomplete colonoscopy. Clin Gastroenterol Hepatol 2007; 5: 879– 83. Rex DK. Accessing proximal aspects of folds and flexures during colonoscopy: impact of a pediatric colonoscope with a short bending section. Am J Gastroenterol 2003; 98: 1504–7. Howell DA, Sheth SG, Shah RJ, Desilets DJ. Successful polyp removal from difficult to visualize areas of the duodenum and

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colon using a prototype oblique viewing therapeutic endoscope. Gastrointest Endosc 2002; 55: AB114. 62 Rex DK. Maximizing detection of adenomas and cancers during colonoscopy. Am J Gastroenterol 2006; 101: 2866–77. 63 Adler A, Papanikolaou IS, Pohl H, et al. Narrow band imaging (NBI) influences the learning curve for conventional endoscopy afinal results of a prospective randomized study in the detection of colorectal adenomas. Gastrointest Endosc 2007; 65: AB116. 64 Matsuda T, Saito Y, Ikehara H, et al. Does autofluorescence imaging video endoscopy system improve the colonoscopic adenoma

detection rage?aA prospective study. Gastrointest Endosc 2007; 65: AB346. 65 East JE, Suzuki N, Arebi N, Bassett P, Saunders BP. Position changes improve visibility during colonoscope withdrawal: a randomized, blinded, crossover trial. Gastrointest Endosc 2007; 65: 263–9. 66 Triadafilopoulos G, Watts HD, Higgins J, Van Dam J. A novel retrograde-viewing auxiliary imaging device (Third Eye Retroscope) improves the detection of simulated polyps in anatomic models of the colon. Gastrointest Endosc 2007; 65: 139–44.

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Polypectomy: Basic Principles Jerome D. Waye Mount Sinai Hospital, New York, NY, USA

Introduction The colonoscopic removal of adenomatous polyps has had a positive impact on the incidence, morbidity, and mortality of colorectal cancer [1,2], and is one of the major landmarks in gastroenterology during the past century. Polyps in the rectum and distal sigmoid colon have been removed by proctologists and colorectal surgeons for many years, but the ability to reach further in the colon and remove these growths nonoperatively became a reality with the introduction of flexible instruments in the last quarter of the twentieth century. Most polyps in the large bowel are relatively small (< 1 cm in diameter), a feature that has enabled their successful treatment and the popularity of polypectomy throughout the world. Only 20% of polyps are over 1 cm in size. Most large polyps (> 2 cm) are adenomas and are usually located in the rectum or right colon. The majority of small (< 5 mm) polyps in the rectum and distal sigmoid colon are non-neoplastic, but throughout the remainder of the colon approximately 60–70% of small polyps are adenomas [3].

Principles of colonoscopic polypectomy Safe polypectomy requires the ability to sever a polyp while achieving hemostasis and maintaining the integrity of the colon wall. A successful snare polypectomy depends on achieving a balance between the forces of cutting and hemostasis that must be achieved whenever a polyp is transected with a wire snare. During the removal of large polyps, the two complementary forces are the shearing force exerted by tightening the wire loop (cutting) and heat, which results in cauterization (hemostasis). Both forces must be used simultaneously to result in a clean, bloodless polypectomy without an excess-

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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ive amount of burn to the colon wall. Heat alone will not sever a polyp, while guillotine force may cut through a polyp but can result in immediate bleeding as there is no capability for heat sealing of blood vessels. Diminutive polyps (< 5 mm in diameter) with small nutrient blood vessels may be successfully snare transected without the use of electric current as their transection does not result in significant bleeding [4].

Coaptive coagulation Most polypectomies are performed without any blood loss, whether the polyp is large or small. This is because the usual principles of hemostasis, occluding, and sealing blood vessels are employed during transection of a polyp through a colonoscope. This is the same technique used for the cessation of bleeding from the upper gastrointestinal tract. During hemostasis of bleeding ulcers, the endoscopist pushes forcefully on the probe in order to tamponade the bleeding site; this coapts (pushes together) the walls of the bleeding vessel and stops blood flow; there is a need for only a small amount of heat to seal a coapted blood vessel in the absence of intravascular blood flow. In similar fashion, the tightened snare around the pedicle of a polyp effectively causes cessation of circulation in that polyp, enabling a relatively small amount of current to seal the coapted walls of the arteriole. This is quite efficient for pedunculated polyps which have a singlevessel blood supply, but is also effective for sessile polyps in which several small nutrient vessels are presentaclosure of the snare loop compresses the arteriolar walls, and the activated snare seals them.

Electrosurgical unit There are no rules concerning the number of watt–seconds or joules used for the separation of sessile or pedunculated polyps. Each electrosurgical generator has a power output that is not often duplicated by using the same dial control settings on another electrosurgical unit. In general, the dial settings should be medium to low and the current may be

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either pure coagulation or blended. Pure cutting current is never used because this type of energy output explodes cells with no hemostatic qualities. The delivery of energy should be continuous once polypectomy has commenced (there is no scientific justification for intermittent tapping of the foot switch), and the person who closes the snare should do so slowly (as opposed to a rapid closure of the slide bar) after having been requested to begin tightening following current application. Most colonoscopists do not change the power output of the electrosurgical unit during a polypectomy or even from one polyp to the next. Once the endoscopist becomes comfortable with the dial settings, the same setting is used for small or large polyps, and is not changed, even for giant polyps or those whose transection is prolonged. The type of current used for polypectomy, whether coagulation or a blend of cutting and coagulation, is a point of some controversy. Both can achieve tissue heating, but coagulation current produces a greater degree of hemostasis, while cutting current is designed to cause cellular disruption of tissue regardless of whether that tissue is a blood vessel. This characteristic of cutting current can result in bleeding from the polypectomy site without adequate hemostasis. A clinical trial has pointed out that use of blended current (a combination of various amounts of both types of current) had a greater incidence of immediate bleeding whereas use of pure coagulation current was associated with a higher rate of delayed postpolypectomy bleeding [5]. However, it is the preference of the author and of several colleagues who perform a large number of polypectomies to use only coagulation current when resecting colon polyps and not to employ any additional cutting current (no use of blended current).

Polypectomy Basic Principles

up the forceps (to elevate the polyp) also causes the snare to rise up. It is possible to use two separate endoscopes [9], one for grasping, and the other for snaring, but that is not commonly employed.

Snares Types of snares (see Chapter 24) Snares are available in a wide variety of shapes and sizes. The standard large snare is about 6 cm in length by 3 cm wide, and the small snare is about 3 cm long by 1 cm wide. The technique is the same in all instances, whether the snare is oval, crescent-shaped, or hexagonal. The diameter of the wire is an important consideration, given that a thin snare wire will cut through a polyp faster than a thick wire [10]. This variable must be considered when switching from one type of snare to another.

Bipolar snares A bipolar snare [11] has been described in the past, but it does not seem to be available at the present time. It did not seem to have any benefit over the standard monopolar electrocautery snare.

Rotatable snares Rotatable snares are not considered necessary by most endoscopists. With the wire loop extended, the combination of torque on the shaft of the colonoscope and rotation of the angulation controls affords much the same effect as snare wire rotation.

The handle can information center

The colonoscope A 133- or 168-cm-long colonoscope with a single 3.2- or 3.7-mm accessory channel is the instrument most preferred for colonoscopy by all experts and most colonoscopists (see Chapter 22). The double-channel scopes are somewhat less flexible, can be difficult to pass through the entire colon, and are associated with more patient discomfort than the one-channel type. There are only limited occasions when two accessory devices must pass simultaneously through a colonoscope, such as grasping a polyp and lifting it while placing a snare [6– 8]. This maneuver would appear to be relatively easy, but in practice can be quite difficult, as the two accessories are obligated to move together (with the tip of the instrument) rather than separately; it is desirable to lift up the portion grasped by the forceps while seating the snare downward over the polyp, but such complex manipulations are not possible. Attempts at use of the instruments passed through both channels require that, before grasping the polyp, the forceps must be passed through the open snare, but, even when this has been accomplished, moving the scope tip to lift

Not only does the snare device permit application of heat for hemostasis during polypectomy and the force required to transect a polyp by wire closure, but, by marking the snare handle, it can also be used to estimate the volume of tissue enclosed within the wire loop and, using that mark, the assistant can prevent inadvertent guillotining of a polyp. The endoscopy assistant who closes the snare around a large polyp feels resistance to closure when the slide bar is retracted to the point at which the wire loop is snug around the polyp. This resistance is perceived as a “spongy” resilient sensation, coupled with the inability to further close the slide bar. This “closure sensation” means that the wire loop has encircled tissue and is tightly closed on it, and further retraction of the slide bar will result in “cheese wiring” transection of the encircled tissue. If the polyp, is soft (e.g., villous tumor) or is small, no closure sensation will be perceived as the snare is closed around the polyp, and the slide bar, in the absence of any closure sensation, can be effortlessly retracted and will inadvertently cut through the encircled tissue, like a wire cutting through a soft cheese. Slicing through a soft polyp could be prevented if the assistant knew when to stop

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slide bar retraction in the absence of any closure sensation. Knowledge of the exact point at which to stop slide bar retraction to prevent guillotining of a polyp can be readily obtained by making a pen mark on the shaft of the polypectomy snare device. This preparation performed prior to snare use requires that the slide bar be retracted toward the thumb hole on the snare handle, stopping when the free tip of the wire loop (snare) is just even with the tip of the plastic sheath. Further closure of the slide bar would result in the snare tip fully entering the plastic sheath (Figure 42.1). The assistant should make a mark on the snare handle using the slide bar as a guide [12]. The mark may be made by pencil or pen, and is a line across the handle where the edge of the slide bar crosses it. The mark must be on the thumbhole side of the slide bar crossing, not toward the plastic sheath. During snare closure, by observing the line on the handle and stopping there, even without perceiving any closure sensation, the assistant will be assured that a polyp is not sliced off unintentionally. Most endoscopists rely on close cooperation with the assistant during polypectomy, and ask the gastrointestinal assistant to close the snare. The assistant can be of the most help when watching the procedure on the monitor (with video endoscopy or with a lecture side-viewing apparatus on the fiberoptic system). With a full view of the snare and polyp, the

(a) Slide bar forward, snare fully open

(b) Slide bar back, snare fully retracted

(c) Mark on handle on thumbhole side of slide bar when tip of wire loop is even with tip of sheath

Figure 42.1 Mark the snare handle. (a) With the slide bar forward the snare is fully open. (b) With the slide bar back, the snare is completely retracted into the sheath. (c) The “information mark” is placed on the thumbhole side of the handle at the edge of the slide bar when the slide bar is at the position when the tip of the wire loop is even with the tip of the sheath.

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assistant can gauge the rapidity of slide bar retraction, and see if the tip of the snare slides over the tissue behind the polyp, or to stop closing the snare if it becomes malpositioned. However, as the tip of the wire loop approaches the tip of the snare sheath (or can no longer be seen as it disappears behind a large polyp), the assistant must then look at the snare handle as it is being retracted and stop at the mark to prevent cutting through the polyp or to note how far the slide bar is from the mark. With a large polyp, complete retraction to the mark may not be possible due to the size of the tissue within the loop.

Estimate of tissue volume in the closed snare When the polyp is large, the endoscopist may wish to know the approximate volume of tissue encircled by the snare. This would be useful whenever an extraordinarily large amount of tissue was captured within the snare loop. If the endoscopy assistant were to communicate to the endoscopist that the volume of tissue within the closed loop was greater than expected for the estimated size of the polyp, then several interpretations of that estimate would be available for consideration: that the snare is seated across a wide area of the polyp (instead of at the narrow base), that the polyp base is too wide for a single transection, or that excess surrounding mucosa is also included within the tightened loop. Using the mark on the handle as noted previously, the amount of wire loop outside the sheath during snare closure can be estimated by the assistant who can see the distance from the edge of the retracted slide bar (when spongy resistance is felt) to the previously drawn mark. If closure sensation has been noted, and the slide bar is at the mark, then there is little likelihood of excess tissue being caught within the snare or that the snare is improperly sited. Some snares with stiff wires or a 2:1 ratchet wheel ratio (allowing full snare opening and closing with a shorter travel distance of the slide bar) may not permit the sensory perception of a “closure sensation.” Using a standard snare, if closure sensation is perceived, but the slide bar is not at the mark, the amount of tissue within the closed snare loop is directly proportional to the distance from the edge of the slide bar to the mark on the handle. If that distance is greater than 3 mm, there is a large volume of tissue within the loop (Figure 42.2). Knowing that a substantial volume of tissue has been captured, the endoscopist must reassess the situation and decide whether to remove the snare by opening and repositioning the loop (presuming that excess tissue has been caught within the snare), or decide that placement is proper (for instance, that the snare is tangential across the polyp but placement is acceptable because piecemeal polypectomy will be necessary). Characteristically, larger portions of a polyp can be removed during the piecemeal technique than would ordinarily be resected by a single application of the wire loop around a single polyp. The decision as to whether large polyps should be removed piecemeal or with one transection is not necessarily related to the size of the

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(a)

Figure 42.2 The “information mark” used to estimate the volume tissue captured within the closed wire loop. The amount of tissue within the loop is directly proportional to the distance between the slide bar and the mark.

(b)

polyp, but to the volume of tissue within the closed snare. Some large polyps may be soft and spongy, permitting a greater amount of slide bar retraction than is possible with a smaller but firmer polyp.

Use of the snare When placing the snare sheath through the instrumentation channel of the colonoscope, the right lower portion of the scope tip should be directed toward the colon lumen rather than close to the wall. This is a safety measure that will prevent the sheath from piercing the wall as it exits the scope. The sheath enters the field of view at the 5 o’clock position, but if that portion of the scope tip touches the mucosa, the sheath will also contact the mucosa, and could, in spite of the blunt tip, be pushed through the wall. When opening the snare loop, it is again necessary to point the sheath toward the lumen. The request to open the snare should be made when there is sufficient clearance to permit the snare to open fully. It may be dangerous to have the sheath close to the polyp as the snare wire is protruded, because the sharp point of the wire tip is relatively stiff as it exits the sheath, and could be advanced through the colon wall. On the other hand, the fully opened snare is quite flexible and can be pushed against the colon wall either to anchor its tip position during placement over a polyp or to widen the loop. An additional safety measure is for the endoscopist to withdraw the sheath into the scope as the wire loop is being extended by the assistant. This maneuver starts after the snare sheath has been passed through the instrument channel. With the sheath tip in the field of view and the slide bar fully retracted, the endoscopist requests that the snare be opened while simultaneously withdrawing the sheath from the accessory port as the assistant advances the slide bar. This technique is performed cooperatively so that just the tip of the wire loop remains in view near the lens of the colono-

scope. This extends the wire loop from the sheath but does not permit the loop to open because it lies compressed inside the instrument channel. Once the loop has been completely extended from the sheath, and lies fully opened within the instrument channel, the endoscopist has complete control of the snare. The endoscopist can push the wire loop into full view or extend only part of the loop as needed by advancing the sheath at the accessory port (which allows the loop to open as it exits the tip of the scope) without requiring further communication commands to the assistant to open the snare. The tip of the sheath is the fixed point in the polyp–snare interaction, and remains stationary during snare closure. If the sheath tip is not against the polyp base or close to it, closure of the slide bar will move the far end of the wire loop closer to the sheath tip; as it closes, the wire will initially catch on the polyp and bend it toward the sheath, and then slide over the polyp as it closes, to the sheath tip, allowing the polyp to escape from the loop (Figure 42.3a). If the open wire loop is placed over a polyp that is in the middle of the open loop, the endoscopist must advance the sheath (not the tip of the colonoscope) as the loop is closed in order to prevent the polyp from escaping (Figure 42.3b). The movements of the assistant in retraction of the slide bar and the endoscopist in advancing the sheath must be fully coordinated. For precise snare loop placement, it is most desirable to position the sheath tip (with the fully opened snare loop) at the junction of the polyp and mucosa. As the slide bar is closed, the wire loop will fit snugly against the far edge of the polyp, ensuring total capture (Figure 42.4). One of the most important aspects of polypectomy is keeping the plane of the wire loop parallel to the colon mucosal surface. If the colonoscope and the extended wire and sheath are parallel to the colon wall, capture is relatively straightforward. When this ideal position cannot be accomplished, and the wire loop approaches the polyp at an angle, the endoscopist must advance the sheath

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Figure 42.3 The tip of the sheath must be advanced to the polyp edge since the wire loop closes toward the sheath. Pushing the sheath in during slide bar retraction will prevent escape of the polyp from the loop.

(b)

(a)

on the far wall of the polyp. The sheath must then be advanced simultaneously with slide bar retraction to keep the polyp within the loop for capture. As the wire snare is electrically activated, the assistant should await the request of the endoscopist to close the snare. Closure usually occurs after a few seconds of current application.

Injector needles

(b)

(c)

(d)

Figure 42.4 The sheath tip must be placed at the junction of the polyp and the colon wall. With the wire loop parallel to the wall, it will close at that same plane on the far side of the polyp.

to the colon wall as the slide bar is retracted by the assistant. This maneuver will obliterate the angle and permit the snare to close flat around the polyp. If the polyp is on a convex fold, capture may be easier by placing the open loop over the polyp, and then withdrawing the sheath to hook the snare tip

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The injector needle is an important component of polypectomy equipment. It must be of sufficient length to traverse the colonoscope, the sheath should be strong enough to prevent buckling when pressure is applied to force it through several loops and convolutions of the scope when in the right colon, and the needle should lock in position when extended to prevent excess play of the needle when attempting to push it into the mucosa. In addition, the bevel of the needle is an important but often overlooked component, as a long bevel may pierce two or more layers and allow simultaneous injection into the submucosa while also spilling fluid into the peritoneal cavity. The distended bowel wall is relatively thin, with the total thickness less than 2.4 mm [13]; each layer (mucosa, submucosa, and muscularis propria) is about 0.8 mm thick, so the bevel must be rather obtusely angulated to allow precise submucosal injection. Even without a sharply angulated bevel, a smaller diameter needle is of benefit when fluid must be delivered into the submucosal layer without extravasation into the colon lumen.

Hot biopsy forceps The hot biopsy forceps is an electrically insulated forceps through which electrical current flows to direct electrical energy

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around the tissue held within the jaws, enabling simultaneous cautery of a polyp base while obtaining a biopsy specimen.

Polypectomy Basic Principles

Polypectomy technique When to remove polyps

Types of polyps There are two basic polyp configurations: pedunculated polyps are attached to the intestinal wall by a stalk, and sessile polyps arise directly from the wall without a pedicle. Pedunculated polyps may be attached by a short and thick or long and thin pedicle. All pedunculated polyps had their origin as a sessile polyp, but the action of peristalsis on the slightly protuberant polyp tissue results in pulling and subsequent elongation of the normal mucosa and submucosa surrounding the polyp base. Most pedunculated polyps occur in the sigmoid colon in the area of strong muscular contractions, although some can be seen in the proximal colon. Sessile polyps are more common than pedunculated polyps and are attached to the mucosal surface in a variety of configurations. Those that are less than 8 mm in diameter frequently have the shape of a split pea, with the base being the largest diameter of the polyp. Larger polyps can assume one of several configurations [12]: • Marbleaspherical with a narrow base, attached to the colon wall by a small connection. • Mountainadistinct edges and a broad base where the attachment is the widest part of the polyp. These are often multilobulated. • Ridgeaa polyp whose length is much longer than its width, attached along its entire base. • Clamshellawrapped around a colon fold. The proximal portion (away from the instrument) may be difficult to visualize completely because part of the mucosal attachment is on the opposite side of the fold. • Carpetaflat and can extend over a wide area. • Extendedaa combination of attachments, with the major component usually being a mountain or clamshell type. The edges of this type of polyp usually extend diffusely into the mucosa. The vast majority of polyps are sessile, with most of the pedunculated polyps located in the left colon where peristalsis is strong. Most sessile polyps are of the mountain and extended type, with the largest found in the rectum and right colon.

Precolonoscopic laboratory testing (see Chapter 8) Routine testing for bleeding disorders prior to colonoscopic polypectomy is not necessary [14]. A history of a bleeding disorder should be obtained, including any tendency to bleed excessively following lacerations, a surgical procedure, or dental extraction. Patients who are about to have a polypectomy do not need to be prescreened with a platelet count, prothrombin time, bleeding time, or clotting time.

Large polyps in the distal portion of the colon should not be removed during the initial intubation. These often require special techniques and may result in deep submucosal excavations. In addition, 50% of patients with one adenoma will have another, and it is important to perform total colonoscopy to seek and remove synchronous adenomas. In general, most colonoscopists do not remove large or difficult polyps during intubation because other unresectable polyps or a malignancy which will require surgery may be encountered more proximally. However, there is no absolute contraindication to removing a polyp of any size during intubation and then continuing the examination to the cecum, despite the probability that the scope will rub against the polypectomy site, air will be pumped in to distend the colon, and loops in the shaft of the colonoscope will push on the freshly denuded submucosa and muscularis propria. Small polyps in any position, when seen during intubation, should be removed at that time, as they may not be easily found during withdrawal. Medium-sized polyps in good position for resection should be removed when visualized because they may not be well positioned during withdrawal.

Small polyps Hot biopsy There are several ways of removing small polyps. Hot biopsy forceps provide a histologically identifiable tissue specimen, while electrocoagulation current ablates the polyp base in most instances [15]. When cold biopsy forceps are used in an attempt to ablate small adenomas, fragments may remain and subsequently proliferate [16]. In order to prevent deep thermal injury to the colon wall during use of the hot biopsy forceps, the polyp head, once grasped wholly or in part, should be tented away from the wall toward the colon lumen. As current is applied, a zone of white thermal injury will become visible on the stretched normal mucosa surrounding the polyp base. When this injury zone is 1–2 mm, current should be discontinued and the specimen retrieved as with any biopsy technique. There is a high rate of residual adenoma when incomplete fulguration occurs [15,17]. Because of reported complications with the hot biopsy forceps [18], there has been some reluctance to use them, but many endoscopists employ them routinely to eradicate polyps in the range of 1–5 mm. No attempt should be made to ablate polyps larger than 5 mm as these cannot be totally destroyed by the hot biopsy forceps.

Snare and cautery Small polyps may also be removed with a wire snare. The mini-snare is suitable (3 cm in length by 1 cm in width), for it can more easily be manipulated around the head of a polyp

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3 cm

Regular snare

(a)

(b)

Mini-snare

(c)

than the standard snare. The standard snare requires that the full 6 cm length of wire be extended before the two wires spread widely apart and form a loop (Figure 42.5). Advancing the snare loop to 6 cm may not be possible in many areas of the colon. Small polyps, less than 4 mm in diameter, can be safely removed by severing the polyp without employing electric current. Since Tappero et al. [4] first described this technique, many endoscopists guillotine small polyps without cautery current. Bleeding is insignificant and stops spontaneously without the need for the application of hemostatic techniques [19]. Tiny polyps, in the range of 1–2 mm in diameter, can be totally extirpated with a biopsy forceps, but for polyps larger than 3 mm fragments of adenoma may fill the cups of the forceps, requiring several passages of the forceps to attempt complete removal. Polyps of this size can be totally removed with a “cold snare,” leaving a “tiny button” of denuded mucosa (Figure 42.6). The specimen can be retrieved into a polyp trap (see Chapter 45).

Placement of the snare catheter tip An important step in polyp capture is to place the catheter tip at the precise site where transection is desired, once the open snare loop has been placed over the polyp [20]. If the polyp is pedunculated, the tip of the sheath should be advanced to the midportion of the stalk. If sessile, the sheath should be advanced to the line of visible demarcation between adenoma and colon wall. Closure of the loop will result in seating the snare on the opposite side of the polyp, as the wire loop

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Figure 42.5 A mini-snare can be used for most polyps since the majority are less than 1 cm in diameter. It is also useful in convoluted colons in which there is not sufficient distance (6 cm) for the standard snare to open fully.

always closes concentrically toward the tip of the snare sheath, which is the fixed point in the polypectomy system. To ensure proper seating of the wire loop, it is important to look for and observe the tip of the wire loop as it is being withdrawn on the far side of the polyp. This will often prevent inadvertent capture of a portion of the wall behind the polyp by the snare tip as it slides across the wall (Figure 42.2).

Pedunculated polyps A pedunculated polyp of any size should be able to be removed by a single transection [12]. Attempts should be made to completely encircle the head of the polyp with the loop and to tighten it on the pedicle. This can usually be accomplished with any of the standard size commercially available polypectomy snares. When seating the snare around a pencil-like pedicle, it is desirable to place the wire about midway on the pedicle, leaving a short stalk. This will permit grasping the residual pedicle with the snare for hemostasis should bleeding occur. Most pedicles are not an organized tubular structure of attachment to the colon wall, and because it is formed by pulling on the surrounding mucosa, the pedicle often quickly disappears when the polyp has been transected, so there may not be any residual protruding tissue to regrasp with the snare. On the other hand, the snare should not be placed at the junction of the adenoma and pedicle in the event that there is malignancy in the polyp. If the polyp is malignant, it is necessary to ensure a clean resection margin in order to decide on the proper treatment schema for the patient.

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Figure 42.6 Cold snare guillotine of small polyps (less than 5 mm in diameter) is safe with minimal bleeding.

Sessile polyps The polyp with a wide attachment to the colon wall may be transected with one application of the wire snare, providing that it is located in the left colon and the base is less than 1.5 cm in diameter. In the right colon, where the wall is somewhat thinner, the endoscopist should consider piecemeal polypectomy or submucosal injection technique for any polyp whose base is over 1 cm. The heat produced by snare activation is localized to the area immediately around the wire loop, but also spreads toward the submucosa and serosa of the colon wall. The larger the polyp, the greater will be the volume of tissue captured within the wire loop, and a greater amount of thermal energy will be required to sever the polyp. This may result in a full-thickness burn of the colon wall, which can result in a perforation of the bowel. It is once again noted that the polyp replaces the mucosa and, once it has been captured in the loop, the submucosal layers and muscularis propria are in total a little over 1 mm thick [13].

junction between adenoma and normal mucosal wall) [20]. The other wire of the loop can then be sited over a portion of the polyp, to encircle a large piece of tissue. Aspiration of air just prior to snare application will result in a decrease in the air-induced wall tension, resulting in a contracted segment of the wall. As the colon diameter decreases with air removal, the footprint (base of attachment) of the sessile polyp becomes smaller also. Because the polyp volume does not change, the polyp actually becomes more elevated in relation to the surrounding mucosa and is easier to ensnare (Figure 42.7). Aspiration of air causes a decrease in the circumference of the cylindrical colon and also a shortening of its length. This requires careful attention to the visual field as the initial relationships may be altered by deflation. If a fold is brought into view and obscures the snare and/or polyp, reinflation or moving the tip of the colonoscope closer to the polyp usually regains the view.

The tip of the snare Air aspiration During the technique of sessile piecemeal polypectomy with or without saline injection, an attempt should be made to place one edge of the wire snare at the edge of the adenoma (the

As the snare is closed slowly, the endoscopist’s attention should be directed toward the tip of the loop as it slides over the mucosal surface behind the polyp. By so doing, it is often possible to see whether a portion of normal mucosa is caught

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Semi difficult

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(a)

Figure 42.8 Approach to a colon lesion for biopsy or polypectomy is easier when the lesion is placed at the 5 o’clock position by rotation of the colonoscope shaft. (b)

Figure 42.7 Aspiration of air decreases both the length and crosssectional diameter of the colon. This causes a decrease in the size of the polyp and increases its thickness and the thickness of the colon wall.

and dragged up into the loop along with the polyp, or whether the tip slides over the mucosa and engages on the far margin of the polyp. This assessment is important, but if the polyp is large it may obscure direct vision. When this occurs, careful attention must be directed to the closure mark previously placed on the snare handle to assess the volume of tissue caught within the closed snare loop.

the lumen to separate the polyp from the submucosa [20]. This will limit the depth of thermal injury when current is applied, because the local zone of heating has less chance of damaging the muscularis propria and serosa because the layers are pulled away from each other. Tenting of the polyp can be accomplished by a variety of movements, with the success of any one being judged by its result; often a combination of efforts will be necessary: insertion or withdrawal of the snare, elevation with the thumb on the up/down dial, or torque. Movements that are too vigorous may result in tearing the polyp away from its attachment.

Position of polyp When full vision is obscured When complete visualization is not possible as the loop is being closed, the assistant should close until resistance is met, or, if no closure sensation, stop at the mark. Once closed, the catheter sheath should be jiggled to and fro at the biopsy port while observing the colon walls around the polyp. If extraneous portions of the mucosa are not caught in the loop, the polyp will be seen to move independently of the surrounding colon walls as the sheath is jiggled. If the polyp and the surrounding wall move simultaneously, there is a strong probability that a portion of adjacent mucosa has been captured within the snare loop. Complete removal of the snare or partially opening the loop for repositioning is then advisable before application of electrocautery current. Transection of a large fragment of inadvertently captured normal mucosa is not a desirable outcome of polypectomy and may lead to perforation. If extra tissue is captured, there is no assurance that it will only consist of mucosa, for submucosa may also be entrapped, and when electrocautery current is applied a deep burn may result.

Tent the polyp away from the base After the wire is seated securely around the polyp, the sheath should be lifted slightly away from the wall, tenting it toward

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To capture a polyp, one of the most important factors is that it be in a proper position relative to the tip of the colonoscope. One of the most frustrating problems encountered during polypectomy is that the polyp is in a poor position for snare capture. All colonoscopes have the suction/instrument channel situated at the 5 o’clock position in reference to the visual field. All accessories are obligated to enter the visual field in the lower right quadrant and progress toward the 11 o’clock position. This fixed reference point results in a relatively easy snare capture of a polyp located in the right lower portion of the field, and occasionally those in the 5 to 11 o’clock axis, but causes considerable difficulty in snaring a lesion which is not on that diagonal. A polyp located between 9 and 12 o’clock in the visual field is much more difficult to lasso than a polyp in the right lower quadrant, and those in the 2 or 8 o’clock position are impossible. An attempt should be made to bring all polyps into the 5 o’clock position to facilitate snare placement [20] (Figure 42.8). This can usually be accomplished by rotation of the scope to reposition its face in relation to the adenoma. Rotation of the scope may be difficult during intubation when the instrument shaft has loops and bends. Advantageous positioning may be best accomplished when the colonoscope shaft is straight, because a straight

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instrument transmits torque to the tip, whereas a loop in the shaft tends to absorb rotational motions applied to the scope. It is often difficult to capture a sigmoid polyp during intubation, when the obligatory sigmoid loop is present. It may not be possible to straighten the scope in the sigmoid because rotation and loop withdrawal result in losing the scope’s position. With a loop in the scope, the angulation controls may no longer work effectively to turn the instrument tip because the cables which transmit motion are maximally stretched by the loop. These two negative forces, the inability to torque effectively and the loss of cable-controlled tip deflection, combine to create an extremely difficult situation when attempting to maneuver the snare into position around a polyp. Maneuvering can be made considerably easier by passing the scope far beyond the polyp, even to the cecum (and thus visualize the rest of the colon), and attempting capture during the withdrawal phase of the examination. As the scope is withdrawn, the loops are removed and the polyp, which proved difficult to position during intubation, may be quite easily ensnared because both torque and tip deflection are responsive when the shaft is straight.

Positional changes and abdominal pressure As noted previously, it is usually easier to properly position polyps for removal following total colonoscopy to the cecum. As the instrument straightens out by virtue of pulling the shaft out of the colon, clockwise or counterclockwise torque combined with angulation control manipulation can result in unimpeded rotation of the colonoscope tip so that a polyp encountered at the 10 o’clock position (which may be difficult to ensnare) can be moved to the 5 o’clock position even if it is located in the ascending colon. Additional methods of shifting a polyp into a more favorable position are to change the patient’s position or apply abdominal pressure. Polyps partially hidden behind folds may come more prominently into view as the patient’s position is altered. Polyps submerged in a pool of fluid can be rotated into a drier field by turning the patient so that fluid flows away from the base.

Summary The removal of colon polyps is part of the performance of colonoscopy and should not be considered as an advanced procedure. The concept of colonoscopy embraces both diagnostic and therapeutic aspects; if a polyp is found, it should be removed at that time, and the endoscopist must know how to perform basic polypectomy but must also have the equipment available to accomplish polyp removal. Knowledge of the approach to polyps, basic polypectomy, and snare handling make up the information base for polyp removal. The endoscopist and gastrointestinal assistant must work as a team to ensure a positive outcome. Sharing the same information base will make polypectomy easier and safer.

Polypectomy Basic Principles

References 1 Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993; 329: 1977–81. 2 Rex DK. Colonoscopy. Gastrointest Endosc Clin N Am 2000; 10: 135– 60. 3 Waye JD, Lewis BS, Frankel A, Geller SA. Small colon polyps. Am J Gastroenterol 1988; 83: 120–2. 4 Tappero G, Gaia E, DeFiuli P, Martini S, Gubetta L, Emmnuelli G. Cold snare excision of small colorectal polyps. Gastrointest Endosc 1992; 38: 310–13. 5 Van Gossum A, Cozzoli A, Adler M, Taton G, Cremer M. Colonoscopic snare polypectomy: analysis of 1485 resections comparing two types of current. Gastrointest Endosc 1992; 38: 472–5. 6 Valentine JF. Double-channel endoscopic polypectomy technique for the removal of large pedunculated polyps. Gastrointest Endosc 1998; 48: 314–16. 7 Akahoshi K, Kojima H, Fujimaru T, et al. Grasping forceps assisted endoscopic resection of large pedunculated GI polypoid lesions. Gastrointest Endosc 1999; 50: 95–8. 8 Kawamoto K, Yamada Y, Furukawa N, et al. Endoscopic submucosal tumorectomy for gastrointestinal submucosal tumors restricted to the submucosa: a new form of endoscopic minimal surgery. Gastrointest Endosc 1997; 46: 311–17. 9 Ng AJ, Korsten MA. The difficult polypectomy: description of a new dual-endoscope technique. Gastrointest Endosc 2002; 55: 430–2. 10 Cohen LB, Waye JD. Treatment of colonic polypsapractical considerations. Clin Gastroenterol 1986; 15: 359. 11 McNally DO, DeAngelis SA, Rison DR, Sudduth RH. Bipolar polypectomy device for removal of colon polyps. Gastrointest Endosc 1994; 40: 489–91. 12 Geenen JE, Fleischer D, Waye JD. Techniques in Therapeutic Endoscopy, 2nd edn. New York: WB Saunders/Gower Medical Publishing, 1992. 13 Tsuga K, Haruma K, Fujimura J, et al. Evaluation of the colorectal wall in normal subjects and patients with ulcerative colitis using an ultrasonic catheter probe. Gastrointest Endosc 1998; 48: 477– 84. 14 Eisen G, Baron TH, Dominitz J, et al. Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 2002; 55: 775–9. 15 Peluso F, Goldner F. Follow-up of hot biopsy forceps treatment of diminutive colonic polyps. Gastrointest Endosc 1991; 37: 604–6. 16 Woods A, Sanowski RA, Wadas DD, Manne RK, Friess SW. Eradication of diminutive polyps: a prospective evaluation of bipolar coagulation versus conventional biopsy removal. Gastrointest Endosc 1989; 35: 536. 17 Vanagunas A, Jacob P, Vakil N. Adequacy of “hot biopsy” for the treatment of diminutive polyps: a prospective randomized trial. Am J Gastroenterol 1989; 84: 383. 18 Wadas DD, Sanowski RA. Complications of the hot biopsy forceps technique. Gastrointest Endosc 1988; 34: 32–7. 19 Uno Y, Obara K, Zheng P, et al. Cold snare excision is a safe method for diminutive colorectal polyps. Tohoku J Exp Med 1997; 183: 243–9. 20 Waye JD. Endoscopic treatment of adenomas. World J Surg 1991; 15: 14–19.

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Difficult Polypectomy Uwe Seitz1, Nib Soehendra2 & Jerome D. Waye3 1

Bergstrasse Medical Center, Heppenheim, Germany Endoshopie am Glockengiesserwall, Hamburg, Germany 3 Mt. Sinai Hospital, New York, NY, USA 2

Introduction This chapter describes various techniques that can be employed to assist in the evaluation and removal of colon polyps that are considered to be large or “difficult.” Size is only one of the features that may cause some hesitation in making the decision to attempt polyp removal. Other factors related to the perceived level of difficulty are polyps that are flat and only slightly elevated above the mucosal surface, location on a wall of the colon that is not accessible to the snare, and a polyp in a segment of severe diverticular disease or wrapped around a fold in clam-shell fashion. A snare may not be able to capture a minimally elevated lesion with no distinct margin, a polyp situated behind a fold can be difficult to expose, and those in the cecum hidden behind the ileocecal valve present a special challenge for resection. These and other problems will be addressed in this chapter, as will the localization of lesions or polypectomy sites for future surgery (in the case of malignant polyps) or for reevaluation following total or incomplete polyp removal. The impossible polyp is one which the endoscopist feels cannot be removed. The feeling of futility when faced with such a polyp is directly dependent on the training, experience, and courage of the endoscopist. What may be “impossible” for one endoscopist may be a relatively “routine” polypectomy for another. In general, there are three criteria that make a polyp “impossible,” and when the three occur in the same lesion, then the polyp may be “really impossible.” The three factors which by themselves or in combination with others may place the polyp into an “impossible” category are size (large, measuring over 2–3 cm in diameter), location of the polyp (sited at the 12 o’clock position on the colon wall or at the limit of intubation, a situation that can occur in the tall, obese or a person with adhesions from prior surgery), and configuration (broad-based, wrapped around a fold, or extremely flat).

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Many polyps that are deemed colonoscopically unresectable and thus referred to surgery can be removed by the expert in polypectomy [1]. Endoscopic resection of large polyps (over 2 cm in diameter) can be successfully performed in most patients, although it is not free from complications. Perforations have been reported in up to 2% of cases, but most bleeding episodes can be controlled colonoscopically [2].

Size It is fortunate that polyps over 3 cm in diameter are not commonly found during colonoscopy, but it is not unusual to have polyps in the 2–3 cm range. During the last 30 years, only a few publications [3–12] have reported on endoscopic removal of large colorectal polyps (Table 43.1). Christie [5] found in 1977 that only 58% of colorectal polyps measuring 20–60 mm were amenable to endoscopic polypectomy. Bedogni et al. [13] reported in 1986 that in their experience 75% of colorectal polyps larger than 30 mm were endoscopically removable (66% of the removed polyps were sessile). Lower malignancy rates of less than 15% in large colorectal polyps have been reported irrespective of their macroscopic and histological growth pattern [4,18]. When a large sessile polyp is identified, several decisions will impact upon the probability of its removal. The first factor to consider is whether the polyp is benign or malignant. A question that arises is whether to perform a biopsy and then bring the patient back for polypectomy based on the subsequent results of biopsy or to depend on the visual impression of whether the polyp is benign. There are no studies on the visual criteria which can be applied to a polyp to determine the presence of malignancy; however, endoscopists in a tertiary referral center in Hamburg, Germany [4], have stated that a benign polyp does not have any of the following features: ulceration, induration, or friability. Japanese endoscopists [8] who endeavored to remove large polyps noted that large flat polyps were usually benign, and that invasive carcinoma was seen only in elevated sessile polyps. Granular-appearing large sessile polyps contained significantly more invasive carcinomas than nongranular-appearing polyps [19]. However,

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Table 43.1 Endoscopic resection of large colorectal polyps. Study

Number of patients

Size (cm)

Sessile lesions (%)

Invasive cancer (%)

Subsequent surgery (%)

Polypectomy complications

Number of patients with malignant recurrence

Christie [5] Bardan et al. [3] Walsh et al. [10]

47 25 108

2–6 3–6 1–8

100 16 100

25 44 23

13 8 27

0 1 1

Binmoeller et al. [4] Kanamori et al. [8] Nivatvongs et al. [9] Bedogni et al. [13] Iishi et al. [7] Hintze et al. [6] Stergiou et al. [14] Doniec et al. [15]

170 32 28 66 56 72 59 184

>3 3–8.5 2–6 3–11 2–5 2–8 >3 3–13

73 100 100 68 100 100 69 76

12 15 29 15 0 4 12 10

9 0 18 11 9 4 1 5

Conio et al. [16] Boix et al. [17]

161 74

1.5–10.0 >4

100 100

13 16

7 7

6% bleeding 12% bleeding 3% bleeding 1% microperforation 3% bleeding 10% minor bleeding 4% bleeding 3% bleeding 7% bleeding 1% bleeding 0% perforation 2% bleeding 0.5% perforation 4% microperforation 4% microperforation

a difference in the carcinoma rate of 14% vs. 7% may be only of little help in clinical practice. The pit pattern classification introduced by Kudo et al. [20] (Chapter 31) affords a schema for in situ evaluation of polyp pathology but is not an intuitive strategy. Using standard colonoscopes, the pit patterns indicating adenoma are usually visible. A loss of structure or a chaotic pit pattern indicate invasive cancer, which is usually obvious to the trained endoscopist. Surface application of dye such as indigo carmine may help to improve visualization of the pit pattern. These visual characteristics may not always be accurate but biopsies are notoriously erroneous for the diagnosis of invasive carcinoma within a polyp because the depth of tissue obtained is usually limited and high-grade dysplasia on biopsy (which used to be called noninvasive carcinoma or carcinoma in situ) is histologically identical to

Figure 43.1 Polyp with indurated submucosal tissue remnants at the center and left margin of the resection site. (a) The polyp initially did not appear malignant and was resected. (b,c) Indurated tissue was suspicious and therefore biopsies were taken in the same session. Histology proved invasive carcinoma.

(a)

1 0 0 1 0 0 0 1 0 0

invasive carcinoma. In addition, the amount of tissue sampled by biopsying a large polyp represents only a fraction of the total polyp volume submitted for histopathology. Most colonoscopists base the decision as to whether a large polyp is benign or malignant on the visual impression when it is identified. If the assessment is that the polyp is benign, the decision for removal should be based on other visual criteria; if it looks like it can be removed, an attempt should be made to resect it (Figure 43.1). There is a general reluctance among endoscopists to remove large polyps because of the possibility of invasive carcinoma. One report stated a 40% incidence of invasive carcinoma in large polyps, but this finding was based on the pathologist’s finding of carcinoma in surgical specimens that were sent to the pathology laboratory, not polyps that were removed endoscopically [21]. Endoscopically resected

(b)

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polyps, which meet the visual criteria of being benign, will actually have an incidence of about 10–15% of invasive malignancy [4,8,13–15,18]. The complete colonoscopic removal of large polyps is not only dependent on the endoscopists but also a function of the polyp, as complete resection of large sessile polyps may require several sessions, and high rates of local recurrences are reported [6,10,13]. This information must be shared with the patient after the initial attempt at removal or before beginning the therapeutic colonoscopy, if the lesion was discovered on a prior imaging procedure [22]. Because of the tendency for recurrence, it is mandatory to confirm complete removal by follow-up examinations. If the polyp appears to be benign on endoscopic visual examination, the average endoscopist (as compared with an expert) must then consider three criteria for its removal. If any of these are present, the endoscopist will be challenged in its removal. These three criteria [23] are: 1 The polyp occupies more than one-third of the circumference of the colon wall. 2 The polyp crosses over two haustral folds.

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Figure 43.2 Extensive laterally spreading flat polyp. (a) This polyp measures 7 cm in length and involves two-thirds of the luminal circumference. It is positioned at 6 o’clock and snare resection is started on one side of the polyp. (b) The ensnared part of the polyp is lifted from the bowel wall prior to resection. (c) The flat lesion is resected completely by piecemeal technique. (d) Follow-up colonoscopy after 6 weeks did not show any remnant polyp tissue. A mild asymptomatic stricture has occurred.

3 The polyp encircles and actually involves the base of the appendix. A polyp which extends more than one-third the circumference of the colon wall will create a large mucosal defect if it is removed. It is possible that polyps of this size could be removed by an expert endoscopist (Figure 43.2), but even the expert may elect to send such a patient for surgical resection rather than face the possibility of multiple colonoscopic examinations, particularly if the colonoscopic approach to the polyp was extremely difficult and demanding. Polyps that cross over two haustral folds present another problem in their total removal, given that it may be difficult and time-consuming to remove the entire polyp, especially the portion that lies in the valley between two haustral folds. Polyps at the ileocecal valve may be problematic to assess, and ones that extend into the ileum can be very difficult to remove (see Figure 43.12). Polyps that involve the appendiceal orifice may extend into the appendix, and, although this phenomenon is rare, total removal of this type of polyp may not be possible (Figure 43.3). Large pedunculated polyps have large nutrient arteries, and may bleed during or after polypectomy. Injection of epinephrine

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Figure 43.3 Removal of large sessile polyp involving the appendiceal orifice. (a) Large sessile polyp at the cecal pole. (b) Injection of epinephrine (1:20 000) lifts the lesion from the muscle layer and allows for easier and safer ensnaring. (c) The appendiceal orifice is visible after piecemeal resection. (d) Argon plasma coagulation is performed to remove the remaining adenomatous tissue at the appendiceal orifice.

(a)

(b)

(c)

(d)

into the stalk may decrease the risk of bleeding. Other measures to control bleeding from resection of pedunculated polyps are application of endoloops, or a technique of using one disposable snare to cut off the blood supply and another to perform the resection [24,25] (Figure 43.4). The complications of both diagnostic and therapeutic colonoscopy are discussed in Chapter 53.

Ambulatory or inpatient polypectomy Most diagnostic colonoscopies are performed on an ambulatory basis. When a large polyp is encountered that meets the criteria for removal, the endoscopist must decide whether the patient should: 1 be admitted to hospital; 2 have the polypectomy in a hospital outpatient setting; 3 have the procedure performed in an office facility remote from a hospital. Literature supports the safety of ambulatory polypectomy [26], and only 1 of 170 patients who had large polyps removed required immediate hospitalization for suspected perforation

Difficult Polypectomy

[4]. Endoscopic resection of large polyps, especially when sessile, is also significantly more time-consuming, and requires more resources than does polypectomy of smaller lesions. If reimbursement does not adequately cover the substantially greater costs, it may be a deterrent to endoscopic resection of large sessile adenomas [27]. Much of the reluctance to remove large polyps is related to the fear of complications. The actual incidence of perforation in removal of large polyps is low, with several series [1,2,4,8, 16,17] of large polypectomies reporting few, if any, patients who required surgical intervention as well as an absence of perforations, and when bleeding during polypectomy occurred in 10% [8] and 24% [4] of patients from two studies, it was successfully handled. The published rate of complications indicates that bleeding occurs in 1.4% of polypectomies and perforation in 0.3% of patients [7] (see Chapter 53).

The colonoscope For difficult polypectomy, a therapeutic colonoscope with a 4.2-mm working channel and an additional channel for a

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(b)

(c)

Figure 43.4 Large pedunculated polyp with a long and thick stalk in a sigmoid with diverticulosis. (a) To prevent bleeding, an endoloop is first placed approximately 5 mm above the base of the polyp. (b) When closing the loop, care should be taken to avoid excessive tightness that may guillotine the pedicle. Appropriate tightening will lead to cyanosis of the polyp. (c) The snare is placed close to the head of the polyp several millimeters above the endoloop.

water pump is recommended. A large working channel allows for sufficient simultaneous suction during the procedure, which is particularly helpful to control severe bleeding. An additional small-bore channel connected to a water pump provides a strong water jet for cleansing the mucosa surface [e.g., in case of oozing during endoscopic mucosal resection (EMR) or piecemeal resection]. However, many experts use a pediatric colonoscope with a 3.2-mm working channel for removal of all polyps, even the most difficult. A side-viewing duodenoscope has successfully been used to remove polyps that were inaccessible to standard straightforward scopes [28]. An upper endoscope used in retroflexion may allow resection of a polyp on the proximal side of fold or turn in the sigmoid colon. High-magnification colonoscopes combined with chromoendoscopy can be used to find and remove colon polyps but require training in their use [22].

Endoscopic mucosal resection Submucosal injection for polypectomy The submucosal injection technique is often used for removal of large sessile adenomas [29,30]. Saline with or without epinephrine solution (1:20 000) is injected into the margins of the polyp. Submucosal injection is suggested for the colonoscopic resection of sessile polyps over 1.5 cm in diameter and may be useful to lift parts of the polyp located in the appendiceal orifice, or behind a haustral fold. However, submucosal injection even with large amounts of saline solution may not avoid perforation if overly large pieces of polyp are ensnared and resected [31]. Diluted epinephrine solution may be used to prevent bleeding during polypectomy. However, a possible drawback of this precaution may be delayed

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bleeding due to the short-lived vasoconstrictive effect of epinephrine. EMR using a double-channel endoscope was introduced by Tada et al. [32] in 1993 to remove large, sessile, and flat polyps. The lesion is lifted by using a forceps to enable ensnaring (“lift and cut” technique). Several modifications of EMR technique have been introduced in the management of early cancer of the stomach and esophagus [33]. In the colon and rectum, EMR is widely performed using the simple snare resection technique. The term “endoscopic mucosal resection” was initially given to this technique used in the upper gastrointestinal tract where the layers of the wall were separated by fluid injection, and resection of the lesion was accomplished by using a snare looped inside a plastic cap or “hood” affixed to the endoscope tip into which the elevated lesion was suctioned, then severed by tightening the loop. Applying suction to draw the colon wall into a cap could compromise the entire thickness of the wall because the colon is much thinner than the stomach. The colon wall is 1.5–2.2 mm in total thickness, and thermal damage to deep layers of the colon is frequently encountered [34]. Injection of fluid into the submucosa beneath the polyp increases the distance between the base of the polyp and the serosa. When current is then applied via a polypectomy snare, the lesion can be more safely removed because of a large submucosal “cushion” of fluid which lessens the likelihood of thermal injury to the serosal surface (see Chapter 26). The fluid, injected through a long and stiff sclerotherapy needle, may be saline (normal or hypertonic) [35], with or without methylene blue to enhance visualization, and with or without epinephrine [36]. Most endoscopists use normal saline only. Epinephrine and hypertonic solutions of saline or dextrose [37] are used to retain the fluid at the site for a longer period, but submucosal saline lasts for 10–15 min, which is sufficient time for removal

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(a)

(b)

(d)

(e)

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(c)

(f)

Figure 43.5 Large sessile polyp extending over the rectosigmoid junction. (a) This 5-cm large polyp was found in the rectosigmoid junction. (b) Prior to resection, injection with epinephrine 1:20 000 is performed to lift the polyp from the muscle layer. (c) Initial piecemeal resection of small portions is performed to avoid perforation. (d) The exposed muscle layer will serve

as a point of orientation for further resection. (e) Remaining parts of polyp behind the fold are removed using the fulcrum technique. Tangential orientation of the snare to the muscle layer allows for safe ensnaring. (f) Minute remnants of adenomatous tissue can be removed by argon plasma coagulation.

of most polyps. A viscous mucinous solution of 0.5% sodium hyaluronate has been used (via a 21 gauge needle) to elevate large flat polyps for EMR [38]. This solution is isotonic and remains at the injection site longer than saline. Further studies need to be performed to assess the practicality of various injection solutions. An interesting new approach is the injection of autologous blood prior to EMR [39]. There is a theoretical advantage to the injection of dilute epinephrine to prevent bleeding at the time of polypectomy or to prevent delayed bleeding (Figure 43.5). However, the incidence of immediate bleeding even without epinephrine injection is low (1 out of 100 procedures) [40] and the long-term effect is nil because the vasoconstrictive action is measured in hours, not days. A prospective study including 561 polyps in 486 patients observed postprocedural bleeding after injection of epinephrine in 12 patients and after injection of saline in 25. However, this trend was not statistically significant [41].

An earlier prospective study including 120 patients with 151 sessile polyps detected a reduction of rebleeding of 2 of 75 polyps after epinephrine compared with 7 of 76 after saline injection [42].

Technique The injection needle may be placed into the submucosa just at the edge of a polyp, or if the polyp is large and flat, multiple injections may be given around or directly into the polyp. If a bleb does not form at the injection site when 1 mL of fluid has been given, the needle should be withdrawn because the tip may have penetrated the wall and pierced the serosal surface. When the needle is in the submucosal plane, continuous injection of saline will result in submucosal infiltration of fluid. A large localized fluid collection is the desired endpoint, with marked elevation of the polyp. When the tissues expand in response to fluid injection, the fluid is being deposited

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in the areolar tissue of the submucosal layer as none of the mucosa, muscularis propria, or the serosa will accept injected substance. If the needle placement is too superficial, the fluid will leak out from the beveled edge and spill into the lumen. This spilling is especially noticeable when a colored fluid is used, such as methylene blue or India ink. Multiple repeated needle placements and attempts at injection may be required to locate the correct plane for polyp elevation. If possible, the approach by the needle injection should be tangential and not perpendicular to the mucosal surface. Elevation of the polyp may take 3–4 mL of saline given in several places, although some authors use up to 30 mL of fluid [8]. During piecemeal polypectomy, injection can be added or repeated to improve the resection procedure. Polyps up to 2 cm in diameter may be removed with one application of the snare, but larger polyps may require several transections in piecemeal fashion [43]. It is permissible to remove a much larger piece with this technique than one would ordinarily snare when in the right colon without a “cushion” of fluid. The pieces should probably not be larger than 2 cm in diameter [8]. With the fluid as protection against deep thermal tissue injury, it is possible to fulgurate the base of the resection site with devices such as a hot biopsy forceps, the tip of the snare, an argon plasma coagulator, or any other thermal device which delivers heat to the residual polyp site. When attempting submucosal injection for polypectomy, there is not a specific volume of fluid which is used, but rather the desired endpoint is a large submucosal swelling beneath the polyp and adjacent portions of the mucosa. When part of the polyp is either hidden from view behind a fold or wrapped around a fold in clamshell fashion, injection of the part nearest to the colonoscope may elevate that portion, but can cause interference with polypectomy because the mound of saline will block vision. The solution to this problem when the proximal edge of the polyp is hidden is to inject the far side of the polyp. This is accomplished by passing the scope beyond the far edge of the polyp. While deflecting the tip toward the polyp, the injection should be made into the normal mucosa just at or near the edge of the polyp (or into the proximal edge of the polyp). Injection into the wall on the far side of the polyp will raise that portion up on the fluid mound, rendering snare application easier (Figure 43.6). Depending on the polyp size, several injections may be required to elevate the polyp so that snare placement is more readily accomplished. After the back portion of the polyp has been removed, then saline may be injected into the area closest to the scope to assist in completing the polypectomy.

The nonlifting sign In general, malignant tumors should not be removed by the submucosal injection technique. If a polyp fails to elevate (the “nonlifting sign”) [44], it may be an indication of infiltration by cancer into the submucosa, with fixation by tumor limiting the expansion of the submucosal layer [45]. Although

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Figure 43.6 The proper location for submucosal injection of saline is into the colon wall (or into the polyp) on the far side of the polyp. This will raise the polyp toward the instrument tip. An injection into the closest part of the polyp may hide the polyp behind the saline bleb.

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deep or superficial needle placement may be the cause for failure to raise a bleb under a polyp, a submucosal bulging or bleb on one side of a polyp in response to injection without visible elevation of the tumor itself is a clue that there is fixation into the submucosa. This phenomenon may also be caused by a prior attempt at polypectomy with healing and scarring of the mucosa and submucosa, preventing their separation by fluid injection.

removal of the snare or partially opening the loop for repositioning is advisable before application of electrocautery current. Transection of a large fragment of inadvertently captured normal mucosa is not a desirable outcome of polypectomy, and may lead to perforation. If extra tissue is captured, there is no assurance that it will only consist of mucosa, for submucosa may also be entrapped, and when electrocautery current is applied a deep burn may result.

Tumor tracking

Piecemeal polypectomy

There is a theoretic possibility that injection through a malignant tumor may cause tracking of cancer cells into and even through the bowel wall. The risk of this happening is minimal, with data gained from direct percutaneous needle aspiration of malignant tumors in other sites throughout the body. The risk of tumor tracking is 1 in 10 000 to 1 in 20 000 cases [46]. Parenthetically, it seems that any tumor that can be elevated with submucosal injection of fluid can be totally removed by endoscopic resection, even if invasive cancer is found on tissue examination. The ability to elevate a tumor indicates that there is only a limited degree of fixation to the submucosal layer, with the possibility of complete removal.

When removing a sessile polyp, the characteristic whitening at the site of wire placement when electrocautery current is applied often cannot be observed because the wire is embedded in the polyp. After a few seconds of current, the wire snare should be slowly closed until separation occurs. Piecemeal resection should be started preferably at a welldelineated margin of a lesion to allow for controlled and safe removal of the first piece. The next placement of the snare may be immediately adjacent to the first, with the edge of the wire positioned into the denuded area just created by removal of the previous piece (Figure 43.7). In this fashion, multiple portions can be sequentially resected in an orderly fashion, with removal of each succeeding piece being facilitated by its predecessor. Several applications may be required, removing fragments until satisfactory polypectomy is achieved [9,15,21,49]. The polyp fragments may be removed by suction into a trap if they are small, or retrieved with a mesh basket or, less effectively, with a dormia basket or a tripod grasper. One or two fragments may be captured in a snare loop for removal. The fulcrum technique may be used for the endoscopic treatment of laterally spreading polyps. The tip of the opened snare is impacted against the colonic wall behind the polyp. By keeping the tip fixed, slightly advancing the snare, and bending the endoscope tip left or right, the snare is pivoted to either side (Figures 43.8 and 43.9). If the tip of the opened snare is placed in front of the polyp, it can be flexed backward along its long axis by advancing the snare and the tip of the endoscope (Figure 43.10). To prevent perforation during snare closure the wire loop should be pressed flat against the bowel wall to ensnare the mucosal and submucosal layers only.

Cap-assisted polypectomy A suction cap may be attached to the colonoscope tip, and a preloaded snare can be placed at the mouth of the cap using the same technique as employed for EMR in the stomach and esophagus. Once the polyp elevated with submucosal injection for polypectomy has been aspirated into the cap, a large piece of the surface can be removed using coagulation current. Caution is urged for using this technique above the peritoneal reflection [47] because of the possibility of capturing the full thickness of the colon wall in the cap. Endoluminal fullthickness resection using a rigid instrument was introduced by Buess et al. [48] to remove sessile and/or malignant polyps in the rectum. This technique may offer a better alternative to endoscopic piecemeal resection or resective surgery in selected cases. However, it does not allow for lymphadenectomy, and has therefore a limited use in malignant lesions that cannot be treated endoscopically.

Stop at the mark on the snare handle When complete visualization is not possible as the loop is being closed, the assistant should close until resistance is met, or, if there is no closure sensation, stop at the line previously drawn by the endoscopy assistant prior to snare placement (see Chapter 42). Once closed, the snare sheath should be jiggled to and fro at the biopsy port while observing the colon walls around the polyp. If extraneous portions of the mucosa are not caught, the polyp will be seen to move independently of the surrounding colon walls as the sheath is jiggled. If the polyp and the surrounding wall move simultaneously, there is a strong probability that a portion of adjacent mucosa or bowel wall has been captured within the snare loop. Complete

Position of polyp Whenever a polyp is to be removed, snare placement is facilitated by rotation of the colonoscope to bring the polyp to the 5 o’clock position. Rotation of the scope is necessary to reposition the instrument tip in relation to the polyp. Rotation of the scope may be difficult during intubation when the instrument shaft has loops and bends. Advantageous positioning may be best accomplished when the colonoscope shaft is straight, because a straight instrument transmits torque to the tip, whereas a loop in the shaft tends to absorb rotational motions applied to the scope. It is often difficult to capture a sigmoid polyp during intubation, when the obligatory sigmoid

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Figure 43.7 Piecemeal resection of an adenoma with flat and elevated parts. (a) The front part of the polyp is ensnared first, the snare is pressed flat against the bowel wall, as the snare is closed the catheter is simultaneously advanced. While closing the snare, suction should not be applied. (b) After the first piece is resected, the exposed muscle layer

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provides orientation on the correct depth of further resections. (c) During application of current, the ensnared portion is lifted from the bowel wall to avoid deep coagulation. (d) Piecemeal resection is continued on the other side. (e) Finally, the elevated middle part is resected. (f) Total piecemeal resection is accomplished.

Figure 43.8 The impacted tip of the snare acts as a fulcrum on the colonic wall. Bending the endoscope tip to the right allows for safe snaring of the polyp alongside the haustral fold.

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Figure 43.9 Resection of a polyp along a fold. (a) Maximum air insufflation of the lumen shows that the polyp is on a fold. (b) The tip of the opened snare is placed behind the polyp. The snare is then pushed and firmly pressed against the bowel wall to spread out the fold, exposing the entire loop. (c) Using the tip of the snare as a fulcrum, the snare is pivoted to the left by bending the tip of the endoscope. The left part of the polyp is engaged into the snare. (d) The ensnared polyp portion is lifted into the bowel lumen and resected under optimal endoscopic control. Complete polypectomy is accomplished with piecemeal technique from the left to the right.

Figure 43.10 Reverse lasso technique. After positioning the tip of the snare in front of the polyp, the open snare is advanced and the tip of the endoscope slightly elevated. Thus, the snare is pivoted back alongside its own axis.

(a)

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loop is present. It may not be possible to straighten the scope in the sigmoid during the intubation phase because rotation and loop withdrawal often result in losing the scope’s position. With a loop in the scope, the dial controls may no longer work effectively to turn the instrument tip because the cables which transmit motion are maximally stretched by the loop.

Difficult Polypectomy

(b)

These two negative forces, the inability to torque effectively, and the loss of cable-controlled tip deflection, combine to create a difficult situation when attempting to maneuver the snare into position around a polyp. Snare placement can be made considerably easier by passing the scope far beyond the polyp, even to the cecum (and thus visualizing the rest of the

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colon), and attempting capture during the withdrawal phase of the examination. As the scope is withdrawn, the loops are removed and the polyp, which proved difficult to position during intubation, may be quite easily ensnared because both torque and tip deflection are responsive when the shaft is straight.

Endoscopic submucosal dissection (see Chapter 44) Using a variety of modified needle knives, endoscopic removal of extended lesions has been developed in Japan. This endoscopic technique of dissecting the submucosa over a large area is mainly used in the stomach where maneuverability of the endoscope and access to lesions is easier than in the colon. The thickness of the gastric muscularis layer provides a higher safety margin than does the thin colon wall. Compared with piecemeal resection with a conventional snare, endoscopic submucosal dissection (ESD) is a longer and more challenging procedure. Unlike reports on ESD for gastric lesions, there are only a few reports on the application in the colorectum. A group with experience of more than 500 ESDs of gastric lesions reported discouraging results when these procedures were used in the colon [50]. Seventy cases of ESD of lateral spreading colorectal lesions of 20 mm and larger were retrospectively evaluated. Prior to resection, injection was performed using sodium hyaluronate diluted four to six times with glycerol, and mixed with small quantities of indigo carmine and epinephrine. The lesions with a mean size of 28 ± 12 mm were resected in a single block in 80% of cases. The average time required for colonic ESD was 70.5 ± 45.9 min (range 15–180 min); 11 perforations (16%) occurred. The rate of perforation markedly decreased with practice although all procedures were carried out by endoscopists who had already performed ESD in more than 100 cases of early gastric cancer. The same group previously reported a series of 81 resections of similar colorectal lesions [51] using optional piecemeal resection, and only one perforation (1%) was noted. Another series of 200 sessile colorectal lesions in 186 patients noted an en bloc resection rate of 91.5% and perforations in 6% [52]. Results from a Western center on ESD of sessile colonic adenomas larger than 3 cm show an en bloc resection rate of only 55% in 29 patients, with a complication rate of 14% [53]. To allow for a safer approach, a resection technique using two endoscopes was described [54]. One endoscope provides traction while resection is performed with the other one. For ESD of a 20-mm lesion in the lower rectum, two endoscopists were needed, and the resection time was 30 min. A simpler ESD may be possible using a sinker (a weight attached to a partially removed flap of the polyp to pull it down by gravity to assist in ESD) [55].

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Taking into account long resection times for polyps with a mean size of less than 3 cm, extensive repeated injections, an en bloc resection rate of only 80%, and the high perforation rate, ESD for colorectal lesions can only be recommended to be performed by experts in centers with extensive experience. A high risk of perforation has to be expected, particularly in the initial period of the learning curve of the Western expert endoscopist with less experience in gastric ESD. The potential benefit, a safer pathologic assessment of a free resection margin of small carcinomas in large polyps resected in one piece, must be weighed against the disadvantages of the complicated resection technique. Unlike in the esophagus and stomach, elective surgical colon resection can be performed without substantial risk.

Polypectomy in a narrow diverticular segment Types of snares (see Chapter 24) For resection of difficult polyps there is probably no significant difference between snares made of braided or monofilament wire, and the selection of the type of snare should follow the personal preference of the endoscopist. As the amount of coagulation effect is mainly determined by the thickness of the wire, a braided wire creates more coagulation effect than a usually thinner monofilament wire. Bleeding may be less frequent with braided wire, but it may carry a higher risk of perforation due to greater thermal penetration depth. In our experience, a monofilament snare made of 0.5-mm steel wire is stiffer, provides greater stability for ensnaring flat polyps (Figure 43.11), and has advantages when the fulcrum technique is used (see Figures 43.8 and 43.9). The standard Erlangen polypectomy snare (Grosse Company, Daldorf, Germany) is 5 × 3 cm in size. In a narrowed bowel lumen, such as encountered in diverticulosis, a smaller floppy snare made of braided wire may be useful. Even after total colonoscopy has been performed and the colonoscope has been straightened, there may still be difficulty in the sigmoid colon when attempting to capture a polyp,

5 cm

12 cm

Figure 43.11 Monofilament Erlangen snare. The snare measures 3 cm × 5 cm and is made of 0.5-mm monofilament stainless steel wire. A 12-cmlong flat wire is built in between the loop and traction wire in the same plane with the loop. It can only be flexed horizontally, and the snare will always be adjusted automatically parallel to the mucosal surface when the endoscope is bent. The outer sheath is a 7F Teflon catheter.

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because of narrowing by diverticula and thickened hypertrophic folds. There are two maneuvers which may permit easier endoscopic polypectomy.

Use of the mini-snare The first is to use a mini-snare, which will allow a full extension of the snare within a short segment of the bowel. The standard regular-sized polypectomy snare may not be able to capture a small polyp in a difficult and “tight” location where there is not enough distance for the wire loop to open sufficiently wide to be placed over a polyp. A problem with the standard snare is that it must be completely extended to its full length of 5 or 6 cm in order for the loop to completely expand. During colonoscopy, it often occurs that the wire loop can only be extended a few centimeters beyond the scope because of a tight bend or because the tip of the loop impacts on an adjacent wall of the colon. When the snare loop cannot be fully extended, the two partially open parallel wires may not spread sufficiently apart to enable polyp capture. In this circumstance, a mini-snare of 3 cm in length and 1 cm in width [56,57] is extremely valuable. This snare will open fully when extended only 3 cm beyond the sheath, making it useful in areas where multiple bends are present (such as in the sigmoid narrowed with diverticulosis), or when polyps are located in the depth of a haustra. Because the vast majority of colon polyps are less than 1 cm in diameter, they are within the limits of this mini-snare.

Gastroscope for better tip reflection The second maneuver is the use of a narrow caliber scope to intubate the colon. A pediatric colonoscope is useful, but not generally available. A standard gastroscope has been demonstrated to be of benefit [58]. The major attributes of the gastroscope are that it has a tighter bending radius of the tip than

(a)

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Difficult Polypectomy

does a colonoscope, and the tip beyond the bending portion is shorter in length. This will frequently allow easy snare positioning in the same location where the colonoscope was both cumbersome and difficult. There is a growing awareness among endoscopists that gastroscopes can easily and readily be used in the colon to intubate difficult and narrowed segments, to be passed through strictures and render a previously inaccessible polyp more readily manageable [59]. The upper intestinal endoscope can be of use even in the rectum, where it may not be possible to snare a polyp on the proximal surface of one of the rectal valves. In this circumstance, the bending section of the colonoscope may be too long to permit a tight turn, whereas a gastroscope with its greater tip deflection capability and shorter “nose” (or straight portion beyond the bending section) may permit easy visualization and removal of polyps.

Clamshell polyps Large sessile polyps wrapped around a fold in a “clamshell” fashion usually permit the distal portion to be readily removed, but resection of the proximal portion on the far side of the fold may be considerably more difficult. This type of polyp is often located in the right colon and should be removed in piecemeal fashion (Figure 43.12). The piecemeal technique usually requires rotation of the colonoscope to place the polyp at the 5–6 o’clock position. Although it would be ideal to resect the total polyp at one session, it may only be possible to remove the portion nearest to the scope, leaving some of the polyp on the far side of the fold for an interval resection. Subsequent scarring may flatten the polypectomy site, bringing the residual polyp into a favorable location for subsequent polypectomy. Often, an injection of fluid into the mucosa on the far side of the polyp will facilitate its removal, as previously described. If total polypectomy is attempted at the first session,

(c)

Figure 43.12 Flat polyp at the proximal lip of the ileocecal valve. (a) The ileum is intubated and a pediatric biopsy forceps is introduced to depress the distal lip of the valve, in order to expose the polyp at the proximal lip. (b) Removal of the polyp is performed with the biopsy forceps in place. (c) Complete removal of the flat polyp is achieved with the view of the prolapsed lipomatous proximal lip. This technique requires the use of a therapeutic colonoscope.

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Figure 43.13 The far portion of a clamshell polyp may be difficult to lasso with the snare. This can be accomplished by pushing on the freshly resected polyp base. Depressing this surface with the sheath may elevate the proximal portion into the opened snare.

the stiffness of the plastic snare catheter can be used as a probe. After endoscopic transection of the portion closest to the scope, and with the loop extended, the tip of the catheter can be positioned on the ridge of the fold in the polypectomy site where a portion of the polyp has just been removed. By a combination of torque and rotation of the large control knob, downward pressure on the ridge at the site of the polypectomy divot will often depress it sufficiently so that a portion of the residual adenoma will elevate into the loop, permitting capture under direct vision (Figure 43.13). Several repeated snare applications and transections of this type will usually result in complete polypectomy. The tip of the instrument must be close to the polypectomy site for this technique to be effective, seeing as the plastic polypectomy sheath becomes quite flexible when it is extended more than a few centimeters beyond the colonoscope. The sheath, with its tip barely protruded from the faceplate of the scope, is stiff and will depress a fold when torque or tip deflection is applied to the colonoscope shaft. A stiff monofilament snare may be used to flatten the fold, exposing the entire polyp. Pushing on a fresh polypectomy site in this manner is not associated with any adverse results.

Retroversion An alternate technique for removal of a polyp located on the far side of a fold is to perform a U turn maneuver. With standard instruments, this can only be accomplished in the cecum, ascending colon, descending colon, and sometimes in the transverse colon, although it is somewhat easier with pediatric colonoscopes. In the rectum and lower sigmoid the use of a gastroscope can be considered. It is difficult but not impossible to resect a polyp in a U turn mode [60] because the tip deflection responses are opposite to those usually expected (Figure 43.14) [12]. Using special scopes with marked tip angulation, it is often possible to achieve total polypectomy in instances where the straightforward approach is not feasible.

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Flat polyps Carpet-like laterally spreading adenomas represent a special challenge for the endoscopist. A helpful maneuver to be considered when the lesion appears too flat to capture with the snare loop is to aspirate air from the colon with the snare device in place. This will collapse the distended colon, causing a decrease in the circumference of the colon wall and, as that occurs, the polyp that had been flattened against the stretched wall will become thicker and more elevated, rendering capture relatively easy so that piecemeal-type resection may be performed. However, ensnaring tissue with the aspiration technique carries the risk of capturing the muscularis propria layer of the relatively thin colon wall, increasing the risk of perforation. Any tissue ensnared should be carefully checked for lifting from the colon wall before current is applied. Alternate possibilities include submucosal injection of fluid to elevate the polyp for safer transection and use of a two-channel colonoscope, in which a forceps can be passed through one channel to grasp the polyp over which the opened snare has been positioned. Once the forceps lifts up the polyp, the snare is tightened to capture the polyp. Special snares such as the “barbed” and “spiral” ones allow polypectomy snares to dig into the tissue and in some cases allow resection of very flat polyps. These snares are generally more traumatic to tissue than standard snares, and caution must be taken not to entrap normal tissue. Very flat polyps may have to be ablated with the argon plasma coagulator.

Residual fragments of adenoma after polypectomy Often the base of a large polyp that was resected in piecemeal fashion has some residual adenomatous tissue at the edge or in the middle of the polypectomy site. If residual tissue is seen at the base, there will be adenomatous tissue at that site on follow-up colonoscopy. The site of polyp resection heals concentrically from the edges toward the center, so that usually only one polypoid excrescence will be present upon complete healing of the site, whether or not several small

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(a)

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Figure 43.14 Retroflexed resection technique. (a) The polyp is in the upper rectum. (b) To achieve better access, epinephrine (1:20 000) is injected submucosally. (c) Piecemeal resection starts from the front part of the polyp. (d) Remaining parts of the polyp are removed in retroflexed position. (e) Argon plasma coagulation is used to remove the adenomatous remnants at the proximal margin. (f) Final result after polypectomy.

islands of adenoma remained at the periphery of the initial resection base. If the polypectomy was adequate, the residual polyp will be smaller than the original size of the polyp, and can be easily removed. The application of thermal energy to the fragments of adenoma remaining at the base and edges of a fresh polypectomy site can reduce the incidence of residual polyp (Figure 43.15). This has been studied with the argon plasma coagulator, with reduction of adenoma on follow-up from 100% to 50% when residual tissue at the fresh base is destroyed [61– 64]. However, coagulation of larger areas of adenomatous tissue may result in adenoma recurrence within a scar not amenable for further endoscopic treatment.

Location of lesion in the colon There are several reasons to mark an area of the colon for future localization. Most of the time, the endoscopist wishes to have a precise identification of the site where a polyp was

removed. When large polyps are resected in piecemeal fashion, although the endoscopist might consider it to be totally removed, there is a strong possibility that residual adenoma will be present at a follow-up examination. It may be difficult to find the exact place where a polyp was removed as the estimate by the endoscopist was wrong, the scar is behind a fold, or the residual adenoma is small. Of equal importance is the knowledge that the polyp was indeed completely resected at the original session, and the site can be declared free of residual adenoma. Now that laparoscopic-assisted surgical colonic resection is becoming as well accepted as primary colonoscopy, there is even greater urgency to have precise lesion location, because the laparoscopist does not have the capability of palpating the colon between the fingers at exploratory laparotomy [65]. For the laparoscopist, it is of great importance to have an easily visible marker which can be seen through the telescopic lens of the laparoscope. It is not acceptable for the endoscopist to state that “a lesion is in the transverse colon,” because a more

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specific localization is needed to avoid subsequent open surgery to find the lesion.

Healing of polypectomy site Even under circumstances when open laparotomy is to be performed, site identification becomes necessary when a specific portion of the large bowel requires resection and the lesion may not be readily apparent by visual or palpatory exploration. Following endoscopic removal of a malignant adenoma, the site may heal completely in 8 weeks or less, and a locator mark may assist both the surgeon and the pathologist in identifying the place where the lesion had been.

Localization by number of centimeters inserted Localization by measurement of centimeters of instrument introduced into the rectum is an extremely poor method for tip localization [66]. During introduction of the instrument, when loops are common, it is possible to advance the full length of a long colonoscope (180 cm) into the rectum, yet the tip may still be at the sigmoid–descending colon junction [67]. However, it is possible, by repositioning the instrument, removal of loops, and straightening, to reach the cecum in that same patient with a total length of only 60 cm of instrument. The actual number of centimeters inserted may bear no relationship with the actual tip location within the colon [68].

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Figure 43.15 (a) A “mountain” polyp with a broad base was elevated by the injection of saline and removed in one piece (b). The base has some residual adenomatous fragments (c), which were fulgurated with the argon plasma coagulator (d).

A report from a previous examiner that “a polyp was found at 100 cm” is meaningless for surgical localization. With the current knowledge of intraluminal landmarks defining the splenic flexure, transverse colon, and hepatic flexure, it is much better to identify the approximate area in which the lesion was discovered instead of noting the distance in centimeters from the anal verge. During withdrawal, there is usually a good correlation between length of scope inserted and tip localization because the loops are removed and the instrument is straightened. It is usual, on withdrawal, to have the splenic flexure at 40–50 cm and the upper sigmoid at 30–35 cm. Because of sigmoid looping, shaft measurements during withdrawal are not usually helpful until the splenic flexure has been reached.

Endoscopic landmarks Landmarks are notoriously imprecise for exact localization of areas between the rectum and cecum. Even the most experienced colonoscopists may err in their estimate of tip location [65,67,69]. Indeed, in a large tortuous sigmoid colon, it may be difficult to localize a lesion to even the mid or upper sigmoid colon. Similarly, a lesion estimated by the endoscopist to be near the splenic flexure may be under the diaphragm, could be either proximal or distal to the flexure, or may even be actually located at the sigmoid–descending colon junction.

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Precise location may be impossible because of tortuosity and multiple bends in that area of the colon. The only invariable localizing landmarks are when a lesion is located within 15 cm of the anus, there is no doubt that it is close to or in the rectum, and a lesion near the endoscopically identified ileocecal valve can be easily found by the surgeon. The problem in the latter case revolves around the endoscopist’s ability to recognize beyond a doubt that the cecum was indeed reached.

Clips Clips may be placed through the colonoscope and onto the mucosa at any location. These will assist in radiographic or ultrasonographic location of the marked segment. However, clips tend to fall off at an average of approximately 10 days [70], with some falling off earlier and others maintaining their attachment for longer intervals. Although it has been suggested that clips may be a helpful marker for surgical localization, the clip devices are too small to be palpated easily. In addition, the surgeon cannot be assured that a palpable clip had not been spontaneously detached just prior to surgery and is at some distance from the original placement during endoscopy. If, indeed, a surgeon palpates a clip in the sigmoid colon and resects that segment, it is possible that the clip had actually been placed at a location near the splenic flexure, become detached, and migrated distally. A report of eight patients with prelaparoscopic clip placement by colonoscopy stated that intraoperative ultrasound readily located the marked areas for surgical resection [71].

Difficult Polypectomy

colon. The magnetic sensors are attracted to electromagnets within the sheath of the colonoscope (or on a wand-like device inserted into the biopsy channel) [73,74]. These methods have replaced such devices as metal detectors for localization of the instrument tip [75]. Unlike a fluoroscopic image which demonstrates both the scope and air in the colon as a contrast media, the electromagnetic field method only shows a computer reconstructed view of the colonoscope itself, but is capable of a three-dimensional format. This technique may be of benefit in localizing the site of a colonic tumor or polyp [76].

Intraoperative colonoscopy It is possible to localize the site of a tumor or a resected polypectomy by performing intraoperative colonoscopy [77,78]. This technique has been avoided by most endoscopists because of the need to perform an endoscopic examination in the operating room with all the constraints of positioning the patient, handling the scope, and trying to use maneuvers such as torque and straightening techniques with the abdomen open. The amount of air insufflated for colonoscopy can create problems with surgical techniques once the endoscopist has completed the necessary localization. Because the base of a polypectomy may heal within a few weeks, there is a possibility that the site may not be seen during an intraoperative endoscopy. Lesion identification can also be accomplished by colonoscopy and submucosal injection of radioactive-labeled albumin microaggregates [79] just prior to surgery. The surgeon can localize the precise area with detection by a gamma probe during laparotomy or laparoscopy.

Barium enema The barium enema is still an acceptable method for determining the location of polyps or cancers [68] but small lesions may not be readily identified on the barium enema radiographic examination. However, owing to newer imaging and opportunities for endoscopic localization with clips or marker injections, barium enema for determining the location of polyps has become less important. Certainly, if a malignant polyp were endoscopically resected, it may be extremely difficult to then try to locate the area where the polyp was removed, as only a small puckering may be present [68,72] or the site may be almost completely healed within 3 weeks. During colonoscopy in a suite where radiographic imaging is possible, either fluoroscopy or a radiograph of the abdomen during endoscopy may assist in locating the site of a lesion. Unfortunately, it may be difficult, with the instrument in a straightened configuration, to state that the tip of the colonoscope is in the distal descending colon or in the midportion of a long redundant sigmoid loop.

Marker injections into the colon wall The ideal method for lesion localization is to have an easily identifiable marker which will immediately draw the attention of the surgeon or endoscopist [69]. This can be achieved with injection of dye solutions. An experimental study demonstrated that of eight different dyes injected into the colon wall in experimental animals, only two persisted for more than 24 h [80]. These were indocyanine green and India ink. The indocyanine green was visible up to 7 days after injection, and it is known that India ink is a permanent marker which lasts for the life of the patient by virtue of submucosal injection of carbon particles. Other dyes, such as methylene blue, indigo carmine, toluidine blue, lymphazurine, and hematoxylin and eosin, were all absorbed within 24 h, leaving no residual stain at the injection site. Indocyanine green is approved by the Food and Drug Administration (FDA) for human use, but India ink has not been so sanctioned. A surgical marker has been FDA approved, and consists of pure carbon in suspension. It is marketed as a prediluted sterile compound in a preloaded syringe [81].

Magnetic imaging (see Chapter 46) New methods of inductive sensing with a low-intensity magnetic field may aid in the moment-to-moment localization of the tip of the colonoscope as it progresses through the

Indocyanine green Indocyanine green is not associated with any significant tissue reaction, and is relatively nontoxic, but ulceration of

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the injection sites have been reported in an animal model [80,82]. Clinical experience with indocyanine green tattoo in 12 patients demonstrated that the dye was easily visualized on the serosal surface of the colon at surgery within 36 h following injection [83] and may remain visible for up to 7 days [80]. Animal experimental models have shown that the dye was not visible after 1 day [82] or lasted up to 2 weeks [84]. The problem with a marker having such a relatively short visible span is that the decision to operate after removal of a malignant polyp may require a few weeks, with slide reviews and multiple consultations. An injection at the time of polypectomy will have disappeared whereas the site itself may become more difficult to localize with the passage of time.

India ink Most experience with dye injection technique has been accumulated with India ink as a permanent marker [85,86]. The stain lasts for at least 10 years with no diminution in intensity at that duration. A permanent marker may be worthwhile for several reasons. A lesion requiring surgery may be injected and, for clinical reasons, surgery may be postponed for several weeks, at which time a vital dye such as indocyanine green will have been absorbed, leaving the operating surgeon with no visible evidence of its having been injected. Sometimes it is desirable to mark the site of a resected polyp for subsequent endoscopic localization when it is anticipated that the area will be difficult to find on a follow-up examination, especially when the lesion is located around a fold or behind a haustral septum. A stain with a permanent marker such as India ink will draw immediate attention to the site, enabling a more accurate and complete assessment. For the surgeon, a locator stain will aid immeasurably the efforts to seek and resect an area of the bowel containing the site of the lesion. When the lesion is relatively small, such as a flat cancer or a previously endoscopically resected malignant polyp which requires surgical resection, the site may not be evident from the serosal surface and may not even be palpable. If the area to be resected is in a redundant sigmoid colon or near the splenic flexure, it may be impossible to locate by either visual means or palpation. Occasionally, even large lesions may not be palpable by the surgeon if they are soft and compressible [87]. As previously mentioned, visible marking can assist in precise surgical intervention for laparoscopicassisted colon resections, or clips may be detected by an ultrasound probe. There have been reported complications with India ink injection, but clinical symptoms resulting from the injection are relatively rare [88,89]. Tissue inflammation has been reported in an animal model [82]. The complications may in part be related to the wide variety of organic and inorganic compounds contained in the ink solution, such as carriers, stabilizers, binders, and fungicides [90]. It is possible that the toxic properties of India ink may be partially ameliorated by

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marked dilution of the ink. Ink diluted to 1:100 with saline produces as dark a spectrophotometric pattern as undiluted India ink, and, in clinical tests, the tattoo made by 1:100 diluted India ink is readily visible by the endoscopist and the operating surgeon. A small-volume injection (0.5 mL) may increase the safety of the procedure [82,91]. India ink is black drawing ink made with carbon particles. Permanent fountain pen ink is not an acceptable substitute. India ink is available from any stationery store, although it is supplied for medical use in nonsterile form as a stain to enhance the diagnosis of cryptococcosis in the cerebrospinal fluid. India ink may be sterilized in an autoclave following dilution or can be rendered bacteriologically sterile by passing the diluted solution through a 0.22-μm Millipore filter which is interposed between the syringe containing the dilute solution and the injection needle [92]. The preparation of India ink prior to injection is no longer required because of a new compound of sterile micronized carbon particles [81]. A standard sclerotherapy needle is utilized, which is of sufficient length to traverse the accessory channel of a 168-cm colonoscope, and stiff enough so that the plastic sheath will not crumple up as it is being forced through the biopsy port when the tip of the instrument is deep in the colon and the colonoscope shaft has several convolutions and loops. Ideally, the needle should enter the mucosa at an angle, to permit injections into the submucosa rather than have the needle pierce the bowel wall. The edges of intrahaustral folds should be targeted (Figure 43.16). If during an injection a submucosal bleb is not immediately seen, the needle should be pulled back slightly, because the needle tip may have penetrated the full thickness of the wall and the ink may be squirting into the peritoneal cavity. An intracavity injection is not a clinical problem [72,73], but can scatter black carbon particles around the abdominal cavity, which may be somewhat disconcerting for the surgeon. A prior submucosal injection of saline may aid the colonoscopist in depositing the carbon suspension in that layer, without risk of either deep or superficial injection (Figure 43.17) [93]. Because the colonoscopist cannot know which portion of the bowel is the superior aspect, multiple injections should be made circumferentially in the wall around a lesion to prevent a single injection site from being located in a “sanctuary” site, which is hidden from the surgeon while the abdomen is opened with the patient lying supine [94]. Each injection should be of sufficient volume to raise a bluish black bleb within the submucosa at the injection site. The injection volume may vary from 0.1 to 0.5 mL. If injections are made a few centimeters from the lesion, the surgeon should be informed whether the injections are proximal or distal to the site. With the proper dilution of India ink, endoscopic visualization is still possible should some of the ink spill into the lumen, whereas with the more concentrated solutions, the endoscopic picture becomes totally black when ink covers

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Figure 43.16 The distal portion of a “clamshell” polyp (a) was resected, but total removal required retroversion (b), which also shows the injection of a permanent surgical marker so the site can be identified at the follow-up examination.

(a)

Difficult Polypectomy

(b)

Figure 43.17 Sessile polyp resected after submucosal injection of saline. The surgical marker was injected into the submucosal blebs to facilitate delivery into the correct plane.

the bowel walls [72]. This is not a problem when using the new carbon particle solution. Most endoscopists who use India ink to mark colonic lesions do not prescribe antibiotics prior to its use, although it has been suggested that prophylactic antibiotics be given before injections of indocyanine green [83].

Injection of carbon particles provides a permanent marker; in every case, endoscopic visualization of the tattoo site without diminution in color is possible on follow-up examination up to an interval of at least 10 years following initial injection (Figure 43.18). Several reports have attested as to the safety as well as the efficacy of this method [88,95,96].

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Figure 43.18 Stain of surgical marker tattoo at 8-year follow-up post polypectomy. The scar is visible between two injection sites.

The extremely difficult colonoscopy If passage to the right colon has been arduous and prolonged, with the discovery of a large sessile polyp having a broad attachment that would require several attempts at piecemeal polypectomy, the wisest approach may be to suggest surgical resection to avoid the necessity of repeated difficult colonoscopies with repeated difficult polypectomies [97,98]. The risk–benefit ratio will depend on the location of the polyp: the right colon is somewhat thinner than the left, increasing the risk of colonoscopic removal. In patients with limited physiological reserves, there may be unacceptable risks associated with surgical laparotomy and colon resection. The advent of laparoscopic partial colectomy may markedly change the attitude of adventurous colonoscopists who attempt removal of large polyps [99]. The ease of laparoscopic resection may make a significant difference in the willingness of the patient and endoscopist to embark on the repetitive number of colonoscopies required to ablate a right colon polyp [100,101]. Conversely, it appears that many “difficult” colon polyps referred for surgical resection can be successfully managed endoscopically [100], and the laparoscopic approach is not free of complications [101]. Both the risks and benefits of an aggressive endoscopic approach will need to be reevaluated.

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82 Price N, Gottfried MR, Clary E, et al. Safety and efficacy of India ink and indocyanine green as colonic tattooing agents. Gastrointest Endosc 2000; 51: 438–42. 83 Hammond DC, Lane FR, Mackeigan JM, Passinault WJ. Endoscopic tattooing of the colon: clinical experience. Am Surg 1993; 59: 205–10. 84 Lee JG, Low AH, Leung JW. Randomized comparative study of indocyanine green and India ink for colonic tattooing: an animal survival study. J Clin Gastroenterol 2000; 31: 233–6. 85 Ponsky JL, King JF. Endoscopic marking of colon lesions. Gastrointest Endosc 1975; 22: 42–3. 86 Cohen LB, Waye JD. Colonoscopic polypectomy of polyps with adenocarcinoma: when is it curative? In: Barkin JS (ed.). Difficult Decisions in Digestive Diseases. Chicago: Year Book Medical Publishers, 1989: 528–35. 87 Richter RM, Littman L, Levowitz BS. Intraoperative fiberoptic colonoscopy. Localization of nonpalpable colonic lesions. Arch Surg 1973; 106: 228. 88 Nizam R, Siddiqi N, Landas SK, Kaplan DS, Holtzapple PG. Colonic tattooing with India ink. Benefits, risks, alternatives. Am J Gastroenterol 1996; 91: 1804– 8. 89 Gopal DV, Morava-Protzner I, Miller HAB, Hemphill DJ. Idiopathic inflammatory bowel disease associated with colonic tattooing with India ink preparation. Gastrointest Endosc 1999; 49: 636– 9. 90 Lightdale CJ. India ink colonic tattooablots on the record. Gastrointest Endosc 1991; 37: 68–71. 91 Poulard JB, Shatz B, Kodner I. Preoperative tattooing of polypectomy site. Endoscopy 1985; 17: 84–5. 92 Salomon P, Berner JS, Waye JD. Endoscopic India ink injection: a method for preparation, sterilization, and administration. Gastrointest Endosc 1993; 39: 803–5. 93 Fu KI, Fujii T, Kato S, et al. A new endoscopic tattooing technique for identifying the location of colonic lesions during laparoscopic surgery: a comparison with the conventional technique. Endoscopy 2001; 33: 687–91. 94 Hyman N, Waye JD. Endoscopic four quadrant tattoo for the identification of colonic lesions at surgery. Gastrointest Endosc 1991; 37: 56–8. 95 Shatz BA, Weinstock LB, Swanson PE, Thyssen EP. Long-term safety of India ink tattoos in the colon. Gastrointest Endosc 1997; 45: 153– 6. 96 McArthur CS, Roayaie S, Waye JD. Safety of preoperation endoscopic tattoo with India ink for identification of colonic lesions. Surg Endosc 1999; 13: 397–400. 97 Pokala N, Delaney CP, Kiran RP, Brady K, Senagore AJ. Outcome of laparoscopic colectomy for polyps not suitable for endoscopic resection. Surg Endosc 2007; 21: 400–3. 98 Schmitt EA. Transabdominal transcolonic polypectomy. World J Surg 2005; 29: 1340–2. 99 Hensman C, Luck AJ, Hewett PJ. Laparoscopic-assisted colonoscopic polypectomy: technique and preliminary experience. Surg Endosc 1999; 13: 231–2. 100 Voloyiannis T, Snyder MJ, Bailey RR, Pidala M. Management of the difficult colon polyp referred for resection: resect or rescope? Dis Colon Rectum 2008; 51: 292–5. 101 Lo SH, Law WL. Laparoscopic colorectal resection for polyps not suitable for colonoscopic removal. Surg Endosc 2005; 19: 1252–5.

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Endoscopic Submucosal Dissection in the Colon Naohisa Yahagi Toranomon Hospital, Tokyo, Japan

Introduction Endoscopic submucosal dissection (ESD) is a novel technique for the resection of superficial neoplastic lesions of the gastrointestinal tract [1–4]. It results in a very high en bloc resection rate, but this requires a high level of skill and long procedure times [5]. This technique is applicable to relatively large and complex lesions, even those difficult to treat with conventional endoscopic mucosal resection (EMR). ESD is a fairly new arrival in the field of endoscopy, but completely redefines the whole concept of endoscopic resection for gastrointestinal neoplasms. Before submucosal injection techniques which permitted EMR, it was very difficult to remove large polyps using conventional polypectomy techniques and, consequently, many large or flat lesions were often subjected to surgery although some of them were benign tumors. Introduced to colonoscopy more than 20 years ago, EMR soon became popular as it enabled the much safer and more reliable removal of relatively large or flat lesions [6]. However, it was often not possible to resect large lesions (more than 2 cm) in an en bloc fashion; hence, piecemeal resection was routinely performed for those larger lesions. Piecemeal EMR became accepted as a relatively quick and easy procedure to perform, even for very large lesions, but precise histological evaluation was difficult and there was a risk of local recurrence [7,8]. Added to this, endoscopic retreatment of recurrent tumors following such piecemeal resection may be difficult as a result of the lack of mucosal lifting from local fibrosis. For the reasons outlined above, a more reliable endoscopic resection technique was desired and consequently the techniques of ESD were transferred from the upper gastrointestinal tract to the colon in order to achieve en bloc resection for large and difficult lesions.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Overview of endoscopic submucosal dissection ESD was originally developed in Japan in order to achieve a reliable method for en bloc resection of early gastric cancers. Initially, the use of this technique was limited to gastric lesions, on account of maneuverability of the endoscope and the wall thickness of the stomach. But, with experience, it became possible to conduct ESD even in the colon [9,10]. The most important aspects of this technique are to incise the mucosa surrounding the lesion (Figure 44.1a), and to dissect completely the submucosa beneath that lesion (Figure 44.1b) to achieve reliable en bloc resection regardless of the size or location of the tumor. In performing ESD, success in terms of cure (complete resection) of the treatment must be evaluated by histological examination. The depth of tumor extension, the degree of tumor differentiation, and the presence of vascular infiltration are all key factors in assessing the risk for lymph node metastases. Margins free from tumor must be confirmed histologically in order to prove the completeness of the resection. En bloc resection is very important in providing histological confirmation of complete tumor removal. The importance of the EST procedure is that local recurrence does not occur if the entire lesion has been removed intact.

Indications for colorectal endoscopic submucosal dissection ESD can be applied to almost all lesions as long as they lie within the mucosa and the superficial submucosa. However, as ESD is time-consuming and involves some risk on account of its technical features, a lesion that is resectable in an en bloc fashion by polypectomy or EMR should be treated by those more conventional techniques. The absolute indications for ESD include lesions that cannot be resected en bloc by standard procedures. Those that require precise histological evaluation on account of a significant malignant potential [11] are depressed lesions and laterally

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(a)

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(a)

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Figure 44.1 Schema of colorectal endoscopic submucosal dissection. (a) An initial mucosal incision is made 3–5 mm outside the edge of the tumor. (b) Submucosal dissection is made under direct vision, utilizing a transparent hood.

Figure 44.2 A large laterally spreading tumor, nongranular type (LST-NG). (a) A large LST-NG on a haustral fold located at the mid-transverse colon. (b) This lesion failed to lift to any degree with submucosal injection. (c) Marked fibrosis was dissected and the lesion was completely resected. (d) The resected specimen revealed a well-differentiated adenocarcinoma; 51 × 39 mm, sm1, ly( −), v(−), cut end ( −).

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Preparation and setting up for colorectal endoscopic submucosal dissection

The patient avoids fiber-rich meals on the day before treatment and takes a 10 mL bottle of picosulfate after their evening meal. A mixture of an electrolyte solution (2 L) with simethicon (10 mL) is used for intestinal lavage on the morning of treatment. In Japan, colonoscopy is usually performed in the afternoon in order to ensure a good preparation as a result of it being taken on the same day. The addition of simethicon with a standard preparation solution markedly reduces adherent residue, making it easier to wash the bowel lumen during ESD.

Bowel preparation

Endoscope

Good bowel preparation is always very important in ensuring optimal vision of the operating field and limiting the degree of peritonitis should a perforation occur.

The maneuverability of the endoscope is the key factor in successful ESD. Retroflex manipulation is required when the oral (proximal) edge of large-sized lesions or those lesions

spreading tumors of the nongranular type (LST-NG, Figure 44.2) [12]. Other indications include lesions with biopsyinduced scars, lesions on haustra or at angulations of the colon, large lesions (Figure 44.3), and small rectal carcinoid tumors (Figure 44.4) for which en bloc resection is impossible by conventional techniques.

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Figure 44.3 A large laterally spreading tumor, granular type (LST-G). (a) A large LST-G of mixed type located at the sigmoid colon. (b) The dissected area is seen to drop down and open widely through the effect of gravity. (c) Complete en bloc resection was achieved. (d) The resected specimen revealed a welldifferentiated adenocarcinoma; 78 × 59 mm, ly(−), v(−), cut end (−).

Figure 44.4 A small rectal carcinoid tumor. (a) A carcinoid tumor located at the lower rectum (Rb). (b) A mucosal incision was made after creating a sufficient submucosal fluid cushion. (c) Complete resection was achieved by dissecting the submucosa beneath the lesion. (d) The resected specimen revealed a carcinoid tumor; 6 × 5mm, ly(−), v(−), cut end (−).

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straddling a fold are to be incised. In this respect, it is better to use an endoscope whose diameter is as small as possible in order to allow smooth maneuverability in the retroflexed position. We usually use an ultra-slim endoscope with an in-built water jet mechanismathis is a prototypeaespecially designed for colonic ESD. Since this scope is not commercially available as yet, it is advisable to use a gastroscope instead of a regular colonoscope for the lesions located in the rectum or distal sigmoid colon. Importantly, ESDs are performed without the need for specialized scopes; ESD is a relatively low-tech but highly skilled procedure.

Distal attachment (hood/cap) To perform ESD safely, a transparent hood or cap should be attached to the tip of the endoscope with tape to prevent dislodgement. The edge of the hood can be used like a surgical forceps to open the incision to achieve a better view of the operating field, or to lift the tissue to help control the knife during incision. A soft distal attachment (D-201–11804, Olympus Company, Tokyo, Japan, Figure 44.5a) is usually used for colorectal ESDs. Importantly, this is a different type of attachment from the hard, grooved cap that is used for

(a)

Figure 44.5 Distal attachments (cap/hood). (a) Soft type distal attachment (D-201–11804, etc.; Olympus Company, Tokyo, Japan). (b) Small-caliber tip transparent hood (DH-16CR; Fujinon Company, Tokyo, Japan).

(b)

EMR. In those cases where it is difficult to open the mucosal incision adequately, a cone-shaped ST (small-caliber tip transparent) hood (DH-16CR, Fujinon Company, Saitama, Japan, Figure 44.5b) is very useful because it has a groove for instruments that is aligned with the accessory channel of the scope.

Knives The insulated tip knife (either the original type 1 or the newer standard type 2) (KD-610L, Olympus Company, Tokyo, Japan, Figure 44.6a) is the most popular electrosurgical knife for ESD procedures in the upper gastrointestinal tract [13]. It is not suitable for colonic ESD, however, because it is very difficult to control within the narrow lumen of the colon. Added to this, the risk of perforation is greater in the colon as a result of its thin wall [14]. The Flex knife (KD-630L, Olympus Company, Tokyo, Japan, Figure 44.6b) is the most maneuverable device, being soft and flexible [15], which makes it ideal for colonic ESD [16]. The tip of the Flex knife is rounded, being fashioned from a twisted, braided wire that looks like a thick wire snare. The length of the protuberant wire is adjustable and therefore the Flex knife is less likely to cause a perforation than a standard

(c)

Figure 44.6 Popular electrosurgical knives for endoscopic submucosal dissection. (a) Insulated tip knife (KD-610L; Olympus Company, Tokyo, Japan). (b) Flex knife (KD-630L; Olympus Company, Tokyo, Japan). (c) Hook knife (KD-620LR; Olympus Company, Tokyo, Japan).

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needle knife. The thickness of the wire at the tip of the Flex knife is in marked contrast to that of the fine wire needle knife which is designed for rapid cutting (a feature not desired for ESD). Another safety feature of the Flex knife is that the tip of the outer sheath is thickened somewhat in its distal few millimeters, and this helps to control the depth of incision. The majority of colonic ESD procedures can be carried out using a Flex knife but, in some cases, or indeed for some portions of a procedure, difficulties may arise from poor endoscopic maneuverability. In such circumstances, the hook knife [2] (KD-620LR; Olympus Company, Tokyo, Japan, Figure 44.6c) can be introducedathe endoscopist can hook and pull the submucosal tissue before cutting it, which again aids safety. A feature common to many ESDs, at whatever site, is that two types of knife may be required; such combinations may include Flex and hook knives, or insulated tip and needle knives. As several pieces of equipment (injection needle, knives, and hemostatic clips) will be needed in rapid succession for ESD, it can be very helpful to have an instrument rack where all accessories are readily available (MAJ 1363; Olympus Company, Tokyo, Japan). In addition to the other tools, a fine-tipped forceps is essential so the assistant can regularly clean charred tissue from the knife.

Hemostatic forceps and endoclips Hemostatic forceps (Pentax Company and Olympus Company, Tokyo, Japan, Figure 44.7a–c) and rotatable clip fixing devices (Olympus Company, Tokyo, Japan) are essential accessories for bleeding and/or perforation. The hemostatic forceps is not the same as a hot biopsy forceps, which is much larger and not pointed at the tip. Bleeding is common during colonic ESD, and is usually easily controlled by locating the point precisely (after washing), accurate pinching of the blood vessel, elevating it slightly (to minimize muscular damage), and then coagulating with a minimal contact area [17]. The use of hot biopsy forceps is not recommended for colonic ESD, mainly because there may be a delayed perforation from focal overcoagulation. Endoscopes

(a)

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Endoscopic Submucosal Dissection in the Colon

that have a built-in water irrigation system are very useful for visualizing the bleeding point, and, when used in combination with a hemostatic forceps, are very effective in controlling bleeding. All bleeding points must be located and treated as they appear. Even tiny amounts of bleeding should not be ignored because the site may be impossible to locate when blood fills the visual field. However, there is a trade off, since overuse of coagulation hardens tissue and makes it more difficult to dissect; the best solution is to ensure that cutting is in a plane relatively close to the muscle, as there are fewer vessels at this level. Should a perforation occur, the endoscopist must close the defect immediately, before there is leakage of intestinal fluid, in order to limit the severity of any resulting peritonitis. Clips with teeth angled at 90° at their tip are useful for this, as the “tooth” of one “jaw” can be pressed into the mucosa and then the scope tip raised to allow the clip to bridge the defect (always starting closure at the narrowest end of the perforation).

Electrosurgical unit The electrosurgical generators from ERBE (ICC 200 and ICC 350, ERBE, Tübingen, Germany), which have Endocut and multiple coagulation modes, are ideal for ESD. Endoscopists must familiarize themselves with what their diathermy unit can provide, what the various settings mean, and the situations in which they are used. In performing ESD, endoscopists and their assistants must realize that different phases of the procedure require different settings, with many changes being made over the course of a case. Different settings are required for incising the mucosa, for submucosal dissection, and for hemostasis. Additionally, one must bear in mind that settings appropriate for the stomach will not be suitable in the thinnerwalled colon. By way of a guide, the following are some suggested settings for colonic ESD using ERBE ICC 200 and 350 units with a Flex knife: 1 mucosal incision, Endocut mode, effect 2, 60 W; 2 submucosal dissection, forced coagulation mode, 40 W hemostatic forceps; 3 hemostasis with a monopolar, soft coagulation mode, 50 W.

(c)

Figure 44.7 Devices for hemostasis. (a) Hemostatic forceps (HDB2422; Pentax Company, Tokyo, Japan). (b) HemoStat-Y (H-S2518; Pentax Company, Tokyo, Japan). (c) Coagrasper (FD-410LR; Olympus Company, Tokyo, Japan).

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Note that coagulation is used for the submucosal dissection in the colon. The ERBE VIO 300D (ERBE, Tübingen, Germany) is a welcome addition to the range of available diathermy units as it has new cutting and coagulation modes, “dry cut” and “swift coag,” which can reduce bleeding during the procedure. Settings that might be used with the Flex knife and hemostatic forceps are: 1 mucosal incision, dry cut mode, effect 2, 40 W; 2 submucosal dissection, swift coagulation mode, effect 4, 40 W; 3 hemostasis, soft coagulation mode, effect 5, 50 W.

Injection solutions Normal saline is the most popular injection fluid for conventional EMR. However, the mucosal protrusion created with the injection of normal saline does not last long enough to provide sufficient time for submucosal dissection [18]. In order to create a longer lasting mucosal cushion, several other fluids have been used for ESD; among those, Glyceol® solution, consisting of 10% glycerin, 5% fructose, and 0.9% sodium chloride, is the most popular. Larger and more difficult lesions require another solution such as sodium hyaluronate [19,20]. Sodium hyaluronate solution at a concentration of 0.4% with an average molecular weight of 800 kDa (MucoUp®, Seikagaku Kougyo Company, Tokyo, Japan; derived from rooster comb) can create a prominent, long-lasting effect and is approved in Japan for use in the endoscopic resection of colorectal lesions [21]. A mixture with a small amount of added epinephrine (0.001%) is effective for the control of bleeding during the procedure. A further additive, indigo carmine dye (0.004%), is useful for providing a clear visualization of the submucosal layer and visual differentiation from muscle. Generally, assistants will have two sets of syringes at their disposal, the majority filled with glycerin, lightly colored with indigo carmine and some filled with hyaluronic acid, again lightly colored. The latter syringes can be used periodically as required. These particular formulations have been adopted in Japan because they have been shown not to induce submucosal damage through hyperosmolar or hypermolecular effect. A large bore, standard injection needle is used to deliver these fluids.

Performing colorectal endoscopic submucosal dissection Insertion of the endoscope and preoperative check In addition to the endoscopist, at least two additional staff are required throughout the procedure. Because of the constant changing of accessories and instrument settings throughout ESD, staff should be trained in depth.

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This procedure ought to be performed with the minimum amount of sedation required for patient comfort. Cultural preferences will influence this, but it should be remembered that a less sedated patient can move position more readily and can tell the endoscopist of any undue pain. In cases where a long procedure time might be predicted, the use of general anesthesia and carbon dioxide insufflation should be considered (see below). Endoscope insertion must be careful and controlled with the avoidance of loop formation; maintaining good maneuverability of the endoscope is essential for a successful procedure. In performing ESD, rotation is a key movement. Once the scope reaches the tumor, the intestinal lumen should be filled with water (including a small amount of simethicon) and thoroughly cleaned. Chromoendoscopy (indigo carmine) is performed to detail the surface and the extent of the tumor. Check the maneuverability of the endoscope as well as the orientation of the bowel in respect to gravity and how the patient’s position affects the access to the polyp. The effect of gravity is important, as it is necessary to know in which direction the dissected tissue will fall and whether this might create difficulties for visualization, etc.

Planning the approach In order to perform colonic ESD successfully, it is important to make a strategy that includes the order of incisions and the direction of the dissection of the mucosa and submucosa. The procedure is usually started from the proximal part of the lesion, along the uppermost side of the lesion (in respect to gravity). If it is possible to keep the endoscope in a retroflexed view, it is better to start the procedure in this position since the endoscope is more stable and the target lesion is often in line with the working channel. When dissection has progressed from the upper side to the central part of the lesion, the position of the patient is shifted so that the side of the lesion that had been lowest is now at the higher level (again, in respect to gravity). The mucosal cushion is kept sufficiently prominent by injecting additional solution into the submucosa.

Submucosal injection and mucosal incision More often than not, the demarcation of colonic lesions is quite obvious and clear, so that initial marking out is generally not necessary for colonic ESD (Figure 44.8a). The target area to be dissected must be elevated with a sufficient amount of submucosal injection (Figure 44.8b). Usually, a few milliliters of solution per site are enough, injecting several sites before incision and dissection. The mucosal incision is started right after creating a sufficient submucosal fluid cushion. The knife must be kept less than 2 mm in length (Figure 44.8c) and is gently applied to the elevated mucosa. The proper position of the Flex knife is achieved by opening it fully and then retracting it back into its sheath until only the barest tip is seen (imagine that the cutting will be accomplished

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Endoscopic Submucosal Dissection in the Colon

(a)

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Figure 44.8 A laterally spreading tumor, nongranular type (LST-NG) located in the transverse colon. (a) The demarcation line of the tumor became very clear with indigo carmine spraying. (b) The nonlifting sign was observed after submucosal injection. (c) The knife length was checked just in front of the lens and kept less than 2 mm. (d) Part of the surrounding mucosa was incised after creating a sufficient submucosal fluid cushion. (e) Submucosal dissection was started immediately after mucosal incision, beginning from the incised part. (f) The fibrous area was dissected under the

(i) direct vision utilizing the transparent hood and after that the dissected area was turned over with the help of gravity. (g) Mucosal incision and submucosal dissection under direct vision was repeated until completion. (h) The lesion was completely resected without any complications. (i) The retrieved specimen was stretched, pinned out, and fixed on a rubber board. The resected lesion was a well-differentiated adenocarcinoma; 45 × 32 mm, sm1 (400 mm), vascular infiltration (−), cut end ( −). The procedure was judged to be curative.

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with the tip of the sheath), although photographs always show the Flex knife to be extended, this is for illustrative purposes only; again, the Flex knife is not a needle knife. During the procedure, the assistant holds the Flex knife handle by its side, not through the finger grips, like a polypectomy snare because it is important to prevent inadvertent opening of the knife. The colonic mucosa is so thin that it is easily incised using the Endocut or the dry cut modes. Unlike with the insulated tip knife in the stomach, it is not useful to incise fully around the lesion. The Flex knife requires a good-sized cushion/ protuberance for safety; by cutting all the way around, fluid will leak out, lessening its effect.

specimens are much larger, an overtube is needed to protect the resected tissue. The retrieved specimen is stretched out and pinned out on a cork, rubber, or polystyrene board (Figure 44.8i). The shape and orientation of the specimen is documented, and then forwarded in fixative for histopathologic evaluation. The large size of ESD specimens when pinned out will require the availability of large containers of fixative. It is important to remember that formaldehyde is toxic and so any such containers must be prepared in advance in a safe environment (under a flow hood).

Evaluation criteria Submucosal dissection Submucosal dissection should be started immediately after mucosal incision, beginning from the incised part (Figure 44.8d and e). Submucosal fibers are very soft and are easily dissected by gently applying the knife using the forced or the swift coagulation mode. It is not necessary to change the knife length during the procedure; the same length, less than 2 mm, is used for both mucosal incision and submucosal dissection. It is very important to allow gravity to help with the submucosal dissection in order to ensure a good operating field. Patient position, therefore, ought to be changed during the procedure in order to let the dissected area fall down and open more widely with the pull of gravityathis makes it much easier to continue submucosal dissection under direct vision (Figure 44.8f).

Removal of the tumor If the tumor is of a size or at a location (e.g., not crossing a fold) that will allow snaring, one can snare the residual pedicle of tissue when most of the dissection has been completed and the tumor is resected (Endocut mode) as if it were a polyp. If the tumor is too large to be included in a snare or is straddling folds, then dissection into the submucosa is continued to completion in order to achieve an en bloc resection (Figure 44.8g). The “bare” area of the resection site should be carefully inspected (Figure 44.8h). Should there be an exposed blood vessel, it is gently pinched with hemostatic forceps, and coagulated using the soft coagulation mode. There is no need to close the resection defect with clips or by other means. Most of the large artificial ulcers, even if they are more than 10 cm in diameter will close within 8 weeks without complication [8].

Handling of the resected specimen The resected specimen should be carefully retrieved from the anus so that it is not torn. A small specimen can be easily retrieved using suction into the soft cap. Employing a retrieval basket or net is useful for moderate-sized lesions but, when

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After resection, the completeness of the procedure must be determined through precise histological evaluation [22]. An intramucosal cancer with resection margins free of tumor can be judged as being radically curative. Even in cases where histological evaluation reveals slight submucosal invasion, if the extent of invasion is limited to 1000 μm or less, and the invading part of the tumor is highly differentiated, then the risk for lymph node metastases is considered to be very low, and subsequent surgery is not necessary [23]. However, surgery is recommended for the high risk of local recurrence or lymph node metastases in the following circumstances: 1 lesions with a positive vertical (deep) margin; 2 lesions with massive submucosal invasion of more than 1000 μm; 3 lesions with vascular infiltration; 4 lesions with poorly or undifferentiated cancer; 5 lesions with budding seen at the deepest part of invasion.

Postoperative clinical course and follow-up The clinical course after a smooth and uneventful colorectal ESD is usually favorable. Soft food is started 1 day after the treatment, presuming no symptoms, and oral intake is then gradually built up. Patients can be discharged from the hospital within 5 days of the treatment, irrespective of resection size. This long hospitalization is because of the potential for delayed complications such as bleeding or perforation. On the other hand, a few days of fasting and intravenous administration of antibiotics are necessary for patients who have had a perforation treated with immediate endoscopic closure, or for the patient who complains of abdominal discomfort or develops fever. Immediate surgical intervention is required when the patient develops abdominal pain and tenderness with guarding. Whereas a follow-up endoscopy prior to discharge is necessary for patients who have had esophageal, gastric, or duodenal ESD in order to check the healing process and identify exposed

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blood vessels, no such postprocedural examination is necessary after colorectal ESD, as the risk for delayed bleeding is relatively low. Indeed, a repeat bowel preparation and colonoscopy would themselves carry some risk for complication. Follow-up colonoscopy is usually carried out 1 year after the treatment, when complete curative resection is confirmed at histology. Follow-up colonoscopy is performed in 6 months, when lateral margin involvement is uncertain on the resected specimen. The follow-up interval is shortened to 3 months, when a lateral margin is positive for mucosal cancer or adenoma.

Treatment results and complications In our case series at the University of Tokyo Hospital from July 2000 to March 2006, ESD was performed on 186 consecutive patients with 200 colorectal epithelial neoplasms who had preoperative diagnoses of mucosal neoplasm with or without marginal submucosal invasion [24]. In addition, these included lesions of large size, those with submucosal fibrosis, or those located on a haustral fold. The targeted lesions consisted of 102 adenomas, 72 with high-grade dysplasia, and 26 invasive carcinomas. Seven lesions (3.5%) were histologically proven to be at substantial risk for lymph node metastasis after ESD. The en bloc resection rate was 91.5% (183/200), and the complete resection rate, which means en bloc resection with tumor-free lateral/vertical margins (R0 resection), was 70.5% (141/200). The en bloc resection rate for colorectal ESD was similar to that for gastric ESD but the complete resection rate for colorectal ESD was less than that for gastric ESD. Only two local recurrences were detected (1.8%) out of 111 lesions followed up by colonoscopy (median follow-up, 18 months; range 12–60 months). Both of these lesions had been resected in a piecemeal fashion due to nonlifting at the time of the original submucosal fluid infiltration. One case of recurrence was successfully treated by argon plasma coagulation but the other required surgical rescue since it recurred as a superficially invasive submuocsal carcinoma. No lymph node or distant metastases were detected in 77 patients with high-grade dysplasia or invasive carcinoma (median follow-up, 24 months; range 6–74 months).

Complications and procedure time Despite excellent treatment results, the major concerns related to this technique are about its complication and the long procedure time required for completion. Minor bleeding occurs in every case but can be successfully controlled with coagulation by hemostatic forceps. No major bleeding, which required blood transfusion, was observed in our case series. Two patients (1%) required emergency colo-

Endoscopic Submucosal Dissection in the Colon

noscopy because of hematochezia following ESD. Eleven (5.5%) perforations occurred at the time of the ESD procedure, but all were treated successfully by clipping and subsequently discharged from hospital without incident. There is no difference in the clinical course of patients after perforation between perforations occurring in the esophagus, stomach, or colon [25]. A single (0.5%) delayed perforation occurred, which required surgery. Others have reported a 10% perforation rate [26]. Procedure time is largely influenced by the size and type of the lesion. Usually, large lesions require a longer procedure time, and difficult situations, such as the presence of fibrosis or the need for severe scope angulation, will certainly lengthen the procedure. Many colonic ESDs require around 90 min for completion, but very difficult cases could take over 3 h. For prolonged procedures, the substitution of carbon dioxide gas insufflation for air is very helpful in reducing abdominal pain and discomfort both during and after the procedure [27]. When an endoscopy unit is committing itself to be a center for ESD, the impact on staffing levels of scheduling long cases and the adverse effect it has on other procedures must be taken into account. Embarking on ESD is a commitment for the whole department, not just the endoscopist. Furthermore, the complete and detailed assessment of large specimens may place extra strain on pathology services. Pathologists may have to undergo specialized training in the handling, assessment, and reporting of ESD specimens.

Summary ESD is a novel endoscopic resection technique for superficial gastrointestinal tumors, which provides a high en bloc resection rate. It allows single specimen resection of much larger and more difficult lesions than can be removed by conventional EMR methods. Using this technique, various lesions, including depressed lesions and lesions with fibrosis, can be removed even in the colon. However, ESD is the most advanced technique within therapeutic endoscopy and so requires a great degree of skill and lengthy procedure times. Colonic ESD involves a relatively higher risk for complication than gastric ESD and, consequently, demands a thorough knowledge of this subject and specific training in its performance. Endoscopists should start with relatively easy lesions (e.g., gastric abnormalities) and graduate to colonic ESD as their skills develop. This stepwise approach will allow ESD to be safe, effective, and reliable in their hands.

Acknowledgment I heartily thank Dr. John Meenan, Guy’s and St. Thomas’ Hospital, London, for reviewing and correcting this manuscript.

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References 1 Yahagi N, Fujishiro M, Kakushima N, et al. Endoscopic submucosal dissection for early gastric cancer using the tip of an electro-surgical snare (thin type). Dig Endosc 2004; 16: 34–8. 2 Oyama T, Tomori A, Hotta K, et al. Endoscopic submucosal dissection of early esophageal cancer. Clin Gastroenterol Hepatol 2005; 3: S67–70. 3 Gotoda T. A large endoscopic resection by endoscopic submucosal dissection procedure for early gastric cancer. Clin Gastroenterol Hepatol 2005; 3: S71–3. 4 Yamamoto H, Yahagi N, Oyama T. Mucosectomy in the colon with endoscopic submucosal dissection. Endoscopy 2005; 37: 764– 8. 5 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: 243–9. 6 Kudo S, Tamegai Y, Yamano H, et al. Endoscopic mucosal resection of the colon: the Japanese technique. Gastrointest Endosc Clin N Am 2001; 11: 519–35. 7 Iishi H, Tatsuta M, Iseki K, et al. Endoscopic piecemeal resection with submucosal saline injection of large sessile colorectal polyps. Gastrointest Endosc 2000; 51: 697–700. 8 Tamura S, Nakajo K, Yokoyama Y, et al. Evaluation of endoscopic mucosal resection for laterally spreading rectal tumors. Endoscopy 2004; 36: 306–12. 9 Yahagi N, Fujishiro M, Imagawa A, et al. Endoscopic submucosal dissection for the reliable en bloc resection of colorectal mucosal tumors. Dig Endosc 2004; 16(Suppl.): S89– 92. 10 Yamamoto H, Kawata H, Sunada K, et al. Successful en-bloc resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood. Endoscopy 2003; 35: 690– 4. 11 Hurlstone DP, Brown S, Cross SS. The role of flat and depressed colorectal lesions in colorectal carcinogenesis: new insights from clinicopathological findings in high-magnification chromoscopic colonoscopy. Histopathology 2003; 43: 413– 26. 12 Kudo S, Shimoda R, Kashida H, et al. Laterally spreading tumor of colon: definition and history (in Japanese with English abstract). Stomach and Intestine 2005; 40: 1721–5. 13 Ohkuwa M, Hosokawa K, Boku N, et al. New endoscopic treatment for intramucosal gastric tumors using an insulated-tip diathermic knife. Endoscopy 2001; 33: 221– 6.

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14 Rosch T, Sarbia M, Schumacher B, et al. Attempted endoscopic en bloc resection of mucosal and submucosal tumors using insulatedtip knives: a pilot series. Endoscopy 2004; 36: 788–801. 15 Kodashima S, Fujishiro M, Yahagi N, et al. Endoscopic submucosal dissection using flexknife. J Clin Gastroenterol 2006; 40: 378–84. 16 Yahagi N, Fujishiro M, Omata M. Endoscopic submucosal dissection of colorectal lesion. Dig Endosc 2004; 16(Suppl.): S178–81. 17 Fujishiro M, Yahagi N, Kakushima N, et al. Management of bleeding concerning endoscopic submucosal dissection with the flex knife for stomach neoplasm. Dig Endosc 2006; 18(Suppl.): S119–22. 18 Fujishiro M, Yahagi N, Kashimura K, et al. Comparison of various submucosal injection solutions for maintaining mucosal elevation during endoscopic mucosal resection. Endoscopy 2004; 36: 579–83. 19 Yamamoto H, Yube T, Isoda N, et al. A novel method of endoscopic mucosal resection using sodium hyaluronate. Gastrointest Endosc 1999; 50: 251–6. 20 Fujishiro M, Yahagi N, Kashimura K, et al. Different mixtures of sodium hyaluronate and their ability to create submucosal fluid cushions for endoscopic mucosal resection. Endoscopy 2004; 36: 584– 9. 21 Yamamoto H, Yahagi N, Oyama T, et al. Usefulness and safety of 0.4% sodium hyaluronate solution as a submucosal fluid “cushion” in endoscopic resection for gastric neoplasms: a prospective multicenter trial. Gastrointest Endosc 2008; 67: 830– 9. 22 Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal Carcinoma. Tokyo: Kanehara, 1997. 23 Kitajima K, Fujimori T, Fujii S, et al. Correlations between lymph node metastasis and depth of submucosal invasion in submucosal invasive colorectal carcinoma: a Japanese collaborative study. J Gastroenterol 2004; 39: 534– 43. 24 Fujishiro M, Yahagi N, Kashimura K, et al. Outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms in 200 consecutive cases. Clin Gastroenterol Hepatol 2007; 5: 678–83. 25 Fujishiro M, Yahagi N, Kashimura K, et al. Successful nonsurgical management of perforation complicating endoscopic submucosal dissection of gastrointestinal epithelial neoplasms. Endoscopy 2006; 38: 1001–6. 26 Tanaka S, Oka S, Kaneko I, et al. Endoscopic submucosal dissection for colorectal neoplasia: possibility of standardization. Gastrointest Endosc 2007; 66: 100–7. 27 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: 537–42.

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Retrieval of Colonic Polyps Bennett E. Roth UCLA, Los Angeles, CA, USA

Introduction

Small polyps

The detection and removal of colon polyps is the most significant benefit colonoscopy provides toward the reduction of colorectal cancer mortality and morbidity [1]. With current high-definition and magnification technology along with various forms of chromoendoscopy and filtered light technology, many small polyps can be identified during the endoscopic examination as being hyperplastic rather than neoplastic. However, those polyps which are clearly not felt to be “innocent” should be removed and evaluated histologically. These new imaging techniques (Chapters 31, 35, 36, 38, and 39) can often identify which polyps are neoplastic as well as those which may contain malignancy. The endoscopist must have two goals after resection of a polyp; to find and retrieve it while maintaining the integrity of the tissue. The limited published data on polyp retrieval suggests that between 2.1% and 16.5% are not retrieved [2–4]. Difficulties are most often encountered when attempting to retrieve small polyps, those resected from the right colon, those removed by piecemeal techniques, or where there is excessive quantities of stool and/or fluid in the colon. Portions of polyps as well as intact whole specimens may be lost in fluid, lost behind folds, or damaged in the act of retrieval. In an effort to enhance the success rates of polypectomy retrieval, a variety of techniques and devices have been developed. The published literature is limited with regard to comparative studies. The overriding factors determining how polyps are retrieved are size and method of resection. This chapter will discuss retrieval techniques and describe available devices.

There are several options for the removal of small polyps (< 6 mm). For those removed with hot or cold biopsy forceps, the tissue will be embedded within the device cups and is retrieved when the forceps is removed from the colonoscope. It is frequently necessary to obtain several “bites” with the forceps to ensure complete excision. However, when small polyps are removed with either hot or cold snare technique, gravity will sometimes pull them to the dependent colonic wall, a site that may be distal from the polyp site. An advantage of cold snaring is that small polyps need not be “tented” to create an artificial stalk and protect the wall before transection. When tenting is not deployed the polyp is more likely to stay on the polypectomy site after transection. One of the more frustrating experiences for an endoscopist is to have a small polyp drop out of site and not be readily found. This can result from polyps falling behind haustral folds or in fluid reservoirs. It is at times difficult to determine in what direction gravity will take a polyp. A maneuver that will aid in focusing the search for a “lost” polyp is to inject water through the biopsy channel or with the water jet and determine the direction in which it flows. Following the direction taken by the water to the locations where it pools will allow an approximation of the polyp location [3]. Other aids in locating a polyp include changing the patient’s position and retroflexion of the instrument. Small polyps may be recovered in a variety of ways. The most common technique employs suction through the instrumentation channel. If the endoscopist believes the polyp has entered the colonoscope, the assistant should promptly verify its collection in a retrieval trap. Moving the polyp through the colonoscope to the retrieval device is facilitated by suctioning fluid from the colonic lumen through the colonoscope. If no fluid is available, water should be added to the lumen using the water jet. If the water jet is unavailable, the polyp can be cleared from the umbilical cord by suctioning water from a syringe tip inserted into the instrument port on the control head. The in-line retrieval specimen trap will catch the polyp before it travels into the larger suction canister.

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Figure 45.1 (a) Specimen retrieval jarbrotating compartments (EZ EM). (b) Removable trayb(eTrap®, US Endoscopy, Mentor, OH, USA). (c) Removable filter (PolypCatcher-S®, Zeon Medical, Tokyo, Japan).

Several dedicated “specimen trap containers” are available. One has four separate chambers which can be accessed by rotation of the jar (Figure 45.1a). Others have removable plastic trays or filters that can be detached, emptied, and repositioned during the procedure (Figure 45.1b and c), permitting the separation of specimens according to their intracolonic location [5]. If several small polyps are within the same segment of the colon, there is no need for site localization. If polyps are retrieved into a single compartment bottle, they are separated from the fluid by filtering it with a gauze or mesh strainer [6–8]. Another technique for suction retrieval of small polyps utilizes either cotton gauze or plastic mesh placed over the open end of the instrument suction port. By removal of the suction valve cap, the polyp will usually be suctioned through the biopsy port and trapped within the gauze or mesh. Polyps may adhere to the cotton gauze, causing difficulty in removal with resultant tissue damage. It is for this reason that plastic mesh is superior for this technique [9,10]. The polyp may bypass the suction port and travel through the usual channel toward the processor, but placement of an in-line retrieval suction trap will prevent inadvertent entry of tissue into the general suction pool. Suction retrieval of polyps may cause distortion of the tissue hindering accurate histological evaluation. Most colonoscopic suction channels vary in internal diameter from 3.2 to 3.8 mm, but soft polyps (or fragments of a piecemeal resected polyp) up to 1 cm can often be successfully retrieved by suction because of tissue compression. Small firm polyps of 4 mm may not permit suction retrieval because of resistance to distortion. Polyps can be removed during insertion of the instrument or before intubation of the cecum. If medium- to large-sized polyps are severed, specimen retrieval may require that the scope be removed and reinserted. In the case of small polyps retrieved via suctioning, the timing of polyp removal during the procedure is not an issue.

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Another technique for the resection and retrieval of small polyps involves a technique in which the polyp is snared and pulled into the suction channel of the scope. With ongoing suctioning and closure of the snare, the polyp is amputated while remaining within the channel. It can then be suctioned and captured. When this “pull and cut” technique was compared with traditional “cut and leave” methods, resection and retrieval rates were comparable [11]. The d-Snare (Figure 45.2) is a new device which facilitates maintenance of control of small polyps during cold snare resection utilizing suction via the snare sheath during the guillotining of the polyp. Depending upon the size of the polyp, the specimen may remain adherent to the tip of the sheath or could be suctioned into the sheath. If the latter occurs, it may remain within the sheath and can be “flushed” out upon withdrawal or may migrate to the proximal portion and reach a plastic trap that will catch the polyp and permit easy retrieval. If the specimen remains adherent to the sheath tip, the snare and polyp can be removed via the biopsy port with care to

Figure 45.2 d-Snare (US Endoscopy, Mentor, OH, USA).

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detach the rubber stopper prior to full withdrawal of the tip of the snare, lest the polyp fall off the sheath as the rubber aperture closes. This technique is limited to “cold snare” removal but the same concept might be applied to traditional “hot snare” resections.

Large polyps The retrieval of larger polyps (> 6 mm) is dependent upon size, location, and method of resection. For polyps removed by snare resection, the snare may be employed to regrasp the polyp

Figure 45.3 (a–f) Retrieval devices. (Courtesy of Olympus Corporation of America, Boston Scientific/Microvasive, Wilson Cook Medical.)

Retrieval of Colonic Polyps

with subsequent removal of the scope. The assistant must close the snare to maintain sufficient grip on the tissue so as not to lose it during retrieval, but overtightening will transect the polyp. Polyps can also be suctioned into the tip of the instrument channel, but larger polyps will obscure the endoscopist’s vision of the bowel as the scope is withdrawn. Because the diameter of the suction channel varies from 3.2 to 3.8 mm, only a small area of the large polyp will be attracted to the instrument tip. The pull of suction, even if strong, often will not suffice to prevent the polyp from falling off the scope tip as it is withdrawn around a bend or through the multiple angulations of the sigmoid colon. When suctioning polyps less

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than 1.5 cm, a retrieval trap is recommended since they may be aspirated through the channel and into the larger suction pool. When polyps repeatedly dislodge during suction retrieval, the use of an alternate retrieval device is recommended.

Retrieval devices There are a variety of mechanical retrieval devices on the market (Figure 45.3). These include pronged grasping forceps, baskets, and nets. The pronged forceps and baskets are manufactured by several companies and are produced both in single-use and reusable form. The nets, Roth Net® and Spider Net®, which are currently available from two manufacturers, are single-use devices. All of these devices are designed to facilitate the secure, atraumatic removal of polypoid tissue without sacrificing visualization of the remaining colonic mucosa [12]. Many of these devices are used in both the colon and the upper digestive tract for polyp retrieval as well as foreign body removal. The essential rule to follow when using a retrieval device is to be able to securely grasp the polyp while avoiding tissue injury or destruction. Following polyp resection, redeployment of the snare to grasp and retrieve the tissue is the most commonly used maneuver. It is time and cost efficient. However, when retrieving tissue through angulated colons or around folds it is not unusual for polyps to slip out of the grasp of the snare. Furthermore, care must be exercised to avoid transecting the tissue. The snare can be pushed forward to allow sufficient field of view for inspecting the remaining

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mucosa during withdrawal. This same technique is recommended for all mechanical retrieval devices. Grasping forceps are produced in three- and five-pronged versions. The tips of the prongs are curved inward, facilitating a firmer grasp upon the tissue. The grasping forceps are effective for withdrawing polyps 1–1.5 cm in size. However, some difficulty may occur when retrieving these or larger polyps with this method, as a result of insufficient grasping strength. A basket or net provides a more secure hold without risking damage to the tissue. The size of the polyp will determine whether a basket retriever can be used. Basket retrieval devices come in varying designs. They may be helical shaped with several wires, or a simple four strut device. While some baskets open to a 3-cm diameter, the space between struts limits the size of polyp that can be grasped. By gently pressing the forward tip of the basket against the colonic wall, the struts can be bent and separatedapermitting entrapment of larger polyps. However, difficulty may be encountered in retrieving polyps larger than 2 cm. The baskets can be opened and reemployed so as to regrasp several polyps or pieces of a large polyp without removal of the colonoscope. However, care must be taken to avoid dislodging of previously engaged tissue. The Tornado® is a new, retractable, and rotatable wire device that purportedly has the ability to resect and then retrieve polyps with a single tool. The Twister® is a basket device used for retrieving resected polyps. The author has had brief experience with the Twister and found that small polyp fragments were difficult to capture and fell between the struts. In addition, when redeployed for retrieval of several specimens during a “piecemeal polypectomy,” previously

Figure 45.4 Roth Net® Platinum retrieval net. (Courtesy of US Endoscopy, Mentor, OH, USA.)

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retrieved fragments often dislodged and had to be reacquired. There are no published clinical studies demonstrating the efficacy of these two devices. Further clinical experience and reports are awaited. The Roth Net retrieval net has become a popular device for capturing large polyps or the fragments produced during piecemeal polypectomy. The net consists of a braided cotton filament secured around a snare wire housed within a catheter sheath. A new version, in which the wire rim has been modified so that it opens in an octagonal form, facilitates better retention of diameter and shape (Platinum Roth Net®) (Figure 45.4). All the available nets can open to a diameter of 2.5–3.0 cm and can be easily reopened and used to grasp additional polyps or pieces without scope removal. The Platinum Roth Net provides a secure grasp upon the tissue without risk of damage and can retain the specimen beyond the tip of the endoscope during withdrawal, facilitating ongoing inspection of the mucosal surface (Figure 45.5). The Spider Net (Figure 45.6) has a wider mesh design in an effort to theoretically provide better visualization during deployment. When deploying a net, the catheter should be advanced to the site of the resected polyp or fragment. The retrieval procedure is considerably easier when the fragments to be recovered are at the 6 o’clock position in the visual field. The entire colonoscope may have to be rotated to achieve this position. The net should be expanded slowly and placed over the tissue. With slight advancement of the catheter exerting gentle pressure toward the colonic wall while moving the large angulation control downward, the net is slowly closed and the tissue is trapped. If additional tissue is to be captured, the procedure can be repeated without much risk of losing the previous specimen, since the resected tissue adheres well to the net material. Caution must be exercised when redeploying the net, to avoid opening it in the opposite direction, reverting the net, and forcing the first specimen(s) out [13].

Figure 45.5 Polyp in net.

Retrieval of Colonic Polyps

Figure 45.6 Spider Net®. (Courtesy of ConMed Endoscopic, Billerica, MA, USA.)

Following withdrawal of the colonoscope and net contents, the net is fully opened and the tissue removed. A variation of the Nakao device (Figure 45.7) is a combination polypectomy snare and retrieval net. This double lumen instrument permits resection of a polyp and subsequent deployment of a retrieval net without removal of the catheter. It is twin handled and has a catheter diameter of 3 mm. Therefore, if used when removing polyps from the upper digestive tract, a large channel scope must be employed [14]. This device can be useful for resection of a single polyp since the captured polyp in the extended net interferes with vision for subsequent snare positioning.

Figure 45.7 Nakao Snare®. (Courtesy of ConMed Endoscopic, Billerica, MA, USA.)

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Summary Histological tissue identification is key to the determination of the significance of polyps and their relationship to the development of colorectal cancer. It is currently the only accurate method for classification of polyps as to the presence of malignancy or premalignant cellularity warranting appropriate follow-up procedures. It is therefore vital for the endoscopist to retrieve all resected specimens for subsequent histological evaluation. Several retrieval methods are described.

References 1 Winawer, SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594–642. 2 Nakao N. Combined cautery and retrieval snares for gastrointestinal polypectomy. Gastrointest Endosc 1996; 44: 602–5. 3 Waye JD, Lewis BS, Atchinson MA, Talbott M. The lost polyp: a guide to retrieval during colonoscopy. Int J Colorectal Dis 1988; 3: 229–31.

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4 Webb WA, McDaniel L, Jones L. Experience with 1,000 colonoscopic polypectomies. Ann Surg 1985; 201: 626–32. 5 Sano Y, Tsukasa K, Ito H, et al. A novel endoscopic device for retrieval of polyps resected from the colon and rectum. Gastrointest Endosc 2004; 59: 716–18. 6 Black HM, Schecter S, Thornton S, et al. Simple method for polyp retrieval during colonoscopy. Dis Colon Rectum 1994; 37: 949. 7 Nilson JW, Gottesman L. A suction retriever to expedite recovery of colonic polyps. Dis Colon Rectum 1987; 30: 644–6. 8 Simon T, Goldberg RI. Rapid retrieval of small resected polyps. Gastrointest Endosc 1997; 46: 472. 9 Khanduja KS, Pons R. Efficient technique for retrieving small polyps from the colon and rectum. Dis Colon Rectum 1994; 37: 190. 10 Massuck DD, Khanduja KS. Revised technique for retrieving small polyps from the colon and rectum after snare polypectomy. Dis Colon Rectum 1999; 42: 543. 11 Deenadayalu VP, Rex DK Colon polyp retrieval after cold snaring. Gastrointest Endosc 2005; 62: 253– 6. 12 Nelson DB, Bosco JJ, Curtis WD, et al. Endoscopic retrieval devices. Gastrointest Endosc 1999; 50: 932. 13 Miller K, Waye JD. Polyp retrieval after colonoscopic polypectomy: Use of the Roth Retrieval Net. Gastrointest Endosc 2001; 54: 505. 14 Nakao NL. Combined cautery and retrieval snares for gastrointestinal polypectomy. Gastointest Endosc 1996; 4: 602–5.

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Magnetic Imaging for Colonoscopy Brian P. Saunders1, Syed G. Shah2 & Christopher B. Williams1 1

St Mark’s Hospital, London, UK Pinderfields General Hospital, Wakefield, UK

2

Introduction “Seeing is believing” is a saying pertinent to the colonoscopist. The amazingly detailed views obtained during video colonoscopy have dramatically improved our understanding and management of many colonic diseases. Understandably, much emphasis has been placed on the development of fiberoptic and video color images for identifying and accurately documenting colonic pathology. However, it is surprising that it has taken until the twenty-first century to develop an effective method to image and guide endoscope insertion through the often tortuous intestine. Three-dimensional magnetic endoscope imaging, now commercially available as “ScopeGuide” (Olympus Corporation, Tokyo, Japan), for the first time provides computer-generated real-time, threedimensional views of the colonoscope shaft during insertion and imparts a new understanding for the endoscopist of the procedure and all its attendant difficulties. It does not make a difficult colonoscopy immediately easy, and is no substitute for good technique, but it does show the exact problem encountered and gives the endoscopist a new insight into the likely maneuvers for straightening the endoscope and ensuring total colonoscopy.

on the endoscopist, who must provide a complete, safe, and accurate examination. Expert centers for colonoscopy report completion rates (corrected to exclude obstructing lesions and failed bowel preparation) of 97–99%, with very few, if any, complications from routine insertion. However, less skilled endoscopists fare considerably worse, and an audit from the British Society of Gastroenterology of over 9000 procedures has shown cecal intubation rates of just 55–77%, with perforation rates of 1 in 800 procedures [2]. These results are unlikely to be a British phenomenon in isolation and are probably representative of “average” practices throughout the world. Even experienced colonoscopists find the procedure technically difficult in 10% of patients [3]. The most common cause of difficulty is recurrent shaft looping within a long and mobile colon [4]. Without imaging, the correct maneuver to straighten the colonoscope must be reached by instinctive feel and, essentially, trial and error. This can make colonoscopy time-consuming and uncomfortable for the patient, and result in a need for heavy sedation. Imaging of the colonoscope tip is also important in order to confirm the anatomic location of lesions encountered and document successful cecal intubation [5].

Colonic anatomy The need for imaging Colonoscopy is established as the procedure of choice for investigating patients with colonic symptoms, and for screening patients considered at high risk for colorectal cancer. In recent years it has also emerged as the preferred method for population screening with recommendations for a colonoscopy every 10 years from age 50 [1]. This imparts a burgeoning colonoscopic workload and imposes a heavy duty of care

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

To understand why colonoscopy can be so difficult, and why it is helpful to be able to see the shaft configuration during insertion, it is important to have an understanding of colonic anatomy and mesenteric attachments. The human colon varies considerably in length between approximately 68 and 159 cm, as measured at laparotomy [6], but under computed tomographic colonography, total colonic lengths of 2.5 m have been recorded [7]. Usually the sigmoid and transverse colon are free on mesocolons and therefore can be greatly increased or decreased in length and mobility according to manipulations of the colonoscope. Most looping during colonoscope insertion is therefore seen within these free segments. Looping of the transverse colon deep into the pelvis is more common in female patients who appear to have a

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longer transverse segment than men [8]. The descending and ascending colons are usually located in a relatively fixed position along left and right paravertebral gutters; however, in 8% of Western patients, the descending colon remains mobile on a persisting descending mesocolon and, in 20%, the splenic flexure is also particularly mobile, thus predisposing to atypical (counterclockwise) colonoscope looping in the left colon [6]. Approximately 17% of patients attending for colonoscopy will have adhesions in the sigmoid colon producing a fixed pelvic loop [6], as may result from diverticulitis or pelvic surgery.

Difficult colonoscopy Several studies have examined the specific causes of difficulty during colonoscopy. One study included 500 patients in whom fluoroscopic imaging was used during colonoscopy performed by expert endoscopists [3]. A difficult examination (defined as no advancement of the colonoscope tip for at least 5 min) was observed in 16% of cases; this was as a result of recurrent looping in the majority of patients (80%), and sigmoid adhesions in the remainder. Endoscopists were frequently incorrect in identifying the site of looping and were mistaken in their assessment as to whether the tip of the colonoscope was in the proximal sigmoid colon or splenic flexure in 30% of patients. Another study assessed barium enema films of patients in whom colonoscopy was considered to have been technically difficult and found that difficulty correlated with the presence of a long transverse colon or sigmoid colon adhesions [8]. Either of these factors may explain why the percentage in whom colonoscopy was considered to be difficult was greater in women than in men (31% vs. 16%) [8]. Other studies identified gender as a major factor in colonoscopy difficulty [9,10]. Slim female patients were particularly difficult to perform colonoscopy on. In the same study, older female patients with diverticular disease (adhesions producing a fixed sigmoid colon) and constipated male patients (long redundant colon) were also groups identified as being technically difficult to colonoscope. A more recent study comparing computed tomographic colonography data on patients with a failed colonoscopy with those with a successful colonoscopy showed that the “difficult to colonoscope” group generally had longer colons, particularly in the sigmoid and transverse colon, had more acute bends, and were more likely to be female [7].

Colonoscope imaging Fluoroscopy The early pioneers of colonoscopy understood the advantages of being able to visualize the procedure for identification of the anatomic location of the colonoscope tip, correction of loops, and documentation of total colonoscopy, and so routinely

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performed colonoscopy in the X-ray suite to benefit from fluoroscopy [11]. With the expansion of endoscopy services in the 1970s and 80s, dedicated endoscopy units were developed, often without access to fluoroscopy. By this time, colonoscopists had gained experience of the technique, and some considered imaging as only of benefit in the learning phase [12]. Today’s new generation of colonoscopists have developed their skills without fluoroscopy and, therefore, are largely unaware of its potential advantages, particularly in the 10– 20% of patients in whom recurrent looping occurs and the endoscopist becomes effectively “lost.” That said, fluoroscopy as an imaging technique for colonoscopy is fundamentally flawed. Fluoroscopy equipment is expensive, as is the initial financial outlay to lead line an endoscopy room. The fluoroscopic views are two-dimensional, fleeting, and localized, showing only a portion of the abdomen at any one time. There is also the radiation risk, necessitating staff to wear cumbersome, protective clothing.

Magnetic imaging In view of the problems associated with the use of fluoroscopy, a nonradiographic real-time method of colonoscope imaging was sought by two independent groups of UK-based researchers [13,14]. Both groups considered several approaches, eventually developing similar systems in 1993 based on the principles of magnetic field position sensing.

Prototype imaging systems and the principles of magnetic imaging The basic principle of three-dimensional magnetic imaging operates by determining the position and orientation of discrete points along the colonoscope and using this information to produce an image of the colonoscope configuration on the display monitor (Figure 46.1) [15]. In the first working prototype, three transmitter coil assemblies, each containing three coils, were situated below the patient and sequentially produced pulsed (at low frequency, 10 kHz, and low strength) magnetic fields external to the patient. The low-strength fields (about 1 × 10 −6 that of the energy of a magnetic resonance imaging scan) ensured safety [15]. The first prototype had miniature receiver coils mounted within a catheter inserted down the instrument channel of the endoscope, which responded to each magnetic pulse with an electrical current proportional to the distance from the transmitter coil. Software determined the three-dimensional position (x, y, and z axes) and orientation of each receiver coil. With the position of the receiver coils calculated, a smooth curve could be fitted through each of the individual data points by a computer graphics program incorporating the mechanical characteristics of the colonoscope tip and shaft. A computer-rendered three-dimensional image of colonoscope shaft configuration was then displayed on the monitor. The positional data from each of the receiver coils was updated every 0.2 s, generating a real-time moving display.

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Monitor Receiver coils in dish Receiver coils detect the magnetic fields generated by transmission coils in the endoscope Magnetic fields

Endoscope with transmission coils Transmission coils generate multiple magnetic fields, each activated at different frequency

Main ScopeGuide unit (high-speed CPU) Real-time endoscope display is computed from the received multifrequency magnetic fields

Patient couch

Figure 46.1 Diagrammatic representation of the Olympus ScopeGuide three-dimensional magnetic imager. Nineteen transmitter coils built in along the endoscope are pulsed several times a second, each at a different frequency, producing low-voltage magnetic fields. Small currents induced in 16 receiver coils in the main unit dish are then used to calculate the position and orientation in space of each transmitter coil. The information is rendered to produce real-time three-dimensional views of scope configuration on the monitorb switchable to either anteroposterior (AP) or combined AP and lateral view.

Figure 46.3 Simplified ScopeGuide monitor screen with patient position icon and indications of anterior/posterior indicators on the lateral view.

The same basic principles apply to current commercialized models, as will be explained below, although they function at even lower power and with modifications to avoiding potential interference from adjacent metal structures.

Imager display The representation of the colonoscope shaft on the computer monitor is rendered three-dimensional by using differential grayscale shading, with those parts of the shaft furthest from the viewer being darker than those that are nearer. The image display may be presented in anteroposterior view, lateral view,

Figure 46.4 Assistant hand-coil. Locates abdominal pressure point precisely.

or a split-screen combination of both anteroposterior and lateral to aid in loop recognition (Figures 46.2 and 46.3).

Hand marker Unlike fluoroscopy, in which the effects of abdominal hand compression are difficult to assess because of the necessity of wearing heavy lead protective gloves, the position of the endoscopy assistant’s hand and its effect on any loop in the colonoscope shaft can be demonstrated easily using an additional external coil held in the assistant’s hand (Figure 46.4). The position of the assistant’s hand in relation to any loop that may have formed is displayed on screen. The hand marker moves in real-time as the hand is positioned and pressure applied, preferably viewing in split screen for maximum accuracy of placement. Figure 46.2 Early Olympus prototype magnetic imager (2000). Anteroposterior view of “reversed alpha” (counterclockwise spiral) loop in the sigmoid colon.

ScopeGuide Since 1995, the magnetic imaging system has undergone further revision and continuing development. A number

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Split-screen button shows AP + Lateral views (when using hand pressure) V.ANGLE/SELECT MENU

RESET

Figure 46.5 An Olympus variable-stiffness/imager colonoscope. Note the additional umbilical needed to connect with ScopeGuide main unit.

of key refinements resulted in improved image representation and overall functionality, culminating in the launch of ScopeGuide in 2002, the only commercialized version of threedimensional magnetic imaging. ScopeGuide is a portable, stand-alone unit, positioned alongside the patient couch, which has a single connection to either a dedicated colonoscope with in-built coils or a coil catheter introduced down the biopsy channel. Generation of magnetic fields has been reversed in ScopeGuide so that the endoscope coils act as transmitters and the receiver coils are situated within the dish, positioned opposite the patient’s abdomen (see Figure 46.1). The advantage of reversing the position of the field transmitters and receiver coils is that it allows catheters or endoscopes of varying design (number and spacing of coils) to be used interchangeably with existing imaging software. The transmitter coils are a series of 19 wire coils 2 mm in diameter mounted at fixed intervals along a flexible catheter built into the insertion tube. The spaces between the coils are filled with silicone so that the catheter is both flexible and less susceptible to damage from the bending forces applied to the colonoscope insertion tube. The use of dedicated instruments with in-built coils (Figure 46.5) frees the instrumentation channel and improves the ability to aspirate air or fluid, a problem with catheter use unless a twin- or large-channel instrument (3.7 mm diameter or more) is used. Because of their water flushing channel, 100 series Olympus imager colonoscopes are significantly bulkier than 200 series ones, and currently it is not possible to incorporate imager coils into slimmer pediatric instruments. The magnetic fields, sequentially generated at different frequencies, are detected by an array of 16 receiver coils in the large dish placed adjacent to the patient. As with earlier prototype imaging systems, the resultant electrical signal induced within each of the receiver coils is digitized, filtered to remove signal noise, amplified, and then fed to a computer

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Figure 46.6 ScopeGuide control panel. The “angle select” lateral switches are used to maintain correct views when the patient changes position.

processor, which calculates the precise three-dimensional position and orientation of each transmitter coil, as described earlier. This information is then used, with a very short delay, to generate and display a three-dimensional computer rendering of the scope configuration. The underlying mathematical formula is shown in the appendix to the chapter, which illustrates some of the complexity involved. During colonoscope insertion (and withdrawal), patient position change is a crucial ancillary maneuver. With early prototypes of the imaging system, three anatomic markers had to be reset each time the patient moved position, to maintain a true anteroposterior view at all times of the procedure, or this could be achieved regardless of patient position by using a belt containing three additional marker coils, which moved with the patient. However in clinical practice, only four patient positions are used during colonoscopy (left lateral, supine, right lateral, and prone) so an easier option, which avoids the use of the patient marker plate, is to have four preset patient positions identified by the system and selected by a button on the ScopeGuide unit control panel (Figure 46.6). Thus, a simple push of a button is necessary each time the patient changes position but, once the endoscopist and nursing assistants become familiar with it, this becomes an easy and automatic response, adjusting the system with each position change.

Impact of magnetic imaging on colonoscopy practice After publication of the prototype imaging systems in 1993 [13,14], the results of the first clinical trials of magnetic endoscope imaging were reported in 1995 [14,15]. The prototype imaging system was shown to accurately display the entire configuration of the colonoscope in three dimensions, correlating closely with fluoroscopic images taken simultaneously.

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Since these early reports, considerable experience has been gained using ScopeGuide. The authors have personal experience of using it in over 15 000 cases, and continue to develop understanding and better control of the complex variety of colonoscopic configurations that can be encountered.

Understanding looping An audit of 100 consecutive colonoscopy cases performed by expert colonoscopists blinded to the magnetic imager view documented the range of looping configurations that occur during routine practice [16]. Typical and atypical loops were encountered and were described using new terminology to indicate the looping state and likely straightening maneuvers. Despite application of the general principles of good insertion technique, loops occurred in most patients, and in the sigmoid colon arose in 79% of patients. The overall frequency of looping was similar in male and female patients, although atypical loops were more common in women. Without reference to the magnetic imager, loops were incorrectly diagnosed in 69% of cases, and unusual loops such as the counterclockwise spiral loops (reverse splenic flexure, reverse alpha loop) and transverse gamma loop were always incorrectly diagnosed. Complete colonoscopy was always achieved in this series but in 6% of cases the full 160 cm of the colonoscope was inserted to push through an uncontrollable loop prior to endoscope straightening. In the majority of cases, however, with good technique and frequent loop straightening, less than 100 cm was inserted at any one time. Abdominal compression, when applied, was generally inaccurate, as a result of either hand misplacement away from the apex of the loop or inaccessibility of the loop deep within the abdomen. In a separate study, pain episodes were documented, corresponding directly with looping seen on magnetic imaging [17]. Looping in the sigmoid colon was most painful, particularly in female patients.

Accuracy of tip location The imaging system accurately locates the colonoscope tip to aid in lesion recognition and cecal intubation. Comparison of contrast studies following imager-guided application of endoclips in predefined anatomic locations during insertion showed good correlation between imager-defined and actual anatomic clip locations [18]. Pilot studies from India, China, and Switzerland have also confirmed that ScopeGuide provides good anatomic location of lesions [19–21]. Imager snapshot views with corresponding endoscopic photos (with or without endoscopic tattooing) represent a convenient method of documenting the location of colonic pathology to guide future endoscopic examinations or surgical intervention.

Colonoscopy performance A series of randomized studies assessing the impact of magnetic imaging on colonoscopy performance have now been published. An early study of 55 consecutive patients under-

Figure 46.7 Prototype split-screen view of a typical sigmoid loop. The hand-coil marker (blue sphere) allows precise location of assistant hand pressure (when required).

going colonoscopy by a single experienced endoscopist (1000 previous cases), with or without the prototype imager view, showed a reduction in the number of straightening attempts when the colonoscope shaft was looped, but without a corresponding decrease in the duration of loop formation or time taken to reach the cecal pole [22]. Abdominal hand compression was significantly improved when the endoscopist and endoscopy assistant were able to visualize the imager view, the lateral view giving increased information as to the depth of looping and correct site for application of assistant hand compression (Figure 46.7). The effect of magnetic imaging was assessed on the colonoscopy performance of a trainee (200 previous cases) and two expert endoscopists (> 5000 previous cases) [23]. Significant improvements in cecal completion rate, insertion time, duration of colonoscope looping, number of straightening attempts, and accuracy of hand pressure were seen with the imaging system when used by the trainee. Similar, although less marked, benefits were recorded with the expert endoscopists, who found that the imaging system dramatically shortened insertion times in technically difficult cases. No differences were seen in patient pain scores or sedation requirements, a finding that is not surprising given the universally low pain scores in the study despite only low-dose sedation given, usually as bolus medication at the start of the procedure. Other studies have shown conflicting results. A randomized study (n = 419) from Norway [24] confirmed improved cecal intubation rates and lower pain scores when ScopeGuide was used by moderately skilled colonoscopists (cecal intubation improved from 74% to 90%). However, no improvements were seen when experienced Chinese endoscopists used the system [19]. In a separate study assessing the impact of magnetic imaging on sedation requirements and utilizing a patient-controlled analgesia

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system, no improvement in sedation requirements was seen with imaging to aid insertion, despite an objective improvement in loop handling [25].

ScopeGuide and variable-stiffness colonoscopes Variable-stiffness colonoscopes have recently been introduced, which allow the endoscopist to change the shaft characteristics of the colonoscope at any time during insertion. This potentially allows easier passage through a fixed sigmoid colon, utilizing the pediatric flexible mode, but an enhanced ability to prevent recurrent looping by increasing shaft stiffness after straightening. Precise utilization of the variable-stiffness function is difficult to ascertain during insertion, and its use is often by “best guess” or trial and error. Two studies have assessed the impact of ScopeGuide on use of the variable-stiffness colonoscope [26]. In the first, magnetic imaging was used to evaluate the success of scope insertion during back-to-back proximal colon randomized insertions with and without the colonoscope maximally stiffened. Stiffening resulted in a more rapid proximal colon insertion, particularly around the splenic flexure, with less recourse to ancillary maneuvers such as hand pressure or position change. In the second study, an experienced endoscopist was randomized to perform consecutive examinations with a variable-stiffness scope, with or without the benefit of the imager view. Not surprisingly, effective use of the variable-stiffness function was significantly more likely when the imager could be seen. New Olympus colonoscopes now combine the variable-stiffness function with in-built imager electronics. These instruments appear to have major advantages over conventional colonoscopes, making management of looping and endoscope characteristics logical and predictable in most cases, and particularly so in longer colons.

Magnetic imaging and colonoscopy training Colonoscopy training has changed little in the last 30 years and still relies heavily on an apprenticeship scheme in which an experienced colonoscopist hands down the “tricks of the trade” to the inexperienced trainee. Training is highly frustrating and unsatisfactory for all parties concerned. For the trainee, it is difficult to appreciate why certain maneuvers are apparently beneficial. For the trainer, it is hard to assess why the trainee is stuck unless the scope is taken over by the trainer and manipulated appropriately, by which time the teaching opportunity has often been lost. Magnetic imaging may address many of these frustrations by allowing a structured interaction between trainer and trainee, allowing the trainee to complete cases under supervision that previously the trainer would have needed to take over, thus accelerating the trainee’s learning curve and acquisition of hand skills. In an initial pilot study, a single beginner colonoscopist (only 15 previous colonoscopies) performed procedures under supervision with examinations randomized to either with or without the imaging system [27]. Benefits in terms of loop management were seen with the imaging system in the

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Figure 46.8 Still from the trainee assessment tri-split video recording (ScopeGuide magnetic imager view and synchronous external and endoscopic videos).

initial stages of training, with a plateau detected at approximately 50 cases, when a 90% completion rate to the cecum was seen. Thereafter, no demonstrable difference was seen comparing cases with or without the imager, suggesting that magnetic imaging is particularly valuable early on in the learning curve. Further work is required to define the longerterm impact on skill acquisition. The recently upgraded Olympus computer training simulator now incorporates a “virtual ScopeGuide” function so that basic hand skills and loop recognition can be taught simultaneously, laying the foundations for hands-on training with the imager in live cases. Performance assessment utilizing expert review to give a specific score from tri-split video recordings combining external and endoscopic video with magnetic imaging may prove a robust tool for ensuring standards and charting trainees’ progress [28] (Figure 46.8). In the UK, formal accreditation to perform bowel cancer screening colonoscopy is now in place involving a hands-on, competency-based assessment. Expert examiners assess applicants’ ability to recognize and manage looping during insertion utilizing the ScopeGuide system.

Tips on using ScopeGuide Although ScopeGuide has eventually “caught on” in the UK and is increasingly popular around Europe (in Denmark especially, where the use of fluoroscopy had previously been the norm for colonoscopy), many other countries have little or no experience of the system. The reasons for this are unclear but may be because of the limited clinical data showing its benefit, a perception that it is not needed, or financial constraints. Endoscopists using ScopeGuide for the first time are often overwhelmed by the additional information it provides, and find interpretation of the real-time image difficult and

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Figure 46.9 Lateral ScopeGuide view of this sigmoid loop shows up preliminary spiral configuration, and the logic of pushing in up the descending colon.

distracting. To become comfortable with the system probably takes more than 100 procedures, and endoscopists must be patient and learn how to use it. The system also does not remove the need for good hand skills and will not suddenly make a difficult case easy. A long and mobile colon will still be difficult to examine but imaging allows precise decisions to be made on the timing of loop withdrawal, application of hand pressure, use of position changes, and accurate utilization of the variable-stiffness function. After nearly 5000 cases using ScopeGuide, the principal author has gleaned the following, hopefully useful, tips related to its use for the difficult colonoscopy: • A large sigmoid “N” spiral loop can rarely be straightened successfully until the tip of the colonoscope is secured in the descending colon. • Accurate assessment of hand pressure location requires simultaneous visualization in anteroposterior and lateral ScopeGuide views (see Figure 46.7). Hand pressure away from the maximum point of looping will be ineffective, so the time spent positioning the hand accurately is essential. Nursing staff enjoy this ability to interact directly in the procedure and see why they are making a difference. • Beneficial spiral looping in the sigmoid colon is often better seen in lateral view (on ScopeGuide split screen), encouraging the endoscopist to progress further up the descending colon before attempting to straighten (Figure 46.9). • Using the split screen (anteroposterior and lateral views) at other times shows up any relooping of the straightened sigmoid at an early stage, allowing better control. • When a long and acute N spiral loop is encountered with difficult passage into the descending colon, withdrawal to the distal sigmoid with a change in patient position to the right

Magnetic Imaging for Colonoscopy

lateral and then inward push with counterclockwise torque tend to manipulate a long sigmoid into a favorable alpha spiral loop. This then allows easy scope passage to the splenic flexure, where the alpha loop can be de-rotated and the scope rapidly straightened. • If a transverse gamma loop appears to be forming, immediate withdrawal to the splenic flexure with application of suction shortens the transverse. Then inward push combined with counterclockwise torque and imager-directed transverse abdominal pressure may allow straighter passage across the transverse, or the formation of a deep transverse loop which is then easily straightened at the hepatic flexure. • Difficulty in passing the sigmoid–descending junction or splenic flexure is nearly always made easier by a position change to the supine or right lateral position. • Reducing large loops on occasions requires withdrawing 60–80 cm of colonoscope accompanied by shaft torque of more than 180° of rotation. During this vigorous rotation, torque may sometimes need to be maintained by the assistant to allow the right hand of the colonoscopist to be repositioned. • At very acute bends, where the view is partially lost due to close apposition of the endoscope tip to the mucosa, reference to the ScopeGuide view can help predict the likely direction of the bend, based on knowledge of the scope tip location (for instance, steering in a medial direction when passing an acute splenic flexure). • Recognition that the scope tip has just passed the mid transverse colon allows rapid withdrawal and air aspiration to shorten the transverse and allow easy (straight) passage to the hepatic flexure, often without further push insertion if the splenic flexure is sufficiently mobile.

Future developments At this point in time, it is not clear whether ScopeGuide will be adopted as standard for colonoscopy practice or will simply be confined to teaching units. Much will depend on making the system more user-friendly and on further clinical evaluation, particularly in the 10% or so of patients on whom it is difficult to perform colonoscopy. For teaching, there is no doubt that the system is beneficial, and if a new generation of colonoscopists become familiar with its use at an early stage, it seems likely that it will gain wider acceptance. Quality assessments are becoming mandatory in many areas of clinical practice, and the use of ScopeGuide will help to demonstrate exemplary practice. The current ScopeGuide system does not allow documentation and routine recording of all cases, other than from video output. It should be possible to incorporate imager snapshots into standard endoscopy reports, ideally through the press of a button on the scope head, in the same way that endoscopic views are captured to help document pathologic findings or cecal landmarks. Alternatively, incorporating the imager screen view “screen in screen” onto

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Figure 46.10 Commercialized ScopeGuide magnetic imager (2002). Receiver dish placed alongside the patient couch.

the main video screen would allow simultaneous capture of imager and endoscopic views. Planned new versions of ScopeGuide will use a simple patient graphic to represent the four standard patient positions rather than the current arrow icons, with simplified split-screen layout (Figure 46.10). Another advantage in terms of modern suite design and functionality would be to radically change the current standalone ScopeGuide unit using a separate pendant-mounted receiver dish or by incorporating the receiver coils into or on the patient cart with electrical functions operated from the endoscope head. A simple and potentially important future improvement could be to increase the degree of stiffness that can be imparted to the shaft of new-generation variablestiffness ScopeGuide compatible instruments. The ability to see that the colonoscope shaft is straight will mean that the increased stiffening function can be applied entirely safely. Data from ScopeGuide may also help in future colonoscope design with the development of semiautomatic instruments which self-adapt when looping occurs.

Conclusions Three-dimensional magnetic imaging of colonoscopy in the form of ScopeGuide provides the endoscopist with important information which, if accurately interpreted, has the potential to improve many aspects of the procedure. With minor software changes and further clinical evaluation, it can become more widely accepted as an essential training tool and also as an aid to insertion in routine clinical practice, especially for patients known, or likely, to have long colons that are liable to complex looping during intubation. In the authors’ opinion it represents an important step toward the ultimate goal of safe, painless, and complete colonoscopy.

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1 Rex DK. Rationale for colonoscopy screening and estimated effectiveness in clinical practice. Gastrointest Endosc Clin N Am 2002; 12: 65–75. 2 Bowles CJ, Leicester R, Romaya C, Swarbrick E, Williams CB, Epstein O. A prospective study of colonoscopy practice in the UK today: are we adequately prepared for national colorectal cancer screening tomorrow? Gut 2004; 53: 277– 83. 3 Williams CB, Macrae FA, Bartram CI. A prospective study of diagnostic methods in polyp follow-up. Endoscopy 1982; 14: 74. 4 Saunders BP, Macrae FA, Williams CB. What makes colonoscopy difficult? Gut 1993; 34: T179. 5 Hancock JH, Talbot RW. Accuracy of colonoscopy in localisation of colorectal cancer. Int J Colorectal Dis 1995; 10: 140. 6 Saunders BP, Phillips RK, Williams CB. Intraoperative measurement of colonic anatomy and attachments with relevance to colonoscopy. Br J Surg 1995; 82: 1491. 7 Hanson ME, Pickhardt PJ, Kim DH, Pfau PR. Anatomic factors predictive of incomplete colonoscopy based on findings at CT colonography. AJR Am J Roentgenol 2007; 189: 774–9. 8 Saunders BP, Halligan S, Jobling C, et al. Can barium enema indicate when colonoscopy will be difficult? Clin Radiol 1995; 50: 318. 9 Anderson JC, Messina CR, Cohn W, et al. Factors predictive of difficult colonoscopy. Gastrointest Endosc 2001; 54: 558–62. 10 Saunders BP, Fukumoto M, Halligan S, et al. Why is colonoscopy more difficult in women? Gastrointest Endosc 1996; 43: 124. 11 Rogers BH. Colonoscopy with fluoroscopy. Gastrointest Endosc 1990; 36: 71. 12 Waye JD. Colonoscopy without fluoroscopy. Gastrointest Endosc 1990; 36: 72. 13 Bladen JS, Anderson AP, Bell GD, Heatley DJ. Non-radiological technique for three-dimensional imaging of endoscopes. Lancet 1993; 341: 719. 14 Williams CB, Guy C, Gillies DF, Saunders B. Electronic threedimensional imaging of intestinal endoscopy. Lancet 1993; 341: 724. 15 Bladen JS, Anderson AP, Bell GD, Heatley DJ. A non-radiological technique for the real-time imaging of endoscopes in 3 dimensions. Conference record of the 1993 IEEE Nuclear Science Symposium and Medical Imaging Conference, 1891–4. 16 Shah SG, Saunders BP, Brooker JC, Williams CB. Magnetic imaging of colonoscopy: An audit of looping, accuracy and ancillary manoeuvres. Gastrointest Endosc 2000; 52: 1. 17 Shah SG, Brooker JC, Thapar C, Williams CB, Saunders BP. Patient pain during colonoscopyaan analysis using real-time magnetic endoscope imaging. Endoscopy 2002; 34: 435–40. 18 Shah SG, Pearson HJ, Moss S, Kweka E, Jalal PK, Saunders BP. Magnetic endoscope imagingaa new technique for localizing colonic lesions. Endoscopy 2002; 34: 900– 4. 19 Cheung HY, Chung CC, Kwok SY, Tsang WW, Li MK. Improvement in colonoscopy performance with adjunctive magnetic endoscope imaging: a randomized controlled trial. Endoscopy 2006; 38: 214–17. 20 Ambardar S, Arnell TD, Whelan RL, Nihalani A, Forde KA. A preliminary prospective study of the usefulness of a magnetic endoscope locating device during colonoscopy. Surg Endosc 2005; 19: 897–901.

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21 Wehrmann K, Frühmorgen P. Evaluation of a new three-dimensional magnetic imaging system for use during colonoscopy. Endoscopy 2002; 34: 905– 8. 22 Saunders BP, Bell GD, Williams CB, et al. First clinical results with a real time, electronic imager as an aid to colonoscopy. Gut 1995; 36: 913. 23 Shah SG, Brooker JC, Williams CB, et al. Effect of magnetic endoscope imaging on colonoscopy performance: A randomised controlled trial. Lancet 2000; 356: 1718. 24 Hoff G, Bretthauer M, Dahler S, et al. Improvement in cecal intubation rate and pain reduction by using 3-dimensional magnetic imaging for unsedated colonoscopy: a randomized trial of patients referred for colonoscopy. Scand J Gastroenterol 2007; 42: 885–9. 25 Shah SG, Brooker JC, Thapar C, et al. Effect of magnetic endoscope imaging on patient tolerance and sedation requirements during colonoscopy: A randomized controlled trial. Gastrointest Endosc 2002; 55: 832. 26 Shah SG, Brooker JC, Williams CB, et al. The variable stiffness colonoscope: Assessment of efficacy by magnetic endoscope imaging. Gastrointest Endosc 2002; 56: 195. 27 Shah SG, Lockett M, Thomas-Gibson S, et al. Effect of magnetic endoscope imaging (MEI) on acquisition of colonoscopy skills. Gut 2002; 50(Suppl. 2): A41. 28 Shah SG, Thomas-Gibson S, Brooker JC, et al. Use of video and magnetic endoscope imaging for rating competence at colonoscopy: validation of a measurement tool. Gastrointest Endosc 2002; 56: 568–73.

Magnetic Imaging for Colonoscopy

Appendix The signal detected by a receiver coil is calculated by a complicated formula derived from the Biot–Savart law. ⎡2(x d − x g)2 − ( y d − y g)2 − (z d − z g)2 ⎡V x ⎤ ⎢V ⎥ = k t ⎢ 3(x d − x g)( y d − y g) ⎢ y ⎥ r5 ⎢ V 3(x d − x g) ⎢ ⎣⎢ z ⎦⎥ ⎣ 3( y d − y g)(x d − x g) 2( y d − y g)2 − (z d − z g)2 − (x d − x g)2 3( y d − y g)(z d − z g) ⎤ ⎡g x ⎤ 3(z d − z g)(x d − x g) ⎥ ⎢g ⎥ 3(z d − z g)( y d − y g) ⎥⎢ y⎥ 2 2 2 2(z d − z g) − (x d − x g) − ( y d − y g) ⎥⎦ ⎢⎣ g z ⎥⎦ where: Vx Vy Vz is the signal detected at receiver coil; xd yd zd is the three-dimensional position of receiver coil; xg yg zg is the three-dimensional position of transmitter coil; gs gy gz is direction of transmitter coil; r = (x d − x g )2 + ( yd − y g )2 + (z d − z g )2 is the distance between the transmitter coil and receiver coil; and

Further reading Brown GJ, Saunders BP. Advances in colonic imaging: technical improvements in colonoscopy. Eur J Gastroenterol Hepatol 2005; 17: 785– 92. Shah SG, Saunders BP. Aids to insertion: magnetic imaging, variable stiffness, and overtubes. Gastrointest Endosc Clin N Am 2005; 15: 673– 86.

kt = −

ωμπa 2d N d I maxa 2gN g 4

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Colonoscopy and Severe Hematochezia Dennis A. Jensen & Gustavo A. Machicado UCLA School of Medicine, Los Angeles, CA, USA

Introduction Bleeding from any lesion below the ligament of Treitz is defined as lower gastrointestinal bleeding. Fortunately, bleeding from the small bowel between the ligament of Treitz and the terminal ileum is infrequent. The term applied to the passage of bright-red blood or maroon-colored stool, with or without clots, per rectum is hematochezia. We prefer to use the clinical term severe hematochezia rather than lower gastrointestinal bleeding. That is because the latter term assumes that all patients with severe hematochezia have lower gastrointestinal bleeding sites, which is incorrect because 15–20% of patients with severe hematochezia have upper gastrointestinal sources of bleeding [1,2]. Most often hematochezia is low grade and self-limited and does not require hospitalization or urgent intervention. Such patients can be managed in an outpatient setting. A smaller group of patients experience severe hematochezia and require hospitalization because of the volume of blood loss or symptoms of severe anemia or comorbidity [1,2]. In addition, another group of severely ill patients develop severe hematochezia while already hospitalized for other medical or surgical conditions (e.g., inpatient hematochezia). The last two groups require a systematic and expeditious approach to their resuscitation, preparation for colonoscopy, diagnosis, and treatment. We recommend an aggressive approach, usually with preparation of the patient with oral purge followed by urgent colonoscopy for diagnosis and treatment rather than angiography or elective gastrointestinal procedures when the bleeding appears to stop. This endoscopic approach is similar to that used for patients with severe upper gastrointestinal hemorrhage. This approach changes outcomes of patients, particularly for those with severe or persistent hematochezia [1,2].

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

The purposes of this chapter are to review a systematic approach to the patient with severe hematochezia, to discuss patient outcomes, and to present the details of colonoscopic treatment of the most common colonic lesions that cause severe colonic bleeding.

Epidemiology Lower gastrointestinal bleeding has been estimated to be onefifth as common as upper gastrointestinal bleeding [3–6]. This ratio may change in the future, however, given the decreasing incidence of peptic ulcer disease and aging of the population which increases the risk of lower gastrointestinal bleeding [3]. Yearly rates of hospitalizations for lower gastrointestinal bleeding have been reported at 20–30 per 100 000 [3]. In this study, the incidence increased from 1 per 100 000 for patients in their third decade to 200 per 100 000 for those in their ninth decade. It is apparent that the incidence of lower gastrointestinal bleeding increases significantly with age. As our population ages, it is likely that we will see an increasing number of patients with this problem. Mortality rates are generally under 5%, although they tend to be higher in patients who have emergency surgery [3]. Similar to upper gastrointestinal hemorrhage, those patients who start bleeding while in the hospital for an unrelated medical/surgical condition have a much higher mortality rate (23%) than those who are admitted to the hospital for gastrointestinal bleeding (2.4%) [3].

Resuscitation and initial evaluation Patients who present with evidence of severe volume depletion such as hypotension and tachycardia require adequate intravenous access and vigorous replacement of intravenous fluids and/or blood. Patients with coagulopathies, i.e., prolonged prothrombin time or international normalized ratio from either liver disease or anticoagulant therapy (warfarin), and ongoing hematochezia usually require administration of fresh-frozen plasma. Those with severe thrombocytopenia or

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Table 47.1 Resuscitation and management of patients with severe hematochezia. Establish one or preferably two large-bore intravenous lines Assess intravenous volume and replace vigorously Evaluate degree of blood loss and replace with packed red blood cells Evaluate coagulation and correct with fresh frozen plasma, platelets, and/or desmopressin acetate Place a nasogastric tube to check for a possible upper gastrointestinal sourcebblood or bile Treat comorbid conditions

chronic renal failure may require platelet transfusions for definitive hemostasis of ongoing hematochezia. Treatment of comorbidities and close monitoring in an intensive care unit or a telemetry unit by skilled nurses is highly recommended (Table 47.1). The patient should be evaluated with a careful history and physical examination. The history in particular may give the physician a clue as to the source of the bleeding. Elderly patients with heart disease who present with abdominal pain and hematochezia may have ischemic colitis. A history of cirrhosis might suggest varices, most often esophageal or gastric, but rectal varices or anastomotic varices can also present as severe hematochezia. Severe heart disease (valvular in particular) and chronic renal insufficiency are associated with gastrointestinal angiomas. A history of inflammatory bowel disease, peptic ulcer disease, diverticulosis, or internal hemorrhoids might indicate potential bleeding sites. A history of recent polypectomy, particularly of a large sessile polyp, should suggest delayed bleeding from a postpolypectomy ulcer. Abdominal pain, weight loss, fever, diarrhea, and vomiting are important in the differential diagnosis of inflammatory, infectious, or malignant lesions. As part of medical history, it is also important to elicit and list all medicines, including over-the-counter drugs, and herbal medications which the patient has taken acutely or chronically. Some of these drugs may cause gastrointestinal lesions or aggravate gastrointestinal bleeding by interfering with intrinsic coagulation of the patient. Aspirin (in any dose, including 81 mg per day), nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, antibiotics, inflammatory bowel disease drugs, or antiarrhythmics may cause either gastrointestinal lesions or gastrointestinal hemorrhage. Herbal medications such as gingko and ginseng may also be associated with hemorrhage from a pre-existing gut lesion.

Diagnostic evaluation We recommend nasogastric (or orogastric) tube lavage to exclude a potential upper gastrointestinal bleeding source as one can be found in approximately 15–20% of patients with

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severe hematochezia. Other risk factors for an upper gastrointestinal source include a history of upper gastrointestinal bleeding from ulcers, portal hypertension, inpatient hematochezia, and hypotension or shock [1,2,7]. However, the value of a nasogastric tube aspirate has been questioned by others [7,8]. In our opinion, gastric lavage should be performed to help exclude the possibility of an upper gastrointestinal bleeding source. When bile is obtained in the presence of ongoing hematochezia, there is continuity with the duodenum, and an upper gastrointestinal lesion is unlikely to be the source of the hematochezia. If no evidence can be found of upper gastrointestinal bleeding, then an urgent colonoscopy (within 12 h) after adequate bowel preparation is highly recommended for diagnosis and possible hemostasis. If the colonoscopy with terminal ileal intubation is negative, we recommend slotted anoscopy (to evaluate internal hemorrhoids and to exclude fissures and anal tumors). This is a safe approach and the diagnostic yield with this urgent endoscopic algorithm approaches 95% [1]. In contrast, colonoscopy in an unprepared colon is often nondiagnostic and can be dangerous. Urgent colonoscopy of a well-prepped patient not only is an effective diagnostic tool but also allows for therapeutic intervention. It is a cost-effective approach to the management of these patients [9]. Figure 47.1 outlines our current approach to patients with severe hematochezia.

Bowel preparation In order to perform a complete colonoscopy in the presence of hematochezia, it is imperative that the colon be adequately cleansed. Cleansing the colon is the major rate-limiting step prior to urgent colonoscopy. After considering an upper gastrointestinal tract site of hemorrhage and after the nasogastric lavage, we administer a polyethylene glycol-based balanced electrolyte purge (e.g., Golytely® or Colyte®) either orally or via a nasogastric tube. Since some of these patients already have a nasogastric tube in place to check for upper gastrointestinal bleeding, it is easier to leave it in place for the purge. A liter of solution is administered every 30–45 min until the rectal effluent clears of solid matter and clots. In our experience, 6–8 L of fluid are usually needed to achieve this goal. Metoclopramide 10 mg may be administered intravenously 15–30 min prior to starting the purge for its prokinetic and antiemetic effects (Table 47.2). For patients with congestive heart failure, ascites, or chronic renal failure on hemodialysis, a very careful assessment of volume status is recommended prior to starting the purge. An increase in third-space fluid and intravascular volume should be treated pre-emptively. If there is clinical evidence of congestive heart failure, diuretics are indicated. In patients with chronic renal failure on dialysis, hemodialysis concurrent with the purge should be considered. In patients with tense ascites, therapeutic paracentesis should be performed

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Colonoscopy and Severe Hematochezia

History of cirrhosis, ulcers, melena, or hematemesis

History of hemorrhoids, radiotherapy, colitis, diarrhea

Enteroscopy

Anoscopy and flexible sigmoidoscopy

+ Treat

–

+ Treat

Negative history, painless hematochezia

– Purge and urgent colonoscopy –

+

Push enteroscopy +

– RBC scan or angiography

Treat +

Figure 47.1 CURE Hemostasis Research Group algorithm for management of patients with severe hematochezia.

Table 47.2 Colon preparation prior to urgent colonoscopy in patients with severe hematochezia. Metoclopramide (if no contraindications) 10 mg intravenously or intramuscularly 5–30 min prior to starting purge Polyethylene glycol-based balanced electrolyte solution (Nulytely® or Colyte®) orally or via nasogastric tube at 1 L every 30–45 min until effluent is clear of clots, stool, and blood Usually, 6–8 L is required over 3–5 h to clean the colon In patients with tense ascites, perform therapeutic paracentesis to prevent respiratory compromise during colonoscopy If patient is in congestive heart failure, treat with intravenous diuretics, or if in renal failure, use concurrent hemodialysis

to diminish the risk of respiratory compromise during colonoscopy. In this subgroup of patients who are also receiving intravenous fluids and blood products, as well as the colon purge, volume overload and worsening of comorbid conditions is common if diuresis, paracentesis, or dialysis are not performed before or simultaneously with the colon purge [1,2]. In case the patient has altered mental status (obtunded or confused) or has respiratory compromise, we protect the airway during gut lavage by intubation or an overtube.

Endoscopes and other equipment It is imperative to consider all the equipment that may be needed for the control of hemorrhage during emergency colonoscopy so that it is readily available for the endoscopist.

Treat

Treat

– Capsule endoscopy and/or surgery

A cart with all necessary equipment can then be taken to the bedside (such as in the intensive care unit). We prefer to use a colonoscope that is 13 mm or less in diameter, with a 3.8-mm suction channel and separate port for waterjet irrigation. The separate waterjet facilitates target irrigation and the large suction channel allows for simultaneous rapid clearing of the water, blood, and liquid stool. The addition of simethicon to the irrigation water is helpful in reducing the formation of bubbles which interfere with visualization, particularly in the presence of blood. For bleeding angiomas, postpolypectomy ulcers, or colonic diverticula a multipolar probe is preferred for coagulation because of its limited depth of coagulation. Endoscopic hemoclips, in contrast to coagulation, do not cause tissue damage and are useful for hemostasis of focal lesions such as postpolypectomy ulcers, diverticula, or rectal ulcers [1,2,9,10]. Epinephrine injection prior to coagulation is useful for postpolypectomy and diverticular bleeds but is not used for angiomas. A sclerotherapy catheter with retractable needle is needed for epinephrine injection or India ink labeling of lesions. A medium-sized slotted anoscope is very useful for diagnosis of bleeding internal hemorrhoids, which can be controlled using a rubber band ligator, and other anal lesions. Small and large capacity forceps should be available for tissue biopsies. Standard and rotatable mini, medium, and large polypectomy snares are needed for polypectomies, submucosal resections, and cold guillotining (shaving down) adherent clots on lesions, after epinephrine injection. A small bowel enteroscope should be available in case colonoscopy (including examination of the terminal ileum) and anoscopy fail to reveal a bleeding site. Lesions such as Dieulafoy’s, diverticula, or ulcerated small bowel tumors that may need

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Table 47.3 Equipment needed for emergency colonoscopy. Video colonoscope with > 3.8 mm suction channel and separate irrigation port Hemostasis probes (multipolar or heater probe), 7F and 10F in size, and corresponding power units Mini, medium, and large polypectomy snares, jumbo forceps, and fixatives for histopathology Needle catheter and epinephrine (1:20 000), India ink, and sclerosant Slotted anoscope and hemorrhoid treatment accessories (such as banding kits) Therapeutic video panendoscope and/or push enteroscope

repeat endoscopy for recurrent bleeding or may require surgical resection are tattooed with India ink after endoscopic treatment. The India ink injection facilitates localization on repeat endoscopy for rebleeding or finding the lesion at surgery (Table 47.3).

Coagulation probes The heater probe (Olympus Corporation, Tokyo, Japan) and multipolar coagulation (Gold Probe®, Microvasive/Boston Scientific Corporation, Natick, MA, USA) have gained popularity with therapeutic endoscopists due to their efficacy, safety, easy portability, and low cost. The power units and catheters should be on the mobile endoscopy cart which is taken to the bedside. The CURE Hemostasis Research Group has studied the technical parameters related to endoscopic coagulation in laboratory [11,12] and clinical studies [1,2, 13,14]. Table 47.4 lists the various parameters recommended for the use of either coagulation probe for treatment of selected

colonic lesions. For most actively bleeding lesions or those with adherent clots in the colon, except angiomas and internal hemorrhoids, combination epinephrine injection and thermal coagulation (with multipolar or heater probe) are used. Either small or large probes may be used depending upon the size of the lesion being treated. The probe is placed directly on the bleeding point with moderate pressure and low power settings, and coagulation is applied until complete hemostasis is achieved. In contrast to coagulation of bleeding ulcers in the upper gastrointestinal tract, only moderate pressure is utilized and shorter pulse duration is all that is required to achieve good hemostasis in the colon.

Endoscopic hemoclips (see Chapter 25) Hayashi et al. [15] and Kuramata et al. [16] developed endoscopically deployable clips in 1975. These have undergone several improvements [17–19] which have made them more user-friendly and highly effective for endoscopic hemostasis of focal lesions. Several companies now manufacture hemoclips for clinical use (Boston Scientific, Resolution® clip; Olympus, QuickClip®; and Wilson-Cook, TriClip®). Several prospective and some randomized clinical trials have been reported using Olympus hemoclips for the control of upper gastrointestinal bleeding with good results. These will be discussed under specific lesions. Our CURE Hemostasis Research Group has studied several endoscopic hemoclips in comparative systematic studies in a dog model of acute and chronic gastric ulcers to evaluate efficacy, duration of retention, and tissue effects [20,21]. One important technical advantage of the Resolution clip is the ability to open, close, and reopen the clip prior to application (e.g., “grasp and release”), which facilitates hemoclipping of focal bleeding sites. The TriClip, with three

Table 47.4 CURE Hemostasis Research Group parameters for heater probe and multipolar coagulation of bleeding colonic lesions. Multipolar probe Pressure Diverticular, delayed bleedinga, ulcer Moderate Activea Nonbleeding visible vessel Moderate Moderate Clotb,c Angioma Light Moderate Cancer/polypsb,c a

Heater probe

Power (W)

Pulse (s)

Pressure

Power (J)

12–16 12–16 12–16 10–16 16–20

1–2 1–2 1–2 1–2 1–2

Moderate Moderate Moderate Light Moderate

10–15 10–15 10–15 10–15 20–25

Delayed bleeding from a postpolypectomy ulcer. For active bleeding, inject 1:20 000 epinephrine in 1- to 2-mL aliquots within 2–5 mm of the bleeding site of clot before thermal coagulation. c For adherent clots on lesions, inject 1:20 000 epinephrine around the pedicle, use cold guillotine removal of clot, and then coagulate the small clot or nonbleeding visible vessel at the point of clot attachment. b

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wiry legs, tends to cut through soft tissue, which is a disadvantage. Partial rotation of the Resolution clip and the QuickClip is possible but not perfect. Both acute and chronic ulcers showed more rapid healing after clipping for hemostasis and ulcer closure than those ulcers treated with coagulation [20,21]. Hemoclips are useful for the control of active bleeding or the treatment of other major stigmata of hemorrhage [nonbleeding visible vessels (NBVVs) or adherent clots] in the colon from diverticula, postpolypectomy ulcers, solitary rectal ulcers, and other focal lesions [22,23]. They are not effective for diffuse lesions such as colonic angiomas or radiation telangiectasia.

Study results Patients admitted for hematochezia The CURE Hemostasis Research Group reported on 568 consecutive patients who were admitted to hospital because of significant hematochezia [23]. The patients included both those with persistent bleeding and those who stopped bleeding after hospitalization. The diagnostic approach in these patients was the same as with the group of persistently bleeding patients, i.e., resuscitation, placement of a nasogastric tube to exclude an upper gastrointestinal bleeding site, colonic purge, and urgent colonoscopy. Upper endoscopy was performed in those patients who had risk factors for or evidence of an upper gastrointestinal bleeding site. Push enteroscopy was performed in those patients who had a negative colonoscopy and negative nasogastric aspirate. Urgent colonoscopy and the other examinations were performed within 6–12 h of our gastrointestinal consultation (see Figures 47.1 and 47.2). Among the 568 patients with severe hematochezia in recent CURE studies [1,2,23], colonic bleeding sites were found in 74.1% (421 patients). An upper gastrointestinal source of the hematochezia (e.g., ulcers, varices, or angiomas) was diagnosed in 16.6% (94 patients). A small bowel source was present in 4.8% (27 patients), and no source was found in 4.6% (26 patients) (Figure 47.2). The most common colonic sources

Small bowel 4.8% (n = 27)

Colonic sites 74.1% (n = 421)

No source 4.6% (n = 26)

UGI sources 16.6% (n = 94)

Figure 47.2 The final sites (location) of hemorrhage in 568 patients hospitalized for severe hematochezia. UGI, upper gastrointestinal.

Colonoscopy and Severe Hematochezia

Table 47.5 Colonic sources of severe hematocheziaa. CURE Hemostasis Research Group Study [2,23]. (n = 421 total severe hematochezia patients with colonic sources of bleeding) Diverticulosis Internal hemorrhoids Ischemic colitis Rectal ulcers Ulcerative colitis or other colitis Colon angiomas or radiation telangiectasia Other lower gastrointestinal disease a

29.5% 12.8% 11.9% 8.6% 7.1% 7.1% 5.0%

Expressed as the percent of all colonic sources of severe hematochezia.

of bleeding were diverticulosis (29.5%), internal hemorrhoids (12.8%), and ischemic colitis (11.9%) (Table 47.5). Less common lesions included rectal ulcer, postpolypectomy ulcer, colon polyp or cancer, colon angiomas, and ulcerative colitis. Identification of major stigmata of hemorrhage (i.e., active bleeding, NBVV, or adherent clot) and endoscopic treatment were possible in patients with focal lesions. Low-risk patients without stigmata of hemorrhage and/or severe comorbidities could be triaged to a less intensive level of care as well as to earlier discharge. A cost analysis, comparing the urgent colonoscopy approach with the traditional approach to hematochezia, was previously reported by our group [9]. The urgent colonoscopy group had fewer hospital days, surgeries, and diagnostic tests. The savings based upon 1990 estimates was a mean of $10 000 per patient.

Specific lesions Diverticular hemorrhage Diverticulosis is the most frequent colonic lesion responsible for severe hematochezia. Diverticular bleeding accounts for 20–55% of all cases of lower gastrointestinal bleeding [1,7,9,13,23–29]. Diverticular bleeding is due to the erosion of a small arteriole, most commonly at the neck of the diverticulum or in the base; therefore, it is usually sudden and significant. Diverticular bleeding was the cause (including definitive diverticular or presumptive diverticular hemorrhage as defined below) of severe hematochezia in 29.5% of all patients admitted with severe hematochezia in our ongoing study of patients with severe hematochezia [1,2,9,23,28,29]. However, of all the patients with colonic diverticulosis who were admitted with severe hematochezia, 54.1% were found to have bleeding from nondiverticular sources. “Presumptive diverticular bleeding” was diagnosed when no definitive source or other potential source of hemorrhage was found. “Definitive diverticular bleeding” was diagnosed when there were stigmata of recent hemorrhage such as active bleeding (Figure 47.3), a nonbleeding visible vessel (Figure 47.4), or an adherent clot (Figure 47.5) on a diverticulum at urgent

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Figure 47.3 Patient with severe hematochezia and a definitive diverticular hemorrhage (active bleeding) in the descending colon. Initially, the diverticulum is injected with epinephrine (1:10 000 in saline) at three sites near the bleeding point. A 10F Gold probe (power setting 14 W and 2-s pulses) was then used to gently tamponade and coagulate the bleeding site to flatten the visible vessel. India ink tattooing and the appearance at the end of the procedure are shown. No complications or rebleeding occurred.

Figure 47.4 A nonbleeding visible vessel on the right side of a splenic flexure diverticulum was identified during urgent colonoscopy in a patient with severe hematochezia. This was coagulated with a Gold probe.

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Figure 47.5 An adherent clot in right colon diverticulum indicates this was the site of hemorrhage. The patient had severe hematochezia and severe anemia, requiring transfusion with three units of red blood cells. This was treated with combination of epinephrine injection, cold guillotining off the clot, and thermal coagulation of the residual small clot at the pedicle.

colonoscopy. Identification of stigmata of hemorrhage on a diverticulum was possible only with adequate colonic cleansing and target waterjet irrigation during urgent colonoscopy. The key to diagnosis is a clean preparation without blood, clots, or stool. The majority of diverticular bleeding that we have seen is at or proximal to the splenic flexure, so careful inspection of diverticula in these areas is important, during both intubation and withdrawal of the colonoscope. Inspect the neck of diverticula and bases for adherent clots or visible vessels since these are the sites from which bleeding occurs. Use glucagon for control of spasm if there is a problem examining segments in the sigmoid colon. Try to perform the examination within 12 h of the severe bleeding episode, but after resuscitation and adequate preparation. In prospective studies of patients with definitive diverticular hemorrhage, we compared medical–surgical with medical– colonoscopic management [23,28–30]. Medical–surgical treatment was given to 26 patients, which defined the natural

Colonoscopy and Severe Hematochezia

history of definitive diverticular hemorrhage [28–30]. These patients underwent emergency colonoscopy for diagnosis but did not receive any colonoscopic treatment. The second group of 34 patients with definitive diverticular hemorrhage received medical treatment and endoscopic hemostasis at the time the stigmata were diagnosed at urgent colonoscopy. Treatment consisted of epinephrine injection, multipolar coagulation, or both; or more recently hemoclipping with or without epinephrine preinjection (1:20 000 in saline) [23] (Figure 47.6). The diverticulum treated was labeled in four adjacent areas with India ink injection to facilitate localization at repeat colonoscopy or surgery (see Figure 47.3). Both groups were very comparable in terms of age, comorbid conditions, recent aspirin and/or NSAID ingestion, and blood transfusion requirements prior to colonoscopy (Table 47.6). Ongoing or recurrent hemorrhage requiring transfusion of two or more units of packed red blood cells was observed in 50% of the medical–surgical treated patients in contrast to 9% of the medical–colonoscopic-treated group. Surgery or angiographic embolization for control of bleeding was required in 38% of the medical–surgical group and in 6% of the medical– colonoscopic group [30]. One patient developed postcoagulation syndrome after multipolar electrocautery coagulation in the right colon, but recovered within 2 days. The median time to discharge was longer (5 days) for the medical–surgical patients than for the medical–colonoscopic patients (2 days) (see Table 47.6). The long-term treatment recommended was fiber, control of constipation, and avoidance of aspirin, NSAIDs, and anticoagulants. Contrary to common teaching about patients with diverticulosis, Strate et al. [31] recently reported that patients who consumed nuts and seeds in their diet had no more complications of diverticular disease (hemorrhage or diverticulitis) and frequent popcorn eaters had lower rates of diverticulitis than age-matched patients whose diets lacked these foods. Some other studies have reported an association between NSAID use and diverticular bleeding [32,38].

Table 47.6 Outcomes of treatments of 60 consecutive patients with definitive diverticular hemorrhage managed by the CURE Hemostasis Research Group [30].

Endoscopic hemostasis Additional bleeding Severe bleeding Emergency surgery or angiographic embolization Median time to discharge after colonoscopy (days) Complications

Medical–surgical group (n = 26)

Medical–colonoscopy group (n = 34)

0 13 (50%)* 10 (38%)* 10 (38%)* 5 2 (8%)

17 (100%) 3 (9%)a 3 (9%)a 2 (6%)a 2 1 (3%)b

a

After anticoagulation. One postcoagulation syndrome. * P < 0.05.

b

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Figure 47.6 A 73-year-old patient with polymyositis, diabetes mellitus, obesity, and arthritis experiences recurrent hematochezia while hospitalized. The CURE Hemostasis Research Group was asked to see this patient after a nondiagnostic colonoscopy with inadequate colon preparation was performed by another endoscopist followed by re-bleeding. After purging with 7 L of Golytel®, which cleared the colon

of all stool, clots, and blood, an urgent colonoscopy was performed. In the base of a sigmoid diverticulum, there was a nonbleeding visible vessel. With a Doppler ultrasound probe, arterial flow was detected and abolished with combination treatment (epinephrine injection and hemoclipping). India ink tattooing was used to label the area. The patient experiences no further bleeding during 1 year of follow-up.

Recently, we reported that patients with documented diverticular hemorrhage (e.g., definitive or presumptive) had low rates of recurrent hemorrhage or diverticulitis during longterm follow-up after an initial severe diverticular bleed [34]. The rates of severe colon rebleeding during a median of 4 years of follow-up were similar for patients treated initially with medical (18.9% re-bled), endoscopic (18.8%), or surgical therapy (25%). However, the incidence of nondiverticular sources for the rebleeding varied, according to treatment, from 43% (medical) or 50% (endoscopic group) to 100%

(surgical group). In other words, at least 50% of all the late rebleeding was from nondiverticular sources of lower gastrointestinal hemorrhage in these patients with documented colon diverticulosis [34].

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Internal hemorrhoids Internal hemorrhoids were responsible for severe hematochezia in 12.8% of our patients who were admitted to hospital. Most gastroenterologists do not include internal hemorrhoids in the differential diagnosis of severe hematochezia

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Table 47.7 Grades of internal hemorrhoids. Grade 1: no prolapse below the dentate line Grade 2: prolapse during defecation with spontaneous reduction Grade 3: prolapse during defecation requiring manual reduction Grade 4: nonreducible prolapse below that dentate line

because the majority of internal hemorrhoidal bleeding is intermittent, low grade, and self-limited. However, some patients with hemorrhoids have sudden, severe bleeding. Bleeding internal hemorrhoids constitutes a significant public health problem in as much as it is estimated that approximately 10.4 million people suffer from hemorrhoid symptoms annually, prompting 3.5 million physician visits per year [35]. We grade internal hemorrhoids with a slotted anoscope from grade 1 to 4 (Table 47.7), depending on the degree of prolapse through the anal sphincter. Although bleeding may occur from any grade of hemorrhoid, severe bleeding causing anemia and hospitalization is most often from grade 3 or 4 internal hemorrhoids. Following enemas to clear the distal colon (Fleets® or tap water), bleeding hemorrhoids can be diagnosed with a flexible sigmoidoscope but the internal hemorrhoids are always better visualized with the use of a slotted anoscope. While outpatients with bleeding from internal hemorrhoids often have cessation of hemorrhage with medical therapy, in our experience, most with severe hematochezia require endoscopic therapy or surgery [1,2]. In the past, we have utilized sclerotherapy or anoscopic coagulation (such as multipolar or heater probes) for patients with internal hemorrhoids and hematochezia [36,37]. Recently, rubber band ligation has been found to be faster and more efficient, particularly for control of severe hematochezia [38,39] (Figure 47.7). Concomitant medical therapy with fiber, stool softeners, and avoidance of aspirin, NSAIDs, and anticoagulants is also highly recommended. Outpatient follow-up and further treat-

Colonoscopy and Severe Hematochezia

ment to completely control bleeding and to reduce the internal hemorrhoids to grade 1 or less should also be considered. Surgical intervention is indicated for those patients who would prefer to have a single procedure despite discomfort and those patients who have failed medical and endoscopic therapy. Surgical hemorrhoidectomy is highly effective in controlling bleeding and eradicating internal as well as external hemorrhoids [40–42]. However, surgical hemorrhoidectomy is not free of complications [43–46]. A new surgical procedure has recently been introduced which utilizes a circular stapling device to create a rectal anastomosis well above the dentate line thereby lifting the hemorrhoidal cushions back into the anal canal. This procedure has been named “staple hemorrhoidopexy” since hemorrhoids are not actually excised [47].

Ischemic colitis Colonic ischemia was responsible for severe hematochezia in 11.9% of our patients hospitalized with hematochezia [2,23]. Other series report an incidence of 3–9% of severe lower gastrointestinal bleeding being caused by ischemic colitis [3, 5,48]. There is usually no identifiable precipitating cause for the acute onset of colonic ischemia. However, most patients with ischemic colitis have underlying atherosclerotic cardiovascular, or peripheral occlusive disease. It can also be seen with acute myocardial infarction, hypercoagulable states, vasculitis, prolonged strenuous exercise, and some medications such as diuretics [49]. Patients usually present with the acute onset of abdominal cramping and pain which can be localized in the right lower quadrant, epigastrum, or left lower quadrant depending on the segment of colon involved. However, the pain tends to radiate throughout the entire abdomen. The splenic flexure and sigmoid colon, which have poor collateral blood flow (e.g., are watershed areas), are most often involved. When present, abdominal pain is usually associated with bloody diarrhea. Occasionally, nausea, vomiting, and fever are present. Signs of hypovolemia, tachycardia, and hypotension may be seen in severe cases of ischemic colitis.

Figure 47.7 A 62-year-old patient was hospitalized for anemia and severe hematochezia requiring transfusion of two units of red blood cells. No colonic lesions were found on urgent colonoscopy and anoscopy except for grade 3 internal hemorrhoids without active bleeding. These were treated with rubber band ligation, utilizing a diagnostic panendoscope and a multishot ligator in retroflexion in the rectum.

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Physical examination of the abdomen may be normal or have findings such as diffuse abdominal tenderness and hyperactive bowel sounds. No localized peritoneal signs are usually present unless there is frank colonic infarction with involvement of the serosa. Thumb printing may be observed on plain abdominal radiographs or barium enema but this is not a frequent finding in our experience [49]. In many cases of ischemic colitis which we see in elderly patients, only painless hematochezia is noted and no other symptoms. The physical examination may reveal mild tenderness only or may be normal. Colonoscopy is the best way to make the diagnosis [1,2,49]. There is usually segmental involvement consisting of mucosal edema, erythema, friability, mucosal hemorrhages, mucosal necrosis, and ulcerations. Colonic biopsies from the affected as well as unaffected areas are usually definitive for ischemia. Colonoscopic and histopathologic findings are useful to differentiate colonic ischemia from inflammatory or infectious colitis. Medical treatment is supportive with intravenous fluids and/or blood transfusions to improve tissue perfusion. Urgent treatment of comorbid conditions is warranted, including peripheral or central vascular disease, cardiac arrhythmias, or severe anemia which may have contributed to bowel ischemia. Antibiotics are indicated if fever or sepsis is present. If there is clinical deterioration of the patient with development or peritoneal signs, fever, leukocytosis, or evidence of bowel perforation, surgical intervention with segmental colon resection is indicated. Therapeutic colonoscopy plays no role in these patients unless a focal ulcer with stigmata of hemorrhage is found at colonoscopy, which usually is not the case [22,48,49].

Solitary rectal ulcer syndrome Solitary rectal ulcers were responsible for 8.6% of the total cases of patients presenting with severe hematochezia, making it the fourth most common diagnosis in this large study [2,23]. In contrast to previous series which reported that this syndrome occurs in younger (third and fourth decades of life) patients [51–53], our patients were olderain their sixth and seventh decades of life [22,54,55]. This syndrome is more common in women and is characterized by rectal bleeding and mucous discharge in 56–89% of patients [52,56]. The etiology of this disorder is not completely understood, but prolapse-induced rectal mucosal trauma or ischemia appear to contribute [57]. Our patients usually presented with symptoms of severe constipation and often fecal impaction. Increasingly, inpatients with prolonged hospitalization and inpatient hematochezia are being seen [54,55]. Pressure-induced mucosal necrosis in elderly patients with fecal impaction must also be considered. On endoscopy, one or more well-demarcated ulcerations are seen with edematous, erythematous, and nodular borders [22,54,55]. In our recent studies, active bleeding or stigmata of recent hemorrhage were found at urgent colonoscopy in most patients with severe hematochezia [54,55] (Figure 47.8). Colonoscopic hemostasis of hemorrhage from rectal ulcers consists of coagulation with a large-contact thermal probe or hemoclipping with or without preinjection of epinephrine. For actively bleeding ulcers or ulcers with an overlying clot, injection of 1:20 000 epinephrine is recommended circumferentially around the bleeding point or pedicle of the clot in four quadrants, prior to coagulation (hemoclipping). In

Figure 47.8 A 71-year-old woman with recent porcine aortic valve replacement had pneumonia and developed severe inpatient hematochezia in the surgical intensive care unit. She had bright-red blood per rectum and an angiogram failed to identify a bleeding site. After purging with 8 L of fluid via a nasogastric tube, an urgent bedside colonoscopy revealed spurting bleeding from a rectal ulcer. This required treatment in retroflexion, and hemostasis was successfully achieved with combination of epinephrine injection and hemoclipping.

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actively bleeding ulcers, after epinephrine injection, irrigation is used to localize the bleeding point and then subsequently coagulate it to completely flatten the vessel or apply hemoclips directly on the vessel. For those ulcers with an overlying clot, following epinephrine injection the clot is removed by cold guillotining with a rotatable polypectomy snare without cautery. This exposes the underlying stigmata, which is usually an NBVV. Subsequently, the NBVV or active bleeding site is either hemoclipped or cauterized (until completely flattened). Rectal ulcers with an NBVV can be coagulated without prior injection of epinephrine. The large thermal probe is placed directly on the visible vessel and cauterized until flattened. Recommended power settings for the multipolar probe are 12–16 W for 5- to 10-s pulses or, for the heater probe, 10–15 J are recommended for this colonic lesion. As with other focal colonic bleeding sites, three or four adjacent areas are tattooed with India ink. Based upon healing studies of upper gastrointestinal ulcers, whenever possible, we recommend closure of chronic ulcers with endoscopic hemoclips to potentiate their healing [20,21,55] (see Figure 47.8).

Delayed postpolypectomy hemorrhage Hemorrhage after an endoscopic polypectomy may occur immediately afterward or may be delayed hours, days, or even weeks [58,59]. Our focus in this chapter is on delayed severe postpolypectomy hemorrhage resulting in hospitalization for severe hematochezia. This is defined as occurring 1 or more days after discharge of the patient from the endoscopy unit after the polypectomy. The incidence of delayed postpolypectomy hemorrhage is reported at less than 1–6% [58,59]. The variation in these reported rates is likely a function of study design, patient population (i.e., age, comorbid conditions, use of antiplatelet drugs or anticoagulants), and the configuration and size of index polyps. Because of changes in colonoscopy practices and with resection of larger sessile colonic polyps in the last two decades, including piecemeal resection or following submucosal saline injection, delayed postpolypectomy hemorrhage appears to be occurring more frequently. In a recent study by the CURE Hemostasis Research Group, severe postpolypectomy bleeding was the cause of severe hematochezia in less than 5% of colonic etiologies [2, 23,59]. The mean size of the polyps was 20 mm in diameter, and most were sessile polyps without carcinoma on histopathology. Delayed hemorrhage occurred a median of 9 days (range 2–73 days) after polypectomy. Most patients (77%) were men with a mean age of 69 years. The majority (77%) were also consuming aspirin or warfarin after polypectomy for comorbid cardiac or vascular conditions. All patients required hospitalization because of severe hematochezia. After colonic purge, urgent colonoscopy revealed ulcerations with a mean diameter of 11 mm. Stigmata of hemorrhage on the ulcers included active bleeding in 23%, NBVV in 23%, clot in 38%, spot in 8%, and clean ulcer in 8%. Ninety-two percent of patients were treated endoscopically, and only one patient

Colonoscopy and Severe Hematochezia

re-bled. One patient with cancer had surgery, and the remainder were treated medically. If the patient with postpolypectomy hemorrhage returns to the original facility where the polyp was removed and the endoscopist knows the exact location of the site in the colon, it is possible to perform an unprepped colonoscopy, but it is usually a difficult examination. Most of our cases had polypectomy performed elsewhere and, in order to locate the site and perform therapy, we prefer to prepare the patient to clear stool, clots, and potentially explosive gases so treatment can be performed during the examination. Bleeding occurring immediately after polypectomy is thought to be due to inadequate cauterization of the polyp vessels during polypectomy, whereas delayed postpolypectomy hemorrhage is thought to be due to sloughing of the necrotic, cauterized tissue in the induced ulcer, with underlying blood vessels. The predominance of visible vessels with or without active bleeding or clots indicates an underlying vessel, probably similar to the anatomy of peptic ulcers as defined by Swain et al. [60]. However, to date there have been no studies reporting on the histology of stigmata of hemorrhage for delayed postpolypectomy ulcers, because most are now successfully treated via colonoscopy [58,59]. There are several effective methods to control bleeding from a postpolypectomy ulcer. We use techniques similar to those used for chronic peptic ulcers to treat major stigmata of hemorrhage. In the case of a postpolypectomy ulcer with active bleeding, epinephrine (1:20 000 in saline) is injected to slow or control the hemorrhage, and then thermal coagulation is applied with multipolar or heater probe on the bleeding vessel. Alternatively, endoscopic hemoclips are applied directly on the vessel. For an adherent clot on the ulcer, we inject epinephrine around the pedicle of the clot in the ulcer base and then shave down the clot using a cold polypectomy snare, similar to other focal ulcers [61]. Rotatable snares facilitate this type of clot removal. Once the visible vessel is exposed, it can be coagulated with a thermal probe or hemoclipped (Figure 47.9). With a multipolar probe, we use a low-power setting of 12– 16 W with 2- to 4-s pulses. For a heater probe, power settings of 10–15 J/pulse are utilized. For an NBVV, thermal coagulation or endoscopic hemoclipping alone may be used. We also label the segment of the colon with India ink. The risk of aspirin and NSAIDs prior to polypectomy remains a concern. However, no significant difference in postpolypectomy bleeding has been found between patients who consume these drugs and those who did not before polypectomy [62,63]. The guidelines from the American Society for Gastrointestinal Endoscopy state that polypectomy in patients consuming standard doses of these drugs, precluding any underlying bleeding disorders, is safe [64].

Colonic angiomas Colonic angiomas or radiation telangiectasia were responsible for severe bleeding in 7.1% of our patients admitted to the hospital for severe hematochezia. In contrast, the majority

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Figure 47.9 A 77-year-old patient on aspirin for coronary prophylaxis was hospitalized 8 days after saline-assisted piecemeal polypectomy of a large (benign) sessile right colon polyp. At urgent colonoscopy a large ulcer with a small adherent clot was found and treated with a 10F Gold probe. The settings were 16 W with 2-s pulses. Moderate tamponade pressure was used to coagulate and flatten the clot and underlying visible vessel.

of patients we have seen (70%) with bleeding angiomas presented with self-limited intermittent bleeding or occult blood positive stools and iron deficiency anemia. These patients are usually hemodynamically stable and can undergo elective colonoscopy in the outpatient setting [65]. A smaller group (30%) of patients with colonic angiomas present with severe, persistent hemorrhage, may be hemodynamically unstable and/or severely anemic, and require hospitalization, blood transfusions, and emergency evaluation.

Table 47.8 Comorbid conditions for patients with hemorrhage from colonic angiomas (n = 108). Condition

Percent of patients

Severe heart disease Valvular heart disease Aortic stenosis Aortic regurgitation Mitral regurgitation Chronic renal failure Hemodialysis Cirrhosis Collagen vascular disorder Osler–Weber–Rendu syndrome

46 29 16 5 8

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16 16 5 5

The CURE Hemostasis Research Group randomized 108 prospective patients with bleeding colonic angiomas to colonoscopic treatment with bipolar coagulation (57 patients) or heater probe (51 patients). Most of these patients were elderly (> 65 years) and suffered from one or more comorbid conditions (Table 47.8). The mean follow-up of these patients was 2 years which was compared with the 2 years prior to endoscopic treatment in terms of number of bleeding episodes, number of blood transfusions, and hematocrit while on iron and not acutely bleeding. At colonoscopy, most angiomas (85%) were in the right colon. The majority of angiomas (80%) were 5–10 mm in size, 18% were 11–20 mm, and 2% were greater than 20 mm (Figure 47.10). The mean number of colonoscopies to control bleeding during the follow-up period was 1.4 with a range of 1–4. The techniques of the CURE Hemostasis Research Group for coagulating angiomas in the colon include using a small probe (2.4 mm diameter) for angiomas under 5 mm or the large probe (3.2 mm) for angiomas larger than 5 mm. Pay close attention so that the colon is not overly distended during colonoscopic coagulation. Light pressure is applied with the probe directly on the angioma being treated. For multipolar coagulation, we use a 50-W generator and coagulate with a setting of 10–16 W and 1- or 2-s pulses. For heater probe coagulation, we use a setting of 10–15 J. Whitening of the entire

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Figure 47.10 A large right colonic angioma was determined to be the cause of severe hematochezia when no other colonic or foregut lesions (by push enteroscopy) were found.

Figure 47.11 During urgent colonoscopy, a right colon angioma was found to be bleeding. This was coagulated with a 7F Gold probe (power setting 14 W and 2-s pulses) using gentle tamponade pressure. No complications or re-bleeding occurred.

angioma is the desired endpoint of treatment (Figure 47.11). All angiomas that are visualized during the course of the examination are coagulated. However, we caution against coagulation of large colonic angiomas in patients who have never had severe gastrointestinal hemorrhage (such as hematochezia), because of the potential for complications. Seventy percent of patients had a good outcome with colonic coagulation, experiencing fewer bleeding episodes,

requiring fewer blood transfusions, and holding a higher hematocrit during follow-up (Figure 47.12). Partial colectomies were performed in 18% of patients who had multiple colon angiomas (usually more than 25 in one segment such as the right colon). However, 38% of these operated patients continued to have recurrent bleeding post hemicolectomy. Complications from colonoscopic coagulation were observed in 5% of patients consisting of delayed hemorrhage due to

40

4

37.3*

Medical Rx Endoscopic Rx

4.3

30 26.8

3

20 2 1

1.3*

Mean Hct

Figure 47.12 Outcome in 108 consecutive patients referred to and treated by the CURE Hemostasis Research Group for recurrent gastrointestinal bleeding from colonic angiomas. The outcomes for the 2 years before referral on medical therapy were compared with outcomes after colonoscopic treatments. *P < 0.05.

Episodes of U RBC/Yr

5

10

1.3 0.6*

0

0 Mean U RBCs/Yr

Mean LGI bleeding episodes/Yr

Mean Hct

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ulceration (four patients) or postcoagulation syndrome due to full thickness coagulation (two patients). No perforations occurred. Two of the patients with delayed hemorrhage who had coagulopathies required surgery.

Summary Severe lower gastrointestinal bleeding is now a more frequently encountered medical–surgical problem. The prevalence appears to be increasing because of recent colorectal cancer screening practices and the aging of referral patient populations. Our recommended approach to these patients is for vigorous resuscitation with intravenous fluids and blood transfusions, close monitoring in an intensive care unit or monitored bed unit, bedside evaluation with nasogastric tube lavage for signs of a possible upper gastrointestinal bleeding source, and urgent colonoscopy (or upper endoscopy or small bowel enteroscopy if colonoscopy is negative) following thorough colonic cleansing with a purge via oral or nasogastric tube. Definitive diagnosis of the bleeding site can be made with this approach in over 95% of cases. In patients with severe hematochezia, a colonic bleeding site is found in 74% of cases. Endoscopic treatment of focal bleeding lesions in the colon or the upper gastrointestinal tract is highly effective and safe in these cases, thereby reducing the need for surgical intervention. In patients with a definitive diagnosis and no stigmata of hemorrhage or low-risk stigmata, early diagnosis may also facilitate downgrading the intensity of medical care and/or early discharge.

References 1 Jensen DM, Machicado GA. Diagnosis and treatment of severe hematochezia: the role of urgent colonoscopy after purge. Gastroenterology 1988; 95: 1569–74. 2 Kovacs TOG, Jensen DM. Acute lower gastrointestinal bleeding. In: Weinstein WM, Hawkey CJ, Bosch J (eds.). Clinical Gastroenterology and Hepatology. London: Elsevier Mosby, 2005: 127–31. 3 Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a populationbased study. Am J Gastroenterol 1997; 92: 419–24. 4 Kollef MH, O’Brian JD, Zuckerman GR, et al. BLEED: a classification tool to predict outcomes in patients with acute upper and lower gastrointestinal hemorrhage. Crit Care Med 1997; 25: 1125–32. 5 Peura DA, Lanza FL, Gostout CJ, et al. The American College of Gastroenterology Bleeding Registry: preliminary findings. Am J Gastroenterol 1997; 92: 924– 8. 6 Velayos FS, Williamson A, Sousa KH, et al. Early predictors of severe lower gastrointestinal bleeding and adverse outcomes: a prospective study. Clin Gastroenterol Hepatol 2004; 2: 485–90. 7 Kovacs TOG, Jensen DM. Upper or small bowel hemorrhage presenting as hematochezia. Tech Gastrointest Endosc 2001; 3: 206–15. 8 Cuellar RE, Gavaler JS, Alexander JA, et al. Gastrointestinal tract hemorrhage. The value of a nasogastric aspirate. Arch Intern Med 1990; 150: 1381– 4.

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9 Jensen DM, Machicado GA. Colonoscopy for diagnosis and treatment of severe lower gastrointestinal bleeding: routine outcomes and cost analysis. Gastrointest Endosc Clin N Am 1997; 7: 477–98. 10 Parra-Blanco A, Kaminaga N, Kojima T, et al. Hemoclipping for postpolypectomy and postbiopsy colonic bleeding. Gastrointest Endosc 2000; 51: 37– 41. 11 Jensen DM, Hirabayashi K. A study of coagulation depths with BICAP and heater probe to improve endoscopic hemostasis of bleeding peptic ulcers. Gastrointest Endosc 1989; 35: 181. 12 Jensen DM. Endoscopic hemostasis and tumor palliationa experimental results and techniques. In: Jensen DM, Brunetaud JM (eds.). Medical Laser Endoscopy. Dordrecht: Kluwer Academic Publishers, 1990: 45–70. 13 Savides T, Jensen DM. Colonoscopic hemostasis of recurrent diverticular hemorrhage associated with a visible vessel: a report of three cases. Gastrointest Endosc 1994; 40: 70–3. 14 Jutabha R, Jensen DM. Acute upper gastrointestinal bleeding. In: Friedman S, McQuaid KR, Grendell J (eds.). Current Diagnosis and Treatment in Gastroenterology. 2nd edn. New York: Lange Medical Books/McGraw-Hill, 2002: 53–69. 15 Hayashi T, Yonezana M, Kanabara T. The study on staunch clip for the treatment by endoscopy. Gastroenterol Endosc 1975; 17: 92–101. 16 Kuramata H, Eto S, Horiguchi K, Unayama F, Kazato K, Tsuboi A. Evaluation of gastrofiberscope for treatment (TGF prototype by Olympus). Stomach Intestine 1974; 9: 355–64. 17 Hachisu T, Yamada H, Satoh SI, Kouzu T. Endoscopic clipping with a new rotatable clip-device and a long clip. Dig Endosc 1996; 8: 127–33. 18 Hachisu T. Evaluation of endoscopic hemostasis using an improved clipping apparatus. Surg Endosc 1988; 2: 13–17. 19 Hachisu T, Miyazaki S, Hamaguchi K. Endoscopic clip-marking of lesions using the newly developed HX-3L clip. Surg Endosc 1989; 3: 142–7. 20 Jensen DM, Machicado GA, Hirabayashi K. Randomized controlled study of three different types of hemoclips for hemostasis of bleeding canine acute gastric ulcers. Gastrointest Endosc 2006; 64: 768–73. 21 Jensen DM, Machicado GA, Singh B, Hirabayashi K. Depth of hemoclipping, gross injury, histologic inflammation and fibrosis with different hemoclips or MPEC in a randomized hemostasis study of chronic canine gastric ulcers. Gastrointest Endosc 2008; 67: AB254. 22 Gralnek IM, Jensen DM. An assortment of colonic lesions that present with severe hematochezia. Tech Gastrointest Endosc 2001; 3: 216–20. 23 Jensen DM, Machicado GA, CURE Hemostasis Research Group. Where to look and how to treat diverticular hemorrhage. Am J Gastroenterol 2006; 101(Suppl.): S202, 474. 24 Schmulewitz N, Fisher DA, Rockey DC. Early colonoscopy for acute lower GI bleeding predicts shorter hospital stay: a retrospective study of experience in a single center. Gastrointest Endosc 2003; 58: 841–6. 25 Strate LL, Orav EJ, Syngal S. Early predictors of severity in acute lower intestinal tract bleeding. Arch Intern Med 2003; 163: 838–43. 26 Tada M, Shimizu S, Kawai K. Emergency colonoscopy for the diagnosis of lower intestinal bleeding. Gastroenterol Jpn 1991; 26(Suppl. 3): 121–4. 27 Ohyama T, Sakurai Y, Ito M, et al. Analysis of urgent colonoscopy for lower gastrointestinal tract bleeding. Digestion 2000; 61: 189–92.

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28 Jensen DM, Machicado GA, Jutabha R, Kovacs TOG. Urgent colonoscopy for the diagnosis and treatment of severe diverticular hemorrhage. N Engl J Med 2000; 342: 78–82. 29 Jensen DM, Kovacs TOG, Dulai G, Jutabha R, Gralnek IM, Machicado GA. Prospective study of urgent endoscopic diagnosis and treatment of patients with diverticulosis and severe hematochezia. Gastrointest Endosc 2005; 61: AB84, 264. 30 Jensen DM, Machicado GA, CURE Hemostasis Research Group. Prevalences and outcomes of different stigmata of definitive diverticular hemorrhage with medical–surgical treatment or colonoscopic hemostasis. Am J Gastroenterol 2006; 101(Suppl.): S207, 487. 31 Strate LL, Liu YL, Syngal S, Giovannucci EL. Can patients with diverticular disease eat nuts, corn and popcorn? Gastro 2007; 132: A110. 32 Aldoori WH, Giovannucci EL, Rimm EB, et al. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998; 7: 255– 60. 33 Laine L, Connors LG, Reicin A, et al. Serious lower gastrointestinal clinical events with non-selective NSAID or coxib use. Gastroenterology 2003; 124: 288–92. 34 Jensen DM, Singh B, Jensen ME, Sun N, Carrico M. How often do patients rebleed during long-term follow-up after an initial documented diverticular hemorrhage? Gastro 2008; in press. 35 Johanson JF. Hemorrhoids. In: Digestive Diseases in the United States: Epidemiology and Impact. NIH publication 94–1447. Washington DC: US Government Printing Office, 1994: 273–98. 36 Randall GM, Jensen DM, Machicado GA, et al. Prospective randomized comparative study of bipolar versus direct cost electrocoagulation for treatment of bleeding internal hemorrhoids. Gastrointest Endosc 1994; 40: 403–10. 37 Jensen DM, Jutabha R, Machicado GA, et al. Prospective randomized comparative study of bipolar electrocoagulation versus heater probe for treatment of chronically bleeding internal hemorrhoids. Gastrointest Endosc 1997; 46: 435– 43. 38 Pfenninger JL. Modern treatments for internal hemorrhoids. BMJ 1997; 314: 1211–12. 39 Su MY, Chin CT, Wu CS, et al. Endoscopic hemorrhoidal ligation of symptomatic internal hemorrhoids. Gastrointest Endosc 2003; 58: 871– 4. 40 Senagore A, Mazier WT, Luchtefeld MA, et al. Treatment of advanced hemorrhoidal disease: a prospective, randomized comparison of cold scalpel vs contact Nd: YAG laser. Dis Colon Rectum 1993; 36: 1042– 9. 41 Andrews BJ, Layer OT, Jackson BT, et al. Randomized trial comparing diathermy hemorrhoidectomy with the scissor dissection Milligan–Morgan operation. Dis Colon Rectum 1993; 36: 580–3. 42 Hodgson WJ, Morgan J. Ambulatory hemorrhoidectomy with CO2 laser. Dis Colon Rectum 1995; 38: 1265– 9. 43 Rosen L, Sipe P, Stasik JJ, et al. Outcome of delayed hemorrhage following surgical hemorrhoidectomy. Dis Colon Rectum 1993; 36: 743– 6. 44 Eu KW, Tech TA, Seow-Choen F, et al. Anal stricture following haemorrhoidectomy: early diagnosis and treatment. Aust N Z J Surg 1995; 65: 101–3. 45 Parickh SR, Molinelli B, Dailey TH. Liver abscess after hemorrhoidectomy. Report of two cases. Dis Colon Rectum 1994; 37: 185–9.

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46 Shanmugan V, Thaha MA, Rabindranath KS, Campbell KL, Steale RJ, Loudon MA. Systematic review of randomized trials comparing rubber band ligation with excisional hemorrhoidectomy. Br J Surg 2005; 92: 1481–7. 47 Singer M, Cintron J. New techniques in the treatment of common perianal diseases: stapled hemorrhoidopexy, botulinum toxin, and fibrin sealant. Surg Clin North Am 2006; 86: 937–67. 48 Zuckerman GR, Prakash C. Acute lower intestinal bleeding. Gastrointest Endosc 1999; 49: 228–38. 49 Jensen DM, Zarimani AI, Kovacs TOG, et al. Ischemic colitis is a common cause of severe hematochezia and patient outcomes are no worse than other colonic diagnoses. Gastrointest Endosc 2004; 59: AB105, 536. 50 Savides TJ, Jensen DM. Endoscopic therapy for severe gastrointestinal bleeding. Adv Intern Med 1995; 40: 243–71. 51 Madigan MR, Morson BC. Solitary ulcer of the rectum. Gut 1969; 10: 871– 81. 52 Tjandra JT, Fazio VW, Church JM, et al. Clinical Conundrum of solitary rectal ulcer. Dis Colon Rectum 1992; 35: 227–34. 53 Sharara AI, Azar C, Amr SS, et al. Solitary rectal ulcer syndrome: endoscopic spectrum and review of the literature. Gastrointest Endosc 2005; 62: 755– 62. 54 Kanwal F, Jutabha R, Dulai D, Jensen DM. Major stigmata of hemorrhage on rectal ulcers and outcomes in patients with severe hematochezia. Gastrointest Endosc 2003; 57: 462–8. 55 Jensen DM, Kovacs TOG, Jutabha R, Ohning GV, Dulai GS, Machicado GA. Rectal ulcers causing severe hematochezia: Update on diagnosis, hemostasis, healing, and outcomes. Gastrointest Endosc 2007; 65: AB258, T1434. 56 Niv Y, Bat L. Solitary ulcer syndrome: clinical endoscopic and histopathological spectrum. Am J Gastroenterol 1986; 81: 486–91. 57 Levine DS. “Solitary” rectal ulcer syndrome. Gastroenterology 1987; 92: 243–53. 58 Rex DK, Lewis BL, Waye JD. Colonoscopy and endoscopic therapy for delayed post-polypectomy hemorrhage. Gastrointest Endosc 1992; 38: 127–9. 59 Jensen DM, Kovacs TOG, Jutabha R, et al. Prospective study of delayed post-polypectomy bleeding compared to other causes of severe hematochezia. Gastrointest Endosc 2001; 53: 182. 60 Swain CP, Storey DW, Bown SG, et al. Nature of the bleeding vessel in recurrently bleeding gastric ulcers. Gastroenterology 1986; 90: 595–608. 61 Jensen DM, Kovacs TOG, Jutabha R, et al. Randomized, controlled trial of medical therapy compared to endoscopic therapy for prevention of recurrent ulcer hemorrhage in patients with nonbleeding adherent clots. Gastroenterology 2002; 123: 407–13. 62 Yousfi M, Gostout CJ, Baron TH, et al. Postpolypectomy lower gastrointestinal bleeding: potential role of aspirin. Am J Gastroenterol 2004; 99: 1785–9. 63 Hui AJ, Wong RM, Ching JY, et al. Risk of colonoscopic polypectomy bleeding with anti-coagulants and antiplatelet agents: analysis of 1657 cases. Gastrointest Endosc 2004; 59: 44–8. 64 Eisen GM, Baron TH, Dominitz JA, et al. Guideline on the management of anticoagulation and antiplatelet therapy for endoscopic procedures. Gastrointest Endosc 2002; 55: 775–9. 65 Machicado GA, Jensen DM. Bleeding colonic angiomas and radiation telangiectasias: endoscopic diagnosis and treatment. Tech Gastrointest Endosc 2001; 3: 185– 91.

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Endoscopy in Inflammatory Bowel Diseases Geert D’Haens,1 Severine Vermeire,2 Gert Van Assche2 & Paul Rutgeerts2 1

Imelda General Hospital, Bonheiden, Belgium University Hospitals Gaithuisberg, Leuven, Belgium

2

Introduction The widespread availability of gastrointestinal endoscopy has changed the management of inflammatory bowel diseases (IBDs) to an important extent. In this chapter we will describe the most characteristic lesions of Crohn’s disease and ulcerative colitis, the value of endoscopy in the initial assessment and monitoring of IBD and therapeutic endoscopic interventions.

Characteristic endoscopic findings in inflammatory bowel disease The nature and distribution of the mucosal abnormalities will often allow an experienced endoscopist to diagnose IBD with a good level of confidence. In some instances, though, the endoscopic picture may have features of both Crohn’s disease and ulcerative colitis, and then the term “unclassified colitis” is more appropriate. Biopsies will confirm the suspected endoscopic diagnosis in the majority of cases, with signs of nonspecific idiopathic inflammation and chronicity, although the latter may be less apparent in recent-onset disease. Only in a minority of cases is the diagnosis of Crohn’s disease confirmed by the presence of granulomas on biopsy [1–3].

Table 48.1 Typical endoscopic findings in active Crohn’s colitis. Aphthous ulcerations Deep irregular-shaped ulcerations Longitudinal ulcerations Cobblestones Discontinuous involvement (patchiness/skip areas) Luminal narrowing Fistulas

is confined to the small bowel in approximately 30% of cases [5,6]. The aphthous ulcer is the earliest and most characteristic endoscopic finding in Crohn’s disease (Table 48.1). It can be found throughout the gastrointestinal tract. An aphthous ulcer is a small (maximum size of 5 mm) superficial ulcer surrounded by a characteristic tiny rim of erythema (Figure 48.1). Aphthous ulcers can appear in a single segment or be spread throughout the colon [6–10]. They are often seen in groups, tend to enlarge concentrically, and give rise to larger and deeper ulcerations. Larger and deeper ulcers are also commonly observed [11]. They have clear margins and are often surrounded by

Crohn’s disease Crohn’s disease can affect any part of the gastrointestinal tract, including the oropharynx and the anorectum. Once the disease has settled in, the extent and location tends to stay the same in most patients, although exceptions do occur, especially following surgical resections [4]. The commonest involvement is ileocecal, observed in 41–55% of patients with Crohn’s disease. Colonic Crohn’s disease without small bowel involvement is less common (5–25%). Crohn’s disease

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Figure 48.1 Array of aphthous ulcers: small hyperemic nodules with central erosions are the first manifestations of Crohn’s disease.

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Figure 48.2 Typical longitudinal ulcers interspersed with nodularity (cobblestoning) in severely active Crohn’s colitis.

normal colonic mucosa with very little reactive change (Figure 48.2). The ulcers can be of various sizes and shapes including deep, punched-out ulcerations, stellate ulcers, or longitudinal, tortuous, or serpiginous ulcerations. The mucosa lying between long linear ulcerations can be normal or very edematous, reddish, and hyperplastic, almost polyp like. This is referred to as the cobblestone appearance (Figure 48.2) [10]. Different areas of the colon can be involved within a specific patient, and larger areas may be completely spared from disease (i.e., patchiness). An example of this is the typical “rectal sparing,” which has been reported in up to half of the cases. If the rectum is involved (5–10% of colonic Crohn’s disease), however, the inflammatory activity in this area is not indicative of the severity more proximally [12]. In the prospective European Cooperative Crohn’s Disease Study (ECCDS), fissure or cleft-like ulcerations and aphthous lesions were the most common abnormalities, followed by pseudopolyps, cobblestone lesions, and stenosis. A segmental pattern was the most common form of ulceration, whereas only 14% of patients had a continuous pattern of ulcerations [13]. Where the inflammation is deep and extensive, luminal narrowing or strictures can occur (Figure 48.3) [9,10]. Strictures virtually always arise in areas of severe ulceration. Both the length and width of the strictures can vary considerably, ranging from less than 3 to more than 10 cm in length and to less than 5 mm in width [5,12]. Features that suggest possible malignancy within a stricture include rigidity, nodularity at the margins, and an eccentric lumen [14,15]. The

Endoscopy in Inflammatory Bowel Diseases

Figure 48.3 Ulcerated stricture in an area of severe Crohn’s inflammation in the colon with surrounding ulcerations. Biopsies should always be taken to exclude malignancy.

inflammation and ulcerations in Crohn’s disease are often transmural and can lead to perforation, inflammatory mass, and/or fistula formation, reported in up to 8% of patients with Crohn’s colitis. Fistulas are most often seen proximal to strictures and are frequently surrounded by extensive inflammatory changes [6]. When the active disease becomes quiescent (Table 48.2), signs of chronic inflammation often remain visible, with a diminished or disturbed vascular pattern, sometimes with fibrosis causing scarring or deformity (Figure 48.4). In patients with more extensive disease, healing may be more irregular and hypertrophic zones may alternate with areas of atrophy. This gives rise to inflammatory polyps, often called pseudopolyps. When Crohn’s disease involves the upper gastrointestinal tract, it is almost invariably accompanied by small bowel or

Table 48.2 Endoscopic findings in chronic or quiescent Crohn’s colitis. Attenuated or loss of vascular pattern Mucosal bridging Pseudopolyps Stricture formation

Figure 48.4 Healing of colonic ulcers may lead to extensive scarring due to fibrosis.

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colonic disease [16–18]. The prevalence of upper gastrointestinal tract involvement is much higher in prospective studies of both symptomatic and asymptomatic patients (17–75% for upper endoscopy) than in retrospective series (0.5–13%) [19–25]. In retrospective series, oral lesions were more frequent (6– 9%) than gastroduodenal (1.8–4.5%) and esophageal (1.8%) involvement. Esophageal involvement is usually seen in seriously ill patients presenting with dysphagia, odynophagia, heartburn, and chest pain. Characteristic endoscopic features in the esophagus include hyperemia, granularity, friable mucosa, erosions or aphthoid lesions, ulcers, nodular thickening, cobblestones, and stenosis [19–25]. The true incidence of gross gastroduodenal involvement by Crohn’s disease is unclear. Reported incidence ranges from 2% to 49% of patients with Crohn’s ileocolitis [26–29]. However, many patients do not have endoscopically detectable lesions in the stomach and duodenum, but examination of biopsies may reveal histopathologic changes suggestive of Crohn’s disease [29–33]. Gastroduodenal involvement often leads to symptoms similar to peptic ulcer disease or nonulcer dyspepsia, such as epigastric pain, anorexia, and, sometimes, signs of gastric outlet obstruction. In isolated duodenal disease, any part of the duodenum can be involved but the second part is most frequently affected, with typical mucosal defects on top of the Kerckring’s folds, called “notching.” In the duodenum stricturing may also occur.

Ulcerative colitis In ulcerative colitis the inflammation extends typically from the anal verge up to a variable distance, which can change during the course of the disease. Since the rectum is virtually always involved in this disease, a rigid proctoscopy or a flexible rectosigmoidoscopy is often sufficient for evaluation during follow-up. In patients whose disease is limited to the left colon, a flexible sigmoidoscopy can be used. However, when topical treatment is being used, the rectum may appear relatively normal in spite of the fact that more proximal segments remain inflamed. With more extensive involvement, a full colonoscopy with ileoscopy is advised to help differentiate ulcerative colitis from Crohn’s colitis [16,34]. It is generally accepted that one should be cautious in performing endoscopic examinations in patients with fulminant colitis, given the increased risk of perforation and toxic megacolon [35–37]. Ulcerative colitis may involve the rectum (proctitis, approximately 30%), the rectosigmoid area (proctosigmoiditis or distal ulcerative colitis), the left colon (left-sided colitis in 30–40%), or the entire colon (total colitis, approximately 30%) [38]. In a large Scandinavian cohort study, extension of disease was reported in up to 40% of patients during long-term followup, although 44% of patients with initial extensive colitis showed regression [39]. The endoscopic appearance of ulcerative colitis is quite characteristic (Table 48.3). Unlike Crohn’s disease, the inflamma-

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Table 48.3 Characteristic endoscopic findings in ulcerative colitis. Continuous involvement Erythema Friability Granular appearance Microulcerations, shallow ulcerations Cecal patch

tion is continuous and circumferential from the anal verge up to the limit of involvement. The mucosa shows erythema, friability, and often frank superficial bleeding (Figure 48.5). Slight edema usually causes a shiny appearance. Additionally, there may be granularity with a typical grayish discharge. In moderate ulcerative colitis, one can appreciate erosions and microulcerations, and in more severe attacks shallow ulcerations may develop (Figures 48.6 and 48.7). Only rarely do deep ulcerations and luminal narrowing occur. “Cecal patch” inflammation represents a limited zone of colitis surrounding the appendiceal orifice in patients with left-sided colitis [40–43]. In patients with longstanding moderate to severe colitis, the colonic mucosa will show signs of chronic inflammation and healing with pseudopolyps and even mucosal bridging and an attenuated or loss of vascular pattern. Once stricture formation is encountered, a high level of suspicion is warranted as this may be a sign of dysplasia or malignancy. It may be difficult to detect dysplastic lesions especially in a scarred colon with many pseudopolyps. Because of this, colonoscopies performed for prevention of colorectal cancer in patients with longstanding pancolitis should always include multiple biopsies from all different segments [44].

Figure 48.5 Active ulcerative colitis: mucosa with disappearance of vascular pattern and presence of mucopus and friability.

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Figure 48.6 Severe ulcerative colitis characterized by superficial ulceration.

Figure 48.7 Spontaneous bleeding mucosa in severe active ulcerative colitis.

Differentiation between Crohn’s disease, ulcerative colitis, and colitis unclassified

areas, and deeper ulcerations [45]. In these patients the term “indeterminate colitis” or “unclassified colitis” should be used as a reminder that the differential diagnosis is not completely clear [46].

In the majority of patients with chronic idiopathic colitis the differential diagnosis between Crohn’s disease and ulcerative colitis will be quite clear (Table 48.4). Pera et al. [45] prospectively examined 357 patients with colonoscopies in order to determine the accuracy and “weight” of various endoscopic signs. Complete colonoscopy allowed a correct differentiation between Crohn’s disease, ulcerative colitis, and “indeterminate colitis” or “colitis unclassified” in 89% of cases, with 4% errors and 7% indeterminate diagnoses. Errors were more frequent in the presence of severe colonic inflammation. The most distinctive endoscopic features in the differential diagnosis were discontinuous involvement, anal lesions, and cobblestoning of the mucosa for Crohn’s disease and erosions, microulcers, and granularity for ulcerative colitis. Between 5% and 10% of patients showed abnormalities that were suggestive of both conditions, and most of these patients had an ulcerative colitis-like endoscopy with one or more features possibly suggesting Crohn’s disease. These so-called “indeterminate features” included anal abnormalities (such as skin tags, an unusual fissure, or an abscess), rectal sparing, skip

Endoscopic assessment of extent and severity of inflammatory bowel disease Knowledge of the location of the intestinal inflammation affects management decisions, since certain medications release their active component in selected segments of the bowel. The extent of inflammation tends to be underestimated in both ulcerative colitis and Crohn’s disease. The severity of the inflammatory lesions also has some prognostic value in a number of situations. In ulcerative colitis, for example, deep ulcers are an indicator of a poor response to medical therapy. In Crohn’s disease, the severity of endoscopic lesions in the neoterminal ileum after an ileocolonic resection is an indicator of the ensuing clinical disease behavior [47]. The French GETAID (Groupe d’Etudes Thérapeutiques sur les Affections Inflammatoires Digestives) study developed

Table 48.4 Differentiation of Crohn’s disease and ulcerative colitis. Crohn’s disease

Ulcerative colitis

Discontinuous involvement Cobblestoning Aphthous ulcers Deep, longitudinal, serpiginous ulcers Rectal sparing or segmental inflammation Anal lesions Ileocecal valve stenotic and ulcerated

Continuous involvement Erosions/microulcers Loss of vascular pattern Rectal involvement Ileocecal valve patulous and free of ulceration

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Table 48.5 Endoscopic indices for ulcerative colitis. Powell-Tuck et al. [53] Sutherland et al. [54] Rutegard et al. [55] Schroeder et al. [56]

0: no bleeding 0: normal 0: normal 0: normal

1: bleeding on light touch 1: mild friability 1: nonvisible vessels; friability 1: disturbed vessels; friability; granularity

and validated a “Crohn’s disease endoscopic index of severity” (CDEIS). The four mucosal lesions that were found to be of significant importance to establish a final formula for CDEIS calculation were deep ulcerations, superficial ulcerations, and nonulcerated and ulcerated stenosis. For each of five colonic segments, the proportion of surface that is ulcerated or affected by any other lesions was also scored. With this score interobserver agreement was excellent (P < 0.001) [48]. Surprisingly, a significant correlation between clinical disease activity index (CDAI), biochemical markers, and CDEIS could not be established with this score [49]. More than a decade later, a Belgian group of investigators developed and validated a simplified endoscopic scoring instrument for Crohn’s disease, the SES-CD (Simple Endoscopic Score for Crohn’s Disease) [50]. This score is based upon four endoscopic lesions which were found to be relevant for disease and symptom severity: ulcer size, ulcerated and affected surface, and stenosis, all scored from 0 to 3 in five different segments. The interobserver agreement for the selected endoscopic variables was excellent (kappa coefficient 0.791–1.000). A strong correlation between the SES-CD and the CDEIS was demonstrated (r = 0.920). Moreover, the SES-CD could be correlated with clinical parameters and serum C-reactive protein level. The visual analog scale for percentages of surface involved by ulcers and by any lesions of Crohn’s disease is important in the calculation of CDEIS, but it also represents the most time-consuming step. To avoid these measurements and conversions, this item was replaced by “percentage of a given segment affected by ulcerations” in the SES-CD. Although stenosis is an uncommon finding (∼4% of cases) [48], its presence is highly relevant clinically. The classification of stenosis in the SES-CD was not only descriptive but also functional, because it differentiates the degree of luminal narrowing based on whether the colonoscope can be passed through the stenosis. In general, SES-CD score appears to be easier to calculate than the CDEIS score. In ulcerative colitis, endoscopic evaluation is important for the assessment of disease activity. The mucosal appearance correlates better with the clinical course of the disease than in Crohn’s disease. Therefore, endoscopic criteria have been included in the majority of clinical trials. Several endoscopic scoring instruments have been developed. All scores distinguish three or four stages of mucosal alterations based on the

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2: spontaneous bleeding 2: moderate friability 2: ulcers, single or scattered 2: loss of vascular pattern; mucopus; spontaneous bleeding

3: exudation, spontaneous bleeding 3: confluent ulcers with pus 3: ulcers; mucopus; spontaneous bleeding

disturbance or disappearance of the vascular pattern, presence of friability and/or bleeding of the mucosa, and presence of several types of ulcers and/or mucopus. An overview of the most important scores is given in Table 48.5 [51–56]. The most commonly used scoring instrument today is the “Mayo score,” based on the study by Schroeder and colleagues. This scoring system was also used for two large registration trials for infliximab in ulcerative colitis, Act-1 and Act-2 [57]. In the Mayo system, a score of “0” represents normal mucosa without friability, “1” disturbed vessels, granularity and friability, “2” loss of vascular pattern, presence of mucopus and spontaneous bleeding, and “3” presence of frank ulcers and mucopus [56]. “Endoscopic remission” should ideally represent “absence of friability” [58], but in the Act trials “endoscopic healing” was defined as a Mayo grade 0 or 1 (including friability) [57]. The interpretation of clinical trial results and comparisons among trials should be carried out with extreme caution since the definition of “healing” that is chosen by the investigators may have a significant impact on the outcome parameters. The extent of inflammation in ulcerative colitis often changes during the course of the disease. Niv et al. [59] reported changes in the extent of inflammation in 77% of patients during a mean follow-up period of 17 months.

Surveillance for cancer in chronic colitis Multiple random biopsies throughout the entire colon with targeted biopsies of any lesion is the standard approach to the early diagnosis and prevention of cancer in colitis. Dye spray of the colon mucosa to enhance the finding of dysplastic areas (see Chapter 35) has been reported to be of benefit.

Endoscopic assessment of the small bowel with video capsule and double-balloon techniques (see Chapter 23) The diagnosis of small bowel Crohn’s disease is sometimes difficult and may be missed by conventional imaging techniques. Video capsule endoscopy (VCE) and double-balloon endoscopy have been developed to allow better and direct

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examination of the small bowel. VCE, in particular, has been promoted and studied widely since it is safe, noninvasive and well tolerated. The most frequent indications for VCE or double-balloon endoscopy of the small bowel have been the assessment of obscure gastrointestinal bleeding, angiodysplasia, Crohn’s disease, celiac disease, hereditary polyposis syndromes, and small bowel tumors [60,61]. However, a suspected critical intestinal stricture is a contraindication for conventional VCE given the risk of impaction of the capsule. Patency capsules with a biodegradable body that disintegrates into small fragments beyond a stipulated time have been developed to overcome this problem [62]. Many prospective studies have compared VCE with conventional radiologic [computed tomography (CT) or magnetic resonance (MR) enterography or enteroclysis, and barium small bowel follow-through] or endoscopic (ileocolonoscopy, push enteroscopy) examinations for the diagnosis of Crohn’s disease. In most studies, however, both patients with suspected Crohn’s disease as well as patients with established Crohn’s disease were included. Since there are no generally accepted criteria for “suspected Crohn’s disease,” it is difficult to calculate the sensitivity, specificity, and positive predictive value of VCE for Crohn’s disease. Although the results of the individual studies were promising, suggesting superiority of VCE over the other modalities, sample sizes were small in most studies [63– 68]. A meta-analysis of nine studies and a total of 250 patients showed that VCE is superior to all other conventional techniques for diagnosing nonstricturing small bowel Crohn’s disease [69]. The yield for VCE versus barium radiography for all patients was 63% and 23%, respectively, giving an increased yield for VCE of 40% [95% confidence (CI) 28–51%], and for VCE versus ileocolonoscopy (n = 114) the corresponding figures were 61% and 46%, respectively, resulting in an increased yield of 15% (95% CI 2–27%). The meta-analysis concluded that the number needed to test to give one additional diagnosis of Crohn’s disease with VCE over small bowel barium radiography was 3 and for VCE compared with ileocolonoscopy was 7. Studies comparing VCE with CT enterography/CT enteroclysis (n = 93 patients) also demonstrated superiority of VCE. However, subgroup analysis reported that the overall positive results were seen only in patients with established nonstricturing Crohn’s disease. There was no significant difference in yield in favor of VCE for diagnosing small bowel Crohn’s disease in patients with a suspected initial presentation of Crohn’s disease. VCE seems to be particularly superior in detecting small mucosal lesions that may be missed by magnetic resonance imaging (MRI) or CT, such as villous denudation, aphthoid ulcerations, or erosions. MRI, in contrast, is helpful in identifying transmural Crohn’s disease and extraluminal lesions, and may also exclude strictures [66]. The two modalities therefore may be complementary. Since not all small lesions detected by VCE will represent Crohn’s ulcerations, differential diagnosis must include nonsteroidal anti-inflammatory

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drug (NSAID)-induced lesions or physiologic lesions seen in normal volunteers. A standard terminology system has been developed, along with a capsule endoscopic CD severity scoring index, and is currently undergoing validation studies [69]. In this way, future clinical trials can be standardized. The role of VCE has also been assessed in the postoperative setting. It is well known that, after curative resection for Crohn’s disease, early endoscopic recurrence predicts recurrence of symptoms. At least two postoperative studies have compared VCE and ileocolonoscopy 6 months following surgery [70,71]. In the first study, the sensitivity of VCE in detecting recurrence in the neoterminal ileum was inferior to that of ileocolonoscopy (62% vs. 90%). In contrast, VCE detected lesions outside the scope of ileocolonoscopy in more than two-thirds of patients. The second study found that VCE had a greater sensitivity and was better tolerated than colonoscopy in the evaluation of recurrence. At present, it seems that VCE should not systematically replace ileocolonoscopy in the follow-up of patients after surgery. However, VCE might be indicated in patients with symptoms in whom ileocolonoscopy was normal to detect lesions outside of the scope of ileocolonoscopy. One of the clinical situations in which VCE or doubleballoon endoscopy would be helpful is in patients with indeterminate colitis or irritable bowel disease (IBD) of type unclassified (IBDU, defined as chronic IBD with inflammation restricted to the colon). Typically, an inconclusive endoscopy and microscopic features of crypt architectural distortion (more than 10% of crypts) and patchy acute and chronic inflammation with no particular diagnostic features for either Crohn’s disease or ulcerative colitis are described. A working group on the molecular classification of IBD suggested that a careful upper gastrointestinal evaluation including gastroscopy and, when normal, video capsule endoscopy or double-balloon enteroscopy may be useful [72]. Two studies have been published in this setting and have come to almost identical conclusions. The first analyzed all VCEs performed between 2001 and 2005 in patients with ulcerative colitis or IBDU [73]. The finding of multiple ulcerations (three or more) on capsule endoscopy was classified as diagnostic of small bowel Crohn’s disease. The authors found that in 19 of 120 patients (16%) VCE showed findings consistent with the diagnosis of Crohn’s disease. Interestingly, among the patients with positive findings on VCE, 18 had previously undergone a small bowel followthrough, but only one showed radiologic findings consistent with Crohn’s disease. In a French multicenter study [74], 30 patients with IBDU and negative serology for ASCA and pANCA underwent VCE, and three or more ulcerations were taken as suggestive of Crohn’s disease. VCE displayed endoscopic features suggestive for Crohn’s disease in 5/30 (17%) patients. These data support the consideration that VCE is a potentially clinically useful technique for categorizing a subgroup of patients with IBDU and that it is more sensitive than serological markers.

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Endoscopic monitoring of therapeutic efficacy and its value in clinical trials The relationship between endoscopic severity and clinical activity is often poor in Crohn’s disease, but not in ulcerative colitis. In Crohn’s disease, the clinical evolution of the disease does not predict or correlate with improvement of the bowel mucosa. The French GETAID study demonstrated that endoscopic healing of ulcerations could be detected in only about one-quarter of patients in clinical remission on corticosteroid treatment. Persistence of lesions was not predictive of early relapse, and adjustment of steroid treatment duration based on endoscopic findings proved to be without benefit. It was concluded at that time that endoscopic monitoring of “healing” is a waste of time and money [11,75,76], although it needs to be emphasized that this statement may be applicable only to treatment with corticosteroids. In general, the pattern of healing of endoscopic lesions under glucocorticoid therapy depends on the location of the lesions: esophageal lesions almost completely and rapidly disappear, whereas gastric lesions hardly show any change, even with symptomatic relief. Ileal lesions have the same tendency to persist, whereas colonic lesions can heal slowly after tapering of the steroids [77]. Data on mucosal healing with anti-inflammatory agents other than glucocorticosteroids are scarce. Azathioprine has been shown to induce significant healing in Crohn’s ileocolitis, colitis, and severe postoperative recurrent ileitis [78,79]. Variable degrees of ileal and colonic healing have also been reported with methotrexate [80]. The most impressive and rapid healing of Crohn’s disease lesions was observed after treatment with the monoclonal antibody against tumor necrosis factor, infliximab [81]. A group of European investigators demonstrated significant healing of colonic lesions only 4 weeks after intravenous administration of a single dose of this drug. All parts of the colon improved to the same extent. A significant correlation between clinical improvement (CDAI) and endoscopic changes (CDEIS) was demonstrated [82]. A few patients in this study developed fibrous strictures, which were dilated endoscopically. Mucosal healing with infliximab was also demonstrated in the endoscopic substudy of the Accent 1 trial [83]. Patients with Crohn’s (ileo)colitis who were treated with infliximab induction with 5 mg/kg at weeks 0, 2, and 6 and who received maintenance therapy with infliximab i.v. every 8 weeks had significantly higher rates of mucosal healing than patients who received episodic therapy on flare of symptoms. In that study mucosal healing was associated with a better outcome of Crohn’s disease, with less hospitalizations and fewer surgeries over the 54-week period of the study. As a consequence, there is currently a lot of interest in the predictive value of mucosal healing for long-term change in the outcome of both Crohn’s disease and ulcerative colitis.

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In ulcerative colitis there is a good correlation between the severity of symptoms and endoscopic severity of bowel inflammation, although the severity of the symptoms is greatly influenced by the extent of the disease. In ulcerative colitis, symptomatic improvement under anti-inflammatory therapy is closely paralleled by mucosal improvement, and patients who achieve remission with absence of blood in the stools mostly also present with endoscopic remission. Endoscopic healing in ulcerative colitis can be achieved with most drugs, including 5-aminosalicylic acid, steroids, immunosuppressives, and infliximab. Endoscopic healing is always an important endpoint in therapeutic trials in ulcerative colitis, and most indexes, such as the widely used Mayo score, include endoscopic activity in the scoring system.

Perioperative endoscopy in Crohn’s disease Up to 70% of the patients with Crohn’s disease will undergo at least one surgical resection of inflamed bowel segments, usually in order to treat complications of the disease. Most often, the surgeon aims to be curative, i.e., to resect all macroscopic disease, although sometimes resections are limited to segments which are responsible for the symptoms, leaving active disease behind (segmental resection). More and more patients are treated with strictureplasties, whereas bypass operations are no longer performed. After surgery, most patients will suffer recurrence of their disease [84]. Risk factors for early symptomatic recurrence are perforating indications for surgery (abscess or fistula), ileocolonic anastomosis, and smoking. Ileocolonoscopy is a key method for planning treatment strategies in the pre- as well as postoperative period. To optimize the outcome of surgery, it is essential to study the anatomical distribution of Crohn’s involvement prior to surgery. This has become even more imperative with the broader use of the laparoscopic surgical approach, since reliable evaluation of disease extent based on serosal inspection may sometimes be difficult. If colonoscopy demonstrates that the colon is spared, the surgeon should perform an ileal resection with ileocecal or ileoascending anastomosis. If right colonic disease is visualized, the surgeon should extend the colonic resection guided by colonoscopic findings and anastomose the neoterminal ileum to uninvolved colon. Systematic endoscopic studies following curative resection in Crohn’s disease have allowed study of the natural history of the evolution of Crohn’s disease from the earliest lesions to full-blown Crohn’s disease. Within weeks to months after resection with ileocolonic anastomosis, “new” lesions can already be visualized in the neoterminal ileum [8,85]. Ileocolonoscopic studies after surgery also allow prediction of the clinical outcome of Crohn’s disease after resection. The severity of recurrent lesions as visualized at endoscopy predicts the clinical evolution in the years following surgery

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Table 48.6 Scoring system for recurrent lesions of Crohn’s disease in the neoterminal ileum. i0: no lesions i1: < 5 aphthous lesions i2: > 5 aphthous lesions with normal mucosa between the lesions or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis i3: diffuse aphthous ileitis with diffusely inflamed mucosa i4: diffuse inflammation with already larger ulcers, nodules and/or narrowing

[47]. The severity of recurrent lesions early after resection is assessed using an endoscopic scoring system (Table 48.6). Patients displaying no or only mild lesions (score i0, i1) do well over time and carry a low risk of rapid symptomatic relapse, whereas patients presenting with diffuse severe endoscopic recurrence (score i3, i4) are at risk of progressive clinical disease. Patients with endoscopic lesions of intermediate severity also have an intermediate risk. This score has been valuable for studies of drug prophylaxis of postoperative recurrence [86,87]. Patients with an ileostomy can also develop recurrent inflammation in the most distal ileal segments, but the risk is much lower than after an ileocolonic reanastomosis. Endoscopic examination of the bowel proximal to the stoma allows easy and precise evaluation of the abnormalities and collection of biopsies.

Endoscopic features of the ileo-anal pouch and pouchitis Restorative coloproctectomy with ileal pouch–anal anastomosis (IPAA) has become an established surgical option for patients with severe ulcerative colitis [88]. The most common long-term complication besides intestinal obstruction is inflammation of the pouch, known as pouchitis. Approximately 50% of patients with an IPAA can be expected to develop an episode of pouchitis [89]. This inflammation becomes chronic in only 5% of patients. Although the inflammation remains limited to the pouch reservoir in the majority of patients, extension into the prepouch ileum can occur. The endoscopic features of pouchitis resemble those of ulcerative colitis: at an early stage erythema, fading of the vascular pattern, granularity, and friability appear. Later, punctiform mucosal hemorrhages, mucus secretion, adherent purulent material, and superficial ulcerations develop. Less frequently, large isolated ulcers with normal surrounding mucosa can be found, as in Crohn’s disease. Undiagnosed Crohn’s disease is a rare but important differential diagnosis, particularly if large ulcers or fistulas (e.g., pouch–vaginal fistulas) are present. Rarely, pseudomembranous lesions may be

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observed, which mandates stool sampling to exclude Clostridium difficile infection. Several scores to assess the severity of pouchitis have been developed, the first of which was proposed by Moskowtiz et al. [90] applying very strict clinical and endoscopic criteria. Sandborn and colleagues [91] introduced the Pouchitis Disease Activity Index (PDAI), combining clinical, endoscopic, and histological findings, which is now most often used in clinical studies. This score evaluates the presence of edema, granularity, friability, faded vascular pattern, mucus, and ulceration. A similar score, the pouchitis activity score (PAS), was proposed by the Heidelberg group and utilizes the same endoscopic criteria but differentiates between mild and severe lesions [92]. The treatment of pouchitis should aim not only at symptomatic improvement, but also at complete healing and restoration of the pouch mucosa. Pouchitis generally involves most of the pouch reservoir and should be differentiated from “cuffitis.” This entity represents a recurrence of ulcerative colitis in the short cuff of the rectoanal transitional zone that has been preserved in case of a double-stapled pouch anastomosis. It usually extends over a distance of 1 cm. The endoscopic feature is that of a distal ulcerative proctitis with a clear demarcation to ileal pouch mucosa. It is important to know that mucosal dysplasia can occur in this transitional zone, although the risk is very low [93].

Endoscopic therapy of strictures in Crohn’s disease Successful endoscopic dilation of anastomotic strictures in Crohn’s disease using through-the-scope (TTS) rigid balloons was first reported in 1981 and has emerged as an alternative to surgery for selected patients. Careful patient selection is of paramount importance to optimize the outcomes of both endoscopic and surgical strictureplasty. Endoscopic balloon dilation is indicated for relatively short (maximally 5 cm), symptomatic strictures in the upper and lower gastrointestinal tract at ileocolonic anastomosis or for intrinsic colonic strictures, which are generally easily accessible. A carefully performed barium meal or CT/MRI enteroclysis to assess the number of strictures, the length and angulation of the targeted lesion, and the presence of prestenotic dilation is mandatory to allow for a proper prediction of successful outcome. Several series have been published in the last 10 years (Table 48.7) with immediate success rates varying between 71% and 100% [94–105]. We usually maintain inflation for 2 min with at least 1 min at maximal pressure (5–7 atm). Several insufflations in one session are possible. Balloon sizes vary up to 25 mm diameter [96]; starting with a smaller diameter and increasing the size may be safer, but even a 10-mm balloon has been reported [105] to result in a perforation.

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Table 48.7 Outcomes and complications of published series on endoscopic balloon dilation for Crohn’s disease strictures. Reference

Number of patients

Percent anastomotic

Short-term success rate (%)

Symptomatic recurrence (mean follow-up months)

No. (%) of complications (perforations)

Blomberg et al. [95] Couckuyt et al. [96] Raedler et al. [101] Sabate et al. [97] Dear and Hunter [99] Thomas-Gibson et al. [104] Morini et al. [113] Singh et al. [105]

27 55 30 38 22 59 43 17

100 62 NS 68 95 90 72 24

85 90 NS 84 99 NS 79 96

33% (19) 6% (34) 53% (12), 20% (budeson)a 63% (60) 73% (46) 41% (29) 42% (64) 76% (18)

15 (7%) 11% (11) NS 9% 0% 2% 6% (0) 10%

Only series with at least 15 patients were selected. a Patients were randomized to azathioprine + budesonide 9 mg or placebo for 12 months. NS, not specified.

Passage of a conventional colonoscope through the dilated stricture is a good predictor of successful dilation, but alleviation of obstructive symptoms is the most important outcome. The major complications of endoscopic dilation include bleeding and perforation. In the reported series, 0–11% of patients presented with a major complication. Perforations after endoscopic dilation are mostly concealed and can usually be managed conservatively. There is a theoretical risk of missing malignancy with endoscopic and surgical strictureplasty. Although isolated reports of ileal adenocarcinoma at the site of surgical strictureplasty have been published [106–108], one should realize that this malignancy is exceedingly rare, even in Crohn’s disease patients. The risk is higher in patients with intrinsic colonic strictures, and multiple biopsies should be obtained from stenotic segments. Symptom recurrence after endoscopic balloon dilation has been reported in 13–100% of patients (Table 48.7). However, not all of these patients need surgery. Repeated dilation is a valid option, but the length of the symptom-free interval will be the main parameter used to decide between surgery and repeat of endoscopic dilation. Because of suboptimal long-term outcomes of endoscopic balloon dilation, adjuvant techniques have been studied. In one series unsuccessful balloon dilation was supplemented by incising the stricture with a sphincterotome [109], which did not result in additional complications. Also, more recently, endoscopic stenting of ileocolonic stenoses has been reported in a limited number of patients with beneficial outcome [110]. The administration of intramural or topical corticosteroids to prevent restenosis is common practice during dilation of caustic esophageal strictures and has been reported in patients with Crohn’s disease. Unfortunately, no prospective randomized study has been published as a full paper, but uncontrolled prospective and retrospective data have suggested beneficial

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effects of this technique [98]. However, a recent controlled prospective trial in a small number of patients showed no benefit of intramural steroid injection and, if anything, there was a trend to an accelerated restenosis [111]. Preliminary data indicate that patients receiving budesonide along with azathioprine after dilation are more likely to experience a good long-term outcome than patients receiving azathioprine alone [101]. Local injection of Crohn’s strictures with the antitumor necrosis factor agent infliximab has not been tested and should be considered experimental. An uncontrolled trial of infliximab injection in patients with postoperative Crohn’s recurrence at the ileocolonic anastomosis has been reported [112], but this approach needs further evaluation as it carries a risk of immunization against infliximab. The choice between endoscopic dilation and surgical strictureplasty is usually evident since both techniques are indicated for different types of strictures. Endoscopic balloon dilation should be reserved for short and isolated Crohn’s diseaserelated stenoses accessible with conventional endoscopes, particularly at the ileocolonic anastomosis [113]. Given the acceptable long-term avoidance of surgery and low complication rates, endoscopic dilation should be considered in these patients to avoid surgical resection. Surgical strictureplasty is indicated for multiple strictures, longer stenoses, and lesions beyond the reach of the endoscope. Ileocolonic or colocolonic anastomoses are notably cumbersome for surgical strictureplasty, leaving endoscopic dilation as the best bowel-preserving option. However, for both endoscopic and surgical strictureplasty, radiological studies are helpful in selecting patients and avoiding unnecessary procedures. Anal or supra-anal dilation is usually performed with a thin endoscope and additional Savary bougie dilation. The procedure can be reinforced by home autodilation of the stenosis. It is our opinion that balloon dilation of the anus is not recommended because of the potential risk of sphincter damage.

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Table 48.8 Indications for (ileo)colonoscopy in Crohn’s disease. 1 Establishing the correct diagnosis of inflammatory bowel disease Differential diagnosis of Crohn’s colitis versus ulcerative colitis Or infective/acute self-limited colitis 2 Assessment of extent and grading of severity 3 Preoperative delineation of the diseased areas 4 Postoperative evaluation of recurrent Crohn’s disease diverted bowel segments 5 Endoscopic balloon dilatation of (ileo)colonic strictures 6 Investigation of radiographic abnormalities (strictures, mass lesions)

Conclusion: indications for endoscopy in inflammatory bowel disease The endoscopic evaluation of patients with IBD is extremely valuable (Table 48.8) and has changed the management of these diseases. Ileocolonoscopy has replaced contrast enema as the first evaluation of patients with suspected IBD. Nonetheless, these procedures are justified only when they are likely to influence therapeutic decisions. Ileocolonoscopy can be necessary to establish an exact (“tissue”) diagnosis, to determine the severity and extent of inflammatory activity, in the preoperative setting to “guide” the surgeon, and to examine the bowel proximal to stomas. Early endoscopic examination of the ileocolonic anastomosis after resection of the terminal ileum and part of the colon enables evaluation of the severity of recurrence of Crohn’s disease, predicting clinical outcome. Endoscopic examination of the upper gastrointestinal tract should be performed whenever upper gastrointestinal symptoms develop in patients with Crohn’s disease. It is important for the treatment to differentiate between intrinsic Crohn’s lesions, peptic disease, or drug-associated lesions in the esophagus, stomach, or duodenum. Endoscopic observations certainly have therapeutic consequences in pouchitis, in patients with Crohn’s disease following surgical resection, and in severe attacks of ulcerative colitis. Complete mucosal healing should be a therapeutic goal in all patients with ulcerative colitis. Whether it should also be a therapeutic goal in Crohn’s disease remains to be established.

References 1 Schmitz-Moormann P, Pittner PM. The granuloma in Crohn’s disease: bioptical study. Pathol Res Pract 1984; 178: 467–76.

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2 Rotterdam H, Korelitz BI, Sommers SC. Microgranulomas in grossly normal rectal mucosa in Crohn’s disease. Am J Surg Pathol 1977; 67: 550– 4. 3 Potzi R, Walgram M, Klozner H, Gangl A. Diagnostic significance of endoscopic biopsy in Crohn’s disease. Endoscopy 1989; 21: 60–2. 4 Louis E, Collard A, Oger A, De Groote E, Belaiche J. Location and behavior of Crohn’s disease according to Vienna classification: evolution over the course of the disease. Gastroenterology 2001; 120: A-141 (abstract). 5 Farmer RG, Hawk WA, Turnbull RB. Clinical patterns in Crohn’s disease: a statistical study of 615 cases. Gastroenterology 1975; 68: 627–35. 6 Mekhjian HS, Switz DM, Melnyk CS, Rankin GB, Brooks RK. Clinical features and natural history of Crohn’s disease. Gastroenterology 1979; 77: 898–906. 7 Watier A, Devroede G, Perey B, Haddad H, Madarnas P, GrandMaison P. Small erythematous mucosal plaques: an endoscopic sign of Crohn’s disease. Gut 1980; 21: 835–9. 8 Rutgeerts P, Geboes K. Crohn’s disease and pre-aphthoid lesions. Lancet 1993; 341: 1443– 4. 9. Hogan WJ, Hensley GT, Geenen JE. Endoscopic evaluation of inflammatory bowel disease. Med Clin N Am 1980; 64: 1083–102. 10 Meuwissen SGM, Pape KSSB. Agenant D, Oushoorn HH, Tytgat GNJ. Crohn’s disease of the colon: analysis of the diagnostic value of radiology, endoscopy and histology. Am J Dig Dis 1976; 21: 81– 8. 11 Modigliani R, Mary JY, Simon JF, et al. Clinical, biological and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Gastroenterology 1990; 98: 811–18. 12 Blackstone MO. Inflammatory bowel disease. In: Blackstone MO (ed.). Endoscopic Interpretation. New York: Raven Press, 1984: 464–94. 13 Lorenz-Mayer H, Malchow H, Miller B, Stock H, Brandes JW. European Cooperative Crohn’s Disease Study (ECDS): colonoscopy. Digestion 1985; 31: 109–19. 14 Waye JD. The role of colonoscopy in the differential diagnosis of inflammatory bowel disease. Gastrointest Endosc 1977; 23: 150–4. 15 Waye J. Colitis, cancer and colonoscopy. Med Clin N Am 1978; 62: 211. 16 Geboes K, Ectors N, D’Haens G, Rutgeerts P. Is ileoscopy with biopsies worthwhile in patients presenting with symptoms of inflammatory bowel disease? Am J Gastroenterol 1998; 93: 201–6. 17 Lescut D, Vanco D, Bonniere P, et al. Perioperative endoscopy of the whole small bowel in Crohn’s disease. Gut 1993; 34: 647–9. 18 Wagtmans MJ, van Hogezand RA, Griffioen G, Verspaget HW, Lamers CBHW. Crohn’s disease of the upper gastrointestinal tract. Neth J Med 1997; 50: S2–7. 19 Witte AMC, Veenendaal RA, van Hogezand RA, Verspaget HW, Lamers CBHW. Crohn’s disease of the upper gastrointestinal tract: the value of endoscopic examination. Scand J Gastroenterol 1998; 225: S1005. 20 Geboes K, Janssens J, Rutgeerts P, Vantrappen G. Crohn’s disease of the esophagus. J Clin Gastroenterol 1986; 8: 31–7. 21 D’Haens G, Rutgeerts P, Geboes K. Esophageal Crohn’s disease: three patterns of evolution. Gastrointest Endosc 1994; 40: 296–300. 22 Decker GAG, Loftus EV, Pasha TM, Tremaine WJ, Sandborn WJ. Crohn’s disease of the esophagus: clinical features and outcomes. Inflamm Bowel Dis 2001; 7: 113–19.

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75 Landi B, Anh TN, Cortot A, et al. Endoscopic monitoring of Crohn’s disease treatment: a prospective, randomized clinical trial. Gastroenterology 1992; 102: 1647–53. 76 Modigliani R, et al. Acute attacks of colonic and ileocolonic Crohn’s disease: Is colonoscopic follow-up useful to adjust steroid treatment duration? Gastroenterology 1990; 98: A193. 77 Olaison B, Sjodahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 1990; 31: 325–8. 78 D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s ileocolitis with azathioprine. Gastrointest Endosc 1999; 50: 667–71. 79 D’Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology 1997; 112: 1475– 81. 80 Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Int Med 1989; 110: 353– 6. 81 Van Dullemen HM, Van Deventer SJH, Hommes DW, et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody(cA2). Gastroenterology 1995; 109: 129– 35. 82 D’Haens G, van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, et al. Endoscopic and histological healing with infliximab antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999; 116: 1029–14. 83 Rutgeerts, et al. Gastrointestinal endoscopy scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006; 63: 433–42. 84 Whelan G, Farmer R, Fazio V, et al. Recurrence after surgery in Crohn’s disease. Gastroenterology 1985; 88: 1826–33. 85 D’Haens G, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 1998; 114: 262–7. 86 Caprilli R, Andreoli A, Capurso L, et al. Oral Mesalazine (Asacol) for the prevention of postoperative recurrence of Crohn’s disease. Aliment Pharmacol Ther 1994; 8: 35–43. 87 Rutgeerts P, Peeters M, Hiele M, et al. A placebo controlled trial of metronidazole for recurrence prevention of Crohn’s disease after resection of the terminal ileum. Gastroenterology 1995; 108: 1617–21. 88 Stocchi L, Pemberton JH. Pouch and pouchitis. Gastroenterol Clin N Am 2001; 30: 223– 41. 89 Meagher AP, Farouk R, Dozois RR, et al. Ileal pouch–anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients. Br J Surg 1989; 85: 800. 90 Moskowitz RL, Sepherd NA, Nicholls RJ. An assessment of inflammation in the resevoir after restorative proctocolectomy with ileoanal ileal reservoir. Int J Colorectal Disease 1986; 1: 167–74. 91 Sandborn WJ, Landers CJ, Tremaine WJ, Batts KP, Pemberton JH, Philips SF. Pouchitis after ileal pouch-anal anastomosis: a pouchitis disease activity index. Mayo Clin Proc 1994; 69: 409–45. 92 Heuschen UA, Autsbach F, Allemeyer EH, et al. Long term followup after ileoanal pouch procedure: algorithm for diagnosis,

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classification and management of pouchitis. Dis Colon Rectum 2001; 44: 487–99. O’Riordain MG, Fazio VW, Lavery JC, et al. Incidence and natural history of the anal transitional zone after ileal pouch–anal anastomosis. Dis Colon Rectum 2000; 43: 1660–5. Sabaté JM, Lemann M. Traitement endoscopique des sténoses dans la maladie de Crohn. Hépato-gastro 2002; 9: 169–73. Blomberg B, Rolny P, Jarnerot G. Endoscopic treatment of anastomotic strictures in Crohn’s disease. Endoscopy 1991; 23: 195–8. Couckuyt H, Gevers AM, Coremans G, Hiele M, Rutgeerts P. Efficacy and safety of hydrostatic balloon dilatation of ileocolonic Crohn’s strictures: a prospective longterm analysis. Gut 1995; 36: 577– 80. Sabate JM, Villarejo J, Lemann M, et al. Hydrostatic balloon dilatation of Crohn’s strictures. Gastroenterology 2001; 120: A449 (abstract). Ramboer C, Verhamme M, Dhondt E, Huys S, Van Eygen K, Vermeire L. Endoscopic treatment of stenosis in recurrent Crohn’s disease with balloon dilation combined with local corticosteroid injection. Gastrointest Endosc 1995; 42: 252–5. Dear KL, Hunter JO. Colonoscopic hydrostatic balloon dilatation of Crohn’s strictures. J Clin Gastroenterol 2001; 33: 315–18. Junge U, Zuchner H. Endoscopic balloon dilatation of symptomatic strictures in Crohn’s disease. Dtsch Med 1994; 119: 1377–82. Raedler A, Peters I, Schreiber S. Treatment with azathioprine and budesonide prevents reoccurrence of ileocolonic stenoses after endoscopic dilatation in Crohn’s disease. Gastroenterology 1997; 112: A1067 (abstract). Lavy A. Triamcinolone improves outcome in Crohn’s disease strictures. Dis Colon Rectum 1997; 40: 184– 6. Brooker JC, Beckett CC, Saunders BP, Benson MJ. Long-acting steroid injections after endoscopic dilation of anastomotic Crohn’s strictures may improve outcome: a retrospective case series. Endosopy 2003; 35: 333–7.

104 Thomas-Gibson S, Brooker JC, Hayward CM, Shah SG, Williams CB, Saunders B. Colonoscopic balloon dilation of Crohn’s strictures: a review of long-term outcomes. Eur J Gastroenterol Hepatol 2003; 15: 485–8. 105 Singh VV, Draganov P, Valentine J. Efficacy and safety of endoscopic balloon dilation of symptomatic upper and lower gastrointestinal Crohn’s disease strictures. J Clin Gastroenterol 2005; 39: 284– 90. 106 Jaskowiak NT, Michelassi F. Adenocarcinoma at a strictureplasty site in Crohn’s disease: report of a case. Dis Colon Rectum 2001; 44: 284– 7. 107 Partridge SK, Hodin RA. Small bowel adenocarcinoma at a strictureplasty site in a patient with Crohn’s disease: report of a case. Dis Colon Rectum 2004; 47: 778– 81. 108 Marchetti F, Fazio VW, Ozuner G. Adenocarcinoma arising from a strictureplasty site in Crohn’s disease. Report of a case. Dis Colon Rectum 1996; 39: 1315–21. 109 Bedogni G, Ricci E, Pedrazolli C, et al. Endoscopic dilation of anastomotic colonic stenosis by different techniques: an alternative to surgery? Gastrointest Endosc 1987; 33: 21–4. 110 Matsuhashi N, Nakajima A, Suzuki A, Yakazi Y, Takazoe M. Long-term outcome of non-surgical strictureplasty using metallic stents for intestinal strictures in Crohn’s disease. Gastrointest Endosc 2000; 51: 343–5. 111 East JE, Brooker JC, Rutter MD, Saunders BP. A pilot study of intrastricture steroid versus placebo injection after balloon dilatation of Crohn’s strictures. Clin Gastroenterol Hepatol 2007; 5: 1065– 9. 112 Biancone L, Cretella M, Tosti C, Palmieri G, Petruzziello C, Geremia A, Calabrese E, Pallone F. Local injection of infliximab in the postoperative recurrence of Crohn’s disease. Gastrointest Endosc 2006; 63: 486– 92. 113 Morini S, Hassan C, Lorenzetti R, et al. Long-term outcome of endoscopic pneumatic dilatation in Crohn’s disease. Dig Liver Dis 2003; 35: 893–7.

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Infections and Other Noninflammatory Bowel Disease Colitides Christina M. Surawicz University of Washington School of Medicine, Seattle, WA, USA

Introduction Colonoscopy plays an important role in diagnosis of the infectious and other noninflammatory bowel disease colitides. Histopathology is an important adjunct both in the evaluation of abnormal mucosa and in diagnosis of microscopic colitides when mucosa is macroscopically normal. This chapter reviews infectious colitis, detailing the colonoscopic patterns of specific pathogens, noninfectious colitides, and evaluation of chronic diarrhea, and focuses on the role of colonoscopy in these entities.

Infectious ileocolitis Colonoscopic appearance Most infectious diarrhea is self-limited and colonoscopy is not needed for diagnosis. Occasionally in severely ill patients or when the diagnosis is in question, colonoscopy can be helpful. Thus, it is important to recognize the colonoscopic features of various infections. The colonoscopic appearance of the mucosa is rarely specific for bacterial infectious colitis compared with inflammatory bowel disease (IBD) [1], but there may be some suggestive features. Mild to moderate infectious colitis is typically characterized by patchy inflammation (Figure 49.1) including focal edema, erythema, and petechial hemorrhage, with frequent rectal involvement [1]. Patchy involvement may mimic Crohn’s disease. In contrast, with ulcerative colitis there is diffuse erythema, granularity, friability, and superficial ulcers. Severe infectious colitis sometimes cannot be distinguished from ischemia or ulcerative colitis. The location of infection may give some clues to the etiology; for example, infections with some organisms, such as Salmonella and Yersinia, cause ileitis as well as colitis. Some

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Figure 49.1 Acute self-limited colitis showing erythema and edema with tiny focal erosions. (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

infections, such as pseudomembranous colitis, have a distinct appearance, and others, such as tuberculosis, have a suggestive appearance.

Stool tests Most bacterial infectious diarrhea will be diagnosed by stool culture, though cultures are positive only in 40–60% of cases. Fecal leukocytes indicate colonic inflammation and when present in large numbers usually indicate infection with invasive pathogens [2] but otherwise do not distinguish infection from other causes such as IBD and microscopic colitis. Leukocytes may be absent with infection; even in culture-positive dysentery they may be present in only 42–72% of cases. Fecal lactoferrin, a by-product of white blood cells, is more sensitive but no more specific for distinguishing infection from inflammation. Stool culture has a good yield for most enteric pathogens. Special media or tests are required for Yersinia (cold enrichment medium) and Shiga toxin E. coli (E. coli O157:H7, STEC) (MacConkey sorbitol agar); Clostridium difficile testing requires identification of toxins A and/or B in stools. Ideally, three specimens should be examined for parasites.

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Colorectal biopsy Colorectal biopsy is very helpful in distinguishing infection from IBD as there is typically preservation of normal architecture and acute inflammation in the former compared with distorted architecture, chronic inflammation, and basilar plasmacytosis and lymphoid aggregates in IBD, especially ulcerative colitis [3]. In ulcerative colitis, diffuse inflammation is common, while focal inflammation is more typical of Crohn’s disease [4]. Resolving infectious colitis may have a similar appearance with focal inflammation. In the cecum, biopsies from normal healthy individuals may show an increase in inflammatory cells (predominantly plasma cells and lymphocytes) compared with the rectum; thus, nonspecific colitis may be misdiagnosed if pathologists are unaware of this [5]. Granulomas are seen in Crohn’s disease (in 20–30% of biopsies) but can also be seen with tuberculosis, yersiniosis, histoplasmosis, and schistosomiasis. Pseudomembranes are most commonly due to C. difficile, but have been reported in patients with Shiga toxin E. coli infection, collagenous colitis [6], salmonellosis (Salmonella enterica serotype Infantis) [7], and in Plesiomonas infection, as well as in patients taking the drugs diclofenac and gold.

Bacterial infections Campylobacter Campylobacter is a common cause of diarrheal illness and the most common cause of invasive diarrhea in the US. C. jejuni and C. coli are most common. Symptoms begin 1–7 days after ingestion with nausea, anorexia, and watery diarrhea, which may become bloody. Ileocolonic involvement is common and the clinical presentation can mimic adenitis, especially when there is mesenteric adentitis. Rectal involvement is common, with erythema, friability, and superficial ulcerations. Complications include postinfectious arthritis, Reiter’s syndrome and, rarely, Guillain–Barré syndrome. Symptoms usually resolve in several days. Stool culture is the usual method of diagnosis.

Figure 49.2 Salmonella colitis showing diffuse erythema with loss of the normal vascular pattern, and granularity with edema.

vehicles. Typical symptoms are vomiting, crampy abdominal pain and a “pea soup” diarrhea. The bacteria invade the ileum and subsequently the colon. Ileocolonoscopic features are friable mucosa, ulcers, often with right-sided predominance, and rectal sparing (Figure 49.2). Pancolitis can occur but is uncommon.

Enteroinvasive E. coli 0157:H7, Shiga toxin E. coli (STEC) Enteroinvasive E. coli (STEC) causes a clinical picture very similar to Shigella. Shiga toxin E. coli, i.e., E. coli 0157:H7, causes a hemorrhagic colitis. As with Shigella, a small number of organisms can cause disease. Undercooked contaminated ground beef is the most common vehicle, but other foods, including raw greens, can transmit the organism. Endoscopically the mucosa is friable with superficial ulcers, most severe in the cecum and ascending colon, and can mimic ischemic colitis (Figure 49.3) [8]. Pancolitis can occur.

Shigella Shigella is a common cause of dysentery worldwide. The most common species are S. dysenteriae, S. flexneri, S. boydii, and S. sonnei. Ingestion of fewer than 100 organisms can cause disease. A prodrome of fever, cramps, and secretory diarrhea occurs 1–4 days after ingestion. This is followed by a dysenteric syndrome with bloody mucoid diarrhea and tenesmus. Rectal and left colon involvement is most frequent. In mild cases there is edema, erythema, and loss of vascular pattern. Severe disease causes discrete or confluent ulcers and exudates and may look like severe ulcerative colitis.

Salmonella The most common nontyphoidal Salmonella species that cause gastroenteritis and enterocolitis are S. heidelberg and S. enterica serovar Typhimurium. Poultry and eggs are common

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Figure 49.3 Hemorrhagic colitis due to Shiga toxin E. coli (E. coli O157:H7) (Courtesy of Dr. Abraham Brass, The DAVE Project: dave1.mgh.harvard.edu.)

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Figure 49.4 Pseudomembranous colitis. (a,b) Clostridium difficile infection may cause a spectrum of mucosal abnormalities, but the characteristic pseudomembranes are unmistakable. (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

(a)

Infections and Other Noninflammatory Bowel Disease Colitides

(b)

Clostridium difficile C. difficile is the most common cause of nosocomial diarrhea. Most commonly, it is related to antibiotic use, but sporadic cases occur and recent severe community-acquired cases have been reported with no prior antibiotic exposure. A hypervirulent strain, Nap1B27, has been described in the US, Canada, and Europe, with epidemics, and many severe cases resulting in colectomy or death [9,10]. The spectrum of colonic involvement ranges from normal mucosa in mild cases to colitis, usually left-sided. Older reports suggest isolated right colonic involvement in 10% of cases. Classic pseudomembranes are demarcated yellow–white mucosal plaques overlying the mucosa, and may be confluent with severe disease (pseudomembranous colitis) (Figure 49.4). Colonoscopy may also show nonspecific erythema, edema and ulcers or even normal mucosa. Diagnosis is by detection of toxins A and/or B in stool specimens. Patients with IBD, especially those with colonic disease and on immunosuppressive therapy, are increasingly at risk of Clostridium difficile-associated infection (CDI), most often contracted at home. These patients have more severe disease and are more likely to require colectomy [11,12]. Typical pseudomembranes may be absent [11,12].

Yersinia species Yersinia spp. (Y. enterocolitica and Y. pseudotuberculosis) cause acute and chronic colitis. Common vehicles are milk and pork, especially pig intestines. Acute infection causes terminal ileitis and mesenteric adenitis with right lower quadrant pain that can mimic appendicitis or Crohn’s disease. Terminal ileal findings are edema, ulcers, and round or oval elevations of the mucosa [13] (Figure 49.5). In the colon, aphthous ulcers or larger ulcers are found, more commonly in the right colon than the left. Stool culture is positive but may take weeks to grow; a cold enrichment medium is necessary. Serology may be helpful as well.

Figure 49.5 Ulcers in Yersinia colitis resembling tuberculosis or Crohn’s disease.

Plesiomonas shigelloides and Aeromonas hydrophila Two other organisms that cause a dysenteric picture are Plesiomonas shigelloides and Aeromonas hydrophila. Rarely, Plesiomonas can cause a chronic colitis that mimics ulcerative colitis, though it is possible that the infection has triggered ulcerative colitis [14].

Tuberculosis and histoplasmosis Symptoms of gastrointestinal tuberculosis are nonspecifica abdominal pain, weight loss, fever, diarrhea, and nausea, There may be a palpable abdominal mass in the right lower quadrant [15]. Patients may even be asymptomatic [16]. Any part of the gastrointestinal tract may be involved, but the cecum and ascending colon are the most common sites, with segmental involvement, ulcers, nodules, and a deformed cecum and ileocecal valve. Strictures, polyps, and mucosal bridges are

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Figure 49.6 Tuberculosis of the right colon. Note the scarring, ulcers, pseudopolyps, and gaping ileocecal valve. (Courtesy of Dr. Alexandra Gutierrez, The DAVE Project: dave1.mgh.harvard.edu.) Figure 49.7 Histoplasmosis with focal ulcerations and edema. (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

less common, as is pancolitis. Ulcers may be circumferential with nodular mucosa or may be shallow, linear, or serpiginous with rolled edges [16]. A colonic mass may mimic cancer. The terminal ileum can be abnormal histologically even with a normal visual appearance. Biopsy is very helpful, with granulomas in 54%, though less than half are caseating, and acidfast bacilli are found in only 5% of biopsies. Because Crohn’s disease is also a granulomatous disease, it is useful to recognize macroscopic and microscopic differences. Crohn’s disease ulcers are typically linear, deep, and tortuous, with normal adjacent mucosa. Cobblestone mucosa and aphthae are common. The ulcers in tuberculosis are transversely oriented with sharp margins and inflamed adjacent mucosa: aphthae are rare (Figure 49.6) [17]. Ileocolonic valve involvement is common in both, but a patulous or destroyed ileocecal valve suggests tuberculosis. Strictures can occur in both, though in tuberculosis they are more likely to be short. Sessile firm polyps adjacent to ulcers and small diverticula are also suggestive of tuberculosis. Histologically, the granulomas in Crohn’s disease are smaller, noncaseating, and some are small enough to be called microgranulomas. In tuberculosis, granulomas are larger, more likely to be multiple and confluent, though may not caseate. Endoscopic biopsies should be taken from both ulcer edge and base. Histology and culture will give a diagnosis in 80% of cases. Polymerase chain reaction (PCR) on tissue can be very helpful if available. Skin testing is positive in 70– 80%, though rates are lower in immunosuppressed individuals. Chest radiographs will be abnormal in fewer than 50% of patients. Colonic histoplasmosis is uncommon but has been described in the ileocecal areal with erythema, edema, ulcers, and pseudopolyps; usually organisms are seen on biopsy (Figure 49.7).

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Parasites Entamoeba histolytica Entamoeba histolytica is a common parasite worldwide, and may be noninvasive or invasive. Patients with noninvasive disease may have nonspecific symptoms such as watery diarrhea with normal mucosa. With invasive disease there may be fever, bloody diarrhea, and weight loss, usually insidious in onset. Most patients will have occult blood in their stools. Early small areas of elevation or necrosis can lead to the classic findings of “flask-shaped” ulcers, which can be large and multiple, in the right or left colon but more commonly in the cecum and ascending colon (Figure 49.8). Ulcers have red borders and central exudates. Pancolitis can occur. Colonic involvement may be the route for liver abscesses, as half of the patients with liver abscess will have colon ulcers, but colon involvement can also be asymptomatic. In a series of patients undergoing colonoscopy for occult gastrointestinal blood loss with no gastrointestinal symptoms, several had irregular small ulcers in the cecum and ascending colon that turned out to be due to ameba with trophozoites in biopsy specimens [18]. In developing countries, most cases are diagnosed by serology and stool examination, including enzyme-linked immunosorbent assay (ELISA) and PCR [19]. On stool microscopy the presence of phagocytosed erythrocytes in pathogenic strains may be the only feature to distinguish them from nonpathogenic strains. Serology (ELISA) has a sensitivity of 65% and specificity of 90% but may be misleading as it will be positive in recovering patients. Stool antigen tests have sensitivity and specificity greater than 95%. The E. histolytica II stool antigen test is best since it distinguishes E. histolytica from nonpathogenic strains. PCR has sensitivity of 72% and speci-

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Figure 49.9 Ulcers in transverse colon due to Strongyloides. Figure 49.8 Amebiasis. Punctate ulcerations in a diffuse pattern caused by invasive amebic trophozoites.

ficity of 99%. All stool tests may be negative early in disease; thus, a high index of suspicion is needed. Biopsy can also be helpful when ameba trophozoites are identified, but acute inflammation may be the only finding in many.

Strongyloides Strongyloides is a soil-dwelling nematode common in the tropical and semitropical areas. A characteristic serpiginous urticarial rash (larva currens) can develop on the feet, buttocks, and perianal area. Nonspecific symptoms include nausea, vomiting, vague abdominal pain, and diarrhea. When carriers become immunosuppressed, a fulminant “reinfection syndrome” occurs as filariform larvae multiply, invade the intestine, and migrate to the lungs and/or brain. Peripheral eosinophilia is seen in 75%. Serology (ELISA) is the best test [20]; it is positive in 84–100% but does not differentiate carriers from those with acute disease. Infection is most common in the duodenum and jejunum but can be found in the colon as the organisms burrow into the colon mucosa, causing friable mucosa, small nodules, ulcers, and fibrosis (Figures 49.9 and 49.10). It is more common in the right than left colon. The organism can occasionally be found in biopsies of normal mucosa. The gold standard for diagnosis is identification of the parasite in colorectal biopsies. Granulomas can form around the organism and local eosinophilic inflammation and peripheral eosinophilia may also be present. Stool tests are positive in only 30%; adding serology to stool tests increases the diagnostic yield to 89%.

Trichiuris trichiura (whipworm) This common nematode often colonizes the colon without causing symptoms, but can cause colitis, especially when there is a high worm burden. Symptoms include a mucoid diarrhea, with occasional blood. Symptoms may be suggestive of irritable bowel syndrome. Rectal prolapse and colonic obstruction have

Figure 49.10 Ulcers on the ileocecal valve due to Strongyloides.

been reported but are uncommon. Diagnosis is usually made by stool examination but worms can occasionally be seen at colonoscopy (Figure 49.11) [21,22]. Eosinophilic colitis has been reported [23].

Enterobius vermicularis (pinworm) The most common symptom of E. vermicularis infection is anal itching, though many patients are asymptomatic. Worms can be seen at colonoscopy (Figure 49.12) [24]. There are several reports of colitis, with symptoms of pain, blood in the stools, and diarrhea that resolves after antiparasitic therapy. In a recent series of children with rectal bleeding and suspected IBD, E. vermicularis was identified at colonoscopy in 31 of 180 (17.2%) [25]. There may be a low-grade visible colitis that is patchy and confirmed by histological features of patchy inflammation, often with eosinophils (Mark Dalzell, personal communication).

Schistosoma Schistoma mansoni and S. japonicum can cause intestinal schistosomiasis. These flukes invade the colon as part of their

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Figure 49.11 Trichuris trichiura (whipworm) seen at colonoscopybits head (arrowed) is characteristically embedded in the mucosal surface (Courtesy of Drs. J Murra-Saca and E Despott.)

than Crohn’s disease. However, most CMV colitis occurs in immunosuppressed individuals. Colonoscopic features range from discrete ulcers to segmental colitis to diffuse colitis. Inflammatory polyps can be seen [30]. Colitis with ulcers or ulcers alone is more common than colitis; multiple ulcers are the rule (Figure 49.13). In the esophagus, biopsies should be taken from the base of ulcers to increase detection of CMV [31]. In contrast, in the case of suspected herpes simplex virus (HSV) infection, biopsies should be taken from the edge of ulcers as HSV is cytopathic in squamous epithelium. These same principles may apply to CMV in the colon but have not been validated. Diagnosis may require multiple modalities. CMV inclusion cells are pathognomonic but require multiple biopsies, serial sections and an experienced pathologist. Several more specific tests include immunohistochemical staining, polymerase chain reaction (PCR), shell viral culture and in situ nucleic acid hybridization. PCR had a sensitivity of 92% and specificity of 100% in a recent study [32]. Serology is not useful since a rise in titers may be delayed, nor does CMV antigenemia prove active disease.

Herpes simplex virus type II Herpes causes a painful proctitis, often with friability, and ulcers are distal (Figure 49.14).

Human papillomavirus Human papillomavirus (HPV) causes anal and genital warts with a typical appearance. Internal anal warts can be found at, but not usually above, the squamocolumnar junction (Figure 49.15).

Fungi Cryptococcus neoformans

Figure 49.12 Enterobius vermicularis (pinworm) (see also Fig. 56.4).

A recent report described a man with HIV infection and diarrhea. Erythematous raised patchy lesions were found in the left colon, with budding yeast in the submucosa. Symptoms resolved with antifungal treatment [33].

Sexually transmitted proctitis life cycle in humans as they migrate to portal and mesenteric veins. Eggs can be deposited in the colon wall, most commonly in the descending colon. Colonoscopic features are edema, friable granular mucosa, focal shallow ulcers, and inflammatory pseudopolyps [26]. Pseudopolyps can contain eggs and on biopsy granulomas can be seen surrounding the ova. Fibrosis and strictures can occur. Immunosuppression may interfere with granuloma formation [27].

Viruses Cytomegalovirus Cytomegalovirus (CMV) occasionally causes colitis in immunocompetent individuals [28]. CMV colitis can either mimic IBD [29] or exacerbate IBD, more commonly ulcerative colitis

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Among men who have sex with men (MSM), proctitis is more frequently infectious than idiopathic IBD. The most frequent pathogens, in order, are Neisseria gonorrhoeae, HSV type II, Chlamydia trachomatis, and the syphilis-causing organism Treponema pallidum [34]. Rectal gonorrhea presents with anal pain and discharge; proctitis is common, with edema, erythema, and mucopurulent discharge. Gram stain and culture will make the diagnosis. Perianal syphilis may begin with a painless anal chancre, followed by discrete or diffuse anal ulcers. Dark-field examination of material shows spirochetes; serology will confirm. It is important to recognize Chlamydia trachomatis proctitis as it may be mistaken for IBD. There are three stages of infection. The primary stage is characterized by painless mucosal or skin ulcers that heal. The secondary stage follows 10–30 days

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Figure 49.13 Cytomegalovirus. (a) Shallow ulcer near anal canal in a retroversion. (b) Isolated ulcer of descending colon. (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

(a)

(b)

Figure 49.14 Herpes simplex virus causes typical round ulcerated lesions on the skin (of the buttock) (a), but may also occur inside the rectum, as seen in this retroversion view (b). (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

(a)

(b)

Figure 49.15 HPVbcondylomata usually affect the skin in the genital area (a), but can appear as a verrucous papillary growth in the rectum (b). (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

(a)

(b)

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Figure 49.16 Chlamydia trachomatis proctitis, with diffusely nodular rectal mucosa. (Courtesy of Dr. Akifumi Ootani, Saga, Japan.)

later, with lymphadenopathy, which can suppurateathese buboes can cause abscesses and fistulae. Without therapy the third stage follows, with stricture formation. Both lymphogranuloma venereum (LGV) and non-LGV strains of Chlamydia trachomatis can affect the colon with a hemorrhagic proctitis, but the LGV strains cause more severe painful proctitis with ulceration, nodularity (Figure 49.16), and scars and inguinal adenopathy. The rectum may show diffuse nodularity with erosions, friability, and normal proximal mucosa [35]. Histologically, there is acute and chronic inflammation and granulomas. Recent clusters of LGV strains have occurred in MSM in the Netherlands, with subsequent outbreaks in Europe and the US [36]. Culture has a low yield. Serology cannot determine which serotype is involved. Most strains respond to azithromycin except serovars L1, L2, and L3, which have a poor response. Proctitis may also be a marker for other sexually transmitted diseases. Current recommendations for MSM with proctitis are empiric therapy for gonorrhea and Chlamydia while tests are pending, and screening of the patient and his partners for other sexually transmitted diseases including syphilis, HPV, HIV, and viral hepatitis [37].

Other causes of colitis Preparation artifacts Some colonoscopy or sigmoidoscopy preparations can cause abnormal colonic mucosa. Fleet Enema “artifact” causes mucosal friability, hyperemia, and loss of the normal vascular pattern [38]. Oral Fleet Phosphosoda preparation causes focal aphthae or erosions in up to 3% of cases (Figure 49.17).

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Figure 49.17 Typical red-ring signs of a phosphosoda preparation. As seen in the rectum.

Figure 49.18 Hydrogen peroxide causes white spots on the colon mucosa that can mimic pseudomembranes. (Courtesy of Dr. Larry Brandt, New York, NY, USA.)

Chemical colitis Two unique chemical colitides have been reported following colonoscopy when improper cleaning leaves residue of hydrogen peroxide or glutaraldehyde in the colonoscope channels. Typically the mucosa is normal on insertion, but abnormal on the way out. The hydrogen peroxide causes a “snow-white” colon with white plaques that can be confused with pseudomembranes [39] (Figure 49.18). Initially described by Meyer et al. in 1981 [40], it was described as “pseudolipomatosis” by Snover et al. [41] as the vacuoles in the mucosa on biopsy mimicked fat vacuoles [42]. Glutaraldehyde colitis causes a more severe colitis that can look like ischemia (Figure 49.19).

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Figure 49.19 Glutaraldehyde causes colonic necrosis that can mimic ischemia. (Courtesy of Dr. Larry Brandt, New York, NY, USA.)

(a)

Colon ischemia Colon ischemia has a spectrum from reversible and transient colitis to chronic colitis, stricture formation, gangrene, and fulminant colitis. Ischemia results from altered blood flow, with resulting hypoperfusion and reperfusion injury, and is especially common after abdominal aortic aneurysm repair. There is usually rectal sparing due to the dual blood supply in the rectum, but the rectum can be involved in severe cases. Early colonoscopy is important in diagnosis, but should be done cautiously to avoid perforation. It is reasonable to stop the procedure when abnormal mucosa is detected. Early findings are edema, petechiae, submucosal pallor and hemorrhage, and violaceous blebs, leading to friability, with ulcers; blueblack mucosa suggests imminent necrosis in severe cases. Serial examinations may help determine need for surgery in severe cases (Figure 49.20) [43]. Biopsy shows “ghosts” of crypts, congestion, and minimal inflammation. Pharmacologic causes include alosetron, antibiotics, appetite suppressants, some chemotherapeutic agents, decongestants, digitalis, diuretics, ergot alkaloids, and hormones [44].

(b)

Radiation colitis Radiation-induced colon injury is usually a consequence of radiation for pelvic cancers. Symptoms are diarrhea, tenesmus, and rectal discharge. Proctocolitis with loss of normal vascular pattern and friable angiectasias in later stages is usually seen (Figure 49.21). Strictures can also occur. (c)

Diversion colitis Diversion colitis occurs in surgically defunctionalized segments of colon, in 50–100% of patients, and resolves when bowel continuity is restored. Endoscopically, the mucosa may look friable, with nodularity, erosions, and ulcers that may mimic ulcerative colitis or Crohn’s disease [45]. In long-standing cases, strictures may develop. Common symptoms are tenesmus with passage of mucus or blood, or less commonly fever and pain.

Figure 49.20 Ischemic colitis. (a) Ulcerated mucosa with adjacent normal area. (b) Severe ischemic changes. (Courtesy of Dr. Ed Despott, London, UK.) ( c) Healing phase or “stripe sign.”

Diverticulitis and diverticular colitis Diverticulitis Colonoscopy is usually contraindicated during an acute attack of diverticulitis due to risk of perforation. Occasionally

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Clinical Use and Results of Colonoscopy usually in the left colon, and encompass areas of diverticulosis. It may result from stasis, prolapse, or local ischemia rather than from acute diverticulitis. Rectal sparing is usual. Endoscopic features are reddened mucosa, often on the top of folds, friable mucosa, and exudates (Figure 49.23). Interestingly, it can be seen that the gross inflammation is not contiguous with diverticular orifices. Discrete ulcers or erosions are not seen. Histology shows acute and chronic inflammation [47]. Biopsies from abnormal and normal areas can help the pathologist distinguish this from IBD.

Microscopic colitides

Figure 49.21 Angioectasias of radiation proctopathy over the prostate gland. (Courtesy of Dr. Jerry Waye, New York, NY, USA.)

a limited examination may be needed acutely to confirm the diagnosis, using a minimal air insufflation. Otherwise, colonoscopy should be delayed for 4– 6 weeks. Classic colonoscopic findings are edematous folds, narrowed lumen, and erythema of the intrahaustral folds of the involved segment (Figure 49.22).

Diverticular colitis Diverticulosis can also cause a chronic segmental colitis that can mimic IBD in its endoscopic appearance with symptoms of left lower quadrant pain and altered bowel pattern [46]. The abnormal areas are adjacent to an area of inflammation,

(a)

(b)

There are two distinct microscopic colitides: collagenous colitis and lymphocytic colitis. Coexisting autoimmune diseases may be present in up to 40% of patients. Collagenous colitis is more common in women than men, whereas lymphocytic colitis is equally common in men and women. Both cause chronic watery diarrhea with a normal gastrointestinal workup, diagnosed only by colon biopsy of normal mucosa. Although colonic mucosa is usually normal, endoscopic abnormalities have been found in up to one-third of cases: erythema (25%), mucosal friability (4%), and ulceration (5%) [48]. In addition, mucosal lacerations seen on insufflation of the colon during colonoscopy were seen (Figure 49.24) [49]. The histologic findings are similar: increased lymphocytes in the lamina propria and increased intraepithelial lymphocytes (Figure 49.25). In collagenous colitis there is also a thickened subepithelial collagen band (> 10 μm) (Figure 49.26). In most cases in one series, biopsies within the reach of a flexible sigmoidoscope will be diagnostic, but the disease can be patchy so multiple biopsies are needed. In 10% of cases right-sided biopsy alone will be positive. Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause some cases [50].

(c)

Figure 49.22 Diverticular disease. (a) Petechial intramucosal hemorrhage may occur from muscular contractions associated with diverticular disease. (b,c) Occasionally, the intramucosal bleeding can be a focus for peristaltic activity, which causes more trauma and the development of large protuberant red folds which are polypoid in appearance. (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

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Figure 49.23 Diverticular colitis with mucosal inflammation confined to the area of diverticulosis. (Courtesy of Dr. Jeffrey Raskin, Miami, FL, USA.)

Figure 49.24 Collagenous colitis with “fractured” mucosa seen on insufflation with air during colonoscopy. The yellow bulge at the bottom is the ileocecal valve. (Courtesy of Dr. Jerry Waye, New York, NY, USA.)

Pneumatosis intestinalis (pneumatosis cystoides intestinalis, gas cysts of the intestines) Gas in the bowel wall can be detected by flat abdominal films or abdominal computed tomography (CT) scan, and is sometimes seen at colonoscopy. Primary pneumatosis intestinalis (PI) is a usually benign condition of adults that occurs spontaneously, is detected incidentally, and is usually in the left colon. This can be seen in adults with emphysema or chronic obstructive pulmonary disease but is more often of unknown etiology. In contrast, secondary PI is a serious condition, involving any part of the small intestine or colon, occurring as a result of significant gastrointestinal tract disease [51–53]. In infants, it often portends necrotizing enterocolitis with a high mortality. In adults, it is associated with bowel obstruc-

Infections and Other Noninflammatory Bowel Disease Colitides

Figure 49.25 Lymphocytic colitis (histology). Note the slight increase in the intraepithelial and lamina propria lymphocytes and normal architecture.

Figure 49.26 Collagenous colitis (histology). In addition to the increased intraepithelial and lamina propria lymphocytes seen in lymphocytic colitis, there is a thickened subepithelial collagen band.

tion or ischemia. In the colon mucosa, the cysts are thin walled and do not communicate with the bowel lumen. The visual appearance can be described as cystic or linear. The cystic form (Figure 49.27) is seen with a wide variety of conditions and is more likely to be benign. The linear form is usually due to serious conditions such as necrotic bowel [54,55]. Clinical evaluation of the patient will determine if this is a benign condition or a marker of serious intestinal disease.

Drugs Several drugs have been associated with colitis. Most common are NSAIDs, which can cause small intestinal and colon injury with strictures (especially with the use of diclofenac), and diaphragm lesions in the small bowel and ulcers and

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Figure 49.27 Pneumatosis cystoides intestinalis. Gas in the colon wall causes mucosal blebs. This is the cystic form. (Courtesy of Dr. Brian Fennerty, The DAVE Project: dave1.mgh.harvard.edu.)

segmental colitis in the colon [56,57]. Other drugs that cause colitis include isotretinoin, penicillamine, oral potassium supplements, gold, penicillamine, methyldopa, and chemotherapeutic agents [58].

Solitary rectal ulcer syndromes (SRUS) Solitary rectal ulcer syndromes (SRUS) is the name given to a syndrome of benign rectal ulcer(s), usually anterior, often associated with constipation and rectal prolapse. However, ulcers can be multiple and higher (Figure 49.28), in which case biopsy is very helpful in diagnosis. Symptoms of rectal bleeding and detection of a firm ulcer with or without associated mass on rectal examination may mislead clinicians to a diagnosis of rectal cancer or Crohn’s disease. Grossly, the rectal lesions may be polypoid, flat, or ulcerative. Histology is diagnostic with hyperplastic mucosa and associated lamina propria fibrosis that can be confused with a desmoplastic reaction seen in cancer, and buried glands that can be mistaken for invasive cancer. In one series, the initial diagnosis was incorrect in 25 of 98 (26%) patients, mostly women, for up to 5 years [59]. Incorrect diagnoses included IBD, villous adenoma, and nonspecific colon ulcers. Diagnosis requires adequate biopsy specimens. Endoscopic ultrasound may be helpful in demonstrating smooth, diffuse thickening of the third layer of the rectal walls, and excluding masses and infiltrating lesions [60].

Stercoral ulcers Stercoral ulcers are due to fecal impaction with hard stool eroding the mucosa, typically in the left colon, where stool can become inspissated. Presentation can be bleeding or perforation, though some may be symptomatic. Ulcers are typically on the antimesenteric border, usually in the sigmoid colon or rectum; the ulcers are large circular, sharply demarcated, and can be multiple. Perforation has a high mortality.

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Figure 49.28 Ulcers of solitary rectal ulcer syndrome can be multiple, and can be proximal in rectum. Biopsy will confirm. (Courtesy of Dr. Ed Despott, London, UK.)

Colitis with systemic vasculitis Polyarteritis nodosa and Churg–Strauss syndrome cause a vasculitis that can affect the colon [61,62]. Petechiae have been described in the colon of patients with Henoch–Schoenlein purpura.

Sarcoidosis Sarcoid in the colon is uncommon but can mimic Crohn’s disease or appendicitis with terminal ileal narrowing. Granulomatous appendicitis has been reported rarely. Biopsies of normal mucosa can show granulomas. In sarcoid, the sigmoid colon is the most common site, with ulcers, friable mucosa, nodularity, or segmental narrowing [63].

Behçet’s syndrome Behçet’s syndrome is a triad of oral, aphthous, and genital ulcers. Typical colonic findings are well-demarcated ulcers involving the ileocecal area [64] that can be confused with Crohn’s disease.

Eosinophilic colitis Eosinophilic gastroenteritis is a chronic IBD with nonspecific symptoms and infiltration of the bowel wall by eosinophils. It can be focal or diffuse. The stomach and small bowel are most commonly involved. Colonoscopic features are nonspecific, and include granular or nodular mucosa, friability or erosions [65]. Ulcers are uncommon. Multiple biopsies are recommended since the disease can be patchy. Parasitic infection must be excluded.

Cat scratch colon Red linear marks in the right colon were reported in a series of 21 cases, most commonly in women. Histology was normal, and more common in women. The authors postulated

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that these may be superficial breaks in the mucosa due to barotraumas [66].

Isolated colon ulcers NSAIDs are a common cause of colonic ulcers, but other etiologies are ischemia, fecal impaction, SRUS, tuberculosis,

Infections and Other Noninflammatory Bowel Disease Colitides and amebiasis [67]. Nonspecific ulcers are most common in the cecum, particularly on the ileocecal valve. Biopsy should be done to exclude cancer, NSAIDs should be discontinued, and repeat colonoscopy should be performed to document healing [67].

Melanosis coli or pseudomelanosis coli Table 49.1 Differential diagnosis of colitis. Idiopathic inflammatory colitides Inflammatory bowel disease Crohn’s disease Ulcerative colitis Indeterminate colitis Diversion colitis Collagenous colitis Microscopic colitis (collagenous and lymphocytic) Infectious colitides Bacteria Parasites Viruses Fungi Ischemia Mesenteric ischemia or thrombosis Drug induced (cocaine, oral contraceptives) Proximal to mechanical obstruction Bacteria (C. difficile, Shiga toxin, E. coli) Physical or mechanical agents Radiation Glutaraldehyde/hydrogen peroxide (endoscopic cleaning solutions) Drug induced Gold Isoretinoin Laxatives Allopurinol Non-C difficile antibiotic induced i.e., ampicillin (usually right-sided colitis) Chemotherapeutics (i.e. 5-fluorouracil) Nonsteroidal anti-inflammatory drugs Solitary rectal ulcer syndrome (prolapse) Diverticulitis Colon cancer with obstruction Diverticular colitis Immunologic Allergic proctitis Eosinophilic colitis Graft-versus-host disease Immunodeficiency syndromes Associated with systemic disease Vasculitis Behçet’s syndrome Sarcoidosis

Anthraquinone laxatives cause a brown discoloration of the colonic mucosa. The pigment in the macrophages is seen in biopsies. This is a helpful clue to laxative use but does not otherwise interfere with colonic function.

The role of colonoscopy and ileoscopy in diagnosis of chronic diarrhea Colonoscopy is important in evaluation of patients with chronic diarrhea. Biopsies of normal mucosa are the only way to diagnose microscopic colitis (lymphocytic and collagenous). Other histologic findings are melanosis coli due to anthraquinone laxatives, which may be a clue to factitious diarrhea, and spirochetosis caused by a non-Treponema pallidum spirochete that may or may not be pathogenic. In one series, histologic findings were reported in 20 out of 100 patients with chronic unexplained diarrhea with normal mucosa, most commonly findings suggestive but not diagnostic of microscopic colitis, melanosis coli radiation change (postradiation), and CMV in an immunosuppressed patient [68]. Similarly, a retrospective study found that 37 of 205 patients (18%) who underwent colonoscopy or sigmoidoscopy to evaluate watery, nonbloody diarrhea had a diagnosis based on abnormal endoscopy and abnormal biopsy [IBD, pseudomelanosis coli, large adenoma (> 5 cm), indeterminate and microscopic colitides, ischemia, pseudomelanosis coli, rectal prolapse and peridiverticulitis] [69]. Biopsy of the 21 with normal mucosa yielded a diagnosis in 12: acute infectious colitis (5), microscopic colitis (4), and pseudomelanosis coli (3). In the other nine cases, mild inflammation on colon biopsy did not correlate with the final clinical diagnosis. A common issue is where to biopsy and how many biopsies to take. In a referral population of patients with chronic diarrhea, 121 of 809 patients (15%) had abnormal colonic biopsies (80 microscopic colitis, 23 Crohn’s disease, eight melanosis coli, five ulcerative colitis, and five other colitis). In all cases, these abnormalities were detected in the distal colon (rectosigmoid and descending colon) [70]. In evaluating patients with chronic diarrhea one should avoid biopsies of the cecum (where inflammatory cells are normally increased) to prevent misdiagnosis of nonspecific colitis [5]. The optimum number of biopsies is not known, but it would be reasonable to take four good-sized specimens at flexible sigmoidoscopyatwo from the rectum and two from more proximal mucosa or from random colon (right, transverse, left, and rectum). All four biopsies may be placed in a

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Table 49.2 Infectious diarrhea.

References

Small intestine

Ileocolonic

Viruses Rotavirus Norovirus (Norwalk agent) Enteric adenovirus Astrovirus Bacteria Vibrio cholera E. coli ETEC (enterotoxigenic) DAEC EPEC (enteropathic) Listeria monocytogenes Parasites Giardia lamblia Cryptosporidia Isospora belli Cyclospora cayatenensis Strongyloides

Viruses CMV HSV (rectal only) Bacteria Campylobacter spp. Salmonella spp. Shigella spp. STEC (E. coli O157:H7 and other strains) Yersinia Clostridium difficile Noncholera Vibrio spp. Aeromonas hydrophila Plesiomonas shigelloides EIEC (enteroinvasive Escherichia coli) Mycobacterium tuberculosis Parasites Strongyloides Entamoeba histolytica Trichuris trichiura

DAEC, diffusely adherent E. coli.

single specimen container to limit pathology costs. It does not make sense to biopsy normal mucosa in the absence of symptoms or for classic irritable bowel syndrome [71–73]. Terminal ileal biopsies have the best yield for known or suspected Crohn’s disease or when ileitis had been detected on radiologic imaging. In one series of 17 patients with normal mucosa and an abnormal biopsy, chronic inflammation was seen in 13; the other three had healed acute injury, granulomas, and crypt distortion [72]. Nonsteroidal drugs are another cause of terminal ileal ulcers, ileitis, or erosions [74]. Thus, the yield is low but occasionally helpful, and reasonable to biopsy in specific situations but not routinely. Ileoscopy with biopsy can sometimes add diagnostic value in the evaluation of both chronic diarrhea and right lower quadrant abdominal pain. A retrospective study of 168 patients evaluated for chronic diarrhea found that colonoscopy and biopsy yielded a new diagnosis in 52 (31%) of patients [75]. Fourteen had a diagnosis made by biopsy of normal mucosa. Biopsy of the normal ileum made a diagnosis in two cases (isolated ileal Crohn’s disease and CMV). Ileoscopy complemented colonoscopy in three other cases. In a retrospective study of the value of ileoscopy during colonoscopy, ileoscopy yielded significant pathology in 1.8% of cases with right lower quadrant abdominal painamost commonly in diagnosis of Crohn’s disease and tuberculosis [76].

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Infections and Other Noninflammatory Bowel Disease Colitides 40 Meyer CI, Brand M, de Luca VA, et al. Hydrogen peroxide colitis: a report of three patients. J Clin Gastroenterol 1981; 3: 31–5. 41 Snover DC, Sandstad J, Hutton S. Mucosal pseudolipomatosis of the colon. Am J Surg Pathol 1985; 84: 575–80. 42 Stein BL, Lamoureux E, Miller M, Vasilevsky CA, Julien L, Gordon PH. Glutaraldehyde-induced colitis. Can J Surg 2001; 44: 113–16. 43 Champagne BJ, Darling RC 3rd, Daneshmand M, et al. Outcome of aggressive surveillance colonoscopy in ruptured abdominal aortic aneurysm. J Vasc Surg 2004; 39: 729–96. 44 Hass DJ, Kozuch P, Brandt LJ. Pharmacologically mediated colon ischemia. Am J Gastroenterol 2007; 102: 1765–80. 45 Ma CK, Gottlieb C, Haas PA. Diversion colitis: a clinicopathologic study of 21 cases. Hum Pathol 1990; 21: 429–46. 46 Peppercorn MA. Drug-responsive chronic segmental colitis associated with diverticula: a clinical syndrome in the elderly. Am J Gastroenterol 1992; 87: 629–32. 47 Lamps LW, Knapple WL. Diverticular disease-associated segmental colitis. Clin Gastroenterol Hepatol 2007; 5: 27–31. 48 Ayata G, Ithamukkula S, Sapp H, et al. Prevalence and significance of inflammatory bowel disease-like morphologic features in collagenous and lymphocytic colitis. Am J Surg Pathol 2002; 26: 1414–23. 49 Smith RR, Ragput A. Mucosal tears on endoscopic insufflation resulting in perforation: an interesting presentation of collagenous colitis. J Am Coll Surg 2007; 205: 725. 50 Giardiello FM, Hansen FC 3rd, Lazenby AJ, et al. Collagenous colitis in setting of nonsteroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 1990; 35: 257– 60. 51 Heng Y, Schuffler MD, Haggitt RC, Rohrmann CA. Pneumatosis intestinalis: a review. Am J Gastroenterol 1995; 90: 1747–58. 52 Boerner RM, Fried DB, Warshauer DM, Isaacs K. Pneumatosis intestinalis. Two case reports and a retrospective review of the literature from 1985 to 1995. Dig Dis Sci 1996; 41: 2272–85. 53 Donati F, Boraschi P, Giusti S, Spallanzani S. Pneumatosis cystoides intestinalis: imaging findings with colonoscopy correlation. Dig Liver Dis 2007; 39: 87–90. 54 Chang Y-T, Chang m-C, Wel S-C, Wong J-M. Pneumatosis cystoides coli. Gastrointest Endosc 2006; 54: 820–1. 55 Pear BL. Pneumatosis intestinalis: a review. Radiology 1998; 207: 13–19. 56 Goldstein NS, Cineza AN. The histopathology of nonsteroidal anti-inflammatory drug-associated colitis. Am J Surg Pathol 1998; 110: 622– 8. 57 Makapugay LM, Dean PJ. Colitis due to nonsteroidal antiinflammatory drugs. Lab Invest 1996; 74: 61A. 58 Pustztaszeri MP, Genta RM, Cryer BI. Drug-induced injury in the gastrointestinal tract: clinical and pathologic considerations. Nat Clin Pract 2007; 4: 442–53. 59 Tjandra JJ, Fazio VW, Petras RE, et al. Clinical and pathologic factors associated with delayed diagnosis in solitary rectal ulcer syndrome. Dis Colon Recturm 1993; 36: 146–53. 60 Hizawa K, Iida M, Suekane H, et al. Mucosal prolapsed syndrome: diagnosis with endoscopic US. Radiology 1994; 191: 527–30. 61 Vavricka SR, Dirnhofer S, Degen L. Polyarteritis nodosa mimicking inflammatory bowel disease. Clin Gastrol Hepatol 2007; 5: A22. 62 Guillevin L, Lhote F, Gallais V, et al. Gastrointestinal tract involvement in polyarteritis nodosa and Churg–Strauss syndrome. Ann Med Interne (Paris) 1995; 146: 260–7.

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63 Vahid B, Spodik M, Braun KN, Ghazi LJ, Esmaili A. Sarcoidosis of gastrointestinal tract: a rare disease. Dig Dis Sci 2007; 52: 3316– 3329. 64 Kurtz MD. Colonoscopoic diagnosis of nonspecific ulcer of the colon. Gastrointest Endosc 1976; 23: 90–1. 65 Lee CM, Changchein C-S, Chen P-C, et al. Eosinophilic gastroenteritis: 10 year experience. Am J Gastroenterol 1993; 88: 70–4. 66 McDonnell WM, Loura F, Pointon MJ, Greenson JK. Cat scratch colon. Endoscopy 2007; 39: 459– 461. 67 Nagar AB. Isolated colonic ulcers: diagnosis and management. Curr Gastroenterol Rep 2007; 9: 422– 8. 68 Marshall JB, Singh R, Diaz-Arias AA. Chronic, unexplained diarrhea: are biopsies necessary if colonoscopy is normal? Am J Gastroenterol 1995; 90: 372– 6. 69 Patel Y, Pettigrew NM, Grahame GR, Bernstein CN. The diagnostic yield of lower endoscopy plus biopsy in nonbloody diarrhea. Gastrointest Endosc 1997; 46: 338– 43. 70 Fine KD, Seidel RH, Do K. The prevalence, anatomic distribution, and diagnosis of colonic causes of chronic diarrhea. Gastrointest Endosc 2000; 51: 318– 26.

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Acute Colonic Pseudo-obstruction Michael B. Kimmey Tacoma Digestive Disease Center, Tacoma, WA, USA

Introduction Sir William Heneage Ogilvie first described acute colonic pseudo-obstruction (ACPO) in 1948 in two patients with far advanced intra-abdominal malignancies [1]. He was the first to postulate an underlying imbalance between the sympathetic and parasympathetic innervation of the colon as the cause of this disorder. Ogilvie’s patients, however, developed subacute symptoms over the course of 2 months and thus represent an atypical presentation of what we now recognize as ACPO. The hallmark features of ACPO consist of acute colonic dilation in the absence of mechanical obstruction. This condition is increasingly recognized and is associated with substantial morbidity and mortality.

Epidemiology and predisposing factors The exact incidence of ACPO in hospitalized patients is unknown. Vanek and Al-Salti [2] analyzed 400 cases of ACPO and found that it occurred most commonly in the sixth decade and was more common in men than in women. More than 90% of patients had significant comorbid disease, thought to be contributing to the syndrome. About 50% of cases occurred in the postoperative state. The diverse underlying medical and surgical problems associated with ACPO are listed in Table 50.1.

Pathophysiology The pathophysiology of ACPO is still not entirely understood, but there is evidence of an imbalance between the sympathetic and parasympathetic nervous system, which leads to a functional obstruction caused by atony of the distal colon

followed by progressive dilation of the cecum and ascending colon [1,3]. Ogilvie favored the sympathetic deprivation theory, leading to unopposed parasympathetic stimulation and thereby resulting in “excessive and probably uncoordinated contraction” of the distal colon [1] mimicking obstruction. More recent theories postulate either an impairment of the sacral parasympathetic outflow [3–5] or excessive sympathetic stimulation [6,7]. The clinical presentation of ACPO resembles Hirschsprung’s disease, supporting the hypothesis of impaired parasympathetic function [5], which is also supported by the commonly observed transition point at the level of the splenic flexure. The parasympathetic innervation of the colon distal to the splenic flexure is via the pelvic splanchnic nerves, whereas the more proximal colon is innervated by the vagus (Figure 50.1). The proponents of the sympathetic stimulation theory [6,7] argue that right-sided colonic motility is impaired by excessive sympathetic activity. This theory is supported by animal experiments performed in the 1920s and 1930s [8] showing that colonic peristalsis is increased after spinal anesthesia, which leads to a temporary paralysis of sympathetic input. This was the rationale for the induction of spinal anesthesia as a successful treatment of adynamic ileus in Europe in the 1920s.

Clinical presentation ACPO is usually seen in middle-aged to elderly critically ill patients in the intensive care unit or postoperatively and is exacerbated by immobility and narcotic pain medications. Symptoms usually develop gradually over 3–7 days. Significant abdominal distension is seen in all patients, often associated with pain (83%), vomiting (57%), constipation (51%), and fever (37%).

Diagnosis Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Abdominal examination shows significant distension, with variable degrees of tenderness. Bowel sounds are variable and

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Table 50.1 Causes of acute colonic pseudo-obstruction [2,11,17,18, 25,37,56–58].

Vagus nerves T10

Neurologic Parkinson’s disease Alzheimer’s disease Cerebrovascular accident Multiple sclerosis Spinal cord disease Craniotomy Cardiovascular Myocardial infarction Congestive heart failure Post cardiac arrest Respiratory Pneumonia Mechanical ventilation Acute respiratory distress syndrome Metabolic Hyponatremia Hypocalcemia Hypomagnesemia Liver failure Renal failure Hypothyroidism

12

Neoplasia Retroperitoneal Metastatic cancer Post surgical Cardiac surgery Cesarean section Gynecologic surgery Pelvic surgery Organ transplantation Orthopedic surgery Post traumatic Pelvic trauma Spinal cord injury Femoral fracture Drugs Narcotics Tricyclic antidepressants Phenothiazines Antiparkinson agents Calcium channel blockers Benzodiazepines Clonidine Vincristine

676

11 Celiac ganglion

12

L1

L1

2

2

Superior mesenteric ganglion

T10-12

Inferior mesenteric ganglion

Pelvic plexus

S2

S2

3

3 4

Infective/inflammatory Acute cholecystitis Pelvic abscess Spontaneous bacterial peritonitis Acute pancreatitis Sepsis Herpes zoster Appendicitis

T10

11

Pudendal nerves

4

Figure 50.1 Schematic diagram illustrating colonic innervation. Parasympathetic pathways (stimulatory/prokinetic): prevertebral ganglia and sacral nerves (red) and vagus (yellow). Sympathetic pathways (inhibitory): thoracic spinal cord to inferior mesenteric plexus and pelvic plexus (green).

can be normal or hyperactive (40%), hypoactive (31%), highpitched (17%), or absent (12%) [2]. If peritoneal signs are present, transmural ischemia or perforation should be suspected and surgical consultation obtained. The diagnosis is confirmed by plain abdominal radiographs, which typically show significant distension of the colon with predominance of the right side in the absence of mechanical obstruction (Figure 50.2). A cut-off sign at the splenic flexure is frequently observed [5]. Initial studies suggested that a cecal diameter of > 12 cm increases the risk of perforation substantially [9]. The case series by Vanek and Al-Salti [2] reported no cecal perforation in patients with a cecal diameter < 12 cm, a 7% risk of perforation in patients with a cecal diameter of 12–14 cm, and 23% risk of perforation in patients with a cecal diameter > 14 cm. However, more recent reports suggest that the duration of significant cecal dilation is more predictive of ischemia than the cecal diameter per se [10]. A water-soluble contrast enema should be cautiously performed to confirm the functional etiology, if a mechanical obstruction (absence of rectal air) cannot be entirely excluded by the initial radiographs.

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transit, such as anticholinergics or opiates, should be discontinued if possible [14]. The abdominal examination needs to be followed carefully and daily abdominal radiographs obtained to monitor for progressive dilation and evidence of perforation. The introduction of a nasogastric tube for decompression is advisable for most patients, and in selected cases a rectal tube might also be of help. Mobilization of the patient with frequent turning might facilitate the passage of flatus. Success rates of supportive management are variable but can be as high as 96%, as reported in a cohort of cancer patients from Sloan-Kettering Cancer Center [15].

Pharmacotherapy

Figure 50.2 Abdominal radiograph of patient with acute colonic pseudoobstruction following internal fixation of a fractured femur.

Barium should not be administered, because this could complicate surgery if perforation is present or endoscopic decompression is required.

Complications The dreaded complication of progressive colonic dilation is transmural ischemia followed by perforation. However, the frequency of this complication, which requires emergency colonic resection, has significantly decreased in recent case series. The risk of perforation was initially reported to be as high as 13% with a mortality of 43% [11]. A summary of more recent studies shows a perforation risk of 3% [12]. The surgical mortality may be as high as 40–50%, if perforation occurs [13].

Management Supportive medical care Initial management for the first 24–48 h is conservative, with close attention to correcting any fluid and electrolyte imbalances that may be present. The medication list should be carefully scrutinized and drugs that might delay intestinal

When colonic dilation persists or progresses despite conservative therapy, specific pharmacotherapy to stimulate the parasympathetic innervation of the colon should be attempted (Table 50.2). Catchpole [16] first proposed the combined use of a sympathetic blocker (guanethidine) followed by a cholinesterase inhibitor (neostigmine) to correct the sympathetic/ parasympathetic imbalance. Subsequent small case series suggested that a majority of patients with ACPO could be effectively treated using neostigmine [17–19]. A double-blind, randomized, placebo-controlled clinical trial reported by Ponec and colleagues [20] conclusively showed a dramatic improvement in clinical status and colonic distension in the majority of patients treated with intravenous neostigmine, making endoscopic intervention unnecessary in most cases. In this study, patients were treated with 2 mg of neostigmine administered over a few minutes by slow intravenous push. Patients were monitored continuously by electrocardiography with atropine available at the bedside, as symptomatic bradycardia is the most significant adverse effect of this treatment. Of 11 patients who received neostigmine, 10 (91%) showed prompt colonic decompression with a median time to response of only 4 min, whereas none of the patients receiving placebo (saline) had a clinical response. Seven patients in the placebo group and the one patient in the neostigmine group who failed initial response received open-label neostigmine 3 h after the initial infusion, with prompt colonic decompression noted in all patients. Only two patients developed recurrent symptoms requiring colonoscopic decompression [20]. Several studies have since confirmed the safety of neostigmine for the treatment of ACPO, with successful colonic decompression reported in 79–93% of cases. Several different neostigmine infusion protocols have been used, including 2-mg and 2.5-mg intravenous boluses and 2.5 mg administered over 60 min [21–25], all with similar success rates. Recurrence of colonic distension following successful decompression using neostigmine occurs in up to 16% of patients. Factors that have been associated with relapse include electrolyte imbalance and use of drugs such as narcotics and antiParkinsonian medications that reduce intestinal motility [25]. In these situations, neostigmine can be safely readministered,

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Table 50.2 Reports of pharmacotherapy of acute colonic pseudo-obstruction. Medication

Reference

Number of patients

Initial compression (%)

Erythromycin

Armstrong et al. [29] Bonacini et al. [30] Rovira et al. [31]

2 1 2

100 100 100

0 0 0

Cisapride

MacColl et al. [7] Pelkmans et al. [32] Mazloum et al. [33]

1 2 1

100 0 100

0 0 0

Neostigmine

Hutchinson and Griffiths [17] Stephenson et al. [18] Turegano-Fuentes et al. [19] Ponec et al. [20] Paran et al. [21] Trevisani et al. [22] Abeyta et al. [23] Van der Spoel et al. [24] Mehta et al. [25]

11 12 16 21 11 28 8 24 27

71 83 75 81 82 93 87 79 84

0 16 0 11 0 0 0 0 6

leading to colonic decompression in approximately two-thirds of cases [21,23]. Administration of oral polyethylene glycol (PEG) solution has been shown in a randomized placebo-controlled trial to reduce relapses following successful decompression with neostigmine or colonoscopy [26]. Recurrent colonic dilation was seen in 33% of patients receiving placebo compared with none of those receiving PEG in this trial. Stool output and flatus were both increased with PEG use. The observed adverse effects of neostigmine, like other cholinesterase inhibitors, include excessive salivation (38%), vomiting (9%), abdominal pain (62%), bradycardia (9%), and bronchospasm. Patients must therefore be closely monitored during drug administration, with continuous electrocardiography and atropine available at the bedside [20]. Symptomatic bradycardia responds to administration of atropine, but this also leads to a reversal of any benefit of neostigmine in relieving colonic dilation. The coadministration of glycopyrrolate, an antimuscarinic anticholinergic agent, may decrease the incidence of bradycardia without reducing neostigmine’s efficacy [27,28]. Suitable candidates for neostigmine administration are patients with ACPO who have no evidence of mechanical bowel obstruction, a resting heart rate greater than 60 beats per minute with a systolic blood pressure greater than 90 mmHg, and no active bronchospasm [14,20]. Neostigmine is contraindicated in patients on β-blockers and those who have significant acidosis or recent myocardial ischemia, because of the risk of inducing cardiac arrhythmias [18]. Anecdotal case reports with other prokinetic agents show variable success rates in the treatment of ACPO. Intravenous

678

Recurrence (%)

erythromycin, which acts as a motilin receptor agonist, showed some success in a total of five reported cases [29–31]. The efficacy of intravenous cisapride, no longer available in the US, was highly variable in case reports of five patients [7,32,33]. The new 5-hydroxytryptamine 5-HT4 receptor agonists (tegaserod, prucalopride) might be theoretically useful for stimulating colonic motility in the setting of ACPO, but no data are yet available using these medications in ACPO [14].

Colonoscopic decompression Pharmacologic treatment of ACPO has markedly reduced the need for urgent colonoscopic decompression. While previously considered to be the treatment of choice for progressive colonic dilation, it is now usually reserved for patients who have failed treatment with neostigmine [34,35] (Figure 50.3).

Success

Conservative measures (NG, rectal tube, stop narcotics, mobilize patient)

Stop

Yes

Colonoscopic decompression

No

Neostigmine 2.0 mg i.v.

Fail

Fail

Bradycardia, active bronchospasm, renal failure?

Figure 50.3 Algorithm for management of acute colonic pseudoobstruction.

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Table 50.3 Reports of colonoscopic decompression of acute colonic pseudo-obstruction. Reference

Number of patients

Initial success, n (%)

Recurrence, n (%)

Complications (death), n (%)

Surgery, n (%)

Kukora and Dent [39] Nivatvongs et al. [5] Strodel et al. [40] Starling [41] Bode et al. [42] Nakhgevany [43] Fausel and Goff [44] Nano et al. [45] Gosche et al. [36] Jetmore et al. [37] Geller et al. [38] Total

6 22 44 17 22 10 12 17 19 45 50 264

5 (83%) 19 (86) 32 (73%) 17 (100%) 20 (91%) 9 (0%) 11 (91%) 13 (76%) 17 (89%) 29 (64%) 39 (78%) 83%

0 4 (21%) 5 (13%) 3 (18%) 4 (20%) 0 3 (25%) 6 (46%) 11 (65) 13 (29%) 9 (18%) 23%

0 0 5% (2%) 12% 5% (5%) 0 0 0 5% 0 2% (2%) 3% (1%)

1 (17%) 4 (18%) 9 (20%) 0 3 (14%) 1 (10%) 2 (17%) 0 2 (11%) 5 (11%) 1 (2%) 11%

No randomized comparative studies of colonoscopic decompression with neostigmine or other treatment modalities are available. A summary of 11 retrospective studies involving 264 patients shows a high initial success rate for colonoscopic decompression (64–100%), with an average recurrence rate of 23% (range 13–65%) [5,36–45] (Table 50.3). Complications were reported in 3% [36,37]. The largest single-center series from the Mayo Clinic shows a similar experience in 50 patients, with an overall success rate of 88% complicated by one procedure-related perforation and an overall in-hospital mortality of 30% [38]. Colonoscopic decompression is technically more challenging than routine colonoscopy since the colon is unprepared and the patients are often critically ill, necessitating performance of the procedure in an intensive care unit. Enemas are not very helpful in preparation for colonoscopy and should be done gently, if at all, due to the risk of perforation. Liquid stool must be suctioned and irrigated at the time of colonoscopy in most cases. Air insufflation should be kept to a minimum to prevent further cecal dilation, which could potentially precipitate perforation. It is important to reach the hepatic flexure in order to achieve significant decompression, although cecal intubation is not required [40]. Jetmore and colleagues [37] reported that colonic decompression was almost twice as successful if the ascending colon was reached (initial success 71% vs. 37%). If mucosal changes suggestive of acute ischemia are encountered, the procedure should be terminated and the patient referred for emergency colectomy. The overall decrease in cecal diameter following colonoscopic decompression is generally quite modest, with an average reduction of only 2 cm [46]. Up to 40% of patients develop recurrence of colonic distension after initial successful colonoscopic decompression. This led to the introduction of decompression tubes, which are inserted at the time of the initial procedure. Harig and

colleagues [47] performed a randomized trial in 20 patients comparing endoscopic decompression alone vs. additional insertion of a modified enteroclysis catheter and demonstrated a reduction in the recurrence of colonic dilation from 44% to 0%. Decompression tubes remained in place for an average of 3–4 days without any reported complications. The two most commonly used decompression tubes are a modified enteroclysis catheter, with additional side holes at the tip, or a 14F colon decompression kit (Cook Medical, Winston-Salem, NC, USA). A flexible guidewire is placed through the endoscope channel and the tip is directed into the cecum under fluoroscopy. The endoscope is then slowly withdrawn, leaving the wire in place. Fluoroscopy is helpful in keeping the wire straight during complete withdrawal of the colonoscope. The decompression tube is then advanced under fluoroscopic guidance, using traction on the wire to keep it straight while the tube is advanced. The decompression tube is then taped to the patient’s buttock and connected to low intermittent suction. It is advisable to flush the tube with water every 4 h to prevent clogging with stool. The patient’s clinical status should be followed carefully with daily abdominal radiographs (Figure 50.4). The catheters are usually left in situ for 2–4 days, until colon decompression is complete and underlying reversible contributors to ACPO are reversed. Use of larger tubes up to 40F in diameter (Levacuator, Mallinckrodt Medical, St. Louis, MO, USA) has been described in case reports, with more rapid decompression and less tube clogging [48]. A minority of patients may not respond to these measures and if there is suspicion of acute ischemia or perforation the patient should be referred for immediate surgery.

Percutaneous cecostomy In the absence of ischemia or perforation, percutaneous cecostomy (PC) should be considered as a minimally invasive

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(b) Figure 50.4 (a) Abdominal radiograph of patient with acute colonic pseudo-obstruction following bone marrow transplantation for leukemia. (b) Abdominal radiograph of same patient immediately following colonoscopy, at which time a 14F decompression tube was placed.

alternative to surgery in those critically ill patients in whom induction of general anesthesia poses a significant risk. Both transperitoneal and retroperitoneal approaches for PC have been described [49–51]. The early work by VanSonnenberg and colleagues [52] showed the technical feasibility and safety of PC tubes. The theoretically safer retroperitoneal approach did not lead to a lower risk of peritonitis than the anterior transperitoneal approach [52]. The technique was recently refined by using additional T-fasteners, which allow for better colonic apposition to the abdominal wall, thereby potentially reducing the risk of fecal soiling of the abdominal cavity [53]. Percutaneous cecostomy at the time of colonoscopy using modifications of the technique for percutaneous endoscopic gastrostomy has also been reported in small case series [54]. As with percutaneous endoscopic gastrostomy, premature dislodgement of the cecostomy tube can lead to peritonitis with potentially catastrophic outcomes [55]. No studies comparing the efficacy and safety of pharmacotherapy, endoscopic intervention, radiographically guided PC, and surgery are available.

Surgery Peritoneal signs or free air on abdominal radiography are clear indications for laparotomy and colectomy [2]. The type of definitive surgical management depends on the viability of

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the cecum and ascending colon at the time of exploration. Partial colectomy is indicated for transmural ischemia and perforation but carries a high mortality in these critically ill patients. Surgical decompression in the absence of perforation, through an open or laparoscopic cecostomy, is an alternative to colectomy if the local expertise is not available to perform colonoscopic or computed tomography-guided PC.

Prognosis The overall mortality of ACPO remains approximately 30%, despite the recent advances in its management [2,38]. This reflects the severity of the underlying disease process leading to ACPO and is not directly related to the colonic complications. The impact of pharmacologic therapy on the outcome of patients with ACPO has not yet been fully assessed.

References 1 Ogilvie H. Large-intestine colic due to sympathetic deprivation: a new clinical syndrome. Br Med J 1948; 2: 671–3. 2 Vanek VW, Al-Salti M. Acute pseudo-obstruction of the colon (Ogilvie syndrome): an analysis of 400 cases. Dis Colon Rectum 1986; 29: 203–10.

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3 Spira I, Rodrigues R, Wolff W. Pseudo-obstruction of the colon. Am J Gastroenterol 1976; 65: 397– 408. 4 Bachulis BL, Smith PE. Pseudo-obstruction of the colon. Am J Surg 1978; 136: 66–72. 5 Nivatvongs S, Vermeulen F, Fang D. Colonoscopic decompression of acute pseudo-obstruction of the colon. Am J Surg 1982; 196: 598– 600. 6 Lee JT, Taylor BM, Singleton BC. Epidural anesthesia for acute pseudo-obstruction of the colon (Ogilvie’s syndrome). Dis Colon Rectum 1988; 31: 686– 91. 7 MacColl C, MacCannell KL, Baylis B, Lee SS. Treatment of acute colonic pseudo-obstruction (Ogilvie’s syndrome) with cisapride. Gastroenterology 1990; 98: 773– 6. 8 Burstein CL. Effect of spinal anesthesia on intestinal activity. Proc Soc Exp Biol Med 1939; 42: 291–3. 9 Gierson ED, Storm FK, Shaw W, Coyne SK. Caecal rupture due to colonic ileus. Br J Surg 1975; 62: 393– 6. 10 Johnson CD, Rice RP, Kelvin FM, et al. The radiologic evaluation of gross cecal distension: emphasis on cecal ileus. AJR Am J Roentgenol 1985; 145: 1211–17. 11 Soreide O, Bjerkeset T, Fossdol J. Pseudo-obstruction of the colon (Ogilvie syndrome): a genuine clinical condition? Review of the literature (1948–75) and a report of 5 cases. Dis Colon Rectum 1977; 20: 487– 91. 12 Rex DK. Colonoscopy and acute colonic pseudo-obstruction. Gastrointest Endosc Clin North Am 1997; 7: 499–508. 13 Wojtalik RS, Lindenauer SM, Kahn SS. Perforation of the colon associated with adynamic ileus. Am J Surg 1973; 125: 601–6. 14 De Diorgio R, Barbara G, Stanghellin V, et al. Review article: the pharmacologic treatment of acute colonic pseudo-obstruction. Aliment Pharmacol Ther 2001; 15: 1717–27. 15 Sloyer AF, Panella VS, Demas BE, et al. Ogilvie’s syndrome: successful management without colonoscopy. Dig Dis Sci 1988; 33: 1391– 6. 16 Catchpole BN. Ileus: use of sympathetic blocking agents in its treatment. Surgery 1969; 66: 811–20. 17 Hutchinson R, Griffiths C. Acute colonic pseudo-obstruction: a pharmacologic approach. Ann R Coll Surg Engl 1992; 74: 364– 7. 18 Stephenson BM, Morgan AR, Salaman JR, Wheeler MH. Ogilvie’s syndrome: a new approach to an old problem. Dis Colon Rectum 1995; 38: 424–7. 19 Turegano-Fuentes F, Munoz-Jimenez F, Del Valle-Hernandez E, et al. Early resolution of Ogilvie’s syndrome with intravenous neostigmine. Dis Colon Rectum 1997; 40: 1353– 7. 20 Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med 1999; 341: 137– 41. 21 Paran H, Silverberg D, Mayo A, Shwartz I, Neufeld D, Freund U. Treatment of acute colonic pseudo-obstruction with neostigmine. J Am Coll Surg 2000; 190: 315–18. 22 Trevisani GT, Hyman NH, Church JM. Neostigmine: safe and effective treatment for acute colonic pseudo-obstruction. Dis Colon Rectum 2000; 43: 599– 603. 23 Abeyta BJ, Albrecht RM, Schermer CR. Retrospective study of neostigmine for the treatment of acute colonic pseudo-obstruction. Am Surg 2001; 67: 265– 8. 24 Van der Spoel JI, Oudemans-van Straaten HM, Stoutenbeck CP, Bosman RJ, Zandstra DF. Neostigmine resolves critical illnessrelated colonic ileus in intensive care patients with multiple organ

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failure: a prospective, double-blind, placebo-controlled trial. Intensive Care Med 2001; 27: 822–7. Mehta R, John A, Nair P, et al. Factors predicting the successful outcome following neostigmine therapy in acute colonic pseudoobstruction: A prospective study. J Gastroenterol Hep 2006; 21: 459– 61. Sgouros SN, Vlachogiannakos J, Vassiliadis K, et al. Effect of polyethylene glycol electrolyte balanced solution on patients with acute colonic pseudo-obstruction after resolution of colonic dilatation: a prospective, randomised placebo controlled trial. Gut 2006; 55: 638– 42. Ostheimer GW. A comparison of glycopyrrolate and atropine during reversal of nondepolarizing neuromuscular block with neostigmine. Anesth Analg 1977; 56: 182–6. Mirakur RK, Briggs LP, Clarke RS, Dundee JW, Johnston HM. Comparison of atropine and glycopyrrolate in a mixture with pyridostigmine for the antagonism of neuromuscular block. Br J Anaesth 1981; 53: 1315–20. Armstrong DN, Ballantyne GH, Modlin IM. Erythromycin for reflex ileus in Ogilvie’s syndrome (letter). Lancet 1991; 337: 378. Bonacini M, Smith OJ, Pritchard T. Erythromycin as therapy for acute colonic pseudo-obstruction (Ogilvie’s syndrome). J Clin Gastroenterol 1991; 13: 475– 6. Rovira A, Lopez A, Cambray C, Gimeno C. Acute colonic pseudoobstruction (Ogilvie’s syndrome) treated with erythromycin. Intensive Care Med 1997; 23: 798. Pelkmans PA, Michielsen PP, Jorens PG, Van Maercke YM. Cisapride in Ogilvie’s syndrome. Gastroenterology 1990; 99: 1194–5. Mazloum BW, Barnes JB, Lee M. Cisapride as a successful treatment for acute intestinal pseudo-obstruction. South Med J 1996; 89: 828–30. Eisen GM, Baron TH, Dominitz JA, et al. Acute colonic pseudoobstruction. Gastrointest Endosc 2002; 56: 789–92. Saunders MD, Cappell MS. Endoscopic management of acute colonic pseudo-obstruction. Endoscopy 2005; 37: 760–3. Gosche JR, Sharpe JN, Larson GM. Colonic decompression for pseudo-obstruction of the colon. Am Surg 1989; 55: 111–15. Jetmore AB, Timmcke AE, Gathright JB Jr., Hicks TC, Ray JE, Baker JW. Ogilvie’s syndrome: colonoscopic decompression and analysis of predisposing factors. Dis Colon Rectum 1992; 35: 1135–42. Geller A, Petersen BT, Gostout CJ. Endoscopic decompression for acute colonic pseudo-obstruction. Gastrointest Endosc 1996; 44: 144– 50. Kukora JS, Dent TL. Colonoscopic decompression of massive non-obstructive cecal dilation. Arch Surg 1977; 112: 512–17. Strodel WE, Nostrant TT, Eckhauser FE, Dent TL. Therapeutic and diagnostic colonoscopy in nonobstructive colonic dilation. Ann Surg 1983; 197: 416– 21. Starling JR. Treatment of nontoxic megacolon by colonoscopy. Surgery 1983; 94: 243–5. Bode WE, Beart RW Jr., Spencer RJ, Culp CE, Wolff BG, Taylor BM. Colonoscopic decompression for acute pseudoobstruction of the colon (Ogilvie’s syndrome). Report of 22 cases and review of the literature. Am J Surg 1984; 147: 243–5. Nakhgevany KB. Colonoscopic decompression of the colon in patients with Ogilvie’s syndrome. Am J Surg 1984; 148: 317–20. Fausel CS, Goff JS. Non-operative management of acute idiopathic colonic pseudo-obstruction (Ogilvie’s Syndrome). West J Med 1985; 143: 50–4.

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45 Nano D, Rindiville T, Pavly M, et al. Colonoscopic therapy of acute pseudo-obstruction of the colon. J Gastroenterol 1987; 82: 145– 8. 46 Pham TN, Cosman BC, Chu P, Savides TJ. Radiographic changes after colonoscopic decompression for acute pseudo-obstruction. Dis Colon Rectum 1999; 42: 1586– 91. 47 Harig JM, Fumo DE, Loo FD, et al. Treatment of acute nontoxic megacolon during colonoscopy: tube placement versus simple decompression. Gastrointest Endosc 1988; 34: 23–7. 48 Yarze JC, Winchell EC. A novel device for colonic tube decompression. Am J Gastroenterol 2000; 95: 2136. 49 Crass JE, Simmons RL, Mathis PF, Charles WM. Percutaneous decompression of the colon using CT guidance in Ogilvie syndrome. AJR Am J Roentgenol 1985; 144: 475– 6. 50 Casola G, Withers C, vanSonnenberg E, Herba MJ, Saba RM, Brown RA. Percutaneous cecostomy for decompression of the massively distended cecum. Radiology 1986; 158: 793– 4. 51 Haaga JR, Bick JR, Zollinger RM. CT-guided percutaneous catheter cecostomy. Gastrointest Radiol 1987; 12: 166– 8. 52 VanSonnenberg E, Varney RR, Casola G, et al. Percutaneous cecostomy for Ogilvie syndrome: laboratory observations and clinical experience. Radiology 1990; 175: 679– 82.

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53 Chevallier P, Marcy PY, Francois E, et al. Controlled transperitoneal percutaneous cecostomy as a therapeutic alternative to endoscopic decompression of Ogilvie’s syndrome. Am J Gastroenterol 2002; 97: 471–4. 54 Ramage JI, Baron TH. Percutaneous endoscopic cecostomy. Gastrointest Endosc 2003; 57: 752–5. 55 Bertolini D, DeSaussure P, Chilcott M, et al. Severe delayed complication after percutaneous endoscopic colostomy for chronic intestinal pseudo-obstruction: A case report and review of the literature. World J Gastroenterol 2007; 13: 2255–7. 56 Romeo DP, Solomon GD, Hover AR. Acute colonic pseudoobstruction: a possible role for colocolonic reflex. J Clin Gastroenterol 1985; 7: 256– 60. 57 Wanebo H, Mathewson C, Conolly B. Pseudo-obstruction of the colon. Surg Gynecol Obstet 1971; 133: 44–8. 58 Wegener M, Boersch G. Acute colonic pseudo-obstruction (Ogilvie’s syndrome): presentation of 14 of our own cases and analysis of 1027 cases reported in the literature. Surg Endosc 1987; 1: 169– 74.

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Endoscopic Treatment of Chronic Radiation Proctopathy Christopher J. Gostout Mayo Clinic, Rochester, MN, USA

Available and evolving endoscopic methods for control of bleeding from chronic radiation proctopathy (CRP) are reviewed. CRP can be a disabling outcome from either external beam radiation or brachytherapy used in the treatment of pelvic malignancies. Morbidity includes diarrhea, impaired defecation, rectal pain, tenesmus, incontinence, fistulas, and bleeding. Bleeding typically presents 6 months to 1 year after completion of radiation therapy in up to one-third of these patients [1]. Although topical treatments, especially the application of dilute formalin, have been used for mild bleeding, endoscopic coagulation techniques are the most effective therapy, especially for patients with anemia and/or transfusion dependency. Unfortunately, well-designed randomized, placebo-controlled trials are lacking and efficacy is based mainly on case series data. Studies have neither had consistent definitions of CRP nor validated outcome measures. The endoscopic findings of CRP include mucosal pallor, friability, spontaneous oozing, angiectasia, and rarely ulceration [2] (Figure 51.1). The angiectasias are primarily responsible for clinically significant bleeding. These will develop at the dentate line and extend into the distal rectum (Figure 51.2). On occasion, in females, there is sigmoid involvement that affects treatment strategy (Figure 51.3). The histology is characteristic: an obliterative endarteritis leading to lamina propria fibrosis, mucosal ischemia, and epithelial atrophy [3].

(a)

General principles Endoluminal endoscopic-guided therapy has become the preferred treatment for control of hematochezia that is frequent and/or the cause of transfusion dependency. Multiple therapeutic modalities are available. Historically, the most common have been the Nd:YAG (neodymium-doped yttrium– aluminum–garnet) and argon lasers, bipolar electrocautery, monopolar electrocautery, argon plasma coagulation, and

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

(b) Figure 51.1 Angioectasias of radiation proctopathy can vary in presentation within the distal rectum. (a) Dense vascular lesions with coalescence. (b) Scattered infrequent lesions.

formalin instillation. Characteristics of the more ideal candidates for endoscopic therapy are shown in Table 51.1 and measures of efficacy are shown in Table 51.2. Treatment with any method can be performed in the outpatient setting after an initial complete colonoscopy to assess extent of involvement.

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Figure 51.2 Angioectasias typically extend down to the dentate line and can be approached from (a) retroflexed or (b and c) straight viewing positions.

Table 51.1 Ideal candidates for endoscopic therapy. Chronic hematochezia Refractory to medical management Transfusion dependency ≥ 6 months No tumor recurrence No active nonrectal bleeding source No postradiation fistula, ulceration or strictures

Table 51.2 Measurements of efficacy. Decreased rectal bleeding Reduced transfusion requirements Increased hemoglobin level Improved endoscopic appearance Improved patient quality of life Figure 51.3 Segmental involvement of the distal sigmoid above and separate from the distal rectal lesions.

A standard complete bowel preparation is used for each treatment session using electrocoagulation (e.g., bipolar or argon plasma coagulation) to eliminate the risk of gaseous explosion. Three critical principles apply to all endoscopic treatment methods and must be emphasized. Attention to these will improve the experience for the endoscopist and the outcome for the patient: 1 Endoscope selection. While it has not been formally studied, the gastroscope has several advantages. The narrow caliber minimizes the potential for scope contact and subsequent contactinduced bleeding, which can hamper any therapy. Access to lesions at and close to the dentate line is dramatically improved due to the increased tip retroflexion of an upper endoscope. 2 Coagulation energy. Minimizing coagulating energy is the most important technical point of thermal therapies to help avoid creation of deep, slowly resolving and problematic thermal ulcers as well as strictures (Figure 51.4). Bleeding from the

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margins of these ulcers can exceed that from the CRP prior to treatment and is not amenable to supplemental endoluminal therapy. Significant rectal and perineal pain is often present as a result of the ulcers (Figure 51.5). Similarly, overtreatment should be avoided when angioectasias bleed during coagulation. Thermally induced edema, which appears within minutes, often stops the bleeding. The endpoint of coagulation should be a uniform white coagulum and not a dark eschar. 3 Complete treatment. All angioectasias should be treated in any single session. Changing the patient’s position and frequent washing with suctioning of blood and clot facilitate this. More dependent areas should be treated first followed by more proximal lesions. These maneuvers most importantly improve access to the vascular lesions during the course of therapy, and also help avoid inadvertent coagulation of clot and surrounding mucosa, the latter decreasing the risk for ulceration. “Refractory bleeding” is often the result of failure to treat to the level of the dentate line. Except for laser therapy, treatments are

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Figure 51.4 (a) Before and (b) after argon plasma coagulation. Note that a white coagulum ablates the angiectasia. Charring and cavitating the mucosa should be avoided.

Endoscopic Treatment of Chronic Radiation Proctopathy

(b)

(a)

in a straight position, with plasma arcing from the tip to the mucosa, or in a retroflexed position. Therapy is interrupted regularly to decompress the colon and reduce patient discomfort. Treatment sessions are repeated every 6–8 weeks until bleeding is controlled.

Efficacy data

Figure 51.5 Thermal ulceration complicating argon plasma coagulation. This ulceration is typically deep, accompanied by anal pain, and gives rise to refractory bleeding. Some may heal in time.

typically repeated every 6– 8 weeks until there is cessation of bleeding symptoms and then repeated as needed.

Argon plasma coagulation The argon plasma coagulator (APC) continues to be the most commonly used treatment modality for CRP. It offers the advantages of portability, noncontact coagulation and shallow depth of injury (2 mm vs. 5 mm with laser and monopolar contact coagulation). Shallow coagulation injury is facilitated by avoiding contact of the probe tip with the mucosa, limiting coagulation time of a focal area, and, most importantly, using the lowest power setting that will produce a coagulum. The gas flow rate should be adjusted to minimize colonic distension; it should be less than 2 L/min but 0.8 L/min will provide an adequate argon gas environment. End-firing probes are satisfactory and result in less mucosal contact than, for example, the side-firing probe. Lesions near the dentate line can be treated with the endoscope either

Silva et al. [4] reported the largest experience to date with 28 patients treated for anemia and/or persistent bleeding despite medical treatment. After a median of 2.9 treatment sessions all patients reported subjective improvement or cessation of bleeding. A quantitative mean severity score bleeding showed a mean decrease from 2.96 to 0.68. Average hemoglobin level increased by 1.2 g/dL (1.9 g/dL in anemic patients) and 70% of patients maintained hemoglobin levels of 12 g/dL or greater. No serious complications or side-effects were observed from the technique itself. APC settings used were 50 W and 1.5 L/min flow rate with single applications of less than 2 s each. Similar studies have shown bleeding control in 70–95% of patients, with complete cessation of bleeding in 47–80% with power settings of 40–50 W [5–11]. The more powerful and efficient second-generation APC units require settings about 50% less than with the original models. The number of treatment sessions required has been 1–4, with bleeding controlled for up to 36 months. Complications rarely reported have included pneumoperitoneum, refractory ulceration, and rectal stenosis.

Bipolar and monopolar coagulation Bipolar and monopolar coagulation can be applied with successful results but are more likely to induce contact bleeding and further traumatize tissue from tissue adherence to the probe tip. Contact coagulation probes are advantageous for lesions in the distal rectum at and just above the dentate line with the endoscope in the retroflexed position. Treatment of distal lesions often has a significant impact on longterm efficacy. Recommended power settings are 12–16 W

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(b)

(c)

Figure 51.6 Flat large surface area multipolar coagulation device which is fitted to the tip of the endoscope. (a) device in relationship to endoscope tip. (b) Surface view of the device. Multipolar arrangement of coagulation wires is evident. (c) Superficial coagulation created by the multipolar device spanning an area involved with angioectasias.

with continuous pulse mode for the bipolar (Gold Probe, Boston Scientific Corporation, Natick, MA, USA) probe and 10–15 J for the heater probe. Alternatively, there is limited experience with the use of flat-surface multipolar coagulating units attached to the tip of the endoscope. These devices have been developed and used primarily for the treatment of Barrett’s esophagus (Figure 51.6).

Efficacy data Jensen et al. [12] performed a randomized prospective study of these two modalities in 21 patients who had failed over 12 months of medical treatment. Patients required a mean of four sessions with either probe for bleeding resolution. The mean fall in severe bleeds was significant for both the heater probe (67% vs. 11%) and the Gold Probe (75% vs. 33%) without a significant difference between the two. The heater probe was favored in the reduction of blood transfusion pre and post treatment and increase in hematocrit from baseline. Tenesmus and general health improved and angiectasias resolved in both groups while no major complications occurred. Other studies have demonstrated similar response rates with power settings of 10–20 J for the Gold Probe or 10–15 W for the heater probe with duration of response up to 12 months [13,14].

Formalin therapy The use of formalin in radiation proctopathy is a natural extension of its use in hemorrhagic cystitis as formalin acts as a chemical sclerosant [15]. Methods of applying a dilute (4%) solution have included instillation directly onto the mucosa with exposure times of 30 s to 15 min or using a rigid proctoscope with application of formalin-soaked gauze pads for up to 45 min [16–20]. The Mayo Clinic Developmental Endoscopy Unit group has been prospectively comparing topical 4% formalin applied with a cotton-tipped endoscopic catheter to APC. Clusters of angiectasias are directly tamponaded with the formalin-soaked applicator for 30 s for each contact area with

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a typical procedure duration of 10 min. Precautions are taken to protect the perianal skin and mucosa proximal to the rectum. These include petroleum jelly coating of the anus/perianal skin and placement of the patient in reverse Trendelenburg position to prevent proximal migration of formalin. This maneuver is very useful to ensure maximal contact with all vascular lesions when treating with freely instilled formalin. In this setting, 30–60 cm3 is instilled via the endoscope working channel. The total volume of formalin used is dependent on visual input. Contact with the affected tissues is also facilitated by evacuating air within the rectum and turning the patient from side to side. Total contact time with this method in our practice is limited to 10 min, after which the formalin is aspirated and the rectum is liberally irrigated with water. Immediate changes with treatment are minimal, but include decreased friability and bleeding, and sometimes blanching of lesions. Subsequently (within 10–15 min), asymptomatic edema develops. Within days there is superficial mucosal ulceration. Because of this, formalin use in patients with preexisting ulceration is contraindicated in order to avoid the superimposed chemical injury and inevitable pain. Based on numerous case series reports with varying techniques, “complete response” has ranged from 67% to 100% with durations of up to 20 months [15–18,21–24]. Most reports involve the use of general anesthesia, but our own experience with a cotton-tipped applicator is readily done with or without conscious sedation. Reported complications include abdominal cramps, anal/perianal pain, self-limited fissures, chemical colitis, and a rectovaginal fistula [15–18,21–24].

Nd:YAG laser The monochromatic light energy of the YAG laser is absorbed more efficiently by the darker ectatic blood vessels than by the surrounding nonvascular mucosa and results in a depth of injury of approximately 5 mm [25]. A starting power of 40 W per pulse with maximum pulse duration of 0.5 s is

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recommended with 5 W reductions in power if charring or cavitation results. The tip is maintained at ≤ 1 cm from the mucosa with treatment proceeding in a proximal to distal sequence. Dependent areas are treated first to avoid subsequent impaired access secondary to pooling of blood. Tangential lesions often require supplemental contact therapy with monopolar or bipolar coagulation. As with APC, frequent colonic decompression is required. Unlike APC, extreme caution must be used in retroflexion to avoid damaging the endoscope. Because of the increased depth of injury, posttreatment ulceration and bleeding typically occurs within a week of treatment. We recommend an interval of 3 months before a follow-up treatment session to allow complete healing of thermal injury and accurate assessment of residual lesions/ bleeding. Response has been similar to other techniques, the proportion of patients experiencing daily rectal bleeding decreasing from 87% to 11% in the largest series of 47 patients [25]. Complications from the deeper injury occur in up to 15% of patients and include transmural necrosis, perforation,

Figure 51.7 (a) Carbon dioxide-based cryotherapy device. (b) View of the endoscope with attached evacuation tubing to accommodate the high flow rate of carbon dioxide gas.

(a)

Figure 51.8 (a) Liquid nitrogen-based cryotherapy device. (b) Heated delivery probe of this low-pressure operating system.

(a)

Endoscopic Treatment of Chronic Radiation Proctopathy

stricture and fistulas [26]. Laser therapy is currently very uncommon and this device has been relegated to a position of providing historical perspective.

Cryotherapy Cryotherapy should be regarded as “all-inclusive” in the application and effects of the treatment, similar to that of topical formalin. It is a form of therapy which has appeal from the standpoint of convenience and efficiency. The treatment is not meticulous and is directed at freezing large areas of mucosa containing the angioectasias. A painting technique is used to ablate the rectal mucosa. Injury is superficial and limited to the submucosa in depth. Two types of cryotherapy devices are clinically available, one liquid nitrogen based and the other carbon dioxide based (Figures 51.7 and 51.8). Experience is limited [27]. There are insufficient data and experience to permit any recommendations regarding this form of therapy.

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Recommendations Patients with minimal, infrequent bleeding without anemia may undergo a trial of medical therapy. Our own practice is to use 10% sucralfate enemas twice daily as this has been shown to be superior to anti-inflammatory treatment in a randomized, prospective, double-blind trial [28]. Bowel habits should be managed to avoid constipation and passage of scyballous stools. Endoscopic therapy should be first-line treatment for patients with frequent bleeding and anemia as a result of their rectal bleeding. Because of its efficacy and ease of use, APC can be considered the first-line coagulation technique. Although more treatment sessions may be required, heater probe or gold probe treatments are convenient alternatives. Sigmoid involvement is often not amenable to endoscopic treatment because of the luminal anatomy and extensive number of lesions. With the argon plasma coagulator, dozens of angioectasias can be treated during one session. Patients refractory to endoscopic therapy and/or with colonic involvement proximal to the rectum are best served with either surgical resection of the segment or a bypass to facilitate adequate management of persistent bleeding. Topical formalin should be considered in patients who are on anticoagulation or vigorous antiplatelet therapy. In this patient group there is minimal risk of exacerbating bleeding from the therapy. There is also no need to discontinue anticoagulation prior to therapy.

References 1 Wasserman T. Radioprotective effects of amifostine. Semin Oncol 1999; 26(Suppl.): 89– 94. 2 Reichelderfer M, Morrissey JF. Colonoscopy in radiation colitis. Gastrointest Endosc 1980; 26: 41–3. 3 Haboubi NY, Schofield PF, Rowland PL. The light and electron microscopic features of early and late phase radiation-induced proctitis. Am J Gastroenterol 1988; 83: 1140– 4. 4 Silva RA, Correia AJ, Dias LM, et al. Argon plasma coagulation therapy for hemorrhagic radiation proctosigmoiditis. Gastrointest Endosc 1999; 50: 221– 4. 5 Fantin AC, Binek J, Suter WR, et al. Argon beam coagulation for treatment of symptomatic radiation-induced proctitis. Gastrointest Endosc 1999; 49(4 Pt 1): 515–18. 6 Kaassis M, Oberti E, Burtin, et al. Argon plasma coagulation for the treatment of hemorrhagic radiation proctitis. Endoscopy 2000; 32: 673–6. 7 Smith S, Wallner K, Dominitz JA, et al. Argon plasma coagulation for rectal bleeding after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51: 636– 42. 8 Taieb S, Rolachon A, Cenni JC, et al. Effective use of argon plasma coagulation in the treatment of severe radiation proctitis. Dis Colon Rectum 2001; 44: 1766–71. 9 Tam W, Moore J, Schoeman M. Treatment of radiation proctitis with argon plasma coagulation. Endoscopy 2000; 32: 667–72.

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10 Tjandra JJ, Sengupta S. Argon plasma coagulation is an effective treatment for refractory hemorrhagic radiation proctitis. Dis Colon Rectum 2001; 44: 1759– 65. 11 Villavicencio RT, Rex DK, Rahmani E. Efficacy and complications of argon plasma coagulation for hematochezia related to radiation proctopathy. Gastrointest Endosc 2002; 55: 70–4. 12 Jensen DM, Machicado GA, Cheng S, et al. A randomized prospective study of endoscopic bipolar electrocoagulation and heater probe treatment of chronic rectal bleeding from radiation telangiectasia. Gastrointest Endosc 1997; 45: 20–5. 13 Fuentes D, Monserat R, Isern AM, et al. Colitis por radiacion: manejo endoscopico con sonda caliente. Gen 1993; 47: 165–7. 14 Maunoury V, Brunetaud JM, Cortot A. Bipolar electrocoagulation treatment for hemorrhagic radiation injury of the lower digestive tract [comment]. Gastrointest Endosc 1991; 37: 492–3. 15 Rubinstein E, Ibsen T, Rasmussen RB, et al. Formalin treatment of radiation-induced hemorrhagic proctitis. Am J Gastroenterol 1986; 81: 44–5. 16 Saclarides TJ, King DG, Franklin JL, et al. Formalin instillation for refractory radiation-induced hemorrhagic proctitis. Report of 16 patients. Dis Colon Rectum 1996; 39: 196– 9. 17 Seow-Choen F, Goh HS, Eu KW, et al. A simple and effective treatment for hemorrhagic radiation proctitis using formalin. Dis Colon Rectum 1993; 36: 135– 8. 18 Counter SF, Froese DP, Hart MJ. Prospective evaluation of formalin therapy for radiation proctitis. Am J Surg 1999; 177: 396– 8. 19 Luna-Perez P, Rodriguez-Ramirez SE. Formalin instillation for refractory radiation-induced hemorrhagic proctitis. J Surg Oncol 2002; 80: 41– 4. 20 Pikarsky AJ, Belin B, Efron J, et al. Complications following formalin installation in the treatment of radiation induced proctitis. Int J Colorectal Dis 20001; 5: 96–9. 21 Reimer E, Rasmussen RB, Rubinstein BE, et al. Formalinbehandling af svaer straleinduceret haemoragisk proctitis. Ugeskrift for Laeger 1987; 149: 1194– 6. 22 Roche B, Chautems R, Marti MC. Application of formaldehyde for treatment of hemorrhagic radiation-induced proctitis. World J Surg 1996; 20: 1092–4; discussion 94–5. 23 Isenberg GA, Goldstein SD, Resnik AM. Formalin therapy for radiation proctitis. JAMA 1994; 272: 1822. 24 Chapuis P, Dent O, Bokey E, et al. The development of a treatment protocol for patients with chronic radiation-induced rectal bleeding. Aust N Z J Surg 1996; 66: 680–5. 25 Viggiano TR, Zighelboim J, Ahlquist DA, et al. Endoscopic Nd:YAG laser coagulation of bleeding from radiation proctopathy. Gastrointest Endosc 1993; 9: 513–17. 26 Alexander TJ, Dwyer RM. Endoscopic Nd:YAG laser treatment of severe radiation injury of the lower gastrointestinal tract: longterm follow-up [comment]. Gastrointest Endosc 1988; 34: 407– 11. 27 Kantsevoy SV, Cruz-Correa MR, Vaughn CA, et al. Endoscopic cryotherapy for the treatment of bleeding mucosal vascular lesions of the GI tract: A pilot study. Gastrointest Endosc 2003; 57: 403– 40. 28 Kochhar R, Patel F, Dhar A, et al. Radiation-induced proctosigmoiditis. Prospective, randomized, double-blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate. Dig Dis Sci 1991; 36: 103– 7.

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Benign and Malignant Colorectal Strictures Todd H. Baron Mayo Clinic, Rochester, MN, USA

Introduction A variety of conditions may lead to the formation of benign and malignant strictures of the colon and rectum [1] (Table 52.1). Most patients with colorectal strictures present with symptoms of large bowel obstruction. Colonoscopy facilitates determination of the clinical and histologic nature of colorectal strictures. Therapeutic interventions performed through the colonoscope may be an adjunct or alternative to surgery in selected patients with symptoms related to colorectal strictures. This chapter will review the use of colonoscopy in the

Table 52.1 Etiology of colorectal strictures. Benign Diverticular disease Anastomosis (including ileocolonic) Inflammatory bowel disease Radiation Ischemia Nonsteroidal anti-inflammatory drugs Infectious Severe acute pancreatitis Endometriosis Malignant Primary colorectal cancer Recurrent colorectal cancer Intracolonic metastases Lymphoma Extrinsic compression Ovarian cancer Prostate cancer Drop metastases Nodal metastases

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

management of benign and malignant strictures of the colon and rectum.

Colonoscopy in the diagnosis of colorectal strictures Colonoscopy allows direct visualization and inspection of colorectal strictures. The appearance of the stricture may suggest the diagnosis, although there is some overlap between benign and malignant strictures. For example, endoscopic features of a malignant stricture include an obvious mass, ulceration, and bleeding, whereas benign strictures usually appear smooth and symmetrical. The combination of the endoscopic features, clinical features (prior cancer or surgery), and radiologic features on computed tomography (CT) (e.g., the presence or absence of a mass or inflammatory changes) often allows a presumptive diagnosis of benign or malignant disease to be made. During endoscopic evaluation or treatment of an obstructive colonic stricture the endoscopist must be careful not to overinsufflate air, since a closed-loop phenomenon is created in the presence of a competent ileocecal valve, which could result in perforation of the right colon [2]. Tissue sampling during colonoscopy allows for a definitive diagnosis of malignancy to be made in a high percentage of patients. Direct forceps biopsy is the standard method of tissue acquisition. Sampling of the entire portion of the stricture may produce a higher yield than sampling of only the distal portion but can be technically difficult because a severely narrowed lumen may prevent passage of the endoscope. It may be necessary to dilate a suspected malignant stricture to allow the endoscope to pass through the stricture so that complete endoscopic evaluation with tissue sampling is possible (Figure 52.1). An alternative to colonic stricture dilation is the use of smallerdiameter endoscopes, including the use of ultrathin upper endoscopes. Although not routinely utilized, brush cytology sampling may increase the diagnostic yield of malignancy over biopsy alone [3]. Colorectal strictures occurring in the setting of established chronic ulcerative colitis (CUC) should be assumed to be

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malignant in nature. Predictors of a malignant stricture in the setting of CUC include long duration of disease (> 10 years), proximal location, and symptomatic large bowel obstruction [4]. Likewise, colorectal strictures occurring in the setting of documented Crohn’s colitis may also be malignant; duration of disease > 20 years and short strictures appear to be associated with malignancy [5]. Most symptomatic benign colorectal strictures are fibrotic in nature. However, patients with inflammatory bowel disease and those with diverticular disease may have a component of luminal compromise from chronic fibrotic changes that become obstructive when acute inflammatory changes are superimposed. Once the acute inflammatory component resolves, usually with medical therapy, obstructive symptoms tend to resolve. Balloon dilation of a stricture in the setting of acute inflammatory changes is likely to be less effective than when the entire obstruction is fibrotic. In the setting of immunosuppression, infections such as cytomegalovirus (CMV) may produce colonic strictures, some of which resemble primary colorectal malignancy [6]. Therefore, in immunosuppressed patients, biopsies should be obtained and processed appropriately for the detection of infectious agents. Severe acute pancreatitis may result in acute and/or chronic inflammatory changes of the colon with fixation and obstruction [7]. It is important for the endoscopist to recognize this well-described, but underappreciated, entity, since stricture dilation is not appropriate for the treatment of these strictures and can result in perforation.

Endoscopic therapy of colorectal strictures Benign disease Anastomotic strictures Most of the data concerning the endoscopic dilation of symptomatic benign strictures come from experience with anastom-

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Figure 52.1 Submucosal recurrence of colorectal cancer. (a) Upon initial inspection, the stricture appears benign. (b) After stricture dilation and further passage of the endoscope, obvious features of malignancy are seen.

otic strictures. Stricture dilation may be achieved using balloon dilators or rigid (bougie) over-the-wire dilators, with or without electrosurgical devices. The data for each disease process will be discussed separately. Colonic anastomotic strictures occur in up to 22% of patients following bowel resection and anastomosis [8]. Factors promoting development of anastomotic strictures include ischemia, anastomotic dehiscence, pre- or postoperative radiation therapy, and cancer recurrence (when resection is for malignant disease). The success rate of endoscopic dilation depends on several factors. Pucciarelli et al. [9] analyzed the outcome following dilation of anastomotic strictures. Factors associated with a successful response to dilation were high anastomosis (> 8 cm from the anal verge), no adjuvant radiotherapy, minimal or no dehiscence, no neoplastic recurrence, simple stricture morphology, and short stenosis (< 1 cm). These authors found that the combination of radiotherapy, local neoplastic recurrence, and large dehiscence was associated with a probability of failure of a single dilation of nearly 100%. When these three factors were absent, the probability of failure of dilation therapy was 5%. Another important concept is that some anastomotic strictures are membranous and more responsive to endoscopic therapy, while others are transmural and concentric and less responsive to endoscopic therapy. The first endoscopic therapy for a postoperative colonic stricture was described in 1984 in which balloon dilation was performed. Since then, there have been numerous reports using through-the-scope (TTS) hydrostatic balloon dilators for dilation of anastomotic strictures. Kozarek [10] published the results of a survey of 3000 endoscopists who were queried about their use of hydrostatic dilation of benign strictures. Of 64 patients who underwent colonic stricture dilation, 44 had anastomotic strictures. Immediate objective and symptomatic relief was reported in 83% and 73% of patients, respectively, while objective and symptomatic relief at > 3 months were achieved in 73% and 86% of patients, respect-

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ively. Additionally, the size of the balloon appears to be important. Among all patients undergoing colonic stricture dilation, immediate symptomatic improvement following balloon dilation was < 50% using balloons with a diameter < 40 French (13 mm), compared with a success rate of > 90% for balloon dilators with a diameter of at least 51 French (17 mm). Taking dilation one step further, 30- to 40-mmdiameter achalasia-dilating balloons have been used to dilate anastomotic colonic strictures [11]. Good long-term results were achieved in 16 of 18 (94%) patients. In a randomized trial, standard TTS balloons were compared with achalasiadilating balloons (over-the-wire, OTW) in 30 patients with benign colorectal anastomotic strictures. The mean number of sessions required was 2.6 in the TTS group and 1.6 in the OTW group (P = 0.009). The duration of response was greater in the OTW group than in the TTS group, 560.8 (248.5) days vs. 294.2 (149.3) days, respectively (P = 0.016) [12]. In another large series of 94 consecutive patients (68 resected for malignant disease, 26 for benign disease) with postoperative colorectal anastomotic stenosis treated endoscopically, dilation was successful in 59% of patients resected for cancer and in 88% of patients resected for benign disease. Complications developed in 17 patients (benign restenosis, perforation, abscess) and were significantly more frequent in the postcancer resection group than after resection for benign disease (P < 0.05) [13]. Overall, success rates for balloon dilation of anastomotic strictures range from 70% to 90% [8]. Over-the-wire rigid dilators (Savary–Gilliard) are also used to treat anastomotic strictures in the left colon, particularly those close to the anus. Werre et al. [14] described the use of this technique in 15 patients. After endoscopic placement of a guidewire across the stricture, 10- to 19-mm dilators were passed under fluoroscopic guidance. The strictures were reevaluated endoscopically 2–3 weeks later. Ten patients had a complete response after three or fewer sessions, whereas five

Figure 52.2 Anastomotic stricture. (a) Smooth, membranous-type anastomotic rectal stricture. (b) Hydrostatic through-the-scope balloon dilation is undertaken using a 20-mm balloon. The membranous nature is more obvious during dilation.

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patients underwent four or more procedures and none had a complete response, suggesting that if patients do not respond to dilation within a few sessions they are not likely to. There are no prospective trials comparing balloon dilators with Savary dilators. In a retrospective comparative study, balloon dilation was found to produce a better response after a single session than bougie dilation (77% vs. 52%, respectively) [15]. Both methods of dilation may lead to complications of perforation and bleeding. There are no specific guidelines on diameters of dilators and number of dilations per session, as there are for esophageal dilation. Although there are no supportive data, it is assumed that more aggressive dilation may be performed in the rectum than in more proximal regions. Additionally, there are no data to support injection of corticosteroids into the stricture to improve the long-term outcome following dilation. In summary, the response rate following dilation of anastomotic strictures is variable and dependent upon several factors. With proper patient selection, balloon or rigid dilation is the initial nonoperative treatment of choice (Figure 52.2). Interestingly, long-term health-related quality of life is significantly impaired following balloon dilation of benign anastomotic colorectal strictures despite reaching an anastomotic diameter ≥ 13 mm [16]. It is postulated that relief of abdominal pain, gas bloat, and alterations in bowel movements may require dilation to a greater circumference.

Electroincision The use of an endoscopic electroincision technique has been described as a method to treat benign anastomotic colorectal stenoses. Brandimarte and Tursi described 39 patients with central, membranous anastomotic “strictures” defined by barium enema and endoscopy [17]. A needle knife electrocautery device [as used for endoscopic retrograde cholangiopancreatography (ERCP) precutting techniques] was used

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to incise the stricture radially in six directions. No other therapy (such as balloon dilation) was performed. Patients were followed clinically and endoscopically for a mean of 25 months without recurrence of stricture or symptoms. The use of this electroincision technique to augment balloon dilation therapy has also been proposed as a treatment for refractory strictures. In a series of 35 patients, Truong et al. [18] performed electroincision, cutting radially in four directions, followed by balloon dilation. Two-thirds of patients required one treatment. A good response was obtained in all patients following 1–3 sessions. Recently, electroincision using a Nd:YAG (neodymium-doped yttrium–aluminum–garnet) laser has been described, with excellent results in 9 of 10 patients [19]. In another study of patients with membranous or short strictures (diameter 3– 8 mm) endoscopic treatment was performed using argon plasma coagulation in combination with diathermy. Scar tissue at the anastomotic line was incised radially with a polypectomy snare. The scar tissue between these radial incisions was reduced by argon plasma coagulation. All patients were treated successfully using the combined endoscopic technique. No complications were encountered [20]. Because of the potential for serious complications, electroincision is best performed by experienced endoscopists in selected patients with membranous-type strictures.

Cutting device Shimada et al. [21] described treatment of anastomotic strictures specifically for patients whose strictures developed after a double stapling technique that had been complicated by leakage. A staple cutter was used to incise the stricture in six patients. Further data are needed before the use of this device can be recommended.

Inflammatory bowel disease Most of the data regarding endoscopic dilation of colonic strictures occurring in the setting of inflammatory bowel disease are derived from the treatment of recurrent Crohn’s disease with stricturing at the site of colocolonic or ileocolonic anastomoses. In nearly all of these reports TTS balloons were used for dilation [22]. Couckuyt et al. [23] prospectively evaluated the outcome of 55 patients with clinically symptomatic ileocolonic strictures following endoscopic TTS balloon dilation. Dilation was performed with balloons ranging in diameter from 18 to 25 mm. Long-term success was achieved in 62% of patients, but perforation occurred in six patients (11%). In another study, balloon dilation was limited to a maximum diameter of 18 mm with similar results and no perforations [24]. Although retrospective studies have suggested that corticosteroid injections may improve the outcome following endoscopic therapy [25–27], a recent randomized trial of

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placebo injection and corticosteroid injection after balloon dilation of Crohn’s disease suggested a worse outcome in the steroid group [28]. Electroincision was used in one series of four patients with ileocolonic anastomotic strictures [27]. One case of successful wire-guided bougienage dilation of an ileocolonic anastomotic stricture after failed TTS balloon dilation has been reported [29]. There are only a few reports of successful balloon dilation of colonic Crohn’s strictures in the absence of previous surgery [27,30,31]. Some authors have used 18-mm dilators at the initial session, while others have reached the 18 mm diameter over several sessions. In one series of 10 Crohn’s patients undergoing endoscopic therapy, six had colonic strictures not involving the ileum, five of which were not postoperative [27]. Endoscopic “dilation” was performed using needle knife electroincision followed by injection of triamcinolone. Unfortunately, the details of follow-up are unavailable and this approach cannot be routinely recommended. More recently, Singh et al. [25] dilated Crohn’s strictures in a variety of locations: rectal (five patients), sigmoid colon (2), colocolonic anastomosis (3), ileocolonic anastomosis (4), descending colon (1), and cecum (1). Three perforations occurred (all colonic). The long-term success rate was approximately 70% regardless of whether balloon diameter was ≥ 15 mm or < 15 mm. Similar results have also been reported by two other groups [32–34]. In summary, endoscopic dilation for the treatment of ileocolonic and colonic strictures in the setting of inflammatory bowel disease is a reasonable nonsurgical alternative, especially for short and isolated stenosis, particularly at the ileocolonic anastomosis. The perforation rate appears to be higher for colonic strictures in the absence of prior surgery. Endoscopic dilation can result in long-term avoidance of surgery and has acceptable complication rates, so it should be considered in these patients to avoid surgical resection [35], though up to one-third of patients will eventually require surgery. The ideal dilation strategy and the efficacy of adjuvant corticosteroid injection are unknown.

Nonsteroidal anti-inflammatory drug-induced strictures One of the adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) is the development of colonic strictures. These strictures are usually symmetrical, 2–4 mm thick, may be multiple, and may occur in the right and transverse colon [36]. There have been only a few reports of endoscopic therapy, but it appears that large-diameter TTS balloon dilation (15– 20 mm) is safe and effective for treating NSAID-induced strictures [37–39].

Miscellaneous strictures There are few to no data on the use of endoscopic dilation for the other benign strictures outlined in Table 52.1. In the report

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by Kozarek [10], 5 of 44 patients undergoing colonic dilation had diverticular strictures. All five patients had objective relief at > 3 months following balloon dilation. There are no other details regarding the acute or chronic nature of the strictures.

Self-expandable plastic stents A self-expandable plastic stent that is approved by the Food and Drug Administration (FDA) for use in patients with benign esophageal disease has been used for treatment of benign postoperative rectosigmoid strictures, in one case in a patient who also had a fistula [40]. Three patients were treated with successful nonsurgical resolution, and, although the stent spontaneously migrated within 4 days in two cases, the patients remained asymptomatic.

Self-expandable metal stents Self-expandable metal stents (SEMS) are currently FDA approved only for the treatment of malignant colorectal obstruction. However, there are reports of their use in benign obstructive colorectal diseases. The main safety concern with the use of uncovered metal stents for benign disease is the long-term consequences of implantation. When a stent is used as a bridge to surgery to relieve acute colonic obstruction and allow a one-stage operation (see preoperative decompression of malignant strictures later in this chapter), long-term safety is not a concern as the device is removed at the time of operation. However, there are few data on the safety of SEMS in the long-term, nonoperative management of patients with benign strictures, and uncovered stents should be used only as the last option for patients in whom the risks associated with surgery are high. SEMS frequently spontaneously migrate from benign strictures, usually in the first month after insertion [41]. Although not designed for endoscopic removal, uncovered SEMS are potentially removable, and it is strongly recommended that a cautious attempt should be made to remove them within 4– 8 weeks of implantation before they become completely embedded in the tissue. Whether the SEMS spontaneously migrates or is removed, stent dilation may be of lasting benefit.

Anastomotic strictures There are several case reports of the use of temporary expandable metal stents to dilate anastomotic strictures in patients with strictures unresponsive to endoscopic dilation. In one case, the stent migrated distally 6 days after insertion [42]. Endoscopically, the colonic lumen remained widely patent at last follow-up 12 months later. In another case, the stent was endoscopically removed 3 months after insertion and no further treatment was required at a follow-up of 18 months [43]. In another case, a covered, retrievable stent was placed with good long-term results [44]. In addition, a small, retrospective series has reported good preliminary results after SEMS placement [45].

Benign and Malignant Colorectal Strictures

Inflammatory bowel disease One group placed uncovered SEMS in two patients for the treatment of refractory Crohn’s strictures as an alternative to surgical strictureplasty [46]. One patient had a symptomatic descending colonic stricture and one patient had small bowel obstruction due to an ileocolonic stricture. The SEMS remained in place for less than 1 month and 5 months, respectively, after which time they spontaneously migrated. In a subsequent report on the follow-up of these patients, the patients remained without stricture recurrence at 3 years and 4.5 years, respectively [47]. In another report, a patient with a nonoperative terminal ileal stricture underwent placement of uncovered Wallstents with a preoperative intent to allow nutritional improvement. At 8 weeks the patient remained asymptomatic [48]. Unfortunately, these devices may also be associated with complications when left in place long term [49]. Diverticular disease Early series of patients who underwent endoscopic SEMS placement for treatment of colonic obstruction [50,51] included patients with diverticular disease as the cause of acute obstruction. SEMS placement provided resolution of obstruction; subsequent one-stage operative resection with primary anastomosis was performed. More recently, Small et al. [52] described the use of uncovered SEMS in 23 patients, 16 of whom had diverticular strictures. Emergent surgery was avoided in the vast majority of patients. In patients in whom the stent remained in place, delayed complications occurred. Radiation-induced strictures There are reports of uncovered SEMS placement for treatment of colonic obstruction from chronic radiation-induced colonic strictures. In the initial report [53], an uncovered SEMS was placed in a patient with complete rectosigmoid obstruction. The stent spontaneously migrated distally from the stricture 19 days after placement. There was clinical and radiographic resolution of the stricture at a follow-up of 43 weeks. In the other case, the stent remained in place for 4 months until the patient died from underlying medical illness unrelated to the stent [54]. Other series have contained patients with radiation strictures [52]. Miscellaneous strictures There are no data on the use of SEMS for the other benign strictures outlined in Table 52.1.

Malignant disease Colonic obstruction secondary to malignancy is the number one cause of emergency large bowel surgery, accounting for as many as 85% of such procedures. There are two clinical scenarios for endoscopic treatment of malignant colorectal strictures: preoperative decompression and palliation. Additionally,

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Figure 52.3 Polypoid primary rectal cancer, which is an ideal lesion for ablation (laser, APC, debulking) therapy.

there are two major endoscopic modalities to decompress the obstructed colon, laser therapy and SEMS. Each of the two endoscopic treatment options and clinical scenarios will be discussed separately.

General comments Laser Laser therapy of primary colorectal neoplasms has been performed for over 20 years. Laser therapy is most useful for treating patients who have intrinsic lesions in the distal colon that are bulky, polypoid, and exophytic (Figure 52.3). One drawback is the inability to treat intrinsic scirrhous lesions and extrinsically compressive lesions. Laser therapy, however, has an advantage over SEMS placement in the ability to control bleeding from primary colorectal cancer. Since laser therapy has been largely supplanted by other modalities, its overall use is declining. Whether newer endoscopic tumorablative modalities, such as argon beam plasma coagulation (APC), delivered at high settings can produce results similar to laser therapy remains to be seen. It is important to note that, if APC is used, a completely prepped colon is required so as to reduce the risk of explosion [55].

Self-expanding metal stents SEMS are composed of a variety of metal alloys and come in varying shapes and sizes depending on the individual manufacturer and organ of placement. The radial expansile forces and degree of shortening differ between stent types [56]. Tissue reactions to SEMS in vivo are known based on animal data as well as autopsy and surgical findings in humans [57]. Once deployed, the tissue response to uncovered SEMS seems to be consistent throughout the gastrointestinal tract. The stent material becomes incorporated in both the tumor and surrounding tissue as a result of pressure necrosis. In the areas

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uninvolved by tumor above and below the stenosis, the stent embeds deep into the wall of the organ. This reaction allows anchoring of the stent and helps to prevent stent migration. In areas of the stent where a covering is applied, this integration does not always occur and a higher rate of stent migration is seen. At the present time, SEMS available in the US specifically designed for use within the colon are uncovered [57]. Covered esophageal stents have been used in the colon to prevent or relieve obstruction due to tumor ingrowth and to close fistulae [58]. Outside the US, dedicated covered colonic SEMS are available. SEMS may produce imaging artifacts on both computed tomography (CT) and magnetic resonance imaging (MRI) scans of the area around the stent that may prevent accurate interpretation. Most SEMS materials appear safe for MRI, but factors such as stent shape, orientation to the magnetic field, and type of alloy composition influence signal intensity in vitro. Thus, this information should be obtained before an MRI is performed in a patient who has undergone colorectal stent placement [59,60].

Preoperative decompression The traditional management of patients with either subtotal or complete malignant colonic obstruction of the left colon involves the creation of a diverting colostomy. Up to 30% of patients with primary colorectal carcinoma present with large bowel obstruction [61]. Frequently, these patients cannot undergo a one-stage operative resection of the lesion and primary colonic reanastomosis because stool present in the uncleansed colon proximal to the obstruction may lead to breakdown of the colonic anastomosis. Therefore, an initial surgery consisting of diverting colostomy with resection of the primary tumor is performed; reanastomosis of the colon is performed later in a second operation. In addition, patients presenting with complete colonic obstruction tend to be acutely ill with more advanced disease, in contrast to those patients who present without obstruction. Preoperative endoscopic decompression allows clinical stabilization of the patient and colonic preparation so that a one-stage operation can be performed and a colostomy is avoided. After successful endoscopic colonic decompression, the patient’s comorbid medical illnesses and extent of malignancy can be addressed. Preoperative decompression allows preoperative chemoradiotherapy to be administered. Yet another advantage of SEMS placement is the ability to perform full colonoscopy to exclude synchronous lesions. Colonoscopy should be delayed for several days after stent placement for several reasons. First, the stent may be dislodged when not yet fully expanded and embedded. Second, in a markedly dilated colon there is a risk of perforation. Finally, until adequate decompression is achieved and a preparation is administered, endoscopic visualization is limited. Whether one uses a pediatric colonoscope or a standard colonoscope is related to expansion and diameter of stent. Vitale

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et al. [62] described successful full colonoscopy with fluoroscopic guidance after colonic SEMS placement in 29 out of 31 patients. After colonic decompression was achieved, colonoscopy was performed using a standard adult colonoscope prior to surgical resection an average of 5 days (range 4–8 days) after stent insertion. Complete colonoscopy was possible in all 22 patients (100%) in whom an Ultraflex Precision stent was placed and in seven of nine patients in whom an Enteral Wallstent was placed. A synchronous cancer was detected in three patients (9.6%), changing the surgical plan. If the patient is a poor candidate for surgical resection because of underlying illnesses such as severe coronary artery disease, or has unresectable or widely metastatic disease discovered by imaging studies, laser therapy and/or SEMS can serve as the palliative approach.

Laser therapy Although most series have described using laser therapy as a palliative modality, it has the potential to serve as a bridge to surgery. Arrigoni et al. [63] used endoscopic modalities to recanalize the large bowel lumen in patients with acute large bowel obstruction due to colorectal cancer. Using a combination of a TTS balloon (18 mm) or Savary dilation (12–18 mm), snare debulking, and Nd:YAG laser therapy, emergent colostomy was avoided in 16 of 17 patients; successful restoration of the colonic lumen and relief of bowel obstruction was achieved. No complications occurred as a result of endoscopic therapy. Although no patients in this series ultimately underwent surgical resection, the data demonstrate the ability to decompress the acutely obstructed colon with this approach. Self-expanding metal stents The use of SEMS as a bridge to surgery has become an accepted approach. SEMS remain in place until surgery, when the stent is resected en bloc with the tumor [50]. Multiple series have been published describing successful preoperative placement of colonic SEMS with subsequent one-stage resections [50,64,65]. Overall, the days in the intensive care unit (ICU), hospital days, need for colostomy, and costs appear to be lower when SEMS are placed preoperatively [66– 68]. In addition, there are now several series demonstrating the ability to perform laparoscopic resection after SEMS placement [69– 72]. The combined endoscopic and laparoscopic procedures are less invasive than a two-stage open operation and recovery is fasteraadditional advantages of preoperative stent placement. Preoperative radiation therapy prolongs survival among patients with rectal cancer [73]. Thus, a further advantage of stent placement in patients with obstructing primary rectal cancer is the ability to provide this treatment. One such case has been reported. After a full course of chemoradiation therapy, the tumor and stent were resected. No adverse pathologic effects were seen in the resected specimen [74].

Benign and Malignant Colorectal Strictures

Palliation of malignant colonic obstruction Laser therapy Laser therapy is useful for palliation of both colonic obstruction and bleeding from primary colorectal cancer. In patients with obstruction, it appears that laser therapy is most effective in treating small tumors. With tumors smaller than 3 cm in diameter, near-universal improvement in obstructive symptoms is seen [75]. Several sessions are required to maintain the lumen in patients with large tumors. Even then, the response rate in this group is not 100% and patients with extensive disease may not be sufficiently treated with laser. Two large series of laser therapy for palliation of colorectal cancer have been published. The largest study included 272 patients undergoing palliative therapy for rectosigmoid cancers [76]. A high immediate success rate (85%) and low major complication rate (2%) were reported for palliation of obstructive symptoms. Gevers et al. [77] evaluated the longterm outcome of laser palliation of rectal cancer in 219 patients. Results were analyzed based upon the predominant symptom of obstruction, bleeding and other symptoms (soiling, tenesmus, and diarrhea). Long-term follow-up was obtained until death (mean 6.7 months). Significantly more patients in the obstruction group (25%) eventually required palliative colostomy. Patients with obstruction required significantly more sessions than the other groups. Palliation of bleeding was achieved in 83% of patients. Notably, major complications of perforation (4.1%), fistula (3.2%), bleeding (4.1%), and abscess formation (1.7%) were seen. This study shows that the outcome of laser therapy is different depending on whether the primary intent is to treat obstruction or bleeding. Overall, laser therapy achieves successful palliation in 80–90% of patients. An average of approximately three procedures is required to achieve sufficient and lasting relief of obstructive symptoms. Serious complications (bleeding, perforation, and severe pain) occur in up to 10–15% of patients [78–80]. Most centers, however, have abandoned laser in favor of APC. Only a small study has been published in which APC, with or without snare debulking, has been used successfully for palliation of obstruction due to advanced colorectal carcinoma [81].

Self-expanding metal stents Patients with colorectal carcinoma and colonic obstruction who have extensive local or metastatic disease, patients who are poor operative candidates for surgical resection, and patients with obstruction secondary to noncolonic pelvic malignancies (e.g., bladder or ovarian carcinoma) or metastatic diseases (e.g., breast carcinoma) are candidates for colonic SEMS placement for palliation. Multiple series have demonstrated successful palliation of obstruction with avoidance of colostomy in 85–100% of patients [64]. In some series, the stents effectively palliated obstruction for more than 1 year. There has been one randomized comparative trial of stent placement versus colostomy for palliation of malignant colonic

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obstruction. Unfortunately, this study was closed prematurely due to an unexpectedly high number of delayed perforations (4/10 patients) in the stent group [82]. Although the authors felt this may have been specifically related to stent design, the same stent has been used by other authors without an increased number of delayed perforations [83]. Since right colon obstruction due to primary colon cancer can be treated with a one-stage operation with an ileocolonic anastomosis, stents are not usually placed in the right colon preoperatively. Palliative placement of colon stents into the right colon appears to have an outcome similar to that of placement in the left colon [84,85]. Following uncomplicated colorectal stent placement, patients may resume oral intake immediately if there was no overt clinical obstruction, or after clinical decompression if there was overt complete obstruction. Following palliative colorectal stent placement, patients are advised to consume a low-residue diet and use stool softeners or laxatives to avoid stent occlusion from stool impaction. Complications of colon SEMS placement may occur during the procedure or early after placement (early complications) or late after insertion. Early complications include perforation, migration, bleeding, stent malposition, and stent occlusion by stool impaction. Free perforation during SEMS insertion may be a devastating complication, as fecal material is spilled into the abdominal cavity resulting in peritonitis. This may be more difficult to manage surgically than diverting colostomy alone. Additionally, the patient may be more acutely ill, producing a potentially worse surgical outcome. Improper deployment of the stent or proximal stent migration after successful placement results in a stent floating freely within the lumen above the stricture. This is usually of no consequence, assuming an additional stent or stents are properly placed to relieve the obstruction (personal experience). Stents placed very distally in the rectum may produce tenesmus, rectal pain, and fecal incontinence. Thus, patients with distal rectal obstruction should be advised of this possibility prior to stent placement. In general, stent placement > 2 cm proximal to the anal canal does not interfere with anal function. Late complications include distal stent migration, bleeding, and perforation [86]. Stent migration may be completely asymptomatic or result in rectal bleeding or tenesmus. Removal of distally migrated stents from the rectum is not technically difficult and is best performed using a rat-toothed forceps. Stent occlusion from tumor overgrowth, ingrowth, or stool impaction requires endoscopic intervention. Obstruction by tumor ingrowth or overgrowth is usually managed with placement of additional stents through the original stent(s). It is unknown whether previous radiation increases the risk of stent-related complications. However, the use of newer chemotherapy agents such as bevacizumab, an angiogenesis inhibitor, has been associated with an increased risk of perforation [87]. Whether this increases the risk of stent-related perforation is unknown.

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Some patients with advanced malignancies and colonic obstruction may not improve following successful stent placement because of other unidentified sites of malignant gastrointestinal obstruction or diffuse peritoneal carcinomatosis with small bowel encasement.

Palliation of malignant fistulae Patients with malignancy within the pelvis may suffer from fistulae to surrounding structures such as the vagina or bladder. In this setting, covered esophageal stents have been used to close such fistulae and produce excellent palliation [58,88].

Materials for and techniques of endoscopic insertion of colonic SEMS General comments The duration of the procedure is highly variable and is dependent on the degree of difficulty one encounters traversing or accessing the stricture. At least one full hour of time should be allotted once sedation is administered. The stent chosen should be at least 3–4 cm longer than the obstruction to allow an adequate margin of stent on either side of the obstruction.

Stent types Although any type of SEMS may be used within the colon, including esophageal, tracheobronchial, and biliary stents, dedicated colonic SEMS are commercially available. Four different colonic SEMS are approved by the FDA for the treatment of malignant obstruction (Table 52.2 and Figure 52.4) [89]. Two of these stents have a longer and smaller predeployment delivery system (10 French) that allows the passage of stents directly through the working channel of therapeutic colonoscopes, improving mechanical advantage. This allows stents to be placed as proximal as the ileocecal valve. Distal lesions producing colonic obstruction are within the reach of a standard flexible sigmoidoscope or upper endoscope. For lesions proximal to the descending colon it is usually necessary to use a SEMS that will pass through a colonoscope. If a stent is chosen that will pass through the working channel of the endoscope, a therapeutic channel (≥ 3.8 mm diameter) is required. Other materials that should be readily available include biliary catheters and guidewires. Hydrophilic biliary guidewires (Terumo, Tokyo, Japan) are especially useful in order to “cannulate” or traverse obstructive lesions. A stiffer 0.035-inch guidewire is needed for stability during stent placement once the lesion has been traversed. Water-soluble radiographic contrast may also be needed to define stricture length as well as to ensure correct passage of catheters within the gastrointestinal lumen. If marking of the tumor margins is desired, injection needles for placement of radiopaque contrast are needed.

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Table 52.2 Expandable metal stents available in the US. Manufacturer/model

Materials

Deployed diameters (mm)

Deployed lengths (mm)

Boston Scientific Ultraflex Precision Colonic

Nitinol

25 (proximal flare 30 mm)

Wallstent Enteral®

Elgiloy® (cobalt–chromium–nickel)

Wallflex Enteral Colonic

Nitinol

20 22 25 mm body, 30 mm proximal flare 22 mm body, 27 mm proximal flare

57 87 117 60 90 60 90 120

Cook Endoscopy Colonic Z-stent

Stainless steel

Patient preparation and positioning Patients with complete obstruction have usually evacuated any stool below the lesion and bowel preparation is not necessary. In those patients in whom obstruction of distal colon is less than total, one or two cleansing enemas are usually adequate. In patients with more proximal lesions and subtotal obstruction, a cautious colonoscopy bowel preparation should be given. Prophylactic antibiotics should be considered in patients with complete obstruction and a markedly dilated colon because introduction of air during the procedure may promote microperforation and bacteremia. The patient should initially be placed in the left lateral decubitus position. Rotating the patient into the supine position allows for a better anatomic view under fluoroscopy, if used. Standard intravenous conscious sedation is usually administered, but is not absolutely necessary for distal lesions.

Figure 52.4 Examples of fully deployed colonic stents. (a) Wallflex Colonic Stent (Boston Scientific). (b) Colonic Z Stent (Cook Endoscopy).

(a)

25

40 60 80 100 120

Description of procedure Placement of SEMS in the rectum and distal sigmoid without the use of TTS stents is analogous to esophageal stent placement. Placement of TTS stents, which are usually necessary for treating more proximal obstruction, is more analogous to ERCP with placement of a metal biliary stent. These two approaches to SEMS placement will be discussed separately. It is imperative to have nursing assistants who are experienced in complex therapeutic endoscopic procedures and SEMS placement to assist with these procedures. Non-fluoroscopic-guided stent placement Non-TTS stent placements For distal left-sided lesions, some authors prefer to assess the entire lesion entirely under endoscopic guidance. If the endoscope cannot be passed through the lesion, the stricture

(b)

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(a)

(b) Figure 52.5 Non-TTS stent placement. (a) Balloon dilation is performed to allow passage of a 9.8-mm upper endoscope. (b) Endoscope is reinserted and passed alongside stent to monitor deployment.

may be cautiously balloon dilated using a 12–15 mm TTS balloon (Figure 52.5a). A small-caliber endoscope is then passed through the stricture to allow placement of an ultrastiff (Savary) guidewire as high as possible above the lesion. The endoscope is withdrawn while the stenosis is measured and the position/orientation of the lumen is assessed. After the undeployed stent is passed across the stricture, the endoscope is reinserted to verify and monitor the exact position of the distal end of the stent during deployment (Figure 52.5b). Alternatively, in patients with intrinsic lesions, some authors have used laser therapy to initially recanalize the lumen to allow passage of the endoscope and guidewire to facilitate placement of SEMS [89]. Both of these methods allow for stent placement without the use of fluoroscopy. TTS stent placement If the endoscope passes easily through the lesion, a 0.035-inch guidewire with a floppy tip is placed through the endoscope

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Endoscopic/fluoroscopic stent placement If the endoscope cannot be passed easily through the lesion, a hydrophilic biliary guidewire preloaded through a standard biliary catheter is used to “cannulate” or traverse the stricture, as is done during ERCP (Figure 52.7a). Once the wire has passed through the stricture, recognized fluoroscopically by the anatomically correct position of the wire passing into an air-filled, dilated proximal bowel, the catheter is advanced over the guidewire through the lesion. The guidewire is removed and water-soluble radiographic contrast is injected to confirm both proper position and luminal patency. At this point the guidewire is exchanged for a stiff 0.035-inch guidewire and the procedure continues as described above (Figure 52.7b–d). Once the stent is fully deployed, the ends of the stent should be carefully inspected fluoroscopically. If either end is not flared or fully expanded to produce a waist, the endoscopist should be suspicious that the stent chosen may have been too short to cover the entire length of the stricture. At this point contrast can be injected into the stent to assess complete patency. If needed, a second (rarely third) overlapping stent may be required to adequately treat the stricture. Limitations and success rates The technical success rate for placement of colonic SEMS in experienced centers is close to 100%. SEMS can be placed endoscopically into the right colon [90], whereas, with radiologic guidance alone, stent placement is almost always limited to the left colon. Limitations of successful placement include inability to pass a guidewire through the stricture and anatomic difficulties such as a severely angulated and “fixed” sigmoid that prevents advancement to the site of the lesion. Avoidance of complications Steps can be taken to avoid intraprocedural perforation [91]. The first is limiting the amount of air insufflation during the examination, especially in patients with a dilated cecum. The second is avoiding aggressive pre- or post-stent dilation [89].

Conclusions Colonoscopy plays a major role in the evaluation and treatment of patients with benign and malignant colorectal strictures. Tissue sampling allows the diagnosis of malignancy. Successful treatment of benign strictures is achieved using colonoscopically directed dilation. Endoscopic placement of expandable metal stents into the colon is useful for both preoperative and palliative relief of colonic obstruction.

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Figure 52.6 Endoscopic placement of a through-the-scope stent using fluoroscopic guidance. (a) The endoscope is advanced to the site of the lesion. A guidewire and catheter are advanced through the area of obstruction. (b) The guidewire is replaced by a stiff guidewire and the delivery system is introduced. (c) The stent is initially deployed at the proximal portion of the lesion under both endoscopic and fluoroscopic guidance. (d) The stent is fully expanded and symmetric in diameter throughout its length.

Figure 52.7 Endoscopic view of throughthe-scope SEMS placement (Wallstent) for palliation of malignant colonic obstruction. (a) A guidewire has been advanced across the lesion. (b) Immediately after deployment of the stent.

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(a)

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(c)

(d)

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(b)

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83 Repici A, De Caro G, Luigiano C, et al. WallFlex colonic stent placement for management of malignant colonic obstruction: a prospective study at two centers. Gastrointest Endosc 2008; 67: 77– 84. 84 Repici A, Adler DG, Gibbs CM, Malesci A, Preatoni P, Baron TH. Stenting of the proximal colon in patients with malignant large bowel obstruction: techniques and outcomes. Gastrointest Endosc 2007; 66: 940– 4. 85 Elsberger B, Rourke K, Brush J, Glancy S, Collie M. Self-expanding metallic stent insertion in the proximal colon. Colorectal Dis 2007; 10: 194– 6. 86 Han YM, Lee JM, Lee TH. Delayed colon perforation after palliative treatment for rectal carcinoma with bare rectal stent: a case report. Korean J Radiol 2000; 1: 169–71. 87 Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol 2007; 14: 1860– 9. 88 Jeyarajah AR, Shepherd JH, Fairclough PD, Patchett SE. Effective palliation of a colovaginal fistula using a self-expanding metal stent. Gastrointest Endosc 1997; 46: 367– 9. 89 Baron TH. Expandable gastrointestinal stents. Gastroenterology 2007; 34: 823– 30. 90 Harris GJ, Senagore AJ, Lavery IC, Fazio VW. The management of neoplastic colorectal obstruction with colonic endolumenal stenting devices. Am J Surg 2001; 181: 499–506. 91 Baron TH. Minimizing endoscopic complications: endoluminal stents. Gastrointest Endosc Clin N Am 2007; 17: 83–104, vii.

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Complications James Church Cleveland Clinic, Cleveland, OH, USA

Introduction Over the last three decades, advances in endoscope design, bowel preparation, and the array of instruments and techniques available have made colonoscopy one of the safest of invasive procedures. Complications and adverse effects still happen, of course, but their frequency is low. The purpose of this chapter is to describe the range of complications that can happen during colonoscopy, to show what their expected frequencies may be, and to provide some advice on how to prevent and how to manage them. A discussion of some general principles that apply to complications of colonoscopy is worthwhile.

Risk management The basis of risk management in a medical setting is to define the risks that apply to each patient for any procedure, and then to consider the benefits to be achieved by that procedure in the light of those risks. Patients are told about the balance of risks and benefits that apply in their own particular situation and participate in the decision-making process that flows from this balance. This is informed consent. For example, a patient with severe chronic obstructive respiratory disease and a positive fecal occult blood test needs a colonoscopy but is at risk of cardiac and respiratory complications from oversedation. That patient must understand that sedation will be light if it is given at all and the endoscopist must appreciate that technique must be gentle and take steps to adapt to this need. Other scenarios include patients with a recent myocardial infarction, in whom a screening colonoscopy may need to be deferred until cardiac status is stable, or patients on coumadin who present for surveillance, in whom the coumadin may not need to be

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

stopped unless a significant polyp is found. Minimizing risk by adapting the clinical approach to the patient is an important aspect of reducing complications. Assessing risk on the basis of a careful history and examination is essential to this process.

The dilemma of teaching The technique of colonoscopy is learned practically, not theoretically, and, although simulators are becoming more realistic, there is no way to avoid supervised patient experience. Both Geenen et al. [1] and Fruhmorgen and Demling [2] have shown that complication rates of colonoscopy are inversely related to the experience of the examiner. The teacher is thereby faced with a dilemma. Trainees need to work through difficult situations to learn the techniques required, yet patients must not be put at increased risk just for the purposes of training. If the trainee is not allowed to attempt difficult examinations, skills will not be readily acquired, but patient safety is paramount. Patients who have had a sigmoidectomy present an opportunity for novice colonoscopists to perform comfortable, minimal-risk examinations. At the other end of the spectrum of difficulty is the elderly patient with severe diverticulosis or a fixed sigmoid loop, when the novice may require considerable assistance from the trainer.

Putting the literature into perspective Several factors must be considered when reading reports of complications of colonoscopy to allow a helpful interpretation of the data. The design of the study is a key to the applicability of the results. A retrospective or multi-institution or multiendoscopist survey will not give accurate incidence rates but will show the range of severity of the problem. A singleendoscopist or single-unit study will not show the range of the problem, but will usually report overoptimistic results as most data come from expert units. A case report may be interesting and illustrative of an approach to the particular problem

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it describes, but it does not allow the authors or their readers to make generalizations based on one or a few patients. The date of the study is as important as its design because several factors that influence colonoscopy complications have changed over the years. The range and quality of available endoscopes and endoscopic instruments have improved significantly, allowing gentler and more efficient examinations. Furthermore, the effectiveness of bowel preparation, sedation, and analgesia is better and the average experience level in endoscopy units has moved well into the “expert” range. Balancing this maturation of experience is a willingness of experts to take on riskier cases. The likely outcome of complications has also changed with time as advances in antibiotics, anesthesia technique, and surgical options (i.e., laparoscopy) have made treatment more effective and less risky. Therefore, a consideration of the risks of diagnostic and therapeutic colonoscopy must be based on today’s realities, and not rely too much on old, perhaps irrelevant, data.

Mortality The worst complication of any procedure is the unexpected, unanticipated death of the patient. Risk management is important in minimizing mortality, and should take into consideration whether colonoscopy should be performed at all, whether to persist with a difficult examination in an elderly, frail patient, or whether to remove a small cecal polyp in an 80-year-old. Selection of patients for colonoscopy should reflect such decision-making. Elective examinations are contraindicated in critically ill patients or patients with a limited life expectancy. However, even in ideal circumstances, patients sometimes die from the complications of colonoscopy. In 1983 Macrae et al. reported a mortality rate of 0.06% in a series of 5000 consecutive examinations [3], and in 1994 Jentshura et al. [4] reported a mortality rate of 0.015%. Most deaths occur after serious complications (perforation, hemorrhage) in patients with serious comorbidity. Waye et al. [5] summarized 12 reports describing 165 perforations out of 99 539 diagnostic colonoscopies and 76 perforations out of 18 659 therapeutic colonoscopies. The overall mortality was 5/83 725 (0.006%). As shown in this chapter, death can occur from any serious complication of colonoscopy: the electrolyte imbalance caused by sodium phosphate preparation, the cardiac events brought on by hypoxia from oversedation, the sepsis that may follow perforation, or the blood loss that can occur with hemorrhage. Prevention and correct management of these complications will minimize mortality.

Bowel cleansing regimens are designed to do this in such a way as to be effective in most patients without being too unpleasant or severe. However, aspiration in elderly patients has been described [6] and vomiting is quite common [7,8]. Sometimes an unusual degree of intolerance to colonoscopy preparation can be the first sign of a coincidental gastrointestinal problem [9]. Various techniques to improve passage of the liquid and to reduce the amount that is drunk have been published and are covered in detail in Chapter 10. The phosphosoda preparation is potentially more dangerous than polyethylene glycol (PEG), as the lavage fluid is drawn out of the patient’s interstitial space into the colon by the hyperosmotic phosphosoda. Dehydration is routine, so patients are encouraged to drink water liberally with their preparation. Hookey et al. [10] recently reviewed 26 studies of liquid sodium phosphate bowel preparation that included 2496 patients. There were no major preparation-related adverse reactions. A review article described 29 patients who did have serious adverse reactions to sodium phosphate lavage, including symptomatic hypocalcemia, hypokalemia, hypernatremia, hypotension, and acute renal failure. Thirteen of these patients were having colonoscopy: two patients died. Sixteen patients received sodium phosphate for other reasons, of whom four died. Most of the patients suffering significant adverse effects either received a dose that was higher than recommended or had conditions that may have predisposed them to a problem (e.g., chronic renal failure, bowel obstruction or ileus, preexisting dehydration, or electrolyte imbalance). The authors of the review concluded that sodium phosphate lavage was safe as long as appropriate exclusions for comorbidity were followed and the recommended dose limits obeyed (two 45-mL doses given 5–12 h apart). In 2004, Markowitz and colleagues [11] reported five cases of acute renal failure following colonoscopy where the preparation had been sodium phosphate. The renal failure, occurring from 3 days to 2 months after the colonoscopy, was associated with nephrocalcinosis. Subsequent comparative studies have established the safety of sodium phosphate bowel preparations as long as patients with baseline renal impairment and those taking renin–angiotensin blocking agents, angiotensin-converting enzyme (ACE) inhibitors, or thiazide diuretics are excluded [12,13]. This issue is covered in more depth in Chapter 10. The increased compliance found with the smaller-volume preparations [14] makes sodium phosphate an attractive first choice, as long as patients have normal renal and cardiac function and are not taking diuretics.

Complications of intubation Complications of bowel preparation A clean colon is a prerequisite to a thorough colonoscopy, and there is no alternative to flushing the stool out of the colon.

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Complications can occur during both intubation or extubation of the colon. Usually, most traumatic damage is done on the way in and most therapeutic damage is done on the way out. Some complications, such as perforation, can be done

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either way. This section will focus on complications due to traumatic intubation. The most serious of these is perforation.

Perforation The reported incidence of traumatic perforation can be very low, 3/82 416 (0.004%) colonoscopies reported by Sieg et al. [15] and 0.02% of 8473 diagnostic colonoscopies reported by Wexner et al. [16]. Waye et al. [5] reviewed 10 series reported from 1974 to 1994, in which 165 perforations occurred during diagnostic colonoscopy (0.17%), with individual series rates ranging from 0 to 0.86%. Wexner et al. [16] reviewed 27 series reported between 1975 and 2000, including 276 202 patients. The average rate of perforation (including both diagnostic and therapeutic examinations) was 0.2% and the range was 0.033– 0.81%. Wexner et al.’s review also shows that perforation rates have halved since the 1980s, falling from an average of 0.34% in the five series reported in the 1970s and 0.33% in the nine series reported in the 1980s to 0.16% in the 14 series reported in the 1990s. Table 53.1 summarizes the perforation rates in more recent series of colonoscopies covering the years from the early 1990s to the early 2000s. Perforation rates vary from 2 per 10 000 cases to 13 per 10 000 cases, and in most series perforations occurred with similar frequency in diagnostic and therapeutic examinations. Traumatic perforation may occur because of direct scope trauma, splitting of the bowel at a stricture or by the sideways pressure of a loop, or pneumatic dilation to pressures high enough to perforate. Most perforations occur in the sigmoid colon, probably as a result of a tear in a fixed loop. A perforation caused by pushing the end of the scope through the bowel wall is uncommon, especially in healthy bowel. Uno and Morita [26] created such a situation in surgically resected bowel and found that at pressures of 2–3 kg/cm2 the muscularis propria ruptures first, followed by a split in the serosa. Tearing of the mucosa is the last event in the sequence and produces the hole. Exerting this degree of force in a clinical situation is very unlikely. The other common cause of perforation is a pneumatic blowout in the right colon, when the pressure of

Complications

insufflated air is unrelieved [27]. Perforations can also occur from biopsy, and Foliente et al. [28] reported five cases of cecal perforation in elderly patients (mean age 79.6 years), three of which were due to routine cold biopsy. The distended cecal wall can become extremely thin in elderly patients, making biopsy potentially dangerous. Another situation in which colonoscopic biopsy is dangerous is in acute colitis [29]. Biopsies should be directed to the mucosa overlying a muscular fold and performed in a collapsed colon, especially in the cecum of elderly patients or in patients with acute colitis.

Prevention of traumatic perforations Ideal colonoscopic technique is gentle, unhurried, and efficient, using an economy of action and minimizing loops [30]. “Pushing through” or “sliding by” are high-risk maneuvers and should be used as a last resort. Pain is a sign to stop pushing and find an alternate approach to a situation. It is surprising how many reports of traumatic complications of colonoscopy describe the insertion as “uneventful” or “easy,” yet there is splenic rupture, colonic perforation, or some other catastrophe. Perhaps the definition of “uneventful” or “easy” needs to be reevaluated in these circumstances. Colonoscopists may also need to accept that examination will sometimes be incomplete. Because completeness “to the cecum” is the most commonly used measure of colonoscopic expertise (inappropriately so), there is a tendency to get there “at all costs.” Sometimes the cost may be a perforation. As colonoscopy becomes more commonly performed, safe technique becomes increasingly important. Patients with diseased colons are more likely to have a perforation and so the incidence of perforation in completely normal colons is tiny. Colonoscopists must be aware of situations in which the risk of perforation is increased: 1 Severe diverticulosis with muscular hypertrophy and a narrow sigmoid, when the colonoscope may become impacted in the sigmoid. A proximal pneumatic blowout may occur as insufflated air distends the right colon, although the scope does not advance. The use of CO2 as an insufflating gas [31] in this situation may not prevent the perforation, but the gas

Table 53.1 Summary of recent series describing perforations of the large intestine associated with colonoscopy. Reference

Dates of study

No. of examinations

No. of perforations

Morbidity (%)

Mortality

Lüning et al. [17] Iqbal et al. [18] Tulchinsky [19] Rathgaber and Wick [20] Levin et al. [21] Viiala et al. [22] García Martínez et al. [23] Misra et al. [24] Cobb et al. [25]

1990–2006 1994–2000 1994–2001 2002–2004 1994–2002 1989–1999

30 366 78 702 12 067 12 407 16 318 23 508 16 285 7425 43 609

35 (0.12%) 66 (0.08%) 7 (0.06%) 2 (0.02%) 14 (0.09%) 23 (0.1%) 15 (0.09%) 10 (0.13%) 14 (0.03%)

40 39

9% (postoperative) 8% (postoperative) 0

1997–2003

1 death 3 deaths 25% (postoperative) 1 death

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will be absorbed more rapidly than will room air. A pediatric colonoscope is less likely to become impacted. 2 Severe Crohn’s colitis, ischemia, acute (sealed) diverticulitis, and deeply invasive cancer may weaken the colonic wall so that it gives way under unusually minor stress. This includes direct forward trauma from the tip of the scope or, more commonly, a tear in the side of the colon on the apex of a loop due to stretch. Strategies to adopt include avoiding use of “slide by” in a diseased colon, use of a pediatric colonoscope, avoiding loops, and abandoning the examination. 3 Intraoperative colonoscopy, or any colonoscopy done under general anesthetic, removes the role of pain as a warning sign to stop pushing. In the unconscious patient, there is a temptation to push through loops with more force than would ordinarily be used. There are few data that speak to this concern, and those that are available report safety in very small numbers of patients [32]. Endoscopists performing colonoscopy in patients under general anesthesia should use the same loop avoidance techniques as they would use in awake patients. Sometimes patients need to be colonoscoped in the immediate postcolectomy period. The most common indication is bleeding, although postoperative distension may also be an indication. Cappell et al. [33] stated that such examinations are safe, although they reported on only 52 patients.

Recognition of perforations Causing a perforation during colonoscopy is unfortunate, but failing to recognize that a perforation has occurred, or to acknowledge the possibility, may be disastrous. Perforation of a clean, well-prepared colon is much easier to repair than a perforated colon containing stool, surrounded by fecal contamination and sepsis. Most traumatic perforations are immediately obvious [34]. Either the peritoneal cavity is visible through the endoscope or the patient’s abdomen becomes grossly distended, with or without pain. If either situation occurs, the examination must be stopped immediately. A markedly distended abdomen, usually with loss of liver dullness to percussion, is an indication for an immediate abdominal radiograph. Free intraperitoneal gas may mean a perforation, or at least a split in the colonic wall that has allowed air to escape through the porous mucosa. The clinical circumstances of the colonoscopy will usually alert the endoscopist to the possibility that an injury occurred. If a pneumatic “split” in the colonic wall is likely, a water-soluble contrast enema will show whether there has been a frank perforation [35]. A surgical consultation is routine, and the decision for surgery is based on the likely cause of the perforation, the state of the bowel (diseased vs. normal), and the comorbidity present in the patient. For traumatic perforations the threshold for surgery should be low [34].

Extraperitoneal perforations Sometimes the colonic perforation is on the mesenteric side of the colon. When escaping air passes into the mesentery it

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may then travel to and through the retroperitoneum [36] into the mediastinum. Often a small amount of free air can be seen in the peritoneal cavity on radiographs, after it has leaked through the peritoneum. Retroperitoneal air can track up into the neck and present with crepitus [37], or it can enter the chest cavity and cause life-threatening pneumothoraces [38]. It may also descend into the scrotum. Retroperitoneal perforations can usually be treated with intravenous antibiotics and observation.

Treatment of perforations Almost all traumatic perforations need surgical repair, because they are often ragged and large. This is in contrast to postpolypectomy perforations, some of which may be managed conservatively. The largest series of colonoscopic perforations has been reported by Garbay et al. [39], who reviewed the outcome of 183 colonoscopic perforations, collected from 54 French medical centers over 12 years. Eighty of the patients were over 70 years of age. Perforation occurred in 68 patients during a therapeutic examination. The patients’ clinical details are given in Table 53.2. In general, surgical options include simple suture repair in the case of small holes, minimal contamination, and a normal bowel, resection and primary anastomosis in patients with abnormal bowel or a large ragged hole, and colostomy in patients who are sick or in whom there is extensive contamination or major comorbidity. Sometimes a repair may be protected by diversion if factors associated with a risk of anastomotic leak are present (e.g., malnutrition, chronic steroid therapy, anemia or extensive blood loss, diseased but unresectable bowel). The advantage of this approach is that closing the loop stoma is much less of an operation than relaparotomy to close a primary Hartmann procedure. The range of surgical procedures reported by Garbay et al. is shown in Table 53.2. Their mortality rate was 12%, and was significantly related to medical comorbidity and the size of the perforation. Seventy-seven patients had postoperative complications, of whom 23 needed a reoperation. Recent series reported by Lüning et al. [17] and Iqbal et al. [18] show similar morbidity (40% and 39%, respectively) and mortality (9% and 8%, respectively) from surgery for colonoscopic perforations. Lüning et al. operated on all 35 patients. Eighteen underwent repair, eight resection and anastomosis, six resection with stoma; in three patients no perforation was found. Iqbal et al. reported that factors leading to a poor prognosis were a delay in diagnosis, extensive contamination, and use of anticoagulants. Both mortality and morbidity may be reduced by the use of minimally invasive techniques to treat perforations [40–42]. One of the biggest series is by Wullstein et al. [43], who also classified perforations according to size. Five of the seven patients were treated by closure of the perforation or laparoscopic resection. There was no mortality, little morbidity, and most patients went home within 5 days of surgery. An even less invasive way of treating colonic perforation was recently

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Table 53.2 Clinical aspects of a large series of colonoscopic perforations [25]. Clinical aspect

No. (%)

Diagnosis Immediate Delayed 1 h to 42 days

75 (42%) 100 (56%)

Presentation Peritonitis Pain without peritonitis Septic shock Generalized sepsis Bleeding Miscellaneous Plain abdominal radiograph Pneumoperitoneum Retroperitoneum Normal Patients operated within 6 h of endoscopy Size of perforation < 2 cm > 2 cm Site of perforation Rectum Sigmoid Left colon Transverse colon Right colon Small bowel None found Surgeries Suture closure Resection Exteriorization Other

76 55 5 3 1 6

116 6 17 84 (48%) 73 (49%) 76 (51%)

12 132 15 6 15 2 2

59 (32%) (20 with stoma) 88 (48%) (53 with stoma) 33 (18%) (33 with stoma) 3 (2%) (two with stoma)

described by Mana and colleagues [44], who used clips applied through the colonoscope to seal a small sigmoid perforation. Other examples of the use of clips have since been published [45]. The decision to treat a perforation nonoperatively is the result of a careful evaluation of the clinical circumstances, and rests on the presence of a well-prepared clean colon with minimal bacterial contamination of the peritoneal cavity. Other essentials are a small or sealed perforation, normal bowel, and a patient with good healing capacity and an intact immune system. Seow-Choen et al. [46] reported five such patients, four of whom underwent therapeutic colonoscopy. All presented with pain from 2 to 12 h after colonoscopy and four had pneumoperitoneum. All responded to conservative therapy. Damore et al. [47] reviewed the literature and found that 58 of 196 (30%) perforations from 12 series were managed con-

Complications

servatively. Orsoni et al. [34] attempted conservative therapy in 21 out of 48 cases but needed to operate on eight. Four of five patients with traumatic perforations managed conservatively ultimately needed surgery. Finally, Iqbal et al. chose nonoperative management of perforations based on the lack of peritoneal irritation in 10 patients out of 66 with perforation. Eight of the 10 did well, one developed an abscess, and one died due to the family’s declining surgery [18]. The lessons from these experiences are that some small perforations from polypectomy can be managed conservatively under close observation with surgery for any deterioration, or even failure to improve. Traumatic perforations usually necessitate urgent surgery. Pneumatic split of the serosa can be distinguished from true perforation by water-soluble contrast enema [35].

Intraluminal bleeding Bleeding is an unusual complication of diagnostic colonoscopy. Dafnis et al. [48] reported no cases in 4677 colonoscopies, Waye et al. [5] found 38 cases in their collective review of 51 378 diagnostic colonoscopies (0.07%), and in the report by Wexner et al. of 13 580 colonoscopies there was no case of bleeding without biopsy [16]. Of the 10 cases in which bleeding did occur, five followed hot biopsy, four were after snare polypectomy, and only one case followed cold biopsy. Kavic and Basson [49] reviewed five studies of colonoscopic complications and found 26 cases out of 101 397 diagnostic colonoscopies (0.03%), most following biopsy. In contrast is the frequency of postpolypectomy hemorrhage, occurring in 284 out of 14 951 cases (1.9%). Significant bleeding from a cold biopsy in a patient with normal coagulation is likely to occur only when a vascular structure is biopsied, such as an hemangioma, an arteriovenous malformation, or a prominent mucosal vein. Cold biopsy forceps will rarely reach deep enough into the submucosa to damage the submucosal arteries. An arteriovenous malformation rarely needs to be biopsied. It is either treated or left alone. Biopsy should also be avoided in patients with coagulopathy or with portal hypertension. Table 53.3 shows recent series reporting bleeding after colonoscopy. The overall rate is between 0.2% and 0.9%; most cases follow polypectomy.

Extraluminal bleeding Bleeding from outside the colonic lumen can also occur during or after colonoscopy. It is invisible, and if it continues will present at some time after the procedure has been completed. The most common cause is damage to the spleen, but mesenteric lacerations, tearing of adhesions, and retroperitoneal bleeds have been reported.

Splenic trauma Splenic injury has been described in several case reports and small series, and Saad and Rex have recently reviewed them

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Table 53.3 Summary of recent series describing hemorrhage associated with colonoscopy. Reference

Dates of study

No. of examinations

Cases of hemorrhage

Viiala et al. [22] Rathgaber and Wick [20] Levin et al. [21] Sawhney et al. [50]

1989–1999 2002–2004 1994–2002

23 508 12 407 16 318 4952

49 (0.2%) 25 (0.2%) 82 (0.5%) 41 (0.9%)

6671

38 (0.6%)

Watabe et al. [51]

[52]. Various mechanisms have been proposed to account for the injury, including simple tearing of the splenic capsule by traction on the splenocolic ligament, direct trauma to the spleen by a loop of colon, and excess fragility of the spleen due to splenomegaly. The intimate anatomic relationship between the spleen and the splenic flexure of the colon raises the question of why the spleen is not damaged more often (Figure 53.1). According to Saad and Rex, splenic perforations usually occur in women (76%), onset of symptoms is usually delayed by some hours, colonoscopy and ultrasound are suitable for diagnosis, and 36% of examinations associated with splenic injury are “difficult.” Almost one-third (31%) of patients could be managed conservatively. Ahmed et al. [53] reviewed 17 cases of splenic rupture secondary to colonoscopy and found that all presented with abdominal pain, usually within 24 h of the examination. Only half of patients were anemic (8/17), but 13 had an elevated white blood cell count. The diagnosis was made by computed tomography (CT) in seven, by laparotomy in six, by ultrasound in one, and by angio-

Risk factors

Post polypectomy 0.46% Anticoagulation resumed within 1 week Polyp size Polyp size Hypertension

graphy in one. Treatment was conservative in four patients while 11 required splenectomy. Stein et al. [54] describe treatment of a splenic injury at colonoscopy with embolization, a technique that has been used in cases of rupture due to trauma. Tse et al. [55] suggested that the spleen may be at more risk when the patient is supine than when the patient is in the left lateral position. A high degree of awareness of the possibility of splenic rupture must be maintained, and no patient complaining of postcolonoscopy abdominal pain should be ignored. The differential diagnosis includes perforation as well as splenic rupture. Radiography of the abdomen, a complete blood count, and, if necessary, an abdominal CT scan should lead to the diagnosis. Treatment can be conservative if the patient is stable and is followed closely. Signs of progressive or ongoing bleeding call for action; usually splenectomy.

Mesenteric damage Mesenteric laceration caused by colonoscopy is a rare phenomenon. Hernandez et al. [56] reviewed the literature in 1999 and found only three reported cases, each one associated with a splenic tear. Their own case was an isolated incident that caused significant abdominal pain and a drop in hematocrit. CT confirmed the diagnosis and laparotomy was required for ligation of a bleeding artery. Yoshimura and Sasaki [57] reported a similar case except that the bleeding was retroperitoneal, coming from an artery on the left psoas muscle. It is likely that subclinical damage to the mesentery occurs more often and is responsible for the relatively common postcolonoscopy abdominal pain that lasts a few days and then spontaneously disappears. Sometimes damage is noticed at laparotomy after a preoperative colonoscopy has been performed (Figure 53.2).

Complications in other organs Figure 53.1 Close anatomic relationship of spleen to splenic flexure. (Courtesy of Dr. C. Delaney.)

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There have been a few case reports describing rare complications. These have been listed comprehensively in reviews by Waye et al. [5] and Kavic and Basson [49]. They include cases

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Figure 53.2 Serosal tear in the sigmoid colon seen at surgery the day after a preoperative colonoscopy. (From ref. 30 with permission.)

of postcolonoscopy priapism [58], small bowel obstruction [59,60], mesenteric ischemia [61], cecal volvulus [62,63], acute pancreatitis [64], appendicitis [65,66], cholecystitis [67], and small bowel perforation [68]. Adhesion obstruction and strangulation of the terminal ileum can occur hours or days after an apparently uneventful colonoscopy [69,70]. In patients with a mobile cecum, colonoscopy can affect the anatomy of the bowel and could predispose to an obstruction or a volvulus. A case of mesenteric ischemia presenting 3 days after colonoscopy in an 89-year-old-man [61] is unlikely to have been directly related to the endoscopy, although dehydration from the preparation may have potentiated a low-flow state. Vender et al. [65] reported three cases of postcolonoscopy appendicitis out of approximately 8000 colonoscopies over 2 years. They speculated that the cause could be preexisting disease in the appendix, barotrauma from overdistension, pushing a fecolith into the appendix, or direct intubation of the appendix. Thomas and Mitre [64] suggest that their case of pancreatitis was due to direct pressure of the colonoscope on the pancreas, an unlikely and unprovable hypothesis. Milman and Goldenberg [67] describe two cases of cholecystitis that closely followed colonoscopy, and speculate that the dehydration caused by bowel preparation may have precipitated the attacks. The cases of small bowel perforation and colonoscopy implicate severe adhesions in the etiology of the damage, although “additional pressure to negotiate the sigmoid colon” is noted in one case [68]. The true incidence of an association between such entities and colonoscopy can never be known. In some cases the association may be coincidental.

Cardiopulmonary complications Vasovagal reaction Shore et al. [69] have suggested that anxiety, the sight of blood or body tissues, visceral pain, and a warm, crowded environment may set the stage for a vasodepressor (vasovagal) reaction. Vasovagal reactions do occur during colonoscopy, and

Complications

in one study were the second most common complication after bleeding (J. Church, unpublished data). The initial presentation is a slowing of the heart rate, down to as low as 30 beats per minute. Hypotension, sweating, pallor, and a feeling of impending fainting can accompany this. Often the vasovagal reaction happens during intubation of a tightly looped sigmoid colon, suggesting that tension on a tight sigmoid mesentery may stimulate the vagal nerve and slow the heart rate [70,71]. In a prospective study of 228 consecutive colonoscopies, Herman and colleagues [72] defined vasovagal reaction (rather liberally) as a fall in heart rate below 60 beats per minute or a drop of more than 10% of baseline for more than 5 min, or a fall in blood pressure to less than 90 mmHg systolic or less than 60 mmHg diastolic; 37 of 223 patients fulfilled these criteria. The only differences between the patients who had a “reaction” and those who did not were a higher dose of midazolam (4.6 mg vs. 3.9 mg, respectively) and more moderate to severe diverticulosis (43% vs. 16%). Treatment of the reactions included increased fluids (24%), naloxone (5%), and atropine (5%). The authors did not stop any procedure because of the reaction and no adverse sequelae followed. Isolated hypotension without bradycardia is more likely to be due to dehydration, potentiated by the combination of benzodiazepines and narcotics. A true vasovagal reaction, defined by profound bradycardia, responds to discontinuation of the vagal stimulation by withdrawing the colonoscope. Hypotension due to oversedation or dehydration is treated with intravenous fluids and narcotic antagonists.

Hypoxia and cardiac events Although serious cardiac events such as infarction and arrest during or after colonoscopy are rare (0.012% [73]), changes in the electrocardiogram (EKG) have been described and include arrhythmias, ST segment depression or elevation, ventricular tachycardia, and ventricular fibrillation [74–76]. These changes are likely to be due to epinephrine release stimulated by anxiety and pain. Their clinical effect is determined by the cardiac status of the patient and the level of oxygen desaturation during the procedure. The incidence of hypoxia is related to the amount of sedation given to the patient, but hypoxia may occur in unsedated patients, as shown by Eckardt et al. [77], who reported 24 cases out of 2384 patients undergoing unsedated colonoscopy. No episode lasted longer than a minute and none was treated. Three patients suffered a “severe vasovagal reaction,” two sedated and one unsedated. In this study the only predictor for adverse cardiopulmonary events was impaired physical status. Ristikankare et al. [78] compared cardiopulmonary complications in patients grouped according to sedation and found significant decreases in oxygen saturation and blood pressure in patients receiving a mean of 2.9 mg of midazolam, but no serious cardiac events occurred. Yano et al. [79] found that the risk of oxygen desaturation was significantly greater in patients over the age of 60 than in those younger than 60 years, despite a reduced dosage

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of midazolam in the elderly patients. The combination of a narcotic and a benzodiazepine is particularly potent in causing hypoxia and hypotension. The potential sequelae of oxygen desaturation were demonstrated by Holm et al. [80], who reported that two patients had EKG evidence of myocardial ischemia and one had runs of extra systoles. Extrapolating the results from these small studies to routine practice is unwise, as they may not reflect the general experience, in which clinically significant cardiac complications of colonoscopy are rare. However, pulse and oxygen saturation should be monitored in all patients undergoing colonoscopy, and EKG should be monitored in those with a significant history of cardiac disease. Even patients within 3 weeks of a myocardial infarction usually tolerate endoscopy well. Cappell [81] reported on 18 such patients who underwent lower gastrointestinal endoscopy for bleeding. Three of the 18 patients had unstable cardiac disease at the time of endoscopy, and two had complications: one developed second-degree heart block and premature ventricular contraction 3 h after sigmoidoscopy while another developed an asymptomatic bradycardia during colonoscopy, leading to an aborted procedure. None of the more stable patients had any cardiac events, showing that a recent infarction is not an absolute contraindication to colonoscopy. Of course, it is not an ideal time for the examination and, if an examination must be done, close monitoring and involvement of the cardiology service is necessary. Patients with severe chronic obstructive pulmonary disease are at risk of hypercapnia if they are oversedated, and may experience respiratory arrest if pain and distress levels rise. Such patients should receive very little sedation, if any, and increasing distress is an indication to stop the examination.

Anxiety reactions Sometimes patients begin colonoscopy in a heightened state of anxiety, regardless of premedication with a benzodiazepine. Such patients are so anxious that they may complain of pain on rectal intubation. Tachypnea can lead to tetanic contraction of the hands and numbness of the face, which can be treated by having the patient breathe into a paper bag to increase blood alkalinity by recirculating CO2. If the examination must be performed, it can be rescheduled under general anesthesia.

Infectious complications of colonoscopy Colonoscopy provides the potential for infection to occur in the patient by introduction of organisms with the colonoscope, by translocation of endogenous organisms into the bloodstream, or by seeding of organisms on to non-biologic implants, and in the endoscopist by contamination with infected bodily fluids. In 1985, Kelley et al. [82] reported subclinical bacteremia in 35% of patients undergoing colonoscopy and endotoxemia in 50%, showing that colonoscopy could result in translocation of bacteria and toxins from the lumen into the circulation. Berger et al. found subclinical endotoxemia in 21 of 32 patients having colonoscopy and bacteremia in one.

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Recent studies demonstrate a low incidence of bacteremia during colonoscopy (2–4%). The rate of infectious complications of colonoscopy is considerably lower than this, possibly because the enteric flora subject to translocation during colonoscopy do not usually cause infective endocarditis. Cases of peritonitis have been reported in patients with cirrhosis [83,84] and in peritoneal dialysis [85], but these cases do not indicate that routine antibiotic prophylaxis is needed. Llach et al. [86] reported that colonoscopy does not induce significant bacteremia in cirrhotic patients with or without ascites. Only a few cases of endocarditis following colonoscopy [87] have been described, and prophylaxis for high-risk cardiac conditions is now not recommended by the American Heart Association although antibiotics may be used at the endoscopist’s discretion on a “case by case” basis (see Chapter 5). [88] Introduction of an infectious agent into a patient through a contaminated colonoscope or endoscopic instrument is a concern of both the endoscopic community and the general public. The risk of this happening has been estimated to be 1 in 1.8 million [87]. Transmission of Salmonella species by colonoscope has been reported [89] as have Klebsiella, Enterobacter, and Serratia infections [90]. Until 2000, there has been no report of HIV transmission but one case of hepatitis B and two of hepatitis C have been described [87].

Preventing infectious complications Cleaning, disinfecting, and sterilizing (see Chapter 5) Standards for the cleaning of endoscopes are now widely published, involving the types of solutions, routines, and methods to be used [89,91–94].

Antibiotic prophylaxis (see Chapter 7) The American Society for Gastrointestinal Endoscopy has published guidelines for antibiotic prophylaxis in endoscopy in 1995 [95]. Protection of the endoscopist and endoscopy assistants Measures to avoid contact with potentially contaminated body fluids (such as gowns, gloves, goggles, and masks) and the use of plastic/nonrecapped needles should be standard in endoscopy units, and should minimize the risks of staff acquiring an infection. All patients should be treated as potential carriers of a bloodborne pathogen [96], and all endoscopy units need to comply with communicable disease guidelines.

Incarceration of the colonoscope The colonoscope may become trapped in the colon under two circumstances: a hernia and a tight, tortuous sigmoid colon. Koltun and Coller [97] and Leisser et al. [98] describe the situation in patients with an inguinal hernia where the scope could not be removed by simply pulling from the anus. In one case, the large loop of the scope in the hernia sac was maintained by the examiner’s fingers while the scope was removed [97]. Incarceration in a tight sigmoid colon is more

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difficult to remove, with time, an antispasmodic, and warm water irrigation [99] all being parts of the solution.

Complications of therapeutic colonoscopy Postpolypectomy bleeding Bleeding occurs after polypectomy because a submucosal artery is either not sealed at all or the seal is broken later. This can happen after both snare excision and hot biopsy. Postpolypectomy bleeding is classically described as immediate or delayed; however, immediate bleeding is usually considered part of the polypectomy. The chances of immediate postpolypectomy bleeding can be minimized by some of the strategies described below. The rate of secondary bleeding is not under the control of the endoscopist. Reviews of the incidence of postpolypectomy bleeding quote rates of 0.66–3.4% with a mean of 1.2% [5,13] (see Table 53.3). Not all polyps are at an equal risk of bleeding: risk factors include the following.

Location Polyps particularly at risk for bleeding seem to be right sided [100], possibly because the bowel wall is thinner here and submucosal arteries are closer to the snare or zone of coagulation. Submucosal arteries may be more numerous in the right colon, although there are no data on this point.

Size and shape The association of polyp size and postpolypectomy hemorrhage is self-evident. Both Sawhney et al. [50] and Watabe et al. [51] found polyp size to predict risk of hemorrhage. The incidence of bleeding after removal of large polyps (> 2 cm) was summarized by Waye et al. [5] at 5.4%. The larger the amount of tissue enclosed in the snare the greater the chance of picking up submucosal arteries, and so piecemeal polypectomy should take pieces no bigger than 2 cm in one bite. Pedunculated polyps with a thick stalk are also a high-risk situation [3] and the stalk can either be injected with 1:10 000 epinephrine or clipped, prior to or after polypectomy.

Patient factors Patients on anticoagulants, including coumadin, aspirin, and platelet-inhibiting agents, or patients with a coagulopathy are at increased risk of bleeding [50,51] (see Chapter 8). Colonoscopy with polypectomy in these patients is a “highrisk” procedure (American Society for Gastrointestinal Endoscopy, ASGE). ASGE Guidelines [101] state that in patients with a high risk of thromboembolism warfarin must be stopped 3–5 days before the procedure, and consideration should be given to the use of heparin while the prothrombin time international normalized ratio (INR) is subtherapeutic. When the risk of thromboembolism is low, warfarin is stopped as before but no heparin is necessary. Colonoscopists should communicate with vascular medicine or internal medi-

Complications

cine colleagues to determine the best course of action in each patient. A recent study by Friedland and Soetikno [102] showed that prophylactic use of clips prevented hemorrhage in 21 patients undergoing 41 polypectomies while on coumadin. ASGE Guidelines also state that there is no evidence to show that aspirin and other NSAIDs increase the risk of postpolypectomy bleeding. Hypertension is also a risk factor for postpolypectomy bleeding in some studies [15] and so patients must be advised to control their blood pressure post polypectomy.

Technique Hot biopsy for removal of polyps is just as likely if not more likely to cause bleeding as snaring, despite the smaller size of polyps treated in this way [103,104]. The zone of coagulation produced by hot biopsy cautery is directed downwards into the submucosa, where it can damage the wall of submucosal arteries resulting in delayed hemorrhage when the area of thermal injury sloughs. This contrasts to the cautery produced by a snare, which is directed parallel to the mucosa, and will not damage submucosal arteries unless they are included in the pedicle. Risk factors for postpolypectomy bleeding included increasing polyp size, resumption of anticoagulation within 1 week of the polypectomy, and hypertension.

Preventing postpolypectomy bleeding Choosing your battles The decision about which polyp to remove and which to refer to surgery is an individual one, based on the experience and confidence of the endoscopist. Alternatives include referring a patient with a difficult polyp to a different endoscopist or to a surgeon.

Stop anticoagulants (see Chapter 8) Coumadin should be stopped at least 5 days before polypectomy. In patients on coumadin, the prothrombin time INR should be normalized before the procedure. The patient’s cardiologist, primary physician, or vascular specialists can help determine the risks of stopping anticoagulation and help decide if heparin or low-molecular-weight heparin is necessary as an interim measure. Good technique Detailed technical advice can be found in Chapters 40 and 41. However, it is wise to use pure coagulation current at all times, and to close the snare slowly. Hot biopsy technique should be reserved for polyps that are too awkwardly placed for a snare and too large to be completely removed by cold biopsy. Preinject with saline or 1:10 000 epinephrine Lifting a polyp on a bed of saline increases the distance from the base of the polyp to the submucosal arteries. This is

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effective in minimizing the risk of bleeding and should be almost routine in large (> 2 cm) cecal and ascending colon polyps. The use of epinephrine makes immediate bleeding even less likely but may not prevent a secondary hemorrhage. Di Giorgio et al. [105] showed that a detachable snare works just as well as epinephrine injection in preventing hemorrhage after snaring of pedunculated polyps.

Treating postpolypectomy bleeding Consent (see Chapter 6) Part of the consenting process is to warn patients of the possibility of postpolypectomy hemorrhage. This involves making sure that the patient is not planning any trip that would make urgent care inaccessible for the next 2 weeks. Patients living more than 2 hours’ travel away from the treating institution should be given a copy of the colonoscopy report with clear descriptions of the site and method of the polypectomy. If necessary, the polypectomy should be deferred.

Immediate bleeding (see Chapter 42) The quickest and most effective way to stop immediate bleeding from the polypectomy site is to inject the area with 1:10 000 epinephrine. If the polyp was pedunculated, the stalk can be resnared and held for several minutes. Other thermal modalities can be applied. Delayed bleeding Delayed postpolypectomy hemorrhage can occur from 1 to 15 days after polypectomy. Regardless of the precautions taken against it, postpolypectomy hemorrhage can occur in any patient, although it is more common in patients with large right-sided or rectal polyps. Often the bleeding has stopped by the time the repeat colonoscopy is done, but if it has not the bleeding site is injected with 1:10 000 epinephrine and treated by a thermal or mechanical modality.

Perforation Perforation of the colon may occur during or after polypectomy because the coagulation current causes full-thickness necrosis of the colonic wall. Sometimes a section of normal colonic wall is inadvertently included in the snare and coagulated along with the polyp. It is wise to compare the apparent

(a)

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(b)

thickness of the tissue enclosed in the snare with the diameter of the stalk or polyp as seen on the screen. Snare excision of a diverticulum or an ileocecal valve can also lead to perforation. Perforation can occur immediately after polypectomy if a full-thickness piece of colonic wall has been removed, or late if a necrotic patch of colon sloughs out (Figure 53.3a and b). The incidence of postpolypectomy perforation ranges from 0.08% to 0.69% with a mean of 0.35% per polyp and 0.41% per patient having polypectomy [5]. Taku et al. [106] reported an overall rate of perforation of 0.15%, with endoscopic mucosal resection (0.58%) and endoscopic submucosal dissection (14%) being significantly more risky than hot biopsy (0.02%) or snare (0.05%).

Prevention of perforation In many aspects of the technical component of polypectomy attention to detail is important in preventing perforation. The placement of the snare is important in allowing the mucosa to be lifted away from the underlying muscle. The fat in lipomas is a poor conductor of electrical current, necessitating a dangerous amount of current for their removal. Cancers invade the colonic submucosa and sometimes the muscle, leading to full-thickness wall resection when they are removed (Figure 53.3a and b). The cecal wall can be very thin and prone to perforation with standard amounts of current. Saline or epinephrine infiltration under polyps will raise them away from the colonic wall and make cautery safer.

Treatment of perforation Successful treatment of postpolypectomy perforation depends on early diagnosis and appropriate decision-making. Unusual abdominal distension or delayed onset of abdominal pain warrants investigation with abdominal examination and radiography. The presence of peritonitis mandates laparotomy. Free intraperitoneal gas means that there has been perforation, or at least thinning of the colonic wall, but does not necessarily indicate surgery unless there is also peritonitis. Without peritonitis, bowel rest and intravenous antibiotics can be effective. Early perforations are less clinically harmful as fecal contamination is minimal. At surgery, simple closure is a realistic option. Late colonic perforations are rarely

Figure 53.3 (a) Mucosal aspect of snare polypectomy of small polypoid cancer; the patient had elective surgery 4 days later (with permission). (b) Serosal aspect of polypectomy site in (a) showing full-thickness necrosis. (From ref. 16 with permission.)

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amenable to closure and usually require resection. These principles have been discussed in some detail in the section on complications of diagnostic colonoscopy.

Postpolypectomy syndrome In the presence of thermal injury to the muscular layers and serosa, the patient may present with all the classic signs and symptoms of a colonic inflammatory process such as caused by appendicitis or diverticulitis. Such patients present with localized pain, tenderness, and fever, with or without signs of peritoneal irritation. This occurred in 9 of 777 polypectomies (1%) reported by Waye et al. [103], with all cases resolving on antibiotic therapy. Conio et al. [107] reported five (3.7%) patients with postpolypectomy syndrome out of 136 having endoscopic mucosal resection for sessile polyps. There was no perforation in this series. Hospitalization and treatment with intravenous antibiotics and bowel rest is usually successful in resolving postpolypectomy syndrome within a few days.

Impaction of snare in polyp If a snare enters a polyp deeply with coagulation current and the endoscopist desires to abandon the resection and remove the wire loop, the snare may be stuck and not retrievable. The easiest way out of this situation is to cut the handle off the snare, remove the colonoscope over the snare, pass the colonoscope again, and resect the polyp head piecemeal until the original snare can be retrieved. Alternatively, one can wait until the incarcerated snare is expelled from the rectum as the enclosed portion of polyp sloughs off.

Complications

mucosa are not seen needs to be followed by another examination with a better preparation. Lesion detection rate can be optimized by a careful withdrawal, as suggested by Rex [112], who showed that the rate of missed adenomas was related to time of withdrawal. The implications of missing a lesion can be minimized by warning the patient that colonoscopy is not perfect, and by asking the patient to return if symptoms persist [113]. A related concern is the inaccurate localization of significant colonic pathology. This can have a disastrous effect on surgery, as shown by Hancock and Talbot [114]. When resection of a colonic lesion is to be done laparoscopically, three- or four-quadrant tattooing may be necessary to prevent removal of the wrong section of bowel. Park et al. [115] tattooed 63 patients prior to laparoscopic resection of colorectal tumors and saw the tattoo intraoperatively in 62. Even with an open resection, on-table colonoscopy may sometimes be needed to make sure the correct section of colon is removed with adequate margins. These issues are discussed more fully in Chapter 42.

Summary Colonoscopy is a complex process that offers several opportunities for misadventures and complications. The continuing increase in demand for colonoscopy as a way of screening for colorectal cancer, diagnosing colorectal disease, and treating colorectal mucosal lesions means that complications are certain to occur in increasing numbers. An awareness of common complications, a routine to minimize or prevent them and a familiarity with the treatment options, and how to apply them is an essential part of every colonoscopist’s practice.

The missed lesion (see Chapter 41) Colonoscopy is not a perfect examination. The “miss rate” of adenomas varies according to size from 27% for diminutive adenomas to 6% for large adenomas [108]. Cancers are missed, usually because they are not reached [109], but sometimes because they are mistaken for colitis or ischemia. Lesions can be missed because they are not seen in an incomplete examination, not seen because they are covered by stool, not seen because of their low profile, or not seen because of their awkward position in a flexure of the colon. Sometimes they are seen but not recognized as abnormal. Recently attention has been refocused on flat neoplasms that may need chromoendoscopy or narrow-band imaging to see easily [110,111]. It is important to examine all the colon completely, including the traditional “blind spots” of the cecum under the ileocecal valve, the hepatic and splenic flexures, and the low rectum. Incomplete colonoscopy must be followed up with air contrast barium enema, CT colonography, or a repeat colonoscopy. A poor preparation in which parts of the

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68 Nemeh HW, Ranzinger MR, Dutro JA. Mid-ileal perforation secondary to colonoscopy. Am Surgeon 1999; 35: 228–9. 69 Shore PS, Salt WB 2nd, Guthrie R. Vasodepressor reaction in an unsedated patient undergoing colonoscopy and observing the video display. Gastrointest Endosc 1993; 39: 218–19. 70 Rankin GB. Indications, contraindications and complications of colonoscopy. In: Sivak M (ed.) Gastrointestinal Endoscopy. Philadelphia: WB Saunders, 1987. 71 Fennerty MB, Earner DL, Hudson PB, Sampliner RE. Physiologic changes during endoscopy. Gastrointest Endosc 1990; 36: 22–5. 72 Herman LL, Kurtz RC, McKee KJ, Sun M, Thaler HT, Winawer SJ. Risk factors associated with vasovagal reactions during colonoscopy. Gastrointest Endosc 1993; 39: 388–91. 73 Rogers BH, Silvis SE, Nebel OT, et al. Complications of flexible fiberoptic colonoscopy and polypectomy. Gastrointest Endosc 1975; 22: 73–7. 74 Gupta SC, Gopalswamy N, Sarkar A, Suryaprasad AG, Markert RJ. Cardiac arrhythmias and electrocardiographic changes during upper and lower gastrointestinal endoscopy. Military Med 1990; 155: 9–11. 75 Alam M, Schuman BM, Duvernoy WF, Madrazo AC. Continuous electrocardiographic monitoring during colonoscopy. Gastrointest Endosc 1976; 22: 203. 76 Davison ET, Levine M, Meyerowitz R. Ventricular fibrillation during colonoscopy: case report and review of the literature. Am J Gastroenterol 1985; 80: 690– 3. 77 Eckardt VF, Kanzler G, Schmitt T, Eckardt AJ, Bernhard G. Complications and adverse effects of colonoscopy with selective sedation. Gastrointest Endosc 1999; 49: 560–5. 78 Ristikankare M, Julkunen R, Mattila M, et al. Conscious sedation and cardiorespiratory safety during colonoscopy. Gastrointest Endosc 2000; 52: 48–54. 79 Yano H, Iishi H, Tatsuta M, Sakai N, Narahara H, Omori M. Oxygen desaturation during sedation for colonoscopy in elderly patients. Hepatogastroenterology 1998; 45: 2138–41. 80 Holm C, Christensen M, Schulze S, Rosenberg J. Effect of oxygen on tachycardia and arterial oxygen saturation during colonoscopy. Eur J Surg 1999; 165: 755– 8. 81 Cappell MS. Safety and clinical efficacy of flexible sigmoidoscopy and colonoscopy for gastrointestinal bleeding after myocardial infarction. A six-year study of 18 consecutive lower endoscopies at two university teaching hospitals. Digest Dis Sci 1994; 39: 473– 80. 82 Kelley CJ, Ingoldby CJ, Blenkharn JI, Wood CB. Colonoscopy related endotoxemia. Surg Gynecol Obstet 1985; 161: 332 –4. 83 Christ AD, Bauerfeind P, Gyr N. Peritonitis after colonoscopy in a patient with ascites. Endoscopy 1993; 25: 553–4. 84 Shrake PD, Troiano F, Rex DK. Peritonitis following colonoscopy in a cirrhotic with ascites. Am J Gastroenterol 1989; 84: 453–4. 85 Ray SM, Piraino B, Holley J. Peritonitis following colonoscopy in a peritoneal dialysis patient. Perit Dial Int 1990; 10: 97–8. 86 Llach J, Elizalde JI, Bordas JM, et al. Prospective assessment of the risk of bacteremia in cirrhotic patients undergoing lower intestinal endoscopy. Gastrointest Endosc 1999; 49: 214–17. 87 Schembre DB. Infectious complications associated with gastrointestinal endoscopy. Gastrointest Endosc Clin N Am 2000; 10: 215– 32. 88 Meyer GW. Infective endocarditis prophylaxis for the 21st century: end of an error? Gastrointest Endosc 2007; 66: 123–4.

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89 Dwyer DM, Klein EG, Istre GR, et al. Salmonella newport infections transmitted by fiberoptic colonoscopy. Gastrointest Endosc 1987; 33: 84– 7. 90 Martin MA, Reielderfer M. APIC guideline for infection prevention and control in flexible endoscopy. Am J Inf Control 1994; 22: 19–38. 91 Nelson D. Transmission of Infection During Gastrointestinal Endoscopy, ASGE position paper 9. no. 3 January 2002. 92 Kinney TP, Kozarek RA, Raltz S, Attia F. Contamination of singleuse biopsy forceps: a prospective in vitro analysis. Gastrointest Endosc 2002; 56: 209–12. 93 Riley R, Beanland C, Bos H. Establishing the shelf life of flexible colonoscopes. Gastroenterol Nurs 2002; 25: 114–19. 94 Wilcox CM, Waites K, Brookings ES. Use of sterile compared with tap water in gastrointestinal endoscopic procedures. Am J Infect Control 1996; 24: 407–10. 95 Anonymous. Antibiotic prophylaxis for gastrointestinal endoscopy. Gastrointest Endosc 1995; 42: 630– 5. 96 Cheung RJ, Di Marino AJ. Risk to the health care worker of HIV infection and how to minimize it. Gastrointest Clin N Am 1998; 8: 769–83. 97 Koltun WA, Coller JA. Incarceration of colonoscope in an inguinal hernia. “Pulley” technique of removal. Dis Colon Rectum 1991; 3: 191–3. 98 Leisser A, Delpre G, Kadish U. Colonoscope incarceration: an avoidable event. Gastrointest Endosc 1990; 36: 637– 8. 99 Church J. Warm water irrigation for dealing with spasm during colonoscopy: simple, cheap, effective. Gastrointest Endosc 2002; 56: 672–4. 100 Church J. Experience in the endoscopic management of large colonic polyps. ANZ J Surg 2003; 73: 988–95. 101 Guideline on the Management of Anti-coagulation and Antiplatelet Therapy for Endoscopic Procedures. Gastrointest Endosc 2002; 55: 775– 9. 102 Friedland S, Soetikno R. Colonoscopy with polypectomy in anticoagulated patients. Gastrointest Endosc 2006; 64: 98–100.

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103 Waye JD, Lewis BS, Yessayan S. Colonoscopy. A prospective report of complications. J Clin Gastroenterol 1992; 15: 347–51. 104 Weston AP, Campbell DR. Diminutive colon polyps. Histopathology, spatial distribution, concomitant significant lesions, and treatment complications. Am J Gastroenterol 1995; 90: 24– 8. 105 Di Giorgio P, De Luca L, Calcagno G, Rivellini G, Mandato M, De Luca B. Detachable snare versus epinephrine injection in the prevention of postpolypectomy bleeding: a randomized and controlled study. Endoscopy 2004; 36: 860–3. 106 Taku K, Sano Y, Fu K, et al. Iatrogenic perforation associated with therapeutic colonoscopy: a multicenter study in Japan. J Gastroenterol Hepatol 2007; 22: 1409–14. 107 Conio M, Repici A, Demarquay JF, et al. EMR of large sessile colorectal polyps. Gastrointest Endosc 2004; 60: 234–41. 108 Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112: 24–8. 109 Haseman JH, Lemmel GT, Rahmani EY, Rex DK. Failure of colonoscopy to detect colorectal cancer: evaluation of 47 cases in 20 hospitals. Gastrointest Endosc 1997; 45: 451–5. 110 Church JM, Muto T, and Appau K. Flat lesions of the colorectal mucosa: differences in recognition between Japanese and American endoscopists. Dis Colon Rectum 2004; 47: 1462–6. 111 Suzuki N, Saunders BP, Brown G. Flat colorectal neoplasms: endoscopic detection, clinical relevance and management. Tech Coloproctol 2004; 8(Suppl. 2): 261–6. 112 Rex DK. Colonoscopic withdrawal technique is associated with adenoma miss rates. Gastrointest Endosc 2000; 51: 33–6. 113 Rex DK, Bond JH, Feld AD. Medical-legal risks of incident cancers after clearing colonoscopy Am J Gastroenterol 2001; 96: 952–7. 114 Hancock JH, Talbot RW. Accuracy of colonoscopy in localization of colorectal cancer. Int J Colorectal Dis 1995; 10: 140–1. 115 Park J, Sohn D, Hong C, et al. The usefulness of preoperative colonoscopic tattooing using a saline test injection method with prepackaged sterile India ink for localization in laparoscopic colorectal surgery. Surg Endosc 2008; 22: 501–5.

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Postpolypectomy Surveillance John H. Bond University of Minnesota, Minneapolis, MN, USA

Introduction Patients who have undergone resection of one or more colorectal adenomatous polyps may have an increased risk for recurrent adenomas and subsequent cancer, and therefore may benefit from long-term follow-up surveillance. Lacking reliable scientific data, physicians in the past often performed this surveillance incorrectly, too frequently, or in the wrong patients. Many physicians still adhere strictly to a routine surveillance program that they learned in the past for all their postpolypectomy patients, rather than trying to use current data to assess risk and tailor follow-up to the specific features of each case. Inappropriate surveillance can result in enormous costs in terms of time and resources, as well as patient inconvenience or risk. In 2002, more than 14 million colonoscopies were performed in the US, of which an estimated 38–45% were for screening and 22% were for surveillance of patients with previously resected neoplasia [1,2]. Obviously, if the type and frequency of follow-up surveillance is inappropriate, many patients will be put at unnecessary risk for developing colorectal cancer or scarce healthcare resources will be wasted. A survey of practicing gastroenterologists and endoscopic surgeons published in 2004 by the National Cancer Institute and the Centers for Disease Control and Prevention showed that surveillance postpolypectomy colonoscopy often is inappropriately performed in excess of current guideline recommendations [3]. It is now generally accepted that in Western countries over 95% of colorectal cancers arise in benign adenomatous polyps that develop and grow slowly in the colon over many years before they turn cancerous [4]. Pathologic correlations indicate that malignancy does not occur in small left-sided hyperplastic polyps, rarely occurs in small tubular adenomas, and is more common in tubulovillous and villous adenomas and in all adenomas as they increase in size. A patient with one

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

known adenoma in the large bowel has a 30–50% likelihood of harboring a second synchronous adenoma elsewhere in the colon at that time, and a 30–50% likelihood of developing a metachronous adenoma some time in the future [5]. Several recent studies, including the landmark US National Polyp Study, have shown that the incidence of colorectal cancer is substantially reduced among patients who have had polypectomy followed by appropriate long-term surveillance [6–8]. Modeling analyses performed by scientists at the National Polyp Study Coordinating Center in New York showed that over 90% of this reduced incidence over the first 5 years is the direct result of the initial colonoscopy and polypectomy [9]. The impact of follow-up surveillance appears to be greatest in a subgroup of polypectomy patients who can be identified as having a higher risk of metachronous advanced adenomas based on well-defined features of their baseline adenomas. The most recent revision of the surveillance guideline, discussed in detail in this chapter, uses newly available postpolypectomy data to stratify polyp patients into a highrisk group that requires intensive surveillance and a much larger lower-risk group that requires less intensive surveillance [10]. Widespread adoption of these new recommendations could free up endoscopic resources that can be shifted to screening and the evaluation of symptoms, thereby increasing the overall benefit and reducing procedure cost and risk. This chapter reviews the rationale and current recommendations for postpolypectomy surveillance, emphasizing the need to tailor surveillance strategies to the carefully considered individualized assessment of cancer risk for each patient.

Colonoscopy is the procedure of choice for postpolypectomy surveillance Colonoscopy is clearly the preferred method for postpolypectomy surveillance for almost all patients. It is substantially more accurate than double-contrast barium enema for the detection of polypoid lesions of all sizes. An earlier, carefully controlled, single-blinded study comparing the accuracy of the two examinations performed in the same patients demonstrated a sensitivity for detecting polyps of 67% and

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94% for double-contrast barium enema and colonoscopy, respectively [11]. More recently, the National Polyp Study reported the results of a similarly controlled comparison of both methods in a large cohort of patients actually undergoing postpolypectomy surveillance [12]. A total of 862 back-to-back double-contrast barium enema examinations and colonoscopies were performed in 680 patients. Expert radiologists or colonoscopists who were blinded to the result of the alternative examination performed all examinations. Barium enema studies were positive in only 39% of patients found to have adenomatous polyps at colonoscopy. Even when patients had adenomas that were 1 cm or more in diameter, the barium enema was negative in 52%. False-positive barium enemas occurred in 14% of cases. A retrospective analysis of cancer cases in 20 medical centers in Indiana showed an accuracy of colonoscopy and barium enema for detecting cancers of 95% and 83%, respectively [13]. In a subset of colonoscopies in this study that were performed by gastroenterologists, who presumably had more training and experience, the sensitivity for detecting cancer was 97%. The entire colon and rectum can be thoroughly examined by colonoscopy performed by experienced endoscopists in over 95% of cases, with minimal discomfort. Most importantly, colonoscopy is both diagnostic and therapeutic, allowing resection of most detected polyps at a single sitting with a single bowel-cleansing preparation. Although the alternative strategy of performing barium enema plus flexible sigmoidoscopy initially may be less costly, the need to do subsequent colonoscopy for those with positive findings makes this approach, on average, equally expensive. The complication rate for colonoscopy is appreciably higher than that of barium enema; however, major complications including perforation are rare provided the examination is performed by a well-trained experienced endoscopist [14]. For example, the VA Cooperative Colonoscopy Screening Trial performed screening colonoscopy in 3121 asymptomatic patients in 13 centers and reported a complication rate of only 0.3% (mainly bleeding after polypectomy), no perforations, and only one major complication in 1492 patients who had a diagnostic study with no polyp resection [15]. Technical modifications directed at increasing colonoscopic detection of polypsaespecially those that are small, sessile, or flatainclude dye spraying of the mucosa (chromoendoscopy) and narrow-band imaging or magnification endoscopy (which may increase colonoscopic resolution for reliably detecting small or flat polyps). Although these techniques may in the future help detect small, sessile, or flat adenomas, at this time there is insufficient evidence that they should be part of routine postpolypectomy surveillance according to current guidelines [10]. Computed tomography (CT) colonography (“virtual colonoscopy”) is now also being studied for follow-up surveillance of patients with colorectal cancer or polyps. CT colonography has already been shown to be more accurate than doublecontrast barium enema for detecting polyps. In addition, some

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but not all studies indicate that this method is nearly as accurate as colonoscopy for detecting large (≥ 1 cm) polypoid adenomas, although accuracy rapidly drops off for medium-sized and small polyps. The published sensitivity of CT colonography for detecting large adenomas (≥ 1 cm) in three experienced centers in the US was 75.2–93.8% [16–18]. However, not all centers currently performing virtual colonoscopy can achieve this level of accuracy. In the best US studies, the sensitivity of virtual colonoscopy for detecting medium-sized polyps (5–10 mm) was 47.2–88.7%. A major limitation of virtual colonoscopy compared with conventional colonoscopy is that, as with barium enema, the study is only diagnostic. Whenever a suspicious lesion or a clinically significant neoplasm is found, the patient must undergo a subsequent colonoscopy to confirm and/or resect the lesion. The need to do two expensive tests would make surveillance costly and inconvenient. The follow-up endoscopy must usually be scheduled on a different day and therefore the patient must undergo a second bowel-cleansing preparation. For these reasons, current surveillance guidelines do not yet recommend CT colonography for routine follow-up postpolypectomy surveillance.

Risk of cancer following polypectomy Two earlier studies from the Mayo Clinic estimated the risk of cancer after polypectomy. In 1984, Spencer and colleagues [19] reported the results of 10 000 person-years of follow-up of 751 patients who had undergone resection of a single small (< 1 cm) polyp from the distal colon during rigid proctosigmoidoscopy. There was no apparent increased incidence of subsequent cancer in this group compared with that of the local age-matched population. In contrast, the same group of investigators reported 2 years later that patients with larger adenomas (≥ 1 cm) had a risk of developing metachronous cancer that was 2.7 times greater than expected, and those with multiple index adenomas had a relative risk that was five times greater than expected [20]. Another study of the risk of cancer after removal of rectosigmoid adenomas was reported in 1992 from St Mark’s Hospital, London, by Atkin and colleagues [21]. A group of 1618 patients who had rectosigmoid adenomas resected during proctosigmoidoscopy with no further colonic surveillance was followed for a mean of 14 years (22 462 person-years). Among patients with index adenomas that were tubulovillous, villous, or large (≥ 1 cm) the subsequent incidence of colorectal cancer was increased 3.6-fold. However, among those with only small tubular adenomas (< 1 cm), whether single or multiple, the subsequent incidence of cancer was less than that of the age-matched general population. These investigators concluded that follow-up surveillance may be warranted in patients with tubulovillous, villous, or large adenomas, particularly if these adenomas were multiple. However, in patients with small tubular adenomas, surveillance may

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not be of value because the risk of subsequent cancer is so low. Lastly, an important prospective postpolypectomy colonoscopy study was performed by Grossman and colleagues [22] on 544 asymptomatic subjects with a past history of adenomas found at screening proctosigmoidoscopy. In 142 patients whose worst index lesion was a single small (< 10 mm) tubular adenoma and who had no first-degree relatives with colorectal cancer, the prevalence of advanced neoplasia (defined as tubular adenomas ≥ 1 cm, tubulovillous or villous adenomas, or adenomas with high-grade dysplasia or invasive cancer) was only 3%, no greater than would be expected in the general population. In contrast, subgroups with advanced or multiple index lesions had prevalences of advanced adenomas ranging from 8% to 18%.

Concept of the advanced adenoma These follow-up experiences, as well as a large and increasing volume of information about the molecular genetic basis for the adenoma–carcinoma sequence, are increasingly shifting the emphasis away from simply finding and harvesting large numbers of clinically insignificant small tubular adenomas toward strategies that focus on ways to reliably detect and resect the less common, but clinically much more dangerous, advanced adenoma (Table 54.1). Defined by both the National Polyp Study and several earlier studies, an advanced adenoma is one that is either large (≥ 1 cm) or contains the advanced histologic features of villous change, high-grade dysplasia, or invasive carcinoma [23]. Large numbers of small simple tubular adenomas develop in large numbers of people: over 30% of the population over age 50 years have these lesions, yet only a small fraction will ever develop colorectal cancer. While it is obvious that all large adenomas were small at some time, most small tubular adenomas never grow, advance, and turn malignant. Colonic carcinogenesis is a complex, nonlinear, multistep process occurring over many years that results from the progressive accumulation of genetic mutations and chromosomal deletions [24]. As neoplasia proceeds from normal-appearing mucosa, through small, medium, and large benign adenomas, and finally to invasive cancer and metastases, genetic changes are found in increasing number. An

Table 54.1 Advanced adenoma. Size 1 cm or larger in diameter Histology Villous change High-grade dysplasia Invasive carcinoma

Postpolypectomy Surveillance

adenomatous polyp is a monoclonal derivative of a single epithelial stem cell that either inherits (familial neoplasia) or acquires (sporadic neoplasia) the first of these many genetic alterations. Each additional genetic “hit,” probably caused by noxious 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 (i.e., oncogene mutations and tumor-suppressor gene alterations) needed to make them advance. A large volume of high-quality scientific evidence published during the past decade indicates that colonoscopic resection of an advanced adenoma is both predictive of recurrent metachronous advanced adenomas during postpolypectomy follow-up surveillance and a highly effective way of preventing colorectal cancer. Thus, our postpolypectomy efforts need to increasingly focus on ways to reliably find and resect advanced adenomas before they turn to cancer. Outcomes and observational studies underscore the different behavior of small tubular adenomas and advanced adenomas. In an earlier study by Hoff and colleagues [25], 215 polyps less than 5 mm in diameter were left in situ in 112 individuals for a 2-year follow-up period to ascertain their growth rate. At the end of the 2 years, 49% of adenomas had increased in size and 14% had regressed. Although total adenoma mass had increased by 136%, none had grown to a size greater than 5 mm and none had developed high-grade dysplasia or carcinoma. In a more recent study from Japan, Obata and colleagues [26] marked 139 small polyps (3–10 mm) with India ink and followed them with yearly colonoscopy. During a mean follow-up period of 33 months, 135 (97%) did not change in form or size. These workers also concluded that small polyps do not appreciably change over 3 years and they advance very slowly if at all. In contrast to these observational studies of the natural history of small polyps, there is considerable evidence that large polyps behave more aggressively. Eide [27] reported that the risk of developing carcinoma in a 1-cm adenoma was 3% per year in a Norwegian population. The National Polyp Study found a strong relationship between adenoma size and the prevalence of high-grade dysplasia: the odds ratio for high-grade dysplasia in a large polyp (≥ 1 cm) was 20.3 compared with that of a diminutive polyp (≤ 5 mm) [28]. Likewise, many reported series of polyp cases indicate a strong linear correlation between adenoma size, more extensive villous configuration, more severe dysplasia, and the presence of invasive carcinoma [29]. Such advanced adenomas also contain a larger fraction of the genetic mutations and chromosomal changes commonly found in the fully developed cancer phenotype [24]. The classic study by Stryker and colleagues [30] clearly showed the considerable malignant potential of large adenomas. Before the availability of colonoscopy, 226 patients who

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had large (≥ 1 cm) polyps detected on barium enema but 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 carcinomas developed at a polyp site, and 11 carcinomas developed at another site. The cumulative risk of cancer at 5, 10, and 20 years was 2.5%, 8%, and 24%, respectively. This study supports the need to find and excise all large colorectal polyps and the need for periodic surveillance of these patients to identify metachronous adenomas at a site in the colon remote from the index polyp.

the context of two large prospective chemoprevention studies carried out by the Polyp Prevention Study Group [35]. The miss rate was determined by comparing findings for patients who had repeat colonoscopies within 120 days, both of which had good preparation and were complete to the cecum. The true 1-year recurrence rate was determined by subtracting this miss rate from the rate of adenoma detection at colonoscopy performed 1 year later as per the study protocol. The adenoma miss rate per patient was 8% and the 1-year recurrence rate was 28%. The authors concluded that there is a significant colonoscopic miss rate for neoplastic polyps at initial colonoscopy as well as a substantial postpolypectomy recurrence rate within 1 year of a clearing colonoscopy.

Missed synchronous versus metachronous polyps Adenomas found by colonoscopy in virtually all reported postpolypectomy surveillance series are generally smaller than those resected at the initial colonoscopy examination [31]. While it is impossible to reliably differentiate between true recurrent adenomas and missed synchronous ones during follow-up colonoscopy, many undoubtedly were missed by the index examination. Direct determination of the colonoscopy miss rate for polyps was evaluated in two prospective “tandem” colonoscopy studies. Hixson and colleagues [32] performed a study in which two colonoscopists performed same-day back-to-back colonoscopies in 90 subjects after a single bowel-cleansing preparation. The investigators alternated the endoscopist who would perform the first examination, during which detected lesions were documented but not removed. The study reported a miss rate for small (≤ 5 mm) and medium-sized (6–9 mm) polyps of 16% and 12%, respectively; however, no large polyps (≥ 1 cm) went undetected. A similarly designed tandem colonoscopy study by Rex and colleagues [33] reported a miss rate for small (≤ 5 mm), medium (6–9 mm), and large (≥ 1 cm) polyps of 27%, 13%, and 6%, respectively, in 183 patients. In order to differentiate between true recurrent and missed synchronous adenomas following surveillance colonoscopy, Hixson and colleagues [34] performed 2-year follow-up examinations in 58 of the original 90 patients who had undergone tandem colonoscopies. In 38% of these 58 patients, 56 adenomas were detected, 31 of which were judged to be new metachronous lesions, defined as a follow-up polyp found in a colonic segment in which a prior lesion of the same histologic classification had not been previously detected during the tandem colonoscopies. Three of these adenomas were large (≥ 1 cm), and therefore the authors concluded that, while most metachronous adenomas found at 2 years of followup are small tubular adenomas, large ones can develop in normal-appearing mucosa in that time period. The miss rate and true 1-year recurrence rate of colorectal adenomas were also determined in a population of patients reflecting a broad spectrum of different gastroenterology practice settings within

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Frequency of postpolypectomy colonoscopic surveillance When colonoscopic polypectomy was introduced in the early 1970s, performing yearly follow-up examinations became common even though its yield appeared to be small and was not supported by scientific evidence. For this reason the National Polyp Study (Table 54.2) was designed by a joint committee of the American Gastroenterology Association, the American Society for Gastrointestinal Endoscopy, and the American College of Gastroenterology [36]. Many of the current recommendations for postpolypectomy surveillance are based on this 10-year prospective, multicenter, landmark study funded by the National Cancer Institute and directed by Winawer. The main objective of the study was to determine if follow-up colonoscopic examinations performed at 3 years after initial polypectomy were as effective in detecting clinically important colonic neoplasia as follow-up evaluations at 1 and 3 years. Patients undergoing colonoscopy in each of the seven participating centers were eligible for the study if they had no personal history of colorectal polyps or cancer. From this group, patients were invited to enroll in the investigation if they had one or more adenomas resected that were less than 3 cm in diameter and did not contain invasive

Table 54.2 National Polyp Study design (seven participating centers, 1418 patients). Patient eligibility No personal or family history of colorectal polyps or cancer One or more adenomas removed on initial colonoscopy (a) Less than 3 cm in diameter (b) No invasive cancer All polyps removed at that time Patients randomized into two follow-up arms Colonoscopy at 1 year and 3 years Colonoscopy at 3 years only

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Table 54.3 National Polyp Study results. Group

Total adenomas at 3 years (%)

Advanced adenomas (%)

Follow-up at 1 year and 3 years Follow-up at 3 years

41.7 32

3.3 3.3

carcinoma, and if the colonoscopist believed that all polyps had been resected at the time of the index colonoscopy. A total of 1418 patients were randomly assigned to have either follow-up colonoscopy at 1 and 3 years and then every 3 years, or just a follow-up colonoscopy every 3 years after the initial polypectomy. The percentage of patients who had adenomas found by 3 years in the group examined at 1 and 3 years was 41.7% compared with 32% for the group examined only at 3 years [37]. However, the number of patients who had advanced adenomas by 3 years was the same in each group (3.3%) (Table 54.3). The study therefore concluded that an interval of at least 3 years is recommended before the first surveillance colonoscopy is performed after resection of colorectal adenomas. The further follow-up of both groups at 3-year intervals also showed that, if the first 3-year follow-up revealed no new adenomas, subsequent follow-up could be safely extended to 5-year intervals.

Repeat clearing colonoscopy after polypectomy Before embarking on a postpolypectomy surveillance program that prescribes follow-up colonoscopy in 3–5 years, the entire large bowel should first be thoroughly examined to clear it of all detectable synchronous lesions. A repeat clearing examination may be indicated for patients with an incomplete initial colonoscopy or for one done with a suboptimal bowel preparation. A second clearing examination should also be considered for selected patients with multiple polyps when the colonoscopist is concerned that clinically significant lesions may have been missed. Repeat clearing colonoscopy to ensure complete polypectomy is essential after piecemeal resection of large sessile polyps. Such polyps often contain multiple acquired genetic abnormalities and appreciable amounts of villous tissue with a high malignant potential, and they tend to rapidly recur locally after colonoscopic resection, even in cases where the initial polypectomy appeared to be complete. A second clearing colonoscopy should be performed in 2–6 months to confirm that resection was complete. Residual neoplastic tissue has been reported in up to one-third of cases after piecemeal snare resection of sessile polyps greater than 2 cm in diameter [38]. If polyp tissue persists after two or three examinations, goodrisk patients should usually be referred for surgical resection.

Postpolypectomy Surveillance

When patients are found to have these large sessile polyps, they need to be educated at the time of 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, was then lost to follow-up, and returned later with an advanced cancer at the polyp site.

Effect of polypectomy on cancer incidence and mortality Resecting advanced adenomatous polyps, both initially and during postpolypectomy follow-up, is a powerful way to prevent cancer. Cohort and case–control studies of the effect of large bowel endoscopy have strongly indicated that polypectomy reduces the subsequent incidence and mortality of colorectal cancer located in the examined segment. Many years ago, Gilbertsen and Nelms at the University of Minnesota [39] reported that annual rigid proctoscopic screening and removal of rectal polyps performed in 2000 volunteers over a 20-year period reduced the incidence of rectal cancer by 85%. Case– control studies of the effect of screening proctosigmoidoscopy by Selby and colleagues [40] and Newcomb and colleagues [41] suggested a reduction in mortality from distal cancer of 60% and 80% respectively. Lastly, a large case–control study involving over 32 000 veterans by Muller and Sonnenberg [42] indicated that patients who had flexible sigmoidoscopy, colonoscopy, and polypectomy had a 50% reduced risk of developing colorectal cancer. Most convincing is the landmark analysis by Winawer and colleagues [6] from the National Polyp Study. All 1418 subjects enrolled in the study were pooled to determine the effect of initial polypectomy plus follow-up surveillance colonoscopies performed every 3 years. Only five new cancers were detected during an average follow-up of about 7 years (8400 person-years), which was 76–90% lower than expected by comparison with three reference populations. Thus, for the first time, a well-designed prospective trial showed that colonoscopic removal of all adenomas in the colon and rectum successfully interrupted the adenoma–cancer sequence, preventing most cancers from developing. Two recent reports from Europe confirm the findings and conclusions of the National Polyp Study. The Telemark Polyp Study from Norway [7] showed in a randomized controlled trial that colonoscopy and polypectomy for those with a positive screening flexible sigmoidoscopy reduced the subsequent incidence of colorectal cancer by 80%. A multicenter Italian study followed 1693 patients who had undergone resection of at least one adenoma greater than 5 mm in diameter [8]. The incidence of metachronous cancer was compared with that of a reference population. After a mean follow-up of 10.5 years (14 211 person-years), only six colorectal cancers were

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detected, indicating a reduction in incidence due to polypectomy of 76%. As discussed above, investigators from the National Polyp Study recently performed a micro-simulation screening modeling analysis (MISCAN) to predict the incidence of colorectal cancer using data from the study [9]. The model demonstrated a dramatic reduction in expected colorectal cancer incidence and indicated that the initial polypectomy accounted for the major component of this incidence reduction. The model predicted a modest benefit from postpolypectomy surveillance after 6 years. This conclusion is consistent with the fact that many more advanced adenomas were resected in the study at the index colonoscopy compared with the number found and resected during follow-up.

Further stratification of postpolypectomy cancer risk Estimates by pathologists as well as an analysis of all patients undergoing colonoscopy in the seven centers of the National Polyp Study indicate that it takes, on average, 10–12 years for an adenoma to develop, advance, and turn to cancer [43,44]. The cumulative recurrence rate of advanced adenomas in this trial was low: 4% at 3 years and 8% at 6 years [45]. Because of the long average natural history of the adenoma–carcinoma sequence and the overall low recurrence rate of advanced adenomas in follow-up studies, recent analyses have focused on ways to safely lengthen postpolypectomy intervals for most patients. Further analysis of follow-up data from the National Polyp Study and data from more recent outcome studies of postpolypectomy surveillance now indicate that it is possible to stratify risk of recurrent advanced adenomas based on the findings at initial polypectomy [45]. In the National Polyp Study, patients with a relatively high risk of developing advanced adenomas during follow-up included those with multiple adenomas (three or more), or large adenomas (≥ 1 cm), or adenomas with villous change or high-grade dysplasia. Patients with a low risk of metachronous advanced adenomas included those with only one or two small simple tubular adenomas. Other studies suggest these and other predictors for recurrence of adenomas. The Polyp Prevention Study Group determined predictors for metachronous adenomas in 479 patients who had one or more polyps detected at their index colonoscopy and then had repeat colonoscopies 1 and 4 years later in a negative chemoprevention trial of antioxidant vitamins [46]. Multivariate analysis showed that multiple adenomas (three or more) or at least one tubulovillous adenoma at initial colonoscopy were associated with an increased incidence of multiple adenomas at follow-up. In this study, no factors predicted an increased incidence of advanced metachronous adenomas. Another follow-up analysis was performed using the Cleveland Clinic Adenoma Registry of 697

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patients who had an adenoma recurrence within 3 years of a positive baseline colonoscopy [47]. Having three or more adenomas on initial colonoscopy, with at least one measuring 1 cm or larger, greatly increased the chance of finding an advanced adenoma at the first 3-year follow-up surveillance colonoscopy. Conversely, patients with only one or two adenomas, all measuring less than 1 cm, were at extremely low risk of having an important adenoma within 3 years. More recently, the Polyp Prevention Trial, a negative randomized trial of the effect of diet on the recurrence of colorectal adenomas, reported a recurrence rate of advanced adenomas at 4 years of 16% [48]. Baseline predictors of a higher risk of metachronous advanced adenomas included age over 65 years, proximal location of baseline adenomas, and villous histology. Current colorectal cancer screening and surveillance guidelines recommend that clinicians assess each patient’s risk of developing metachronous advanced adenomas and tailor postpolypectomy surveillance strategies accordingly [49,50]. Based on the available clinical and pathologic data reviewed in this chapter, patients with colorectal adenomas can now be stratified into high- and low-risk groups. After the colon has been satisfactorily cleared of all synchronous adenomas, repeat colonoscopy is recommended in 3 years for patients who are at high risk. These include those who at baseline colonoscopy have (1) large (≥ 1 cm) or multiple (three or more) adenomas or (2) an adenoma with the advanced pathologic features of villous change, high-grade dysplasia, or invasive carcinoma. Patients with a low risk of metachronous advanced adenomas include those who initially have only one or two small (< 1 cm) tubular adenomas without villous change, high-grade dysplasia or cancer. For these low-risk patients, the first postpolypectomy follow-up colonoscopy can be safely delayed for 5 –10 years or, in the case of advanced age, significant comorbidity, or personal preference, no follow-up may be indicated. Patients with only one or two small simple tubular adenomas account for 70–80% of all adenomabearing patients in most series. Because there have been only a few studies with long-term follow-up lasting 5 years or more, surveillance for this large low-risk group remains controversial. Some argue that since their risk of subsequent colorectal cancer does not appear to measurably exceed that of the average-risk population, no surveillance is indicated. Many, however, noting the discrepant findings in the different follow-up studies, are uncomfortable eliminating all surveillance for these patients, or they wish to reduce cancer risk to a level below that of the averagerisk population. To date, the largest long-term prospective follow-up of patients undergoing screening colonoscopy is provided by a recently published follow-up analysis of patients who participated in the large VA Cooperative Colonoscopy Screening Trial [51]. This study (Table 54.4) described the most advanced findings in 3121 asymptomatic veterans who previously had volunteered to have screening colonoscopy.

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Table 54.4 Veterans Administration Cooperative Colonoscopy Screening Study: 5-year follow-up. Baseline finding

Relative risk for advanced neoplasia

95% confidence interval

No neoplasia One or two tubular adenoma(s) < 10 mm More than three tubular adenomas < 10 mm Tubular adenoma > 10 mm Villous adenoma High-grade dysplasia Cancer

–

– 0.83 –4.42 2.10 –11.96 2.74–14.90 2.48–14.71 2.61–18.07 5.54–33.18

The primary objective was to determine the incidence of advanced neoplasia within 5.5 years of screening colonoscopy, during which the colon had been cleared of all neoplasia, as a function of baseline findings. Nearly 1200 patients with baseline neoplasia were assigned to follow-up colonoscopic surveillance. In addition, 501 subjects with no neoplasia at baseline were also offered surveillance as a comparison group. Relative risks of any adenoma and of all advanced neoplasia were calculated based on initial baseline findings and were expressed relative to follow-up findings in the group without any baseline neoplasia. Eight hundred and ninety-five (76.4%) patients with neoplasia and 298 subjects (59.5%) without neoplasia at baseline had colonoscopy within 5.5 years; 2.4% of patients with no neoplasia had interval advanced neoplasia. The relative risk of advanced interval neoplasia in patients with one or two baseline simple tubular adenomas < 1 cm was 1.92 [95% confidence interval (CI) 0.83–4.42], with three or more tubular adenomas < 1 cm was 5.01 (95% CI 2.10–11.96), with a tubular adenoma ≥ 1 cm was 6.40 (95% CI 2.74–14.94), and with a villous or tubulovillous adenoma was 6.05 (95% CI 2.48–14.71), with an adenoma with high-grade dysplasia was 6.87 (95% CI 2.61–18.07), and with cancer was 13.56 (95% CI 5.54–33.18). The authors of this 13-center prospective follow-up study concluded that there was a strong linear association between the results of baseline screening and the incidence of serious lesions during 5.5 years of follow-up surveillance. Patients with one or two tubular adenomas ≤ 1cm represented a low-risk group compared with other patients with colonic neoplasia found during screening colonoscopy. These important data are thus consistent with conclusions from other clinical trials and case series in which patients were followed for usually shorter intervals, and form the basis of the current surveillance guideline recommendations as listed below. The totality of evidence now indicates that multiplicity (≥ 3 adenomas), size (≥ 1 cm), villous features, and high-grade dysplasia are predictors of future advanced adenomas or cancers. Family history of colorectal cancer or adenomas, advancing age [52], and proximal location of neoplasia may predict

1.92 5.01 6.40 6.05 6.87 13.56

metachronous advanced adenomas but have not yet been adequately studied.

Hyperplastic polyps and the serrated adenoma It is widely accepted that patients whose only lesion at colonoscopy is a small left-sided hyperplastic polyp have a risk of metachronous colorectal cancer that is no higher than that of average-risk patients [53]. Such patients should therefore be offered standard screening as appropriate for average-risk people, not surveillance. However, considerable recent pathologic and clinical evidence supports the concept of a nontraditional polyp to cancer pathway involving a variant of the hyperplastic polyp that also contains histologic and genetic features of an adenoma with dysplasia, called a serrated adenoma [54]. Variants of the serrated adenoma have been linked to the development of sporadic microsatellite instability (MSI) adenocarcinomas (lesions with genetic changes that when inherited are responsible for the hereditary nonpolyposis colon cancer syndrome). Hyperplastic polyps at risk for this pathway show special histologic and genetic features. They often are large and sessile, and are usually located in the proximal colon. Families with the rare syndrome of hyperplastic polyposis also appear to be prone to the development of these MSI cancers. This syndrome has been clinically defined by the finding of at least five hyperplastic polyps found proximal to the sigmoid colon, of which two are > 1 cm. Patients also likely have the syndrome if they have proximal hyperplastic polyps and a first-degree relative with hyperplastic polyposis or more than 30 hyperplastic polyps of any size distributed throughout the colon [55]. Patients who may develop MSI cancers because they have serrated adenomas, right-sided large or multiple hyperplastic polyps, or the syndrome of hyperplastic polyposis, likely will benefit from surveillance. Although the type and frequency of follow-up colonoscopy have not yet been determined, many investigators recommend complete removal of these lesions followed

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by colonoscopic surveillance, as is recommended for those with multiple or advanced traditional adenomas [10].

Postpolypectomy surveillance recommendations A comprehensive guideline based on a review of all available high-quality postpolypectomy evidence was recently prepared by a combined panel of the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society [10]. A careful analytic approach was designed to address the evidence and determine predictors of metachronous advanced pathology (cancers and advanced adenomas) so patients can be better stratified according to baseline colonoscopic findings into lower-risk or higher-risk groups for developing important metachronous neoplasia. This guideline was also endorsed by the governing boards of the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the American Gastroenterology Association. The following are this guideline’s recommendations for postpolypectomy surveillance: 1 Complete high-quality colonoscopy should be done at the time of initial polypectomy to detect and resect all synchronous adenomas. 2 Additional clearing examinations may be required after resection of a large sessile adenoma, or if, because of multiple adenomas, inadequate colon cleansing preparation, or other technical reasons, the colonoscopist is not reasonably confident that all adenomas have been found and removed. 3 After a complete clearing colonoscopy has been accomplished following an initial polypectomy, repeat colonoscopy to check for recurrent adenomas should be performed in 3 years for patients at high risk for developing metachronous advanced adenomas. This includes those who at baseline examination have multiple (≥ 3 adenomas), a large (≥ 1 cm) adenoma, or an adenoma with villous histology or high-grade dysplasia. If the 3-year follow-up colonoscopy is normal or shows only one or two small tubular adenomas with low-grade dysplasia, then the interval for the subsequent colonoscopy should be 5 years. 4 Repeat colonoscopy to check for metachronous adenomas should be performed in 5–10 years for most patients at low risk for developing advanced adenomas. This includes those who at baseline examination have only one or two small simple tubular adenomas (< 1 cm). The precise timing within this interval should be based on other clinical factors (such as age, comorbidity, prior colonoscopy findings, family history, and the preferences of the patient and judgment of the physician). 5 Selected patients at low risk for metachronous advanced adenomas may not require follow-up surveillance. 6 Patients with only small, left-sided hyperplastic polyps should not undergo surveillance colonoscopy.

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7 Patients with large sessile adenomas that are removed piecemeal should undergo follow-up colonoscopy in 2–6 months to verify complete removal. Once complete removal has been verified, subsequent surveillance needs to be individualized based on the endoscopist’s judgment. 8 Follow-up surveillance should be individualized according to the age and comorbidity of the patient, and should be discontinued in patients with less than 10 years of life expectancy, according to the clinician’s judgment. 9 Endoscopists should make clear recommendations to primary care physicians about when the next colonoscopy is needed. The guideline panel concluded that, although some studies suggest that family history of colorectal cancer or proximal location of adenoma may be predictive of future advanced neoplasia, the data are insufficient to make this a recommendation for more intense surveillance at this time. Other patient factors evolving in recent literature that require additional study include the predictive role of age and male gender. Since there are several evolving issues, it is important that physicians remain in contact with their postpolypectomy patients so that future surveillance can reflect additional changes in the guideline recommendations.

Quality in the technical performance of colonoscopy Screening and surveillance colonoscopy are highly effective ways to reduce both the incidence and mortality of colorectal cancer provided they are good-quality examinations performed carefully by well-trained, experienced endoscopists. Also, only high-quality colonoscopy can accurately define baseline adenoma characteristics so they can be used for the planning of postpolypectomy surveillance intervals. The US Multi-Society Task Force on Colorectal Cancer defined a high-quality colonoscopy as one that is performed by an experienced, welltrained endoscopist, intubates the cecum, is performed after an adequate colon cleansing preparation, and has a minimal time of withdrawal from the cecum of about 6 min [56]. The colonoscopy preparation should be considered adequate if it leaves little fecal residue and allows detection of polyps > 5 mm. The task force concluded that the sensitivity of colonoscopy for detecting adenomas could be increased by employing a continuing quality improvement program in each endoscopy practice. An important related question is “Should the quality of preparation impact postpolypectomy follow-up recommendations?” Recommendations in the current surveillance guideline are based on the results of large outcome studies, such as the National Polyp Study, in which all patients had a high-quality baseline “clearing” examination. The American Society for Gastrointestinal Endoscopy/American College of Gastroenterology Task Force on Quality in Endoscopy suggested

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that the quality of bowel preparation should be described as “excellent” if no or minimal solid stool and only small amounts of clear fluid requiring suctioning are present, “good” if no or minimal solid stool with large amounts of clear fluid requiring suction are found, “fair” if there are collections of semisolid debris that are cleared with difficulty, and “poor” if solid or semisolid debris that cannot be effectively cleared is encountered [57]. Recent surveys indicate that there is considerable interobserver variability in preparation assessment and, alarmingly, up to 25% of colonoscopy preparations are considered poor or inadequate [58– 60]. It also is a common practice for endoscopists to deviate from the guidelines and recommend shorter follow-up surveillance intervals in patients with perceived suboptimal preparations. This practice is not supported by any direct investigation. Not only is it based on poorly validated, subjective criteria for preparation quality, but there are no prospective controlled studies proving that it is a safe practice in the best interest of patients. Best practice may be to attempt in every case to reliably determine if the preparation is either adequate or inadequate [61]. An inadequate preparation calls for prompt repeat examination to attempt adequate cleansing of the colon, followed by strict adherence to the follow-up recommendations contained in the guidelines.

Cost and cost-effectiveness of postpolypectomy surveillance Adoption of these recommendations would substantially reduce the cost of postpolypectomy surveillance because many clinicians still perform surveillance more frequently than is necessary. For example, Ransohoff and colleagues [62] estimated that postpolypectomy surveillance that leads only to the detection and resection of small tubular adenomas is unlikely to appreciably reduce colorectal cancer incidence or mortality. They performed a cost-effectiveness analysis of available data and concluded that the cost of excessively frequent surveillance of those with a low subsequent risk of colorectal cancer, such as those with a single small tubular adenoma, is prohibitive. Based on their assumptions in 1991, it would cost $80 000– 300 000 per life saved for a surveillance program of colonoscopy every 3 years for all 50-yearold patients with small adenomas followed for 30 years. In another cost-effectiveness mathematical modeling analysis, Lieberman [63] concluded that conventional postpolypectomy surveillance accounts for 19–34% of the total cost of a colorectal cancer screening program. According to his calculations, if postpolypectomy surveillance focused solely on the detection of advanced adenomas, this cost could be reduced by over 40%. In 1996, a large practice in Minneapolis consisting of 19 gastroenterologists analyzed the economic impact of adopting the postpolypectomy recommendations of the National Polyp Study [64]. A survey of 500 prior cases indicated

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that this group of physicians had deviated from these recommendations in 45% of their cases (range 15–80%); most were performing more frequent follow-up examinations than were needed. After implementing a practice guideline based on the National Polyp Study findings, follow-up practice in the next 500 polypectomy cases deviated by only 12% (mostly a result of physicians deciding against any follow-up when polyps were found in elderly or ill patients). During the next 12 months, this group documented savings of more then $600 000 in facility and professional charges for colonoscopy that were directly attributable to adopting a rational evidencebased guideline for postpolypectomy surveillance. Rex and Lieberman [65] recently analyzed the feasibility of performing direct colonoscopy screening in the US. They concluded that some of the capacity currently unavailable to carry out this screening could be created by shifting resources away from unnecessary postpolypectomy surveillance to colonoscopy screening. If postpolypectomy surveillance were designed to detect only advanced adenomas, two-thirds of the colonoscopies currently being done annually for surveillance could instead be used for screening. Another important cost-saving strategy is to eliminate screening for patients who are already participating in a postpolypectomy colonoscopy surveillance program. No additional colorectal cancer screening of any type is needed when a patient is asymptomatic and has had normal results on surveillance colonoscopy within 3–5 years.

Summary Following removal of benign adenomatous polyps, there is a 30–50% likelihood of developing a metachronous adenoma in the future. Removal of colon polyps will, to a large extent, interrupt the adenoma–carcinoma sequence and protect the patient from developing carcinoma. Not all patients have the same likelihood of developing metachronous adenomas. The timing of follow-up colonoscopic examinations needs to take into account each patient’s risk for developing metachronous advanced adenomas and tailor postpolypectomy surveillance strategies accordingly. Patients with colorectal adenomas should be stratified into high- and low-risk groups. Interval colonoscopic examination is recommended in 3 years for patients who are at high risk. These high-risk patients are those who have had the removal of large or multiple adenomas, an adenoma with the advanced pathologic features of villous change, high-grade dysplasia, or invasive carcinoma. Patients with a low risk of metachronous advanced adenomas can safely have their first follow-up colonoscopy at 5–10 years. This group of low-risk patients includes those who initially have only one or two small tubular adenomas without high-grade dysplasia or cancer. Stratification of patients into various colonoscopic follow-up strategies will permit the medical profession to conserve precious resources while

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providing the best and most efficient protection against the possibility of developing colon cancer.

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40 Selby JV, Friedman GD, Quesenberry CP, et al. A case–control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326: 653–7. 41 Newcomb PA, Norfleet RG, Storer BE, et al. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992; 84: 1572–5. 42 Muller AD, Sonnenberg A. Prevention of colorectal cancer by flexible endoscopy and polypectomy: a case–control study of 32 702 veterans. Ann Intern Med 1995; 123: 904–10. 43 Muto T, Bussy HJR, Morson BC. The evolution of cancer of the colon and rectum. Cancer 1975; 36: 2251–70. 44 Winawer SJ, Zauber A, for the National Polyp Study Workgroup. The National Polyp Study: temporal sequence of evolving colorectal cancer from the normal colon (abstract). Gastrointest Endosc 1987; 33: 167. 45 Winawer SJ. Appropriate intervals for surveillance. Gastrointest Endosc 1999; 49: S63– 6. 46 Van Stolk RU, Beck GJ, Baron JA, et al. Adenoma characteristics at first colonoscopy as predictors of adenoma recurrence and characteristics at follow-up. Gastroenterology 1998; 115: 13–18. 47 Kairasp C, Noshirwani MD, van Stolk RU, et al. Adenoma size and number are predictive of adenoma recurrence: implications for surveillance colonoscopy. Gastrointest Endosc 2000; 51: 422– 7. 48 Mysliwiec PA, Pfeiffer R, Lanza E, Schatzkin A. Characteristics of baseline colorectal adenomas as predictors of adenoma recurrence (abstract). Gastroenterology 2002; 122: A570. 49 Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997; 112: 594– 642. 50 Bond JH, for the Practice Parameters Committee of the American College of Gastroenterology. Polyp guideline: diagnosis, treatment, and surveillance for patients with colorectal polyps. Am J Gastroenterol 2000; 95: 3053– 63. 51 Lieberman DA, Weiss DG, Harford WV, et al. Five-year colon surveillance after screening colonoscopy. Gastroenterology 2007; 133: 1077– 85. 52 Brenner H, Hoffmeister M, Stegmaier C, et al. Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 84,149 screening colonoscopies. Gut 2007; 56: 1585– 9.

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53 Bensen SP, Cole BF, Mott LA, et al. Colorectal hyperplastic polyps and risk of recurrence of adenomas and hyperplastic polyps. Polyp Prevention Study. Lancet 1999; 354: 1873–4. 54 Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP. Serrated polyps of the large intestine. A morphologic and molecular review of an evolving concept. Am J Surg Pathol 2005; 124: 380–91. 55 Burt R, Jass JR. Hyperplastic Polyposis. Lyon: IARC Press, 2000. 56 Rex DK, Bond JH, Winawer SJ, et al. Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: Recommendations of the U.S. MultiSociety Task Force on Colorectal Cancer. Am J Gastroenterol 2002; 97: 1296–1308. 57 Rex DK, Petrini JL, Baron TH, et al. for the ASGE/ACG Task Force on Quality in Endoscopy. Quality indicators for colonoscopy. Gastrointest Endosc 2006; 63: 516– 28. 58 Ben-Horin S, Bar-Meir S, Avidan B. The impact of colon cleanliness assessment on endoscopists’ recommendations for followup colonoscopy. Am J Gastroenterol 2007; 102: 2680–5. 59 Froehlich F, Wietlisbach BA, Gonvers JJ, et al. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: The European Panel of Appropriateness of Gastrointestinal Endoscopy European Multicenter Study. Gastrointest Endosc 2005; 61: 378–84. 60 Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc 2003; 58: 76–9. 61 Bond JH. Should the quality of preparation impact postcolonoscopy follow-up recommendations? Am J Gastroenterol 2007; 102: 2686–7. 62 Ransohoff DF, Lang CA, Kuo HS. Colonoscopic surveillance after polypectomy: considerations of cost effectiveness. Ann Intern Med 1991; 114: 177– 82. 63 Lieberman DA. Cost-effectiveness model for colon cancer screening. Gastroenterology 1995; 109: 1781–90. 64 Allen JI. Rational management of colorectal polyps: how to prevent colorectal cancer yet keep the health care system solvent. Med J Allina 1996; 5: 16–20. 65 Rex DA, Lieberman DA. Feasibility of colonoscopy screening: discussion of issues and recommendations regarding implementation. Gastrointest Endosc 2001; 54: 662–7.

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Colonoscopy after Colorectal Cancer Resection Charles J. Kahi & David A. Haggstrom Indiana University, Indianapolis, IN, USA

Introduction Colorectal cancer (CRC) is a common malignancy that is diagnosed in about 1 in 20 persons living in Westernized countries [1]. In the US, CRC is the third most common malignancy, with about 150 000 new cases diagnosed annually, and the second leading cause of cancer deaths, with over 50 000 deaths per year [2]. Surgical resection is the mainstay of therapy, along with adjuvant chemotherapy and/or radiotherapy in selected cases. An estimated 70–80% of patients present with cancers that are amenable to resection with curative intent [3–5]; thus, 105 000–120 000 new patients become eligible for postoperative surveillance every year, and about 500 000 undergo such surveillance annually in the US [3,6]. The central aim of postoperative surveillance is to improve survival by allowing early detection and surgical resection of recurrences and metachronous (second primary) CRCs, and surveillance strategies usually include a combination of history and physical examination, laboratory tests, radiographic studies, and endoscopy. While the components and intensity of the optimal surveillance regimen have yet to be defined, colonoscopy is widely used after CRC resection to detect recurrences and metachronous cancers, and to detect and remove precancerous adenomatous polyps. This chapter will present an overview of post-CRC resection surveillance strategies, and then focus on the role of colonoscopy in this setting, particularly its yield in perioperative clearing and postoperative surveillance, and impact on patient outcomes.

Surveillance strategies Clinicians involved in the surveillance of patients after CRC resection commonly use a combination of modalities in con-

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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junction with clinical assessment by history and physical examination. These include laboratory tests (e.g., carcinoembryonic antigen, CEA), radiographic studies (computed tomography, ultrasonography, barium studies), and endoscopy (colonoscopy and sigmoidoscopy) [4]. Other tests such as complete blood counts, liver tests, fecal occult blood tests, and chest radiography are not routinely recommended for surveillance in the absence of symptoms [3,7]. The aim of surveillance is to detect recurrent and metachronous neoplasms at a stage that would allow curative re-resection, or at least palliation. However, the individual components of surveillance have not been well studied, and the optimal test combination and follow-up intensity of post-CRC resection surveillance are not well defined. To date, eight randomized controlled trials have assessed the effectiveness of surveillance strategies after curative CRC resection [8–15]; these studies have recently been analyzed in a Cochrane systematic review [1]. Seven of the trials compared varying levels of postoperative follow-up intensity [8–14], and the eighth assessed the impact of follow-up setting (general practice versus surgical based) on patient quality of life, anxiety and depression, satisfaction with care, number and timing of recurrences, and death [15]. Overall, the studies included 2141 patients randomized to an intensive follow-up group or a control group, and the main outcome in seven of the eight trials was 5-year survival after curative CRC resection. The follow-up strategies that were used, including investigation type and frequency, varied greatly. For example, two studies performed the same investigations at different frequencies [8,11], while in other trials patients randomized to intensive surveillance received selected additional tests. Two studies followed a minimalist follow-up strategy in the control group, consisting predominantly of diagnostic testing for symptoms [10,14]; other trials incorporated scheduled laboratory tests, radiographs, and endoscopy into the follow-up of the control group. In some instances, the “control” approach used certain tests (for example, CEA) with the same frequency as the intensive approach [8,9,13], and the follow-up of the control group in one study [13] would have qualified as the follow-up of the intensive group in another study [8]. One

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study used predefined prognostic criteria to predict individual risk of cancer recurrence, and this was used to determine the type and timing of clinical assessments and diagnostic testing [14]. Despite the methodologic heterogeneity of these studies, several meta-analyses and systematic reviews have incorporated some or all of their results to attempt to overcome sample size limitations of individual reports [1,4,16,17]. In a recent Cochrane systematic review [1], meta-analysis of six trials [8–13] showed significantly improved 5-year survival for the intensive follow-up strategy [odds ratio (OR) 0.73; 95% confidence interval (CI) 0.59– 0.91]. The mean time to recurrence was reduced by the intensive approach (−6.75 months, 95% CI –11.06 to −2.44], and the performance of more tests was associated with improved survival (OR 0.64, 95% CI 0.49– 0.85). Additionally, liver imaging (versus no liver imaging) was associated with improved survival (OR 0.64, 95% CI 0.49– 0.85), in contrast to CEA measurement (OR 0.57; 95% CI 0.26–1.29). Another meta-analysis incorporating five of the trials [8–11,13] reported that the mortality reduction associated with intensive follow-up was most pronounced in trials that used computed tomography and frequent CEA measurements [17]. An older meta-analysis of nonrandomized studies found that the improved survival of patients undergoing intensive surveillance was observed only when CEA measurements were part of the follow-up program [18]. One study attempted to ascertain whether the efficacy of intensive surveillance varied within the 5-year period of time since surgical resection, and found that re-resectability rate was lower in the first 2 years than in the last 3 years [12]. However, it was not clear whether this reflected inadequate surveillance in the early postoperative period or more aggressive tumor behavior in a subset of patients [12]. The overall conclusion that can be derived is that there is a survival benefit to intensive surveillance after curative CRC resection. However, the wide variation in follow-up strategies does not allow definitive conclusions about the optimal combination and frequency of investigations.

Colonoscopy as a surveillance modality The yield, optimal frequency, and impact on outcomes of postoperative colonoscopy are not well defined [19,20]. Frequent performance of colonoscopy after surgery does not appear to have a high yield for recurrent cancer: Ohlsson et al. [10] reported no metachronous cancers in the group undergoing intensive surveillance (four colonoscopies in 5 years) after a median follow-up of 6.8 years. In the Schoemaker study, only one patient was found to have an asymptomatic metachronous cancer among 167 patients undergoing annual colonoscopy for 5 years [13]. The pooled results of the randomized trials of surveillance strategies suggest a relatively low rate of metachronous and interval cancer detection (34 tumors in eight studies) [1]. In the Renehan meta-analysis, the detection rate of intraluminal recurrence and metachronous cancer

Colonoscopy after Colorectal Cancer Resection

was low (3.2% and 1.3%, respectively), and there were no differences between follow-up regimens [17]. The aforementioned randomized trials suggest a limited benefit of colonoscopy in the first few years after resection; however, the studies tested integrated strategies incorporating several modalities. Thus, it is difficult to draw conclusions regarding the effectiveness of any one modality without taking into account the impact of co-interventions. Additionally, the risk for the development of metachronous disease is lifelong and cumulative [3]; thus, the long-term benefit of colonoscopy cannot be determined within the finite and limited duration of each study. The impact of colonoscopy may also have been underestimated: in the randomized controlled trial conducted by Rodriguez-Moranta et al. [12], colonoscopy was responsible for the highest rate of detection (44%) of resectable recurrent tumors in the intensive follow-up arm, and the benefit in terms of resectability was maintained for up to 5 years. In the following sections, we will focus on colonoscopy’s role in surveillance after curative CRC resection, and review the pertinent literature. Generally, patients with stage I, II, and III CRC, and selected patients with stage IV CRC are candidates for postoperative surveillance colonoscopy [21]. Patients with CRC may harbor synchronous cancers and precancerous polyps, mandating complete colonoscopic clearing (visualization and resection of polyps) at the time of the diagnosis of the index primary tumor [4]. After surgery, patients remain at increased lifelong risk for developing recurrent colonic neoplasms (local recurrences, second primary tumors, and adenomatous polyps); thus colonoscopy is a key component of follow-up.

Literature review We performed a literature search to identify studies in which patients with CRC underwent surgical resection with curative intent, and were followed up with colonoscopy to detect recurrent disease (including anastomotic recurrences) and metachronous cancer and/or polyps. A total of 25 studies published between 1990 and 2006 were included [8–13,22–40]; their methods and results are summarized in Tables 55.1 and 55.2, respectively.

Qualitative aspects of selected studies The selected studies were conducted in the US, Europe, Australia, Japan, Singapore, and Taiwan and accrued subjects between 1972 and 2003. Study design was variable and included retrospective analyses of existing databases, analyses of prospectively updated databases, prospective cohort studies, analyses of historical cohorts, and randomized controlled trials. Perioperative clearing of the colon to exclude synchronous neoplasms was accomplished in various ways: most studies employed complete preoperative colonoscopy, with or without barium enema and/or flexible sigmoidoscopy

731

732

Setting/accrual dates

Italy, 1980–1990

France, 1986– 1992

Spain, 1987– 1990

Australia, 1972– 1990

Germany, 1978– 1987

Sweden, 1981– 1990

Barillari et al. [22]

Barrier et al. [23]

Castells et al. [24]

Chen and Stuart [25]

Eckardt et al. [26]

Granqvist and Karlsson [27] Retrospective

Prospective

Prospective

Prospective

First colonoscopy 12 ± 6 months; second colonoscopy 30 ± 12 months; third colonoscopy 54 ± 12 months Annual colonoscopy

Preoperative colonoscopy on subgroup of 61 patients

Preoperative colonoscopy, or barium enema and flexible sigmoidoscopy if stenosis. If inadequate preoperative clearing, repeat endoscopy within 3 months postoperatively Preoperative colonoscopy and/or colonoscopy at first year postoperatively

Preoperative colonoscopy, or barium enema and flexible sigmoidoscopy if stenosis. If inadequate preoperative clearing, repeat endoscopy within 3 months postoperatively Preoperative colonoscopy or within 6 months postoperatively

61a

199

231

212

390 (600)

Colonoscopy at 2 years postoperatively, then every fourth year. If adenomas, annual colonoscopy until clear

Annual colonoscopy for 5 years, then every 3 years

Colonoscopy at first year postoperatively, then every 3 years. If adenomas, annual colonoscopy until clear

Group 1: first colonoscopy at 12 months, then at mean intervals of 12 months; group 2: first colonoscopy at 12 months, then at mean intervals of 24 months

Preoperative colonoscopy

481

Not present at time of preoperative colonoscopy or first postoperative colonoscopy, then developed elsewhere in colon

Neoplasm arising more than 5 cm from anastomosis and more than 1 year after surgery

Definition metachronous CRC

Local recurrence

“Locoregional”: restricted to anastomosis or region of primary operation

Intraluminal lesion within 5 cm from surgical anastomosis

Intraluminal lesion within 5 cm from surgical anastomosis

Definition anastomotic recurrence

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Retrospective

Endoscopic follow-up schedule

Perioperative clearing

No. of patients (no. of colonoscopies

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Retrospective

Design

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Reference

Table 55.1 Methodologies of postcancer resection surveillance colonoscopy studies.

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Surveillance

US, 1978–1985

US, 1984–1994

Denmark, 1983– 1994

Taiwan, 1981– 2001

Finland, 1988– 1990

UK, 1998–2003

UK, 1980–1991

Juhl et al. [30]

Khoury et al. [31]

Kjeldsen et al. [8]

Lan et al. [32]

Makela et al. [9]

Mathew et al. [33]

McFarland et al. [34]

Retrospective

Prospective

Retrospective

Preoperative colonoscopy

Colonoscopy and barium enema perioperatively Perioperative colonoscopy

Complete colonoscopy or incomplete colonoscopy plus barium enema

Preoperative colonoscopy or at 6 months postoperatively

Preoperative colonoscopy or at 3 months postoperatively (intensive subgroup)

Preoperative colonoscopy or postoperative in emergency cases (up to 1 year after surgery) Colonoscopy as close as possible to time of resection Perioperative colonoscopy

318

133b (316)

389 (3889)

597 (intensive subgroup: 290)

3846

106 (intensive subgroup: 52)

105 (140)

74 (237)

444

Colonoscopy or barium enema and flexible sigmoidoscopy at diagnosis

Colonoscopy every 3 years

Annual colonoscopy for 5 years, then every 2 years

Colonoscopy 2 and 5 years postoperatively

Intensive: colonoscopy once a year, plus flexible sigmoidoscopy every third month for rectal/sigmoid cancers; control: barium enema at 12 months then once a year. If rectal/sigmoid cancer, rigid sigmoidoscopy every 3 months for 2 years, then every 6 months for 3 years

Colonoscopy at 1 year. If negative or one polyp < 5 mm, then 2–3 years later. If one polyp > 5 mm, or ≥ 2 polyps, then 1 year after polypectomy. If two negative colonoscopies, then 5-year intervals

Intensive: colonoscopy at 6, 12, 18, 24, 30, 36, 48, 60, 120, 150, 180 months; control: colonoscopy at 60, 120, 180 months

Variable, median interval between procedures: 13 months

Annual colonoscopy for 6 years

Colonoscopy at 1-, 3-, and 5-year intervals postoperatively

Colonoscopy at 6, 12, 18 months then annually (study guidelines), or at 6 months then every 18–24 months (physician discretion)

Arising from the mucosa at a site other than anastomosis line, after at least 12 months from initial resection and/or at least a negative postoperative colonoscopic surveillance

At least 12 months after primary cancer

At least 1 year postoperatively

Arising from a preexisting polyp or found at a site distant from primary tumor (not at anastomosis), without evidence of penetration from bowel serosa

“Local”: endoluminal at anastomosis site

“Local recurrence”: restricted to the anastomosis and its surroundings

“Local recurrence”: tumor growth in the region of the primary radical operation including surgical wound

CHAPTER 55

RCT

Retrospective

RCT

Retrospective

Prospective

Prospective

3278

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Canada, 1976– 1992

Italy, 1999–2004

Hassan et al. [29]

Historical cohort

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Obrand and Gordon [35]

US, 1989–1993

Green et al. [28]

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733

734 Prospective

RCT

Prospective

RCT

RCT

Prospective

Ireland, 1983– 1988

Italy, 1987–1990

Australia, 1996– 2002

Spain, 1997– 2001

Australia, 1984– 1990

Singapore

Patchett et al. [36]

Pietra et al. [11]

Platell et al. [39]

RodriguezMoranta et al. [12]

Schoemaker et al. [13]

Skaife et al. [37]

Japan, 1992– 1995 Retrospective

Annual colonoscopy

Colonoscopy at 12 months or every 3 years Intensive: annual colonoscopy for 5 years; control: colonoscopy at first and third year if family history of HNPCC or synchronous neoplasms, otherwise only if symptoms or abnormal laboratory results Intensive: annual colonoscopy for 5 years; control: colonoscopy only if clinical or screening test abnormality, and after 5 years of follow-up Annual colonoscopy until no polyps, then every 3–5 years Annual colonoscopy or on request for first 5 years, then every 2 years

Preoperative colonoscopy or at 3 months postoperatively

Preoperative colonoscopy or at 3 months postoperatively Preoperative colonoscopy or postoperative if preoperative colonoscopy could not be performed

Perioperative colonoscopy

Colonoscopy at time of cancer resection “Clean colon before surgery”

Preoperative colonoscopy or barium enema. If stenosis, barium enema

322

341 (1569)c

611 (609)

325 (intensive subgroup: 167) (733)

259 (intensive subgroup: 127)

253 (227)

207 (intensive subgroup: 104)

b

Variable

Colonoscopy at 6, 12, 18, 30, 48 months

Colonoscopy after operation

132

Subgroup which underwent complete preoperative colonoscopy (total patients: 175). Subgroup excludes patients with rectal cancer treated by abdominoperineal resection (total patients: 174). c Mean number of procedures per patient reported as 4.6 (range 2–15). RCT, randomized controlled trial.

a

Togashi et al. [38]

Intensive: colonoscopy at 3, 15, 30, 60 months, plus endoscopic control of anastomosis (flexible sigmoidoscopy or colonoscopy) at 9, 21, and 42 months

Preoperative barium enema, then colonoscopy and barium enema within 3 months postoperatively

107 (intensive subgroup: 53)

All cases detected after surgery

At least 2 years after surgery

Remote from anastomosis

Definition metachronous CRC

Located at, or adjacent to, anastomotic line

“Locoregional”: restricted to anastomosis or region of primary operation

“Intraluminal local recurrence”: involves only suture or staple line of bowel anastomosis

Intraluminal recurrence within 5 cm of anastomosis

Definition anastomotic recurrence

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Retrospective

RCT

Sweden, 1983– 1986

Ohlsson et al. [10]

Endoscopic follow-up schedule

Perioperative clearing

No. of patients (no. of colonoscopies

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Stigliano et al. Italy, 1970–1988 [40]

Design

Setting/accrual dates

Reference

Table 55.1 (cont’d )

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Surveillance

1–5 years

Hassan et al. [29]

1.6

Median 18.4 months (range 3.4–70.1 months )

Green et al. [28]

10 At 1 year: 4 At 3 years: 5 At 5 years: 1

42 Dukes’ A or B: 23 Early: 24

12 Early: 7 Reoperated: 10

Granqvist and Karlsson [27] 0.5–7 years

26e Reoperated: 7 Asymptomatic: 13

4 Earlyd: 0 Reoperated: 4 Asymptomatic: 4

0

12 Dukes’ A or B: 9 Reoperateda: 7

Eckardt et al. [26]

2.8

Mean 7.75 years (range 3–17 years)

Mean 14 months (range 7–26 months)

Chen and Stuart [25]

6.6

Barrier et al. [23]

Median 25 months (range 10–73 months)

Metachronous CRC

14 Rectal/sigmoid: 9 Early: 14 Reoperated: 8

e

42 Locoregional Asymptomatic: 5 Reoperated: 13

4 All distal colon/ upper rectum All within 26 months All asymptomatic Reoperated 73%c

34 All rectal Intraluminal only: 10 Reoperated: 10

Anastomotic CRC

104 non-advanced adenomas; 19 advanced adenomas

106 ≥ 10 mm: 24; highgrade dysplasia 11

130 TA

9 TA, all < 10 mm

Metachronous adenomas

Cumulative incidence of CRC and advanced adenomas (excluding 1year lesions): 3 years 2.9%; 5 years 5.6% (2.2/100 patient-years)

14 of 42 (33%) died within study period; CRC incidence 274/100 000 patient-years; cumulative incidence 1.5% at 5 years

Metachronous: 7 of 10 reoperated alive after 1–5 years; anastomotic: 6 of 8 reoperated alive after 0.5 year

5-year survival: compliant 80%; noncompliant 59%; asymptomatic recurrence 42%; symptomatic recurrence 8%

Metachronous CRC incidence: 1 per 324.5 patient-years of follow-up

5-year survival: compliant 63%; noncompliant 37%

5-year survival: metachronous CRC 50%; anastomotic 45.4%; asymptomatic recurrence 41%; symptomatic recurrence 12.5%

Outcomes

More than half of patients did not adhere to surveillance protocol

Asymptomatic: 14 of 26 (7 Dukes’ A or B)b; symptomatic: 12 of 26 (3 Dukes’ A or B)b

Postoperative endoscopic surveillance leads to early tumor detection and improves survival

Systematic postoperative surveillance increases rate of tumor recurrence amenable to curative-intent surgery and improves overall and cancer-related survival

Second CRC within 24 months: 24 of 46 (52%)b; asymptomatic 22 of 46 (48%)b; 81% of rectal recurrences detected within 18 months

Comments

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Compliant patients: 13 ± 21 months; noncompliant: 15 ± 9 months

3.3

Barillari et al. [22]

Time to CRC diagnosis

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Castells et al. [24]

Synchronous CRC (%)

Reference

Table 55.2 Results of postcancer resection surveillance colonoscopy studies.

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2 Reoperated: 2 44 Rectal: 29 Reoperated: 20 2h Reoperated: 2 Asymptomatic: 1 Re-recurrence: 2

2

0 0

0h

Metachronous 2 and 5 years; recurrence 2 years At 2 years

Mathew et al. [33]

McFarland et al. [34]

Median 1.7 years (range 0.3–7.6 years)

Range 7–43 months

Ohlsson et al. [10]

Patchett et al. [36]

2 Asymptomatic: 0

3

1 Reoperated: 1

Intensive 10 ± 5 months; control 15 ± 10 months

Makela et al. [9]

6 Asymptomatic: 0

22 TA

6 patients with “adenomas with varying degrees of atypia”

31 TA: ≥ 1 cm 12

TA in 24 patients (5 patients with advanced adenomas)

13 TA, 4 TVA (including 2 polyps with highgrade dysplasia)

5-year survival: intensive 75%; control 67% (P > 0.05)

47% of re-resected patients alive at mean of 80 months

5-year survival: intensive: 59%; control: 54% (P = NS)

Metachronous CRC group: 5-year survival 90%; 10-year survival 71%; annual incidence 0.18%

5-year survival: intensive 70%; control 68% (P = NS)

Outcomes

Rectal 4 of 8b; reoperated 4 of 8b; Dukes’ B 5 of 8b; Dukes’ C 5 of 8b

Intensive follow-up did not prolong survival

Anastomotic recurrence higher for rectal than colon cancer (20.3% vs. 6.2%, P = 0.001)

Intensive follow-up led to earlier detection of recurrence, but not significantly increased re-resectability or improved 5-year survival

Intensive follow-up led to earlier diagnosis of recurrence (by 9 months) and more reoperations, but no improvement in survival

Comments

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Mean 16.2 months

3 Rectal/sigmoid: 2 Dukes’ B: 1 Dukes’ C: 2 Reoperated: 3 Asymptomatic: 2

43 Early (20-month interval): 5 Dukes’ A or B: 31 Reoperated: 35

Mean 71 ± 47 months (range 14–240 months)

Lan et al. [32]

4

91g Reoperated: 14 Asymptomatic: 16

10 Reoperated: 8 Asymptomatic: 8

Intensive 18 months; control 27 months

Kjeldsen et al. [8]

240 neoplastic polyps: > 10 mm 4 (all at first colonoscopy)

< 1 cm 123; > 1 cm 37 (7 villous polyps)

Metachronous adenomas

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Obrand and Gordon [35]

2

1

13–56 monthsf

Khoury et al. [31]

9 All LAR: reoperated 5 for palliation (4 inoperable), all symptomatic

4 Dukes’ A or B: 4 Early: 0 Reoperated: 4 Asymptomatic: 4

Metachronous > 2 years; anastomotic: 12–30 months

1.7

Juhl et al. [30]

Anastomotic CRC

Metachronous CRC

Time to CRC diagnosis

Synchronous CRC (%)

Reference

Table 55.2 (cont’d )

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22j Early: 9 Dukes’ A or B: 10 Reoperated: 22j

Third or eighth year

< 24 months 9; 25–60 months 9; > 61 months 4

Stigliano et al. [40]

5 Early 1; 5 with no “extracolonic disease” 22 All rectal/distal sigmoid Early: 20 Reoperated: 16

4 Early 1; 2 with no “extracolonic disease”

3

24 patients with adenomas (all < 1 cm)

18 TA, 39 TVA, 1 VA

Overall 5-year survival 65% (rectal 57%, colon 71%)

8 metachronous or locally recurrent tumors detected by colonoscopyb: early 5; Dukes’ A or B 5; symptomatic 1 5-year survival: intensive 75%; control 70% (P = 0.2)

b

Reoperations with curative intent, unless otherwise specified. Combined metachronous CRCs and local recurrences. c Eight of 11 (73%) total anastomotic recurrences in both patient subgroups (with and without preoperative colonoscopy). d “Early”: within 24 months of primary curative-intent resection, unless otherwise specified. e All tumor recurrences (separate data for metachronous and anastomotic not presented). f Median time from preceding colonoscopy. Metachronous cancer found at first colonoscopy (median 13 months from surgery), anastomotic recurrences found at second colonoscopy (median 15 months from first colonoscopy) and fourth colonoscopy (median 14 months from third colonoscopy). g Local recurrence with or without distant spread (local recurrence without distant spread: 74 patients). h Intensive follow-up group undergoing scheduled endoscopic surveillance (n = 53). One symptomatic metachronous cancer occurred after 3 years and two anastomotic recurrences in the control group (n = 54). i Excluding synchronous stage 0 (Tis) cancers. j Twenty-two metachronous cancers, including 12 stage 0 (Tis) cancers confined to the mucosa. Nine of 12 Tis cancers treated by endoscopic resection (3 of 12 required colectomy). LAR, low anterior resection; TA, tubular adenoma; TVA, tubulovillous adenoma.

a

6.7%i

Median 36 months (range 6–67 months)

Skaife et al. [37]

Togashi et al. [38]

5 Early: 0 Dukes’ A: 5

7–42 months

Schoemaker et al. [13]

Intensive follow-up associated with higher survival in patients with stage II tumors (hazards ratio 0.34, 95% CI 0.12–0.98; P = 0.045) and those with rectal lesions (hazards ratio 0.09; 95% CI 0.01–0.81; P = 0.03), due to higher rate of re-resectability; colonoscopy responsible for detection of highest proportion (44%) of resectable recurrences in intensive arm

65% of preoperative colonoscopies performed outside study center and reports not available to authors

Intensive follow-up led to improved survival, primarily because local recurrences are more resectable when detected early

After median follow-up of 48 months, no difference in probability of overall survival (hazards ratio 0.87, 95% CI 0.49–1.54; P = 0.62)

5-year survival: intensive: 73.1%; control 58.3% (P < 0.02)

1:16 PM

5

6

Intensive 39 ± 21 months; control 38 ± 19 months

RodriguezMoranta et al. [12]

62 TA (≥ 1 cm 6), 9 TVA, 10 VA; overall prevalence of advanced adenomas 7.9%

21 patients with adenomas

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24

3 All rectal, all metastatic

0

12 months

Platell et al. [39]

2 Rectal: 1

1

Intensive 10.3 ± 2.7 months; control 20.2 ± 6.1 months

Pietra et al. [11]

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in cases of malignant obstruction. In some instances, this was supplemented with a postoperative colonoscopy (within 3–6 months after surgery) if preoperative assessment was felt to be inadequate. The endoscopic surveillance regimen and the duration of follow-up after surgery were highly variable (Table 55.1). Many studies did not provide a definition of metachronous cancers. When the term “metachronous” was defined, it was based on the location of the second tumor with respect to the surgical anastomosis, or time of diagnosis relative to the time of the index surgery, or a combination of these two parameters. Anastomotic recurrences were in several instances defined as an intraluminal recurrence of cancer within a small distance (usually 5 cm) from the surgical anastomosis. However, some studies did not separate anastomotic from local and locoregional recurrences, and, in some instances, metachronous and anastomotic recurrences were reported together. Some studies specifically excluded patients with inflammatory bowel disease and HNPCC; many made no mention of whether patients with these conditions were excluded and, in one instance, a small subgroup of patients with HNPCC was included [12]. Prospective studies and randomized trials frequently specified whether colonoscopy was performed routinely in asymptomatic individuals or for the evaluation of symptoms or abnormal laboratory findings; however, such information was often lacking in retrospective studies. The results and outcomes reported were also heterogeneous: while all studies reported data on yield of colonoscopy for metachronous cancers, adenomas, and/or anastomotic recurrences, other important parameters such as stage and re-resectability of the recurrent cancer, mortality, and complication rates were variably reported. Despite the acknowledged limitations of the literature, important trends and conclusions can be inferred and are discussed next.

however, this usually relies on preoperative barium enema and intraoperative palpation of the colon to exclude synchronous lesions, and the risk of reoperation to resect missed lesions with this approach is increased [23,42]. Several studies have shown that patients with CRC and synchronous adenomas have a higher risk of developing metachronous adenomas [20,23,25,29,43] and metachronous cancer [23,38] after surgery. Barrier and colleagues [23] reported 175 patients undergoing surveillance colonoscopy after curative CRC resection, 61 of whom had received complete preoperative colonoscopy. No metachronous cancers and nine adenomas (all < 10 mm) were detected in this subgroup, whereas three cancers and 35 adenomas (6 of 35 > 10 mm) were found in the subgroup without preoperative colonoscopy within 12 ± 6 months of surgery [23]. In Chen and Stuart’s report [25], 73% of patients with synchronous adenomas developed metachronous adenomas, compared with 52% of patients without synchronous adenomas. Additionally, all four patients with metachronous cancers had multiple synchronous adenomas [25]. A recent Italian multicenter study evaluated the incidence of neoplasms at the 1-, 3-, and 5-year colonoscopic follow-up of 318 patients after curative CRC resection [29]. Patients with synchronous neoplasms (including nonadvanced adenomas, advanced adenomas, and carcinomas) had a cumulative 5-year neoplastic incidence of 70%, compared with 30.2% in patients without synchronous neoplasms, a trend that was maintained after excluding lesions detected at the 1-year examination. A neoplastic lesion was detected more frequently in the group with synchronous lesions at 1 year (30.5% vs. 14.7%, P = 0.0013), 3 years (21.4% vs. 7.6%, P = 0.0008), and at 5 years (18.1% vs. 7.8%, P = 0.02) [29]. These data underscore the importance of adequate perioperative colonoscopy to detect and remove synchronous neoplasms in patients with CRC.

Perioperative clearing and postoperative surveillance

Metachronous neoplasm detection

Perioperative clearing The prevalence of synchronous cancers of the colon and rectum ranges from 1.6% to about 7% in patients with CRC [22,23,27,29,30,35,38]. Thus, complete colonoscopy to exclude synchronous tumors and to remove all visualized polyps is the critical first step in the management of patients with CRC. The examination is preferably performed preoperatively [3,41]; however, it can be deferred for 3– 6 months postoperatively if colonoscopy is not feasible due to complete malignant obstruction or other factors such as perforation [3,21]. Intraoperative colonoscopy is another, albeit not commonly used, option [21]. The emerging role of computed tomographic colonoscopy (CTC) in perioperative clearing is discussed in the section “Alternatives to colonoscopy.” Replacing preoperative colonoscopy by a postoperative examination has been proposed to avoid subjecting patients to multiple procedures;

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A major benefit of colonoscopy after CRC resection is the detection of intraluminal metachronous CRCs at a curable stage, and the detection and removal of precursor adenomatous polyps. It is estimated that about 1 in every 10 postoperative patients will develop an advanced adenoma or cancer, and up to 50% will develop a neoplasm (including nonadvanced adenomas, advanced adenomas, and invasive cancers) within 5 years of the initial surgery [29]. The majority of intraluminal metachronous cancers present at an early stage are asymptomatic, and re-resectable for cure [21]. The pooled data from the studies selected for this review show that 87 of 133 (65%) metachronous cancers were Dukes’ stage A or B [22,28,30,32, 37,38,40], 29 of 46 (63%) were asymptomatic [8,25,26,30,36], and 98 of 134 (73%) were reoperated with curative intent [8,9,22,25–27,30,32,38]. Metachronous intraluminal cancers are generally similar to index tumors in terms of distribution of tumor stages, histology, and degree of pathological differentiation [32]. The molecular and genetic features of

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metachronous cancers have not been well studied. One study found that the analysis of microsatellite instability (MSI) in sporadic cancers of the distal colon and rectum (but not proximal colon) may be predictive of the development of subsequent metachronous cancer [44]. These provocative findings await further study.

Surveillance intervals The cumulative incidence of metachronous cancers of the colon and rectum is estimated to be about 0.3–0.35% per year [21,28,45], and metachronous cancers can present at any time, even decades, after the index malignancy [8,11–13,22,25–33, 36–38,40]. Luchtefeld et al. [46] described 24 patients with metachronous colorectal cancer identified in an operative series of 707 patients, discovered at intervals ranging from 3 to 35 years. Sixteen (67%) metachronous lesions occurred 11 years or more after the original cancer [46]. Lan and colleagues [32] reported 43 metachronous tumors in a group of 3846 patients diagnosed at a range of 14 months to 20 years after curative surgery for CRC. Thus, postoperative surveillance with colonoscopy is indicated lifelong or at least until advanced age, or decreased life expectancy due to competing comorbidity, outweighs the benefit of continued surveillance. The incidence and timing of metachronous CRCs determine the optimal intervals at which surveillance colonoscopy should be performed [21]. As discussed previously, there is no direct evidence from randomized controlled trials to support the performance of annual colonoscopies for the detection of metachronous colon cancers. Extrapolation of data from the National Polyp Study has led to the development of clinical practice guidelines that generally recommended surveillance colonoscopy 3 and 5 years after surgery, provided an adequate clearing perioperative colonoscopy has been performed [3,7,47,48]. However, recent studies have shown an alarmingly elevated incidence of “early metachronous” CRCs, or cancers that are detected within the few years after surgery, despite seemingly adequate perioperative clearing [28]. In 2002, Green and colleagues [28] described a cohort of 3278 patients with resected stage II and III colon cancer who had participated in trial of 5-fluorouracil-based adjuvant chemotherapy (Intergroup 0089). There were 42 cases of second primary colon cancer over 15 345 person-years of follow-up, yielding an incidence rate of 274 per 100 000 person-years and a cumulative incidence of 1.5% at 5 years. These rates were significantly higher than those expected based on incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program (standardized incidence ratio 1.6, 95% CI 1.2–2.2) or the National Polyp Study (standardized incidence ratio 6.8, 95% CI 2.7–22.0). Of the 42 metachronous cancers, 24 were detected within the first 2 years after surgery, 19 had normal results on a surveillance procedure (15 colonoscopies) within 1 year of the original diagnosis, and 17 were detected

Colonoscopy after Colorectal Cancer Resection

at the first postoperative follow-up examination [28]. In the post-CRC resection studies included in this review, there were 213 (1.6%) metachronous cancers in 13 421 patients [8–13, 22–40,43], and more than one-third were detected within 2 years of resection for the index malignancy (Table 55.2). There are many possible reasons for the observed high incidence of early second primary cancers. The most straightforward explanation is that most of these tumors are actually synchronous cancers that were present at the time of the diagnosis of the index cancer but missed by perioperative clearing (missed synchronous cancers). Recent literature has highlighted the limitations of colonoscopy and its variable sensitivity for the detection of CRC and adenomatous polyps. Tandem colonoscopy studies have shown that the colonoscopy miss rate for large adenomas ranges from 0% to 6% [49,50], and the sensitivity of colonoscopy for CRC is 85–96% [51–53]. When CT colonography with segmental unblinding is used as the gold standard, the reported miss rates for optical colonoscopy are even higher and range from 12% to 17% [54,55]. The factors involved in the occurrence of so-called interval cancers (which develop between colonoscopic examinations, regardless of indication), are conceivably the same in the case of missed synchronous cancers and missed synchronous advanced adenomas: some lesions may be challenging to visualize because they are located in flexures or behind haustral folds [55], or detection with white-light technology may be difficult due to a flat or depressed morphology [56,57]. Incomplete polypectomy is an important factor, especially in the case of large sessile polyps that require piecemeal resection [58,59]. Incomplete polypectomy may also be a factor in cases in which visualized polyps are simply left behind because of an assumption that they will be removed during surgery, but they are actually far enough from the cancer that they are not included within the resection margins. This underscores the importance of complete removal of all polyps visualized during perioperative clearing colonoscopy, with the possible exception of polyps in the immediate vicinity of the index malignancy. Inadequate bowel preparation is associated with failed detection of small and large adenomas, and may be a factor in failure to detect small cancers [60]. An important issue affecting the sensitivity of colonoscopy is suboptimal technique and operator variability, and this is highlighted by substantial variability in the detection of large adenomas among gastroenterology subspecialists [61,62], and in the detection of CRC between gastroenterologists and primary care physicians [53]. These factors are interrelated and have considerable impact in clinical practice: in Platell et al.’s [39] study, 253 patients underwent colonoscopy 12 months after surgery, and advanced adenomas were identified in 7.9%, which is nearly twofold higher than expected. However, 65% of perioperative colonoscopies were performed outside the study center, and the reports were not available to the study authors [39,63]. Thus, difficulty with polyp visualization, incomplete polypectomy, poor bowel preparation, and

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suboptimal technique may all have contributed to the unusually high prevalence of advanced adenomas at the 1-year colonoscopic surveillance examination [63]. Another factor that may be involved in the occurrence of early metachronous CRCs is aggressive tumorigenesis with accelerated transformation from adenoma to invasive carcinoma [64]. This affects patients with HNPCC, polyposis syndromes, and inflammatory bowel disease and, as mentioned before, many of the studies included in this review do not specifically exclude patients with such conditions. Finally, the extent of patient and physician adherence to recommended surveillance guidelines is an important factor in the development of second primary cancers. Castells and colleagues studied the effect of patient compliance with postoperative surveillance (which included annual colonoscopy) on tumor recurrence, resectability, and survival [24]. Although there were no differences in overall recurrence rates between compliant and noncompliant patients, curative reoperation was possible in significantly more patients in the compliant subgroup than in the noncompliant one (34% vs. 12%, P = 0.05) [24]. Additionally, 5-year overall survival (63% vs. 37%, P < 0.001) and 5-year cancer-specific survival (69% vs. 49%, P < 0.02) were higher in the compliant cohort, and regression analysis revealed that advanced TNM stage and noncompliance were the only variables with an independent negative impact on survival [24]. Similarly, Eckardt et al. [26] found that 5-year survival was significantly higher in compliant patients than in noncompliant patients (80% vs. 59%, P < 0.0002), and noncompliance increased the risk of early death by a factor of 2.5. In the study by Green, more than half of the patients who presented with metachronous cancer 2 or more years after resection did not adhere to the surveillance protocol [64]. The alarmingly elevated incidence of apparently metachronous cancers in the first 2 years after resection has led the United States Multisociety Task Force (USMSTF) on Colorectal Cancer and the American Cancer Society (ACS) to develop updated, unified guidelines in 2006 [21]. These guidelines recommend a colonoscopy at 1 year after surgery (or after the perioperative clearing colonoscopy), in addition to high-quality perioperative clearing to exclude synchronous neoplasia [21]. Since the publication of the updated guidelines, new evidence has emerged that provides additional support for follow-up colonoscopy 1 year after resection. In a study conducted within a large health maintenance organization (HMO) in Washington state, 1002 patients who had undergone curative resection for CRC were evaluated for surveillance colonoscopy findings and survival [20]. Twenty patients (3.1%) were diagnosed with a second primary CRC, including nine cancers that were detected within 18 months of the initial cancer diagnosis. Additionally, patients who underwent colonoscopy within 18 months were less likely to have advanced neoplasia on subsequent surveillance than

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patients whose follow-up occurred between 30 and 60 months after surgery (6.9% vs. 15.5%, P = 0.02) [20]. The 5-year follow-up findings of Veterans Administration cooperative study no. 380 were similar [65]. In this prospective study, 3121 asymptomatic subjects aged 50–75 years underwent screening colonoscopy in the Department of Veterans Affairs between 1994 and 1997. Cohorts were defined according to baseline findings, with neoplasia-free patients serving as controls, and relative risks for advanced neoplasia within 5.5 years were calculated. The relative risk in patients with baseline adenoma with high-grade dysplasia was 6.87 (95% CI 2.61–18.07, P < 0.001), and 13.56 (95% CI 5.54–33.18, P < 0.001) in patients with baseline cancer. Fifteen of 21 (71%) interval cancers or adenomas with high-grade dysplasia were found in the first 36 months after baseline colonoscopy, and four were discovered within 12 months. Five cancers recurred in patients who had CRC at baseline, and four of five were detected within 18 months [65]. While early-occurring apparently metachronous cancers may represent missed synchronous cancers, it is often impossible in practice to distinguish between the two [21]. As stated by Green and colleagues [28], “missed synchronous cancer is relevant precisely because it was missed,” and the fact that metachronous and synchronous cancers are sometimes missed reflects the imperfect nature of perioperative clearing and postoperative surveillance colonoscopy.

Anastomotic recurrence detection In contrast to its established indication for metachronous neoplasm detection, colonoscopy is generally not recommended for the purpose of detection of intraluminal anastomotic recurrences, for several reasons. First, the yield of colonoscopy for anastomotic recurrences is low, and is estimated to range from 2% to 4% [17,21]. The pooled data from studies selected for this review reveal that 340 anastomotic recurrences were detected in 5407 patients (6%); however, this figure may be an overestimate because several studies did not separate intraluminal anastomotic recurrences from local and locoregional recurrences, and, in some instances, from metachronous cancers [8–13,22–24,26,27,30,31,33–37,39,40]. Second, anastomotic recurrences are generally accompanied by locally advanced or metastatic disease [9,23], and re-resection with curative intent is possible in only a minority of patients (91 of 267, 34%) [8–10,22–24,27,30,34,35,40]. Third, unlike metachronous cancers, most anastomotic recurrences are heralded by symptoms and few patients are diagnosed during routine surveillance: in studies which reported such data, only 28 of 157 patients (18%) were asymptomatic at the time of discovery of anastomotic cancer recurrence [8–10,23,24, 30,36]. An important distinction has to be made at this point between colon cancer and rectal cancer, because the latter has a higher propensity for local recurrence. In the studies compiled for this review which distinguished between the

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two types of cancer, 104 of 126 anastomotic recurrences (83%) involved patients with cancer of the rectum or distal colon [9,11,22,23,27,35,39,40]. The local recurrence rate of rectal cancer is largely dependent on surgical technique: blunt dissection of the rectal fascia is associated with recurrence rates up to 45% compared with less than 10% with total mesorectal excision, in which the rectum and mesorectal fascia (first plane outside the adventitia) are resected by precise sharp dissection [66]. In a study in which patients received neoadjuvant chemoradiation followed by total mesorectal excision, the rate of local recurrence was as low as 2.4%, which is similar to the anastomotic recurrence rate of nonrectal colon cancer [66]. Thus, in cases in which total mesorectal excision is not employed, there is a rationale for periodic examination of the rectum using rigid or flexible sigmoidoscopy and endoscopic ultrasound. The updated USMSTF–ACS guidelines recommend these examinations every 3–6 months for the first 2 or 3 years after surgery, in addition to colonoscopic surveillance for metachronous neoplasms [21]. The impact of this strategy on patient survival is not known.

Health outcomes and health care utilization Health outcomes Several retrospective studies using large administrative databases have studied the effect of post-CRC resection surveillance colonoscopy on all-cause and disease-specific mortality. Fisher and colleagues [67] used national VA administrative data to study 3546 veterans diagnosed with CRC in 1995 and 1996 (mean age 67.6 years), and developed a Cox proportional hazards model adjusting for demographics, comorbidities, and treatment. Among patients who received follow-up colonoscopy, 52% had their first follow-up colonoscopy within the first year, and 88% within 2 years. The risk of all-cause death was decreased by 43% in the group who had at least one follow-up colonoscopy compared with patients who had no follow-up colonoscopy; the absolute difference in the 5-year mortality rate was approximately 12%. Limitations of this study included limited information about health status (claims-based Charlson comorbidity index) and cancer stage (metastatic or not). Based upon a greater likelihood of treatment (radiation and chemotherapy) among the group receiving follow-up colonoscopy, the authors suggested that the colonoscopy group potentially had more advanced cancer, which would bias against a mortality benefit; an alternative explanation of the findings would be that healthier patients, who were more likely to benefit from both treatment and follow-up colonoscopy, were included in the colonoscopic surveillance group. Ramsey and colleagues used SEER-Medicare data, which links cancer registry information with administrative claims, to perform a retrospective case–control study [68]. In their

Colonoscopy after Colorectal Cancer Resection

analysis, they included 8130 patients who died of CRC and 20 079 matched control subjects with CRC who did not die of CRC; all patients were diagnosed with local or regional stage disease between 1986 and 1996. In this Medicare population, 78% of patients were 75 years of age or older. Among those with at least one bowel surveillance procedure, the average time to first procedure was 16 months after diagnosis. Logistic regression models were performed controlling for race, comorbidity (claims-based Charlson index), and initial treatment (radiation, chemotherapy, or a combination). Surveillance endoscopy was not associated with improved colorectal cancerspecific survival (OR = 1.01; 95% CI 0.95–1.06); however, surveillance was associated with improved survival when considering all-cause mortality (OR = 0.62; 95% CI 0.60–0.65). Limitations of this study included an elderly population that does not generalize to all CRC patients as well as the inability to distinguish symptom-based diagnostic colonoscopy from routine surveillance, a problem common to most claims-based research. However, this latter bias would likely make surveillance appear worse, with increased mortality; to address the issue, the investigators excluded procedures occurring immediately after diagnosis and 6 months prior to censoring events, including death. The studies of both Fisher et al. and Ramsey et al. demonstrated a reduction in all-cause mortality with colonoscopic surveillance. Again, one possible explanation for this common finding is that physicians do not perform surveillance procedures on patients with an unmeasured illness burden that limits life expectancy, although both studies adjusted for comorbidity using a claims-based Charlson index, which, while imperfect, has been associated with 2-year noncancer mortality in other cancer populations [69]. A potential explanation for the discordant findings in the Ramsey et al. study between disease-specific and all-cause mortality is an observational variant of “sticky diagnosis” bias, i.e., deaths from other causes in the surveillance group are falsely attributed to disease, so that disease-specific mortality is reportedly higher in the screened group even though screening is effective [4]. Rulyak and colleagues [20] performed another outcomes study of colon surveillance [colonoscopy (97%) or sigmoidoscopy and barium enema] using automated clinical records from 1002 colorectal cancer patients enrolled in a health maintenance organization (HMO) and diagnosed with local or regional CRC between 1993 and 1999. Most patients (78%) were 60 years of age or older. Among patients who received follow-up colonoscopy, 74% had their first follow-up colonoscopy within 18 months and 91% within 36 months. Colon surveillance was associated with decreased all-cause mortality (hazards ratio = 0.58; 95% CI 0.44–0.75) after adjusting for age, gender, race, American Joint Committee on Cancer stage (unlike the Fisher study), tumor site (colon vs. rectum), Charlson comorbidity index, and treatment. Limitations of

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the study included many of those already mentioned in relation to the Fisher et al. and Ramsey et al. studies, including potential unmeasured comorbid illness and the uncertainty about whether colonoscopies represented routine surveillance or symptomatic examinations. Overall, these observational studies [20,67,68] provide early evidence that patients who receive surveillance colonoscopy have improved overall mortality. Concerns about unmeasured comorbidity leading to physicians selecting healthier patients for surveillance likely represent the greatest threat to these studies’ external validity. The lack of reduction in disease-specific mortality in the Ramsey study raises questions about what the mechanism of any mortality reduction associated with colonoscopy may be, although Rulyak and others provide pathologic evidence of a plausible biologic pathway. Future observational studies would benefit from careful measurement of comorbid illness among representative populations, potentially by supplementing administrative claims with electronic medical record data. Randomized controlled trials isolating the effect of colonoscopy would clearly add further to the existing evidence of mortality benefit.

Health care utilization Several studies using large administrative databases have investigated patterns of utilization of surveillance endoscopy among CRC patients undergoing curative-intent surgery. Among the veterans studied by Fisher et al. and diagnosed with CRC between 1995 and 1996, 64% had one or more follow-up colonoscopies over a median follow-up period of 5 years [67]. Among 52 283 patients aged 65 or over with Medicare coverage and diagnosed with CRC between 1986 and 1996, 54% did not receive bowel surveillance (colonoscopy, flexible sigmoidoscopy, or barium enema) within 14 months of curative surgery and 17% received no surveillance at all [70]. In this cohort, elderly blacks were less likely than non-Hispanic whites to receive bowel surveillance [71]. Cooper and Payes [72] performed a retrospective cohort study using SEER-Medicare data and identified 62 882 CRC patients who were followed up for 1 year and 35 784 who were followed up for 3 years. Colonoscopy within 1 year was performed in 25.9% of patients, within 18 months in 53.8%, and within 3 years in 70.3%; thus, more than 25% of patients who underwent curative treatment did not receive surveillance colonoscopy. Other patterns of care studies examining colon surveillance among CRC survivors have been done in the setting of HMOs. Among the HMO enrollees studied by Rulyak and colleagues with CRC diagnosed between 1993 and 1999, colon surveillance was performed in 61% of patients within 18 months of diagnosis and in 80% of patients within 5 years of diagnosis; there was a trend toward lower utilization among African-American patients (relative risk = 0.70; P = 0.14). A study in another large urban HMO described 251 patients age ≥ 40 diagnosed with CRC from 1990 to 1995 and found that,

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within 18 months of treatment, 55% of patients received bowel surveillance [73].

Alternatives to colonoscopy While colonoscopy is the procedure of choice for perioperative clearing and for the detection of metachronous neoplasms after CRC resection, there are alternative modalities which may be considered in specific settings, and emerging technologies may provide additional options in the future. Double-contrast barium enema is inferior to colonoscopy for the detection of polyps and it is generally reserved for perioperative clearing in cases of malignant obstruction [21]. CT colonography and MR colonography are also options for perioperative clearing and postoperative surveillance [74–77]; however, neither modality has been adequately studied in this setting [21]. Guaiac-based fecal occult blood testing (FOBT) has poor positive predictive value after clearing colonoscopy (about 10–30% for local recurrences and metachronous cancers) and is not recommended as a routine component of follow-up [3,21]. Fecal DNA testing has not been studied in the setting of post-CRC resection surveillance. Immunochemical fecal occult blood testing (i-FOBT) appears to improve the yield of colonoscopy in patients with a history of colonic neoplasia [78]. In one study, 611 patients with resected CRC underwent i-FOBT and colonoscopy. Fifty-nine (13.6%) were categorized as i-FOBT-positive. Of these, nine had biopsy-proven recurrent or metachronous cancer, 12 patients had one or more adenomatous polyps, one patient had radiation proctitis, and two patients had pancolonic mucositis following chemotherapy. In the remaining 552 i-FOBT-negative patients, no cancers were found. Thirty-eight patients had polyps that were removed. The sensitivity and specificity for detecting cancer by immunological FOBT was 100%, and sensitivity and specificity for detecting adenomatous polyps was 24% and 93%, respectively [37].

Evaluation of the anastomosis Besides its role in perioperative clearing and postoperative surveillance for neoplasms, colonoscopy is the procedure of choice to evaluate the anastomosis. One study reported 117 consecutive colonoscopies in patients with colonic anastomosis which were prospectively studied during a 12-month period [79]. Nine common anastomotic features were identified: neovascularity, 105 (89.7%); white anastomotic edge, 64 (54.7%); disruption of haustral pattern, 64 (54.7%); radial suture tracks, 35/92 (38.0%); exposed suture, 11/92 (11.9%); exposed staples, 6/25 (24%); scar tissue adjacent to anastomotic line, 8 (6.8%); non-distensibility of the anastomosis, 5 (4.3%); blind colonic pouch, 10 (8.5%). No recurrent carcinomas were

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noted. In three of four patients who required dilation because of strictures, neovascularity was not seen, leading the authors to conclude that the lack of neovascularity at a colonic anastomosis may be an indicator of relative ischemia, predisposing to stricture formation [79]. In another report, inflammatory polyps at the anastomosis were the most common abnormality [80]. Recurrent cancer usually appears as ulcerated submucosal lesions, bulky luminal masses, or polypoid lesions; rarely, mucosal erythema, edema, and friability are the only clues to an underlying malignancy [81]. Benign strictures may occur at the anastomosis in up to 22% of patients after colorectal resections [81]. Pneumatic dilation is effective to resolve symptoms in most patients, although complications including bleeding and perforation can occur in up to 8% of cases [82– 84]. Adjunctive therapies such as incision with an endoscopic needle knife, or laser therapy, have been used in addition to pneumatic dilation for refractory strictures [85,86]. Although bougienage has been used to treat postoperative colonic strictures (especially in patients with low anterior resections [87]), pneumatic dilation is generally preferred because of better effectiveness [88].

Patients with a colostomy Patients may have a diverting colostomy for protection of a distal anastomosis. This colostomy is typically a loop of bowel with two limbs, proximal and distal. If colonoscopy is performed prior to closure of the colostomy to exclude synchronous lesions, then both limbs must be intubated. The preparation is similar to that for an intact colon, but irrigation into the distal limb may be required or enemas per rectum can be administered to cleanse that portion. Intubation of both limbs can be accomplished with the patient supine, but the left lateral position may afford the best visualization of the rectum. If the colostomy is an end colostomy, it is necessary to know whether the rectum and anus have been resected or whether there is a segment of rectum that has been closed and left in situ (Hartmann pouch). End colostomies can be prepped and intubated as above, but inspection of the rectal segment can usually be accomplished without the requirement for enemas since that blind pouch is not in continuity with the fecal stream [81]. Postresection surveillance principles and guidelines are the same for patients with a colostomy as for those with reanastomosed large bowel. Diversion colitis may occur in segments of the colon that have been diverted from the fecal stream by surgery. This condition resembles inflammatory bowel disease, and most affected patients are asymptomatic. When symptoms occur, they are usually mild and may include rectal bleeding, tenesmus, mucus discharge, and abdominal pain [89]. Diversion colitis likely results from a deficiency of short-chain fatty acids (SCFAs) in the diverted segment [90], and restoration of bowel continuity is curative. Irrigation with SCFA enemas is an alternative in patients

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who have symptoms and who are not candidates for surgical restoration of bowel continuity [90]; however, SCFAs have a very offensive smell, which limits their use.

References 1 Jeffery M, Hickey BE, Hider PN. Follow-up strategies for patients treated for non-metastatic colorectal cancer. Cochrane Database Syst Rev (Online) 2007(1): CD002200. 2 Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA: a Cancer Journal for Clinicians 2007; 57: 43– 66. 3 Anthony T, Simmang C, Hyman N, et al. Practice parameters for the surveillance and follow-up of patients with colon and rectal cancer. Dis Colon Rectum 2004; 47: 807–17. 4 Pfister DG, Benson AB 3rd, Somerfield MR. Clinical practice. Surveillance strategies after curative treatment of colorectal cancer. N Engl J Med 2004; 350: 2375– 82. 5 Easson AM, Cotterchio M, Crosby JA, et al. A population-based study of the extent of surgical resection of potentially curable colon cancer. Ann Surg Oncol 2002; 9: 380–7. 6 Goldberg RM, Fleming TR, Tangen CM, et al. Surgery for recurrent colon cancer: strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 1998; 129: 27–35. 7 Desch CE, Benson AB 3rd, Somerfield MR, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2005; 23: 8512–19. 8 Kjeldsen BJ, Kronborg O, Fenger C, Jorgensen OD. A prospective randomized study of follow-up after radical surgery for colorectal cancer. Br J Surg 1997; 84: 666– 9. 9 Makela JT, Laitinen SO, Kairaluoma MI. Five-year follow-up after radical surgery for colorectal cancer. Results of a prospective randomized trial. Arch Surg 1995; 130: 1062–7. 10 Ohlsson B, Breland U, Ekberg H, Graffner H, Tranberg KG. Follow-up after curative surgery for colorectal carcinoma. Randomized comparison with no follow-up. Dis Colon Rectum 1995; 38: 619– 26. 11 Pietra N, Sarli L, Costi R, Ouchemi C, Grattarola M, Peracchia A. Role of follow-up in management of local recurrences of colorectal cancer: a prospective, randomized study. Dis Colon Rectum 1998; 41: 1127–33. 12 Rodriguez-Moranta F, Salo J, Arcusa A, et al. Postoperative surveillance in patients with colorectal cancer who have undergone curative resection: a prospective, multicenter, randomized, controlled trial. J Clin Oncol 2006; 24: 386–93. 13 Schoemaker D, Black R, Giles L, Toouli J. Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 1998; 114: 7–14. 14 Secco GB, Fardelli R, Gianquinto D, et al. Efficacy and cost of riskadapted follow-up in patients after colorectal cancer surgery: a prospective, randomized and controlled trial. Eur J Surg Oncol 2002; 28: 418– 23. 15 Wattchow DA, Weller DP, Esterman A, et al. General practice vs surgical-based follow-up for patients with colon cancer: randomised controlled trial. Br J Cancer 2006; 94: 1116–21.

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34 McFarland RJ, Becciolini C, Lallemand RC. The value of colonoscopic surveillance following a diagnosis of colorectal cancer or adenomatous polyp. Eur J Surg Oncol 1991; 17: 514–8. 35 Obrand DI, Gordon PH. Incidence and patterns of recurrence following curative resection for colorectal carcinoma. Dis Colon Rectum 1997; 40: 15–24. 36 Patchett SE, Mulcahy HE, O’Donoghue DP. Colonoscopic surveillance after curative resection for colorectal cancer. Br J Surg 1993; 80: 1330– 2. 37 Skaife P, Seow-Choen F, Eu KW, Tang CL. A novel indicator for surveillance colonoscopy following colorectal cancer resection. Colorectal Dis 2003; 5: 45–8. 38 Togashi K, Konishi F, Ozawa A, et al. Predictive factors for detecting colorectal carcinomas in surveillance colonoscopy after colorectal cancer surgery. Dis Colon Rectum 2000; 43(Suppl. 10): S47–53. 39 Platell C, Salama P, Barwood N, Makin G. Performing a colonoscopy 12 months after surgery for colorectal neoplasia. ANZ J Surg 2005; 75: 282–5. 40 Stigliano V, Fracasso P, Grassi A, et al. Endoscopic follow-up in resected colorectal cancer patients. J Exp Clin Cancer Res 2000; 19: 145– 8. 41 Tate JJ, Rawlinson J, Royle GT, Brunton FJ, Taylor I. Pre-operative or postoperative colonic examination for synchronous lesions in colorectal cancer. Br J Surg 1988; 75: 1016–18. 42 Barlow AP, Thompson MH. Colonoscopic follow-up after resection for colorectal cancer: a selective policy. Br J Surg 1993; 80: 781–4. 43 Kronborg O, Hage E, Deichgraeber E. The remaining colon after radical surgery for colorectal cancer. The first three years of a prospective study. Dis Colon Rectum 1983; 26: 172–6. 44 Masubuchi S, Konishi F, Togashi K, et al. The significance of microsatellite instability in predicting the development of metachronous multiple colorectal carcinomas in patients with nonfamilial colorectal carcinoma. Cancer 1999; 85: 1917–24. 45 Cali RL, Pitsch RM, Thorson AG, et al. Cumulative incidence of metachronous colorectal cancer. Dis Colon Rectum 1993; 36: 388– 93. 46 Luchtefeld MA, Ross DS, Zander JD, Folse JR. Late development of metachronous colorectal cancer. Dis Colon Rectum 1987; 30: 180– 4. 47 Benson AB 3rd, Desch CE, Flynn PJ, et al. 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 2000; 18: 3586– 8. 48 Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationaleaUpdate based on new evidence. Gastroenterology 2003; 124: 544–60. 49 Hixson LJ, Fennerty MB, Sampliner RE, Garewal HS. Prospective blinded trial of the colonoscopic miss-rate of large colorectal polyps. Gastrointest Endosc 1991; 37: 125–7. 50 Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997; 112: 24–8. 51 Brady AP, Stevenson GW, Stevenson I. Colorectal cancer overlooked at barium enema examination and colonoscopy: a continuing perceptual problem. Radiology 1994; 192: 373–8. 52 Bressler B, Paszat LF, Vinden C, Li C, He J, Rabeneck L. Colonoscopic miss rates for right-sided colon cancer: a population-based analysis. Gastroenterology 2004; 127: 452– 6.

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53 Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997; 112: 17–23. 54 Van Gelder RE, Nio CY, Florie J, et al. Computed tomographic colonography compared with colonoscopy in patients at increased risk for colorectal cancer. Gastroenterology 2004; 127: 41– 8. 55 Pickhardt PJ, Nugent PA, Mysliwiec PA, Choi JR, Schindler WR. Location of adenomas missed by optical colonoscopy. Ann Intern Med 2004; 141: 352– 9. 56 Rembacken BJ, Fujii T, Cairns A, et al. Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 2000; 355: 1211–14. 57 Saitoh Y, Waxman I, West AB, et al. Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology 2001; 120: 1657– 65. 58 Binmoeller KF, Bohnacker S, Seifert H, Thonke F, Valdeyar H, Soehendra N. Endoscopic snare excision of “giant” colorectal polyps. Gastrointest Endosc 1996; 43: 183– 8. 59 Brooker JC, Saunders BP, Shah SG, Williams CB. Endoscopic resection of large sessile colonic polyps by specialist and nonspecialist endoscopists. Br J Surg 2002; 89: 1020– 4. 60 Rex DK. Maximizing detection of adenomas and cancers during colonoscopy. Am J Gastroenterol 2006; 101: 2866–77. 61 Barclay RL, Vicari JJ, Doughty AS, Johanson JF, Greenlaw RL. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med 2006; 355: 2533– 41. 62 Chen SC, Rex DK. Endoscopist can be more powerful than age and male gender in predicting adenoma detection at colonoscopy. Am J Gastroenterol 2007; 10: 856– 61. 63 Ee HC, Yusoff IF. Colonoscopic surveillance after curative surgery for colorectal cancer. ANZ J Surg 2005; 75: 257– 8. 64 Limburg PJ, Ahlquist DA. Second primary colorectal cancer: the consequence of management failure at several potential levels. Ann Intern Med 2002; 136: 335–7. 65 Lieberman DA, Weiss DG, Harford WV, et al. Five-year colon surveillance after screening colonoscopy. Gastroenterology 2007; 133: 1077– 85. 66 Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638– 46. 67 Fisher DA, Jeffreys A, Grambow SC, Provenzale D. Mortality and follow-up colonoscopy after colorectal cancer. Am J Gastroenterol 2003; 98: 901– 6. 68 Ramsey SD, Howlader N, Etzioni R, Brown ML, Warren JL, Newcomb P. Surveillance endoscopy does not improve survival for patients with local and regional stage colorectal cancer. Cancer 2007; 109: 2222– 8. 69 Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol 2000; 53: 1258– 67. 70 Knopf KB, Warren JL, Feuer EJ, Brown ML. Bowel surveillance patterns after a diagnosis of colorectal cancer in Medicare beneficiaries. Gastrointest Endosc 2001; 54: 563–71. 71 Ellison GL, Warren JL, Knopf KB, Brown ML. Racial differences in the receipt of bowel surveillance following potentially curat-

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ive colorectal cancer surgery. Health Services Res 2003; 38: 1885– 903. Cooper GS, Payes JD. Temporal trends in colorectal procedure use after colorectal cancer resection. Gastrointest Endosc 2006; 64: 933– 40. Elston Lafata J, Simpkins J, et al. Routine surveillance care after cancer treatment with curative intent. Med Care 2005; 43: 592–9. Choi YJ, Park SH, Lee SS, et al. CT colonography for follow-up after surgery for colorectal cancer. AJR 2007; 189: 283–9. Leonardou P, Striggaris K, Pappas P, et al. Screening of patients after colectomy: virtual colonography. Abdominal Imaging 2006; 31: 521–8. Titu LV, Nicholson AA, Hartley JE, Breen DJ, Monson JR. Routine follow-up by magnetic resonance imaging does not improve detection of resectable local recurrences from colorectal cancer. Ann Surg 2006; 243: 348–52. Wong TY, Lam WW, So NM, Lee JF, Leung KL. Air-inflated magnetic resonance colonography in patients with incomplete conventional colonoscopy: Comparison with intraoperative findings, pathology specimens, and follow-up conventional colonoscopy. Am J Gastroenterol 2007; 102: 56–63. Bampton PA, Sandford JJ, Cole SR, et al. Interval faecal occult blood testing in a colonoscopy based screening programme detects additional pathology. Gut 2005; 54: 803–6. Harris MT, Laudito A, Waye JD. Colonoscopic features of colonic anastomoses. Gastrointest Endosc 1994; 40: 554–7. Weinstock LB, Shatz BA. Endoscopic treatment of a colonic anastomotic mucosal bridge. Gastrointest Endosc 1994; 40: 773–4. Rossini FP, Waye JD. Colonoscopy after colon cancer resection. In: Waye JD and Williams CB (eds.). Colonoscopy: Principles and Practice. Oxford: Blackwell Publishing, 2003: 468–77. Aston NO, Owen WJ, Irving JD. Endoscopic balloon dilatation of colonic anastomotic strictures. Br J Surg 1989; 76: 780–2. Kozarek RA. Hydrostatic balloon dilation of gastrointestinal stenoses: a national survey. Gastrointest Endosc 1986; 32: 15–19. Venkatesh KS, Ramanujam PS, McGee S. Hydrostatic balloon dilatation of benign colonic anastomotic strictures. Dis Colon Rectum 1992; 35: 789– 91. Hagiwara A, Togawa T, Yamasaki J, Shirasu M, Sakakura C, Yamagishi H. Endoscopic incision and balloon dilatation for cicatricial anastomotic strictures. Hepato-gastroenterol 1999; 46: 997–9. Luck A, Chapuis P, Sinclair G, Hood J. Endoscopic laser stricturotomy and balloon dilatation for benign colorectal strictures. ANZ J Surg 2001; 71: 594–7. Werre A, Mulder C, van Heteren C, Bilgen ES. Dilation of benign strictures following low anterior resection using Savary-Gilliard bougies. Endoscopy 2000; 32: 385– 8. Pietropaolo V, Masoni L, Ferrara M, Montori A. Endoscopic dilation of colonic postoperative strictures. Surg Endosc 1990; 4: 26–30. Whelan RL, Abramson D, Kim DS, Hashmi HF. Diversion colitis. A prospective study. Surg Endosc 1994; 8: 19–24. Harig JM, Soergel KH, Komorowski RA, Wood CM. Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 1989; 320: 23–8.

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Pediatric Colonoscopy Marsha Kay & Robert Wyllie Cleveland Clinic, Cleveland, OH, USA

Colonoscopy is frequently performed by pediatric endoscopists. The indications for the procedure and procedure technique differ significantly when compared with colonoscopy in adults. In addition, pediatric patients require modification of sedation and preparation regimens. The advantage of having trained and dedicated pediatric gastrointestinal endoscopists is their familiarity not only with age-related anatomy and physiology, but also with the spectrum of disease in pediatric patients.

Personnel and facilities Specially trained pediatric endoscopy assistants are an important component of the endoscopy team. Procedure anxiety can be diminished by an assistant who has previously met the child and parent(s), explained the procedure, and greeted them in the endoscopy suite. The same person can hold and reassure the child throughout the procedure. If anesthesia is used, that person can help obtain and process tissue during the procedure and assist with other equipment needs but, if the patient is under conscious sedation, a second assistant is required [1]. Psychological preparation prior to colonoscopy has been shown to reduce procedure-related anxiety, improve patient cooperation, decrease autonomic nervous system stimulation during the procedure, and reduce the amount of sedation required [2]. Physicians performing endoscopy on infants and children should ideally have completed a pediatric gastroenterology fellowship or have experience with pediatric gastrointestinal diseases and adequate training in pediatric endoscopy [3]. Guidelines for procedure competency have been established by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the American Society for Gastrointestinal Endoscopy [4–6].

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

Sedation Routine endoscopy in infants and children is frequently typically performed in an outpatient setting using parenteral sedation. Intravenous sedation should be used only by physicians competent in administration of drugs and certified in resuscitation in children. Continuous cardiopulmonary monitoring including pulse oximetry should be the standard of care during endoscopic procedures and in the recovery phase, and appropriately sized resuscitation equipment should be available [7]. As with any sedation schema, there is a continuum from conscious sedation to deep sedation to general anesthesia, and the progression through this continuum may be especially rapid in pediatric patients. Physicians administering sedation should be familiar with the three levels of sedation in children and have appropriate credentialing. Most pediatric endoscopists use a combination of a benzodiazepine such as midazolam and a narcotic such as meperidine or fentanyl for conscious sedation [8,9]. A variety of other agents such as ketamine/midazolam have also been used in pediatric patients [10–14]. Oral midazolam premedication prior to conscious sedation has been shown to be effective in some pediatric series [15]. Transient reactions to the various medications administered are similar to those that occur in adults and are discussed elsewhere (Chapter 9). Medication dosage adjustment is required in neurologically impaired patients, those with underlying cardiopulmonary disease, and in patients who have recently lost weight, such as patients with inflammatory bowel disease, malignancy, or anorexia nervosa, in whom the volume of drug distribution may be altered. Naloxone is indicated only for narcotic-induced respiratory depression, because its use is usually associated with marked irritability in infants and young children. Routine administration of flumazenil after endoscopy appears to be of questionable benefit in pediatric patients because of the risk of resedation and its side-effect profile [16]. The reader is referred to other sources for recommended doses of intravenous sedation medications and reversal agents in pediatric patients [1,13]. Large pediatric series have reported on the efficacy and safety of parenteral sedation with combined minor and major

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complication rates of less than 0.5% for both esophagogastroduodenoscopy (EGD) and colonoscopy [8,9,17]. Some pediatric endoscopists prefer to utilize the services of pediatric anesthesiologists to administer sedation [12,18–20]. Currently, propofol is considered a sedative anesthetic and requires administration by an anesthesiologist. More invasive or therapeutic procedures such as polypectomy, percutaneous endoscopic cecostomy, dilation of strictures, and therapeutic endoscopy for gastrointestinal bleeding or procedures in whom patient cooperation cannot be anticipated, such as younger patients or neurologically impaired patients, are more likely to be performed using the assistance of an anesthesiologist.

Equipment Colonoscopy in infants is usually performed with instruments designed for upper endoscopy because of their smaller diameter. Polypectomy snares can be passed via a standard sized upper endoscope with a 2.8-mm channel. Colonoscopy using an upper endoscope may be more challenging due to different flexibility characteristics of the endoscope. Colonoscopy in normally developed children over 2–3 years of age is usually performed with a pediatric colonoscope. Pediatric colonoscopes, including those with variable stiffness capabilities, have a distal end with an outer diameter in the range of 11.3–11.6 mm with a 3.2- to 3.8-mm channel compared with an outer diameter of 12.8 mm for adult colonoscopes (endoscope information courtesy of Olympus America Inc., Melville, NY, USA, and Pentax Precision Instrument Corporation, Orangeburg, NY, USA). Variable-stiffness colonoscopes are available for use in older pediatric patients. However, variable stiffening of the endoscope should be used with caution and should not be used to replace good endoscopic technique, which emphasizes avoidance of loop formation and rapid loop reduction.

Figure 56.1 Endoscopic appearance of ulcerative colitis in an adolescent patient. Note loss of normal vascular appearance of the colon, superficial ulceration and marked friability.

Indications The indications for colonoscopy vary with the age of the pediatric patient. The major indications in infants and children include rectal bleeding, unexplained diarrhea, and abdominal pain associated with abnormal growth, weight loss, or other constitutional symptoms [1,21,22]. Colonoscopy is also performed to investigate abnormalities identified by radiographic studies. Colonoscopy is typically the initial investigation for patients with suspected mucosal disease. If inflammatory bowel disease is suspected, endoscopy provides visual evidence of the nature and extent of disease, and biopsies obtained at the time of the procedure may define the nature of the underlying inflammation (Figures 56.1 and 56.2). Infectious colitis may be difficult to distinguish visually from inflammatory bowel disease of recent onset, both visually and histologically, especially in patients less than 10 years of age [23,24]. Crohn’s

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Figure 56.2 Crohn’s disease of the colon in a teenager. In distinction to ulcerative colitis, the colonic mucosa is nodular with deep ulcerations, overlying exudate and pseudopolyp formation.

disease involving only the colon may also present with a focal active colitis pattern of injury similar to that seen with infection. Some patients may require follow-up endoscopic examination with biopsy to establish evidence of chronicity prior to establishing the diagnosis of inflammatory bowel disease. Visualization and biopsy of the terminal ileum may be helpful in the diagnosis of infectious ileitis. In some infections, such as ileocecal tuberculosis, colonic schistosomiasis, and amebiasis, stool cultures are usually negative but the organisms can be identified on biopsy specimens or cytologic brushing. Pinworm

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Figure 56.3 Endoscopic appearance of Enterobius vermicularis noted incidentally at endoscopy. The worms are typically mobile at the time of the endoscopy and may be numerous as shown.

infection may be identified at colonoscopy as the small motile worms are readily seen endoscopically (Figure 56.3), although colonoscopy is not the preferred method of diagnosis. Lymphonodular hyperplasia of the colon, although not an indication for colonoscopy, may be a cause of painless rectal bleeding identified at endoscopy. Thinning of the surface epithelium over the protruding lymphatic tissue with subsequent trauma from the passage of fecal material is thought to lead to ulceration and hematochezia. Prominent lymphatic nodules can be found throughout the large and small bowel in healthy pediatric patients (Figure 56.4). They appear as smooth,

Pediatric Colonoscopy

round 2- to 4-mm nodules with normal overlying mucosa. Occasionally larger nodules may have central umbilication or overlying erosion. This nodular lymph node tissue is thought to represent a self-limited response to antigenic stimulation and does not require any additional evaluation or therapy. In children with suspected polyps, colonoscopy is both diagnostic and therapeutic. In diseases associated with an increased rate of malignancy, such as ulcerative colitis, Crohn’s disease, or familial polyposis, colonoscopic surveillance for dysplastic changes is usually performed at regular intervals. Colonoscopy has been reported for diagnosis and evaluation of smooth muscle tumors in children with acquired immunodeficiency syndrome. These lesions may appear as a submucosal nodule with central umbilication [25]. Colonoscopy is usually not indicated in children complaining of chronic abdominal pain or constipation with unremarkable physical examinations and laboratory studies because of the infrequent occurrence of colon cancer in the pediatric age group. However, changes of mucosal prolapse in patients with chronic constipation may be identified at endoscopy. Indications for therapeutic colonoscopy in pediatric patients include polypectomy, vascular ablation, retrieval of a foreign body, placement of a percutaneous cecostomy tube (PEC), and colonic decompression in toxic megacolon. Colonoscopy with therapeutic intervention for vascular lesions can eliminate the need for surgery in some cases. Lesions encountered in childhood include cavernous hemangiomas and small telangiectasias. Syndromes associated with vascular lesions in the gastrointestinal tract which may present in the pediatric age group include Osler–Weber–Rendu, CREST syndrome (calcinosis cutis, Raynaud’s phenomenon, sclerodactyly, and telangiectasis), dyschondroplasia (Maffucci’s syndrome), blue rubber bleb nevus syndrome, diffuse neonatal hemangiomatosis, Turner’s syndrome, and pseudoxanthoma elasticum. Colonic strictures can also be dilated through the endoscope using through the channel-controlled external diameter balloon dilators. Intussusception has been identified and reduced during colonoscopy, but air–contrast reduction remains the procedure of choice if this condition is suspected. Colonoscopy has been used as an alternative to surgery to direct colonic Gastrografin administration in patients with cystic fibrosis and distal intestinal obstruction syndrome refractory to medical therapy [26]. Only practitioners with adequate experience should undertake technically advanced therapeutic endoscopic procedures in pediatric patients.

Contraindications

Figure 56.4 Lymphonodular hyperplasia of the terminal ileum in a pediatric patient. Although nodular, the overlying mucosa is smooth and glistening with no evidence of ulceration. This appearance is normal in children and adolescents.

Contraindications to pediatric colonoscopy are similar to those in adults. Absolute contraindications include suspected perforation of the intestine and peritonitis in a toxic patient. Relative contraindications include patients who are severely neutropenic or have bleeding disorders and children with

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a recent history of bowel surgery. In addition, patients with connective tissue disease, especially Ehlers–Danlos and Marfan’s syndromes, are at increased risk of perforation during endoscopy [27]. Toxic dilation of the bowel carries an increased risk of perforation during colonoscopy, although the procedure may relieve the distension. Other relative contraindications include partial or complete bowel obstruction.

Antibiotic prophylaxis Antibiotic prophylaxis for pediatric colonoscopic procedures should be administered according to the current guidelines of the American Heart Association [28]. Antibiotic prophylaxis is also discussed in Chapter 7.

Preparation In addition to an age-appropriate period of fasting or dietary modification, successful colonoscopy in children and adolescents requires a colon that is free of fecal debris. Many bowel preparations have been used to successfully cleanse the colon in pediatric patients [1,29–32]. The method depends on the age and cooperation of the child, the individual experience of the examiner, and the safety profile of the bowel preparation. In infants who are totally breast or bottle fed, adequate preparation can usually be obtained with the use of small-volume enemas and substituting clear liquids for breast or bottle feeding for 12–24 h. In older children and adolescents, the best preparation is usually obtained with the use of colonic lavage solutions that contain a nonabsorbable solution of polyethylene glycol and electrolytes (PEG-ELS), which causes an osmotic diarrhea [30]. The risk of dehydration is minimal because of the limited transmural flux of sodium and water. To be effective, a large volume of solution must be ingested over a relatively short period of time. In adolescents of adult size, the usual regimen is 240 mL every 10 min until the fecal effluent is clear. This often requires 3 or 4 L of solution. Appropriate volume reductions can be made for infants and smaller children and, occasionally, nasogastric administration may be necessary. A combination of oral bisacodyl and PEG-ELS is commercially available and can reduce the volume of the PEG-ELS solution that is required for an adequate clean-out [33,34]. This may be particularly beneficial in pediatric patients, who may experience greater difficulty taking a standard adult preparation. A progressive 4-day regimen of nonabsorbable PEG without electrolytes and dietary modification has also been shown to be an effective preparation in pediatric patients undergoing colonoscopy [35]. Minor electrolyte changes may be noted with this regimen. For children unable to tolerate a large-volume lavage preparation, some endoscopists will use an alternative regimen of clear liquids for 48–72 h accompanied by magnesium citrate the night

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before the procedure and saline enemas administered the night before and the morning of the procedure to clear any residual stool [1]. As in adults, there have been concerns regarding the use of oral sodium phosphate bowel preparations [36–38]. While effective, there are a number of case reports of serious adverse effects, primarily related to inappropriate dosing, inappropriate patient selection, or noncompliance with the prescribed regimen of medication dilution or administration of additional fluids [39,40]. The cathartic effects of oral sodium phosphate may result in significant hypovolemia and electrolyte abnormalities [41]. Extra caution must be used in patients vulnerable to minor shifts in intravascular volume or transient increases in serum phosphate [40,41]. Aphthous ulcerations of the colon have been observed following sodium phosphate bowel preparation. Current consensus guidelines, literature review, and manufacturer’s and Food and Drug Administration (FDA) recommendations should be carefully followed if these types of bowel preparations are utilized in patients ≤ 18 years of age [6,37].

Technique Colonoscopy and terminal ileal intubation Colonoscopy in pediatric patients utilizing conscious sedation is traditionally performed in the left lateral decubitus position with knees bent. To facilitate passage of the colonoscope to the right side of the colon, some endoscopists elect to turn the patient to the supine position during the procedure. Procedures being performed under general anesthesia may be more easily accomplished with patients supine with their legs bent in a frog leg position. The fundamentals of colonoscopy in children are similar to those in adults: (1) advance the endoscope under direct observation; (2) use as little air as possible while maintaining adequate visualization; (3) avoid forming loops, but when loops are formed, reduce them as quickly as possible; and (4) pull back and telescope the bowel onto the colonoscope whenever possible. The technique of colonoscopy, including the types of loops formed and techniques of loop reduction, are discussed in Chapter 40. Pediatric patients have less tolerance of loop formation than their adult counterparts, and their smaller size requires modification of the endoscopic technique. Excellent endoscopic technique is essential in order to avoid complications, including perforation of the colon and/or premature termination of the procedure and therefore incomplete examination. In addition, pediatric endoscopists typically routinely perform intubation of the terminal ileum because examination and tissue sampling of the terminal ileum is essential in any pediatric patient being evaluated for Crohn’s disease because of the high likelihood of involvement of this site [1,3,17,42]. Upon reaching the cecum, the ileocecal valve can be identified on the lateral surface of the prominent ileal fold as a slight

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irregularity of the valve contour. Occasionally the valve can be directly intubated, but usually it must be approached indirectly. The tip of the endoscope is brought to a position parallel to the valve, and the dials are used to deflect the tip 90° toward the valve. The maneuver is designed to catch the proximal lip of the valve with the tip of the endoscope. If the maneuver is successful, the lumen of the ileum will open, and adjustment of the tip will advance the instrument several centimeters. Several attempts may be needed to achieve success. Rotating the patient and suctioning the air from the cecum to draw the valve opening closer to the endoscope may be helpful. The mucosa of the ileum is easily identified by the presence of valvulae conniventes and the presence of lymphoid aggregates, which appear as submucosal 2- to 4-mm mounds of tissue with normal overlying mucosa (Figure 56.4). The presence of lymphoid aggregates in adults has been associated with immunoglobulin A (IgA) deficiency but is normal in children and adolescents; the volume of lymphoid aggregates tends to decrease with advancing age. If the valve cannot be cannulated and pathologic evaluation is needed, the forceps can sometimes be gently advanced through the valve and biopsy material obtained. Because of the different spectrum of disease in children and adolescents compared with adults, mucosal biopsy of the ileum and throughout the colon in addition to histopathologic evaluation of any identified lesions is the usual practice of pediatric endoscopists. This differs from current endoscopic practice in adults, which is frequently oriented to colon cancer screening [43]. In addition to the diagnosis of inflammatory bowel disease and infectious colitis [44], biopsies from macroscopically normal mucosa may be useful in the diagnosis of collagenous colitis, lymphocytic colitis, graft versus host disease, amyloidosis, microscopic colitis, and chronic schistosomiasis [45]. Complications after biopsy may include perforation and bleeding. A more detailed discussion of endoscopic biopsy and complications is discussed in Chapters 34 and 53.

Pediatric Colonoscopy

with minimal air insufflation to avoid anastomotic trauma. Subsequently, the endoscope can be advanced further with both random and directed endoscopic biopsies. Indications for small bowel ileoscopy after transplantation include routine surveillance, fever, bacteremia, increased stoma output, diarrhea, and bleeding [47] (Figure 56.5a and b). Rejection can be diagnosed macroscopically in about 60% of cases; endoscopic biopsy increases the diagnostic rate. New techniques such as zoom video endoscopy may increase the macroscopic detection rate [46]. In addition to detection of rejection, this technique is helpful for detection of infection such as Epstein–Barr virus and cytomegalovirus infection, and posttransplant lymphoproliferative disorder [46,47].

(a)

Ileoscopy Pediatric patients represent up to one-half of the patients undergoing small bowel transplantation in most large centers. Regular surveillance ileoscopy with biopsy is being increasingly utilized in pediatric patients who have undergone a small intestinal transplantation and is considered the standard for diagnosing graft rejection [46]. Depending on the size, an appropriate scope should be chosen after a finger has been inserted into the ileal opening. The length of bowel that can be examined is usually dependent on whether adhesions have formed. Advancement of the instrument around flexures in the small bowel involves repeated advancement, withdrawal, and torque of the insertion tube. Ileoscopy of the allograft after transplantation is typically performed using an instrument designed for upper endoscopy with antibiotic prophylaxis but usually without sedation [47]. In the immediate postoperative period the endoscope is advanced only 5–10 cm

(b) Figure 56.5 (a, b) Terminal ulcerative ileitis in a pediatric patient following small bowel transplant with a normal endoscopic appearance of the native colon, jejunal and proximal ileal portions of the graft. Endoscopic biopsy reveals ulceration without evidence of rejection. This complication is unusual prior to stoma take-down but may have a variable course ranging from indolent to stricture formation. (Images courtesy of Stuart S. Kaufman, MD.)

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Flexible proctosigmoidoscopy Routine flexible proctosigmoidoscopy is useful in selected pediatric patients. In compliant older children with inflammatory bowel disease, routine office examination to assess the extent and severity of disease when the history is unclear or prior to initiating topical therapy for localized disease is useful. Examinations can be routinely performed with the same instruments that are used for full colonoscopy. If it is necessary to sedate pediatric patients for their comfort, it is usually appropriate to be prepared to perform a full colonoscopy. If pathology is encountered that is compatible with the patient’s symptoms and therapeutic options do not rest on establishing the extent of the disease, the procedure can be terminated without attempting to examine the entire colon. Flexible sigmoidoscopy with biopsy is frequently performed in the infant with rectal bleeding with suspected cow’s milk or soy protein allergy. Use of a small-diameter upper endoscope, in the range of 6 mm, and the brief nature of the examination often allow the procedure to be performed without sedation.

Polypectomy Types of polyps The rationale for colonoscopy for suspected polyps in adults is based on the belief that cancers arise from preexisting adenomas or neoplastic polyps. Most polyps in the pediatric population are simple juvenile polyps and have no premalignant potential. However, recently a greater frequency of adenomas has been identified in pediatric patients, and all polyps removed at colonoscopy should be sent for histopathologic evaluation. Polyps in the pediatric patient are typically discovered at colonoscopy that is performed for anemia, rectal bleeding, prolapse, or, less frequently, following an episode of intussusception. Up to one-third of patients with simple juvenile polyps develop iron-deficiency anemia and require polypectomy to prevent ongoing blood loss. It is not uncommon for more than one juvenile polyp to be present at colonoscopy, and therefore a complete examination to the cecum is required even if a polyp is identified in the sigmoid colon or rectum [48]. Polyps may also be discovered on flexible sigmoidoscopy or colonoscopy performed as part of a screening procedure for a polyposis syndrome. Juvenile polyps or adenomas, when multiple, recurrent, or associated with extraintestinal abnormalities in pediatric patients, may occur as part of a polyposis syndrome. With advances in genetic testing these syndromes have been further characterized and are discussed in detail elsewhere [49–51]. Syndromes that are associated with colonic polyps that present in the pediatric and adolescent age group include adenomatous polyposis coli (APC), attenuated APC, Gardner’s syndrome, Turcot’s syndrome, and hereditary nonpolyposis colorectal cancer (HNPCC), all characterized by the presence of adenomatous polyps. Juvenile intestinal polyposis, generalized juvenile polyposis with pulmonary arteriovenous malformation, macrocephaly multiple lipomas and

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hemangiomata syndrome (MMLH), Cowden disease, juvenile polyposis of infancy, hereditary mixed polyposis syndrome (MPSH), Peutz–Jeghers syndrome (PJS), intestinal ganglioneuromatosis, and multiple intestinal polypoid neurofibromas in association with neurofibromatosis type 1 are characterized by the presence of hamartomatous ( juvenile or PJS type), ganglioneuromatous, or serrated polyps. Juvenile polyps associated with a polyposis syndrome are thought to have a premalignant potential unlike isolated juvenile polyps.

Technique As in adult patients, adequate colonic preparation is required for polypectomy. Diminutive polyps ≤ 5 mm are typically removed with biopsy forceps. Cold snare technique should be avoided in pediatric patients. Large polyps > 5 mm are usually removed with snare electrocautery. Most polyps in the pediatric population are pedunculated with a moderate to long stalk (Figure 56.6). The snare should be positioned to perform electrocautery closer to the polyp head than to the bowel wall or base of the polyp stalk. This allows for grasping of the stalk and coagulation or clipping if postpolypectomy bleeding occurs. This is in distinction to adenomas in the adult patient, in whom carcinoma in situ may be suspected and the endoscopist is trying to achieve as complete a resection as possible. The head of the polyp should be lifted off the mucosa prior to electrocautery; contact between the polyp head and opposing mucosa should be avoided to prevent a mucosal burn on the opposite colonic wall. The shaft of the snare should be approximated to the polyp head as the snare is closed, bringing the distal aspect of the snare toward the polyp head. To remove large polyps ≥ 2 cm piecemeal resection may be necessary. After the head is reduced in size, it is usually possible to then snare the stalk and safely remove the remainder of the polyp.

Figure 56.6 Typical appearance of a juvenile polyp in a 3 year old with rectal bleeding. The polyps are pedunculated with a large head and a typically vascular stalk.

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After the polyp has been snared but prior to amputation, a current is passed through the snare, which is slowly closed by the assistant. Rapid closure results in bleeding from vessels in the stalk that have been amputated but not coagulated. Most pediatric endoscopists use a combination of coagulation and cutting settings for snare polypectomy. Use of cutting current alone, particularly with vascular juvenile polyps, is likely to result in significant postpolypectomy bleeding. Coagulation current alone, without cutting, can also be effective due to the cutting properties of the snare. Lower settings are typically used in the right side of the colon than in the left. As the snare coagulates tissue, there is a whitish discoloration of the polyp. Large or broad-based polyps must be removed with care and may be removed piecemeal or with the assistance of submucosal saline injection. Both of these techniques are discussed elsewhere in the text. Some polyps may not be amenable to endoscopic resection and surgical resection may be required in some cases. Although uncommon, a variety of neoplastic lesions may present as polypoid masses in the colon or small intestine of pediatric and adolescent patients. Some of these lesions may have extension outside of the bowel wall, and representative sampling rather than attempted resection may be the safest course of action in cases that are not well characterized. When multiple polyps are encountered, the most proximal polyp should be removed first so that subsequent passage of the endoscope will not precipitate hemorrhage over the base of an already amputated polyp. In the patient with large numbers of polyps, representative polyps should be removed or biopsied for pathologic analysis. In pediatric patients with APC there are too many polyps typically present to biopsy or remove all of them. Larger polyps should be biopsied or removed for histologic analysis. Following polypectomy, amputated polyps should be retrieved and sent for histologic analysis. Ancillary equipment should be available prior to starting polypectomy, including needles for injection of saline or epinephrine, detachable polypectomy loops, and hemostatic clips for postpolypectomy bleeding. Detachable polypectomy loops should be used with caution due to the possibility of inadvertent transection or inadequate hemostasis of the polyp stalk [52]. A sterile surgical marker containing carbon particles can be injected for tattooing if the polyp site needs to be marked for future surgical or endoscopic procedures. This tattooing is permanent and should be used for limited indications [53,54].

Therapeutic colonoscopy for gastrointestinal bleeding (see Chapter 47) Colonic lesions treatable with endoscopic therapy in the pediatric age group include angiomata, polyps and bleeding polyp stalks, and ulcerative lesions with evidence of bleeding. Diffusely bleeding colonic lesions are typically not managed with endoscopic intervention with the exception of radiation proctitis (discussed below). The techniques employed most

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frequently in pediatric patients include injection, coagulation or thermal therapy, including argon plasma coagulation (APC), application of endoscopic hemostatic devices, and ligation therapy. The specific techniques employed depend on equipment availability and endoscopist experience. The techniques appear to have roughly equivalent efficacy, but some lesions are more amenable to a particular type of therapy. Therapeutic endoscopy, although most easily accomplished using a two-channel and/or therapeutic scope, is usually performed in pediatric patients using a single-channel scope due to size restrictions this group.

Injection Nonvariceal injection therapy is usually performed by injecting a sclerosing agent at three or four sites around an exposed bleeding vessel. Maximal volumes of sclerosant have been established in adults to minimize the risk of perforation. Maximum volumes of sclerosants in pediatric patients have not been studied; however, maximal adult volumes should not be exceeded. Complications including perforation may occur with volumes of injection even less than the recommended maximum volumes. Although submucosal saline injection has been employed to assist in resection of colonic polyps, optimal colonic volumes of injection of a number of agents used in the management of gastrointestinal bleeding in pediatric patients have not been established.

Thermocoagulation Thermocoagulation can be performed utilizing the heater probe and multipolar electrocoagulation (MPEC) utilizing the principles of coaptive coagulation. In cases of colonic bleeding, the number of joules per pulse of the heater probe should be reduced, especially in right-sided colonic lesions, and MPEC settings also need to be modified when this technique is used in the colon compared with the upper gastrointestinal tract. Angiodysplasia, predominantly of the colon, has been treated successfully by endoscopic electrocoagulation. Hemorrhagic proctocolitis with recurrent bleeding after radiation therapy has also been successfully treated with MPEC, but recently APC has increasingly been utilized for this indication [55,56]. APC has also been employed to treat a variety of colonic lesions, including hemostasis of superficial vascular ectasias, for resection of residual adenoma following polypectomy, or for coagulation of postpolypectomy bleeding [56–59], although pediatric experience with this modality to date is limited [60]. Hot biopsy forceps are used primarily in the colon for small diminutive polyps. This modality combines the principles of endoscopic biopsy and monopolar electrocoagulation while preserving the histologic integrity of the specimen. Lower settings are used in the right colon than in the left. Lasers have been used for congenital vascular lesions (hereditary hemorrhagic telangiectasia, blue rubber bleb nevi syndrome) as well as superficial vascular lesions, including angiodysplasia, telangiectasia, and arteriovenous malformation.

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Asymptomatic, non-bleeding angiodysplasias are usually not treated. One problem after laser photocoagulation of a lesion is that the histologic diagnosis is difficult to confirm. Endoscopic laser therapy has fallen out of favor as other thermal methods emerge due to expense and equipment limitations. Complication rates vary among the various hemostatic techniques discussed; perforation and rebleeding have been reported after monopolar electrocoagulation, MPEC, laser therapy, and APC. Hemostatic clips (discussed below), when properly applied, are rarely associated with the development of complications.

Endoscopic hemostatic devices Band ligation Band ligation has been used for the management of bleeding from colonic varices, hemorrhoids, angiectasias, and polypectomy sites [61]. Band ligation is most effective for bleeding lesions in nonfibrotic tissue. Ligation is typically performed using an upper endoscope due to the size of the commercially available friction fit adaptors. The presence of more bands on the friction fit adaptor limits the endoscopic view. Because of this, some pediatric gastroenterologists choose to deploy a number of the bands prior to endoscope insertion when a multiband ligator is used.

Hemostatic clips (see Chapter 25) Endoclips have significantly increased in popularity and ease of use in the last 5–10 years and represent the hemostatic modality most likely to be currently employed by pediatric endoscopists [1,62]. Hemoclip application requires an endoscope with a minimum channel size of 2.8 mm. Preloaded and rotatable clips are available in different lengths, allowing use with both upper endoscopes and colonoscopes. Endoscopic clipping is used primarily for endoscopic hemostasis but also has been applied for securing tubes or catheters to the GI wall, closure of fistulas, leaks and perforations, and marking anatomic landmarks for subsequent therapy or surgery [63,64]. Causes of pediatric lower GI bleeding amenable to endoscopic clipping include bleeding polypectomy stalks, bleeding after biopsy, ulcerative lesions, solitary rectal ulcer syndrome (SRUS), and hemorrhoidal bleeding [61,65]. Clipping is often performed in conjunction with endoscopic injection therapy, although some authors prefer to clip first prior to injection to ensure that hemostasis is achieved and is not a transient effect of the epinephrine injection [65]. The clips dislodge spontaneously after application and have not been associated with long-term sequelae, although different types of clips appear to be associated with differential durations of attachment [66].

Endoloops (see Chapter 25) Endoloops are primarily utilized for the management of potential or actual postpolypectomy hemorrhage. Loops are placed either prior to placement of the standard polypectomy

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snare or following polypectomy to a transected stalk to reduce the rate of postpolypectomy hemorrhage. Detachable loops work mechanically as a ligating device but are not capable of electrocautery [62,65]. Incorrect closure of the loop device can result in inadvertent transection of the polyp stalk with resultant bleeding (due to the lack of cautery) or, if placed too loosely, postpolypectomy bleeding. Correct placement is indicated by change in the color of the polyp head without transection. Loop placement prior to snare polypectomy can be associated with entanglement of the loop within the polypectomy snare. Because of the vascular nature of most juvenile pedunculated polyps, endoloops are used primarily as adjunctive therapy if postpolypectomy bleeding occurs but are not to be substituted for adequate coagulation at the time of polypectomy. The lift and ligate technique has been used for endoloop placement on a retracted polypectomy stalk [67].

Other colonoscopic techniques in pediatric patients Dilation of colonic strictures Cicatricial anastomotic strictures of the colon have been dilated with air- and water-filled balloons or with a mechanical dilator (e.g., Savary dilator) placed over an endoscopically directed guidewire.

Percutaneous cecostomy Percutaneous endoscopic cecostomy (PEC) and percutaneous colostomy of the left colon have recently emerged as endoscopic techniques at selected centers to assist in the management of intractable constipation in children [68,69]. The PEC tube is used to administer antegrade continence enemas and represents a modification of the surgical approach to this problem [68]. The procedure is similar in technique to PEG placement and requires bowel preparation, prophylactic antibiotic administration (metronidazole and gentamycin or cefotaxime and metronidazole), and a sterile skin preparation. Tube placement has been reported in the cecum and in the left colon at the junction of the descending and sigmoid colon [68]. Complications of this procedure include granulation tissue formation, local or generalized infection, dislodgement of the tube, misplacement of the tube, pain, pressure necrosis, and abdominal distension [68,69]. Surgical appendicostomy is an alternative to PEC [68,70].

Motility catheter placement Colonic motility is increasingly being used to evaluate pediatric patients with conditions such as chronic intestinal pseudoobstruction. After initial colonoscopy, a guidewire is placed into the cecum and subsequently the monitoring catheter is placed in the cecum over the guidewire followed by removal of the guidewire. Monitoring can be initiated once the effects

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of anesthesia have worn off. Colonic motility catheter placement is facilitated by performing a relatively “loopless” colonoscopy, allowing for “one to one” movement of the catheter over the wire. An abdominal x-ray is done prior to initiation of monitoring to verify catheter placement.

Complications Complications following colonoscopy are discussed in Chapter 53. Limited studies are available that assess the unique rates and factors contributing to complications of upper endoscopy and colonoscopy in pediatric patients. In the three largest endoscopic series in pediatric patients from two large centers, serious endoscopic complication rates were in the range of 0.1– 0.3% [8,9,17]. In those series, serious complications included medication-related complications and perforations. Although there is a prospective database study of the complications of EGD in pediatric patients, to date, no large prospective series has been reported of the incidence of both sedation and procedure-related complications of colonoscopy in pediatric patients [71]. Poor preparation quality, patient age < 10, inadequate sedation, as well as the presence of underlying disease such as a stricture are associated with lower rates of cecal and terminal ileal intubation [3,9]. Endoscopist experience, fellow participation in the procedure, and equipment limitations are also believed to impact procedure time and ileal intubation rate [3,17,72]. Bleeding following colonoscopy is usually minimal but may follow mucosal biopsy or polypectomy. Perforation is the most serious complication of colonoscopy in children. It is infrequent and thought to occur in less than 0.2% of pediatric colonoscopies [17]. It is frequently related to polypectomy or underlying disease and usually successfully managed with surgery. Spontaneous bowel perforation has been reported in patients with Ehlers–Danlos syndrome type 4, and patients with this condition may be at higher risk for perforation during or after gastrointestinal endoscopy, an important consideration for pediatric and adult endoscopists [27]. Advanced endoscopic procedures such as thermocoagulation and percutaneous cecostomy are likely to be associated with a higher complication rate, and further studies are indicated in pediatric patients.

Summary Colonoscopy is safe and well tolerated in pediatric patients. The indications for colonoscopy differ in children and adolescents compared with adults. Endoscopists performing colonoscopy on pediatric patients should have adequate training in pediatric colonoscopy as well a thorough knowledge of the unique spectrum of disease in children and limitations of the procedure.

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Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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Virtual Colonoscopy in the Evaluation of Colonic Diseases Perry J. Pickhardt University of Wisconsin, Madison, WI, USA

Introduction Virtual colonoscopy, also referred to as computed tomography (CT) colonography, is a relatively new radiologic examination of the large intestine that was first introduced in the mid1990s. Since that time, virtual colonoscopy has undergone rapid evolution, which has resulted in greatly improved diagnostic capabilities. Virtual colonoscopy is now poised to join optical colonoscopy as a frontline diagnostic tool for total colonic examination, with attributes that complement the therapeutic gold standard. This chapter will provide an overview of CT virtual colonoscopy, including technical principles, clinical indications, and performance characteristics. Although magnetic resonance (MR) imaging can also be used for noninvasive examination of the colon and rectum, this approach remains largely investigational and will not be covered herein.

General principles and technique The general idea behind virtual colonoscopy is fairly straightforward. First, a multidetector CT scanner is used to image a patient with a properly prepared and gas-distended colon. This is the only portion of the examination that requires the presence of the patient and lasts approximately 10–15 min in total. The CT images are then sent to a dedicated software system that is capable of displaying the large intestine in a variety of two-dimensional (2D) and three-dimensional (3D) projections (Figure 57.1). The 3D endoluminal projection provides a virtual reality navigational view that simulates conventional (optical) colonoscopy. Meanwhile, the patient has already returned to his or her regular activities, hence the term “virtual colonoscopy.” Interpretation of the 3D display allows for facile detection of relevant (i.e., nondiminutive) colorectal polyps and masses, which can then be confirmed

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

on the 2D display (Figure 57.2). If all facets of the examination, as discussed below, are adequately addressed, effective evaluation is readily achievable. However, it is important to note that any weak link in this chain of events can lead to poor results. For example, even the best virtual colonoscopy software system will fail in the setting of inadequate colonic preparation or distension. Likewise, optimal preparation and distension cannot compensate for an inadequate software system or an ineffective interpretive approach. As with any new colorectal screening test, there are relative advantages and disadvantages of virtual colonoscopy compared with existing strategies that should be taken into consideration. In comparison with optical colonoscopy, the relative benefits of virtual colonoscopy include that it is less invasive, requiring only the insertion of a small flexible rectal catheter, and does not require intravenous sedation or pain control. For asymptomatic screening, the risk of complications such as perforation or bleeding likely approach zero [1]. Furthermore, patients are able to drive themselves home or back to work without delay. In the event that polypectomy is needed, which occurs in less than 10% of our screening population [2], sameday or next-day therapeutic colonoscopy can be arranged, which avoids the need for a second bowel preparation. In our experience, virtual colonoscopy screening is a highly costeffective practice, particularly when diminutive lesions are ignored [3,4]. The major drawbacks of virtual colonoscopy are that a cathartic bowel preparation is still needed and that polypectomy is not possible. The remainder of this section will briefly review our approach to bowel preparation, colonic distension, CT scanning, and image interpretation for virtual colonoscopy at the University of Wisconsin. For current protocols and other information, please visit www.virtuoctc.com.

Bowel preparation Robust preparation is important for accurate polyp detection at virtual colonoscopy and requires both cleansing and tagging. Our current low-volume preparation has proven highly effective and combines three basic components: a laxative for catharsis, dilute (2%) barium for tagging of any solid residual stool, and water-soluble iodinated contrast (diatrizoate) for

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Figure 57.1 The virtual colonoscopy software system used at the University of Wisconsin (V3D Colon, Viatronix, Inc., Stony Brook, NY, USA) is currently the only product with FDA approval for screening. Automated 3D endoluminal fly-through along a predetermined centerline allows immediate 2D correlation for suspicious findings. Secondary 2D evaluation for polyps can supplement 3D evaluation.

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Figure 57.2 Screening examination in asymptomatic 54-year-old woman. (a) 3D endoluminal image shows a 10-mm sessile polyp in the descending colon. (b) Prone 2D transverse image with polyp window settings [width 2000 Hounsfield units (HU), level 0 HU] demonstrates the soft-tissue composition of the lesion (arrow). (c) The polyp was confirmed and removed at optical colonoscopy on the same day as virtual colonoscopy to avoid need for repeat bowel preparation. The polyp proved to be a tubular adenoma.

opacification of residual luminal fluid [5]. This preparation is taken the evening before the examination, in conjunction with a clear liquid diet. In our experience with over 5000 examinations, we have yet to encounter any significant complications, preparation-related or otherwise. The specific laxative choice depends on the health status of the individual. We provide referring physicians with our guidelines and have them choose the most appropriate cathartic agent for their patients. Previously our standard laxative was magnesium citrate, which was employed in nearly 90% of cases and was well

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tolerated in screening adults without known or suspected renal or cardiac insufficiency. We generally avoided sodium phosphate in elderly patients with hypertension, particularly those on angiotensinconverting enzyme (ACE) inhibitors, and patients with known or suspected renal or cardiac disease [6]. Although we did not detect any problems using two 45-mL doses of sodium phosphate spaced 3 h apart during the original screening trial [7], we later showed that a single dose is equally effective, and this now represents our current approach [8]. If further purgation was needed beyond the single 45-mL dose of sodium phosphate, we added a 296-mL

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bottle of magnesium citrate in lieu of a second dose of sodium phosphate. Given the recent concerns for renal complications related to sodium phosphate, we recently switched over to magnesium citrate as our standard laxative. Because we find a single 296mL bottle of magnesium citrate to be somewhat less effective than sodium phosphate, we routinely employ a second bottle that is taken during step 2 along with the 2% barium. For severely compromised patients who cannot tolerate even moderate fluid or electrolyte shifts, we resort to polyethylene glycol (PEG), which is given as a 4 L solution. Although the safety profile of PEG is most favorable for such tenuous patients, this preparation is associated with the poorest patient compliance. Fortunately, this preparation is only rarely necessary, accounting for less than 1% of our screening volume. Regardless of which laxative is employed, the dual oral contrast regimen is held constant. We feel that the complementary actions of the dilute barium and diatrizoate provides for optimal bowel preparation for virtual colonoscopy. The basic rationale behind the specific order of the three preparation components is as follows. The laxative provides catharsis for the bulk removal of fecal material, the barium tags any residual solid stool that remains, and the diatrizoate serves the dual purpose of uniform fluid tagging and secondary catharsis. We strongly prefer the dilute 2% CT barium over 30– 40% barium preparations, which are unnecessarily dense, less well tolerated, and may even cause problems with clogging of channels at same-day colonoscopy. In our experience, the 2% barium has never caused a significant problem at same-day colonoscopy, which includes well over 1500 same-day virtual and optical colonoscopy examinations dat-

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ing back to our original screening trial. We suspect that the diatrizoate represents our true “secret to success” by providing both uniform opacification of the residual luminal fluid and a moderate secondary cathartic-like effect. The use of dual oral contrast tagging improves the accuracy of virtual colonoscopy in several ways: it increases specificity by both tagging residual stool (barium effect) and decreasing the amount of adherent stool (diatrizoate effect), and it increases sensitivity by allowing for polyp detection in opacified fluid (diatrizoate effect). Given the improved performance characteristics seen with the use of oral contrast tagging in virtual colonoscopy, we believe it should be regarded as standard technique and utilized whenever possible. With proper contrast tagging, false-positive interpretations from residual stool are quite rare (Figure 57.3). In our experience with same-day virtual colonoscopy following incomplete optical colonoscopy, the lack of contrast tagging has resulted in a number of false positives that would have almost certainly been eliminated with our dedicated virtual colonoscopy preparation. Attempts at same-day oral contrast administration following incomplete colonoscopy have been disappointing, which is forcing us to reconsider same-day virtual colonoscopy in some cases. With regard to computer-aided detection (CAD), most algorithms to date have been developed and tested on cases without tagging. To be successful moving forward, we believe that CAD systems will need to address this issue and demonstrate acceptable performance for tagged cases [9,10]. The potential for a non-cathartic approach to virtual colonoscopy is often hailed as the ultimate “holy grail”. However, one must carefully consider both the advantages and disadvantages related to foregoing the cathartic preparation. The

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Figure 57.3 Tagged adherent stool at virtual colonoscopy. (a) 3D endoluminal image shows a polypoid lesion situated on a rectal valve. (b) 3D image with superimposed translucency rendering shows that the lesion is labeled white, which indicates contrast tagging of residual stool, not a polyp. (c) Prone 2D sagittal image with soft-tissue window settings confirms internal contrast tagging of adherent stool (arrow). Potential pitfalls of virtual colonoscopy interpretation can be avoided with proper technique and reader training.

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major advantage of a laxative-free approach is the potential for further increases in screening compliance, particularly from those seeking to avoid cathartic preparation. Unfortunately, there are a host of relative disadvantages that are usually not considered but which may temper the actual benefit in terms of both increased participation and effective resource utilization. Among the potential drawbacks include the fact that current laxative-free regimens are far from “prepless” (a euphemistic misnomer that should be avoided), the negative impact upon accuracy could lead to both missed lesions (false negatives) and unnecessary colonoscopy from more false positives, and the lack of cathartic preparation precludes same-day therapeutic colonoscopy. Therefore, patients must undergo a full cathartic preparation for polypectomy following a “positive” non-cathartic virtual colonoscopy (whether falsepositive or true-positive), amounting to two bowel preps and several days of effort. Furthermore, the cumulative experience with our low-volume cathartic preparations suggests a very favorable safety profile and good patient acceptance.

Colonic distension Adequate luminal distension of the colon, like proper bowel preparation, is a critical component of technical success in virtual colonoscopy. Of course, adequate distension does not necessarily imply maximal distension, since patient comfort and safety must be taken into account if virtual colonoscopy is to be widely embraced. Our distension protocol has continued to evolve and improve, resulting in inadequate segmental distension in well under 1% of cases. When short-segment collapse persists on all views in the same area, it almost always involves a sigmoid colon that is affected by severe diverticular disease. As such, examination of the remainder of the colon is almost always diagnostic, resulting in much greater coverage than an incomplete optical colonoscopy due to the same underlying process. The use of large rigid retention balloon catheters designed for the barium enema is rarely needed for performing virtual colonoscopy. Rather, the smallcaliber flexible catheters with low-pressure retention cuffs specifically designed for virtual colonoscopy are generally more appropriate. For a number of reasons, automated carbon dioxide (CO2) delivery represents the frontline distension technique in virtual colonoscopy, with manual room air insufflation serving as a seldom used back-up. Of note, nearly all reported perforations at virtual colonoscopy have involved the use of manual staff-controlled room air insufflation in patients with significant colonic disease, whereas the risk of perforation with automated or patient-controlled distension methods is extremely low [1]. With regard to both the degree of colonic distension and postprocedural discomfort, automated CO2 is superior to the manual room air technique [11]. An additional factor that receives relatively little attention yet is nonetheless very important is staff preference. Our CT technologists strongly prefer the automated CO2 technique over room air insufflation.

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Significant time and energy may be required to coach individual patients to adequately self-insufflate with room air, whereas automated CO2 requires little explanation and the endpoint determination is more straightforward. From the radiologist’s perspective, the decreased operator dependence with the automated CO2 technique results in less variability between studies. The need for spasmolytics during virtual colonoscopy examination has been debated. In our opinion, spasmolytics are generally unnecessary and are best avoided. Previous studies evaluating the efficacy of spasmolytics have found mixed but largely negative results. Furthermore, the need for needle administration of such a drug adds invasiveness and patient discomfort, creates an opportunity for possible new side-effects, increases examination duration, and increases overall costs. Perhaps most importantly, with our current distension protocol, nondiagnostic segmental distension is so infrequent that the potential role for spasmolytics is greatly diminished from the start. Even if a mild net benefit with Buscopan exists compared with glucagon, this agent is not currently available in the US. We have gradually refined our protocol over time for optimizing colonic distension at virtual colonoscopy. To maintain efficiency, we have trained our CT technologists to generally obtain the entire examination, from placement of the rectal catheter to colonic distension, image acquisition, and assurance of adequate examination. The radiologist is needed only for difficult or unusual situations, thus allowing more time for study interpretation. Immediately before the examination begins, the patient is encouraged to use the rest room and the technologist inquires about the fidelity of the preparation. Following rectal catheter placement, the patient remains in the left lateral decubitus for the initial 1–1.5 L of CO2 delivered by the automated device. To reduce transient discomfort related to rectal spasm, we initially set the equilibrium pressure to about 20 mmHg. The patient is then placed in the right lateral decubitus until about 2.5 L has been delivered in total, followed by supine positioning until a steady-state equilibrium has been reached, at which time scanning commences. The positional change generally prevents under-distension related to CO2 blockage from a fluid channel or kink. The volume of CO2 “dispensed” can vary widely not only from actual differences in colonic volume but also from variable degrees of reflux through the ileocecal valve, loss around the catheter, and continuous colonic resorption. Therefore, the total volume reading has relatively little meaning and can range from 3 liters to more than 10 liters in some cases. As a practical point, any CO2 lost from the large intestine must be actively replaced during scanning. We perform the supine and prone scans at end expiration to raise the diaphragm and allow more room for the splenic flexure and transverse colon. Although the CT scout image provides a general indication of overall colonic distension, we have found that it is unreliable for assessing distension of the sigmoid and descending

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Figure 57.4 Diverticular stricture of the sigmoid colon. (a) Supine CT scout radiograph from screening virtual colonoscopy shows a narrowed luminal caliber to the sigmoid colon (arrowheads), but no apparent areas of frank collapse or non-distension. 2D transverse images with supine (b) and prone (c) positioning show extensive sigmoid diverticular disease. Wall thickening with focal luminal nondistension is seen at the same point on both views (arrowheads). The patient was offered same-day unsedated flexible sigmoidoscopy for further evaluation of this area. (d) Flexible sigmoidoscopy confirmed fixed narrowing from benign diverticular disease (arrow). Mild erythema is present from superimposed inflammation (from ref. 37 with permission).

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colon (Figure 57.4) [12]. Consequently, we have trained our CT technologists to immediately recognize inadequate distension at online review of the 2D transverse images at the console. If focal collapse persists at the same point on both supine and prone scans, a third set of images are obtained, typically in the right lateral decubitus position. These steps ensure adequate distension of the left colon, resulting in nondiagnostic segmental evaluation in well under 1% of cases. In rare cases of persistent collapse (or true stricture) on all views, which again is almost always due to severe sigmoid diverticular disease, we will usually offer the patient same-day unsedated flexible sigmoidoscopy (Figure 57.4). In rare instances, manual room

air insufflation may help maintain adequate distension when CO2 has failed but must be used with caution.

Multidetector CT scanning Unlike temporally demanding protocols like CT angiography for the coronary arteries, virtual colonoscopy is a very forgiving examination with regard to scanner requirements. Reasons for this include the fact that virtual colonoscopy typically does not employ intravenous contrast, the gas-filled large intestine is a relatively static structure, and the target lesion is relatively large (5–6 mm or greater). As such, neither submillimeter collimation nor 64-channel scanners are really necessary.

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On the contrary, the increased dose required for submillimeter collimation may outweigh any theoretical benefit for improved polyp detection. In fact, although we currently prefer a 16-channel CT scanner with 1.25 collimation, most virtual colonoscopy examinations from our screening trial were performed on four-channel scanners utilizing a 4 × 2.5 mm detector configuration [7]. Our current multidetector CT scanning protocol remains fairly straightforward. The well-established practice of obtaining both supine and prone scans remains firmly entrenched, given the invaluable complementary data provided and the ability to confirm suspected lesions detected on another view. Typical 16-channel multidetector CT scanning factors include a 0.5 s rotation time, 1.25 mm collimation, 1.375:1 pitch, 1.0 mm reconstruction interval, and 120 kVp. Given the nature of the soft tissue–air interface for polyp detection at CTC, it is widely recognized that the radiation dose can be significantly lowered from the levels typically employed for diagnostic intravenous contrast-enhanced CT examinations of the abdomen and pelvis. To optimize the delivered dose, we prefer a tube current modulation system and set a very high noise index, which has yielded significant dose reduction yet uniformly diagnostic examinations. With this approach, the total effective dose for virtual colonoscopy is approximately 5 mSv, which is roughly equal to 1–2 years of typical background radiation. For multidetector CT scanners that are not equipped with a tube current modulation system, one can generally employ a technique in the range of 35–75 mAs (effective), with individualized increases as necessary for morbidly obese individuals. Although further dose reduction is obviously a desirable goal for screening evaluation of asymptomatic adults, it is reassuring to note that the very small theoretical risk of lowdose radiation exposure is clearly outweighed by the actual risk of not being screened for colorectal cancer [13,14]. Because of the high diagnostic accuracy of virtual colonoscopy when oral contrast tagging and 3D polyp detection are employed (see below), the use of intravenous contrast is not indicated for asymptomatic screening. Without a clear benefit over our noncontrast protocol, the disadvantages of introducing intravenous contrast for virtual colonoscopy screening, such as increased time, costs, invasiveness, and risks, do not warrant its routine use at this time. However, intravenous contrast is typically utilized in the setting of incomplete colonoscopy from an occlusive carcinoma and occasionally for suspected submucosal lesions. In brief, this protocol entails obtaining a low-dose prone scan first, followed by a postcontrast supine scan with standard diagnostic technique.

Virtual colonoscopy interpretation A prerequisite for successful interpretation of virtual colonoscopy is a solid foundation in CT interpretation, including the use of advanced visualization software. Virtual colonoscopy interpretation requires frequent correlation between the 3D

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volume-rendered and 2D multiplanar reformat displays in order to ensure accurate results. Although the 3D endoluminal view is very sensitive and allows for facile detection of polypoid lesions, this display is nonspecific, requiring 2D correlation to distinguish true soft-tissue polyps from a host of false-positive pitfalls [5]. Virtual colonoscopy cannot be interpreted from the 3D display alone, since the low specificity would render almost every examination positive, albeit mostly due to false positives. Although virtual colonoscopy can theoretically be read from the 2D display alone, prior studies using this approach have shown disappointing results, as discussed below. In addition, the primary 2D polyp search pattern is too onerous to allow for a high-volume screening practice. Diagnostic redundancy is the key to accurate polyp detection with virtual colonoscopy. The more chances one has to detect a lesion without expending too much effort, the less likely a significant polyp will be missed. Having said that, it is critical to understand that the old “standard” interpretive approach of “primary 2D with 3D problem solving” is inadequate for low-prevalence screening, primarily because it fails to incorporate the obvious benefit of primary 3D detection. Our hybrid 3D–2D interpretive approach emphasizes 3D detection but also retains the complementary value of 2D detection. The basic concept behind our interpretive approach is that the more sensitive but less specific display (3D endoluminal) is best for initial polyp detection, whereas the more specific but less sensitive display (2D) is used for confirmation of suspected lesions and for secondary polyp detection. While the 2D display is vital for confirming the soft-tissue nature of polyps, it is a rather ineffective and tedious method for initially detecting them, largely due to their poor conspicuity among the colonic folds (Figure 57.5). Primary 2D evaluation, however, can be quite useful for annular lesions, fluid-filled areas (assuming oral contrast tagging has been applied), and segments with partial or total luminal collapse. Despite the existing data that strongly support the importance of 3D polyp detection, several preexisting conditions during the early development of virtual colonoscopy likely explain why primary 2D was long regarded as the frontline detection method. First, 2D multiplanar reformatted (MPR) displays were already fully matured at this time. Second, a comfort level with 2D was already in place among radiologists reading CT examinations. Third, a time-efficient 3D endoluminal evaluation was not yet feasible at that time [15]. Consequently, nearly all virtual colonoscopy systems were initially based on the primary 2D paradigm. Some studies intending to compare 2D and 3D detection have unfortunately utilized CTC systems with either poor or inefficient 3D capabilities. Long interpretation times for 3D endoluminal evaluation have been reported, but these are highly system dependent and continue to rapidly decline. Furthermore, although primary 2D detection can typically perform well in small, polyp-rich cohorts, it is incorrect to extrapolate such results to the

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Figure 57.5 Screening virtual colonoscopy study in an asymptomatic average-risk 54-yearold man. (a) 3D map with oblique orientation shows the location of a 10-mm rectosigmoid polyp (red dot) that was identified at primary 3D evaluation but missed at primary 2D evaluation. The blue arrow indicates the 3D endoluminal vantage point shown in (b). The green line represents the automated center line for endoluminal navigation. The large polyp was confirmed at same-day optical colonoscopy. (b) 3D endoluminal virtual colonoscopy image shows a large ovoid, sessile polyp (asterisk), which extends off the edge of a fold, obvious at real-time 3D fly-through evaluation, confirmed on secondary 2D correlation, and given the highest diagnostic confidence score by the interpreting radiologist. (c) Magnified 2D transverse image with polyp window settings shows the polyp (arrowhead), which is difficult to distinguish from the fold it arises from and was missed at primary 2D evaluation. (d and e) The lesion (arrowheads) is somewhat more conspicuous on coronal (d) and sagittal (e) 2D displays compared with the transverse projection (from ref. 36 with permission).

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screening setting, in which significant polyps are more akin to a needle in a haystack. In our experience, the initial learning curve for 3D polyp detection is much easier and a sustained level of high performance is easier to achieve [5]. Because polyps are so much more conspicuous on 3D than on 2D images, reader fatigue is much less of an issue. Overall, we believe that the previous reliance on 2D polyp detection is clearly giving way to primary 3D detection, particularly as more virtual colonoscopy software systems continue to improve their 3D capabilities. At the University of Wisconsin, we use the Viatronix V3D software system for virtual colonoscopy interpretation. At the time of this writing, the Viatronix V3D remains the only virtual colonoscopy system that is approved for screening by the US Food and Drug Administration (FDA), since it has proven effective repeatedly in this setting [2,7]. Continued software improvements since the time of our original screening trial have resulted in ever more efficient and accurate interpretations. With our hybrid interpretive approach, the reader employs both 3D and 2D polyp detection modes. However, it should be noted that the vast majority of significant polyps can be readily detected on the 3D endoluminal display, rendering 2D detection supplementary and clearly secondary. Primary 3D endoluminal review entails automated centerline fly-through of the supine and prone models with manual navigation as needed for further inspection of suspicious areas. Bidirectional fly-through is employed with a 90° field of view, but we have recently found that one-way fly-through with a wider field of view angle of 120° is just as effective yet significantly reduces interpretation times. In either case, a tool for rapidly reviewing any missed areas assures proper coverage of the colonic mucosa [16]. A major drawback with the 3D endoluminal display on most other virtual colonoscopy systems is the lack of unrestricted manual navigation. Rapid interrogation of polypoid lesions detected on 3D can be accomplished by the usual 2D MPR correlation or with 3D translucency rendering, which provides information on the internal density of a lesion [17]. For most screening cases, the entire virtual colonoscopy study can be read in 10–15 min or less. Although the Viatronix V3D system allows for electronic cleansing of the opacified residual luminal fluid [18], we have kept this function disabled since we believe the artifacts that are introduced currently outweigh the potential benefits [19]. Several studies have found that at least some appropriately trained nonradiologists can accurately interpret virtual colonoscopy [20–25].

Clinical indications The appropriate clinical indications for performing virtual colonoscopy continue to evolve. In general, virtual colonoscopy may be divided into two main clinical categories, namely “diagnostic” and “screening” examinations. A wide variety of

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clinical indications exist for diagnostic virtual colonoscopy, including recent incomplete optical colonoscopy, evaluation of a suspected submucosal lesion, a preexisting condition that renders colonoscopy unsuitable, a complicated prior colonoscopy, and surveillance of small unresected colorectal polyps. Noninvasive CTC surveillance of previously detected 6–9 mm polyps is a recognized alternative to polypectomy [4,26], but a broad consensus has yet to be reached on this controversial issue [27–29]. Examples of patients with preexisting conditions that make optical colonoscopy more risky include patients who are debilitated or elderly, on anticoagulation or with a bleeding diathesis, or at significant risk for sedation. Potential additional indications for diagnostic virtual colonoscopy include postpolypectomy surveillance and patients with a history of colorectal cancer resection. The utility of virtual colonoscopy in these surveillance populations remains somewhat uncertain. There are a number of factors that can contribute to failure to intubate the cecum at optical colonoscopy. In addition to the commonly recognized patient associations of older age, female gender, and prior abdominal surgery, there are also common associations with regard to colonic anatomy. The use of virtual colonoscopy to evaluate the proximal colon for polyps and masses following incomplete optical colonoscopy is well established [30–32]. Virtual colonoscopy also allows for detailed assessment of colonic anatomy in this setting. Comparison of virtual colonoscopy findings in patients who have undergone incomplete versus complete optical colonoscopy reveals significant differences in average length (167 cm vs. 211 cm), number of acute angle bends or flexures (9.6 vs. 11.9), and prevalence of advanced sigmoid diverticular disease (22% vs. 34%) [33]. These findings may have relevance for training of endoscopists and for development of new endoscopic technology. Additional reasons for incomplete optical colonoscopy include occlusive cancers, benign strictures, coloncontaining hernias, intestinal malrotation, and poor bowel preparation (Figure 57.6). In patients with inadequate bowel preparation for colonoscopy despite reasonable efforts, virtual colonoscopy can still generally exclude large polyps and masses if oral contrast tagging is employed. Performing virtual colonoscopy after failed colonoscopy presents a number of protocol challenges. From the patient’s perspective, same-day virtual colonoscopy is most convenient as it avoids the need for a second bowel preparation and can often be performed as soon as the patient has recovered from sedation, assuming CT scanner availability. The disadvantage of this approach, however, is that oral contrast tagging cannot be employed, which significantly reduces the accuracy of the virtual colonoscopy examination. Attempts at a same-day salvage regimen for oral contrast have shown mixed results in our experience, and the risk of aspiration may be increased if virtual colonoscopy is attempted too soon after sedation. Possible alternative options in this setting include the use of either intravenous contrast or rectal enema contrast to offset

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Figure 57.6 Screening virtual colonoscopy study in an asymptomatic average-risk 50-year-old woman. (a) 3D endoluminal image shows a large lobulated mass in the ascending colon. (b) Prone 2D image confirms a large, semiannular soft-tissue mass (arrowheads) compatible with invasive adenocarcinoma. (c) A 2D image caudal to (b) shows a separate area of annular luminal narrowing in the sigmoid colon with less bulky soft-tissue

prominence (arrowheads), impassable at same-day optical colonoscopy. The patient subsequently underwent an open surgical procedure, which confirmed adenocarcinoma in the ascending colon. The sigmoid stricture that precluded full endoscopic evaluation was found to be due to unsuspected endometriosis.

the lack of oral contrast. Some have even suggested the routine use of oral contrast administration as part of the standard bowel preparation for optical colonoscopy, just in case completion virtual colonoscopy turns out to be necessary. Aside from the option of using intravenous contrast, these measures are probably a bit extreme. From a purely clinical standpoint, having the patient return on another day following a dedicated virtual colonoscopy bowel preparation is the best option, as it will yield the most accurate examination. Having said that, most completion virtual colonoscopy studies are performed on the same day as the incomplete colonoscopy for the sake of patient convenience. Diagnostic indications aside, screening of asymptomatic adults clearly represents the greatest potential indication for virtual colonoscopy. Although colorectal carcinoma is largely preventable through effective screening, it remains the second leading cause of cancer-related death in the US because so many adults are not being screened at all [34,35]. As discussed below, virtual colonoscopy has been shown to represent a very effective screening tool when properly performed. Virtual colonoscopy should not be viewed as a replacement for optical colonoscopy screening, but rather as an additional effective option that has the potential to significantly increase overall compliance rates for screening. The introduction of a parallel virtual colonoscopy screening program at our institution has not had a negative impact upon referrals for optical colonoscopy screening [36], which implies that we are bringing in new folks off the screening “sidelines” rather than exchanging one test for another. By providing more screening options to patients, particularly tests that are less invasive but still highly

effective, the size of the unscreened population will hopefully start to decline.

Performance results for lesion detection The test performance characteristics of virtual colonoscopy for lesion detection have been derived by using optical colonoscopy as the reference standard, preferably with segmental unblinding of results to minimize the number of discordant cases. The early single-center virtual colonoscopy trials involving small, polyp-rich cohorts [37–39] provided encouraging initial results, which demonstrated the feasibility of the concept and led the way to larger multicenter trials. Two early multicenter trials by Cotton et al. [40] and Rockey et al. [41], which included approximately 600 subjects each, reported a per patient sensitivity for large polyps of only 55% and 59%, respectively. However, these two studies did not evaluate true screening populations, nor did they apply the now preferred techniques of oral contrast tagging, automated CO2 for bowel distension, and primary 3D polyp detection. Subsequently, the Department of Defense multicenter screening trial, which evaluated 1233 asymptomatic adults and introduced the techniques of stool tagging and primary 3D polyp detection, reported a 94% sensitivity for large adenomas, with a per patient sensitivity for adenomas ≥ 6 mm of 89%. Since then, a number of additional virtual colonoscopy trials have either been completed or are still ongoing. Results from smaller 3D screening trials by Cash et al. [42] and Graser et al. [43] have shown performance characteristics similar to that of

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Pickhardt et al. [44], providing a measure of independent validation for this screening technique. In addition, retrospective review of virtual colonoscopy cases from the Department of Defense, performed by experienced radiologists using a primary 2D approach, recapitulated the poor sensitivities seen in the previous 2D trials [44]. This provides direct evidence of the clear benefit of 3D endoluminal polyp detection over 2D approaches. Also of interest is the recently published American College of Radiology Imaging Network (ACRIN) Study 6664 trial, which involved a screening cohort of approximately 2500 patients across 15 institutions. The findings showed adequate performance for polyp detection, including a per patient sensitivity of 90% for large adenomas, although the specificity (86%) and positive predictive value (25%) for large adenomas were lower than in previous studies [7,34,45]. The ability of virtual colonoscopy to detect invasive colorectal cancer has been uniformly high (Figure 57.6), with one metaanalysis showing an overall sensitivity of 96%, which is similar to that of optical colonoscopy [46–48]. Beyond validation in clinical trials, we recently demonstrated the efficacy of virtual colonoscopy screening in actual clinical implementation [2]. In a nonrandomized study comparing primary screening with either virtual colonoscopy or optical colonoscopy in over 6000 patients at our institution, we found strikingly similar detection rates for advanced neoplasia. However, the total number of polyps removed was over four times greater in the optical colonoscopy group (2434 vs. 561) and there were no significant complications in the virtual colonoscopy group but seven perforations in the optical colonoscopy group (a rate of more than 1 per 500). Although this rate of perforation was higher than expected based on previous screening colonoscopy studies, these findings indicate that virtual colonoscopy can achieve the same goals of advanced neoplasia detection, but perhaps in a safer and more costeffective manner than optical colonoscopy.

Summary Virtual colonoscopy has rapidly evolved and now shows enormous potential for helping to address the major challenges facing colorectal cancer screening [49]. To optimize its clinical benefit, virtual colonoscopy should be viewed not as a potential replacement for optical colonoscopy but rather as an effective complement to improve patient care. In addition to screening, there are a number of diagnostic indications for which virtual colonoscopy can provide valuable information. Regardless of the specific indication, clinical success with virtual colonoscopy requires careful attention to all facets of the examination, including proper bowel preparation, colonic distension, CT scanning, and image interpretation. Furthermore, close collaboration among radiologists, gastroenterologists, and colorectal surgeons will be critical to maximize the potential yield from this powerful imaging test.

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References 1 Pickhardt PJ. Incidence of colonic perforation at CT colonography: Review of existing data and implications for screening of asymptomatic adults. Radiology 2006; 239: 313–16. 2 Kim DH, Pickhardt PJ, Taylor AJ, et al. CT colonography versus colonoscopy for the detection of advanced neoplasia. N Engl J Med 2007; 357: 1403–12. 3 Pickhardt PJ, Hassan C, Laghi A, Zullo A, Kim DH, Morini S. Cost-effectiveness of colorectal cancer screening with computed tomography colonographyaThe impact of not reporting diminutive lesions. Cancer 2007; 109: 2213–21. 4 Pickhardt PJ, Hassan C, Laghi A, et al. Small and diminutive polyps detected at screening CT colonography: a decision analysis for referral to colonoscopy. AJR Am J Roentgenol 2008; 190: 136–44. 5 Pickhardt PJ. Screening CT colonography: how I do it. AJR Am J Roentgenol 2007; 189: 290– 8. 6 Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: An underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005; 16: 3389– 96. 7 Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med 2003; 349: 2191–200. 8 Kim DH, Pickhardt PJ, Hinshaw JL, Taylor AJ, Mukherjee R, Pfau PR. Prospective blinded trial comparing 45-mL and 90-mL doses of oral sodium phosphate for bowel preparation before computed tomographic colonography. J Comp Assist Tomogr 2007; 31: 53–8. 9 Summers RM, Yao JH, Pickhardt PJ, et al. Computed tomographic virtual colonoscopy computer-aided polyp detection in a screening population. Gastroenterology 2005; 129: 1832–44. 10 Summers RM, Franaszek M, Miller MT, Pickhardt PJ, Choi JR, Schindler WR. Computer-aided detection of polyps on oral contrastenhanced CT colonography. AJR Am J Roentgenol 2005; 184: 105–8. 11 Shinners TJ, Pickhardt PJ, Taylor AJ, Jones DA, Olsen CH. Patient-controlled room air insufflation versus automated carbon dioxide delivery for CT colonography. AJR Am J Roentgenol 2006; 186: 1491–6. 12 Choi M, Taylor AJ, VonBerge JL, Bartels CM, Pickhardt PJ. Can the CT scout reliably assess for adequate colonic distention at CT colonography? AJR Am J Roentgenol 2005; 184: 21–2. 13 Radiation Risk In Perspective: Position Statement Of the Health Physics Society. Health Physics Society, adopted January 1996, revised August 2004. 14 Brenner DJ, Georgsson MA. Mass screening with CT colonography: Should the radiation exposure be of concern? Gastroenterology 2005; 129: 328–37. 15 Pickhardt PJ. Three-dimensional endoluminal CT colonography (virtual colonoscopy): Comparison of three commercially available systems. AJR Am J Roentgenol 2003; 181: 1599–606. 16 Pickhardt PJ, Taylor AJ, Gopal DV. Surface visualization at 3D endoluminal CT colonography: Degree of coverage and implications for polyp detection. Gastroenterology 2006; 130: 1582–7. 17 Pickhardt PJ. Translucency rendering in 3D endoluminal CT colonography: A useful tool for increasing polyp specificity and decreasing interpretation time. AJR Am J Roentgenol 2004; 183: 429–36.

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18 Pickhardt PJ, Choi JHR. Electronic cleansing and stool tagging in CT colonography: Advantages and pitfalls with primary threedimensional evaluation. AJR Am J Roentgenol 2003; 181: 799–805. 19 Pickhardt PJ. Differential diagnosis of polypoid lesions seen at CT colonography (virtual colonoscopy). Radiographics 2004; 24: 1535–56. 20 Ray Q, Kim C, Scott T, Duncan B, Brown G, Jensen D, Cash BD. Gastroenterologist interpretation of CTC: pilot study demonstrating feasibility and similar accuracy compared to radiologists. Gastroenterology 2007; 132: A92–3. 21 Patrick A, Jackson L, Bell J, Epstein O. High proficiency reading of V3D virtual colonoscopy by experienced optical endoscopists and endoscopy nurses; a new era in colonoscopy? Gastrointest Endosc 2007; 65: AB129. 22 Bodily KD, Fletcher JG, Engelby T, et al. Nonradiologists as second readers for intraluminal findings at CT colonography. Acad Radiol 2005; 12: 67–73. 23 Taylor SA, Halligan S, Burling D, et al. CT colonography: effect of experience and training on reader performance. Eur Radiol 2004; 14: 1025–33. 24 European Society of Gastrointestinal and Abdominal Radiology CT Colonography Study Group Investigators. Effect of directed training on reader performance for CT colonography: multicenter study. Radiology 2007; 242: 152– 61. 25 Jensch S, van Gelder RE, Florie J, et al. Performance of radiographers in the evaluation of CT colonographic images. AJR Am J Roentgenol 2007; 188: W249–55. 26 Zalis ME, Barish MA, Choi JR, et al. CT colonography reporting and data system: A consensus proposal. Radiology 2005; 236: 3–9. 27 Rex DK, Lieberman D. ACG colorectal cancer prevention action plan: update on CT-colonography. Am J Gastroenterol 2006; 101: 1410–3. 28 Rockey DC, Barish M, Brill JV, et al. Standards for gastroenterologists for performing and interpreting diagnostic computed tomographic colonography. Gastroenterology 2007; 133: 1005–24. 29 Rex DK. Colonoscopy is justified for any polyp discovered during computed tomographic colonographyaPRO: Patients with polyps smaller than 1 cm on computed tomographic colonography should be offered colonoscopy and polypectomy. Am J Gastroenterol 2005; 100: 1903–5. 30 Morrin MM, Kruskal JB, Farrell RJ, Goldberg SN, McGee JB, Raptopoulos V. Endoluminal CT colonography after an incomplete endoscopic colonoscopy. AJR Am J Roentgenol 1999; 172: 913– 18. 31 Macari M, Berman P, Dicker M, Milano A, Megibow AJ. Usefulness of CT colonography in patients with incomplete colonoscopy. AJR Am J Roentgenol 1999; 173: 561– 4. 32 Copel L, Sosna J, Kruskal JB, Raptopoulos V, Farrell RJ, Morrin MM. CT colonography in 546 patients with incomplete colonoscopy. Radiology 2007; 244: 471– 8. 33 Hanson ME, Pickhardt PJ, Kim DH, Pfau PR. Anatomic factors predictive of incomplete colonoscopy based on findings at CT colonography. AJR Am J Roentgenol 2007; 189: 774– 9.

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34 Seeff LC, Manninen DL, Dong FB, et al. Is there endoscopic capacity to provide colorectal cancer screening to the unscreened population in the United States? Gastroenterology 2004; 127: 1661–9. 35 Cooper GS, Doug Kou T. Underuse of colorectal cancer screening in a cohort of Medicare beneficiaries. Cancer 2007; 112: 293–9. 36 Schwartz DC, Dasher KJ, Said A, et al. Impact of a CT colonography screening program on endoscopic colonoscopy in clinical practice. Am J Gastroenterol 2007; 102: 346–51. 37 Hara AK, Johnson CD, Reed JE, et al. Detection of colorectal polyps with CT colography: initial assessment of sensitivity and specificity. Radiology 1997; 205: 59–65. 38 Fenlon HM, Nunes DP, Schroy PC 3rd, Barish MA, Clarke PD, Ferrucci JT. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med 1999; 341: 1496–503. 39 Yee J, Akerkar GA, Hung RK, Steinauer-Gebauer AM, Wall SD, McQuaid KR. Colorectal neoplasia: performance characteristics of CT colonography for detection in 300 patients. Radiology 2001; 219: 685– 92. 40 Cotton PB, Durkalski VL, Pineau BC, et al. Computed tomographic colonography (virtual colonoscopy): a multicenter comparison with standard colonoscopy for detection of colorectal neoplasia. JAMA 2004; 291: 1713–19. 41 Rockey DC, Poulson E, Niedzwiecki D, et al. Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison. Lancet 2005; 365: 305–11. 42 Cash BD, Kim C, Jensen D, et al. Accuracy of computed tomographic colonography for colorectal cancer screening in asymptomatic individuals. Gastroenterology 2007; 132: A92-A. 43 Graser A, Stieber P, Nagel D, et al. Comparison of CT colonography colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population. Gut 2009; 58: 241–8. 44 Pickhardt PJ, Lee AD, Taylor AJ, et al. Primary 2D versus primary 3D polyp detection at screening CT colonography. AJR Am J Roentgenol 2007; 189: 1451–6. 45 Johnson CD, Chen MH, Toledano AY, et al. Accuracy of CT colonography for detection of large adenomas and cancers. N Engl J Med 2008; 359: 1207–17. 46 Halligan S, Altman DG, Taylor SA, et al. CT colonography in the detection of colorectal polyps and cancer: Systematic review metaanalysis and proposed minimum data set for study level reporting. Radiology 2006; 238: 893–904. 47 Bressler B, Paszat LF, Vinden C, Li C, He JS, Rabeneck L. Colonoscopic miss rates for right-sided colon cancer: A population-based analysis. Gastroenterology 2004; 127: 452–6. 48 Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for detection of colorectal cancer in clinical practice. Gastroenterology 1997; 112: 17–23. 49 Pickhardt PJ, Kim DH. CT colonography (virtual colonoscopy): a practical approach for population screening. Radiol Clin North Am 2007; 45: 361–75.

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New Colonoscopes and Assist Devices Simon Bar-Meir Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel

Colonoscopy with polypectomy has been shown to reduce the rate of colon cancer by 76–90% compared with a reference population [1]. At Digestive Diseases Week (DDW) 2007, the National Polyp Study investigators extended their observations to describe a significant long-term reduction in colorectal cancer mortality associated with polypectomy [2]. However, patient compliance is limited [3]. Patients avoid colonoscopy because they consider it embarrassing, painful, and invasive. They are concerned about the sedation and the risk of perforation. Colonoscopy using the current commercially available systems also requires significant training. In many countries there are not enough skilled physicians to perform colonoscopy. For these reasons there has been interest in new platforms that allow endoscopic imaging of the colon but which are safer, less painful, and/or less skill dependent than current commercial systems. Several new devices to examine the colon have been developed; some of them may become an alternative technique to traditional colonoscopy. Others will assist conventional colonoscopy to become more comfortable for the patient and not require the skill set necessary for total intubation by a physician for every examination [4]. NeoGuide Systems (Los Gatos, CA, USA) has developed a system to address the problem of looping in colonoscopy. Conventional colonoscopy consists in inserting a flexible scope into a flexible, highly distensible organ. In order to advance, the colonoscope is pushed into the colon, moving it, stretching it, and elongating it. When the scope is advanced, forces are not directly transmitted to the tip. Instead, the colonoscope deflects the colon wall and stretches the mesentery. Studies have demonstrated that looping, which occurs in virtually all cases, is responsible for more than 90% of the pain in colonoscopy and adds significantly to the insertion time [5]. The NeoGuide colonoscope works in a different way than conventional endoscopy systems. It employs computer-assisted

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

technology, with the scope shaft composed of multiple independent bendable segments designed to reduce looping during the procedure. The system constantly monitors the insertion depth of the scope and the position of the colonoscope’s tip, combing this information to build a real time, threedimensional map of the patient’s colon. As the scope is inserted, the system uses the map developed by the leading segment to direct each of the bendable segments to follow the path taken by the tip. As with conventional colonoscopy, the physician inserts the scope and steers the tip using the image on the monitor. The angulation controls are similar to those for standard colonoscopy but a recent modification has replaced the current steering mechanism with a joystick thumb control. During insertion, the NeoGuide instrument can be made flaccid to allow straightening of the instrument shaft and colon, which is followed by reactivation of the system with readvancement of the now straightened shape. Potential benefits of the NeoGuide colonoscope include a reduction in procedure time, a reduction or elimination of the need for sedation by reducing loop formation, and making the colonoscopy procedure physically and technically easier for the operator. The NeoGuide technology produces a three-dimensional map of the colon which can be used for “marking” and remembering the location of polyps, thus facilitating identification and resection of polyps during withdrawal. Also, if polyps are found to be malignant, the map can be used by surgeons. Studies with a realistic bench-top colon model demonstrated a significant reduction in looping compared with a conventional colonoscope [6]. The only report on this system was conducted at Klinikum Ludwigshafen, Germany, and included only 10 patients with a 100% cecal intubation rate over 20 min [7]. Two of the patients had diverticulosis. In nine patients the ileum was entered as well. Three of the patients had polyps, which were removed during the procedure. Most patients were sedated for the examination. The Neo Endoscopy System differs from some of the other emerging colonoscopy concepts in two fundamental ways. First, it is not a screening-only device. The NeoGuide scope has a standard working channel, allowing biopsies, polypectomies,

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Figure 58.2 The Aer-O-Scope scanning balloon. The capsule endoscope is on the right and the supply cable is to the left.

Figure 58.1 The Aer-O-Scope console. (Photo courtesy of GI View Ltd and reproduced with permission.)

and other therapies to be performed with standard tools. For the significant number of screening colonoscopies in which polyps are found, a second procedure is not required. Second, the NeoGuide scope can be cleaned and disinfected with standard reprocessing techniques. Endoscopes that can be reprocessed generally have much lower costs per case than disposable scopes. At present time the development of this promising technology is postponed since the company has decided to invest its resources in NOTES, which uses the same Neotechnology, and it does not expect to the Neo colonoscope to be commercially available in the near future.

(a)

(b)

Aer-O-Scope is a device that is composed of a disposable component and a workstation (Figure 58.1) [8]. The disposable unit consists of a rectal introducer, a supply cable, and an endoscope embedded within a scanning balloon (Figure 58.2). The introducer is inserted into the rectum with its outer balloon. The endoscope and its scanning balloon are passed through the hollow tube of the introducer (Figure 58.3). The silicone balloon on the introducer seals the anus to prevent gas leakage. CO2 is insufflated between the two inflated balloons and gas pressure advances the scanning balloon with its electro-optical capsule together with the trailing supply cable for electricity, air, water, and suction. Three automated, independent pressure regulators ensure that the preset maximal colonic pressure is not exceeded. The capsule at the distal tip of the supply cable contains a camera and white-light emission diodes (LEDs) within the transparent dome, which provide illumination. The scanning balloon has a hydrophilic coating to minimize friction with the walls of the colon. The user interface is provided via a PC-based workstation with integrated interface for the electronic medical record. The workstation is connected to the colonoscope via a disposable supply cable. The operator follows the advancement of the scope on a dedicated monitor. Once the Aer-O-Scope reaches the maximal

(c)

Figure 58.3 Schematic demonstration of the Aer-O-Scope propulsion system. (a) The stationary rectal balloon is positioned and inflated. The scanning balloon is inflated. (b) Carbon dioxide is inflated between the balloonsbgas pressure (P2) pushes the scanning balloon forward. (c) After reaching the cecum, gas distal to the scanning balloon is removed and gas is injected proximal to the scanning balloon, reversing its direction.

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Figure 58.4 Schematic of the angle of view of the Aer-O-Scope’s imaging system, which includes a 90° forward-viewing lens and a circumferential (OMNI) lens with 25° of both forward and retro vision.

insertion depth the reverse mode is activated. Automatically, the pressure behind and inside of the balloon is reduced, while the colon in front of the balloon is insufflated with CO2, thus creating a small pressure gradient in front of the balloon, and the direction of travel is reversed. The device has no instrument channel and neither biopsy nor therapeutic procedures are possible. Aer-O-Scope provides a circumferential 360° view of the colon (Figure 58.4). There is also a 25° retro vision, which facilitates inspection of the proximal aspect of colonic folds without the need for tip manipulation. The sensitivity for detecting beads of any size in a colonic pig model was 97%, with a high rate of agreement between different operators [9]. The system is operated by a single control mechanism and is not operator dependent. The part that enters the patient is disposable, thus reducing the chance of cross-infection, but at a higher cost than conventional colonoscopy. The company (GI View, Israel) has reported on more than 40 humans who underwent the examination. A publication exists on 12 unsedated volunteers who underwent the procedure; in 10 the cecum was successfully reached. Only two patients requested sedation [10]. No complications were reported. The Aer-O-Scope is not commercially available. Stryker’s ProtectiScope® (Stryker Endoscopy, San Jose, CA, USA) utilizes advanced microelectronic video technology, without the need for fiberoptic illumination [11]. Full-color video together with an integrated LED light source provide real-time viewing of the colon. The scope has a nondisposable core structure used in conjunction with disposable components that include a thin, pliable, protective outer sleeve and disposable inner channels. These disposable components eliminate the need to disinfect the scope between procedures. The ProtectiScope provides diagnostic and therapeutic colonoscopy capability. The ProtectiScope navigates through the tortuous colon by using two types of insufflation: traditional intracolonic insufflation and a sealed sleeve insufflation. This

New Colonoscopes and Assist Devices

second insufflation capacity is the main component of the air-assisted technology used to deploy the disposable sheath during the insertion of the scope. As air is insufflated to the area just below the distal tip of the device, the sleeve unfolds from a canister just outside the anus (held in place by a special diaper), thus creating minimal forward force. The ProtectiScope allows greater protection from cross-contamination. All parts of the ProtectiScope that come in contact with contaminated organic materials during normal use are disposable. As a result, the possibility of disease transmission is reduced. The company reported studies on 169 patients, with cecal intubation in 91% and with no complications. Based on information given by the company, in the last 50 cases, using the most recent device model, the success rate for reaching the cecum was 98% and there were no immediate or delayed complications. Biopsies and polypectomies were also performed. Bacteriological cultures obtained post procedure from various areas of the scope that were protected by the sheath showed the sheath barrier to be effective in protecting the nondisposable components and the physician. The disposable parts make it significantly more expensive than traditional colonoscopy. However, there is no need for cleaning or disinfection, and only one upper core structure and one lower core structure are required in each procedure room, where the turnover of cases can be rapid, with a 5-min turnaround time while the assistant replaces the soiled apparatus with a fresh set-up. The ProtectiScope is currently not commercially available. Invendo Medical (Weinheim, Germany) has developed a single-use colonoscope [11] consisting of an endoscope sheath, a tip which is electrohydraulically deflected, and an inverted sleeve (Figure 58.5 and 58.6). The 3.2-mm working channel can be used for biopsies and polypectomies (Figure 58.7). After the examination the colonoscope is completely discarded, eliminating any potential cross-infection risk and any need for cleaning, disinfection, and sterilization. Compared with conventional colonoscopy, Invendo’s endoscope is not manually pushed or pulled, but, with the support

Figure 58.5 Schematic of the propulsion system of the Invendoscope. Rollers in the motor advance the sheath (black arrows). As the sheath rolls forward and everts from inside to outside (red arrows) it extends the length of the instrument and advances the instrument tip. Force is applied at the tip rather than along the instrument shaft, reducing pushing force on the mesentery.

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Figure 58.6 The opened hydraulic system of the Invendoscope.

Figure 58.8 The PillCam Colon compared with the esophageal and small bowel capsules. Compared with the small bowel capsule, the colon device is 5 mm longer, has two viewing heads and a frame speed of 2/s on each end. The newer version will have wider angles of view and faster frame speeds. (Photo courtesy of Given Imaging, Yoqneam, Israel.)

Figure 58.7 The tip of the Invendoscope. The light source is light-emitting diodes. The imaging chip is CMOS. The instrument has a working channel.

of a handheld control and an endoscope driving unit, it is driven in and out of the colon. The physician controls the device by activating the “Forward drive” and “Backward drive” keys on the handheld control unit. By manipulating the joystick of the hand control unit the physician can electrohydraulically deflect the endoscope tip 180° in every direction and can therefore steer the colonoscope during the drive through the colon. The sheath of the Invendo colonoscope is very flexible, allowing for a small bending diameter. Combined with Invendo’s innovative inverted sleeve technology, it enables the endoscope to move very gently through the colon, minimizing possible pain. The Invendo colonoscope is intended to be

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used without sedation. The outer wall of the sheath is completely motionless and may be held at the anus with no need to push it forward. Intubation is achieved by the continuous eversion of an inner portion of the sleeve which carries the optical system and the instrument channel. According to the company, examinations were performed on more than 200 unsedated volunteers; cecal intubation was achieved in more than 80% with only minimal discomfort and without complications. In a recent study, Rosch et al. [12] reported on 28 healthy asymptomatic volunteers who underwent the examination with the aim of reaching the cecum. In four cases there were different technical failures of the scope mechanisms. Among the 24 remaining examinations, the cecum was reached in 19 cases (79%); in two of them passage beyond the sigmoid colon was not possible due to pain. The mean time to reach the cecum was 26 min. No complications were reported. All procedures were performed without sedation. At the present time the company is trying to produce a longer scope in order to achieve a better rate of cecal intubation. A longer tube, however, increases friction to a point at which operation is difficult. At the present time this device is not commercially available. The PillCam Colon capsule (Given Imaging, Yoqneam, Israel) (see Chapter 23) is a new capsule for visualization of the colon [13,14], building on the technology successfully applied to the small bowel. The 11 × 31 mm capsule (Figure 58.8) has dual cameras which obtain two frames per camera per second, i.e., a total of four frames per second. The camera has wide-field view optics (Figure 58.9), automatic light con-

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Figure 58.9 Images of the colon taken with the first version of the PillCam Colon. (Photo courtesy of Given Imaging, Yoqneam, Israel.)

trol, and a total operating time of approximately 10 h. On ingestion, the capsule is turned on for 3 min. It then switches off to a delay mode for almost 2 h and spontaneously turns on for another 8 h. Such a program also allows the visualization of the gastroesophageal junction, the terminal ileum, and the colon. It therefore has the added benefit of enabling viewing the esophagus and screening for Barrett’s esophagus and also detecting pathology in the terminal ileum. Like the PillCam Small Bowel capsule, the system includes sensors array and a data recorder, which are connected to the patient during the procedure. Following the procedure, the recorded data are downloaded into the Given Imaging Rapid® workstation for review of the colonic video. The preparation procedure uses standard, commercially available, laxative and prokinetic agents but the cathartic regimen is quite vigorous to ensure a clear view of a clean colon. During the procedure there is no need for intubation or insufflation of the colon. The PillCam Colon capsule is currently under evaluation in relation to conventional colonoscopy in several trials. Two of the trials (Israeli and Belgian) have been published [13,14]. In the Israeli trial [13], 84 patients underwent both capsule endoscopy and colonoscopy. Ten hours following capsule ingestion, 78% of the patients had excreted the capsule. In the rest the capsule was detected in the rectosigmoid region. The detection rate for significant polyps was similar with both capsule endoscopy and colonoscopy, 70% and 80%, respectively. The examination was not associated with any complication. In the Belgian trial [14], the sensitivity of the capsule for significant polyps was slightly higher, at 77%. An additional trial, presented at the annual meeting of the American College of Gastroenterology [15], found the sensitivity of polyp detection to be 79% and 89% for capsule endoscopy

and conventional colonoscopy, respectively. Both tests were significantly better than virtual colonoscopy, with a sensitivity of 32%. However, the specificity of the capsule in this study was only 53%, less than the 97% and 100% for the virtual and conventional colonoscopy, respectively. An interim analysis of a multicenter pan-European trial was presented at the 2007 United European Gastroenterology Week (UEGW) [16]. A total of 166 patients underwent screening with the PillCam Colon capsule endoscopy. For significant polyps, the sensitivity was 72%, the specificity 80%, and the negative predictive value 77%. The colonic capsule may turn out to be a useful examination for colon cancer polyp screening. CathCam is a rescue colonoscope that facilitates the completion of colonoscopy when a regular colonoscope fails [17]. It is nonsteerable but more flexible than a standard colonoscope and is advanced over a looped guidewire continually extruded from the tip of the device. The weight of the CathCam endoscope is 565 g compared with 1240 g for a standard colonoscope. The lightness permits an easier passage over the guidewire. Following its own guidewire makes the tortuous path toward the cecum easier and possibly reduces patient discomfort. In comparative studies in pigs, this system has been shown to improve advancement and reduce the push force required for colonoscopy. In the first human study of CathCam for failed colonoscopies, the cecum was reached in 12 out of 13 cases [18]. However, CathCam is not an independent technique. It is based on performing colonoscopy first and, when further advancement is impossible, a guidewire is inserted and the colonoscope removed. The CathCam is then advanced over the guidewire. Such a procedure is time-consuming and should be reserved only for the very few difficult cases. CathCam is

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Figure 58.11 The USGI ShapeLock device. On top is the reusable tube of metal links. The blue handle is opened to place the device in the flexible and closed to place it in the locked mode. On the bottom is the disposable sheath which lines both the inside and outside of the metal links. The soft white tip reduces mucosal trauma during insertion.

Figure 58.10 The Endo-Ease device (photo courtesy of Spirus Inc.). Two lengths of the device are available.

not commercially available, and efforts to further develop it at this time have been temporarily postponed. Spirus Medical (Stoughton, MA, USA) developed the EndoEase™ Endoluminal Advancement System. It is a single-use device that slides over and is preloaded onto the colonoscope. This flexible 65-cm overtube has two spiral ridges applied along the outer walls of the device. It is coupled with the colonoscope with a nonleak seal as it is twisted clockwise over the shaft to “screw” the scope through the sigmoid colon (Figure 58.10). The spiral has a natural tendency to follow the lumen of the colon as it is rotated with gentle forward pressure. Once the sigmoid colon has been traversed, it is stabilized by the Endo-Ease overtube while the scope is independently advanced through the remainder of the colon. The USGI ShapeLock device was originally developed as an assist device for colonoscopy (Figure 58.11). The ShapeLock is an overtube that is backloaded onto the colonoscope and utilized to resist loop formation. The device is made in lengths of 60 and 80 cm and can be used with both pediatric and standard colonoscopes. The inner sheath is reusable and consists of a series of metal rings linked together. When the handle of the device is opened, the rings separate slightly and the tube becomes lax and flexible. When the handle is closed, the rings move together and the tube becomes rigid in whatever position it was in. A disposable sheath with a hydrophilic

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inner lining is pulled over the reusable metal ring tube and covers the rings on both the inside and the outside. A soft tip on the end protects the mucosa during insertion of the device. Clinical trials [19] have shown the device to be as safe as an overtube with no significant mucosal trauma, as is often seen with older overtubes that leave gaps between the tube and the colonoscope. The device has been used to complete colonoscopy in difficult cases in which sigmoid looping and redundancy could not be overcome [20]. USGI is now developing the technology primarily as a platform for NOTES. The device is available for use in colonoscopy but is too expensive for routine cases and required only very occasionally by experts for very difficult cases of redundant colons. A novel retrograde-viewing auxiliary imaging device (Third Eye Retroscope, Avantis Medical Systems, Sunnyvale, CA, USA) improves the visualization of the proximal aspect of the colonic folds. It is positioned within the channel of the adult colonoscope. As the tip of the device enters the colon lumen it bends 180° and is positioned with its lens 4 cm beyond the tip of the colonoscope [21]. The auxiliary device is connected to its external power source and video processing system. Its integrated LED eliminates the need for fiberoptics and an external light source. Images from the colonoscope and the auxiliary device are viewed simultaneously on side by-side monitors. In the simulated pig model, the retrograde viewing auxiliary imaging device significantly improved detection rates of simulated polyps that were on the proximal aspect of colonic folds to 81% vs. 12% with the conventional colonoscope. In summary, there are alternative and complementary new techniques to examine the colon, only the capsule being non-invasive. Many claim to reduce pain and use less or no sedation. All instruments, except NeoGuide, are fully disposable or have a disposable portion. Disposability may be advantageous because it eliminates the potential risk of cross-infection, but, at the same time, it may significantly increase cost. Therapeutic option exists in only some of these

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new technologies/devices, and two of them (Aer-O-Scope and capsule endoscopy) are not operator dependent, thus making them attractive for screening colonoscopy.

References 1 Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993; 329: 1977– 81. 2 Zauber A, Winawer S, O’Brien M, Shi W, Payuga S. Significant long term reduction in colorectal cancer mortality with colonoscopic polypectomy: findings of the National Polyp Study. Gastroenterology 2007; 132: A-50. 3 Gili M, Roca M, Ferrer V, Obrador A, Cabeza E. Psychosocial factors associated with the adherence to a colorectal cancer screening program. Cancer Detect Prevent 2006; 30: 354– 60. 4 Rösch T, Eickhoff A, Fritscher-Ravens A, Eliakim R, Arber N. The new scopesabroadening the colonoscopy marketplace. Digestion 2007; 76: 42–50. 5 Shah SG, Brooker JC, Thapar C, Williams CB, Saunders BP. Patient pain during colonoscopy: an analysis using real-time magnetic endoscope imaging. Endoscopy 2002; 34: 435– 40. 6 Eickhoff A, Jakobs R, Kamal A, Mermash S, Riemann JF, van Dam J. In vitro evaluation of forces exerted by a new computerassisted colonoscope (the NeoGuide Endoscopy System). Endoscopy 2006; 38: 1224– 9. 7 Eickhoff A, van Dam J, Jakobs R, et al. Computer-assisted colonoscopy (the NeoGuide Endoscopy System): results of the first human clinical trial (“PACE study”). Am J Gastroenterol 2007; 102: 261– 6. 8 Pfeffer J, Grinshpon R, Rex D, et al. The Aer-O-Scope: proof of the concept of a pneumatic, skill-independent, self-propelling, self-navigating colonoscope in a pig model. Endoscopy 2006; 38: 144– 8. 9 Arber N, Grinshpon R, Pfeffer J, Maor L, Bar-Meir S, Rex D. Proof-of-concept study of the Aer-O-Scope omnidirectional colonoscopic viewing system in ex vivo and in vivo porcine models. Endoscopy 2007; 39: 412–17.

New Colonoscopes and Assist Devices

10 Vucelic B, Rex D, Pulanic R, et al. The Aer-O-Scope: proof of concept of a pneumatic, skill-independent, self-propelling, selfnavigating colonoscope. Gastroenterology 2006; 130: 672–7. 11 Bar-Meir S, Wallace MB. Diagnostic colonoscopy: the end is coming. Gastroenterology 2006; 131: 992–4. 12 Rosch T, Adler A, Wiedenmann R, Hoepffner N. A prospective pilot study to assess technical performance of a new single use colonoscope with inverted sleeve technology. Gastrointest Endosc 2007; 65: A340. 13 Eliakim R, Fireman Z, Gralnek IM, et al. Evaluation of the PillCam Colon capsule in the detection of colonic pathology: results of the first multicenter, prospective, comparative study. Endoscopy 2006; 38: 963–70. 14 Schoofs N, Devière J, Van Gossum A. PillCam colon capsule endoscopy compared with colonoscopy for colorectal tumor diagnosis: a prospective pilot study. Endoscopy 2006; 38: 971–7. 15 Lewis B, Rex D, Lieberman D. Capsule endoscopyaan interim report of a pilot 3 arm, blinded trial of capsule endoscopy, virtual colonoscopy and colonoscopy [abstract]. Am J Gastroenterol 2006; 101: S559. 16 Schoofs N, Munoz-Navaz M, Fernandez-Urien I, et al. PillCam Colon capsule endoscopy compared with colonoscopy in detection of colon polyps and cancers: interim analysis of a prospective multicenter trial. Endoscopy 2007; 39(Suppl. I): A71. 17 Long G, Fritscher-Ravens A, Mosse CA, Mills T, Swain P. The Cath-Cam: a new concept in colonoscopy. Gastrointest Endosc 2006; 64: 997–1001. 18 Fritscher-Ravens A, Fox S, Swain CP, Milla P, Long G. CathCam guide wire-directed colonoscopy: first pilot study in patients with a previous incomplete colonoscopy. Endoscopy 2006; 38: 209–13. 19 Rex DK, Khashab M, Raju GS, Pasricha J, Kozarek R. Insertability and safety of a shape-locking device for colonoscopy. Am J Gastroenterol 2005; 100: 817–20. 20 Rex DK, Chen SC, Overhiser AJ. Colonoscopy technique in consecutive patients referred for prior incomplete colonoscopy. Clin Gastroenterol Hepatol 2007; 5: 879– 83. 21 Triadafilopoulos G, Watts HD, Higgins J, Van Dam J. A novel retrograde-viewing auxiliary imaging device (Third Eye Retroscope) improves the detection of simulated polyps in anatomic models of the colon. Gastrointest Endosc 2007; 65: 139–44.

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The Future of Colonoscopy Pankaj J. Pasricha, Michael J. Krier & R.D. Brewer Stanford University School of Medicine, Stanford, CA, USA

Introduction Colonoscopy, more than any other procedure, has become the defining symbol for gastroenterology today. Although impressive progress has been made in imaging technology, the basic instrument and techniques for colonic intubation have changed little over the past few decades. Further, until now, gastroenterologists have also shown limited imagination in expanding the indications for this procedure. It is the purpose of this chapter to look beyond these constraints, whether they be conceptual or real, and speculate on what the next 10–20 years may bring. Rather than provide details of specific embodiments, we will take a more philosophic approach to predict broad concepts about how colonoscopy will change in the next decade or so. In this regard, it is useful to distinguish screening colonoscopy from colonoscopy for other uses (diagnostic and therapeutic) as future developments are likely to differ dramatically in the two instances.

ing and technical assistance, as well as by the indirect costs of missed work. Further, at present there exists a great gulf between the supply and demand for colonoscopy. It has been estimated that it would take an additional 5–10 years and over 32 700 more gastroenterologists just to cover the current unscreened US population of 41.8 million [1,2]. Finally, it is also clear that colonoscopy is at best a tarnished gold standard. There is now a well-substantiated concern that traditional colonoscopy might not be actually delivering completely on its promise of detecting premalignant lesions and hence preventing colorectal cancer. Computed tomography colonography (CTC) and the utilization of segmental unblinding (colonoscopy performed in light of CTC findings) have led to estimates of new colonoscopy miss rates for adenomas (> 1 cm) of between 12% and 17%, much higher than previously thought [2,3]. This could merely be highlighting known weaknesses of current colonoscopy methods, i.e., anatomical factors, with lesions lying behind folds and flexures, variability in endoscopic skill levels producing detection rates varying 4- to 10-fold within the same practice, and inadequate time spent on inspection of the mucosa [5,6].

The future of screening colonoscopy Innovations in screening endoscopy Unmet needs and drivers of change After a 20-year drought in endoscopic innovation, a variety of new technologies have recently emerged. Much of this effort is almost exclusively focused on screening colonoscopy and driven by several converging factors. First, from the perspective of patient convenience, colonoscopy is far from ideal. It involves an elaborate and disruptive preparation, a missed day of work, and has the potential, albeit small, for discomfort and complications. Second, there are significant socioeconomic issues with using colonoscopy as a screening modality. Colonoscopy as currently practiced is a very expensive procedure, driven by the fact that it requires a highly trained physician, with nurs-

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

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With the above as a background one can conceptually classify current and future innovations for screening colonoscopy using the present platform in one of three, partially overlapping, categories. • making intubation quicker and less painful; • making intubation easy enough for nonphysicians to perform colonoscopy; • ensuring detection of all significant lesions. These developments are covered in detail in other chapters in this book. We will confine our remarks to technologies with the broadest potential impact.

Capsule and microrobotic technology Following up the success with the small bowel is a specially designed capsule for colonoscopy. Theoretically, this could be an ideal technologyaease of use, minimal operator training, sedationless operation, and low perforation risk. Recently, in 2006, the first generation of such a capsule became available

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in the form of PillCam Colon® (Given Imaging Ltd., Yoqneam, Israel). The capsule is an 11 × 32 mm dual-camera device that provides for a wide coverage area, twice that of the familiar small bowel capsule. The dual-camera system operates at four frames per second and has a total operating time of nearly 10 h. After being turned on and then swallowed, the capsule can operate in a pre-program delay mode (approximately 2 h), after which it spontaneously “wakes up” and restarts to capture images of the colon. A large three-center pilot trial in Israel (n = 91) compared the device with standard colonoscopy [7]. When compared with conventional colonoscopy, the capsule had a sensitivity of 56% and a specificity of 69% in finding polyps of any size; for polyps ≥ 6 mm, the corresponding figures were 69% and 81%. A smaller Belgian study showed a similar, if slightly higher, overall sensitivity of 77% for identifying polyps ≥ 6 mm or finding three (or more) polyps of any size [8]. Interestingly, seven polyps greater than 6 mm in size were identified by the capsule that were not seen by colonoscopy. Unfortunately, there was no further comment on the morphology or other characteristics of these lesions. Although the detection rates published in these early studies are clearly not acceptable, the concept of a “screening pill” is immensely appealing, and will continue to drive efforts to overcome the many formidable technological hurdles that are inherent in this approach. In addition to polyp detection, the technology can also be used to detect other lesions of interest such as diverticulosis, arteriovenous malformations, colitis, and melanosis coli [9]. Just as the small bowel capsule is now providing a further tool for irritable bowel disease investigators, it is easy to speculate that this benefit might be extended to the colon. A significant limitation of capsule endoscopy technology has been an inability to control orientation or movement of the capsule within the gastrointestinal tract. However, progress has been made toward developing microrobotic systems (capsules with controllability) that provide the ability to redirect capsules in position and orientation. These systems generally fall into two categories: maneuverable capsules that are swallowed and self-propelling microrobots that are rectally inserted.

Maneuverable capsules The Olympus Corporation (Tokyo, Japan), in collaborative efforts with others, is currently developing a maneuverable capsule in which locomotion is provided through the use of an external magnetic field [10]. The system uses three sets of electromagnets aligned in the x, y, and z direction to create a uniform magnetic field within the colon. A capsule embedded within a “magnetic shell” will align with an external magnetic field such that redirecting this field can reorient the capsule to obtain new views. When the external magnetic field is rotated around an outer spiral structure, the capsule is “threaded” forward or backward in a screw-like motion (Figure 59.1).

The Future of Colonoscopy

Propelling direction

S

Rotational magnetic field

N

Permanent magnet

S Spiral

Capsule N

Figure 59.1 (a–c) Olympus Guidance System: An omnidirectional capsule with propulsion capability by a spiral arrangement that interacts through a rotating magnetic field “screwing” the capsule forward or backward.

Another approach to capsule propulsion is inducing peristalsis through electrostimulation or vibration. Mosse et al. [11] developed a small capsule that can propel itself forward or backward in the small intestine by inducing wall contraction through a small applied electrical current. In vivo porcine experiments showed that currents of approximately 20 mA produced reliable, safe motion in both directions at speeds of up to 4.5 mm/s, including around small bends.

Self-propelled microrobots In contrast to ingestible capsules, there are many microrobotic systems that can be rectally inserted. The vast majority of these systems propel themselves through an “inch-worm” cycle of gaining traction on the colon wall at the base of the robot, extending the central section forward by a small amount, and then regaining traction at a new location. Methods of gaining traction include using the passive friction between many mobile contact points and the collapsed colon wall [14], applying vacuum suction to the walls [15,16], expanding a pneumatic bladder radially to stretch the walls [17–19], and mechanically clamping onto the walls [20]. However, with the exception of mechanical clamping, all of these traction methods currently suffer from weak, unreliable grips that prove impractical. One approach that obtained reliable traction is a combination of suction and mechanical clamping developed by Phee et al. [16], which was able to propel itself up to 50 cm from the anus. One robot which uses traction with the colon wall without the use of “inch-worm” motion is the endoscope developed by Takada [20], which has tracks on its outside, much like the treads on a tank, to maintain continuous traction. From magnetically steered capsules to robots that crawl or “inch” through the colon, there are many novel robotic

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approaches to “active” capsule endoscopy. Although many of these technologies may be years from clinical practice, they provide an innovative glimpse into the future of capsule and microrobotic endoscopy.

to reduced laxative regimens while maintaining accuracy in polyp detection, directly addresses a common complaint leveled at conventional colonoscopy, “the bowel preparation” [32].

The end of screening colonoscopy CT colonography (CTC) and variants CTC presents a promising new technology for the detection of colorectal polyps and cancers. Initially derided and opposed by most gastrointestinal societies, the American Gastroenterological Association (AGA) has now published new guidelines for its incorporation into practice in select patient cases [21]. And although a final role in the screening armamentarium is still undecided, it will most certainly be a part of the spectrum of technologies available for the future. As the technology continues to improve and mature with multidetector-row CT, three-dimensional data sets, and postprocessing computeraided detection (CAD), the imaging modality will stake a larger claim in screening. Several comprehensive reviews have recently been published and, while it is not the role of this chapter to elaborate fully on its technique, an examination of the current merits and inherent weaknesses of the technology will be addressed [22–24]. Despite many current advances, several unresolved issues remain before CTC becomes a prime screening modality. Most importantly, a clearer understanding of the natural history of small polyps (6–10 mm) may be necessary before adopting paradigm-shifting strategies to “leave them behind” [25]. Flat or depressed lesions are also causes of missed lesions with eight-detector row CTC, although the concern is also valid for conventional colonoscopy [26]. As a related concern, because most CTC protocols call for the use of an obscuring rectal tube for insufflation, rectal lesions may be overlooked [27]. Further advances that may include identifying characteristic molecular signatures with the incorporation of positron emission tomography or Raman spectroscopy may overcome some of these issues in the future, but at a higher cost [28,29]. From a safety standpoint, new evidence has emerged raising concern for the potential carcinogenic risk of cumulative radiation doses accompanying many current CTC screening strategies [30]. And finally, as with colonoscopy, widespread use of this technique may be limited by the availability of adequately trained examiners (radiologists). There is a steep learning curve associated with this procedure (the threshold for competence has been estimated at about 50 proctored cases), and it still takes an experienced radiologist about 25 min or more to read a case, several times longer than a regular CT series [31]. However, it is also clear that as this technology advances, addressing the above issues, many patients will most certainly welcome the screening option. Indeed, the inherent appeal of CTC in terms of comfort, convenience, and, perhaps, safety (lower complication rate) will become even more compelling as fecal tagging and “electronic cleansing” technology, leading

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All of the above advances presuppose a need for a screening procedure that requires full colonic intubation. However, the vast majority of patients undergoing screening colonoscopy will not have a detectable polyp. Further, if one takes all its attributes into account, colonoscopy is a very unlikely candidate as the first choice for a screening procedure. Indeed, it is difficult to compare it to screening procedures for other common malignancies such as cervical, prostatic, or breast cancer. Narrowing the current risk pool (i.e., anyone over the age of 50 years) using some other technique is an imperative that will inevitably happen within the next 5–10 years. Many such techniques are already in development and include the following.

Genetic screening Despite a variety of promising candidates, there is currently no clinically acceptable blood test for screening for sporadic colorectal cancer [33]. However, given the rapid advances in proteomic and genomic technology, it is conceivable and quite likely that within a few years either a “genetic profile” or a reliable biomarker of sporadic CRC risk will become available. From a public health perspective, this would be enormously valuable even if it enabled 50% reduction in the target population for colonoscopy.

Biomarkers and field defect detection Current paradigms of colorectal carcinogenesis have focused almost exclusively on molecular and cellular events within the neoplastic tissue. However, recent evidence suggests that normal-appearing mucosa also displays subtle alterations in cell turnover and death, accompanied by changes in gene and protein expression. Thus, individuals at risk for CRC may have generalized changes affecting their entire colonic mucosa, the so-called field defect. This phenomenon, if valid, provides several opportunities for screening and surveillance through the use of biomarkers that can identify this vulnerability. Taking this a step further, one can imagine that the technology to detect such a molecular signature can be adapted for use in a primary care setting by simply inserting a probe in the rectum in the place of the usual digital examination. Proof of principle has already been demonstrated in patients with pancreatic cancer. Using light-scattering technology, optical analysis of normal duodenal mucosa from the periampullary region was found to distinguish between pancreatic cancer patients and normal control subjects with 95% sensitivity and 91% specificity [34]. The same group has shown that experimental colorectal carcinogenesis is also associated with an increase in mucosal microvascular flow in conjunction with an increase in inducible nitric oxide synthase (iNOS) activity [35]. If this is proven to be an early

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and characteristic field defect in patients at risk of CRC, then technologies to detect it can theoretically identify not only patients at future risk for developing CRC but also patients harboring polyps or CRC elsewhere in the colon, and target them for a follow-up colonoscopy.

Implications for screening colonoscopy Any one of the potential breakthroughs mentioned above will have a profound impact on screening colonoscopy and may even do away with it altogether, if the predictive value of these tests is high enough. This will also have profound implications for device development in this field: reducing the size of the risk pool may make the demand for screening colonoscopy much more manageable by the current pool of gastroenterologists. More importantly, the population undergoing screening will be far more likely to harbor a polyp and hence it would be cost-effective to have the colonoscopy done by a person who can also perform the polypectomy. Thus, the pressure to create technologies for lesser skilled operators will be significantly mitigated.

Beyond screening: the real future of colonoscopy It is therefore clear that under a variety of reasonably probable scenarios, colonoscopy will shift significantly, if not exclusively, toward nonscreening procedures both for neoplastic and non-neoplastic indications. These will now be discussed in detail.

Future colonoscopy for neoplastic indications Comprehensive lesion detection Once a patient has been identified by screening methods as possibly harboring a neoplastic or preneoplastic lesion, it is of crucial importance that the next diagnostic procedure can guarantee its detection. As mentioned previously, current methods of colonoscopy may miss 10–20% of adenomas,

The Future of Colonoscopy

which is clearly unacceptable. Several innovative approaches to address this problem have been proposed and can be conceptually classified as either those able to identify subtle lesions (e.g., small flat polyps) or hidden ones (around a corner or behind a fold). Much of the innovation in imaging in recent years has been directed toward the former indication, and includes techniques such as magnification endoscopy and a variety of so-called optical biopsy methods, attempting to replace cumbersome and messy dye-based chromoendoscopy. These are discussed in detail in other chapters in this book but at the time of writing few, if any, have been tested with any great scientific vigor to add real value to conventional endoscopy. Other innovations represent a class of auxillary devices that expose lesions hidden behind folds, valves, and flexures which are often missed by conventional forward-viewing colonoscopy. These include simple measures such as the addition of a transparent cap to depress semilunar folds and keep a fixed distance between the endoscope and the colonic mucosa. This method has been shown to result in improved accuracy of polyp detection (49.3% vs. 39.1%, P = 0.04) [36]. Another example of this approach is the wide-angled colonoscope outfitted with a convex lens containing an adjustable angle of view from 160° to 210°, a prototype (Olympus) of which was shown to have a lower miss rate for all polyps versus standard colonoscope (20% vs. 31%; P = 0.046); however, a difference in the detection of adenomas was not demonstrated [37]. Finally, systems such as the Third Eye Retroscope® (Avantis Medical Systems, Sunnyvale, CA, USA) (Figure 59.2) represent a far more elaborate method of providing comprehensive views of the proximal surfaces of folds and valves. Using anatomic colon models with artificial polyps randomly placed including in proximal edges of flexures and folds, the auxiliary camera on average improved proximal lesion detection rates by almost 70% (81% vs. 12% detection rates) when compared with standard forwardviewing colonoscopy [38]. Human trials are currently under way to define the utility of the technology in clinical practice.

Figure 59.2 Third Eye Retroscope® (Avantis Medical Systems, Sunnyvale, CA, USA). A “rear-view mirror” for the colonoscope to peer around those hidden flexures, folds, and valves.

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It is very likely that in a couple of generations the standard colonoscope will evolve into a multimodality imaging tool that will incorporate all the above features along with the new optical biopsy techniques (discussed elsewhere in this volume) into one embodiment.

Simplified resection of neoplastic lesions The increasing recognition of cancerous and precancerous lesions will bring with it several challenges, particularly in the case of complex nonpedunculated lesions. In the last few years, elaborate approaches involving endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been described to deal with these polyps. However, currently these techniques are generally too complicated, timeconsuming, and risky for average gastroenterologists to adopt in their practice. Indeed, even experts frequently refer many of these patients (particularly those suspected of having submucosal extension) for colectomy. Although previous attempts at wedge resection of the colon using endoscopic techniques proved to be impractical, this is a situation in which disruptive technology is likely to play a major role, especially given the overwhelming patient preference for nonsurgical approaches. In the next few years, it is very likely that both superficial and deep cancers will be resectable using colonoscopic techniques that community gastroenterologists can perform easily and safely.

Future colonoscopy and NOTES Natural orifice transluminal endoscopic surgery (NOTES) is part of a revolution in gastrointestinal endoscopy and surgery that has caught the imagination of the specialty. Although much needs to be learnt about its safety and feasibility, the concept presents several opportunities for colonoscopic application. Transanal or transcolonic endoscopy also provides a facile approach to NOTES procedures that are directed at the upper abdomen, thus avoiding the difficult and cumbersome retroflexed maneuvering that is needed with transgastric access. Although there are several theoretical disadvantages of the transcolonic approach, including a greater potential for infectious complications, future studies may well show this to be preferred for certain specific procedures. A more indirect, but perhaps more important, impact of NOTES on colonoscopy is that gastroenterologists can afford to be far more aggressive inside the lumen, taking comfort from the fact that if one can quickly repair a gastrointestinal perforation endoscopically then the outcome is likely to be good. Previously, such an event resulted in a knee-jerk response calling for laparotomy and surgical repair and was a major deterrent for even the most expert of gastroenterologists. Along with developments for simplified mucosal resection and innovations in endoscopic anastomotic techniques, this will greatly accelerate the movement toward nonsurgical resection of colonic lesions. In this context, a transcolonic NOTES approach can also facilitate the exploration and resection of

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regional lymph nodes as part of a complete resective procedure that eliminates the need for surgery altogether.

Future colonoscopy and the submucosal space Access to the nervous system Historically, gastroenterologists have only been interested in examining the lumen of the gastrointestinal tract; more recently, their attention is beginning to be directed at transluminal endoscopic opportunities (i.e., NOTES). However, there is a third, albeit virtual, “space” that is represented by the wall of the tubular organs. As we have shown recently in the esophagus, this zone can also be accessed endoscopically, opening up both diagnostic and therapeutic possibilities. An example is the ability to biopsy deeper layers of the gastrointestinal wall including those that harbor nerves, muscle, and interstitial cells of Cajal (ICC). These tissues have been historically beyond the access of the conventional biopsy forceps. Evolving experimental techniques have already demonstrated the feasibility of this approach to obtain specimens that include the muscularis propria and associated nerves and ICC in the stomach. If adapted to the colon, these methods can provide not only a quantum leap in our understanding of motility and inflammatory disorders, but also a clinically useful diagnostic assay. Further, because changes in the enteric nervous system may parallel those in the central nervous system, this approach may also provide a much more practical way to diagnose and monitor neurological disorders such as Parkinsonism.

Submucosal drug delivery Although the colon is arguably as accessible as the skin, most colonic disorders, unlike dermatological conditions, are not treated topically. There is no good reason for this state of the affairs except for a lack of imagination. Thus, patchy inflammation such a Crohn’s can be treated by injection of drugs at site-specific areas, limiting systemic toxicity. Both superficial and deeper layers of the colonic wall can be targeted and the use of special formulations can provide for sustained longterm release. Submucosal drug delivery in the GI tract can also be used to target liver and pancreatic diseases, taking advantage of the portal circulation to deliver high concentrations of medications.

Future colonoscopy and unmet clinical needs Motility disorders If one looks at the GI “disease pie”, the vast majority of disorders are as yet not approached via a device or procedurebased solution. Further, effective pharmacological therapies also do not exist for many of these problems. An example is that of irritable bowel syndrome (IBS), arguably one of the most common reasons for a patient to see a gastroenterologist. In the future, colonoscopy may well provide a solution for IBS by providing a means of manipulating neuromuscular elements responsible for symptom generation. An example

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Transverse colon

Ascending colon Electrode

Descending colon

The Future of Colonoscopy

this concept of a human as a “supraorganism” is valid, then the colon assumes supreme importance as the residence for our microbiological partners. The colonoscope, with its unique access to this microbiome, can therefore be viewed as an important means of observing and manipulating human physiology and we need to direct our thinking along those lines.

Summary

Ileum

Cecum Sigmoid colon

Figure 59.3 Implanted electrodes for transmural electrical stimulation in the treatment of constipation and pain. From Shafik A, Shafik AA. El-Sibai O, Ahmed I. Colonic Pacing. A therapeutic option for the treatment of constipation due to total colonic inertia. Arch Surg 2004; 139: 775–9.

of such an approach is the use of colonoscopically implanted electrodes for the treatment of pain and constipation (Figure 59.3). Another example is the “silent epidemic” of fecal incontinence resulting from sphincteric incompetence. For years, gastroenterologists have ignored this problem even as they have blithely passed by the sphincter on their way to more proximal sites. Many prosthetic devices for incontinence have been attempted but have not gained popularity because of their complicated nature and invasive method of placement. Recent advances in polymer technology and stem cell biology are providing opportunities to change that. A promising approach in this regard is the use of autologous skeletal muscle cells from the calf muscles that can easily be injected into the sphincter endoscopically; clinical trials in urinary incontinence are under way and being planned for the gastrointestinal tract as well.

Obesity There has been a flurry of developments in minimally invasive approaches to obesity, all directed at the upper gastrointestinal tract. However, the distal ileum and colon also play important roles in the generation of satiety and metabolic regulation via neurohormonal reflexes. These represent significant opportunities for colonoscopically based therapies, via anatomical manipulations, devices, or drugs.

Manipulation of enteric microflora Our concept of what constitutes a human being has been challenged by the recognition that the number of bacteria most of us harbor is 10 times greater than the number of our own cells within our bodies and that these microbial symbionts are important in determining our physiological phenotype, providing valuable supplemental metabolic traits. If

The future of colonoscopy is bright. However, to really exploit its potential, gastroenterologists have to think beyond their current constraints. Both technological developments and advances in biology will need to be incorporated into how we use this procedure to influence profound changes in human health in the coming years.

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36

37

38

opposing crescent appearance as sign of compressed polyp. AJR Am J Roentgenol 2007; 189: W1–3. Gollub MJ, Akhurst T, Markowitz AJ, et al. Combined CT colonography and 18F-FDG PET of colon polyps: potential technique for selective detection of cancer and precancerous lesions. AJR Am J Roentgenol 2007; 188: 130– 8. Li X, Lix, Lei M, Wang D, Lin J. Detection of colon cancer by laser induced fluorescence and Raman spectroscopy. Conf Proc IEEE Eng Med Biol Soc 2005; 7: 6961–4. Brenner, DJ, Hall EJ. Computed tomographyaan increasing source of radiation exposure. N Engl J Med 2007; 357: 2277–84. Ferrucci, JT, Schroy PC. Virtual colonoscopy: good results and not so good resultsawhy the difference? Gastroenterology 2004; 127: 1633–5; discussion 1635–6. Johnson CD, Manduca A, Fletcher JG, et al. Noncathartic CT colonography with stool tagging: performance with and without electronic stool subtraction. AJR Am J Roentgenol 2008; 190: 361–6. Hundt S, Haug U, Brenner H, et al. Blood markers for early detection of colorectal cancer: a systematic review. Cancer Epidemiol Biomarkers Prev 2007; 16: 1935–53. Liu Y, Brand RE, Turzhitsky V, et al. Optical markers in duodenal mucosa predict the presence of pancreatic cancer. Clin Cancer Res 2007; 13: 4392– 9. Roy HK, Wali RK, Kim Y, et al. Inducible nitric oxide synthase (iNOS) mediates the early increase of blood supply (EIBS) in colon carcinogenesis. FEBS Lett 200; 581: 3857– 62. Kondo S, Yamaji Y, Watabe H, et al. A randomized controlled trial evaluating the usefulness of a transparent hood attached to the tip of the colonoscope. Am J Gastroenterol 2007; 102: 75–81. Rex DK, Chadalawada V, Helper DJ. Wide angle colonoscopy with a prototype instrument: impact on miss rates and efficiency as determined by back-to-back colonoscopies. Am J Gastroenterol 2003; 98: 2000–5. Triadafilopoulos G, Watts HD, Higgins J, Van Dam J. A novel retrograde-viewing auxiliary imaging device (Third Eye Retroscope) improves the detection of simulated polyps in anatomic models of the colon. Gastrointest Endosc 2007; 65: 139 – 44.

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Notes: Page numbers in italics refer to figures. As the subject of this book is colonoscopy, entries under this term have been kept to a minimum. Readers are advised to refer to more specific terms. A abciximab, discontinuation, 98 abdominal pain, colonoscopy indications, 170 pediatric colonoscopy, 750 abdominal pressure gastrointestinal assistant, 59 ScopeGuide, 623, 623, 625 sessile polyp polypectomy, 581 sigmoid loops, 547 transverse colon insertion techniques, 554, 554 absolute contraindications, 174 absorbance spectra, narrow band imaging, 285 video colonoscope, 285 absorption of light, 474–5, 475 absorptive staining method, chromoendoscopy, 463 accessories, 306–17 see also specific accessories AccuTouch, 157, 158 ACG see American College of Gastroenterology (ACG) acriflavine, endomicroscopy, 528 ACRIN see American College of Radiology Imaging Network (ACRIN) ACS see American Cancer Society (ACS) acute colonic pseudo-obstruction (ACPO), 675–82 clinical presentation, 675 complications, 677 diagnosis, 675–7 radiography, 676, 677 epidemiology, 675 management, 677–80 colonoscopic decompression, 677, 678, 678–9, 679 (table) percutaneous cecostomy, 679–80 pharmacotherapy, 677–8, 678 (table) radiographic monitoring, 679, 680 supportive medical care, 677 surgery, 680 pathophysiology, 675 sympathetic deprivation theory, 675, 676 predisposing factors, 675, 676 (table) prognosis, 680 additive primary colors, video colonoscope color reproduction, 280, 280, 281

adenocarcinomas familial adenomatous polyposis (FAP), 433 optical coherence tomography (OCT), 489 stricture therapy, 654 adenoma(s), 381–6 classification, 381–2 depressed, 386 flat, 386 tubular, 382, 382 tubulovillous, 382, 382 villous, 382, 383 colonoscopy indications, 169, 171, 172 colorectal cancer screening, 208–9 depresses see depressed adenomas diagnostic yield (of colonoscopy), 185 detection miss rate, 199 endomicroscopy, 531 dysplasia, 383, 383 high-grade, 383, 384, 384 low-grade, 383, 383 flat see flat adenomas gross appearance, 414–15 histology, 415 intramucosal carcinoma, 384, 384–5 invasive carcinoma, 385–6, 386 iron deficiency anemia, 185 misplaced mucosa, 385, 385 narrow diverticular segment polypectomy, 594–5, 596 pedunculated see pedunculated adenomas pit patterns, 414–15, 414 (table), 415 progression to invasive carcinoma, 415 see also adenoma–carcinoma hypothesis sessile see sessile adenomas sporadic, 353 adenoma–carcinoma hypothesis, 358, 382–3, 403, 404, 428, 719, 721 APC gene, 382, 428 β-catenin, 382, 428 K-ras activation, 382, 428 p53 gene, 383, 428 time scales, 724 tumor-suppressor genes, 382–3 see also specific genes Wnt signaling pathway, 382 see also advanced adenoma concept adenoma-like mass (ALMs), 457 age, 457

dysplasia-associated lesion or mass (DALMs) vs., 532 Paris grade, 457 adenomatous polyposis coli (APC), pediatric polypectomy, 754 adenomatous polyps familial adenomatous polyposis (FAP), 433, 433 hyperplastic polyps, 474 hyperplastic polyps vs., 474 light-induced fluorescence endoscopy (LIFE), 479, 481 narrow-band imaging, 517 normal tissue vs., 487 Raman spectroscopy, 487 Sano–Emura classification, 522, 524 (table) tissue autofluorescence, 481 adjuncts gut lavage, 117 sedation, 103–4 adjustable stiffness colonoscopes, 294, 294 studies, 295 (table) administration area, colonoscopy suite, 38–9 adrenal adenomas, familial adenomatous polyposis (FAP), 434 advanced adenoma concept, 721, 721–2 advanced techniques, training, 128 adverse events, reports, 256, 256 (table) Aeromonas hydrophilia infection, 661 Aer-O-Scope, 778, 778–9, 779 AGA see American Gastroenterological Association (AGA) age-relationship adenoma-like mass lesion, 457 cancer screening, 173–4 colonoscopy diagnostic yield, 179 colonoscopy indications, 169, 170 colorectal cancer detection, 179 gut lavage, 118 inflammatory bowel disease (IBD), 179 polyp detection, 179 malignant neoplastic polyps, 402–3 prevalence, 359 (table), 361 air aspiration, sessile polyp polypectomy, 579, 580 air conditioning, colonoscopy suite, 35–6 air suction, insertion techniques, 542 air systems, video colonoscope see video colonoscopes algorithms, fluorescence point spectroscopy, 478 aligning agenda, teaching methods, 145

Colonoscopy: Principles and Practice. 2nd edition Edited by Jerome D. Waye, Douglas K. Rex and Christopher B. Williams. © 2009 Blackwell Publishing Ltd. ISBN: 978-1-405-17599-9

791

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“alpha” spiral loop, insertion techniques, 548, 548, 549 alternatives (to colonoscopy), 169–70 see also specific techniques ambulatory facilities, colonoscopy suite, 21, 29 America, colonoscopy history, 8, 8–10, 9, 10 American Cancer Society (ACS) indication recommendations, 167 surveillance recommendations, 726, 740 American College of Gastroenterology (ACG) indication recommendations, 167, 171 lesion removal guidelines, 47 National Polyp Study design, 722 optimal withdrawal time, 563 quality definitions, 43 American College of Radiology (ACR), indication recommendations, 171 American College of Radiology Imaging Network (ACRIN) alternatives to colonoscopy, 170 virtual colonoscopy studies, 772 American Cystoscope Makers Inc., 8–9 shaft characteristics, 15 American Gastroenterological Association (AGA) computed tomographic colonography guidelines, 786 fellowship training, 129 indication recommendations, 171 propofol sedation, 106 training, 127 American Heart Association (AHA), infective endocarditis prevention, 90, 91 American Society for Anesthesiology (ASA) sedation definition, 101 sedation guidelines, 58 American Society for Gastrointestinal Endoscopy (ASGE) antibiotic prophylaxis, 91 anticoagulant agent recommendations, 94, 95, 95 (table) low-molecular weight heparin substitution, 97, 97 (table) follow-up patient satisfaction survey, 50 (table) indication recommendations, 167 lesion removal guidelines, 47 Minimal Standard Terminology (MST), 238 National Polyp Study design, 722 nonsteroidal anti-inflammatory drugs (NSAIDs) discontinuation guidelines, 95 optimal withdrawal time, 563 postpolypectomy bleeding guidelines, 711 quality definitions, 43 report guidelines, 254 contents, 237 training guidelines, 33, 127 fellowship training, 128–9 5-aminolevulinic acid exogenous photosensitizer-induced fluorescence, 483–4, 485 fluorescence point spectroscopy, 484 amoebiasis, 662–3, 663 ampullary polyps, familial adenomatous polyposis (FAP), 433, 433 Amsterdam criteria, hereditary nonpolyposis colorectal cancer, 438, 439

792

anal dilation, Crohn’s disease, 654 analog-to-digital converter, video colonoscopes, 289 anastomoses, postcolorectal cancer resection colonoscopy, 738, 742–3 anastomotic strictures, 690–1, 691 self-expandable metal stents (SEMS), 693 ancillary training curriculum, 128 anesthesia informed consent material risks, 81–2 mortality, 41 preprocedure assessments, 58 anesthesiologists, 60, 108 angioectasias chronic radiation proctopathy (CRP), 684 Minimal Standard Terminology (MST), 244 angiomas, hematochezia, 633 “angled” biopsy forceps, 309 angle of view, video colonoscope, 279 angulation system single-handled insertion techniques, 538, 539 video colonoscope, 272–3 animal models/studies immunophotodiagnostics, 490 quantum dot method, 492, 493, 494 optical coherence tomography (OCT), 489 perforation, clips, 322–3 teaching courses, 138 anorectum insertion see insertion techniques anoscopes, 6 anoscopic coagulation, internal hemorrhoids, 639 antagonists, sedation, 103 antibiotic(s) hematochezia, 632 ischemic colitis, 640 antibiotic prophylaxis, 90–3, 710 cirrhosis, 91 immunocompromised patient, 91–3 infective endocarditis prevention, 90–1 orthopedic prostheses, 91 pediatric colonoscopy, 752 prosthetic joints, 91 recommendations, 92 (table) vascular grafts, 91 anti-carcinoembryonic antigen antibodies, 490 anticoagulant agents, 94–100 American Society for Gastrointestinal Endoscopy (ASGE) recommendations see American Society for Gastrointestinal Endoscopy (ASGE) deep vein thrombosis (DVT), 95 discontinuation polypectomy, 95 postpolypectomy bleeding prevention, 711 risks, 94–5 hematochezia, 632 indications for, 94 low-molecular weight heparin substitution, 96–7, 97 (table) short-term heparin substitution, 96 see also specific agents antioxidant vitamins, 367 antiplatelet agents, 94–100 aspirin controversy, 97–8 discontinuation, 98

risks, 94–5 nonaspirin antiplatelet agents, 98 anxiety reactions, complications, 710 APAP see attenuated familial adenomatous polyposis (APAP) APC gene, 350 adenoma–carcinoma hypothesis, 382, 428 β-catenin, 354 CpG island methylator phenotype (CIMP), 355 familial adenomatous polyposis (FAP), 352 identification, 353 mutations familial adenomatous polyposis (FAP), 432 stool DNA tests, 208, 209 serrated carcinogenesis pathway, 354 sporadic adenomatous polyps, 353 aphtha, Minimal Standard Terminology (MST), 240 aphthous ulcer, Crohn’s disease, 646, 646 appendiccal orifice polyps, polypectomy, 584–5, 585 appendicitis, postcolonoscopy, 709 “appendix trick,” ileocecal valve insertion techniques, 556, 556 argon plasma coagulation (APC), 314, 331, 338–42 beam shape, 341–2, 342 chronic radiation proctopathy (CRP), 683, 685, 685 coagulation depth, 341, 342 equipment, 341, 341–2 malignant colorectal stricture therapy, 694 principles, 338–41, 340 safety aspects, 342 ascending colon anatomy, 620 insertion techniques see insertion techniques ASGE see American Society for Gastrointestinal Endoscopy (ASGE) aspiration, colon cleansing methods complications, 704 aspirin American Society for Gastrointestinal Endoscopy (ASGE) discontinuation guidelines, 95 discontinuation, 97–8 duration of action, 97–8 hematochezia, 632 assessments colonoscopy suite planning, 21 training see training/teaching training/teaching completion, 151 assistants see gastrointestinal assistants assist devices, 777–83 see also specific devices attenuated familial adenomatous polyposis (APAP), 352 familial adenomatous polyposis (FAP), 434 autofluorescence flat lesion detection, 567, 568 see also tissue autofluorescence automated carbon dioxide delivery, virtual colonoscopy, 766 automated endoscope reprocessers, cleaning/disinfection, 72

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autopsy studies, polyp prevalence, 358–9, 360 (table) average cost-effectiveness ratio (ACER), 216–17 average daily caseload calculation, 21–2 average-risk populations capsule colonoscopy, 304 screening, 173, 206, 207 (table) azathioprine, 652 B Bacillus infections, 69 (table) bacterial infections, 69–70, 69 (table), 660–1 see also specific infections Bacteroides fragilis infections, endocarditis, 90 balanced electrolytes, gut lavage, 115 balloon therapy benign colorectal stricture therapy, 690 Crohn’s disease, 653– 4 see also through-the-scope (TTS) hydrostatic balloon dilators bands, 318, 318 (table), 324–5 advantages, 325 bleeding rectal varices, 324–5, 325 esophageal variceal hemorrhage, 324–5 pediatric colonoscopy, 756 Bannayan–Riley–Ruvalcaba syndrome (BRR), 442 barium, colon cleansing methods, virtual colonoscopy, 765 barium colon imaging, radiographic studies, 208 barium enema, polyp location, 597 Barrett’s esophagus capsule colonoscopy, 304 immunophotodiagnostics, 492, 493 Raman spectroscopy, 482, 486 “basic colonoscopy,” training, 128 basic life support training, gastrointestinal assistant, 58 basic skill training, 141–2, 147 BAT-26, stool DNA tests, 208 battery, informed consent, 84 B-cell lymphomas, 396 marginal cells, 396, 396 Behçet’s syndrome, 670 bending section, video colonoscope, 272 bending sections, video colonoscope, 272–3 benign neoplastic polyps, 380 (table) colorectal stricture therapy see colorectal strictures endoscopic ultrasonography (EUS) see endoscopic ultrasonography (EUS) benzodiazepine, 102–3 opioid combination, 104–5 propofol combination, 105 Bethesda criteria, hereditary nonpolyposis colorectal cancer (HNPCC), 438, 438 (table), 439 biannual surveillance, ulcerative colitis screening/prevention, 227 biliary catheters, 696 biohazards, disposable item disposal, 64 biomarkers future work, 786–7 immunophotodiagnostics, 495

biopsies, 446–61 colorectal, infectious ileocolitis, 660 continuous quality improvement (CQI), 47 gastrointestinal assistant, 61 improvements, 451–3 feedback, 453 processing improvement, 451–2 terminology improvement, 452–3 indications chronic diarrhea, 453, 454, 671, 672 Crohn’s disease see Crohn’s disease dysplasia-associated lesions or masses (DALMs), 458 graft-versus-host disease, 453 optical coherence tomography (OCT), 489–90 ulcerative colitis see ulcerative colitis ulcerative proctitis, 455, 455 instruments, 446 large-cup, 446, 446 see also specific instruments pathologist–endoscopist communication, 449–51 information, 449, 450 (table) medications, 449–51, 450 (table) patient history, 449, 450 (table) questions for pathology, 451 pediatric colonoscopy, 750, 753 pinch biopsy techniques, 448–9 tenting maneuver, 448, 448 (table) specimen handling, 447–8 timing/positions, 453 tissue handling quality, 447, 447 biopsy cup jaws, 309 biopsy forceps, 308, 308–9 ileocecal valve insertion techniques, 557, 557 video colonoscope, 272 bipolar high-frequency surgery, 333, 333 bipolar/monopolar electrocautery chronic radiation proctopathy (CRP), 683, 685–6, 686 coagulation, 335, 335 see also electrosurgery bipolar snares, 573 bisacodyl, gut lavage, 117 bleeding clips see clips as complications of colonoscopy, 49 pediatric colonoscopy, 757 delayed complications (of colonoscopy), 49 postpolypectomy bleeding, 712 endoscopic submucosal dissection (ESD), 611 immediate complications (of colonoscopy), 49 postpolypectomy bleeding, 712 intraluminal, 707–8, 708 (table) polypectomy, 95 rectal varices, 324–5, 325 bleeding disorders, pediatric colonoscopy contraindications, 751–2 block diagrams, colonoscopy suite arrangement, 28, 29 blood pressure monitoring, sedation, 107 blood supply, polypectomy, 585, 586

blue light physical principle see narrow band imaging (NBI) BMPR1A gene, juvenile polyposis syndrome (JOPS), 441 BMPR1 gene, hamartomatous polyposis, 353 body mass index (BMI) polyp growth, 373 polyp prevalence, 363–4 bovine tissue models, simulators, 156, 157 bowel habits, chronic radiation proctopathy (CRP), 688 bowel preparation virtual colonoscopy see virtual colonoscopy see colon cleansing methods box plots, diagnostic yield (of colonoscopy), 179 Bozzini, Philip, 3, 4 B-raf kinase, 354 hyperplastic polyps, 388 serrated polyps, 408 sessile serrated polyps, 388 brightness, colorchip video imaging, video colonoscope, 283 broadband Internet connections, colonoscopy suite, 37 “buffer zone,” sessile adenomas, 405 Burkitt lymphoma, 396 C cabling, colonoscopy suite, 34, 34, 37 calcium, polyp prevalence, 364 Campylobacter infections, 660 cap-fitted endoscopes, flat lesion detection, 568, 568 CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), antiplatelet agent discontinuation, 98 capsule colonoscopy, 301–5 colon cleansing methods, 302 future work, 304 cost-effectiveness analysis, 222, 223 future work, 304, 784–5 indications, 301 lesion location, 251 lesion size, 251 maneuverable capsules, 785, 785 Minimal Standard Terminology (MST), 251 mucosal abnormalities, 251 multicenter comparative study, 303 PillCam Colon Capsule endoscope see PillCam Colon Capsule endoscope pilot studies, 302–3, 303 Rapid5 software, 302 results, 302 self-propelled microrobots, 785–6 carbohydrates, polyp prevalence, 364 carbonization, thermal effects, 330 carcinogenesis, multistep, 353–5 carcinoid tumors endoscopic submucosal dissection (ESD), 605 endoscopic ultrasonography (EUS), 508 mucosal prolapse associated polyps, 397, 397 carcinomas adenomas, progression from, 415 see also adenoma–carcinoma hypothesis Crohn’s disease, 654

793

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carcinomas (cont’d) intramucosal adenomas, 384, 384–5 malignant neoplastic polyps, 401, 402 invasive, 402 adenomas see adenoma(s) depressed adenomas, 418 narrow-band imaging, 519–20 polypectomy, 583 see also malignant neoplastic polyps; specific types cardiac disease, colonoscopy indications, 168 cardiopulmonary complications, 709–10 sedation, 110 cardiopulmonary monitoring, pediatric colonoscopy, 749 carpet polyps, 577 β-catenin adenoma–carcinoma hypothesis, 382, 428 APC gene, 354 cathartics see colon cleansing methods CathCam colonoscope, 781–2 cat scratch colon, 670–1 CD-ROM, teaching aids, 135 cecal diameter, acute colonic pseudo-obstruction diagnosis, 676 “cecal patch” inflammation, ulcerative colitis, 648 cecostomy, percutaneous see percutaneous cecostomy cecum intubation documentation, missed neoplasms, 562, 562 cecum intubation rates, continuous quality improvement (CQI), 44–5 celecoxib, familial adenomatous polyposis treatment, 437 Centers for Medicare and Medicaid Services (CMS), 209 ceroid, autofluorescence, 476 (table) certification ambulatory colonoscopy suites, 21 colonoscopy suite licensing, 39 CF-SB-type short colonofiberscope (Olympus), 12, 12 changing rooms, colonoscopy suite, 26 charge-coupled devices (CCDs), 269, 274–5 array, 275, 275 digital images, 257 distal tip, 272 frame transfer, 275, 276, 276–7 historical aspects, 277, 277– 8 image fidelity, 276 image reading, 275–6 image standardization/exchange, 247 instantaneous single-plate, 282 interline transfer, 275, 277, 277 light sensitivity, 280 line transfer, 275, 275, 275–6 types of, 276–7 charting surfaces, colonoscopy suite, 35 chemical colitis, 666 chemical disposal regulations, 36 chemoprevention, 225 colonoscopy quality issues, 211 children colonoscopy see pediatric colonoscopy informed consent, 85

794

Chlamydia trachomatis infection, 666, 666 chromic agents, spray catheters, 310 chromoendoscopy, 412, 462–71 colitis-associated cancer, 466–7 cost-efficiency, 462 definition, 463 depressed adenomas, 419, 420 depressed colorectal cancer, 413 flat lesion detection, 567 historical aspects, 462 intraepithelial neoplasia, 467–9, 468, 469 Minimal Standard Terminology (MST), 250 modified Kudo criteria, 463, 464 (table) morphological lesion classification, 464–5 narrow-band imaging vs., 516 pancolonic, 465 selective (targeted), 465–6 staining methods, 412, 463–4 in vivo staining, 466, 466, 468, 469 techniques, 464–5 TNM classification, 464 ulcerative colitis, 467–9, 532 chromosomal instability (CIN), 351, 351 chronic obstructive pulmonary disease (COPD), 710 chronic radiation proctopathy (CRP), 683–8 angioectasias, 684 endoscopic findings, 683, 683 recommendations, 688 therapy, 683 argon plasma coagulation, 683, 685, 685 bipolar/monopolar electrocautery, 683, 685–6, 686 coagulation energy, 684 completion of, 684–5 cryotherapy, 687, 687 endoscope selection, 684 formalin instillation, 683, 686, 688 indications, 684 (table) Nd:YAG laser therapy, 683, 686–7 see also specific options CIMP, 386–7 cirrhosis, antibiotic prophylaxis, 91 cisapride, gut lavage, 117 clamshell polyps, 577 polypectomy, 593, 593–4, 594 piecemeal, 593 cleaning/disinfection (of colonoscopes), 67–75 automated endoscope reprocessers, 72 colonoscopy suite see colonoscopy suite current standards, 72 compliance, 72, 73 drying, 70, 72 endoscope design, 73 high-level disinfection, 67–8, 70, 71–2 improper, colitis cause, 666 infection prevention, 710 liquid-chemical germicides, 67, 71, 71 (table) potency testing, 72, 73 manual cleaning, 70 mechanical cleaning, 71 reports, 238, 255 rinsing, 70, 72 Spaulding criteria, 68 steps in, 70–2

see also specific effects sterilization, 67–8 storage, 70, 72 training, 73 clearing colonoscopy, colon cancer diagnostic yield, 190, 191–3 (table) clear liquids, colon cleansing diet, 114, 115 (table) Cleveland Clinic Adenoma Study, 724 clinical history, reports, 254–5 Clinical Outcomes Research Initiative (CORI) polyp prevalence, 361 reports, 235 clinical trials lack of, colorectal cancer screening, 210 low-molecular-weight heparin substitution, 96 narrow-band imaging, 517 polyp prevalence, 359, 361 ulcerative colitis endomicroscopy, 532 clinicians, malignant neoplastic polyp management, 409–10 clips, 310–12, 311, 318–23, 318 (table), 319 bleeding, 320–3, 320 (table), 321, 322 delayed prevention, 321, 321 Mallory–Weiss tears, 320 rebleeding risk, 320 clinical experience, 320 colonic decompression tube fixation, 312, 312 composition, 311 delayed postpolypectomy hemorrhage, 641 disadvantages, 318 fixing device, 310, 311 hematochezia, 634–5 lesion marking, 310 pediatric colonoscopy, 756 perforation, 321–3, 322 animal models, 322–3 broad-spectrum antibiotics, 322 National Cancer Center in Tokyo studies, 322 polypectomy hemostasis, 312 polyp location, 597 “three-layered,” 319, 319 “two-layered,” 319 washing, 318 clonality, tumor genetics, 349 clopidogrel, discontinuation, 98 Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), antiplatelet agent discontinuation, 98 “close-focus” colonoscopes, 279 Clostridium difficile infection, 661, 661 endoscopic transmission, 70 “closure sensation,” snares, 573 coaching technique, practical teaching, 147 coagulation anoscopic, internal hemorrhoids, 639 coaptive, polypectomy, 572 high-frequency surgery see high-frequency surgery lasers, 343 thermal effects, 330 coagulation current high-frequency surgery, 339 polypectomy, 573 coagulation depth, argon plasma coagulation (APC), 341

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coagulation energy, chronic radiation proctopathy therapy, 684 coagulation mode, electrosurgery, polypectomy, 337 coagulation probes, 634, 634 (table) cobblestone ulcers, Crohn’s disease, 647, 647 cohort studies, low-molecular weight heparin substitution, 97 cold biopsy forceps, small polyp retrieval, 613 cold snare polypectomy complications, perforation, 49 small polyps, 579 colectomy, familial adenomatous polyposis treatment, 437 colitides diagnostic yield (of colonoscopy), 185 microscopic, 668, 669 colitis associated neoplasia chromoendoscopy, 466–7 endomicroscopy, 531 causes, 666–71 colon ischemia, 667, 667 differential diagnosis, 671 (table) diversion, 667 diverticular, 668, 668, 669 drug-evoked, 450–1, 669–70 infections see infections; specific infections ischemic see ischemic colitis nonsteroidal anti-inflammatory drugs, 669–70 preparation artifacts, 666, 666 radiation, 667, 668 with systematic vasculitis, 670 collagen autofluorescence, 476 (table) thermal coagulation, 330 thermal desiccation, 330 collagenous colitis, differential diagnosis, 453 colo-EASIE™, simulators, 156, 156 colon anatomy, 619–20 cancer see colorectal cancer; specific cancers descending see descending colon distention, virtual colonoscopy see virtual colonoscopy diverticula, 633 dysplastic polyps, tissue autofluorescence, 483 endoscopic mucosal resection (EMR), 586 gas introduction, pain, 109 gland structure, 414–15 ischemia, 667, 667 length variation, 619 lipomas, loops, 325 mucins, 492 pit pattern classification, 413–14, 414 (table) strictures, pediatric colonoscopy, 751, 756 surface pit pattern, 414–15 surface structures, 413 wall marker injections, 597–9 thickness, 328, 329 coloncameras, colonoscopy history, 7–8 colon cleansing methods, 114–20 capsule colonoscopy, 302, 304 colostomies, 120

complications, 704 continuous quality improvement (CQI) see continuous quality improvement (CQI) contraindications, 120 diet and cathartics, 114–15 clear liquids, 114, 115 (table) regimens, 115 (table) diverticular hemorrhage, 637 economics, 116 (table) endoscopic submucosal dissection (ESD), 604 endoscopic ultrasonography (EUS), 502 gut lavage, 115–17 adjuncts, 117 administration options, 118–19 balanced electrolytes, 115 in elderly, 118 flavoring, 117 instructions for use, 119 palatability, 117 pediatrics, 118 polyethylene glycol electrolyte lavage solutions (PEG-ELS), 115–16, 117–18 reduced-volume, 117 safety, 118, 118 (table) saline, 115 sulfate-free electrolytic solution, 116–17 hematochezia, 632–3, 633 (table) histology, 120 inflammatory bowel disease, 120 instructions, 120–1 laxatives, 115 limitations, 561–2 lower gastrointestinal hemorrhage, 120 pain, 109 pediatric polypectomy, 754 phosphates, 119 “split-dose administration,” 121 sulfates, 120, 120 (table) virtual colonoscopy see virtual colonoscopy colonic angiomas see hematochezia colonic decompression tube fixation, clips, 312, 312 colonoscopes choice of, 297–8 difficult polypectomy, 585–6 new models, 777–83 polypectomy, 573 see also specific types colonoscopic decompression acute colonic pseudo-obstruction management, 677, 678, 678–9, 679 (table) pediatric colonoscopy, 751 colonoscopy provider metrics, informed consent, 82–3 colonoscopy suite, 19–40 administration area, 38–9 air conditioning, 35–6 ambulatory facilities, 21, 29 arrangement, 26–8 block diagrams, 28, 29 critical relationships, 27, 27 flow diagrams, 26–7 movement patterns, 27–8, 28 patient flow patterns, 26, 27, 28 staff flow patterns, 27–8, 28 changing rooms, 26

charting surfaces, 35 communication systems, 36–7 computers, 19 connectivity, 37–8 construction materials, 35 walls, 34–5 design development, 30–2 doors, 35 economic constraints, 19 emergency facilities, 35 environmental concerns, 19, 39 equipment arrangement, 32–9 cable provision, 34, 34 comparative diagrams, 33, 33 drug cabinets, 35 endoscopy carts, 34 patient monitoring equipment, 34 suction, 35 TV monitors, 33–4 vertical arrangements, 32 heating, 35–6 licensing, 39–40 lighting, 36 odor maintenance, 64 office space, 20–1 operational efficiency, 23 planning of, 20–3 assessment and programming, 21 average daily caseload calculation, 21–2 floor plans, 28–9, 29 new technology impacts, 22 number of procedure rooms, 21–3 past procedure numbers, 21 patient base effects, 22 preliminary solutions, 28–9 procedures per room (PPR), 22–3 use projection, 22, 22–3 plumbing, 36 procedure rooms, 30, 30–2 corner layout, 30–1, 31 general-purpose rooms, 31–2 numbers of, 21–3 parallel room plan, 30, 31, 32 patient flow patterns, 26 sedation, 107 US licensing laws, 30 project schedule, 19–20, 20 reception area, 38, 38 recovery space, 23–4 patient flow patterns, 26 room size standards, 24, 26 scope cleaning, 24 patient flow patterns, 26 scope storage, 24 soundproofing, 35 technology-based video imaging, 19 ventilation, 35–6 waiting room, 39 written programs, 24, 25, 26, 26 (table) colon polyps see polyp(s) colon retroflexion, withdrawal techniques, 566, 566, 567 colorchip video imaging narrow band imaging, 287, 287–8 video colonoscope see video colonoscopes

795

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Page 796

Index

colorectal adenomas see adenomatous polyps colorectal bleeding, gastrointestinal assistant, 61 colorectal cancer adenocarcinomas endoscopic ultrasonography (EUS) see endoscopic ultrasonography (EUS) high-frequency ultrasonography (HFUS) see high-frequency ultrasonography (HFUS) capsule colonoscopy pilot studies, 302 detection age-relation, 179 colonoscopy history, 16 miss rate, 199, 199 diagnostic yield (of colonoscopy), 181, 185 endomicroscopy, 531 endoscopy effects, 560–1, 560 (table) immunophotodiagnostics, 493– 4 incidence, 560–1, 730 polypectomy surveillance, 723– 4 iron deficiency anemia, 185 lower gastrointestinal tract bleeding, 185 mortality, 560–1 MYH gene associated polyposis (MAP), 437 risk stratification, polypectomy surveillance, 724–5 screening for see below surveillance, 730–1, 742 colonoscopy see postcolorectal cancer resection colonoscopy colorectal cancer screening, 173– 4, 173 (table), 209–13 advantages, 210 Centers for Medicare and Medicaid Services (CMS), 209 continuous quality improvement (CQI) see continuous quality improvement (CQI) diagnostic yield (of colonoscopy) see diagnostic yield (of colonoscopy) elderly, 173– 4 issues/uncertainties, 210–13 clinical trial lack, 210 cost, 211 quality issues, 211–12, 212 (table) safety, 210–11 screening interval, 212 programmatic see programmatic colorectal cancer screening rationale for, 209–10, 210 (table) risk stratification, 212–13 timing of, 212 colorectal strictures, 689–702 benign disease therapy, 690–3 anastomotic strictures, 690–1, 691 dilation, 690–3 electroincision, 691–2 inflammatory bowel disease, 692 self-expandable metal stents (SEMS) see selfexpandable metal stents (SEMS) self-expandable plastic stents, 693 chronic ulcerative colitis, 689–90 cytomegalovirus infections, 690 diagnosis, 689–90 tissue sampling, 689, 690 diverticular disease, 690

796

endoscopic therapy, 690–8 benign disease see above malignant disease see below etiology, 689, 689 (table) immunosuppressed patients, 690 inflammatory bowel disease, 690 malignant disease therapy, 693–6 argon beam plasma coagulation (APC), 694 laser therapy, 694, 694, 695 palliative therapy, 695–6 preoperative decompression, 694–5 self-expandable metal stents (SEMS) see selfexpandable metal stents (SEMS) severe acute pancreatitis, 690 color image display, video colonoscope, 283–4 color reproduction, video colonoscope see video colonoscopes colostomies colon cleansing methods, 120 percutaneous, tube placement, 751 postcolorectal cancer resection colonoscopy, 743 colostomy, percutaneous, tube placement, 751 common familial colon cancer, 431–2 screening, 431, 432 (table) communication systems, colonoscopy suite, 36–7 comparative diagrams, colonoscopy suite, 33, 33 competence informed consent, 84, 85 retraining, 131–2 training, 127 assessment, 130–1, 130 (table), 142 formative assessment, 151 complete colonoscopy insertion techniques, 555 polypectomy surveillance, 720 compliance cleaning/disinfection, 72, 73 fecal occult blood testing, 220 complications (of colonoscopy), 211, 703–16 anxiety reactions, 710 cardiopulmonary, 709–10 continuous quality improvement (CQI) see continuous quality improvement (CQI) delayed bleeding, 49 endoscope incarceration, 710–11 extraluminal bleeding, 707 immediate bleeding, 49 infections, 710 intraluminal bleeding, 707–8, 708 (table) literature, 703–4 pancreatitis, 709 pediatric colonoscopy, 757 postcolonoscopy appendicitis, 709 reports, 256 therapeutic colonoscopy, 711–13 see also postpolypectomy bleeding treatment of, 49 see also specific complications; specific procedures compression algorithms, image standardization/exchange, 247 computed tomographic colonography (CTC) colorectal cancer surveillance, 742 cost-effectiveness analysis, 221–2 future work, 784, 786

with radiographic studies, 208–9 sensitivity, 720 in surveillance, 720, 738 see also virtual colonoscopy computed tomography (CT) colonoscopy indications, 171 colorectal adenocarcinomas, endoscopic ultrasonography (EUS) vs., 505 familial adenomatous polyposis screening, 436 self-expandable metal stents (SEMS), 694 computer-aided detection (CAD), virtual colonoscopy, 765 computerized images, polyp size estimation, 368–9 computers colonoscopy suite, 19 teaching aids, 134 conclusions, reports, 256 conflict of interest, informed consent, 83 confocal microscopy, endomicroscopy, 527–8 congenital hypertrophy of retinal pigment epithelium, familial adenomatous polyposis (FAP), 434 congested mucosa, Minimal Standard Terminology (MST), 240 connective tissue disease, pediatric colonoscopy contraindications, 752 conscious competence, teaching methods, 145–6 consent implied, 85 informed see informed consent constipation colonoscopy indications, 170 functional, 197, 198 (table), 199 contact thermal devices, 313–14 containment area cleaning, gastrointestinal assistant, 63 continuous practice, training/teaching, 143 continuous quality improvement (CQI), 41–54 anesthesia mortality, 41 biopsy guidelines, 47 cecal intubation rates, 44–5 colon cancer screening, 43 prevention lack problems, 45–6 colon cleansing methods, 44 colon disorder diagnosis/treatment, 43 complications, 48–9 development of, 50–1 follow-up, 49–50 ASG patient satisfaction survey, 50 (table) incomplete examinations, 44–5 initial action plans, 42 lesion removal, 47 outcomes management, 42–3 outcomes research, 42 patient interactions, 43–4 patient satisfaction, 49, 50 (table) polyp detection, 45–6 problem identification, 43 quality definitions, 42, 43–50 American College of Gastroenterology (ACG), 43 American Society for Gastrointestinal Endoscopy (ASGE), 43 Institute of Medicine, 42

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success rate measurement, 41 theory of, 41 training, 33 withdrawal times, 46–7 contraindications (to colonoscopy), 174, 175 (table) colon cleansing methods, 120 contrast agents chromoendoscopy, 463 endomicroscopy see endomicroscopy tissue autofluorescence, 482 control panel, ScopeGuide, 622, 622 cooling systems, video colonoscope illumination system, 274 CORI see Clinical Outcomes Research Initiative (CORI) corner layout, procedure rooms, 30–1, 31 corticosteroids benign colorectal stricture therapy, 691 Crohn’s disease therapy, 654 cost(s) colorectal cancer screening, 211 polypectomy surveillance, 727 cost-effectiveness, 216–31 alternative screening procedures, 219–22 average cost-effectiveness ratio (ACER), 216–17 decennial colonoscopy, 219 capsule colonoscopy, 222, 223, 304 chromoendoscopy, 462 competing strategies, 222, 222–3 computed tomographic colonography, 221–2, 223 cost variations, 224 decennial colonoscopy, 218–19, 222 (table), 223 decision tree, 218, 218 Markov process, 218, 218 fecal DNA testing, 220–1, 223 fecal occult blood testing, 220, 222 (table), 223 flexible sigmoidoscopy, 219, 219–20, 222 (table) inconclusive tests, 223, 223– 4 of individual features, 224–5 limitations, 227–8 polypectomy surveillance, 727 quality-adjusted life years (QALYs), 216, 217 resource scarcity, 217 screening effectiveness, 216 single colonoscopy, 219, 222 (table), 223 small costs in many vs. great effects in few, 217, 217 ulcerative colitis screening/prevention, 225–7 biannual surveillance, 227 decision tree, 225–6, 226 cotton gauze, small polyp retrieval, 614 Cowden’s syndrome, 432, 442 facial trichilemmomas, 442 ganglioneuromas, 392 PTEN gene, 442 CpG island methylator phenotype (CIMP), 351, 355 serrated polyps, 408 cresyl violet, endomicroscopy, 528 Crohn’s disease, 646–8 aphthous ulcer, 646, 646 benign colorectal stricture therapy, 692 biopsy, 455–6 sites, 456

cobblestone ulcers, 647, 647 Crohn’s disease endoscopic index of severity, 650 diagnosis, 455 double-balloon endoscopy, 650–1 endoscopic assessment, 646 (table), 649–50 endoscopic monitoring, 652 esophagus, 648 established, colonoscopy indications, 171–2 immunophotodiagnostics, 493 incidence, 648 infections vs., 660 larger/deeper ulcers, 646–7, 647 light-induced fluorescence endoscopy (LIFE), 479 location, 646 luminal narrowing (strictures), 647, 647 lumps and bumps, 456–8 management, 457–8 pediatric colonoscopy, 750, 752–3 perioperative endoscopy, 652–3 quiescence (chronic disease), 647, 647 (table) recurrent lesion scoring, 653 (table) scarring/deformity, 647, 647 (table) SES-CD (Simple Endoscopic Score for Crohn’s Disease), 650 strictures, 653–4, 654 (table) colonoscopy indications, 168 terminal ileal biopsies, 672 traumatic perforation, 706 tuberculosis vs., 662 ulcerative colitis vs., 649, 649 (table) endoscopic ultrasonography (EUS), 508–9 upper gastrointestinal tract, 647–8 visual analog scale, 650 Crohn’s disease endoscopic index of severity, 650 “crow’s foot” sign, 555, 556 CRP see chronic radiation proctopathy (CRP) cryotherapy, chronic radiation proctopathy (CRP), 687, 687 Cryptococcus neoformans infection, 664 Cryptosporidium parvum infection, 70 crypts, endomicroscopy, 529 crystal violet, chromoendoscopy, 463–4 CTC see computed tomographic colonography (CTC) cuffitis, pouchitis vs., 653 CURE (Clopidogrel in unstable angina to prevent recurrent events), antiplatelet agent discontinuation, 98 CURE Hemostasis Research Group treatment see hematochezia current density, high-frequency surgery, 333–4 cutaneous lesions, familial adenomatous polyposis (FAP), 434 cutting current high-frequency surgery see high-frequency surgery polypectomy, 337, 573 cyclooxygenase-2 (COX-2) inhibitors chemoprevention, 225 familial adenomatous polyposis treatment, 437 prevention role, 363

cystoscopes, history of colonoscopy, 5 cytokines, gene polymorphisms, 367 cytomegalovirus infection, 664, 665 colorectal strictures, 690 cytosine–guanine island methylation phenotype, 355 D daily training, intensive training vs., 130 damage, cleaning/disinfection, 73 data analysis, selective (targeted) chromoendoscopy, 465–6 data exchange, Minimal Standard Terminology (MST), 246–7 data transmission, informed consent, 87 DaveProject.org website, 136 decennial colonoscopy, cost-effectiveness analysis see cost-effectiveness decision aids, informed consent, 80 decision training, 147 decision tree decennial colonoscopy, 218, 218 ulcerative colitis screening/prevention, 225–6, 226 decompression see colonoscopic decompression dedicated time, practical teaching, 147 deep sedation, 101 deep submucosal invasive cancer (capillary pattern type IIIB), Sano–Emura classification, 522, 524 (table) deep vein thrombosis (DVT), anticoagulant drugs, 95 deliberate practice, training/teaching, 143 demonstrations, training/teaching, 143 dental abnormalities, familial adenomatous polyposis (FAP), 434 Department of Defense studies, virtual colonoscopy, 772 depressed adenomas, 386, 412–22, 416, 417, 418 chromocolonoscopy, 419, 420 concerns, 474 definition, 425 diagnosis, 418–19 endoscopic submucosal dissection (ESD), 603 gross appearance, 412–21 invasive carcinoma, 418 Japanese Research Society for Cancer of the Colon and Rectum, 412–13, 413 magnifying colonoscopy, 419 metastatic risk, 463 see also flat adenomas depressed colorectal cancer, chromoendoscopy, 413 depth, high-frequency surgery coagulation, 336 cutting, 335, 336 depth of field, video colonoscope, 278 depth of invasion, serrated polyps, 409 descending colon anatomy, 620 insertion techniques, 551, 551 sigmoid colon junction, 625 virtual colonoscopy, 766–7, 767 desiccation, thermal effects, 330 desk space, administration area, 38

797

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desmoid tumors familial adenomatous polyposis (FAP), 434 treatment, 437 detachable loops, 312–13, 313 detachable sutures, 324 devitalization, thermal effects, 328, 330 dextrose, hypertonic, 586–7 diagnostic accuracy, polyps, 379 diagnostic colonoscopy anticoagulant drug discontinuation, 95 Minimal Standard Terminology (MST), 239 reliability, 199 virtual colonoscopy, 770 diagnostic redundancy, virtual colonoscopy interpretation, 768 diagnostic yield (of colonoscopy), 178–205 after fecal occult blood testing (FOBT), 190, 194, 194, 194–5 (table) age relation, 179 clinical indications, 179–86 box plots, 179 hematochezia, 180–5 lower gastrointestinal bleeding see below colon cancer screening, 186, 186–99, 189, 190 clearing colonoscopy, 190, 191–3 (table) follow-up studies, 189–90 definition, 178 family history, 179 functional abdominal pain syndrome, 197, 197, 198 (table), 199 functional bowel disorders, 197, 199 functional constipation, 197, 198 (table), 199 gender relation, 179 HIV patients with chronic diarrhea, 194, 196–7 differential diagnosis, 196, 196, 196 (table) iron deficiency anemia, 184 (table), 185, 185 irritable bowel syndrome, 197, 198 (table), 199 lower gastrointestinal bleeding, 180 (table), 181, 181 chronic, 181, 182–3 (table), 185 occult gastrointestinal bleeding see fecal occult blood testing (FOBT) patient characteristics, 179 polyp follow-up studies, 186, 186, 187–8 (table) diarrhea in abnormal endoscopy, biopsy, 453, 454 chronic, 671–2 colonoscopy indications, 170 in normal endoscopy, biopsy, 453, 454 pediatric colonoscopy, 750 diatrizoate, colon cleansing methods, 765 diazepam, 103 DICOM (Digital Imaging and COmmunication in Medicine), 247, 248, 259–60 Minimal Standard Terminology (MST), 246 reports, 235 diet colon cleansing methods see colon cleansing methods polyp growth, 367, 373 polyp prevalence, 363– 4 dietary fat, polyp incidence, 366 dietary fiber, polyp incidence, 364, 366 diffusion effects, electrosurgery, 331, 332

798

digital images, 257–62 charge-coupled devices (CCDs), 257 file compression, 258, 258–9 clinically acceptable, 260, 260–1, 261 (table) DICOM (Digital Imaging and Communication in Medicine), 247, 248, 259–60 GIF files, 259 JPEG files, 259 picture archiving and communication systems (PACS), 259 file size, 257–8 image enhancement, 262 necessary images, 261–2 pathology, 261–2, 262 pictures vs. video, 261 pixel density, 257, 258 VGA (video graphics array), 258 retroflexed view, 261 digital rectal examination colorectal adenocarcinomas, endoscopic ultrasonography (EUS) vs., 505 insertion techniques, 539 digital storage, administration area, 38 digital-to-analog converter, video colonoscope, 289–90 dilation, benign colorectal stricture therapy, 690–3 diphenhydramine, 103–4 directly observed procedural skills (DOPS), training/teaching, 151 disclaimers, reports, 255 disclosures, informed consent material risks, 81, 87 disinfection procedure see cleaning/disinfection (of colonoscopes) disposable biopsy forceps, reusable vs., 309 disposable equipment, 64 distal attachment (hood/cap), endoscopic submucosal dissection (ESD), 606, 606 distal tip, video colonoscope see video colonoscopes distention, withdrawal techniques, 565 distributed practice, “hands-on” training/teaching, 146 distributed processing, image standardization/exchange, 248–9, 249 diversion colitis, 667 colostomy patients, 743 diverticular colitis, 668, 668, 669 diverticular disease colorectal strictures, 690 insertion techniques see insertion techniques mucosal prolapse associated polyps, 394, 395 self-expandable metal stents (SEMS), 693 diverticular hemorrhage, hematochezia see hematochezia diverticulitis, 667–8, 668 traumatic perforation, 706 diverticulosis with muscular atrophy, traumatic perforation, 705–6 DNA integrity analysis (DIA), 208 DNA testing, fecal, 220–1, 223 documentation informed consent, 85–6 ScopeGuide, 625–6

document type definitions (DTDs), image standardization/exchange, 249 doors, colonoscopy suite, 35 Doppler optical coherence tomography, 489 double-balloon endoscopy, 298 Crohn’s disease, 650–1 double bites, pinch biopsy techniques, 448–9 double-channel endoscope, endoscopic mucosal resection (EMR), 586 double-contrast barium enema, 169 colorectal cancer surveillance, 742 polypectomy surveillance vs., 720 double contrast tagging, colon cleansing methods, 765 drug cabinets, colonoscopy suite, 35 drugs/medications biopsy, 449–51, 450 (table) evoked colitis, 450–1, 669–70 evoked hematochezia, 632 evoked ischemic colitis, 450–1 metabolism, sedation economics, 111 preprocedure assessments, 58 sedation, 102–4 drying cleaning/disinfection, 70, 72 reusable equipment reprocessing, 63 d-Snare, small polyp retrieval, 614, 614–15 dual-task interference, teaching methods, 146 Duck-bill® snares, 307, 307 duodenum adenoma treatment, 437 familial adenomatous polyposis (FAP), 433, 433 durable power of attorney, informed consent, 85 DVD, teaching aids, 134, 135 dye-based image-enhanced endoscopy, 474 nonpolyploid colorectal neoplasms (NP-CRNs), 427, 427 (table) dye surface application, polypectomy, 583, 583 dysplasia adenomas see adenoma(s) definition, 456 grading of, 456 ileoanal pouches, 456 polyp prevalence, 362–3, 363 (table) serrated polyps see serrated polyps ulcerative colitis vs., exogenous photosensitizer-induced fluorescence, 484 Vienna classification, 456 dysplasia-associated lesions or masses (DALMs), 456–7 adenoma-like mass (ALMs) vs., 532 biopsies, 458 definition, 456 light-induced fluorescence endoscopy (LIFE), 479, 480 terminology, 457 E EASIE™, simulators, 155 economics colon cleansing methods, 116 (table) colonoscopy suite, 19 sedation, 110–11 educational contract, training/teaching, 145

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educational programs, colon cleansing methods, 121 effective cut phase, electrosurgery, 337, 338 elastin, autofluorescence, 476 (table) e-learning, teaching aids, 135–6 electrical grounding, 60 electric arcs, electrosurgery, 333– 4 electric light–rigid rectoscopes, 5, 5–6 electrocardiography, 59 electrocautery, piecemeal polypectomy, 589 electro-hydro-thermal probes, 334, 334 electroincision, benign colorectal stricture therapy, 691–2 electronic devices, high-frequency surgery safety aspects, 339 electronic endoscopes, 14 electronic media, teaching aids, 134–5 electrosurgery, 328–45 applications, 344 (table) electric arcs, 333–4 endoscopic submucosal dissection (ESD), 607–8 gastrointestinal assistant, 60 heater probes, 332, 332 heat generation, 331, 331–4 diffusion effects, 331, 332 unintentional damage prevention, 331, 331, 333 high-frequency surgery see high-frequency surgery polypectomy see polypectomy elements of consent, informed consent, 84–5 elliptical polypectomy snares, 307 “emancipated minors,” informed consent, 85 embryology, insertion techniques, 537–8, 538 emergency facilities, colonoscopy suite, 35 emergency situations, informed consent exceptions, 85 emission spectra, tissue autofluorescence, 477 EMR see endoscopic mucosal resection (EMR) endoclips, endoscopic submucosal dissection (ESD), 607 EndoEase™ Endoluminal Advancement System, 315, 782, 782 EndoGuide, 315 endoloops, pediatric colonoscopy, 756 endometriosis, endoscopic ultrasonography (EUS), 508 endomicroscopy, 527–34 colon pathology, 529–32 adenomas, 531 classification, 530, 531 (table), 532 colitis-associated neoplasia, 531 colorectal cancer, 531 diagnostic studies, 529–30, 530 goblet cells, 529 postpolypectomy, 530 resected specimens vs., 530 confocal microscopy, 527–8 consequences of, 532–3 contrast agents, 528–9 equipment, 528, 529 fluorescence confocal imaging, 528 Minimal Standard Terminology (MST), 250 normal colon, 529

reflectance confocal imaging, 528 ulcerative colitis, 532 endoscope(s) design, cleaning/disinfection, 73 diagnosis, Minimal Standard Terminology (MST), 239 lenses, polyp size estimation, 368, 368 number, reports, 238 single-use, 779, 779–80, 780 storage, colonoscopy suite, 24 see also colonoscopes; specific models; specific techniques endoscope incarceration, 710–11 endoscopic atlases/video, fellowship training, 129 endoscopic biopsy see biopsies endoscopic landmarks, polyp location, 596–7 endoscopic mucosal resection (EMR), 586–92 cap-assisted polypectomy, 589 colon, 586 future work, 788 “lift and cut” technique, 586 Minimal Standard Terminology (MST), 251 nonpolyploid colorectal neoplasm treatment, 427 piecemeal polypectomy, 589, 590, 603 fulcrum technique, 589, 590, 591 polyp position, 589, 591–2 rectum, 586 snare handle marking, 589 snare resection technique, 586 submucosal injection, 586–9, 587 double-channel endoscope, 586 epinephrine, 586–7 hypertonic dextrose, 586–7 hypertonic saline, 586–7 multiple repeated needle placement, 588, 588 nonlifting sign, 588–9 technique, 587–8 tumor tracking, 589 endoscopic submucosal dissection (ESD), 592, 603–12 colon cleansing methods, 604 complications, 611 distal attachment (hood/cap), 606, 606 electrosurgical unit, 607–8 endoclips, 607 endoscope choice/preparation, 604, 606 evaluation criteria, 610 follow-up, 610–11 future work, 788 hemostatic forceps, 607, 607 indications, 603–4 carcinoid tumor, 605 laterally spreading tumors of the nongranular type (LST-NG), 603–4, 604, 605, 611 non-resectable lesions, 603 injection solutions, 608 epinephrine, 608 saline, 608 sodium hyaluronate, 608 knives, 606, 606–7 needle knives, 592 Minimal Standard Terminology (MST), 251 postoperative clinical course, 610–11

procedure time, 611 results, 611 surrounding tissue excision, 603, 604 techniques, 608–10 approach, 608 endoscope insertion, 608 mucosal injection, 608, 610 preoperative check, 608 resected specimen handling, 610 submucosal dissection, 609, 610 submucosal injection, 608, 610 tumor demarcation, 611 tumor removal, 609, 610 tumor margins, 603 two endoscopes, 592 endoscopic tattoo, 61 endoscopic ultrasonography (EUS), 501–13 adenocarcinomas, 503–8 computed tomography vs., 505 digital rectal examination vs., 505 locally advanced rectal cancer, 505–6 local recurrence detection, 507 lymph node metastases, 506–7 MRI vs., 505 node size, 506 N-stage assessment, 503, 506–7 overstaging effects, 505, 506 sessile adenomas, 505 TNM classification, 503, 504 T-stage assessment, 503, 505–6 understaging effects, 506 anatomical considerations, 502–3 benign tumors, 508 fine-needle aspiration, 502 high-frequency see high-frequency ultrasonography (HFUS) inflammatory bowel disease, 508–9 instruments, 501–2 patient preparation, 502 endoscopy carts, 34 endoscopy directors, fellowship training, 129 endoscopy reports see reports Endo-Trainer, simulators, 155 “end-to-end” method (intestinal pull-up), 13 enemas, pediatric colonoscopy preparation, 752 ENG gene, juvenile polyposis syndrome (JOPS), 441 Entamoeba histolytica II stool antigen test, 662–3 Entamoeba histolytica infection, 662–3, 663 enteric microflora manipulation, 789 Enterobacter infections endoscopic transmission, 69 (table), 70 postcolonoscopy, 710 Enterobius vermicularis infection see pinworm enteroinvasive Escherichia coli infection, 660 enterovirus infections, 68 environmental concerns, colonoscopy suite, 19, 39 enzyme-linked immunosorbent assays (ELISAs) Entamoeba histolytica infection, 662 Strongyloides infection, 663 eosinophilic colitis, 670 epinephrine injections colorectal bleeding, 61 delayed postpolypectomy hemorrhage, 641

799

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Page 800

Index

epinephrine injections (cont’d) endoscopic mucosal resection (EMR), 586–7 endoscopic submucosal dissection (ESD), 608 gastrointestinal assistant, 61 hematochezia, 633 pediatric polypectomy, 755 postpolypectomy bleeding prevention, 711–12 epithelioid schwannomas, 391, 391 eptifibatide discontinuation, 98 equipment arrangement, colonoscopy suite see colonoscopy suite Erlangen models, simulators, 155, 155 erosions, Minimal Standard Terminology (MST), 240, 244 erythema, Minimal Standard Terminology (MST), 240 erythematosus mucosa, Minimal Standard Terminology (MST), 240, 244 Escherichia coli infection enteroinvasive, 660 immunocompromised patients, 92 infective endocarditis, 90 O157:H7, 660, 660 ESD see endoscopic submucosal dissection (ESD) esophageal cancer, 493 esophageal variceal hemorrhage, bands, 324–5 esophagogastroduodenoscopy, endoscopy suite planning, 20 esophagus, Crohn’s disease, 648 ethics, teaching aids, 138 e-training, teaching aids, 135–6 European Cooperative Crohn’s disease Study (ECCDS), 647 European Panel of Appropriateness of Gastrointestinal Endoscopy (EPAGE), colonoscopy indications, 174 European Society for Gastrointestinal Endoscopy (ESGF), DICOM (Digital Imaging and Communication in Medicine), 260 European Society of Gastroenterology, Minimal Standard Terminology (MST), 238 EUS see endoscopic ultrasonography (EUS) evaluation, retraining, 131 examination, withdrawal techniques, 566 excitation wavelengths, tissue autofluorescence, 475, 480, 481 exercise, polyp prevalence, 363–4 exogenous photosensitizer-induced fluorescence, 483–5 5-aminolevulinic acid, 483–4 clinical evaluation, 484–5 efficacy, 483 hematoporphyrin derivatives, 483 hexaminolevulinate, 485 extended polyps, 577 external shaft loops, insertion techniques, 550 extracolonic findings, radiographic studies with computed tomographic colonography (CTG), 209 extraluminal bleeding, 707 extraperitoneal traumatic perforation, 706 ex vivo colon polyp studies, fluorescence point spectroscopy, 477–8 ex vivo tissue studies, optical coherence tomography (OCT), 488

800

eye-hand coordination, simulators, 154 eye protection gastrointestinal assistant, 63 lasers, 343 EZ Clip, 319 F facial trichilemmomas, Cowden’s syndrome, 442 FAD, autofluorescence, 476 (table) false-positive results light-induced fluorescence endoscopy (LIFE), 479, 480 tissue autofluorescence, 482 familial adenomatous polyposis (FAP), 351–2, 432–7 APC gene, 352, 432 attenuated familial adenomatous polyposis, 434 clinical presentation, 432–4 adenocarcinoma progression, 433 adenomatous polyps, 433, 433 adrenal adenomas, 434 ampullary polyps, 433, 433 congenital hypertrophy of retinal pigment epithelium, 434 cutaneous lesions, 434 dental abnormalities, 434 desmoid tumors, 434 duodenal polyps, 433, 433 extragastrointestinal malignancies, 434 extraintestinal manifestations, 434 fundic gland polyps, 433, 433 gastrointestinal manifestations, 432–3 nasal angiofibromas, 434 small bowel adenomas, 434 epidemiology, 432 etiology, 432 Gardner’s syndrome, 434 genetic testing, 435 nonsteroidal anti-inflammatory drugs, 352 screening, 435–6, 435 (table), 436 (table) treatment, 437 Turcot’s syndrome, 434–5 familial colon cancer, 351–3 see also specific types family history colonoscopy diagnostic yield, 179 polyp prevalence, 363 reports, 255 fecal bacteria, tissue autofluorescence, 482 fecal DNA testing, cost-effectiveness analysis, 220–1, 223 fecal immunochemical test (FIT), 207–8 fecal occult blood testing (FOBT), 169 colonoscopy diagnostic yield, 190, 194, 194, 194–5 (table) colorectal cancer surveillance, 742 compliance, 220 cost-effectiveness analysis, 220, 222 (table), 223 flexible sigmoidoscopy combination, 208 guiaic-based, 207 rectal bleeding, 170 feedback, biopsy improvements, 453 fellowship training see training/teaching fentanyl, 102 propofol preinduction, 105

fiberoptics history of, 6–7, 8–9, 12–13 three-glass method, 12 two-glass method, 12 video colonoscope illumination system, 274 fibroblastic polyps, 392 field defects, future work, 786–7 file size compression see digital images digital images, 257–8 filling defects, colonoscopy indications, 170–1 findings, reports, 255–6 fine-needle aspiration, endoscopic ultrasonography (EUS), 502 fixing device, clips, 310, 311 flat adenomas, 386, 415–19 characteristics, 417–18 concerns, 474 definition, 425 diagnosis, 418–19 laterally spreading, 415, 416, 416–17 light-induced fluorescence endoscopy (LIFE), 479, 480 malignant neoplastic polyps, 404 Western hemisphere, 423–30 Germany, 426 North America, 425 Sweden, 426 UK, 426 see also depressed adenomas flat polyps/lesions detection improvement, 567–8, 567 (table) technologies, 568–9 metastatic risk, 463 polypectomy, 594 flavoring, gut lavage, 117 flexibility, video colonoscope see video colonoscopes flexible endoscopes history of, 9, 9 reprocessing, 63, 67 flexible proctosigmoidoscopy, pediatric colonoscopy, 754 flexible sigmoidoscopy, 208 cost-effectiveness analysis, 219, 219–20, 222 (table) Flex knife, endoscopic submucosal dissection (ESD), 606, 606–7 floor plans, colonoscopy suite planning, 28–9, 29 flow diagrams, colonoscopy suite arrangement, 26–7 fluid suctioning insertion techniques, 542 withdrawal techniques, 565 flumazenil, 103 fluorescein, endomicroscopy, 528 fluorescence confocal imaging, endomicroscopy, 528 fluorescence point spectroscopy, 477, 477–8 algorithms, 478 5-aminolevulinic acid, 484 ex vivo colon polyp studies, 477–8 steady-state vs. time-resolved studies, 478 in vivo studies, 477, 478, 479 fluorescence rectosigmoidoscopy, 494–5

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fluorescence spectrum, tissue autofluorescence, 475 fluorophores, tissue autofluorescence, 476 (table) fluoroscopic guided stent procedure, 698 fluoroscopy, 620 folic acid, polyp prevalence, 364 follow-up examinations continuous quality improvement (CQI), 49–50 endoscopic submucosal dissection (ESD), 610–11 polyp incidence, 365 Food and Drug Administration (FDA), liquidchemical germicide approval, 71 foreign body removal, pediatric colonoscopy, 751 formalin instillation, chronic radiation proctopathy (CRP), 683, 686, 688 formative assessment see training/teaching forward-viewing colonoscopes, 10–11, 11 fospropofol disodium, 106 fractionation, “hands-on” training/teaching, 146 frame transfer, charge-coupled devices, 275, 276, 276–7 Fuji Intelligent Color Enhancement (FICE) system, video colonoscope image processing, 288 fulcrum technique, piecemeal polypectomy, 589, 590, 591 functional abdominal pain syndrome, 197, 197, 198 (table), 199 functional bowel disorders, 197, 199 functional constipation, 197, 198 (table), 199 fundic gland polyps, familial adenomatous polyposis (FAP), 433, 433 fungal infections, 69 (table), 70, 664 see also specific infections future examination needs, continuous quality improvement (CQI), 50 future work (in colonoscopy), 784–90 comprehensive lesion detection, 787–8 enteric microflora manipulation, 789 irritable bowel syndrome, 788–9 motility disorders, 788–9 nervous system access, 788 obesity, 789 submucosal drug delivery, 788 G gamma looping ScopeGuide, 625 transverse colon insertion techniques, 554, 554 ganglioneuromas, 392 Gardner’s syndrome familial adenomatous polyposis (FAP), 434 pediatric polypectomy, 754 gastric cancer diagnosis, 16 gastrocameras, 7–8, 8 Eindhorn, 7, 7 with fiberscope, 8 Kelling, 7, 7 gastrointestinal assistants, 57–66 basic life support training, 58 biopsy, 61 colorectal bleeding, 61 containment area cleaning, 63 cytology, 61

disposable item disposal, 64 duties, 57 see also specific duties endoscopic tattoo, 61 endoscopy suite odor maintenance, 64 external abdominal pressure, 59 guidelines, 57 Occupational Safety and Health Administration Regulations, 62 patient monitoring, 58–9 pediatric colonoscopy, 749 personal protective equipment, 59, 62–4 eye protection, 63 gloves, 62, 63 postprocedure care, 62 during procedure, 59–63 see also specific procedures reusable equipment processing, 63 sedation, 58–9, 108 setting up the room, 58 snare operation, 60–1 Society of Gastroenterology Nurses and Associates (SGNA), 57 supply ordering, 64 troubleshooting tips, 64–5 gastrointestinal stromal tumors, endoscopic ultrasonography (EUS), 508 gastrointestinal tract bleeding, pediatric colonoscopy, 755 lower bleeding see lower gastrointestinal tract bleeding upper see upper gastrointestinal tract gastrointestinal tumor-associated biomarkers, immunophotodiagnostics, 492 “gastrophotor,” 7, 7 gastroscopes history of, 4–5 narrow diverticular segment polypectomy, 593 gender relationship colonoscopy diagnostic yield, 179 insertion techniques, 537–8 polyp growth, 373 polyp prevalence, 359 (table), 361 general anesthesia, 101, 108 impact of, 110 general-purpose procedure rooms, 31–2 generator impedance (R), high-frequency surgery, 336 genetic deletions, tumor genetics, 350–1 genetic screening, future work, 786 Germany colonoscopy history, 16 flat adenomas, 426 nonpolyploid colorectal neoplasms (NP-CRNs), 426 germline mutations, tumor genetics, 349 GETAID study, 649–50 GIF files, digital image file compression, 259 GI Mentor, computer simulators, 157, 158, 159 gloves, 62 gastrointestinal assistant, 63 glutaraldehyde chemical colitis, 666, 667 cleaning/disinfection, 71, 71 (table)

glycoprotein IIb/IIIa receptor antagonist discontinuation, 98 goblet cells endomicroscopy, 529 hyperplastic polyps, 388 gonorrhea, 664 grading adenoma dysplasia, 383 dysplasia, 456 graft-versus-host disease, biopsy, 453 granular cell tumors, 391–2, 392 grasp biopsy, 446 guiaic-based fecal occult blood testing, 207 Guidelines for Design and Construction of Hospital and Health Care Facilities, 21 guidewires, 696 guiding splitsigmoidoscope, history of colonoscopy, 13 gut lavage see colon cleansing methods H hairpin bends, insertion techniques, 546, 546 “hairy” polypectomy snares, 307, 308 hamartomatous (Peutz–Jeghers) polyps, 353, 393, 393–4 hand marker, ScopeGuide, 621, 621 hand preparation, insertion techniques, 543 “hands-on” experience see training/teaching hazardous substances, Occupational Safety and Health Administration Regulations, 62 health care utilization, postcolorectal cancer resection colonoscopy, 742 Health Insurance Portability and Accountability Act (HIPAA) (USA) informed consent, 87 recovery space, 23 health maintenance organizations (HMOs), postcolorectal cancer resection colonoscopy, 742 health outcomes, postcolorectal cancer resection colonoscopy, 741–2 heater probes, 313, 314 electrosurgery, 332, 332 heat generation, electrosurgery see electrosurgery heating, colonoscopy suite, 35–6 Helicobacter pylori infection, 69 (table), 70 hematochezia, 631–45 angiomas, 633 coagulation probes, 634, 634 (table) colon cleansing methods, 632–3, 633 (table), 637 diverticular hemorrhage, 637 colonic angiomas, 641–4, 642, 643 comorbidities, 642 (table) CURE Hemostasis Research Group treatment, 642–3 hematocrit, 643, 643 colonic diverticula, 633 CURE Hemostasis Research Group treatment algorithm, 633 coagulation probes, 634, 634 (table) colonic angiomas, 642–3 delayed postpolypectomy hemorrhage, 641 studies, 635, 635, 635 (table) delayed postpolypectomy hemorrhage, 641

801

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Page 802

Index

hematochezia (cont’d) diagnostic evaluation, 632 diagnostic yield (of colonoscopy), 180–5 diverticular hemorrhage, 635, 636, 637, 637–8 medical–surgical vs. medical–endoscopic therapy, 637, 637 (table), 638 drug-induced, 632 endoscopic hemoclips, 634–5 epidemiology, 631 epinephrine injection, 633 equipment, 633–4, 634 (table) initial evaluation, 631–2 internal hemorrhoids, 638–9 grading, 639, 639 (table) rubber band ligation, 639, 639 ischemic colitis, 632, 639–40 postpolypectomy ulcers, 633 resuscitation, 631–2, 632 (table) solitary rectal ulcer syndrome, 640, 640–1 studies, 635 hematocrit, colonic angiomas, 643, 643 hematoporphyrin derivatives, exogenous photosensitizer-induced fluorescence, 483 hemoclips see clips hemorrhages see bleeding hemorrhagic proctocolitis with recurrent bleeding, thermocoagulation, 755 hemorrhoids internal, hematochezia see hematochezia rectal bleeding, 181 hemostasis, 318 electrosurgery, 337 high-frequency surgery, 336 pediatric colonoscopy, 756 see also bands; clips hemostatic clips see clips hemostatic forceps, endoscopic submucosal dissection (ESD), 607, 607 heparin, anticoagulant agent short-term substitution, 96 hepatic flexure, insertion techniques, 554–5, 555 hepatitis B, 68 endoscopic transmission, 69 (table) hepatitis C endoscopic transmission, 68 patient-to-patient transmission, 68–9 hereditary colorectal cancer, 431–45 genes, 431 see also specific diseases/disorders hereditary nonpolyposis colorectal cancer (HNPCC), 350, 432, 437–40 clinical presentation, 438 Bethesda criteria, 438, 438 (table) distribution, 362 etiology, 437–8 genetic testing, 439 pediatric polypectomy, 754 risk reductions, 561 screening, 439–40 treatment, 440 variations, 439 hereditary syndromes screening colonoscopy, 206 see also specific syndromes/conditions herpes simplex virus (HSV) infection, 664, 665

802

hexaminolevulinate, exogenous photosensitizerinduced fluorescence, 485 high-definition endoscopes, flat lesion detection, 568 high-frequency surgery, 332–4 bipolar, 333, 333 coagulation, 334–5 bipolar instruments, 335, 335 depth, 336 electro-hydro-thermal probes, 334, 334 current density, 333–4 cutting, 335, 335–6 depth, 335, 336 modes, 335–6 monopolar, 333, 333 polypectomy, 337–8 safety aspects, 339 high-frequency ultrasonography (HFUS), 501–2 anatomical considerations, 502–3 colorectal adenocarcinomas, 507–8 accuracy rate, 507 Japanese Cancer Society classifications, 507 patient preparation, 502 high-grade adenomas, 383, 384, 384 high-grade malignant neoplastic polyps, 401, 403 high-level disinfection see cleaning/disinfection (of colonoscopes) high-risk groups, anticoagulant agent recommendations, 95 Hippocratic oath, informed consent, 79 “Hirschowitz fibergastroscope,” 8, 9 histoplasmosis, 661–2, 662 history (of colonoscopy/endoscopy), 3–18 America, 8, 8–10, 9, 10 coloncameras, 7–8 colorectal disease diagnosis, 16 electronic endoscopes, 14 gastric cancer diagnosis, 16 gastrocameras see gastrocameras Germany, 16 Italy, 16 Japan, 10–13, 11, 16 forward-viewing, 10–11, 11 oblique-viewing, 11–12, 12 side-viewing, 10–11 polypectomy see polypectomy proximal colon, 13 rigid endoscopes see rigid endoscopes shaft characteristics, 15, 15–16 3-D magnetic imaging systems, 16, 16 sigmoidocamera, 7–8 United Kingdom, 16 videocolonoscopes, 14 image differentiation, 14, 15 HIV infection colonoscopy diagnostic yield see diagnostic yield (of colonoscopy) endoscopic transmission, 69 hMLH1 gene, 351, 352 serrated carcinogenesis pathway, 386 serrated polyps, 408 hMSH2 gene, 352 hMSH6 gene, 352 HNPCC see hereditary nonpolyposis colorectal cancer (HNPCC)

home television, teaching aids, 137 hook knife, endoscopic submucosal dissection (ESD), 606, 607 hot biopsy forceps, 446 polypectomy, 576–7 small polyp polypectomy, 577 small polyp retrieval, 613 hPMS2 gene, 352 human papillomavirus (HPV) infection, 664, 665 hydrogen chloride, peracetic acid combination, 71 (table) hydrogen peroxide chemical colitis, 666, 666 cleaning/disinfection, 71 (table) hyperemia, Minimal Standard Terminology (MST), 240 hyperplastic colon, Raman spectroscopy, 487 hyperplastic polyposis syndrome, 442 hyperplastic polyps adenomatous polyps vs. see adenomatous polyps polypectomy surveillance, 725–6 Sano–Emura classification, 521–2, 524 (table) hypertonic dextrose, endoscopic mucosal resection (EMR), 586–7 hypertonic saline, endoscopic mucosal resection (EMR), 586–7 hypotension, complications, 709 hypoxia, complications, 709–10 hysterectomy with ovariectomy, hereditary nonpolyposis colorectal cancer treatment, 440 I ileoanal pouches, dysplasia, 456 ileocecal valve insertion techniques see insertion techniques pediatric colonoscopy, 752–3 polypectomy, 584 ileocolitis, infectious see infectious ileocolitis ileo pouch–anal anastomoses (IPAA), 653 ileoscopy HIV patients with chronic diarrhea, 197 pediatric colonoscopy, 753 illumination system, video colonoscopes, 274, 290 image(s) display ScopeGuide, 621, 621 video colonoscope, 279, 279–80 fidelity, charge-coupled device (CCD), 276 management see below processing see video colonoscopes quality, 290 reading, charge-coupled device (CCD), 275–6 resolution, 278, 278 image management, 236, 254–65, 257 digital see digital images standardization/exchange, 247–50 charge-coupled devices (CCDS), 247 compression algorithms, 247 DICOM system see DICOM (Digital Imaging and COmmunication in Medicine) distributed processing, 248–9, 249 document type definitions (DTDs), 249 image production, 247 information object definitions (IODs), 249 JPEGs, 247

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management, 247–9 service class providers, 249 service elements, 249 video endoscopes, 247, 248 text with, teaching aids, 134 use of, 249–50 imaging, 620–2 see also specific methods imaging shaft, colonoscopy history, 15–16 immediate bleeding see bleeding Immersion Medical stimulator, 160 immunocompromised patients antibiotic prophylaxis, 91–3 Escherichia coli, 92 immunohistochemistry, hereditary nonpolyposis colorectal cancer (HNPCC), 438, 439 immunophotodiagnostics, 490–5 animal studies see animal models/studies anti-carcinoembryonic antigen antibodies, 494 cathepsin B, 491 clinical evaluation, 493–4 biomarkers, 495 peptide labeling, 495 tumor-associated targets, 495 labeling molecules anti-carcinoembryonic antigen antibodies, 490 cathepsin B, 491 colonic mucins, 492 gastrointestinal tumor-associated biomarkers, 492 mRNA, 491 peptide sequences, 491 pharmacokinetics, 491 tumor-associated enzymes, 491 quantum dot method, 492 animal models, 492, 493, 494 Barrett’s esophagus, 492, 493 immunostaining, narrow-band imaging, 520–1, 521 immunosuppressed patients, colorectal strictures, 690 implied consent, 85 incomplete examinations, continuous quality improvement (CQI), 44–5 index examination, polyp incidence, 365 India ink, polypectomy lesion location, 598–9 indications (for colonoscopy), 167–74 abdominal pain, 170 abnormal radiographs, 170–1 abnormal sigmoidoscopy, 170–1 adenomas, 169, 171 age, 169, 170 American Cancer Society (ACS) recommendations, 167 American College of Gastroenterology (ACG) recommendations, 167, 171 American College of Radiology (ACR) recommendations, 171 American Gastroenterological Association (AGA) recommendations, 171 American Society for Gastrointestinal Endoscopy (SGE) recommendations, 167 appropriate indications, 174 cardiac disease, 168

chronic diarrhea, 170 classification, 167–9 diagnostic vs. therapeutic, 167–8, 198 (table) high-risk vs. low-risk, 168 high-yield vs. low-yield, 168–9, 169 (table) colorectal cancer, 169 computed tomography, 171 constipation, 170 Crohn’s disease, 171–2 Crohn’s strictures, 168 established ulcerative colitis, 171 European Panel of Appropriateness of Gastrointestinal Endoscopy (EPAGE), 174 filling defects, 170–1 male gender, 169 polypectomy surveillance see polypectomy surveillance positron emission tomography, 171 postcancer resection surveillance, 172–3 radiographic studies, 172, 173 (table) pulmonary disease, 168 rectal bleeding, 169, 170 reports, 254–5 US Multisociety Task Force, 172 indigo carmine chromoendoscopy, 412, 463 pancolonic chromoendoscopy, 465 indocyanine green, polypectomy lesion location, 597–8 infections, 659–74 as complication, 710 Crohn’s disease vs., 660 pediatric colonoscopy, 750–1 ulcerative colitis vs., 660 see also specific infections infectious ileocolitis, 659–66 colonoscopic appearance, 659, 659 colorectal biopsy, 660 inflammatory bowel disease vs., 660 stool tests, 659 infective endocarditis American Heart Association (AHA) guidelines, 90, 91 antibiotic prophylaxis, 90–1 Escherichia coli, 90 pathogenesis, 90 risk of, 90, 90 (table) inflammatory bowel disease (IBD), 649–58 age-relation, 179 benign colorectal stricture therapy, 692 biopsy sites, 454 cancer surveillance, 650 colon cleansing methods, 120 colorectal strictures, 690 differential diagnosis, 649, 649 (table) endoscopic ultrasonography (EUS), 508–9 endoscopy assessment, 649–50 indications, 655 monitoring of therapy, 652 HIV patients with chronic diarrhea, 197 infectious ileocolitis vs., 660 self-expandable metal stents (SEMS), 693 of type unclassified (IBDU), 651 see also Crohn’s disease; ulcerative colitis

inflammatory cap polyps, 395–6, 396 inflammatory polyps, 394, 394 infliximab, Crohn’s disease therapy, 652, 654 information object definitions (IODs), image standardization/exchange, 249 informed consent, 58, 79–89 colonoscopy provider metrics, 82–3 data transmission, 87 documentation, 85–6 elements of consent, 84–5 exceptions, 85 failure to obtain, 83, 84 Health Insurance Portability and Accountability Act, 87 historical aspects, 79 informed refusal, 85 legal history, 79–80 malpractice actions, 84 material risks, 81–2 missed neoplasms, 562 open-access colonoscopy, 86–7 postpolypectomy bleeding treatment, 712 process (elements) of consent, 84 provider–patient relationship, 79 reports, 255 scope of consent, 85 sedation, 82, 110 shared-decision making, 80–1 special situations, 86–7 “stop” vocalization, 86 unsettled areas, 82 from whom, 85 withdrawal of, 86 informed refusal, 85 initial action plans, continuous quality improvement (CQI), 42 initial assessment, training/teaching, 145 inject and cut method, nonpolyploid colorectal neoplasm treatment, 427 injection needles, 309–10, 310 polypectomy, 576 Innoflex (Olympus), 15, 15 insertion length polyp location, 596 insertion techniques, 537–59 anorectum insertion, 539–40, 540 ascending colon/ileocecal region, 555, 555 “crow’s foot” sign, 555, 556 “Mercedes-Benz” sign, 555, 556 complications, 704–7 see also traumatic perforation descending colon, 551, 551 diverticular disease, 545, 545–6 efficient handling, 540–1, 541 embryology, 537–8, 538 endoscopic submucosal dissection (ESD), 608 failure, virtual colonoscopy, 770 hepatic flexure, 554–5, 555 ileocecal valve, 556–7 “appendix trick,” 556, 556 biopsy forceps, 557, 557 retroversion, 557, 557 instrument choice, 537–8 intubation and steering, 541–3 air suction, 542 fluid suction, 542

803

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insertion techniques (cont’d) hand preparation, 543 insufflation, 541–2, 542 position changes, 543 restricted views, 543, 543 sigmoid colon elasticity, 541, 541, 542 speed, 543 steering direction prediction, 542–3 visual cues, 542, 542 patient position, 539 preprocedure checks, 538 sex relevance, 537–8 sigmoid colon anatomy, 543, 543–4, 544 navigation, 544, 544–5, 545 sigmoid loops, 546, 546–50 abdominal pressure, 547 “alpha” spiral loop, 548, 548, 549 external shaft loops, 550 hairpin bends, 546, 546 insertion speed, 546–7 longer colon, 549, 549–50, 550 “N” looping, 546, 548 pain, 546 patient position, 547 “push and go” approach, 548, 548 “push through” approach, 548–9 removal, 549 “reversed alpha,” 550, 550 short/painful colon, 547, 547 single-handled approach, 538, 538–9 angulation controls, 538, 539 splenic flexure, 551, 551–2, 552 “reversed alpha,” 552, 552 symptomatology effects, 537–8 terminal ileum, 558 transverse colon, 553, 553–4 gamma looping, 554, 554 hand pressure, 554, 554 mobile splenic flexure, 553–4, 554 tumor genetics, 350–1 two-handled approach, 538–9 two-person approach, 538–9 insertion time, reports, 255 insertion tube, 292–300 adjuncts, 296 construction, 293 definition, 292 internal components, 292–3 internal stiffeners, 296 magnetic endoscopic imaging, 296 overtubes, 296 variable flexibility, 293, 293 video colonoscope see video colonoscopes in situ measurement, polyp growth problems, 369 Institute of Medicine, quality definitions, 42 institutional forms, informed consent, 84 instructions, gut lavage, 119 instructor feedback, computer simulators, 161 instrument withdrawal see withdrawal techniques insufflation, insertion techniques, 541–2, 542 intensive training, daily training vs., 130 intercom system, colonoscopy suite, 37 interleukin-10, 367

804

interline transfer, charge-coupled device (CCD), 275, 277, 277 intermediate-length colonoscope, 296 internal hemorrhoids, hematochezia see hematochezia internal stiffeners, insertion tube, 296 International Classification of Disease (ICD), 256 internet, teaching aids, 135–6 Internet 2 project, teaching aids, 136 interval cancers, 562–3, 562 (table) interventional studies, polyp growth, 370, 370, 371, 372 intestinal pull-up (“end-to-end” method), 13 intraepithelial neoplasia see chromoendoscopy intraluminal bleeding, 707–8, 708 (table) intraluminal landmarks, 596 intramucosal and superficial submucosal cancer (capillary pattern type IIIA), Sano–Emura classification, 522, 524 (table) intramucosal carcinomas see carcinomas intraoperative colonoscopy, traumatic perforation, 706 introductory skills courses, training/teaching, 152 intubation see insertion techniques intussusception, pediatric polypectomy, 754 invasive carcinoma see carcinomas Invendo Medical, single-use endoscopes, 779, 779–80 in vitro training, electrosurgery, 338 in vivo comparative studies, optical coherence tomography (OCT), 489 in vivo histology, endomicroscopy, 533 in vivo staining, chromoendoscopy see chromoendoscopy in vivo studies, fluorescence point spectroscopy, 477, 478, 479 iron, polyp prevalence, 364 iron deficiency anemia colonoscopy diagnostic yield see diagnostic yield (of colonoscopy) prevalence, 185 irritable bowel syndrome (IBS) colonoscopy diagnostic yield, 197, 198 (table), 199 future work, 788–9 HIV patients with chronic diarrhea, 197 ischemic colitis drug-evoked, 450–1 hematochezia see hematochezia isolated colon ulcers, 671 Italy, colonoscopy history, 16 J Japanese Cancer Society, colorectal adenocarcinoma classifications, 507 Japanese Research Society for Cancer of the Colon and Rectum classification systems, 423, 423 depressed adenomas, 412–13, 413 Japanese Society for Gastrointestinal Endoscopy, Minimal Standard Terminology (MST), 238 JPEG files digital image file compression, 259 image standardization/exchange, 247

juvenile polyposis syndrome (JOPS), 432, 441–2 clinical presentation, 441, 441 juvenile polyps, 392–3, 393 polypectomy, 754 K key qualities, trainers, 144 (table) Ki67 staining, sessile serrated polyps, 389 Klebsiella infections endoscopic transmission, 69 (table) postcolonoscopy, 710 K-ras oncogene, 350 activation, adenoma–carcinoma hypothesis, 382, 428 hyperplastic polyps, 388 mutations, sporadic adenomatous polyps, 353 polyp prevalence, 364 serrated carcinogenesis pathway, 354 stool DNA tests, 208 Kussmaul, A gastroscope, 4–5 history of endoscopy, 4–5 L laboratory tests, colorectal cancer surveillance, 730 LAN (local area network), colonoscopy suite, 37 laparotomy, polyp location, 595–6 large-cup biopsy, 446, 446 large polyps see polyp(s) laser fibers, 314 laser therapy, 342–3 forward vs. side-firing, 343 malignant colorectal stricture therapy, 694, 694, 695 pediatric colonoscopy, 755–6 power vs. distance, 344 laterally spreading flat adenomas, 415, 416, 416–17 laterally spreading tumors of the nongranular type (LST-NG), 603–4, 604, 605, 611 laxatives, colon cleansing methods, 115, 763–4 learning objectives, teaching methods, 145 legal implications informed consent, 79–80 shared-decision making, 81 missed neoplasms, 561–2 propofol sedation, 110 legal mandate, informed consent exceptions, 85 lesion(s) borders, narrow-band imaging, 516 location, capsule endoscopy, 251 marking, clips, 310 removal, continuous quality improvement (CQI), 47 size see size (of lesion) see also polyp(s) licensing, colonoscopy suite, 39–40 “lift and cut” technique, endoscopic mucosal resection (EMR), 586 light absorption of, 474–5, 475 scattering of, 474–5, 475 tissue penetration, 475 video colonoscope, 271–2

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light guide lens, video colonoscope illumination system, 274 light-induced fluorescence endoscopy (LIFE), 478–9 dysplasia-associated lesion or mass, 479, 480 false-positive lesions, 479, 480 flat adenomas, 479, 480 hyperplastic vs. adenomatous polyps, 479, 481 lighting, colonoscopy suite, 36 light-scattering spectroscopy, 487 clinical evaluation, 487 light sensitivity, charge-coupled device (CCD), 280 line transfer, charge-coupled device (CCD), video colonoscope, 275, 275, 275–6 lipofuscin, autofluorescence, 476 (table) lipomas, endoscopic ultrasonography (EUS), 508 liquid-chemical germicides see cleaning/disinfection (of colonoscopes) literature complications, 703– 4 postcolorectal cancer resection colonoscopy see postcolorectal cancer resection colonoscopy live teaching courses, 137–8 loops/looping, 323, 323– 4, 324 advantages, 324 colonic lipomas, 325 detachable loops, 312–13 pediatric colonoscopy, 293 postpolypectomy hemorrhage, 324, 324 ScopeGuide, 623 lower gastrointestinal tract bleeding acute, 181, 181 colon cleansing methods, 120 colonoscopy diagnostic yield see diagnostic yield (of colonoscopy) definition, 631 epidemiology, 631 see also hematochezia low-grade adenomas, 383, 383 low-molecular weight heparin, 96–7, 97 (table) American Society for Gastrointestinal Endoscopy anticoagulant agent recommendations, 97, 97 (table) lumen deflation, withdrawal techniques, 565 lymphangiomas, endoscopic ultrasonography (EUS), 508 lymphatics, pedunculated adenoma invasion, 405 lymph node metastases chromoendoscopy, 466 nonpolyploid colorectal neoplasm treatment, 427 lymphocytic colitis, differential diagnosis, 453 lymphoid polyps, 396–7 lymphomas, 396–7 mantle cell, 396 lymphonodular hyperplasia, pediatric colonoscopy, 751, 751 Lynch syndrome, 352–3 see also hereditary nonpolyposis colorectal cancer (HNPCC) M macroscopic tissue autofluorescence, 481, 482 macro-simulation screening modeling analysis (MISCAN), National Polyp Study, 724

magnesium, polyp prevalence, 364 magnesium citrate, colon cleansing methods, 764, 765 magnetic resonance imaging (MRI), 620–1 colonoscopy training, 624 colorectal cancer surveillance, 742 endoscopic ultrasonography (EUS) vs., 505 impact of, 622–5 insertion tube, 296 need for, 619 polyp location, 597 self-expandable metal stents (SEMS), 694 three-dimensional colonoscopy history, 16, 16 principles, 620–1, 621 software, 620 see also ScopeGuide magnification, Minimal Standard Terminology (MST), 250 magnifying colonoscopy, 412–22 depressed adenomas, 419 historical aspects, 412 video colonoscope see video colonoscopes male gender, colonoscopy indications, 169 malignancies see carcinomas malignant neoplastic polyps, 380 (table) assessment, 401–2 definition, 401 flat adenomas, 404 high-grade dysplasia, 401, 403 initial evaluation, 404, 404–5 localization, 405, 405 intramucosal carcinomas, 401, 402 invasive, 402 management, 401–11 abdominal surgery, 409, 409 (table) clinician role, 409–10 removal, 409 see also specific methods pathology, 401, 401–2 pedunculated, 402 pseudoinvasion, 402 risk factors, 402–4, 403 (table) age, 402–3 National Polyp Study, 402 size, 402, 403–4 villous histology, 403–4 serrated polyps, 408 sessile adenomas, 401, 402, 402 surgery vs. follow-up, 405–8 see also carcinomas Mallory–Weiss tears, clips, 320 malpractice actions, informed consent, 84 maneuverable capsule colonoscopy, 785, 785 mantle cell lymphoma, 396 manual cleaning, 70 MAP see MYH gene associated polyposis (MAP) marble polyps, 577 marginal cells, B-cell lymphomas, 396, 396 marking polyp location, 595 snare handle, 574, 574 Markov process, decennial colonoscopy, 218, 218 massed practice, “hands-on” training/teaching, 146

masses, Minimal Standard Terminology (MST), 244 material risks, informed consent, 81–2 Mayo score, ulcerative colitis, 650 mechanical cleaning, 71 mechanical models see simulators medical decision analysis, cost-effectiveness analysis limitations, 227–8 medical history biopsy, 449, 450 (table) hematochezia, 632 medications see drugs/medications medicolegal implications see legal implications melanosis coli, 671 meperidine, 102 “Mercedes-Benz” sign, ascending colon/ileocecal region insertion techniques, 555, 556 mesenteries, endoscopic trauma, 708 meshed capillary vessels, narrow-band imaging, 518–19, 519, 520, 521 meta-analyses, colorectal cancer surveillance, 731 metachronous polyps missed synchronous polyps vs., 722 postcolorectal cancer resection colonoscopy, 738–9 methylene blue, chromoendoscopy, 463–4 metoclopramide, gut lavage, 117 MGMT gene, CpG island methylator phenotype (CIMP), 355 microorganism transmission, 68–70, 69 (table) frequency of, 68 mycobacteria, 69 (table), 70 protozoa, 70 viruses, 68–9, 69 (table) see also specific microorganisms microrobotic technology, future work, 784–5 microsatellite instability hereditary nonpolyposis colorectal cancer (HNPCC), 438 serrated carcinogenesis pathway, 386 tumor genetics, 355 microscopic colitides, 668, 669 microscopy see endomicroscopy microvesicular hyperplastic polyps, 388 midazolam, 103 propofol preinduction, 105 minimally invasive techniques, traumatic perforation treatment, 706–7 minimal sedation, 101 Minimal Standard Terminology (MST), 235–6, 238–47, 262–3, 264 adaptation, 250–2 advantages, 246 American Society for Gastrointestinal Endoscopy, 238 capsule endoscopy, 251 chromoendoscopy, 250 clinical benefits, 246–7 endoscopic microscopy, 250 endoscopic mucosal resection (EMR), 251 endoscopic submucosal dissection (ESD), 251 European Society of Gastroenterology, 238 “high-definition endoscopy,” 250 history of, 238 issues, 263

805

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Minimal Standard Terminology (MST) (cont’d) Japanese Society for Gastrointestinal Endoscopy, 238 magnification, 250 maintenance of, 251–2 new techniques, 250–2 see also specific techniques new therapeutic procedures, 250–1 polypectomy, 251 shortcomings, 263 structure, 238–9, 239 structured language modeling, 246 terms, 239– 45, 241–3 (table) angioectasia, 244 aphtha, 240 congested mucosa, 240 erosions, 240, 244 erythema, 240 erythematosus mucosa, 240, 244 hyperemia, 240 major headings, 240 (table) mass, 244 obstruction, 244 occlusion, 244 problems, 263 red mucosa, 240 scar, 244 stenosis, 240, 240 tumors, 244 ulcerated mucosa, 244–5, 245 validation, 245–6 descriptions, 245 (table) testing results, 246 (table) miniprobes, endoscopic ultrasonography (EUS), 501–2 mini-snares narrow diverticular segment polypectomy, 593 small polyp polypectomy, 577–8, 578 mismatch repair processes, hereditary nonpolyposis colorectal cancer (HNPCC), 438 misplaced mucosal adenomas, 385, 385 missed neoplasms, 560–71, 713 cecum intubation documentation, 562, 562 inaccurate localization, 713 informed consent, 562 medicolegal risks, 561–2 polypectomy surveillance, 722 surveillance impacts, 561–2 withdrawal time documentation, 562 see also interval cancers mixed lesions, colonoscopy quality issues, 211–12 mixed serrated adenomas, 387 (table), 389–90, 390 MLH1 gene, 355 hereditary nonpolyposis colorectal cancer (HNPCC), 437 MMR genes, 352–3 mobile splenic flexure, transverse colon insertion techniques, 553– 4, 554 models practical teaching, 148 teaching aids, 134, 141–2 moderate sedation, 101 modified Kudo criteria, chromoendoscopy, 463, 464 (table)

806

monitoring, training formative assessment, 151 monopolar high-frequency surgery, 333, 333 coagulation, 334 polypectomy snares, 306 monopolar hot biopsy forceps, 309 Monte Carlo simulation, narrow-band imaging, 514–15, 515 mortality, 704 colorectal cancer screening effects, 209 informed consent material risks, 82 polypectomy surveillance effects, 723–4 postcolorectal cancer resection colonoscopy effects, 741 mortality rate, 704 motility catheter placement, pediatric colonoscopy, 756–7 motility disorders, future work, 788–9 motion reproduction, colorchip video imaging, 284, 284 motivation, training/teaching, 143–4 mountain polyps, 577 movable parts, cleaning/disinfection, 73 movement patterns, colonoscopy suite arrangement, 27–8, 28 mRNA, immunophotodiagnostics, 491 MSH2 gene, hereditary nonpolyposis colorectal cancer (HNPCC), 437 MSH6 gene, hereditary nonpolyposis colorectal cancer (HNPCC), 437 MST see Minimal Standard Terminology (MST) mucin poor hyperplastic polyps, 388 mucosa defects/abnormalities capsule endoscopy, 251 polypectomy, 584, 584 endoscopic submucosal dissection (ESD), 608, 610 prolapse associated polyps see polyp(s) Muir–Torre syndrome, 439 multibite forceps, 309 multicenter comparative study, capsule colonoscopy, 303 multidetector computed tomography, virtual colonoscopy, 767–8 multimedia, teaching aids see teaching aids multiple endocrine neoplasia type IIb, ganglioneuromas, 392 multiple polyps pediatric polypectomy, 755 treatment, 408–9 multiple repeated needle placement, endoscopic mucosal resection (EMR), 588, 588 multipolar electrocautery devices, injection needles, 310 multitangled snares, polypectomy snares, 307 mutational signatures, tumor genetics, 351 mutations tumor genetics see tumor genetics see specific genes Mycobacterium infection, endoscopic transmission, 69 (table), 70 MYH gene associated polyposis (MAP), 353, 432, 437 colorectal cancer risk, 437 myocardial infarctions, endoscopy following, 710

N NADH, autofluorescence, 476 (table) Nakao Snare®, 617, 617 naloxone, 103 pediatric colonoscopy, 749 nanoparticles, Raman spectroscopy, 487 narrow band imaging (NBI), 514–26 blue light physical principle, 514–15, 515 wavelengths, 514, 515, 515–16, 516 chromoendoscopy vs., 516 flat lesion detection, 567, 568 future work, 523–4 historical background, 514 invasive colorectal cancer, 519–20 lesion borders, 516 meshed capillary vessels, 518–19, 519, 520, 521 neoplastic lesions, 517–18 noninvasive colorectal cancer, 519–20 nonmagnifying system, 519 non-neoplastic lesions, 517–18 rationale for, 514 Sano–Emura classification, 521–2, 524 (table) screening colonoscopy, 517 small colorectal polyps, 519 technique, 516–17, 517 ulcerative colitis dysplastic areas, 523 vessel diameter immunostaining, 520–1, 521 Toppan test, 521, 522 video colonoscope see video colonoscopes narrow diverticular segments, polypectomy see polypectomy narrow point imaging, wide-beam imaging vs., 480 nasal angiofibromas, familial adenomatous polyposis (FAP), 434 National Cancer Center in Tokyo studies, 322 National Cancer Institute (NCI), National Polyp Study design, 722 National Polyp Study adenoma development time data, 724 advanced adenoma concept, 721 colorectal cancer screening evidence, 210 design of, 722, 722 (table) effects on incidence/mortality, 561 failure rates, 462 flat adenoma diagnosis, 418 incidence/mortality effects, 723 macro-simulation screening modeling analysis (MISCAN), 724 malignant neoplastic polyps, 402 polypectomy surveillance, 719 polyp follow-up studies, 186 polyp growth, 367 polyp prevalence, 363 postcolorectal cancer resection colonoscopy, 739 postpolypectomy risk factors, 366 results of, 723 surveillance cost effectiveness, 727 Nd:YAG laser therapy, chronic radiation proctopathy (CRP), 683, 686–7 near-infrared light, Raman spectroscopy, 485 needle/anchor-tipped polypectomy snares, 307, 308

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needle knives, endoscopic submucosal dissection (ESD), 592 negligence, informed consent, 84 Neisseria gonorrhoeae infection, 664 NeoGuide colonoscope, 777–8 Neopapilla™ attachment, 156, 156 neoplastic lesions malignant see malignant neoplastic polyps missed see missed neoplasms narrow-band imaging, 517–18 tissue autofluorescence, 480–1 see also specific types of lesion neostigmine acute colonic pseudo-obstruction management, 677 adverse effects, 678 nervous system access, 788 neurofibromas, 392 neurogenic polyps, 390– 4 epithelioid schwannomas, 391, 391 fibroblastic polyps, 392 ganglioneuromas, 392 granular cell tumors, 391–2, 392 hamartomatous (Peutz–Jeghers) polyps, 393, 393– 4 inflammatory polyps, 394, 394 juvenile polyps, 392–3, 393 neurofibromas, 392 perineuriomas, 392 spindle cell schwannomas, 391, 391 new techniques, retraining, 131 new technology, colonoscopy suite planning, 22 “N” looping, insertion techniques, 546, 548 Nomesco Classification of Surgical Procedures (NCSP), 256 nonaspirin antiplatelet agent discontinuation, 98 nonbleeding visible vessels, hematochezia, 635 noncontact thermal devices, 313–14 noncritical devices, Spaulding criteria, 68 nondysplastic serrated polyps see serrated polyps non-fluoroscopic guided stent procedure, selfexpandable metal stents (SEMS), 697–8 noninvasive colorectal cancer, narrow-band imaging, 519–20 noninvasive tests, colorectal cancer screening, 206–8 nonlifting sign, endoscopic mucosal resection (EMR), 588–9 non-neoplastic polyps, 380 (table) narrow-band imaging, 517–18 nonpolyploid colorectal neoplasms (NP-CRNs), 423–30 biology, 429 detection and diagnosis, 426–7 dye-based image-enhanced endoscopy, 427, 427 (table) patient preparation, 426–7, 427 (table) epidemiology, 425–6 prevalence, 426 (table) treatment, 427–8 nonpolyploid neoplasms, definition, 423, 424 non-resectable lesions, endoscopic submucosal dissection (ESD), 603 non serious risks, informed consent, 82

nonsteroidal anti-inflammatory drugs (NSAIDs) adverse effects, 225 American Society for Gastrointestinal Endoscopy (ASGE) discontinuation guidelines, 95 benign colorectal stricture therapy, 691 biopsies, 450 chemoprevention, 225 colitis, 669–70 familial adenomatous polyposis (FAP), 352 familial adenomatous polyposis treatment, 437 hematochezia, 632 polyp prevention, 366 prevention role, 363 nonvariceal injection therapy, pediatric colonoscopy, 755 normal colonic mucosa (capillary pattern type I), Sano–Emura classification, 521, 524 (table) North America flat adenomas, 425 nonpolyploid colorectal neoplasms (NP-CRNs), 425 Norwalk virus infection, 68 NOTES (natural orifice transluminal endoscopic surgery), 788 “N” spiral loop, ScopeGuide, 625 N-stage assessment, colorectal adenocarcinomas, 503, 506–7 Nurse’s Health Study, polyp prevalence, 363 nutrient effects, polyp growth, 373 O obesity, future work, 789 oblique-viewing colonoscopes, 11–12, 12 observational studies advanced adenoma concept, 721 polyp growth see polyp growth obstructions, Minimal Standard Terminology (MST), 244 occlusions, Minimal Standard Terminology (MST), 244 Occupational Safety and Health Administration Regulations, 62 office space, colonoscopy suite, 20–1 Olympus Colonoscopy Simulator, 158, 158 oncogenes, 350 see also specific oncogenes Onco-LIFE®, 483 one-way valves, 273 open-access colonoscopy, informed consent, 86–7 open forceps polyp size estimation, 368 opioids, 102 benzodiazepine combination, 104–5 propofol combination, 105 optical coherence tomography (OCT), 487–90 animal studies, 489 clinical evaluation, 489–90 detection studies, 489 Doppler, 489 ex vivo tissue studies, 488 mechanism of action, 488 optical filters, light-induced fluorescence endoscopy (LIFE), 478

optical techniques, 473–500 basic tissue optics, 474–5 tissue autofluorescence see tissue autofluorescence option review, practical teaching, 147 orthopedic prostheses, antibiotic prophylaxis, 91 ortho-phthalaldehyde, cleaning/disinfection, 71 (table) outcomes management, continuous quality improvement (CQI), 42–3 outcomes research advanced adenoma concept, 721 continuous quality improvement (CQI), 42 output voltage, high-frequency surgery, 336 oval polypectomy snares, 307, 307 overstaging effects, endoscopic ultrasonography (EUS), 505, 506 over-the-wire rigid dilators (Savary–Gilliard dilators), benign colorectal stricture therapy, 691 overtubes, 315 insertion tube, 296 oxygen administration, 59 sedation, 107 P p16 gene, CpG island methylator phenotype (CIMP), 355 p53 gene adenoma–carcinoma hypothesis, 383, 428 serrated carcinogenesis pathway, 354 sporadic adenomatous polyps, 353 stool DNA tests, 208 pacemakers, high-frequency surgery safety, 339 PACS (picture archiving and communication systems), digital image file compression, 259 pain colon cleansing methods, 109 colonic gas introduction, 109 patient position, 109 sigmoid looping, 108–9, 110, 546 vasovagal reaction, 109 visceral stretching, 109 palatability, gut lavage, 117 palliative therapy, 695–6 pancolonic chromoendoscopy, 465 pancreatitis complications, 709 severe acute, 690 parallel room plan, procedure rooms, 30, 31, 32 parasitic infections, 69 (table), 70, 662–4 endoscopic transmission, 69 (table), 70 see also specific infections Paris classification adenoma-like mass lesion, 457 small colorectal polyps, 519 PAS (pouchitis activity score), 653 passive viewing bundles, history of colonoscopy, 13 patient(s) autonomy, 81 colonoscopy diagnostic yield, 179 colonoscopy suite planning, 22, 26, 27, 28 continuous quality improvement (CQI), 43–4 demographic reports, 254

807

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patient(s) (cont’d) flow patterns, 26, 27, 28 monitoring, 58–9 equipment, 34, 37 preparation endoscopic ultrasonography (EUS), 502 high-frequency ultrasonography (HFUS), 502 nonpolyploid colorectal neoplasms (NPCRNs), 426–7, 427 (table) see also colon cleansing methods privacy administration area, 38–9 recovery space, 23– 4 satisfaction benzodiazepine–opioid combination, 104–5 continuous quality improvement (CQI), 49, 50 (table) sedation expectations, 82 sedation variability, 102 selection, 57–8 practical teaching, 148 unsedated colonoscopy, 104 shared-decision making, 80–1 patient-based standards, informed consent, 80 patient-controlled sedation, 106 patient position insertion techniques, 539 sigmoid loops, 547 pain, 109 pattern recognition motifs, endomicroscopy, 533 PDAI (Pouchitis Disease Activity Index), 653 pediatric colonoscopes, 293 advantages, 267 disadvantages, 267 pediatric colonoscopy, 749–59 antibiotic prophylaxis, 752 band ligation, 756 colonic stricture dilation, 756 complications, 757 sedation, 750 contraindications, 751–2 endoloops, 756 endoscopic hemostatic devices, 756 equipment, 750 facilities, 749 flexible proctosigmoidoscopy, 754 gut lavage, 118 hemostatic clips, 756 ileoscopy, 753 post small bowel transplantation, 753, 753 indications, 750, 750–1 Crohn’s disease, 750, 752–3 gastrointestinal bleeding, 755 lymphonodular hyperplasia, 751, 751 motility catheter placement, 756–7 nonvariceal injection therapy, 755 percutaneous cecostomy, 756 personnel, 749 preparation, 752 sedation, 749–50 techniques, 752–7 see also specific techniques terminal ileal intubation, 752–3

808

therapeutic, 751 thermocoagulation, 755–6 pedunculated adenomas biopsies, 457–8 lymphatic invasion, 405 surgery vs. follow-up, 405, 406 pedunculated polyps, 577 malignant neoplastic, 402 pediatric polypectomy, 754, 754 polypectomy, 578, 754, 754 prevalence, 363 stalk biopsy, 447–8 penetration depth, electrosurgery, 337 Pennington, J R, 6 peptide labeling, immunophotodiagnostics, 495 peptide sequences, immunophotodiagnostics, 491 peracetic acid, cleaning/disinfection, 71 (table) percutaneous cecostomy acute colonic pseudo-obstruction management, 679–80 pediatric colonoscopy, 756 percutaneous colostomy, tube placement, 751 perforations see traumatic perforation perfusion systems, simulators, 155–6 perineuriomas, 392 periodic acid–Schiff (PAS) staining, granular cell tumors, 392 perioperative clearing, postcolorectal cancer resection colonoscopy, 738 perioperative endoscopy, Crohn’s disease, 652–3 personal protective equipment see gastrointestinal assistants personnel, pediatric colonoscopy, 749 Peutz–Jeghers syndrome (PJS), 393–4, 432, 440–1 clinical presentation, 440, 440 pharmacokinetics, immunophotodiagnostics, 491 picture archiving and communication systems (PACS), digital image file compression, 259 PillCam Colon Capsule endoscope, 301–2, 302, 780, 780–1, 781, 785 pinch biopsy techniques see biopsies pinworm, 663–4, 664 pediatric colonoscopy, 750–1, 751 piroxicam, intervention studies, 373 pit patterns adenomas, 414–15, 414 (table), 415 classification, 583 pits, pattern classification, 413–14, 414 (table) pixel density see digital images plastic mesh, small polyp retrieval, 614 platelet transfusions, 632 Plesiomonas shigelloides infection, 661 plumbing, colonoscopy suite, 36 PMS2 gene, hereditary nonpolyposis colorectal cancer (HNPCC), 437 pneumatosis cystoides intestinalis, 669, 670 pneumatosis intestinalis, 669, 670 point mutations, tumor genetics, 350 polyethylene glycol (PEG) acute colonic pseudo-obstruction management, 678 colon cleansing methods hematochezia, 632 virtual colonoscopy, 765 polyethylene glycol 3350, gut lavage, 117–18

polyethylene glycol electrolyte lavage solution (PEG-ELS), 115–16 magnesium citrate combination, 117 pediatric colonoscopy preparation, 752 sodium sulfate/ascorbic acid combination, 117 polyp(s), 358–78 adenomatous see adenomatous polyps biology, 349–57 tumor genetics see tumor genetics definition, 358, 423, 424 detection, 178 age-relation, 179 continuous quality improvement (CQI), 45–6 miss rate, 199 sensitivity, 45 detection rates, 46 diagnostic accuracy, 379 growth see polyp growth histological artifacts, 379–80 incidence, 364–7 follow-up examination, 365 at index examination, 365 at polypectomy, 364–5, 364 (table) polyp-free individuals, 365–6, 366 (table) postpolypectomy risk factors, 366–7 Prostate, Lung, Colorectal Cancer Screening Trial, 366 recurrence rates, 365 location endoscopic mucosal resection (EMR), 589, 591–2 postpolypectomy bleeding, 711 mucosal prolapse associated, 394–7 carcinoid tumors, 397, 397 diverticular disease, 394, 395 inflammatory cap polyps, 395–6, 396 lymphoid polyps, 396–7 polypoid lymphomas, 396–7 solitary rectal ulcer syndrome (SRUS), 394–5 multiple see multiple polyps orientation, 380–91 pathology, 379–99 clinical correlation, 381 pediatric colonoscopy, 751 prevalence, 358–64 age-relation, 359 (table), 361 autopsy studies, 358–9, 360 (table) Clinical Outcome Research Initiative database, 361 colonoscopy studies, 361, 362 (table) dysplasia, 362–3, 363 (table) endoscopy studies, 359, 361 gender-relation, 359 (table), 361 multiplicity, 363 National Polyp Survey, 363 “numbers needed to endoscope,” 361 peduncular polyps, 363 risk factors, 363–4 sessile polyps, 363 sigmoidoscopy studies, 361, 362 (table) size, 362–3, 363 (table) subsite distribution, 361–2, 362 (table) villous structure, 362–3 sampling, 380–91 sampling errors, 380

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transection margin, 380–91, 381 two dimensional slides, 380 size/shape, 379–80 histological artifacts, 379–80 postpolypectomy bleeding, 711 prevalence, 363 (table) see also polyps, large; polyps, small treatment/removal; see polypectomy types of, 577 clamshell see clamshell polyps pedunculated see pedunculated polyps sessile see sessile polyps see also specific types see also lesion(s) polypectomy, 572–81 anticoagulant drug discontinuation, 95 cap-assisted, endoscopic mucosal resection (EMR), 589 coaptive coagulation, 572 colonoscope, 573 complications bleeding see postpolypectomy bleeding cancer risk following, 720–1 perforation, 48–9, 712–13 traumatic perforation, 712–13 ulcers, 633 difficulties, 582–602 ambulatory vs. inpatient, 585 colonoscope characteristics, 585–6 endoscopic mucosal resection see endoscopic mucosal resection (EMR) endoscopic submucosal dissection see endoscopic submucosal dissection (ESD) extremely difficult colonoscopy, 600 see also specific problems electrosurgery, 336–9, 572–3 coagulation mode, 337 cut mode, 337 effective cut phase, 337, 338 hemostasis, 337 high-frequency generators, 337–8 penetration depth, 337 precut phase, 337, 338 snare catheters, 339 snare handles, 339 snares, 339 unintended thermal effects, 338, 340 in vitro training, 338 endomicroscopy, 530 gastrointestinal assistant, 60 hemostasis, clips, 312 history of, 13–14 hot biopsy forceps, 576–7 injector needles, 576 large polyps see polyps, large lesion location difficulties, 595–9 barium enema, 597 clips, 597 colon wall marker injections, 597–9 endoscopic landmarks, 596–7 exploratory laparotomy, 595–6 insertion length localization, 596 intraluminal landmarks, 596 intraoperative, 597

magnetic imaging, 597 marking, 595 site healing, 596 Minimal Standard Terminology (MST), 251 narrow diverticular segments, 592–5 clamshell polyps, 593, 593–4, 594 flat polyps, 594 gastroscopes, 593 mini-snares, 593 rectum, 593 residual adenoma fragments, 594–5, 596 retroversion, 594, 595 sigmoid colon, 592–3 snare types, 592, 592–3, 594 pediatric patients, 751, 754–5 pedunculated polyps, 754, 754 pedunculated polyps, 578, 754, 754 piecemeal technique clamshell polyps, 593 endoscopic mucosal resection (EMR) see endoscopic mucosal resection (EMR) polyp incidence, 364–5, 364 (table) polyp retrieval, 613–18 large polyps, 615, 615–16 retrieval devices, 615, 616, 616–17, 617 see also specific devices small polyps, 613–15, 614 precolonoscopy laboratory testing, 577 sessile polyps see sessile polyps size problems, 582–5, 583 (table) appendiccal orifice location, 584–5, 585 blood supply, 585, 586 dye surface application, 583, 583 ileocecal valve location, 584 invasive carcinoma risk, 583 large see polyps, large mucosal defects, 584, 584 pit pattern classification, 583 polyp characteristics, 584 removal criteria, 584 sessile polyps, 582 small polyps see polyps, small tiny polyps, 578, 578 snares see snare(s) surveillance see polypectomy surveillance techniques, 577–81 timing, 577 training, 128 polypectomy surveillance, 172, 719–29 adenomas, 172 advanced adenoma concept see advanced adenoma concept cancer incidence effects, 723–4 cancer risk stratification, 724–5 colonoscopy diagnostic yield see diagnostic yield (of colonoscopy) cost effectiveness, 727 cost of, 727 double-contrast barium enema vs., 720 frequency of, 722–3 full colonoscopy, 720 hyperplastic polyps, 725–6 missed synchronous vs. metachronous polyps, 722 mortality effects, 723–4

National Polyp Study, 719 as preferred method, 719–20 recommendations, 726 repeat clearing colonoscopy, 723 routine system, 719 serrated adenomas, 725–6 technical quality effects, 726–7 US Multisociety Task Force, 172, 172 (table) polyp-free individuals, 365–6, 366 (table) polyp growth, 367–77 National Polyp Survey, 367 observational studies, 370–1 interventional studies, 370, 370, 371, 372 problems, 369 ethical problems, 369–70 risk factors, 371, 373 size estimation, 367–9 computerized images, 368–9 endoscope lens, 368, 368 open forceps method, 368 reliability, 368 transformation, 367 Polyp Prevention Study Group, 724 polyps, large pedunculated, 313 polypectomy pediatric, 755 polyp retrieval, 615, 615–16 timing, 577 sessile, 582 types of, 577 polyps, small narrow-band imaging, 519 polypectomy, 577–8 cold snare guillotine, 579 mini-snares, 577–8, 578 polyp retrieval, 613–15, 614 pontamine sky blue, 7 porphyrins autofluorescence, 476 (table) tissue autofluorescence, 482 portable media, DICOM (Digital Imaging and Communication in Medicine), 260 positron emission tomography (PET), colonoscopy indications, 171 postcolonoscopy appendicitis, 709 postcolonoscopy care, 62 sedation, 106–7 postcolorectal cancer resection colonoscopy, 730–45 anastomosis recurrence, 738 evaluation, 742–3 surveillance intervals, 740–1 colonoscopy indications, 172–3 colostomy patients, 743 health care utilization, 742 health outcomes, 741–2 as ideal method, 731 literature reviews, 731, 738 methods, 731–4 results, 735–7 metachronous neoplasms, 738–9 perioperative clearing, 738 surveillance intervals, 739–41 anastomotic recurrence detection, 740–1

809

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postcolorectal cancer resection colonoscopy (cont’d) guideline adherence, 740 National Polyp Study, 739 sensitivity factors, 739– 40 Surveillance, Epidemiology and End Results (SEER) program, 739 tumor aggressiveness, 740 postpolypectomy bleeding, 95, 312–13, 711–12 continuous quality improvement (CQI), 48 delayed, hematochezia, 641 loops, 324, 324 postpolypectomy syndrome, 713 potency testing, liquid-chemical germicides, 72, 73 pouchitis, 653 cuffitis vs., 653 pouchitis activity score (PAS), 653 Pouchitis Disease Activity Index (PDAI), 653 practical teaching see training/teaching practice, training/teaching, 143 prasugrel discontinuation, 98 precolonoscopy care, sedation, 106–7 precolonoscopy laboratory testing, 577 precut phase, electrosurgery, 337, 338 preinduction, propofol, 105 preoperative decompression, malignant colorectal stricture therapy, 694–5 preoperative radiation therapy, self-expandable metal stents (SEMS), 695, 696 preparation (for colonoscopy), 114–24 artifacts, colitis, 666, 666 drug discontinuation, 95, 98 goals of, 114 impact of, 114 pediatric colonoscopy, 752 teaching methods, 145 see also colon cleansing methods preprocedure assessments, 58 insertion techniques, 538 pressure-induced mucosal necrosis, solitary rectal ulcer syndrome, 640 prevalence (of colonoscopy), 178 previous endoscopy, reports, 255 previously credentialed endoscopists, retraining, 131–2 probes, argon plasma coagulation (APC), 341, 341 procedure rooms see colonoscopy suite procedures numbers of, “hands-on” training/teaching, 154 reports, 256 see also specific techniques procedures per room (PPR), colonoscopy suite planning, 22–3 process (elements) of informed consent, 84 processors, video colonoscopes, 289–90 proctitis, sexually transmitted, 664, 666 proctoscopes, 6 proctosigmoidoscopes, 5–6, 6 prognosis, size (of lesion) vs., 473 programmatic colorectal cancer screening, 206–9 adenoma detection, 208–9 noninvasive tests, 206–8 see also specific tests programming, colonoscopy suite planning, 21 project schedule, colonoscopy suite, 19–20, 20

810

prokinetic agents, acute colonic pseudoobstruction management, 678 promethazine, 104 promoter methylation, tumor genetics, 351 propofol, 103, 105–6 gastroenterologist-directed, 110 prospective studies, colon cleansing diet, 114–15 Prostate, Lung, Colorectal Cancer Screening Trial, polyp incidence, 366 prosthetic joints, antibiotic prophylaxis, 91 ProtectiScope® (Stryker), 779 Proteus infections, 69 (table) protozoal infections, 70 protruding lesions, 425 provider-based standards, informed consent, 80 provider–patient relationship, informed consent, 79 proximal colon, 13 pseudoinvasion, malignant neoplastic polyps, 402 pseudomelanosis coli, 671 Pseudomonas aeruginosa infection, 69, 69 (table), 70 pseudopolyps, definition, 456 psychomotor skills, training/teaching, 149 PTEN gene Cowden’s syndrome, 442 CpG island methylator phenotype (CIMP), 355 hamartomatous polyposis, 353 pulmonary disease, colonoscopy indications, 168 pulse oximetry, sedation, 107 purgatives, capsule colonoscopy, 302 “push and go” approach, sigmoid loop insertion techniques, 548, 548 push endoscopes, 296 “push through” approach, sigmoid loop insertion techniques, 548–9 PY12 receptor antagonists discontinuation, 98 Q qualifications, sedation, 108 quality-adjusted life years (QALYs), costeffectiveness analysis, 216, 217 quality definitions, continuous quality improvement (CQI) see continuous quality improvement (CQI) quality indicators, informed consent, 83 quality issues, colorectal cancer screening, 211–12, 212 (table) quantum dot method, immunophotodiagnostics, 492 QuickClip, 635 QuickClip2, 319 R radiation colitis, 667, 668 radiation-induced strictures, self-expandable metal stents (SEMS), 693 radiation therapy, self-expandable metal stents (SEMS), 695, 696 radiography acute colonic pseudo-obstruction, 676, 677, 679, 680 colon imaging with barium, 208 colonoscopy indications, 170–1, 172, 173 (table) colorectal cancer surveillance, 730

with computed tomographic colonography (CTG), 208–9 pediatric colonoscopy, 750 Raman spectroscopy, 485–7 artifacts, 486 clinical evaluation, 486–7 Barrett’s esophagus, 482, 486 ex vivo normal vs. malignant tissue, 486 mechanism of action, 485 near-infrared light, 485 surface-enhanced scattering, 487 ultraviolet light, 486 Rapid5 software, capsule colonoscopy, 302 reception area, colonoscopy suite, 38, 38 recommendations, reports, 256 recording equipment, colonoscopy suite, 37 recovery space, colonoscopy suite, 23–4 rectoscopes, 6 rectosigmoidoscopy, fluorescence, 494–5 rectum bleeding acute, 181 colonoscopy diagnostic yield, 180, 181 colonoscopy indications, 169, 170 fecal occult blood tests, 170 hemorrhoids, 181 pediatric colonoscopy, 750 endoscopic mucosal resection (EMR), 586 endoscopic ultrasonography (EUS), 502 locally advanced cancer, endoscopic ultrasonography (EUS), 505–6 polypectomy, 593 varices bleeding, 324–5, 325 endoscopic ultrasonography (EUS), 508 recurrence rates, 462 polyps, 365 recurrent lesion scoring, Crohn’s disease, 653 (table) red blood cells, endomicroscopy, 529 redetection, polyp growth problems, 369 red, green and blue sequential imaging, 281, 281–2, 282, 285 narrow band imaging, 286, 286–7 red mucosa, Minimal Standard Terminology (MST), 240 “red out,” withdrawal techniques, 565 reduced-volume gut lavage, 117 referrer information, reports, 254 reflectance, white-light endoscopy (WLE), 478 reflectance confocal imaging, endomicroscopy, 528 Regenbogen, G, 6, 7 reidentification, polyp growth problems, 369 relative contraindications, 174 renal failure chronic, 632 colon cleansing method complications, 704 renal insufficiency, colon cleansing methods, 44 repeat clearing colonoscopy, polypectomy surveillance, 723 reports, 235–53, 254–65 American Society for Gastrointestinal Endoscopy (ASGE), 254 Clinical Outcomes Research Initiative (CORI), 235

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content, 237, 237–8, 237 (table) data, 236, 236, 237 organization of, 236–7, 237 text data see below DICOM (Digital Imaging and COmmunication in Medicine), 235 images see image management International Classification of Disease (ICD), 256 Nomesco Classification of Surgical Procedures (NCSP), 256 objective features, 256 organization of, 236–8 standardized terminology, 235, 262–3 World Organization of Digestive Endoscopy, 262 see also Minimal Standard Terminology (MST) text, 236, 254–7 adverse events, 256, 256 (table) cleansing procedure, 255 comorbidities, 255 complications, 256 conclusions, 256 diagnoses, 256 endoscopist, 254 family history, 255 findings, 255–6 free text vs. structured input, 256–7 impression, 256 indication/clinical history, 254–5 informed consent/disclaimers, 255 insertion time, 255 objective features, 256 patient demographics, 254 previous endoscopy, 255 procedures, 256 recommendations, 256 referrer information, 254 report elements, 254 risk assessment, 255 sedation, 255 technical information, 255 withdrawal time, 255 reproducible training, 147 resected specimens, endomicroscopy, 530 residue diet, colon cleansing diet, 115 Resolution® Clip, 319, 635 resolving power, video colonoscope, 277, 278 resource scarcity, cost-effectiveness analysis, 217 respiratory failure, sedation complications, 102 restricted views, insertion techniques, 543, 543 resuscitation equipment, 107–8, 107 (table) hematochezia, 631–2, 632 (table) retraining see training/teaching retrieval devices, 308, 615, 616, 616–17, 617 see also specific devices retroversion ascending colon/ileocecal region insertion techniques, 555 ileocecal valve insertion techniques, 557, 557 narrow diverticular segment polypectomy, 594, 595 reusable biopsy forceps, disposable vs., 309 reusable equipment processing, 63, 67

“reversed alpha” sigmoid loop insertion techniques, 550, 550 splenic flexure insertion techniques, 552, 552 “reversed splenic flexure,” 552 Rhodotorula rubra infection, 69 (table) ridge polyps, 577 rigid endoscopes, 3–7 early endoscopes, 3–5, 4, 5 electric light–rigid rectoscopes, 5, 5–6 photography, 6–7 primitive specula, 3, 3 proctosigmoidoscopes, 5–6, 6 rigid scope photography, 6–7 rinsing cleaning/disinfection, 70, 72 reusable equipment reprocessing, 63 risk assessment, reports, 255 risk management, 703 risk stratification, colorectal cancer screening, 212–13 room size standards, colonoscopy suite, 24, 26 “rotatable” forceps, 309 rotatable polypectomy snares, 307, 308, 573 “rotating prism” colonofiberscope, 11 rotavirus infection, 68 Roth Net®, 616, 616, 617 rubber band ligation, internal hemorrhoids, 639, 639 RUNX3 gene, 355 S safety argon plasma coagulation (APC), 342 gut lavage, 118, 118 (table) safety features, video colonoscope, 274 saline injections endoscopic mucosal resection (EMR), 586–7 endoscopic submucosal dissection (ESD), 608 gastrointestinal assistant, 60 gut lavage, 115 pediatric polypectomy, 755 Salmonella infections, 660, 660 endoscopic transmission, 69, 69 (table) postcolonoscopy, 710 sampling errors, polyp sampling, 380 Sano–Emura classification, narrow-band imaging, 521–2, 524 (table) sarcoidosis, 670 scars/scarring Crohn’s disease, 647, 647 (table) Minimal Standard Terminology (MST), 244 scattering of light, 474–5, 475 Schistosoma infections, 663–4 sclerotherapy catheters, 633 India ink marking, 598, 599, 600 internal hemorrhoids, 639 ScopeGuide, 621–2, 626 abdominal pressure, 623, 623 colonoscopy training, 624 control panel, 622, 622 documentation, 625–6 endoscopy performance, 623, 623–4 future work, 625–6 hand marker, 621, 621

imager display, 621, 621 looping, 623, 625 gender effects, 623 simulators, 148 software, 620 techniques, 624–5 spiral looping, 625, 625 tip location, 623 variable-stiffness colonoscopes, 624 scope of consent, informed consent, 85 screening colonoscopy, 206–15 average-risk populations, 206, 207 (table) early cancer detection, 206 end of, 786 familial hereditary syndromes, 206 future work, 784–5, 787 hereditary nonpolyposis colorectal cancer (HNPCC), 439–40 interval, 212 narrow-band imaging, 517 US Preventive Services Task Force (USPSTF), 206 virtual colonoscopy, 770 secondary loop ligation, detachable loops, 313 security systems, colonoscopy suite, 38 sedation, 101–13 adjunctive agents, 103–4 anesthesiologists, 108 antagonists, 103 blood pressure monitoring, 107 continuum of, 101, 101 country variation, 101 deep, 101 definition, 101 drug pharmacology, 102–4 economics, 110–11 equipment for, 107–8 gastrointestinal assistant, 58–9 impact of, 109–10 informed consent, 82 lack of see unsedated colonoscopy minimal, 101 moderate, 101 oxygen administration, 107 patient-controlled, 106 patient variability, 102 pediatric colonoscopy, 749–50 persistence of, 106–7 postcolonoscopy care, 106–7 precolonoscopy care, 106–7 preprocedure assessments, 58 pulse oximetry, 107 reports, 255 respiratory failure, 102 resuscitation equipment, 107–8, 107 (table) risk management, 110 “sidestream” capnography, 107 staff, 108 standards of practice, 106–8 syringe, 107 technical issues, 108–9 training, 102, 108 see also specific drugs SEER (Surveillance, Epidemiology and End Results) program, 739

811

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segmentation, “hands-on” training/teaching, 146 selective (targeted) chromoendoscopy see chromoendoscopy selenium, polyp prevalence, 364 self-expandable metal stents (SEMS), 693, 694, 695 benign disease, 693 biliary catheters, 696 complications, 696 avoidance, 698 fluoroscopic guided stent procedure, 698 guidewires, 696 limitations, 698 malignant disease colonoscopy combination, 694–5 palliative therapy, 695–6 preoperative radiation therapy, 695, 696 materials, 696–8 non-fluoroscopic guided stent procedure, 697–8 non-TTS, 697–8, 698 TTS, 698, 699 patient preparation/positioning, 697 stent types, 696, 697, 697 (table) success rate, 698 technique, 697 self-expandable plastic stents, benign colorectal stricture therapy, 693 self-propelled microrobots, capsule colonoscopy, 785–6 semicritical devices, Spaulding criteria, 68 serious risks, informed consent, 81 serrated adenomas, 387 (table), 389, 390 polypectomy surveillance, 725–6 serrated polyps, 386–7, 387 (table) B-raf, 408 CPG island methylation, 408 dysplastic, 389–90 mixed serrated adenomas, 389–90, 390 pathway, 354–5, 386–7, 403, 408–9 serrated adenomas, 389, 390 histological risk measures, 409 hMLH1 gene, 408 malignant, 408 mixed serrated adenomas, 387 (table) nondysplastic, 387–9 hyperplastic polyps, 387–8, 387 (table), 388 sessile serrated polyps, 387 (table), 388–9, 389 serrated adenomas, 387 (table) treatment, 408–9 Serratia infections endoscopic transmission, 69 (table) postcolonoscopy, 710 service class providers, image standardization/exchange, 249 service elements, image standardization/exchange, 249 SES-CD (Simple Endoscopic Score for Crohn’s Disease), 650 sessile adenomas, 401, 402, 402 endoscopic ultrasonography (EUS), 505 surgery vs. follow-up, 405, 407, 407–8 “buffer zone,” 405 sessile polyps, 577 polypectomy, 579–80

812

abdominal pressure, 581 air aspiration, 579, 580 polyp position, 580, 580–1 polyp prevalence, 363 serrated, 474 severe acute pancreatitis, colorectal strictures, 690 sexually transmitted proctitis, 664, 666 SFRP2 gene, 355 SG-1 ShapeLock, 315 shaft characteristics, colonoscopy history see history (of colonoscopy/endoscopy) ShapeLock device (USGI), 296, 782, 782 shared-decision making, informed consent, 80–1 Shiga toxin Escherichia coli (STEC) infection, 660, 660 Shigella infections, 660 short skill training/teaching courses, 151–2 shrinkage, thermal desiccation, 330 “sidestream” capnography, sedation, 107 side-viewing colonoscopes, 10–11 sigmoid colon anatomy, 619 descending colon junction, 625 elasticity, 541, 541, 542 insertion techniques see insertion techniques narrow diverticular segment polypectomy, 592–3 virtual colonoscopy, 766–7, 767 sigmoid looping insertion techniques see insertion techniques pain, 108–9, 110 “sigmoidocamera,” 7–8, 8 sigmoidoscopes, 6 sigmoidoscopy, 169 colonoscopy indications, 170–1 polyp prevalence, 361, 362 (table) simethicone, gut lavage, 117 simulators, 141–2, 154–63 animal tissue models, 155–7 bovine tissue models, 156, 157 colo-EASIE™, 156, 156 EASIE™, 155 Endo-Trainer, 155 Erlangen models, 155, 155 Neopapilla™ attachment, 156, 156 perfusion systems, 155–6 benefits, 154 computer simulators, 157–62 AccuTouch, 157, 158 advantages, 157, 161–2 construction, 157 costs, 158 GI Mentor, 157, 158, 159 Immersion Medical stimulator, 160 instructor feedback, 161 Olympus Colonoscopy Simulator, 158, 158 validation, 159, 159 (table), 160 (table) eye-hand coordination, 154 fellowship training, 129 mechanical models, 154–5, 155 University Hospital of Tübingen, 154, 155 ScopeGuide, 148 types, 154–62 see also specific types “simulcast” production, 137

single-agent propofol, 105 single-bite biopsy forceps, 308 single colonoscopy, cost-effectiveness analysis, 219, 222 (table), 223 single-handled approach see insertion techniques single-use endoscopes, 779, 779–80, 780 site healing, polyp location, 596 size (of lesion) adenoma classification, 381 capsule endoscopy, 251 estimation see polyp growth malignant neoplastic polyps, 402, 403–4 prognosis vs., 473 skill maintenance, training, 130, 131 slow withdrawal, cost-effectiveness analysis, 224 SMAD4 gene, hamartomatous polyposis, 353 small bowel adenomas, familial adenomatous polyposis (FAP), 434 small bowel transplantation, pediatric colonoscopy, 753, 753 small group sessions, teaching courses, 137 small polyps see polyp(s) SMART, learning objectives, 145 SMARTER, learning objectives, 145 smoking, polyp incidence, 366 snare(s), 306, 306–7, 573–6 bipolar snares, 573 “closure sensation,” 573 electrosurgery, 339 gastrointestinal assistant, 60–1 “hairy” snares, 307, 308 handles, 573–4 electrosurgery, 339 marking, 574, 574 hematochezia therapy, 633–4 loop shape, 307 loops vs., 323 mini-snares see mini-snares multitangled snares, 307 narrow diverticular segment polypectomy, 592, 592–3, 594 needle/anchor-tipped, 307, 308 oval shape, 307, 307 polyp impaction, 713 rotatable, 307, 308 rotatable snares, 573 sessile polyp polypectomy, 579–80 spiral snares, 307, 308 techniques, 575–6, 576 tissue volume estimation, 574–5, 575 snare and cautery technique perforation, 49 small polyp polypectomy, 577–8 snare catheters electrosurgery, 339 tip placement, 578 snare polypectomy, 572 pediatric polypectomy, 755 snare resection technique, endoscopic mucosal resection (EMR), 586 SNOMED (Systematic Nomenclature of Medicine), Minimal Standard Terminology (MST), 246 Society of American Gastrointestinal Endoscopy Surgeons (SAGES), training assessment, 130

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Society of Gastroenterology Nurses and Associates (SGNA), gastrointestinal assistant, 57 sodium hyaluronate, endoscopic submucosal dissection (ESD), 608 sodium phosphate, 704 acute nephropathy, 44 colon cleansing methods, 44, 119, 764 pediatric colonoscopy preparation, 752 software ScopeGuide, 620 video colonoscopy, 288 virtual colonoscopy, 764, 768 solid-state image capture, video colonoscope, 274–5 solitary rectal ulcer syndrome (SRUS), 394–5, 670, 670 hematochezia, 640, 640–1 somatic mutations, 349 “somatoscopes,” 5 soundproofing, colonoscopy suite, 35 spasmolytics, colonic distention, 766 Spaulding classification, reusable equipment processing, 63 Spaulding criteria, cleaning/disinfection, 68 specimen handling, biopsy see biopsies “specimen trap containers,” small polyp retrieval, 614, 614 Spider Net®, 616, 617, 617 spindle cell schwannomas, 391, 391 spiral looping, ScopeGuide, 625, 625 spiral polypectomy snares, 307, 308 splenic flexure anatomy, 620 insertion techniques see insertion techniques splenic trauma, intraluminal bleeding, 707–8, 708 “splinting tubes,” 13 “split-dose administration,” colon cleansing methods, 121 sporadic polyps, 353 spray catheters, 310, 311 SRUS see solitary rectal ulcer syndrome (SRUS) staff flow patterns, 27–8, 28 sedation, 108 staining methods, chromoendoscopy see chromoendoscopy standards of practice, sedation, 106–8 Staphylococcus infection, 70 steam autoclaving, 67 steering direction prediction, 542–3 insertion techniques see insertion techniques stenosis, Minimal Standard Terminology (MST), 240, 240 stercoral ulcers, 670 sterilization, cleaning/disinfection, 67–8 “sticky diagnosis” bias, postcolorectal cancer resection colonoscopy, 741 STKI1 gene, Peutz–Jeghers syndrome, 440, 441 stool tests DNA tests, 208 infectious ileocolitis, 659 see also specific tests

“stop” vocalization, informed consent, 86 storage, cleaning/disinfection, 70, 72 “straight pullback” withdrawal techniques, 564, 565, 568 Strauss-type sigmoidoscopes, 6, 6 strictures, Crohn’s disease, 647, 647 Strongyloides infection, 663, 663 endoscopic transmission, 69 (table), 70 structure, Minimal Standard Terminology (MST), 238–9 structured language modeling, Minimal Standard Terminology (MST), 246 structured template, training/teaching feedback, 149 submucosal drug delivery, 788 submucosal injection, endoscopic mucosal resection (EMR) see endoscopic mucosal resection (EMR) subsequent disease, informed consent, 83 success rate measurement, continuous quality improvement (CQI), 41 suction biopsy, 446 colonoscopy suite, 35 failure, 65 large polyp retrieval, 615 small polyp retrieval, 613 video colonoscope see video colonoscopes sulfate-free electrolytic solution, 116–17 sulfates, colon cleansing methods, 120, 120 (table) sulindac intervention studies, 373 polyp prevention, 366 supplemental oxygen administration, 59 supply ordering, gastrointestinal assistant, 64 supra-anal dilation, Crohn’s disease, 654 surface-enhanced scattering, Raman spectroscopy, 487 surface pit pattern, 414–15 surgery acute colonic pseudo-obstruction management, 680 malignant neoplastic polyp management, 409, 409 (table) traumatic perforation treatment, 705 (table), 706 Surveillance, Epidemiology and End Results (SEER) program, 739 surveillance intervals, postcolorectal cancer resection colonoscopy see postcolorectal cancer resection colonoscopy sutures, detachable, 324 Sweden flat adenomas, 426 nonpolyploid colorectal neoplasms (NP-CRNs), 426 “swing jaw” biopsy forceps, 309 sympathetic deprivation theory, acute colonic pseudo-obstruction (ACPO), 675, 676 sympathetic stimulation theory, acute colonic pseudo-obstruction (ACPO), 675 synchronization circuitry, video colonoscope, 290 syphilis, 664

Systematic Nomenclature of Medicine (SNOMED), Minimal Standard Terminology (MST), 246 systematic review, selective (targeted) chromoendoscopy, 465 systematic vasculitis, with colitis, 670 T tapered colonoscope, 294 teaching aids, 133–40, 134 (table) computer tools, 134 electronic media, 134–5 model simulations, 134, 141–2 multimedia, 135–7 CD-ROM, 135 DVD, 134, 135 e-learning, 135–6 e-training, 135–6 home television, 137 internet, 135–6 Internet 2 project, 136 new techniques, 136 role of, 133–4 teaching courses, 137–8 text with photographic images, 134 virtual reality, 134 see also simulators teaching courses see teaching aids teaching methods see training/teaching team approach, training/teaching, 142 technical information, reports, 255 technology-based video imaging, colonoscopy suite, 19 Telemark Polyp Study (Norway), 723–4 telemedicine centers, teaching courses, 138 telephones, colonoscopy suite, 36 television monitors, colonoscopy suite, 33–4 tenting pinch biopsy techniques, 448, 448 (table) sessile polyp polypectomy, 580 small polyp retrieval, 613 terminal ileum Crohn’s disease biopsies, 672 insertion techniques, 558 pediatric colonoscopy, 752–3 terminology, biopsy improvements, 452–3 text with photographic images, 134 reports see reports therapeutic colonoscope(s), 296 pediatric colonoscopy see pediatric colonoscopy therapeutic privilege, informed consent exceptions, 85 therapeutic procedures, contraindications, 174 thermal effects, 328–30, 329 carbonization, 330 coagulation, 330 desiccation, 330 devitalization, 328, 330 vaporization, 330 thermocoagulation delayed postpolypectomy hemorrhage, 641 hemorrhagic proctocolitis with recurrent bleeding, 755 pediatric colonoscopy, 755–6

813

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thin colonoscopes see pediatric colonoscopes Third Eye retroscope, 782, 787, 787 flat lesion detection, 568, 568–9 three-dimensional magnetic resonance imaging see magnetic resonance imaging (MRI); ScopeGuide three-glass method, fiberoptics, 12 “three-layered” clips, 319, 319 threshold analysis, cost-effectiveness analysis, 223–4 threshold numbers, training assessment, 130–1 thrombocytopenia, 631–2 through-the-scope (TTS) hydrostatic balloon dilators benign colorectal stricture therapy, 690–1 self-expandable metal stents (SEMS), 698, 699 ticlopidine, discontinuation, 98 time taken, sedation economics, 110–11 timing of colorectal cancer screening, 212 tiny polyps, polypectomy, 578, 578 tirofiban discontinuation, 98 tissue autofluorescence, 475–6 clinical evaluation, 476–83 colonic dysplastic polyps, 483 contrast agents, 482 emission spectra, 477 excitation wavelengths, 475, 480, 481 factors in, 479–80 fluorescence spectrum, 475 fluorophores, 476 (table) macroscopic, 481, 482 narrow point vs. wide-beam imaging, 480 neoplasia, 480–1 normal vs. adenomatous polyps, 481 problems with, 481–3 false positives, 482 fecal bacteria, 482 porphyrins, 482 tissue depth, 478 ultraviolet light effects, 480 see also fluorescence point spectroscopy tissue depth, tissue autofluorescence, 478 tissue sampling, colorectal stricture diagnosis, 689, 690 tissue volume estimation, snares, 574–5, 575 TNM classification chromoendoscopy, 464 endoscopic ultrasonography (EUS), 503, 504 toluidine blue, history of colonoscopy, 7 Toppan test, vessel diameter immunostaining, 521, 522 torque steering, insertion techniques, 540 trainees see training/teaching trainers see training/teaching training lists, 142 training programs, 127–8 training provision, 141 training/teaching, 127–32, 141–53, 142 advanced techniques, 128 American Gastroenterological Association (AGA), 127 American Society for Gastrointestinal Endoscopy (ASGE) guidelines, 33, 127 ancillary training curriculum, 128 assessment, 130–1

814

competency, 130–1, 130 (table) threshold numbers, 130–1 “basic colonoscopy,” 128 basic training equipment, 141–2 cleaning/disinfection, 73 competence assessment, 142 to competency, 127 completion of, 151 complications, 703 continuous quality improvement (CQI), 33 daily basis vs. intensive training, 130 decision training, 147 demonstrations, 143 directly observed procedural skills (DOPS), 151 forms, 150, 151 endoscopic training and, 142 feedback, 149 fellowship training, 128–30 American Gastroenterological Association (AGA), 129 American Society for Gastrointestinal Endoscopy (ASGE), 128–9 endoscopic atlases/video, 129 endoscopy directors, 129 simulators, 129 trainers, 129 “hands-on” experience, 128, 142, 146–7 procedure numbers, 154 hands-on training, 145–9 historical aspects, 133 instruction, 149 magnetic resonance imaging (MRI), 624 motivation, 143–4 polypectomy, 128 practical teaching, 147–9 basic skill training, 147 coaching technique, 147 dedicated time, 147 instrument withdrawal, 148 models, 148 option review, 147 patient selection, 148 reproducible training, 147 trainer interventions, 147–8 practice, 143 retraining, 131–2 scaffolding in, 144–5 ScopeGuide, 624 sedation, 102, 108 short skill courses, 151–2 skill maintenance, 130, 131 teaching aids see teaching aids teaching methods, 145–9 aligning agenda, 145 conscious competence, 145–6 dual-task interference, 146 educational contract, 145 initial assessment, 145 instrument handling, 147 learning objectives, 145 preparation, 145 team approach, 142 trainees, 142–3 motivation, 145 trainers, 144

fellowship training, 129 key qualities, 144 (table) learning how to train, 143 one-to-one support, 144–5 practical teaching interventions, 147–8 training lists, 142 training programs, 127–8 training provision, 141 training units, 142 upper gastrointestinal endoscopy, 129–30 virtual colonoscopy, 770, 771 training units, 142 tramadol, 104 transection margin invasive carcinoma, 386 polyp sampling, 380–91, 381 transforming growth factor-β receptor II (TGF-βII), 355 transmissible spongiform encephalopathies (TSEs), 70 transparent caps, 314–15 transverse colon anatomy, 619 insertion techniques see insertion techniques traumatic perforation, 705–7, 705 (table) causes, 705 clinical aspects, 707 (table) clips see clips cold snare polypectomy complications, 49 continuous quality improvement (CQI), 48–9 Crohn’s disease, 706 diverticulitis, 706 diverticulosis with muscular atrophy, 705–6 extraperitoneal, 706 incidence, 705 intraoperative colonoscopy, 706 pediatric colonoscopy complications, 757 polypectomy, 712–13 polypectomy complications, 48–9 prevention, 705–6 recognition, 706 snare cautery complications, 49 treatment, 706–7 surgery, 705 (table), 706 Treponema pallidum infection, 666 Trichosporon infection, 69 (table), 70 trichromatic vision, video colonoscope color reproduction, 280, 280 Trichuris trichiura infection, 663, 664 TriClip, 319, 634–5 tryptophan, autofluorescence, 476 (table) T-stage system chromoendoscopy, 466 endoscopic ultrasonography (EUS), 503, 505–6 TTS see through-the-scope (TTS) hydrostatic balloon dilators tuberculosis, 661–2, 662 Crohn’s disease vs., 662 tuberous sclerosis, ganglioneuromas, 392 tubular adenomas, 382, 382 tubulovillous adenomas, 382, 382 tumor(s) associated enzymes, 491 associated targets, 495

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budding, 409 demarcation, 611 endoscopic mucosal resection (EMR), 589 endoscopic submucosal dissection (ESD), 611 genetics see tumor genetics immunophotodiagnostics, 491, 495 margins, 603 Minimal Standard Terminology (MST), 244 postcolorectal cancer resection colonoscopy, 740 tracking, 589 see also carcinomas tumor genetics, 349–52 chromosomal instability, 351, 351 clonality, 349 cytosine–guanine island methylation phenotype, 355 genes, 349–50 expression silencing, 351 oncogenes, 350 tumor-suppressor genes, 350 see also specific genes germline mutations, 349 microsatellite instability, 355 mutational signatures, 351 mutations causes, 350 deletion, 350–1 insertion, 350–1 point mutations, 350 types of, 350–1 promoter methylation, 351 somatic mutations, 349 tumor-suppressor genes adenoma–carcinoma hypothesis, 382–3 tumor genetics, 350 Turcot’s syndrome, 439 familial adenomatous polyposis (FAP), 434–5 pediatric polypectomy, 754 Twister®, 616–17 twisting, insertion techniques, 540 two dimensional slides, polyp sampling, 380 two-glass method, fiberoptics, 12 two-handled insertion techniques, 538–9 “two-layered” clips, 319 two-person insertion techniques, 538–9 U ulcerated mucosa, Minimal Standard Terminology (MST), 244–5, 245 ulcerative colitis, 648 biopsy, 451, 455–6 sites, 456 “cecal patch” inflammation, 648 chromoendoscopy, 532 colonoscopy indications, 171 colorectal strictures, 689–90 Crohn’s disease vs. see Crohn’s disease dysplasia vs., exogenous photosensitizerinduced fluorescence, 484 dysplastic areas, narrow-band imaging, 523 endomicroscopy, 532 endoscopic appearance, 648, 648 (table), 649 endoscopic assessment, 650, 650 (table) endoscopic monitoring of therapy, 652

infections vs., 660 intraepithelial neoplasia, 467–9 light-induced fluorescence endoscopy (LIFE), 479 location, 648 lumps and bumps, 456–8 Mayo score, 650 optical coherence tomography (OCT), 489 screening/prevention, cost-effectiveness analysis see cost-effectiveness stricture formation, 648 ulcerative proctitis progression, 455 ulcerative proctitis, 455 differential diagnosis, 455, 455 ulcerative colitis progression, 455 ulcers coaptive coagulation, 572 Crohn’s disease, 646–7, 647 stercoral, 670 ultraviolet light, Raman spectroscopy, 486 uncommon risks, informed consent material risks, 81 understaging effects, endoscopic ultrasonography (EUS), 506 “underwater” colonoscopy, diverticular disease, 545–6 United Kingdom (UK) Basic Skills Colonoscopy Course, 151–2 colonoscopy history, 16 flat adenomas, 426 nonpolyploid colorectal neoplasms (NP-CRNs), 426 United States of America (USA), procedure room licensing laws, 30 University Hospital of Tübingen, mechanical models, 154, 155 unsedated colonoscopy, 104 upper gastrointestinal tract bleeding, 631 Crohn’s disease, 647–8 endoscopy training, 129–30 familial adenomatous polyposis screening, 435–6 upper scopes in endoscopy, 296 US Multisociety Task Force on Colorectal Cancer colonoscopy indications, 172 (table) quality recommendations, 726 surveillance recommendations, 726, 740 US National Colorectal Cancer Roundtable reports, 238 US Preventive Services Task Force (USPSTF) polyp prevalence, 363 screening colonoscopy, 206 V validation, computer simulators, 158, 159 (table), 160 (table) valves, video colonoscope, 274 vaporization lasers, 343 thermal effects, 330 variable flexibility, insertion tube, 293, 293 vascular ablation, pediatric colonoscopy, 751 vascular ectasia, diagnostic yield (of colonoscopy), 185

vascular grafts American Society for Gastrointestinal Endoscopy antibiotic prophylaxis recommendations, 91 antibiotic prophylaxis, 91 vasovagal reactions complications, 709 pain, 109 ventilation, colonoscopy suite, 35–6 vertical arrangements, colonoscopy suite, 32 vessel diameter immunostaining, narrow-band imaging, 520–1, 521 Veterans Administration Cooperative Colonoscopy Screening Trial, cancer development data, 724–5, 725 (table) Veterans Affairs Study, failure rates, 462 VGA (video graphics array), 258 video analysis, teaching courses, 138 video-based teaching courses, 137 video capsule endoscopy (VSE), Crohn’s disease, 650–1 video colonoscopes, 15, 269–91, 270 air system, 273, 273–4 distal tip, 272 angle of view, 279 angulation system, 272–3 bending section, 272, 272–3 charge-coupled device (CCD) see chargecoupled devices (CCDs) colonoscopy history, 14 colorchip video imaging, 282–3, 283 advantages, 284–5 color image display, 283–4 motion reproduction, 284, 284 color reproduction, 280–5 additive primary colors, 280, 280, 281 colorchip video imaging see above red, green and blue sequential imaging, 281, 281–2, 282, 285 trichromatic vision, 280, 280 distal tip, 271–2, 272 evaluation, 290 flexibility, 269–71 adjustable, 271, 271 column strength, 270 variation over length, 270–1 illumination system, 274 distal tip, 271–2 image display shape, 279, 279–80 image processing, 288, 288–9 image resolution, 278, 278 image standardization/exchange, 247, 248 insertion tube, 269, 270 flexibility variation over length, 270–1, 271 manufacture, 271 narrow band imaging, 285–8 absorbance spectra, 285, 285 colorchip video imaging, 287, 287–8 red, green and blue sequential imaging, 286, 286–7 selective enhancement, 285, 286 processor functions, 289, 289–90 resolving power, 277, 278 solid-state image capture, 274–5 CCDs see charge-coupled devices (CCDs)

815

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video colonoscopes (cont’d) specifications, 267 (table) suction system, 273, 273– 4 water system, 273, 273– 4 distal tip, 272 zoom, 278–9 video graphics array (VGA), 258 video recordings, training/teaching, 152 videotape, teaching aids, 134–5 Vienna classification, dysplasia, 456 villous adenomas, 382, 383 distribution, 362 immunophotodiagnostics, 494 light-induced fluorescence endoscopy (LIFE), 479 villous structure malignant neoplastic polyps, 403– 4 polyp prevalence, 362–3 virtual colonoscopy, 763–73 advantages, 763 bowel preparation, 763–6 barium, 765 computer-aided detection (CAD), 765 diatrizoate, 765 double contrast tagging, 765 false-positives, 765, 765 laxatives, 763– 4 magnesium citrate, 764, 765 polyethylene glycol, 765 sodium phosphate, 764 colonic distention, 766–7 descending colon, 766–7, 767 sigmoid colon, 766–7, 767 disadvantages, 763 indications, 770–1 training, 770, 771 interpretation, 768, 769, 770 lesion detection efficacy, 771–2 multidetector CT scanning, 767–8 software, 764 technique, 763

816

3D display, 763, 768, 769, 770 2D display, 763, 768 see also computed tomographic colonography (CTC) virtual reality, teaching aids, 134 virus infections, 68–9, 69 (table), 664 endoscopic transmission, 69 (table) see also specific infections; specific viruses visceral stretching, pain, 109 visual analog scale, Crohn’s disease, 650 visual cues, insertion techniques, 542, 542 vital signs, gastrointestinal assistant, 59 vitamin A, 367 polyp prevalence, 364 vitamin B, polyp prevalence, 364 vitamin C, 367 polyp prevalence, 364, 366 vitamin E, 367 volume status, hematochezia, 632 vomiting, colon cleansing method complications, 704 von Recklinghausen’s neurofibromatosis type I, 392 W waiting room, colonoscopy suite, 39 waivers, informed consent, 85 “walking-stick handle,” insertion techniques, 541, 541, 551 walls, colonoscopy suite, 34–5 water system, video colonoscope see video colonoscopes weight-to-volume ratio, PillCam Colon Capsule endoscope, 301–2 whipworm, 663, 664 white-light endoscopy (WLE), 473 disadvantages, 481, 482 reflectance, 478 wide-angle endoscopy flat lesion detection, 568 future work, 787–8

wide-area networks (WANs), digital images, 261 wide-beam imaging, narrow point imaging vs., 480 wireless systems, colonoscopy suite, 36–7 withdrawal techniques, 560–71 colon retroflexion, 566, 566, 567 distention, 565 examination, 566 fluid suctioning, 565 lumen deflation, 565 practical teaching, 148 “red out,” 565 “straight pullback,” 564, 565, 568 withdrawal times continuous quality improvement (CQI), 46–7 definition, 46 missed neoplasms, 562 optimal, 563–4 reports, 255 Wnt signaling pathway, adenoma–carcinoma hypothesis, 382 women, colonoscopy in, 298 World Health Organization (WHO), hyperplastic polyposis syndrome classification, 442 World Organization of Digestive Endoscopy, reports, 262 written programs, colonoscopy suite, 24, 25, 26, 26 (table) X xenon arc lights, video colonoscope illumination system, 274 xeroderma pigmentosum, 350 Y Yersinia infections, 661, 661 Z zinc, polyp prevalence, 364 zoom colonoscopy see magnifying colonoscopy